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Transfusion Practices in the Management of Sickle Cell Disease among Florida Physicians

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Permanent Link: http://ufdc.ufl.edu/UFE0021442/00001

Material Information

Title: Transfusion Practices in the Management of Sickle Cell Disease among Florida Physicians
Physical Description: 1 online resource (53 p.)
Language: english
Creator: Dunbar, Levette N
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2007

Subjects

Subjects / Keywords: cell, sickle, transfusions
Clinical Investigation (IDP) -- Dissertations, Academic -- UF
Genre: Medical Sciences thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Limited data exist on physician transfusion prescribing preferences in the management of sickle cell disease (SCD). To assess current practices, we conducted a survey of Florida hematologists/oncologists between fall 2005 and spring 2006. The 31-item survey addressed practice characteristics, SCD patient populations, practice guidelines, transfusion settings, indications and techniques, red blood cell (RBC) phenotype specifications/modifications, iron overload, and educational resource utilization. A total of 155 physicians (75% adult- oriented, 25% pediatric) completed the survey. The primary location was private practice (77%). Pediatric practices had more patients with SCD, overt strokes and receiving hydroxyurea than adult practices. The majority of pediatric practices (61%) had specific transfusion guidelines to follow in contrast to adult practices (8%). A minority of respondents requested limited (16%) or extended (23%) phenotypically matched RBCs on a routine basis when compared to not matching until antibodies were identified (61%). We queried several acute and chronic transfusion therapy indications with differences noted among pediatric and adult practices. Analysis of clinical vignette data revealed differences among physicians in the transfusion management of elective cholecystectomy, splenic sequestration, acute chest syndrome and secondary stroke prevention after prolonged chronic transfusion therapy. While most respondents from pediatric practices used the NIH management of SCD monograph, only a small percentage of adult practice respondents used it. The data indicate variability in the incorporation of evidence-based approaches in transfusion management of SCD. These results provide insights into the need for the development of clinical tools and guidelines tailored to pediatric and adult practices.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Levette N Dunbar.
Thesis: Thesis (M.S.)--University of Florida, 2007.
Local: Adviser: Garvan, Cynthia W.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2007
System ID: UFE0021442:00001

Permanent Link: http://ufdc.ufl.edu/UFE0021442/00001

Material Information

Title: Transfusion Practices in the Management of Sickle Cell Disease among Florida Physicians
Physical Description: 1 online resource (53 p.)
Language: english
Creator: Dunbar, Levette N
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2007

Subjects

Subjects / Keywords: cell, sickle, transfusions
Clinical Investigation (IDP) -- Dissertations, Academic -- UF
Genre: Medical Sciences thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Limited data exist on physician transfusion prescribing preferences in the management of sickle cell disease (SCD). To assess current practices, we conducted a survey of Florida hematologists/oncologists between fall 2005 and spring 2006. The 31-item survey addressed practice characteristics, SCD patient populations, practice guidelines, transfusion settings, indications and techniques, red blood cell (RBC) phenotype specifications/modifications, iron overload, and educational resource utilization. A total of 155 physicians (75% adult- oriented, 25% pediatric) completed the survey. The primary location was private practice (77%). Pediatric practices had more patients with SCD, overt strokes and receiving hydroxyurea than adult practices. The majority of pediatric practices (61%) had specific transfusion guidelines to follow in contrast to adult practices (8%). A minority of respondents requested limited (16%) or extended (23%) phenotypically matched RBCs on a routine basis when compared to not matching until antibodies were identified (61%). We queried several acute and chronic transfusion therapy indications with differences noted among pediatric and adult practices. Analysis of clinical vignette data revealed differences among physicians in the transfusion management of elective cholecystectomy, splenic sequestration, acute chest syndrome and secondary stroke prevention after prolonged chronic transfusion therapy. While most respondents from pediatric practices used the NIH management of SCD monograph, only a small percentage of adult practice respondents used it. The data indicate variability in the incorporation of evidence-based approaches in transfusion management of SCD. These results provide insights into the need for the development of clinical tools and guidelines tailored to pediatric and adult practices.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Levette N Dunbar.
Thesis: Thesis (M.S.)--University of Florida, 2007.
Local: Adviser: Garvan, Cynthia W.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2007
System ID: UFE0021442:00001


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TRANSFUSION PRACTICES IN THE MANAGEMENT OF SICKLE CELL DISEASE
AMONG FLORIDA PHYSICIANS






















By

LEVETTE NICOLE DUNBAR


A THESIS PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
MASTER OF SCIENCE

UNIVERSITY OF FLORIDA

2007




































O 2007 Levette Nicole Dunbar

































To those living with sickle cell disease everyday









ACKNOWLEDGMENTS

I thank the members of my supervisory thesis committee and my research mentors for

guidance.












TABLE OF CONTENTS


page


ACKNOWLEDGMENT S .............. ...............4.....


LI ST OF T ABLE S ........._..... ...............7.._.._ ......


LI ST OF FIGURE S .............. ...............8.....


AB S TRAC T ......_ ................. ............_........9


CHAPTER


1 INTRODUCTION ................. ...............11.......... ......


Sickle Cell Disease ................. ...............11................

Epidemi ology ................. ...............12................
Clinical Manifestations ................. ...............14.................
Sickle Cell Crisis ................ ...............15........... ....
Infecti on ................... ............ ...............16.......
Liver and Gall Bladder Disease ................. ...............17...............
Skin D disease .............. ...............18....

Eye Disease .............. ...............18....
Renal Disease .............. ...............18....
Cardiovascular Disease .............. ...............19....

Pulmonary Disease ................. ...............19.......... .....
Stroke ................. ...............21.................

Pregnancy .............. ...............23....
Treatm ents .............. ...............23....

Surgery .............. ........... ................2
Hematopoietic Stem Cell Transplant............... ...............2

Hydroxyurea ................. ...............25.................
Blood Transfusions............... ..............2


2 RE SEARCH STUDY ................. ...............29................


Rationale ................. ........... ...............29.......
Methods and Materials .............. ...............30....

Study Design .............. ...............31....
Survey Analysis............... ...............31
R e sults................... ............... ...............32.......
Use of Transfusion Guidelines .............. .. ............ ... ...... .........3

Administration Techniques, Selections and Modifications of RBCs ............................34
Acute and Chronic Transfusion Indications ..........._._ .. ......_ ....._..__..........3

Iron Overload and Iron Chelation therapy............... ...............37
Clinical Vignettes .............. ...............38....
Educational Resources............... ...............3













3 DI SCUS SSION ............. ...... .__ ...............44..


Limitations ............. ...... ._ ...............46...

Conclusion ............. ...... ...............47...


REFERENCE S .............. ...............49....


BIOGRAPHICAL SKETCH .............. ...............53....










LIST OF TABLES

Table page

2-1 SCD patients according to practice type ....._......__. ..........._ ..........4

2-2 Clinical vignettes according to practice type ......___. ........ __. ......_..........4










LIST OF FIGURES


Figure page

2-1 Use of practice specific guidelines and NIH monograph by respondents, p-values
<0.0001 and <0.001 respectively. .............. ...............42....

2-2 Frequency ofRBC modifications requested by respondents. LR, leukocyte reduced.......42

2-3 Importance of reasons for not using deferoxamine. ....._____ .... ... ._. ...........__....43









Abstract of Thesis Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master
of Science

TRANSFUSION PRACTICES IN THE MANAGEMENT OF SICKLE CELL DISEASE
AMONG FLORIDA PHYSICIANS

By

Levette Nicole Dunbar

December 2007

Chair: Cynthia Garvan
Major: Medical Sciences-Clinical Investigation

Limited data exist on physician transfusion prescribing preferences in the management of

sickle cell disease (SCD). To assess current practices, we conducted a survey of Florida

hematologi sts/oncologi sts between fall 2005 and spring 2006. The 31i-item survey addressed

practice characteristics, SCD patient populations, practice guidelines, transfusion settings,

indications and techniques, red blood cell (RBC) phenotype specifieations/modiaications, iron

overload, and educational resource utilization. A total of 155 physicians (75% adult- oriented,

25% pediatric) completed the survey. The primary location was private practice (77%). Pediatric

practices had more patients with SCD, overt strokes and receiving hydroxyurea than adult

practices. The maj ority of pediatric practices (61%) had specific transfusion guidelines to follow

in contrast to adult practices (8%). A minority of respondents requested limited (16%) or

extended (23%) phenotypically matched RBCs on a routine basis when compared to not

matching until antibodies were identified (61%). We queried several acute and chronic

transfusion therapy indications with differences noted among pediatric and adult practices.

Analysis of clinical vignette data revealed differences among physicians in the transfusion

management of elective cholecystectomy, splenic sequestration, acute chest syndrome and

secondary stroke prevention after prolonged chronic transfusion therapy. While most










respondents from pediatric practices used the NIH management of SCD monograph, only a small

percentage of adult practice respondents used it. The data indicate variability in the incorporation

of evidence-based approaches in transfusion management of SCD. These results provide insights

into the need for the development of clinical tools and guidelines tailored to pediatric and adult

practices.









CHAPTER 1
INTTRODUCTION

Sickle Cell Disease

Sickle cell disease (SCD) is a blood disorder characterized by a genetic mutation of

hemoglobin (Hb) causing polymerization of sickle hemoglobin (HbS) [1]. Hb is composed of

two alpha (a) and two beta (P) globin chains. In SCD, a chains are normal and the P chains are

abnormal. The HbS is due to a single point mutation resulting in a valine instead of a glutamic

acid in position six of the P chain [2]. So, the abnormal P chains paired with two normal a

chains form the abnormal HbS. These sickle hemoglobin polymers in sufficient concentrations

form an insoluble gel with soluble normal hemoglobin molecules and cause red blood cell (RBC)

membrane damage, decreased RBC deformability and the sickle-shaped morphology for which

the disease is named [1]. The red cell abnormalities cause dehydration of the red cells, which

leads to stiff, irreversibly sickled cells that result in sickle red cell adhesion to the vascular

endothelium, hemolysis and ultimately blocks the normal blood flow through the

microvasculature leading to anemia and vaso-occlusion [3].

Although the polymerization of HbS is the central event in the pathophysiology of the

disease, nitric oxide depletion (NO) is also a key contributor as well [1, 3, 4]. NO depletion

results from the release of large quantities of hemoglobin and red cell arginase from the chronic

breakdown of red cells that occurs in SCD plasma [3]. The hemolysis and red cell adhesion

leads to a pro-inflammatory state with white cell adhesion and platelet aggregation [4]. Also as a

result of the NO depletion, the down-regulating effects of NO on both inflammation and

activation of coagulation are lost [3]. NO normally causes vasodilation in smooth muscle. So,

unregulated vasoconstriction promotes vaso-occlusion and contributes to tissue hypoxia.









Elevated concentrations of fetal hemoglobin (HbF), which is observed in some patients

with SCD, inhibit HbS polymerization and correlate with less severe manifestations of sickle cell

disease [1]. The inhibition of HbS polymerization occurs by two distinct mechanisms [1]. First,

as HbF increases, HbS must decrease to have a total RBC hemoglobin concentration that is

constant and second, HbF dimers mix with HbS dimers and form hybrids that are not capable of

polymerization (note that normal hemoglobin/HbS hybrids are capable of HbS polymerization).

Epidemiology

SCD affects one in every 350 African American newborns in the United States every year

and more than 72,000 Americans live with SCD currently [5]. Individuals with HbSS disease

(the homozygous condition) have sickle cell anemia. Those with one gene encoding HbS and the

other encoding normal hemoglobin (HbA) have sickle cell trait (the heterozygous condition or

HbAS). Others have one sickle hemoglobin gene and a gene encoding a different hemoglobin

mutation, such as hemoglobin C or hemoglobin thalassemia (resulting in HbSC disease or HbSP-

Thal+ or HbSP-Thalo) [2]. Individuals with HbSC or HbSP-Thal+ have the disease but often have

less severe manifestations whereas HbSS and HbSP-Thalo are considered more severe forms of

the disease. Chronic hemolytic anemia is observed in all patients with SCD. People with sickle

cell trait do not have the disease but are at risk of passing the disease to their offspring if they

mate with someone who also has the trait or the disease. Rare problems associated with sickle

cell trait include persistent hematuria, inability to concentrate the urine and sickling associated

with severe infection, flying in unpressurized aircraft and more rarely, exercise-induced

dehydration and hyperthermia [2].

Brambilla et al. reported that Sir John Dacie described SCD as a disease of childhood in

1960 with relatively few patients surviving to adulthood [6]. In 1972, the National Sickle Cell

Disease Control Act was passed by Congress. As a result, the National Sickle Cell Disease









Program mandated that scientific research programs should be funded to improve care and

quality of life of patients with SCD [5]. Health related quality of life (HRQOL) is one of the

most important health outcome measures in any disease. This need to address SCD-HRQOL

measures has basically evolved because SCD is no longer a disease of childhood since more

patients survive into adulthood. The Cooperative Study of Sickle Cell Disease (CSSCD) started

in 1979 as a large, multi-institutional study because very little information had been collected

prospectively on the clinical course of SCD [7]. The CSSCD is the main source of the medical

advances for SCD, especially with respect to transfusions in SCD.

Maj or medical advancements in SCD have occurred over the past 30 years to improve

survival. These include the development of conjugate vaccines and prophylactic penicillin in

infants and children with SCD to prevent overwhelming pneumococcal sepsis, chronic blood

transfusions to prevent first and recurrent strokes, and HU to reduce the number of painful

episodes [8]. As a result, SCD life span has increased and resulted in a new and growing

population of adult SCD patients with a need for coordinated care beyond the pediatric arena.

In 1994, the CSSCD estimated median survival for individuals with HbSS was 42 years for

males and 48 years for females [6]. The median survival age for HbSC was 60 years for males

and 68 years for females. Accordingly, the pediatric hematologist' s responsibility must now

include collaboration with adult health care professionals to achieve successful continuity of care

for their pediatric sickle cell patients to achieve a better quality of life as adults living longer

with the significant impact of SCD complications. An important component of achieving

improved quality of care for SCD patients which warrants further investigation is the treatment

management practices of SCD among physicians caring for this population of patients. A

tremendous amount of variation in the treatment of SCD complications exist among healthcare










providers. One maj or reason for the variation in the treatment management of SCD patients may

be that individuals with SCD are now living longer and therefore requiring care from adult

providers who may not be as familiar with the disease once considered a childhood disease.

Also, some controversies exist for accepted SCD therapy. In some cases, there are different

ways of approaching a single problem with no supported standard of care. So, many areas of

debate exist in the management of SCD. The best supported practice guidelines for the

management of SCD are represented by a few randomized controlled trials (RCTs) [9]. To truly

understand proper management of SCD, one must understand the pathogenesis of the clinical

manifestations of the disease in order to address how to treat them properly.

Clinical Manifestations

Clinical manifestations of SCD are variable. Some individuals are completely without

symptoms while others experience varying degrees of anemia, sickle cell crisis, damage to

organs (including but not limited to eyes, skin, spleen, liver, lungs, heart and kidneys), increased

infection and strokes. The anemia (as a result of a lower than normal number of RBCs or

hemoglobin, or both) results in symptoms such as a tachycardia, fatigue, generalized weakness,

headache or dizziness. The anemia is generally well tolerated secondary to cardiovascular

compensation, but there are conditions in which the anemia is symptomatic and requires

intervention in the form of RBC transfusions. The normal RBC has a life span of approximately

120 days. However, the deformed sickle RBC life span is shortened to roughly 15-25 days

resulting in the moderate to severe hemolytic (the abnormal breakdown of blood cells) anemia,

with a usual steady state hematocrit of 24% (range 18-32%) in HbSS disease [10]. The

hematocrit is a blood test that gives the percentage of RBCs in whole blood and normally ranges

from 36-40%. The range varies based on age and gender. Laboratory abnormalities for









individuals with SCD include low hemoglobin and hematocrit, elevated bilirubin levels,

increased numbers of circulating reticulocytes, and elevated leukocyte levels.

Sickle Cell Crisis

Vaso-occlusive crises are acute, often painful events that are one of the hallmarks of SCD.

Any tissue that does not have blood flow constantly (and therefore is ischemic) is severely

damaged and leads to problems. Vaso-occlusion leads to tissue ischemia, infarction and

inflammation. Acute pain is one of the maj or symptoms of vaso-occlusion that can strike at

anytime without warning and is generally sharp and/or throbbing [3]. The pain can occur

anywhere in the body, and be localized to one area or generalized. The pain can also be

neuropathic in nature and feel like burning or tingling. When chronic vaso-occlusive events

occur in the bones, it is called avascular necrosis or osteonecrosis (literally bone death) and often

leads to a need for replacement, for example of knees or hips. When vaso-occlusion occurs in

the penis, the result is a painful, prolonged erection or priapism. When standard therapies are

unsuccessful for acute priapism, some physicians try transfusions acutely. However, close

attention must be given to avoiding hyperviscosity and therefore automated exchange transfusion

is recommended [9, 11]. Some physicians advocate chronic transfusions or HU for recurrent

priapism since the risk of impotence is high [9]. When vaso-occlusion occurs in the lungs, it

results in serious lung injury and hypoxia and is known as acute chest syndrome and is

considered a medical emergency (see the acute chest syndrome section). Vaso-occlusion in the

brain can result in a stroke. This can lead to devastating complications and limitations of

cognition, speech and/or movement (see the stroke section).

Acute splenic sequestration crisis is a significant cause of death in children with SCD [9].

It is a rapid crisis that results in massive enlargement of the spleen secondary to trapping of red

blood cells. Splenic sequestration can result in hypotensive shock with cardiac compromise









because of severe anemia, and requires emergent red blood cell transfusions. If splenic

sequestration recurs, splenectomy is sometimes considered.

Transient aplastic crisis is the result of a viral infection known as parvovirus Bl9 causing

suppression of the bone marrow activity (i.e., production of new RBCs) leading to severe anemia

in SCD [12]. Other viral and bacterial infections in SCD may also induce an aplastic crisis

resulting in bone marrow suppression. Infections causing aplastic crises are usually self-limiting

and resolve spontaneously without the need for therapy. However, there are aplastic episodes

that require multiple red blood cell transfusions to avoid cardiac compromise in SCD patients.

Infection

Bacterial infections contribute to a higher proportion of deaths in children with SCD than

any other single cause. The increased risk of infection is the result of splenic dysfunction [2].

The spleen normally provides protection from infection because of antibody production and

phagocytosis [2]. As a result of functional asplenia/splenic dysfunction, individuals with SCD,

especially children, are more susceptible to severe bacterial infections especially from organisms

such as Streptococcus pneumoniae [13].

With the advent of prophylactic penicillin and appropriate conjugate vaccines against

Streptococcus pneumoniae and Haemophilus influenza type b, there has been a tremendous

decrease in the number of infections and deaths of children with SCD and infections [8]. An

important randomized clinical trial published in 1986 demonstrated that prophylactic penicillin

reduced the risk of Streptococcus pneumoniae infections by 84% when compared to placebo

[13]. This study concluded that all neonates should be screened for sickle hemoglobinopathies,

and those with SCD should be placed on prophylactic penicillin. In a published report on a large

Dallas newborn cohort, the widespread use of the conjugated pneumococcal vaccine (PCV-7)

reduces the risk of invasive pneumococcal infections as well [8].









Ideally, all children with SCD should be treated with daily oral penicillin from birth until

age Hyve (the age at which the risk of infection is deemed no different from the general

population) [14]. Also, all children with SCD should receive immunizations per the

recommended schedule for healthy children (which include the PCV-7 and the Haemophilus

influenza type b vaccine) and additionally receive the pneumococcal polysaccharide vaccine

PPV23 at two years and Hyve years and then every ten years [3]. The lower mortality rate from

infections can be attributed to improved care with universal newborn screens, vaccines and

penicillin prophylaxis, but also with coordinated SCD care including continuous parental

education about information relevant to SCD.

Liver and Gall Bladder Disease

Liver and gall bladder complications are common in SCD. Chronic hemolysis leads to a

constant turnover of red blood cells leading to accumulation of bilirubin. The accumulation of

bilirubin leads to pigmented gallstones cholelithiasiss) which in turns leads to acute and chronic

cholecystitis and choledocholithiasis [9]. Fever, nausea, vomiting abdominal pain and increased

jaundice may occur acutely. Laparoscopic cholecystectomy on an elective basis is the standard

approach to symptomatic patients [9].

Vaso-occlusive crisis may occur in the liver and consists of right upper quadrant pain, liver

enlargement, fever, jaundice, and elevated liver transaminases. It is treated like a vaso-occlusive

pain crisis. Sequestration also occurs in the liver with similar consequences to splenic

sequestration. In liver sequestration, the liver enlarges rapidly with a sudden drop in the

hemoglobin/hematocrit and a significant rise in the number of reticulocytes. The preferred

treatment is exchange transfusion since simple transfusions may be accompanied by the return of

sequestered RBCs in to the circulation leading to a hyperviscosity syndrome [9]. The return of

sequestered RBCs may also be seen in transfused splenic sequestration patients and thus carries









the same caution. Iron overload results from frequent blood transfusions and the excess iron may

deposit in the liver and lead to a high liver iron load and liver dysfunction [15].

Skin Disease

Leg ulcers occur in 10-20% of SCD patients [9]. The etiology of the leg ulcers likely

relates to the hypoxia and infarction of the distal ankle skin. Some resolve quickly while others

can take years and they do recur. Most importantly, the ulcers can be extremely painful and

become infected. Treatments generally involve pain management, antibiotics for infections, bed

rest and leg elevation as well as local topical care and dressings such as those used for burn

victims. Ulcers may correlate with the degree of anemia and therefore transfusion may be

helpful but there is no evidence to support the use of transfusion for leg ulcers [9].

Eye Disease

Sickle cell vaso-occlusive events can also affect the vascular beds in the eyes. Often the

disease has progressed significantly before visual problems are observed by the individual.

Therefore, comprehensive eye exams are recommended regularly, regardless of signs or

symptoms. Ocular manifestations of SCD are classified by the presence or absence of

neovascularization in the eye [16]. Progression to neovascular changes can result in vitreous

hemorrhages and retinal detachment, retinal artery occlusion and ischemia and risk for visual

loss. Surgical intervention may be necessary but also comes with great risk of ocular ischemia,

recurrent hemorrhage and elevated eye pressure [9].

Renal Disease

The kidney is often a site of injury and abnormalities in SCD because the kidney is very

susceptible to dysfunction because it promotes HbS polymerization and red cell sickling [17].

One of the most frequent renal abnormalities is an inability to concentrate the urine which can

lead to dehydration, which in turns leads to a vaso-occlusive crisis [9]. This may be avoided by









encouraging individuals to drink liberal amounts of fluids in order to compensate for the fluid

losses. Hematuria, proteinuria and renal failure may occur in SCD patients as well. Chronic

renal insufficiency occurs in up to 30% of adults [1l]. Erythropoietin levels may fall with

worsening renal function in individuals with SCD requiring erythropoietin therapy or frequent

blood transfusions [17]. Some individuals with SCD progress to end stage renal disease requiring

dialysis and/or renal transplantation.

Cardiovascular Disease

Cardiomegaly is usually observed in most individuals with SCD secondary to a

cardiovascular compensatory mechanism for the anemia [18]. Myocardial infarctions are not

common but do occur [9]. Congestive heart failure may also occur and may be associated with

fluid overload. Patients with falling hemoglobin and congestive heart failure may benefit from

slowly correcting their severe anemia with transfusions [9]. In the CSSCD study of heart

disease, the two factors most important to cardiac disease were increasing age and decreasing

hemoglobin and no specific cardiomyopathy was observed [18]. Also, significant cardiac

dysfunction does occur in the setting of iron overload in the heart.

Pulmonary Disease

Acute chest syndrome (ACS) is a type of vaso-occlusive crisis observed in SCD that

involves lung injury leading to the onset of chest pain. ACS is defined as new lung infiltrates on

chest X-ray with the presence of fever and chest pain and respiratory symptoms such as cough,

wheezing and tachypnea [19]. ACS results in acute decompensation of the patient respiratory

status and sometimes requires oxygen supplementation and/or ventilation assistance. ACS is a

leading cause of hospitalizations and death in the SCD population [6, 20]. High morbidity and

mortality in ACS is also linked to repeated episodes of ACS and may result in chronic lung

disease [19].









Predisposing factors for ACS included asthma, pain crisis of the chest or any area of severe

pain crisis resulting in narcotic use and hypoventilation, pulmonary fat embolism (a piece of fat

that usually travels from an area of bone marrow injury to the lungs through blood vessels),

underlying infection (typical and atypical bacteria, viruses, mixed infections), and/or recent

surgery (postoperative status) [19]. Management of ACS includes oxygen, pain management,

aggressive incentive spirometry (a small bedside device to encourage ventilation by blowing into

plastic tubing to take deep breaths) to counteract hypoventilation from the effects of the narcotics

and/or pain itself leading to splinting (restriction of the breathing pattern), antibiotics, IV

hydration, bronchodilators such as albuterol to open up the airways, simple blood transfusions,

and exchange transfusions if simple transfusion is ineffective [19]. Exchange transfusions

involve the incremental removal of the patient' s blood with HbS and replacement with fresh

blood free of HbS [9]. Exchange transfusion is considered a more aggressive treatment since it

involves more units of blood than a simple transfusion and therefore is associated with more

transfusion-related reactions and complications. Exchange transfusions are often preferred in

certain situations such as ACS for an individual with HbSC to avoid hyperviscosity.

Pulmonary hypertension (PH) is also a common manifestation of SCD and it is also

associated with high mortality [21]. PH increases the risk for right sided heart failure, syncope,

and sudden death [21]. Thirty percent of adults with SCD have PH and PH is associated with a

mortality rate up to 50% at 24 months after diagnosis and around 40% at 40 months [21-22]. PH

is defined as an elevation of the pressure in the pulmonary vasculature (either pulmonary arterial

or venous system) [22]. Pulmonary arterial pressure above 25 mmHg is considered to represent

PH. PH is thought to be directly related to NO depletion as a result of chronic hemolysis in SCD

[21-22]. Some of the other causes of PH postulated include systolic hypertension, chronic










oxygen desaturation or sleep hypoventilation, chronic pulmonary damage from recurrent ACS,

repeated episodes of thromboembolism, and high pulmonary blood flow from chronic anemia

[21]. PH is also associated with iron overload and, therefore may be caused by iron overload

[21-22].

There are no controlled trials of treatments for PH associated with SCD. Therefore, most

therapies are based on what is known about primary pulmonary hypertension treatments.

Hydroxyurea and chronic transfusions are being explored as possible therapies to improve

outcomes for patients with SCD to prevent the underlying complications of SCD that increase

the risk of PH.

Stroke

Stroke is one of the most debilitating and devastating aspects of SCD. Stroke occurs in

approximately 1 1% of individuals with HbSS under the age of 20 and 24% by the age of 45 [23].

Cerebral infarction occurs mainly in children whereas hemorrhage occurs mainly in adults [23].

The signs and symptoms associated with ischemic strokes include speech disturbances, gait

disturbances secondary to hemiparesis and altered sensation, seizures, headaches, abnormal

behavior and confusion. Hemorrhagic strokes may present with headaches, vomiting, stupor or

coma [9]. Silent infarcts present with deficits in cognitive areas such as deficits in mathematics,

reading, and/or memory. Silent infarcts may predispose individuals for ischemic strokes [24].

The silent infarct transfusion (SIT) trial is a prospective multi-center study currently underway to

determine the effectiveness of blood transfusions for the prevention of recurrent silent infarcts

[24].

As a result of acute and chronic SCD problems such as anemia, ACS, vaso-occlusive

crisis, aplastic crisis, and nocturnal hypoxemia leading to decreased oxygenation, ischemic injury

occurs in the brain. Treatments for acute strokes involve the acute management of the signs and










symptoms such as seizures, cerebral bleeding or clotting with anticonvulsants, hematoma

evacuation and anticoagulation but, most importantly, involve blood transfusions (specifically

exchange transfusion) to reduce the amount of HbS immediately. The prevention of morbidity in

SCD (POMS) study has been designed to evaluate the effectiveness of overnight continuous

positive airway pressure in patients with low nocturnal oxygen saturations to see if it has an

effect on future central nervous system events such as strokes or vaso-occlusive events [24].

Recurrence of stroke occurs in two-thirds of the SCD patients after an initial stroke,

usually within two to three years [25]. Several studies have demonstrated the effectiveness of

chronic transfusions for the reduction of recurrent stroke rate [25, 26]. Currently, transfusions

are recommended indefinitely for the prevention of a second stroke [25, 27]. Limited data

demonstrated the use of HU and phlebotomy may be an effective alternative treatment to blood

transfusion for the prevention of secondary strokes in a single institution prospective study of 35

patients, and a national multi-center trial is currently underway [24, 28]. Several reports have

also documented the effectiveness of stem cell transplants in the prevention of stroke recurrence

by eliminating the sickle P globin gene and replacing sickle cells with healthy donor cells [29].

The most common cause of cerebral infarction is an occlusion of the intracranial internal

carotid and middle cerebral arteries [30]. These abnormal occlusions can be detected by

transcranial Doppler (TCD) ultrasonography measuring blood flow velocity. An abnormal TCD

velocity of greater than 200 cm/sec was associated with a 40% risk of stroke in HbSS [3 1]. In

the stroke prevention in sickle cell anemia (STOP) trial, 130 children who were at risk for a

stroke based on abnormal TCD velocities were randomized to either chronic transfusion or

standard care/observation [30]. A 92% reduction in stroke risk was observed in the group that

received transfusion. In the STOP II trial, the length of transfusion therapy for first stroke










prevention was explored [32]. Discontinuation of transfusion in this group resulted in a high rate

of stroke and reversion to abnormal blood flow velocities. The study concluded a high risk

associated with stopping regular transfusion and stressed the importance of continuing chronic

transfusion until an effective alternative is available.

Pregnancy

A healthy pregnancy and delivery in women with SCD is very possible. However,

special multi-disciplinary care must be given before, during and after to reduce mortality and

morbidity of the fetus and mother. Increased pre-eclampsia, preterm labor and low birth weight

newborns have been observed in women with SCD [33]. However, prophylactic transfusion

from the onset of pregnancy did not change the outcomes for the fetus and mother in a RCT of

72 pregnant patients with SCD [34]. In a retrospective study, data supported the use of

prophylactic transfusions for uncomplicated pregnancies beginning at 20 weeks [33]. The study

revealed a reduction in pain crises, ACS, low birth weight and perinatal deaths. Prophylactic

transfusions are generally not used in uncomplicated pregnancy and are reserved for those

women with complications such as pre-eclampsia, ACS, severe anemia, increasing episodes of

pain crises [34].

Treatments

The maj or therapies for the management of SCD include blood transfusions, hydroxyurea

(HU), and hematopoietic stem cell transplants. SCD pain leads to frequent hospitalization for

painful episodes necessitating intravenous opioid medications and aggressive hydration as

therapy. Many of the complications of SCD can be life-threatening and/or life-limiting, such as

acute chest syndrome, strokes, infections, transfusion-related reactions and iron overload,

acute/chronic vaso-occlusive pain crisis and depression. The only cure for SCD is a bone

marrow transplant, which is not available to most people, and is also associated with an









increased risk of death secondary to the complication of the transplant itself [29]. Therefore, the

mainstay of therapy is treatment and prevention of clinical complications.

Surgery

Individuals with SCD often require surgery for many of the complications of the disease

such as cholelithiasis, recurrent splenic sequestration, avascular necrosis, vitreous hemorrhage,

retinal detachment, and nocturnal hypoxemia secondary to obstructive sleep apnea. However,

patients are at increased risk of complications before, during and after surgery because of their

anemia, the tendency of the red blood cells to sickle and occlude the microvasculature especially

during times of stress, and the risk of hypoxia [35]. The morbidity and mortality can be

significantly increased surrounding surgery, especially post-operatively. Pre-operative, peri-

operative and post-operative complications include ACS, stroke, vaso-occlusive pain, renal

dysfunction/failure, infection, and even death [35-37]. Therefore, many hematologists prepare

SCD patients for surgery with blood transfusions (as well as other supportive measures such as

hydration and good oxygenation) in hopes of reducing their risk of post-operative complications

[9]. Buck et al suggested that the risk of post-operative complications has more to do with the

risk of the surgical procedure itself than having or not having pre-transfusion [37], whereas other

authors debate the type of transfusion to be given (no transfusion, simple transfusion, or

exchange transfusion) [35,36]. Current recommendations from the National Institute of Health

(NIH) monograph on the management of SCD include simple transfusion to increase the

hemoglobin to no more then ten grams per deciliter prior to all but the lowest risk procedures in

HbSS and HbSP-Thalo and exchange transfusion may be warranted for HbSC to avoid

hyperviscosity [9].









Hematopoietic Stem Cell Transplant

In the US, over 200 patients with severe SCD have been transplanted using matched

sibling donors and conventional myeloablative therapy with an 83% event free survival [29].

The limiting factors are still the availability of a suitable matched sibling donor for the individual

with SCD, and the risk of short-term and long-term toxicities are still present. Several reports

demonstrate less favorable outcomes with reduced intensity regimens [29]. In adults, morbidity

and mortality risks may be even higher so very few transplants are performed in adults [38].

Current studies are exploring partially matched relatives and matched unrelated donors using

umbilical cord transplants with promising results [39].

Hydroxyurea

Hydroxyurea (HU) is the only pharmacologic agent FDA-approved for preventing

complications of SCD. HU has been shown to significantly decrease the number of painful

sickle cell episodes, hospitalizations for painful episodes, acute chest syndrome and the total

number of blood transfusions [40]. Increased painful episodes are associated with increased

mortality in SCD [6]. If the numbers of painful episodes are reduced with a drug such as HU, it

stands to reason that the mortality rate will also decrease.

HU offers a very important option to improve healthcare in SCD patients. Yet, HU

remains underused [41]. The concern about the potential carcinogenic effects of HU likely

contributes to the underuse [41]. However, follow up on patients in the original Multicenter

Study of Hydroxyurea in Sickle Cell Anemia (MSH), three malignancies were noted in the HU

group: one carcinoma in situ of the cervix, one multi-focal carcinoma in situ of the breast and

one endometrial carcinoma. There were no leukemias or lymphomas in the cohort [42]. All three

patients died but the first two died of complications unrelated to their cancers [42].









HU is a ribonucleotide reductase inhibitor, which prevents DNA synthesis [1]. The benefit

to SCD patients is that it increases fetal hemoglobin levels which inhibit polymerization of HbS

[40]. Therefore, the amount of sickled red blood cells is decreased. High levels of HbF as a

result of HU may reduce SCD complications [40, 42]. HU has other possible mechanisms as

well, which include increasing nitric oxide, decreasing expression of red cell and endothelial

adhesion, slight neutropenia (therefore less leukocyte adhesion) and diminished reticulocytes

(which are the cells with the greatest adhesiveness) [4, 42].

Blood Transfusions

Acute and chronic blood transfusions are important in the management of SCD

complications. Along with the drug HU, transfusions are the only other widely available

treatment for SCD complications at this time. Transfusions are useful under certain

circumstances of SCD such as splenic sequestration, aplastic crisis, prevention of primary or

secondary strokes, hypoxia with acute chest syndrome, complicated pregnancy, recurrent

priapism, surgeries, and any acute central nervous system injury such as seizure or central

nervous system infarction [9]. Transfusions raise the oxygen-carrying capacity of blood and

decrease the proportion of sickle RBCs. When used properly, transfusions are beneficial and

often save lives of SCD patients on a daily basis. When they are improperly performed, more

problems are created that can be life-threatening. Pre-operative transfusions are often given for

the prevention of potential intra-operative and post-operative complications in SCD patients [35-

37]. Also, transfusions greatly reduce recurrent stroke in children with SCD [25, 26], and the

risk of first stroke in children with SCD who have abnormal results on TCD [30]. In light of the

increasing number of transfusion indications, transfusions remain the mainstay of SCD therapy.

Despite the proven benefits of transfusions, there are limitations. Transfusions are

associated with adverse effects which include but are not limited to transmission of infectious









diseases (such as HIV, CMV, hepatitis B & C), volume overload, hyperviscosity, hemolytic

reactions, alloimmunization (development of antibodies or proteins that attack/destroy donated

RBCs), and iron overload [15, 43-45].

Many of the transfusion complications may be minimized by appropriate administration

techniques, selection, and modification ofRBC products. RBC products are often modified prior

to a transfusion in SCD. The RBC product is leukocyte reduced to decrease the risk of

alloimmunization. The RBC product is also usually specified to be sickle cell trait negative and

fresh (obtained within the last five days of transfusion). Other modifications of RBCs are

usually not standard for SCD unless they have had a prior reaction to RBC during infusion

(which require the product is washed before a transfusion), or they have had a bone marrow

transplant (which would require an irradiated and leukocyte reduced product).

In one report, 60% of chronically transfused adults become alloimmunized [45].

Alloimunization leads to increase delayed hemolytic reactions and life threatening events.

However, performing limited RBC phenotypic matching with C, E, and Kell (since these

antigens account for 60-98% of antibody detected previously in SCD) can reduce the rate of

alloimmunization [45, 46]. Vinchinsky et al. demonstrated a reduction in the rate of

alloimmunization from three percent to half a percent per unit and a reduction in hemolytic

transfusion reactions by 90% by using limited phenotypic RBC matching in a study for stroke

prevention in SCD [45]. Josephson et al have provided a set of guidelines for the transfusion

management of SCD and recommend the practice of limited phenotypic RBC matching as a

standard of care for all transfused SCD patients [47].

The toxicity of iron overload may be reduced with iron chelation therapy [15, 48-50].

Regular transfusions lead to the accumulation of iron in multiple organs with resultant









irreversible damage if left untreated [15, 50]. Iron overload is monitored using measurements

such as serum ferritin levels, number of RBC units transfused, magnetic resonance imaging of

the liver or heart, and liver biopsy [15, 48, 50]. Iron overload can be effectively managed with

iron chelation therapies such as deferoxamine and deferasirox. Deferoxamine requires eight to

twelve hours of continuous subcutaneous infusion five to seven times a week resulting in many

limitations of its use by the patient [48, 49, 51]. Deferasirox is an oral chelator now available for

the treatment of transfusional iron overload [48, 49]. Our study was conducted prior to the FDA

approval of deferasirox to evaluate the issues surrounding transfusional iron overload and

chelation therapy.









CHAPTER 2
RESEARCH STUDY

Rationale

The application of evidence-based medicine for the transfusion management of sickle cell

disease (SCD) is based on observational studies and the opinions of experts in SCD with just a

few randomized controlled trials (RCTs) to guide decision making [1l]. The few RCTs

available support the use of prophylactic chronic transfusions for primary stroke prevention in

high risk children identified by abnormal transcranial Doppler (TCD) and prevention of recurrent

stroke in children or adults who have already experienced a stroke [26, 27, 30]. One of the RCTs

also recommends that all SCD patients be antigen matched for E, C, and Kell [45]. Another

provides evidence that a conservative transfusion program (simple transfusions that increase the

hemoglobin to ten grams per deciliter) is just as effective as an aggressive transfusion program

(exchange transfusion to reduce sickle hemoglobin (HbS) levels to below 30%) in preventing

SCD complications in patients requiring major surgery [35]. A RCT also demonstrated that

transfusions to maintain a hematocrit of more than 30% do not reduce complications of

pregnancy [34]. Therefore, chronic transfusions are not recommended for the management of

uncomplicated pregnancy.

Although a recent critical review of the literature and transfusion guidelines provided

some insight into transfusion management of the patients with SCD [47] and the National

Institute of Health (NIH) monograph provides a thorough and comprehensive outline for the

management of SCD [9], limited data exist on actual hematologist prescribing practices in either

academic or community-based settings. In this study, we set out to evaluate the physician

prescribing practices in these settings for the transfusion management of SCD. Evaluating the

current practices of physicians with respect to the transfusion management of SCD, providing a










universal set of practice guidelines, and Einally, actively making physicians aware of the

information based on the best scientific evidence are all necessary steps to improve healthcare

management of SCD patients. The objective of this study was to examine current Florida

hematologi st/oncologi st transfusion practices in the management of SCD. We tested the

hypothesis that the transfusion prescribing practices vary among Florida physicians in the

management of SCD.

Methods and Materials

A literature search was performed to obtain references addressing current

recommendations for transfusion management and to catalog items to be considered for inclusion

in the survey. Basic survey development was pursued [37, 52-54] and basic transfusion and

sickle cell research were explored [27, 30, 35-37, 43, 45, 55]. A draft of the survey was

developed and reviewed by a health service researcher with expertise in physician surveys, blood

bank specialists, and a highly regarded hematologist with expertise in transfusion medicine for

SCD. The survey was refined with the input from a group of academic hematologists in other

regions of the US with particular interest in SCD. Face and content validity were evaluated by

pilot testing the survey with current and previous trainees (residing out of state of Florida) of the

University of Florida hematology/oncology fellowship programs. Feedback was obtained and

revisions were implemented accordingly, with input from two other healthcare provider survey

experts. The survey and accompanying cover letter were submitted and approved by the

Institutional Review Board.

A thirty-one item, fiye page self administered questionnaire was created to collect

information about the background and professional practice characteristics of physicians, their

SCD patient population, and their transfusion practices. Questions regarding transfusion

practices included the settings used for non-emergent transfusions, the use of practice site









defined criteria/guidelines, the use of phenotypically matched red blood cells (RBCs), and how

RBCs were modified. We asked about the availability and frequency of automated exchange

transfusion, transfusion recommendations for acute and chronic transfusions, and experience

with iron overload and deferoxamine. We also asked about the availability of educational

resources such as information on transfusions of SCD patients, the attendance of at least one

conference or presentation on the management of SCD in the past two years and the use of the

Management of Sickle Cell Disease monograph published by the National Institutes of Health

[9]. Four clinical vignettes were presented and physicians were asked to choose the single most

likely treatment recommendation (based on their experience with SCD patients). There were

several other forms of questions, including simple binary questions requiring a yes or no answer,

multiple choice questions with the ability to circle all that apply, and open-ended questions.

Likert scaling was used for several questions in which the respondent was asked to rate their

level of agreement as never, rarely, sometimes, or always or as very important, somewhat

important or not important.

Study Design

The survey was mailed to hematologi sts/oncologists in the state of Florida from fall 2005

through spring 2006. A list of possible participants was compiled from membership directories

of the American Society of Hematology (ASH), the American Society of Clinical Oncology

(ASCO) and the Florida Association of Pediatric Tumor Programs (FAPTP). Surveys were

mailed to physicians via three mailing attempts, with telephone and email follow-up for non-

responders.

Survey Analysis

Data were processed by checking for item non-response, distributional forms (e.g.,

normality of continuous data elements), and creating derived variables. SAS Version 9. 1 (SAS










Institute Inc., Cary, N.C.) statistical software was used for all statistical analyses. Frequencies

and percent were calculated for categorical data and means and standard deviations were

calculated for numerical data. Associations between numerical measures were tested using

Spearman correlations. Chi-square and Fisher' s exact tests were used to test relationships

between bivariate categorical data. Groups were compared using Wilcoxon rank sum tests. P-

values < 0.05 were considered significant. We focused on comparing differences between

pediatric and adult practice responses as analysis factors since these are the two maj or practice

types that care for SCD patients and would likely exhibit the most important aspects of variation

if it existed. Also, physician-specialists are generally either in an academic or private practice

location and would also demonstrate variation if it existed. We set out to determine if maj or

differences existed in SCD management between pediatric and adult practices and also between

academic and private practices.

Results

One hundred fifty fiye hematologi st/oncologists completed the survey out of 474 requested

(33% response rate). Twenty-five percent were pediatric and 75% were adult physicians. An

academic setting was reported as the location for 23% of the practices and 77% were in private

practice. The majority of the respondents were adult providers in private practice. The highest

numbers of SCD patients were reported in the pediatric practice respondents; whereas the

majority of adult practice respondents reported fewer SCD patients (Table 2-1). When

comparing private and academic practice respondents, 49% of the academic respondents had 5 1

or more patients in comparison to only 17% of the private practice respondents.

The highest numbers of stroke patients were noted in the pediatric practice respondents

with 87% having six or more overt stroke patients in comparison to 90% of the adult practice

respondents having fiye or fewer overt stroke patients. Sixty-four percent of the adult practice










respondents had no stroke patients. Fifty-four percent of the private practice respondents had no

stroke patients in comparison to 23% of the academic practice respondents.

The maj ority of the academic and pediatric practice respondents had higher numbers of

patients receiving hydroxyurea (HU). For instance, 95% of the pediatric practice respondents

had three or more patients receiving HU with 38% having 16 or more patients receiving HU. In

contrast, 71% of the adult practice respondents had two or fewer patients on HU with 32% of the

adult practices having no patients receiving HU. Sixty-one percent of academic practice

respondents had three or more receiving HU while 57% of the private practice respondents had

two or fewer patients receiving HU.

Use of Transfusion Guidelines

There was a statistically significant difference between adult and pediatric practice

respondents with respect to practice guidelines and the use of the monograph (Figure 2-1).

Physicians were asked if their practice had specific transfusion guidelines and 61% of pediatric

practice respondents answered yes whereas 8% of adult practice respondents answered yes.

Fifty-six percent of pediatric practice respondents reported usage of the 2002 management of

SCD monograph published by the NIH while only 26% of adult practice respondents reported

they used the monograph for the management of SCD. Sixty-three percent of the academic

practices and 83% of the private practices reported they did have defined criteria/guidelines for

the transfusion management of SCD patients. Forty-six percent of the academic practices and

72% of the private practices reported they did not use the NIH monograph. Several physicians

were not aware of the monograph and were pleased to learn of its existence by means of

completing the survey.









Administration Techniques, Selections and Modifications of RBCs

In spite of the evidence that limited/extended phenotypic matching reduces

alloimmunization, a minority of respondents requested limited (16%) or extended/complete

(23%) phenotypic matching of RBCs on a routine basis when compared to not matching until

antibodies were identified (61%). An automated exchange transfusion on an emergent basis is

often vital to saving the lives of individuals with SCD, especially acutely when acute chest

syndrome (ACS), stroke, sepsis and multi-system organ failure occurs. Emergent automated

exchange transfusion was available in the maj ority of pediatric (94%) and adult practice

respondents (71%) as well as academic (97%) and private practice respondents (71%).

Noticeably, the academic and pediatric practice respondents had much higher percentages in

comparison to the adult and private practice respondents. Ten physicians reported from one to

ten patients on chronic transfusion programs using automated exchange transfusion. Six were in

pediatric practices (five were academic and one private) and four were in adult practices (two

academic and two private).

We asked respondents how often certain RBC products are requested for a sickle cell

patient who has not had a bone marrow transplant. Choices were always, sometimes, rarely or

never. RBC products listed were leukocyte reduced, non-leukocyte reduced, irradiated, washed,

sickle cell negative and other products (please specify). Overall, respondents "always" requested

leukocyte reduced products (83%). There was variability in the request for sickle negative,

irradiated, and washed blood products (Figure 2-2).

Acute and Chronic Transfusion Indications

We asked respondents when they considered certain indications for acute (episodic)

transfusion for sickle cell anemia (HbSS) patients. Choices were always, sometimes, rarely or

never. The indications for acute transfusions listed for the respondents included: acute painful










episodes, ACS, acute priapism, acute stroke, pre-operative for general anesthesia, and

vitreoretinal surgery. Other acute indications were specified by respondents as a write-in and

included aplastic crisis, bone marrow transplant, severe symptomatic anemia, multi-organ system

failure, hepatic sequestration, hospitalization for infection in a non-acute pain crisis, pregnancy

with and without complications, non-healing ulcers, and hypoxia with pneumonia. Seventy-eight

percent of the respondents thought that acute transfusion was "always" indicated for acute stroke.

Fifty-five percent of respondents would "always" transfuse acutely for ACS. Fifty-two percent

would "always" transfuse for acute priapism, and 49% would "always" transfuse for pre-

operative general anesthesia. Forty-one percent of respondents thought acute transfusion was

"sometimes" indicated for acute painful episodes, and 44% thought vitreoretinal surgery was

"sometimes" an indication for acute transfusion.

There were statistically significant differences among pediatric and adult practice

respondents with respect to acute transfusion indications, most notably with acute painful

episodes, acute stroke and preoperative general anesthesia. The maj ority of pediatric practice

respondents "rarely" considered acute painful episodes an indication for acute transfusion in

comparison to adult practice respondents (76% versus 25%). In contrast, 53% of adult practice

respondents "sometimes" consider acute painful episodes as an indication for acute transfusion

compared to 3% of pediatric practice respondents. Pediatric practice respondents were more

likely to view an acute stroke as an indication for acute transfusion with 95% reporting "always"

in comparison to 72% of adult practice respondents. Pre-operative for general anesthesia was

"always" an indication for acute transfusion in 71% of pediatric practices and 42% of adult

practices.










There were statistically significant differences between academic and private practice

respondents with respect to acute transfusion indications, most notably with acute painful

episodes and acute priapism. Academic practice respondents were less likely to transfuse for

acute pain and priapism when compared to their adult practice respondents. Sixty percent of

academic practice respondents reported they "rarely" transfused acutely for pain whereas 51% of

private practice respondents reported they "sometimes" did. Priapism was "sometimes" an

indication for acute transfusion in 62% of the academic practices and "always" an indication for

58% of the private practices.

We queried chronic transfusion indications in the same manner we approached the acute

indications. We asked respondents when they considered certain indications for chronic

transfusion for SCD patients. The chronic transfusion indications listed for the respondents were

primary prevention of stroke, prevention of recurrence of stroke, history of ACS, renal failure,

congestive heart failure, pulmonary hypertension, recurrent debilitating painful episodes, non-

healing leg ulcers, prevention of recurrence of priapism, uncomplicated pregnancy. Other

indications were specified by respondents such as an abnormal TCD.

Pediatric practice respondents were more likely to use chronic transfusions for primary

stroke prevention than adult practice respondents. Forty-one percent of pediatric providers

"always" use chronic transfusions for primary stroke prevention. In contrast, only seven percent

of adult providers "always" transfuse. However, there was as many pediatric practice

respondents (22%) as adult practice respondents (30%) who "never" use chronic transfusion for

primary stroke prevention. Prevention of stroke recurrence was "always" an indication for

chronic transfusion in 95% of pediatric practice respondents, compared to only 27% of the adult

practice respondents.









A history of ACS was "always" or "sometimes" an indication for chronic transfusion in

77% of pediatric and 42% of adult practice respondents. Fifty-seven percent of pediatric practice

respondents thought that renal failure was "always" or "sometimes" an indication for chronic

transfusion compared to 30% of the adult practice respondents. Recurrent debilitating painful

episodes were "always" or "sometimes" an indication for chronic transfusion in 64% of pediatric

and 50% of adult practice respondents. There was not a statistically significant difference

between pediatric and adult practice respondents for congestive heart failure, pulmonary

hypertension, non-healing ulcers, or recurrent priapism.

Uncomplicated pregnancy was "never" an indication for chronic transfusion in 37% of all

adult respondents and "sometimes" in 37%. The majority (59%) did transfuse on a regular basis.

There was not a statistically significant difference between pediatric and adult practices or

academic and private practices with respect to uncomplicated pregnancy indications for

transfusions. There was not a statistically significant difference between the academic and

private for any of the chronic transfusion indications.

Iron Overload and Iron Chelation therapy

Iron overload and chelation therapy, specifically deferoxamine, were explored in the

survey. There were no statistically significant differences in other measures used to assess iron

levels when starting deferoxamine therapy between pediatric and adult or private and academic

practices, except between pediatric (36%) and adult (1 1%) respondents in terms of percentage

that used liver biopsy as a measure to assess iron overload. Liver biopsy is considered the most

accurate measurement [9]. Other measures used by physicians included steady state ferritin

levels, radiologic imaging (MRI, CT), and number of RBC units transfused. Despite having an

indication for deferoxamine, many patients are not receiving it. Therefore, we investigated the

reasons why physicians felt deferoxamine was not being used. Physicians were asked to evaluate









the importance of each reason listed for not using deferoxamine as very important, somewhat

important or not important. The results of the reasons are displayed in Figure 2-3.

Noncompliance and patient's refusal were cited most frequently as very important reasons for

not using deferoxamine. Fear of side effects, poor understanding of iron overload and iron

chelation by patient/family, lack of healthcare providers to supervise treatment, and cost were

cited most frequently as somewhat important reasons.

Clinical Vignettes

The vignettes revealed statistically significant differences between pediatric and adult

(Table 2-2). In clinical vignette one, a sixteen year old male with HbSS is scheduled for elective

laparoscopic cholecystectomy with a baseline hematocrit (hct) of 22% and hemoglobin (hb) of

7.2. The treatment options were (1) perform an exchange transfusion to reduce the HbS fraction

to 30%, (2) transfusion of RBCs to an hct of 30%, (3) transfusion of RBCs to an hct of 36%, or

(4) no pre-operative transfusion is indicated. Ninety-two percent of pediatric and 56% adult

practice respondents indicated transfusion to hct of 30% was the treatment of choice. However,

seventeen percent of adult practice respondents indicated no pre-operative transfusion. Sixty-

nine percent of academic and 64% private practice respondents chose transfusion to an hct of

30%.

In vignette two, a four year old girl with splenic sequestration presents to the emergency

room with an hct of 12% and transfusion recommendations are requested. The treatment options

were (1) transfusion of packed red blood cells (PRBCs), (2) transfusion of whole blood, (3)

performing an exchange transfusion, or (4) transfusion is not indicated. Ninety-two percent of

the pediatric practice respondents recommended transfusion of PRBCs in comparison to 43% of

adult practice respondents. Thirty-five percent of adult practice respondents recommended

perform an exchange transfusion in comparison to five percent of the pediatric practices. Sixty










percent of academic and 55% of the private practice respondents also recommended transfusion

of PRBCs for this vignette. Forty percent of the academic practices recommended exchange

transfusion in comparison to 24% of the private practices.

In vignette three, a twenty-eight year old woman has ACS with progressive hypoxemia,

despite oxygen supplementation. Treatment options were (1) transfusion of two units PRBCs,

(2) exchange transfusion with target hct 30%, (3) exchange transfusion to hct 38% or (4)

transfusion is not indicated. Sixty-nine percent of pediatric and 64% of adult practice

respondents indicated exchange transfusion to hct of 30% was the treatment of choice. Eighty-

two percent of academic and 60% of private practices also recommended exchange transfusion

to hct of 30% for the vignette. Eighteen percent of pediatric and 23% of adult practices

recommended transfusion of two units of PRBCs for the scenario.

In the fourth vignette, we queried recommendations for a twenty-one year old male who

had undergone chronic transfusion for nine years for secondary stroke prevention. Continuation

treatment options were (1) continue transfusions at four week intervals, (2) begin automated

exchange transfusions at four week intervals, (3) discontinue transfusions and begin HU therapy

or (4) discontinue transfusions. Overall for all respondents, both "discontinuation of transfusions

and beginning HU" and "continuation of transfusions at four week intervals" were considered

treatments of choice with 37% for each option and few indicating no further therapy or

beginning automated exchange transfusion at four week intervals. The private and academic

practices' responses essentially mirrored the pediatric and adult practices for this vignette.

Educational Resources

Educational resources were also investigated. Physicians were asked if information was

readily available on transfusion of SCD patients. Eighty-two percent of the pediatric and 64% of

the adult practice respondents answered yes. Eighty-nine percent of academic and 62% of










private practices answered yes. Physicians were also asked if they had attended at least one

conference or presentation on the management of SCD in the past two years. Twenty-eight

percent of the pediatric and 18% of the adult practices answered yes. Sixty percent of the

academic and 24% of the private practices responded yes. In response to an open-ended question

about materials that would be helpful, 35% of physicians that requested materials wanted

specific transfusion guidelines for the management of SCD.

















Table 2-2. Clinical vignettes according to practice type
Case 1: A 16 year old boy with sickle cell anemia (Hb SS) is scheduled for elective
laparoscopic cholecystectomy. The baseline labs reveal Hct is 22% and Hb is 7.2.
Responses Adult (%) Pediatric (%)
Perform an exchange transfusion to reduce the Hb S to 15 5
30%
Transfuse RBCs to a Hct of 30% 56 92
Transfuse RBCs to a Hct of 36% 10 0
No pre-operative transfusion is indicated 17 3

Case 2: A 4 year old girl with known sickle cell anemia (Hb SS) presents to the Emergency
Department with a 12 hour history of abdominal pain, nausea, vomiting, and lethargy.
Physical examination reveals an easily palpable and tender spleen. The CBC shows WBC
29,000/CIL with 80% neutrophils and 12% bands, Hct 12%, platelets 88,000/CIL. The
physician in charge requests assistance in transfusion recommendations.
Responses Adult (%) Pediatric (%)
Transfusion of packed RBCs 43 92
Transfusion of whole blood 3 0
Perform an exchange transfusion 35 5
Transfusion is not indicated 5 3

Case 3: A 28 year old woman with Hb SC disease has acute chest syndrome with progressive
hypoxemia, despite oxygen supplementation. Review of the CBC reveals WBC
22,000/CIL, Hct 28%, platelets 530,000/CLL.
Responses Adult (%) Pediatric (%)
Transfusion of 2 units packed RBCs 23 18
Exchange transfusion with target Hct 30% 64 69
Exchange transfusion with target Hct 38% 9 3
Transfusion is not indicated 4 3

Case 4: A 21 year old male with sickle cell anemia (Hb SS) would like to enter your practice.
The patient has been undergoing transfusions of 2 units packed RBCs, every 4 weeks
since a stroke at age 12 with a goal to maintain his Hb S level at ~50%. He has been on
deferoxamine therapy over the past 7 years.
Responses Adult (%) Pediatric (%)
Continue transfusion at 4 week intervals 36 39
Begin automated exchange transfusion at 4 week intervals 14 15
Discontinue transfusions and begin hydroxyurea therapy 40 28
Discontinue transfusions 8 0


Table 2-1. SCD patients according to practice type
Number of SCD patients Pediatrics (%) Adult (%)
0-15 2 94
16 or more 98 6


P-value
< 0.0001















60 -1 56


50 2







Y es pr actice specific guidelines Y es N IH uonograph usage


Figure 2-1. Use of practice specific guidelines and NIH monograph by respondents, p-values
<0.0001 and <0.001 respectively.






56 54


151514


NonLR LR Irradiated Washed Sickle cell negative

I Never a Rarely Sometimes Always


Figure 2-2. Frequency ofRBC modifications requested by respondents. LR, leukocyte reduced.


I Pediatric
I Adult










29 8





39


33



0 Not (%)


Patient decliles I

N on compliance~ ~

Poor Understandhg C~ (~I i

No provider supervision P

cost BMf 4

Fear of sideeffects M

III Very Important (%i) o Sor


48


Figure 2-3. Importance of reasons for not using deferoxamine.


01

0 [


m ewh at (%b)









CHAPTER 3
DISCUSSION

The results support the hypothesis that there is variation in the transfusion management of

SCD among Florida hematologi sts/oncologists. Although the private and adult practices are

largest in number, the academic and pediatric practices have the most SCD patients and readily

use the resources available for SCD management. As noted in a brief review of evidence-based

approaches for the treatment of SCD, the application of evidence based medicine to the

transfusion management of SCD patients is based on a few RCTs. However, comparison of

evidence-based recommendations and transfusion practices of respondents revealed variability

between what is actually suggested based on the best evidence and what is actually practiced.

In a survey of 1 182 North American laboratories, the maj ority did not determine the red

cell antigen phenotype of non-alloimmunized SCD patients beyond ABO and D, even with

evidence to support phenotype matching for C, E and K to drastically prevent alloimmunization

and delayed hemolytic transfusion reactions [46]. In our study, just as the study noted above,

the maj ority of the respondents did not routinely request phenotypically matched RBCs for SCD

patients until the patient makes an antibody. The maj ority of respondents used leukocyte reduced

products, consistent with current recommendations [45]. There was variability in the request of

sickle negative product, which is consistent with the local blood bank practices [46]. The

indications for washed and irradiated RBC product are limited to specific situations such as

previous anaphylactic transfusion reactions or bone marrow transplant, respectively. Of note, we

specified the request was for a SCD patient who had not had a bone marrow transplant. Even

with this information provided, 15% of physicians responded they "always" request irradiated

blood and six percent responded that they "always" request washed blood, which is not

necessary.









Our study results are consistent with current literature on iron overload and chelation

therapy. Most providers use multiple measures to assess iron levels as was the case in our study.

Deferoxamine is an effective treatment of chelation therapy. However, many factors contribute

to the discrepancy between the number of SCD patients with indications and the number of

patients prescribed deferoxamine with patient compliance being the most frequently cited reason

in our study as well as others [51]. Deferasirox shows great promise as an oral iron chelator with

less compliance issues since it is an once a day oral medication compared to deferoxamine's

nightly ritual of subcutaneous infusions. Deferasirox has similar efficacy as deferoxamine in the

treatment of iron overload in SCD patients [49]. The survey data may serve as a point of

reference in future discussions comparing the use of deferoxamine and deferasirox in chelation

therapy.

A randomized clinical trial (RCT) demonstrated no benefit of prophylactic transfusion in

pregnancy in terms of maternal and perinatal complications [34]. In concordance with these

findings, the maj ority of respondents do not routinely transfuse for uncomplicated pregnancy. A

RCT comparing conservative to aggressive transfusion in elective surgery demonstrated

equivalent efficacy [35]. Cholecystectomy is a commonly performed surgery for SCD patients

[9]. The maj ority of adult and pediatric as well as private and academic practice respondents

indicated conservative transfusion management of laparoscopic cholecystectomy. However, this

approach was more prevalent among pediatric practices.

Randomized clinical trials support chronic transfusions for the primary prevention of

stroke in high risk children [30-32]. There was variability in adherence to this recommendation

with only 41% of pediatric practice respondents indicating they "always" transfuse and 22%

indicating "never" transfusing for primary stroke prevention in children. A higher number of










pediatric practice respondents were expected to "always" use chronic transfusion for primary

stroke prevention given the significant reduction of strokes observed in the Cooperative Study of

Sickle Cell Disease (CSSCD) group of participants with abnormal TCDs. However, in our

study, the terms primary prevention of stroke does not specify high risk children due to an

abnormal TCD and may represent the source of such a low number for "always" and the high

percentage for "never".

Observational data supports indefinite transfusion for secondary stroke prevention in

children [27]. Ninety-five percent of pediatric practices "always" adhere to this recommendation,

while only 26% of adult practices follow this recommendation. There are currently no standard

of care guidelines or supportive studies for adults for secondary stroke prevention. So it is not

unexpected that as many physicians opted to "discontinue transfusions and begin HU" as there

were to "continue transfusions". Clearly, there is no one option for the clinical vignette scenario

especially in light of studies such as the stroke with transfusions changing to HU (SWITCH) trial

that is currently underway to compare treatments for the prevention of a recurrent stroke and the

treatments of iron overload in children with sickle cell anemia [24]. The standard chronic

transfusions for stroke prevention and iron chelation for the prevention of iron overload will be

compared with HU to prevent recurrent stroke and phlebotomy to treat iron overload.

Limitations

As a result of non-response bias, the completed responses may not be a true representation

of a larger sample. Although we attempted to specifically contact only hematologists/

oncologists prescribing transfusions to SCD patients, our sample size of 474 represents all

physicians listed in the directories and not actually the number of hematologi sts/oncologi sts

managing SCD patients with transfusions. Therefore, the response rate calculation based on our

denominator is likely inaccurate. Florida Medicaid population data identified 265 unique










providers that prescribed transfusions for the management of SCD. Although primary care

providers are included in the Medicaid data, the data suggest as we speculate that our sample

requested is an overestimate of hematologists that actually prescribe transfusions in the

management of SCD. One solution to this problem we are exploring is conducting follow-up

phone calls to the non-respondents to Eind out if they actually care for SCD patients and if so, to

ask if they have transfused a SCD patient in the past year. Therefore, non-respondents can be

determined to be the same or different from the sampled population that completed the survey

and conclusions drawn will be stronger.

Generalization of the results is also limited by the fact that only one state (Florida) was

sampled. It may be useful to survey physicians from other states and investigate if the practices

observed are universal. Also, evidence-based medicine recommendations do not represent a

definitive standard of care. Therefore, comparing results to evidence-based medicine

recommendations may not be a true point of reference for intervention. A few survey questions

were specific for pediatric practice providers such as the questions about primary stroke

prevention and splenic sequestration. Therefore, adult practices may not be as familiar with

current recommendations as their pediatric practice colleagues.

Conclusion

The data indicate variability in the incorporation of evidence-based approaches, use of

routine clinical guidelines, and availability of emergent exchange transfusion when comparing

pediatric and adult physician practices and academic and private practices. The high variation

may relate to the fact that there are no standard of care guidelines established and there is a lack

of experience in managing SCD patients in many provider populations. The differences in

transfusion practices for stroke prevention in this study indicate a need to explore the challenges

that exist in adequately providing these services. There exist opportunities to provide educational









materials based on evidence-based medicine to all physicians caring for SCD patients. The

differences in characteristics of pediatric and adult practices in the state of Florida indicate a

need for tailoring the available materials for individual practice needs.

In a recent literature review of transfusion management of patients with SCD, Josephson et

al. recommended a set of transfusion guidelines which offer an excellent resource for physicians

in the transfusion management of patients with SCD [47]. One of the most valuable lessons

learned from this study was that many physicians who care for patients with SCD are not aware

of the useful resources that are available to guide physicians in the management of SCD. A great

starting point to reduce the variation in the transfusion management of the SCD is to come up

with an efficient and effective way to disseminate the current information to those caring for

patients with SCD. Many points of reference for SCD treatments are considered controversial

and therefore many different approaches are acceptable. However, if there is less variation in the

care of SCD, there will be less unnecessary transfusions and fewer complications from improper

transfusions and therefore more effective treatment of SCD complications and ultimately better

quality of care and life for individuals with SCD. Removing controversy surrounding treatments

and having an agreed upon approach is extremely important for future research and universal

guidelines. Fortunately, many who care for patients with SCD recognize the need to provide

universal transfusion guidelines not only in the literature but also among the Florida

hematologi st/oncologi st who completed the survey. Given that there are so many acute and

chronic complications associated with transfusions and that transfusions are so important in the

treatment of almost every SCD complications, many studies are not only looking for effective

alternatives to transfusion therapy, but also acceptable ways to improve the current use of

transfusions.









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BIOGRAPHICAL SKETCH

Levette Nicole Dunbar was born in Augusta, Georgia. She graduated from Augustus

Richard Johnson High School and then pursued her undergraduate degree at Tuskegee University

(TU), in Tuskegee, Alabama. After completing her B.S. in biology at TU in 1991, she completed

her Master of Public Health (MPH) at the University of Michigan School of Public Health in

Ann Arbor, Michigan in 1993. Levette was an eighth grade science teacher after completing her

MPH from the fall 1993 until spring 1994 at East Augusta Middle School in Augusta, Georgia.

After teaching for 1 year, Levette earned a certificate of completion from the Southern Illinois

University School of Medicine medical education preparatory program in Carbondale, Illinois in

1997. Levette entered medical school in 1997 and earned her medical degree from the

University of South Carolina School of Medicine in May 2001. After completing three years of

a pediatric residency and three years of a pediatric hematology/oncology fellowship at the

University of Florida, Levette accepted a faculty position at the University of Florida Department

of Pediatric Hematology/Oncology as a Clinical Lecturer in July 2007.





PAGE 1

1 TRANSFUSION PRACTICES IN THE MA NAGEMENT OF SICKLE CELL DISEASE AMONG FLORIDA PHYSICIANS By LEVETTE NICOLE DUNBAR A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2007

PAGE 2

2 2007 Levette Nicole Dunbar

PAGE 3

3 To those living with sick le cell disease everyday

PAGE 4

4 ACKNOWLEDGMENTS I thank the members of my supervisory thes is committee and my research mentors for guidance.

PAGE 5

5 TABLE OF CONTENTS page ACKNOWLEDGMENTS...............................................................................................................4 LIST OF TABLES................................................................................................................. ..........7 LIST OF FIGURES................................................................................................................ .........8 ABSTRACT....................................................................................................................... ..............9 CHAPTER 1 INTRODUCTION..................................................................................................................11 Sickle Cell Disease............................................................................................................ .....11 Epidemiology................................................................................................................... .......12 Clinical Manifestations........................................................................................................ ...14 Sickle Cell Crisis.............................................................................................................15 Infection...................................................................................................................... .....16 Liver and Gall Bladder Disease.......................................................................................17 Skin Disease................................................................................................................... .18 Eye Disease.................................................................................................................... .18 Renal Disease..................................................................................................................18 Cardiovascular Disease...................................................................................................19 Pulmonary Disease..........................................................................................................19 Stroke......................................................................................................................... ......21 Pregnancy...................................................................................................................... ..23 Treatments..................................................................................................................... .........23 Surgery........................................................................................................................ ....24 Hematopoietic Stem Cell Transplant...............................................................................25 Hydroxyurea....................................................................................................................25 Blood Transfusions..........................................................................................................26 2 RESEARCH STUDY.............................................................................................................29 Rationale...................................................................................................................... ...........29 Methods and Materials.......................................................................................................... .30 Study Design...................................................................................................................31 Survey Analysis...............................................................................................................31 Results........................................................................................................................ .............32 Use of Transfusion Guidelines........................................................................................33 Administration Techniques, Selec tions and Modifications of RBCs..............................34 Acute and Chronic Transfusion Indications....................................................................34 Iron Overload and Iron Chelation therapy.......................................................................37 Clinical Vignettes............................................................................................................38 Educational Resources.....................................................................................................39

PAGE 6

6 3 DISCUSSION..................................................................................................................... ....44 Limitations.................................................................................................................... ..........46 Conclusion..................................................................................................................... .........47 REFERENCES..................................................................................................................... .........49 BIOGRAPHICAL SKETCH.........................................................................................................53

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7 LIST OF TABLES Table page 2-1 SCD patients according to practice type............................................................................41 2-2 Clinical vignettes according to practice type.....................................................................41

PAGE 8

8 LIST OF FIGURES Figure page 2-1 Use of practice specific guidelines a nd NIH monograph by re spondents, p-values <0.0001 and <0.001 respectively.......................................................................................42 2-2 Frequency of RBC modifi cations requested by respondent s. LR, leukocyte reduced.......42 2-3 Importance of reasons fo r not using deferoxamine............................................................43

PAGE 9

9 Abstract of Thesis Presen ted to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science TRANSFUSION PRACTICES IN THE MA NAGEMENT OF SICKLE CELL DISEASE AMONG FLORIDA PHYSICIANS By Levette Nicole Dunbar December 2007 Chair: Cynthia Garvan Major: Medical Sciences-Clinical Investigation Limited data exist on physician transfusion pr escribing preferences in the management of sickle cell disease (SCD). To assess current practices, we conducted a survey of Florida hematologists/oncologists between fall 2005 and spring 2006. The 31-item survey addressed practice characteristics, SCD pa tient populations, practice guidel ines, transfusion settings, indications and techniques, re d blood cell (RBC) phenotype sp ecifications/modifications, iron overload, and educational resource utilization. A total of 155 physic ians (75% adultoriented, 25% pediatric) completed the survey. The primar y location was private practice (77%). Pediatric practices had more patients with SCD, overt strokes and receivi ng hydroxyurea than adult practices. The majority of pedi atric practices (61%) had specific transfusion guidelines to follow in contrast to adult practices (8%). A mi nority of respondents requested limited (16%) or extended (23%) phenotypically matched RBCs on a routine basis when compared to not matching until antibodies were identified (61 %). We queried several acute and chronic transfusion therapy indications with differences noted among pe diatric and adult practices. Analysis of clinical vignette data revealed differences am ong physicians in the transfusion management of elective cholecystectomy, sple nic sequestration, acute chest syndrome and secondary stroke prevention after prolonged chronic transfusion therapy. While most

PAGE 10

10 respondents from pediatric practices used the NIH management of SCD monograph, only a small percentage of adult practice respondents used it. The data indicate variabi lity in the incorporation of evidence-based approaches in transfusion management of SCD. These results provide insights into the need for the development of clinical t ools and guidelines tailored to pediatric and adult practices.

PAGE 11

11 CHAPTER 1 INTRODUCTION Sickle Cell Disease Sickle cell disease (SCD) is a blood disorder characterized by a genetic mutation of hemoglobin (Hb) causing polymerization of sickle hemoglobin (HbS) [1]. Hb is composed of two alpha ( ) and two beta ( ) globin chains. In SCD, chains are normal and the chains are abnormal. The HbS is due to a single point muta tion resulting in a valine instead of a glutamic acid in position six of the chain [2]. So, the abnormal chains paired with two normal chains form the abnormal HbS. These sickle he moglobin polymers in suffi cient concentrations form an insoluble gel with soluble normal he moglobin molecules and ca use red blood cell (RBC) membrane damage, decreased RBC deformability and the sickle-shaped morphology for which the disease is named [1]. The red cell abnor malities cause dehydration of the red cells, which leads to stiff, irreversibly sickled cells that re sult in sickle red cell adhesion to the vascular endothelium, hemolysis and ultimately blocks the normal blood flow through the microvasculature leading to anem ia and vaso-occlusion [3]. Although the polymerization of HbS is the cen tral event in the pathophysiology of the disease, nitric oxide depletion (NO) is also a key contributor as well [1, 3, 4]. NO depletion results from the release of larg e quantities of hemoglobin and red cell arginase from the chronic breakdown of red cells that occurs in SCD plas ma [3]. The hemolysis and red cell adhesion leads to a pro-inflammatory state with white cell adhesion and platelet aggregation [4]. Also as a result of the NO depletion, the down-regula ting effects of NO on both inflammation and activation of coagulation are lost [3]. NO normally causes vasodilation in smooth muscle. So, unregulated vasoconstriction promotes vaso-o cclusion and contributes to tissue hypoxia.

PAGE 12

12 Elevated concentrations of fetal hemoglobin (HbF), which is observed in some patients with SCD, inhibit HbS polymerization and correlate with less severe manifestations of sickle cell disease [1]. The inhibition of HbS polymerization occurs by two distinct mechanisms [1]. First, as HbF increases, HbS must decrease to have a total RBC hemoglobin co ncentration that is constant and second, HbF dimers mix with HbS di mers and form hybrids that are not capable of polymerization (note that normal hemoglobin/HbS hybrids are capable of HbS polymerization). Epidemiology SCD affects one in every 350 African American newborns in the United States every year and more than 72,000 Americans live with SCD curre ntly [5]. Individuals with HbSS disease (the homozygous condition) have sickle cell anemia Those with one gene encoding HbS and the other encoding normal hemoglobin (HbA) have sick le cell trait (the heterozygous condition or HbAS). Others have one sickle hemoglobin ge ne and a gene encoding a different hemoglobin mutation, such as hemoglobin C or hemoglobin thalassemia (resulti ng in HbSC disease or HbS Thal+ or HbS -Thal0) [2]. Individuals with HbSC or HbS -Thal+ have the disease but often have less severe manifestati ons whereas HbSS and HbS -Thal0 are considered more severe forms of the disease. Chronic hemolytic anemia is observe d in all patients with SCD. People with sickle cell trait do not have the disease bu t are at risk of passing the dis ease to their offspring if they mate with someone who also has th e trait or the disease. Rare problems associated with sickle cell trait include persistent hematuria, inability to concentrate the urine and sickling associated with severe infection, flying in unpressurized aircrafts and more ra rely, exercise-induced dehydration and hyperthermia [2]. Brambilla et al. reported that Sir John D acie described SCD as a disease of childhood in 1960 with relatively few patients surviving to adulthood [6]. In 1972, the National Sickle Cell Disease Control Act was passed by Congress. As a result, the National Sickle Cell Disease

PAGE 13

13 Program mandated that scientif ic research programs should be funded to improve care and quality of life of patients with SCD [5]. Health related quality of life (HRQOL) is one of the most important health outcome measures in a ny disease. This need to address SCD-HRQOL measures has basically evolved because SCD is no longer a disease of childhood since more patients survive into adulthood. The Cooperative Study of Sickle Cell Disease (CSSCD) started in 1979 as a large, multi-institutional study because very little information had been collected prospectively on the clinical cour se of SCD [7]. The CSSCD is the main source of the medical advances for SCD, especially with re spect to transfusions in SCD. Major medical advancements in SCD have occurred over the past 30 years to improve survival. These include the development of conj ugate vaccines and proph ylactic penicillin in infants and children with SCD to prevent ove rwhelming pneumococcal sepsis, chronic blood transfusions to prevent first and recurrent st rokes, and HU to reduce the number of painful episodes [8]. As a result, SCD life span ha s increased and resulted in a new and growing population of adult SCD patients with a need fo r coordinated care beyond the pediatric arena. In 1994, the CSSCD estimated median survival for individuals with HbSS was 42 years for males and 48 years for females [6]. The median survival age for HbSC was 60 years for males and 68 years for females. Accordingly, the pedi atric hematologists responsibility must now include collaboration with adult health care professionals to achi eve successful continuity of care for their pediatric sickle cell pa tients to achieve a better quality of life as adults living longer with the significant impact of SCD compli cations. An important component of achieving improved quality of care for SCD patients which wa rrants further investigation is the treatment management practices of SCD among physicians caring for this population of patients. A tremendous amount of variation in the treatmen t of SCD complications exist among healthcare

PAGE 14

14 providers. One major reason for the variation in the treatment management of SCD patients may be that individuals with SCD are now living longer and ther efore requiring care from adult providers who may not be as familiar with th e disease once consider ed a childhood disease. Also, some controversies exist for accepted SCD therapy. In some cases, there are different ways of approaching a single pr oblem with no supported standard of care. So, many areas of debate exist in the management of SCD. The best supported practice guidelines for the management of SCD are represented by a few randomi zed controlled trials (RCTs) [9]. To truly understand proper management of SCD, one must understand the pathogenesis of the clinical manifestations of the disease in order to address how to treat them properly. Clinical Manifestations Clinical manifestations of SCD are variable. Some individuals are completely without symptoms while others experien ce varying degrees of anemia, si ckle cell crisis, damage to organs (including but not limited to eyes, skin, sp leen, liver, lungs, heart and kidneys), increased infection and strokes. The anemia (as a resu lt of a lower than normal number of RBCs or hemoglobin, or both) results in symptoms such as a tachycardia, fatigue, generalized weakness, headache or dizziness. The anemia is generally well tolerated secondary to cardiovascular compensation, but there are conditions in whic h the anemia is symptomatic and requires intervention in the form of RBC transfusions. The normal RBC has a life span of approximately 120 days. However, the deformed sickle RBC lif e span is shortened to roughly 15-25 days resulting in the moderate to severe hemolytic (the abnormal breakdown of blood cells) anemia, with a usual steady state he matocrit of 24% (range 18-32%) in HbSS disease [10]. The hematocrit is a blood test that gives the percenta ge of RBCs in whole blood and normally ranges from 36-40%. The range varies based on ag e and gender. Laboratory abnormalities for

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15 individuals with SCD include low hemoglobin and hematocrit, elevated bilirubin levels, increased numbers of circulating reticulo cytes, and elevated leukocyte levels. Sickle Cell Crisis Vaso-occlusive crises are acute, of ten painful events that are one of the hallmarks of SCD. Any tissue that does not have blood flow constant ly (and therefore is ischemic) is severely damaged and leads to problems. Vaso-occlusio n leads to tissue ischemia, infarction and inflammation. Acute pain is one of the major sy mptoms of vaso-occlusion that can strike at anytime without warning and is generally sharp and/or throbbing [3]. The pain can occur anywhere in the body, and be loca lized to one area or generalized. The pain can also be neuropathic in nature and feel like burning or tingling. When chronic vaso-occlusive events occur in the bones, it is called avas cular necrosis or oste onecrosis (literally bone death) and often leads to a need for replacement, for example of knees or hips. When vaso-occlusion occurs in the penis, the result is a painful, prolonged erec tion or priapism. When standard therapies are unsuccessful for acute priapism, some physicians try transfusions acutely. However, close attention must be given to avoiding hyperviscos ity and therefore automated exchange transfusion is recommended [9, 11]. Some physicians advoc ate chronic transfusions or HU for recurrent priapism since the risk of impotence is high [9]. When vaso-occlusion occurs in the lungs, it results in serious lung injury and hypoxia and is known as acute chest syndrome and is considered a medical emergency (see the acute chest syndrome section). Vaso-occlusion in the brain can result in a stroke. This can lead to devastating complica tions and limitations of cognition, speech and/or movement (see the stroke section). Acute splenic sequestration crisis is a significant cause of deat h in children with SCD [9]. It is a rapid crisis that results in massive enla rgement of the spleen secondary to trapping of red blood cells. Splenic sequestration can result in hypotensive sh ock with cardiac compromise

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16 because of severe anemia, and requires emer gent red blood cell transfusions. If splenic sequestration recurs, splenectomy is sometimes considered. Transient aplastic crisis is the result of a viral infecti on known as parvovirus B19 causing suppression of the bone marrow activity (i.e., produc tion of new RBCs) leading to severe anemia in SCD [12]. Other viral and bacterial infections in SCD may also indu ce an aplastic crisis resulting in bone marrow suppression. Infections causing aplastic crises are usually self-limiting and resolve spontaneously without the need for therapy. Howeve r, there are aplastic episodes that require multiple red blood cel l transfusions to avoid cardiac compromise in SCD patients. Infection Bacterial infections contribute to a higher proportion of deaths in children with SCD than any other single cause. The increased risk of inf ection is the result of splenic dysfunction [2]. The spleen normally provides protection from infection because of antibody production and phagocytosis [2]. As a result of functional aspl enia/splenic dysfunction, individuals with SCD, especially children, are more susceptible to severe bacterial infections es pecially from organisms such as Streptococcus pneumoniae [13]. With the advent of prophylactic penicillin a nd appropriate conjugate vaccines against Streptococcus pneumoniae and Haemophilus infl uenza type b, there has been a tremendous decrease in the number of infections and deaths of children with SCD and infections [8]. An important randomized clinical tr ial published in 1986 demonstrated that prophylactic penicillin reduced the risk of Streptococcus pneumoniae infections by 84% when compared to placebo [13]. This study concluded that all neonates shou ld be screened for sickle hemoglobinopathies, and those with SCD should be pl aced on prophylactic penicillin. In a published report on a large Dallas newborn cohort, the widespread use of the conjugated pneumococcal vaccine (PCV-7) reduces the risk of invasive pneumoc occal infections as well [8].

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17 Ideally, all children with SCD should be treated with daily oral penici llin from birth until age five (the age at which the risk of inf ection is deemed no different from the general population) [14]. Also, all children with SCD should re ceive immunizations per the recommended schedule for healthy children (w hich include the PCV-7 and the Haemophilus influenza type b vaccine) and additionally r eceive the pneumococcal polysaccharide vaccine PPV23 at two years and five years and then every ten years [3]. The lower mortality rate from infections can be attributed to improved care with universal newborn screens, vaccines and penicillin prophylaxis, but also with coordi nated SCD care including continuous parental education about information relevant to SCD. Liver and Gall Bladder Disease Liver and gall bladder complications are common in SCD. Chronic hemolysis leads to a constant turnover of red blood cells leading to accumulation of bilirubin. The accumulation of bilirubin leads to pigmented gallstones (cholelithi asis) which in turns leads to acute and chronic cholecystitis and choledocholithi asis [9]. Fever, nausea, vomiti ng abdominal pain and increased jaundice may occur acutely. Laparoscopic cholecys tectomy on an elective ba sis is the standard approach to symptomatic patients [9]. Vaso-occlusive crisis may occur in the liver a nd consists of right upper quadrant pain, liver enlargement, fever, jaundice, and elevated liver tr ansaminases. It is treated like a vaso-occlusive pain crisis. Sequestration also occurs in the liver with similar consequences to splenic sequestration. In liver sequestra tion, the liver enlarges rapidl y with a sudden drop in the hemoglobin/hematocrit and a significant rise in the number of reticulocytes. The preferred treatment is exchange transfusion since simple transfusions may be accompanied by the return of sequestered RBCs in to the circul ation leading to a hyperv iscosity syndrome [9 ]. The return of sequestered RBCs may also be seen in transfused splenic sequestr ation patients and thus carries

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18 the same caution. Iron overload results from fre quent blood transfusions and the excess iron may deposit in the liver and lead to a high liv er iron load and liver dysfunction [15]. Skin Disease Leg ulcers occur in 10-20% of SCD patients [9]. The etiology of the leg ulcers likely relates to the hypoxia and infarction of the distal ankle skin. Some resolve quickly while others can take years and they do recur. Most importa ntly, the ulcers can be extremely painful and become infected. Treatments generally involve pain management, antibiotics for infections, bed rest and leg elevation as well as local topical care and dressing s such as those used for burn victims. Ulcers may correlate with the degree of anemia and therefore transfusion may be helpful but there is no eviden ce to support the use of transfusion for leg ulcers [9]. Eye Disease Sickle cell vaso-occlusive events can also aff ect the vascular beds in the eyes. Often the disease has progressed significan tly before visual problems ar e observed by the individual. Therefore, comprehensive eye exams are reco mmended regularly, regardless of signs or symptoms. Ocular manifestations of SCD ar e classified by the presence or absence of neovascularization in the eye [16]. Progression to neovascular changes can result in vitreous hemorrhages and retinal detachment, retinal artery occlusion and ischemia and risk for visual loss. Surgical intervention may be necessary but also comes with great risk of ocular ischemia, recurrent hemorrhage and elevated eye pressure [9]. Renal Disease The kidney is often a site of injury and a bnormalities in SCD because the kidney is very susceptible to dysfunction because it promotes Hb S polymerization and red cell sickling [17]. One of the most frequent renal abnormalities is an inability to concentrate the urine which can lead to dehydration, which in turns leads to a va so-occlusive crisis [9]. This may be avoided by

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19 encouraging individuals to drink liberal amounts of fluids in orde r to compensate for the fluid losses. Hematuria, proteinuria and renal failu re may occur in SCD patients as well. Chronic renal insufficiency occurs in up to 30% of adu lts [11]. Erythropoietin levels may fall with worsening renal function in individuals with SC D requiring erythropoietin therapy or frequent blood transfusions [17]. Some individuals with SCD progress to end stage renal disease requiring dialysis and/or renal transplantation. Cardiovascular Disease Cardiomegaly is usually observed in most individuals with SCD secondary to a cardiovascular compensatory mechanism for the anemia [18]. Myocardial infarctions are not common but do occur [9]. Congestive heart failure may also occur and may be associated with fluid overload. Patients with fa lling hemoglobin and congestive heart failure may benefit from slowly correcting their severe anemia with tr ansfusions [9]. In the CSSCD study of heart disease, the two factors most important to card iac disease were increasing age and decreasing hemoglobin and no specific cardiomyopathy was observed [18]. Also, significant cardiac dysfunction does occur in the setting of iron overload in the heart. Pulmonary Disease Acute chest syndrome (ACS) is a type of vaso-occlusive cr isis observed in SCD that involves lung injury leading to th e onset of chest pain. ACS is defined as new lung infiltrates on chest X-ray with the presence of fever and ches t pain and respiratory symptoms such as cough, wheezing and tachypnea [19]. ACS results in acute decompensation of the patient respiratory status and sometimes requires oxygen supplementati on and/or ventilation assistance. ACS is a leading cause of hospitalizations and death in the SCD population [6, 20]. High morbidity and mortality in ACS is also linke d to repeated episod es of ACS and may result in chronic lung disease [19].

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20 Predisposing factors for ACS included asthma, pain crisis of the chest or any area of severe pain crisis resulting in narcot ic use and hypoventilation, pulmonary fat embolism (a piece of fat that usually travels from an area of bone ma rrow injury to the lungs through blood vessels), underlying infection (typical and atypical bacteria, viruses, mi xed infections), and/or recent surgery (postoperative status) [19]. Management of ACS includes oxygen, pain management, aggressive incentive spirometry (a small bedside device to encourage ven tilation by blowing into plastic tubing to take deep breaths) to counteract hypoventilation from the effects of the narcotics and/or pain itself leading to splinting (restri ction of the breathing pa ttern), antibiotics, IV hydration, bronchodilators such as albuterol to op en up the airways, simple blood transfusions, and exchange transfusions if simple transfusi on is ineffective [19]. Exchange transfusions involve the incremental removal of the patien ts blood with HbS and replacement with fresh blood free of HbS [9]. Exchange transfusion is considered a more aggressive treatment since it involves more units of blood than a simple transf usion and therefore is associated with more transfusion-related reactions and complications. Exchange transfusions are often preferred in certain situations such as ACS for an indi vidual with HbSC to avoid hyperviscosity. Pulmonary hypertension (PH) is also a co mmon manifestation of SCD and it is also associated with high mortality [21]. PH increases the risk for right side d heart failure, syncope, and sudden death [21]. Thirty percent of adults with SCD have PH and PH is associated with a mortality rate up to 50% at 24 months after diag nosis and around 40% at 40 months [21-22]. PH is defined as an elevation of the pressure in th e pulmonary vasculature (either pulmonary arterial or venous system) [22]. Pulmonary arterial pressure above 25 mmH g is considered to represent PH. PH is thought to be directly related to NO depletion as a resu lt of chronic hemolysis in SCD [21-22]. Some of the other causes of PH pos tulated include systolic hypertension, chronic

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21 oxygen desaturation or sleep hypoven tilation, chronic pulmonary damage from recurrent ACS, repeated episodes of thromboembolism, and hi gh pulmonary blood flow from chronic anemia [21]. PH is also associated with iron overload and, therefor e may be caused by iron overload [21-22]. There are no controlled trials of treatments fo r PH associated with SCD. Therefore, most therapies are based on what is known about primary pulmonary hypertension treatments. Hydroxyurea and chronic transfusions are being explored as possible therapies to improve outcomes for patients with SCD to prevent the underlying complications of SCD that increase the risk of PH. Stroke Stroke is one of the most debilitating and deva stating aspects of SCD. Stroke occurs in approximately 11% of individuals with HbSS under the age of 20 and 24% by the age of 45 [23]. Cerebral infarction occurs mainly in children wher eas hemorrhage occurs ma inly in adults [23]. The signs and symptoms associated with isch emic strokes include speech disturbances, gait disturbances secondary to hemiparesis and a ltered sensation, seizures, headaches, abnormal behavior and confusion. Hemorrhagic strokes may present with headaches, vomiting, stupor or coma [9]. Silent infarcts presen t with deficits in cognitive areas such as deficits in mathematics, reading, and/or memory. Silent infarcts may pr edispose individuals for ischemic strokes [24]. The silent infarct transfusion (SIT) trial is a prospective multi-center study currently underway to determine the effectiveness of bl ood transfusions for the prevention of recurrent silent infarcts [24]. As a result of acute and chronic SCD problems such as anemia, ACS, vaso-occlusive crisis, aplastic crisis, and nocturnal hypoxemia l eading to decreased oxygenation, ischemic injury occurs in the brain. Treatments for acute stroke s involve the acute management of the signs and

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22 symptoms such as seizures, cerebral bleedi ng or clotting with an ticonvulsants, hematoma evacuation and anticoagulation but, most importan tly, involve blood transf usions (specifically exchange transfusion) to reduce the amount of HbS immediately. The prevention of morbidity in SCD (POMS) study has been designed to evalua te the effectiveness of overnight continuous positive airway pressure in patients with low noc turnal oxygen saturations to see if it has an effect on future central nervous system events su ch as strokes or vaso-occlusive events [24]. Recurrence of stroke occurs in two-thirds of the SCD patie nts after an initial stroke, usually within two to three year s [25]. Several studies have de monstrated the effectiveness of chronic transfusions for the redu ction of recurrent stroke rate [25, 26]. Currently, transfusions are recommended indefinitely for the prevention of a second stroke [25, 27]. Limited data demonstrated the use of HU and phlebotomy may be an effective alternative treatment to blood transfusion for the prevention of secondary stro kes in a single instituti on prospective study of 35 patients, and a national multi-center trial is cu rrently underway [24, 28]. Several reports have also documented the effectiveness of stem cell tr ansplants in the preventio n of stroke recurrence by eliminating the sickle globin gene and replacing sickle ce lls with healthy donor cells [29]. The most common cause of cerebral infarction is an occlusion of the intracranial internal carotid and middle cerebral arte ries [30]. These abnormal o cclusions can be detected by transcranial Doppler (TCD) ultr asonography measuring blood flow velocity. An abnormal TCD velocity of greater than 200 cm/sec was associated with a 40% risk of str oke in HbSS [31]. In the stroke prevention in sickle cell anemia (STOP) trial, 130 ch ildren who were at risk for a stroke based on abnormal TCD velocities were randomized to either chronic transfusion or standard care/observation [30]. A 92% reduction in stroke risk was observed in the group that received transfusion. In the STOP II trial, the length of transfusion therapy for first stroke

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23 prevention was explored [32]. Disc ontinuation of transfusio n in this group resulted in a high rate of stroke and reversion to abnormal blood flow velocities. The study concluded a high risk associated with stopping regular transfusion and stressed the im portance of continuing chronic transfusion until an effective alternative is available. Pregnancy A healthy pregnancy and deliv ery in women with SCD is very possible. However, special multi-disciplinary care must be given be fore, during and after to reduce mortality and morbidity of the fetus and mother. Increased pr e-eclampsia, preterm labor and low birth weight newborns have been observed in women with SCD [33]. Howe ver, prophylactic transfusion from the onset of pregnancy did not change the outcomes for the fetus and mother in a RCT of 72 pregnant patients with SCD [34]. In a retros pective study, data supported the use of prophylactic transfusions for uncomplicated pr egnancies beginning at 20 weeks [33]. The study revealed a reduction in pain crises, ACS, low birth weight and perina tal deaths. Prophylactic transfusions are generally not used in uncomp licated pregnancy and are reserved for those women with complications such as pre-eclampsi a, ACS, severe anemia, increasing episodes of pain crises [34]. Treatments The major therapies for the management of SCD include blood tran sfusions, hydroxyurea (HU), and hematopoietic stem cell transplants. SCD pain leads to frequent hospitalization for painful episodes necessitating intravenous opioi d medications and aggressive hydration as therapy. Many of the complications of SCD can be life-threatening and/or life-limiting, such as acute chest syndrome, strokes, infections, tr ansfusion-related react ions and iron overload, acute/chronic vaso-occlusive pa in crisis and depression. The only cure for SCD is a bone marrow transplant, which is not available to mo st people, and is also associated with an

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24 increased risk of death secondary to the complicati on of the transplant itself [29]. Therefore, the mainstay of therapy is treatment and pr evention of clinical complications. Surgery Individuals with SCD often re quire surgery for many of the complications of the disease such as cholelithiasis, recurrent splenic sequest ration, avascular necrosis vitreous hemorrhage, retinal detachment, and nocturnal hypoxemia seconda ry to obstructive sleep apnea. However, patients are at increased risk of complications before, during and after su rgery because of their anemia, the tendency of the red blood cells to si ckle and occlude the microvasculature especially during times of stress, and the risk of hypoxia [35]. The morbidity and mortality can be significantly increased surrounding surgery, especi ally post-operatively. Pre-operative, perioperative and post-operative comp lications include ACS, stroke vaso-occlusive pain, renal dysfunction/failure, infection, and even death [3 5-37]. Therefore, many hematologists prepare SCD patients for surgery with blood transfusions (as well as other supportive measures such as hydration and good oxygenation) in hopes of reducing their risk of post-operative complications [9]. Buck et al suggested that the risk of pos t-operative complications has more to do with the risk of the surgical procedure itself than having or not having pre-transf usion [37], whereas other authors debate the type of transfusion to be given (no transfusion, simple transfusion, or exchange transfusion) [35,36]. Current recomme ndations from the National Institute of Health (NIH) monograph on the management of SCD in clude simple transfusion to increase the hemoglobin to no more then ten grams per deciliter prior to all but the lowest risk procedures in HbSS and HbS -Thal0 and exchange transfusion may be warranted for HbSC to avoid hyperviscosity [9].

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25 Hematopoietic Stem Cell Transplant In the US, over 200 patients with severe SC D have been transplanted using matched sibling donors and conventional myeloablative therapy with an 83% event free survival [29]. The limiting factors are still the av ailability of a suitable matched sibling donor for the individual with SCD, and the risk of shortterm and long-term toxicities ar e still present. Several reports demonstrate less favorable outcomes with reduced in tensity regimens [29]. In adults, morbidity and mortality risks may be even higher so very few transplants are performed in adults [38]. Current studies are exploring partially matched relatives a nd matched unrelated donors using umbilical cord transplants with promising results [39]. Hydroxyurea Hydroxyurea (HU) is the only pharmacol ogic agent FDA-approved for preventing complications of SCD. HU has been shown to significantly decrease th e number of painful sickle cell episodes, hospitalizations for painful episodes, acute chest syndrome and the total number of blood transfusions [ 40]. Increased painful episodes are associated with increased mortality in SCD [6]. If the numbers of painfu l episodes are reduced with a drug such as HU, it stands to reason that the mortal ity rate will also decrease. HU offers a very important option to improve healthcare in SCD patients. Yet, HU remains underused [41]. The concern about th e potential carcinogeni c effects of HU likely contributes to the underuse [41] However, follow up on patients in the origin al Multicenter Study of Hydroxyurea in Sickle Ce ll Anemia (MSH), three mali gnancies were noted in the HU group: one carcinoma in situ of the cervix, one multi-focal carcinoma in situ of the breast and one endometrial carcinoma. There were no leukemias or lymphomas in the cohort [42]. All three patients died but the first two died of comp lications unrelated to their cancers [42].

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26 HU is a ribonucleotide reductase inhibitor, whic h prevents DNA synthesis [1]. The benefit to SCD patients is that it increases fetal hem oglobin levels which inhibit polymerization of HbS [40]. Therefore, the amount of sickled red blood cells is decrease d. High levels of HbF as a result of HU may reduce SCD complications [40, 42]. HU has other possible mechanisms as well, which include increasing n itric oxide, decreasing expressi on of red cell and endothelial adhesion, slight neutropenia (the refore less leukocyte adhesion) and diminished reticulocytes (which are the cells with the gr eatest adhesiveness) [4, 42]. Blood Transfusions Acute and chronic blood transfusions ar e important in the management of SCD complications. Along with the dr ug HU, transfusions are the only other widely available treatment for SCD complications at this tim e. Transfusions are useful under certain circumstances of SCD such as splenic sequestra tion, aplastic crisis, pr evention of primary or secondary strokes, hypoxia with acute chest syndrome, complicated pregnancy, recurrent priapism, surgeries, and any acute central nervous system injury such as seizure or central nervous system infarction [9]. Transfusions raise the oxygen-carrying capacity of blood and decrease the proportion of sickle RBCs. When us ed properly, transfusions are beneficial and often save lives of SCD patients on a daily basi s. When they are improperly performed, more problems are created that can be life-threatening. Pre-operative tr ansfusions are often given for the prevention of potenti al intra-operative and post-operative complications in SCD patients [3537]. Also, transfusions greatly reduce recurrent stroke in children with SCD [25, 26], and the risk of first stroke in children with SCD who ha ve abnormal results on TCD [30]. In light of the increasing number of transfusion indications, transfusions remain the mainstay of SCD therapy. Despite the proven benefits of transfusions, there are limitations. Transfusions are associated with adverse effects which include bu t are not limited to transmission of infectious

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27 diseases (such as HIV, CMV, hepatitis B & C), volume overload, hyperviscosity, hemolytic reactions, alloimmunization (development of anti bodies or proteins that attack/destroy donated RBCs), and iron overload [15, 43-45]. Many of the transfusion complications may be minimized by appropriate administration techniques, selection, and modifi cation of RBC products. RBC products are often modified prior to a transfusion in SCD. The RBC product is leukocyte reduced to decrease the risk of alloimmunization. The RBC product is also usually specified to be sickle cell trait negative and fresh (obtained within the last five days of transfusion). Ot her modifications of RBCs are usually not standard for SCD unless they ha ve had a prior reaction to RBC during infusion (which require the product is washed before a transfusion), or they have had a bone marrow transplant (which would re quire an irradiated and le ukocyte reduced product). In one report, 60% of chronically transfus ed adults become alloimmunized [45]. Alloimunization leads to increase delayed hemolytic reactions and life threatening events. However, performing limited RBC phenotypic matc hing with C, E, and Kell (since these antigens account for 60-98% of antibody detected pr eviously in SCD) can reduce the rate of alloimmunization [45, 46]. Vinchinsky et al demonstrated a reduc tion in the rate of alloimmunization from three percent to half a percent per unit and a reduction in hemolytic transfusion reactions by 90% by using limited phenotypic RBC matching in a study for stroke prevention in SCD [45]. Josephson et al have provided a set of guidelines for the transfusion management of SCD and recommend the prac tice of limited phenotypic RBC matching as a standard of care for all tran sfused SCD patients [47]. The toxicity of iron overload may be redu ced with iron chelation therapy [15, 48-50]. Regular transfusions lead to the accumulati on of iron in multiple organs with resultant

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28 irreversible damage if left unt reated [15, 50]. Iron overload is monitored using measurements such as serum ferritin levels, number of RBC un its transfused, magnetic resonance imaging of the liver or heart, and liver biopsy [15, 48, 50]. Iron overload can be effectively managed with iron chelation therapies such as deferoxamine a nd deferasirox. Deferoxamine requires eight to twelve hours of continuous subcutaneous infusion five to seven times a week resulting in many limitations of its use by the patient [48, 49, 51]. Defe rasirox is an oral chel ator now available for the treatment of transfusional iron overload [ 48, 49]. Our study was conducted prior to the FDA approval of deferasirox to evaluate the issu es surrounding transfusi onal iron overload and chelation therapy.

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29 CHAPTER 2 RESEARCH STUDY Rationale The application of evidence-based medicine fo r the transfusion manage ment of sickle cell disease (SCD) is based on observa tional studies and the opinions of experts in SCD with just a few randomized controlled trials (RCTs) to guide decision making [11]. The few RCTs available support the use of prophyl actic chronic transfusions for primary stroke prevention in high risk children identified by abnormal transcranial Doppler (T CD) and prevention of recurrent stroke in children or adults who have already experienced a st roke [26, 27, 30]. One of the RCTs also recommends that all SCD patients be antig en matched for E, C, and Kell [45]. Another provides evidence that a conservative transfusion program (simple transfusions that increase the hemoglobin to ten grams per deciliter) is just as effective as an aggressive transfusion program (exchange transfusion to reduce sickle hemogl obin (HbS) levels to below 30%) in preventing SCD complications in patients requiring major su rgery [35]. A RCT also demonstrated that transfusions to maintain a hematocrit of more than 30% do not reduce complications of pregnancy [34]. Therefore, chronic transfusi ons are not recommended fo r the management of uncomplicated pregnancy. Although a recent critical review of the literature and tr ansfusion guidelines provided some insight into transfusion management of the patients with SCD [47] and the National Institute of Health (NIH) monograph provide s a thorough and comprehensive outline for the management of SCD [9], limited data exist on actua l hematologist prescribi ng practices in either academic or community-based settings. In this study, we set out to evaluate the physician prescribing practices in these se ttings for the transfusion manage ment of SCD. Evaluating the current practices of physicians with respect to the transfusion management of SCD, providing a

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30 universal set of practice guide lines, and finally, actively making physicians aware of the information based on the best scientific evidence are all necessary steps to improve healthcare management of SCD patients. The objective of this study was to examine current Florida hematologist/oncologist transfus ion practices in the management of SCD. We tested the hypothesis that the transfusion prescribing practices vary am ong Florida physicians in the management of SCD. Methods and Materials A literature search was performed to obtain references addressing current recommendations for transfusion management and to catalog items to be considered for inclusion in the survey. Basic survey development wa s pursued [37, 52-54] and basic transfusion and sickle cell research were explored [27, 30, 35-37, 43, 45, 55]. A draft of the survey was developed and reviewed by a health service researcher with expert ise in physician surveys, blood bank specialists, and a highly regarded hematologist with expertise in tr ansfusion medicine for SCD. The survey was refined with the input from a group of academic hematologists in other regions of the US with particul ar interest in SCD. Face and content validity were evaluated by pilot testing the survey with current and previous trainees (residing out of st ate of Florida) of the University of Florida hematology/oncology fello wship programs. Feedback was obtained and revisions were implemented accordingly, with inpu t from two other healthcare provider survey experts. The survey and accompanying cover letter were submitted and approved by the Institutional Review Board. A thirty-one item, five page self administ ered questionnaire was created to collect information about the background and professional practice characteristic s of physicians, their SCD patient population, and their transfusion pr actices. Questions re garding transfusion practices included the settings used for non-emer gent transfusions, the use of practice site

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31 defined criteria/guidelines, th e use of phenotypically matched red blood cells (RBCs), and how RBCs were modified. We asked about the availability and frequency of automated exchange transfusion, transfusion recommendations for acu te and chronic transfusions, and experience with iron overload and deferoxamine. We also asked about the availa bility of educational resources such as information on transfusions of SCD patients, the attendance of at least one conference or presentati on on the management of SCD in the past two years and the use of the Management of Sickle Cell Disease monograph pub lished by the National Institutes of Health [9]. Four clinical vignettes were presented and physicians were asked to choose the single most likely treatment recommendation (based on thei r experience with SCD patients). There were several other forms of questions, including simple binary questions requi ring a yes or no answer, multiple choice questions with th e ability to circle all that apply, and open-ended questions. Likert scaling was used for seve ral questions in which the res pondent was asked to rate their level of agreement as never, rarely, sometimes or always or as very important, somewhat important or not important. Study Design The survey was mailed to hematologists/oncolog ists in the state of Florida from fall 2005 through spring 2006. A list of possible participants was compiled from membership directories of the American Society of Hematology (ASH), the American Society of Clinical Oncology (ASCO) and the Florida Associ ation of Pediatric Tumor Progr ams (FAPTP). Surveys were mailed to physicians via three mailing attempts, with telephone and email follow-up for nonresponders. Survey Analysis Data were processed by checking for ite m non-response, distributional forms (e.g., normality of continuous data elements), and cr eating derived variables. SAS Version 9.1 (SAS

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32 Institute Inc., Cary, N.C.) statistical software wa s used for all statistical analyses. Frequencies and percents were calculated fo r categorical data and means a nd standard deviations were calculated for numerical data. Associations be tween numerical measures were tested using Spearman correlations. Chi-square and Fishers exact tests were used to test relationships between bivariate categorical data. Groups we re compared using Wilcoxon rank sum tests. Pvalues < 0.05 were considered significant. We focused on comparing differences between pediatric and adult practice responses as analysis factors since these ar e the two major practice types that care for SCD patients and would likely exhibit the most important aspects of variation if it existed. Also, physician-specia lists are generally either in an academic or private practice location and would also demonstrat e variation if it existed. We set out to determine if major differences existed in SCD management between pediatric and adult prac tices and also between academic and private practices. Results One hundred fifty five hematol ogist/oncologists completed the survey out of 474 requested (33% response rate). Twenty-five percent we re pediatric and 75% we re adult physicians. An academic setting was reported as the location for 23% of the practices and 77% were in private practice. The majority of the respondents were adult providers in privat e practice. The highest numbers of SCD patients were reported in th e pediatric practice respondents; whereas the majority of adult practice respondents reporte d fewer SCD patients (Table 2-1). When comparing private and academic practice respondents, 49% of the academic respondents had 51 or more patients in comparison to only 17% of the private practice respondents. The highest numbers of stroke patients were noted in the pediatric practice respondents with 87% having six or more overt stroke patie nts in comparison to 90% of the adult practice respondents having five or fewer ove rt stroke patients. Sixty-four percent of the adult practice

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33 respondents had no stroke patients. Fifty-four pe rcent of the private practice respondents had no stroke patients in comparison to 23% of the academic practice respondents. The majority of the academic and pediatric practice respondents had higher numbers of patients receiving hydroxyurea (HU) For instance, 95% of the pediatric practice respondents had three or more patients receiv ing HU with 38% having 16 or mo re patients receiving HU. In contrast, 71% of the adult pract ice respondents had two or fewer patients on HU with 32% of the adult practices having no patients receiving HU. Sixty-one percent of academic practice respondents had three or more r eceiving HU while 57% of the pr ivate practice respondents had two or fewer patients receiving HU. Use of Transfusion Guidelines There was a statistically significant differe nce between adult and pediatric practice respondents with respect to prac tice guidelines and the use of the monograph (Figure 2-1). Physicians were asked if their practice had spec ific transfusion guidelines and 61% of pediatric practice respondents answered yes whereas 8% of adult practice respondents answered yes. Fifty-six percent of pediatric practice responde nts reported usage of th e 2002 management of SCD monograph published by the NIH while only 26% of adult practice respondents reported they used the monograph for the management of SCD. Sixty-three percent of the academic practices and 83% of the private practices reported they did have defined criteria/guidelines for the transfusion management of SCD patients. Forty-six percent of the academic practices and 72% of the private practices reported they di d not use the NIH monograph. Several physicians were not aware of the monograph and were plea sed to learn of its existence by means of completing the survey.

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34 Administration Techniques, Select ions and Modifications of RBCs In spite of the evidence that lim ited/extended phenotypic matching reduces alloimmunization, a minority of respondents re quested limited (16%) or extended/complete (23%) phenotypic matching of RBCs on a routine basis when compared to not matching until antibodies were identified (61%). An automated exchange transfusion on an emergent basis is often vital to saving the lives of individuals with SCD, especi ally acutely when acute chest syndrome (ACS), stroke, sepsis and multi-system organ failure occurs. Emergent automated exchange transfusion was available in the ma jority of pediatric (94%) and adult practice respondents (71%) as well as academic (97%) and private practice respondents (71%). Noticeably, the academic and pediatric practice respondents had much higher percentages in comparison to the adult and priv ate practice respondents. Ten phys icians reported from one to ten patients on chronic transfusi on programs using automated exchange transfusion. Six were in pediatric practices (five were academic and one pr ivate) and four were in adult practices (two academic and two private). We asked respondents how often certain RBC products are requested for a sickle cell patient who has not had a bone marrow transplant. Choices were always, sometimes, rarely or never. RBC products listed were leukocyte reduced, non-leukocyt e reduced, irradiated, washed, sickle cell negative and other produ cts (please specify). Overall, respondents always requested leukocyte reduced products (83%). There was vari ability in the request for sickle negative, irradiated, and washed bl ood products (Figure 2-2). Acute and Chronic Transfusion Indications We asked respondents when they considered certain indications fo r acute (episodic) transfusion for sickle cell anem ia (HbSS) patients. Choices were always, sometimes, rarely or never. The indications for acute transfusions listed for the respondents included: acute painful

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35 episodes, ACS, acute priapism, acute stroke pre-operative for general anesthesia, and vitreoretinal surgery. Other acute indications were sp ecified by respondents as a write-in and included aplastic crisis, bone marrow transplant, severe symptomatic anemia, multi-organ system failure, hepatic sequestration, hosp italization for infection in a non-acute pain crisis, pregnancy with and without complications, non-healing ulcers and hypoxia with pneumonia. Seventy-eight percent of the respondents thought th at acute transfusion was always indicated for acute stroke. Fifty-five percent of respondent s would always transfuse acutely for ACS. Fifty-two percent would always transfuse for acute priapism and 49% would always transfuse for preoperative general anesthesia. Forty-one per cent of respondents thought acute transfusion was sometimes indicated for acute painful episode s, and 44% thought vitreoretinal surgery was sometimes an indication for acute transfusion. There were statistically si gnificant differences among pedi atric and adult practice respondents with respect to acute transfusion indications, most notably with acute painful episodes, acute stroke and preoperative general anesthesia. The majority of pediatric practice respondents rarely considered acute painful ep isodes an indication for acute transfusion in comparison to adult practice respondents (76% vers us 25%). In contrast 53% of adult practice respondents sometimes consider acute painful ep isodes as an indication for acute transfusion compared to 3% of pediatric practice respondents. Pediatric practice respondents were more likely to view an acute stroke as an indicati on for acute transfusion with 95% reporting always in comparison to 72% of adult practice responden ts. Pre-operative for general anesthesia was always an indication for acute transfusion in 71% of pediatric practices and 42% of adult practices.

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36 There were statistically significant differe nces between academic and private practice respondents with respect to acute transfusion indications, most notably with acute painful episodes and acute priapism. Academic practice respondents were less likely to transfuse for acute pain and priapism when compared to thei r adult practice respondents. Sixty percent of academic practice respondents reported they rarel y transfused acutely for pain whereas 51% of private practice respondents reported they som etimes did. Priapism was sometimes an indication for acute transfusion in 62% of the aca demic practices and always an indication for 58% of the private practices. We queried chronic transfusion indications in the same manner we approached the acute indications. We asked respondents when they considered certain i ndications for chronic transfusion for SCD patients. The chronic transf usion indications listed for the respondents were primary prevention of stroke, prev ention of recurrence of stroke, history of ACS, renal failure, congestive heart failure, pulmonary hypertension, recurrent debilitating painful episodes, nonhealing leg ulcers, prevention of recurrence of priapism, unc omplicated pregnancy. Other indications were specified by responde nts such as an abnormal TCD. Pediatric practice respondents were more likely to use chronic transfusions for primary stroke prevention than adult practice respondents. Forty-one percent of pediatric providers always use chronic transfusions for primary st roke prevention. In cont rast, only seven percent of adult providers always transfuse. Ho wever, there was as many pediatric practice respondents (22%) as adult pract ice respondents (30%) who never use chronic transfusion for primary stroke prevention. Prevention of st roke recurrence was always an indication for chronic transfusion in 95% of pe diatric practice respondents, comp ared to only 27% of the adult practice respondents.

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37 A history of ACS was always or sometimes an indicatio n for chronic transfusion in 77% of pediatric and 42% of adult practice respondents. Fifty-seve n percent of pediatric practice respondents thought that renal fa ilure was always or sometim es an indication for chronic transfusion compared to 30% of the adult pract ice respondents. Recurre nt debilitating painful episodes were always or sometimes an indica tion for chronic transfusi on in 64% of pediatric and 50% of adult practice respondents. There was not a statistically significant difference between pediatric and adult practice respondents for congestive heart failure, pulmonary hypertension, non-healing ulcers, or recurrent priapism. Uncomplicated pregnancy was never an indica tion for chronic transfusion in 37% of all adult respondents and sometimes in 37%. The ma jority (59%) did transf use on a regular basis. There was not a statistically significant differe nce between pediatric a nd adult practices or academic and private practices with respect to uncomplicated pregnancy indications for transfusions. There was not a statistically significant difference between the academic and private for any of the chronic transfusion indications. Iron Overload and Iron Chelation therapy Iron overload and chelation therapy, specifica lly deferoxamine, were explored in the survey. There were no statistically significant di fferences in other measures used to assess iron levels when starting deferoxamine therapy between pediatric and adult or private and academic practices, except betw een pediatric (36%) and adult (11%) respondents in terms of percentage that used liver biopsy as a measure to assess ir on overload. Liver biopsy is considered the most accurate measurement [9]. Other measures used by physicians included steady state ferritin levels, radiologic imaging (MRI, CT), and numbe r of RBC units transfused. Despite having an indication for deferoxamine, many patients are not receiving it. Therefore, we investigated the reasons why physicians felt deferoxamine was not be ing used. Physicians we re asked to evaluate

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38 the importance of each reason listed for not usi ng deferoxamine as very important, somewhat important or not important. The results of the reasons are displayed in Figure 2-3. Noncompliance and patients refusal were cited mo st frequently as very important reasons for not using deferoxamine. Fear of side effects, poor understa nding of iron overload and iron chelation by patient/family, lack of healthcare pr oviders to supervise treatment, and cost were cited most frequently as somewhat important reasons. Clinical Vignettes The vignettes revealed statis tically significant differences between pediatric and adult (Table 2-2). In clinical vignett e one, a sixteen year old male with HbSS is scheduled for elective laparoscopic cholecystectomy with a baseline he matocrit (hct) of 22% and hemoglobin (hb) of 7.2. The treatment options were (1) perform an exchange transfusion to reduce the HbS fraction to 30%, (2) transfusion of RBCs to an hct of 30% (3) transfusion of RBCs to an hct of 36%, or (4) no pre-operative transfusion is indicated. Ninety-two percent of pediatric and 56% adult practice respondents indicated transf usion to hct of 30% was the tr eatment of choice. However, seventeen percent of adult practice respondents indicated no pre-operative transfusion. Sixtynine percent of academic and 64% private practic e respondents chose transfusion to an hct of 30%. In vignette two, a four year ol d girl with splenic sequestrati on presents to the emergency room with an hct of 12% and transfusion reco mmendations are requested. The treatment options were (1) transfusion of packed red blood cells (PRBCs), (2) transfusion of whole blood, (3) performing an exchange transfusi on, or (4) transfusion is not i ndicated. Ninety-two percent of the pediatric practice respondents recommended transfusion of PR BCs in comparison to 43% of adult practice respondents. Thir ty-five percent of adult pr actice respondents recommended perform an exchange transfusion in comparison to five percent of the pediatric practices. Sixty

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39 percent of academic and 55% of the private pr actice respondents also recommended transfusion of PRBCs for this vignette. Forty percent of the academic practices recommended exchange transfusion in comparison to 24% of the private practices. In vignette three, a twenty-e ight year old woman has AC S with progressive hypoxemia, despite oxygen supplementation. Treatment options were (1) transfusion of two units PRBCs, (2) exchange transfusion with target hct 30%, (3) exchange tr ansfusion to hct 38% or (4) transfusion is not indicated. Sixty-nine percent of pediat ric and 64% of adult practice respondents indicated exchange transfusion to hc t of 30% was the treatment of choice. Eightytwo percent of academic and 60% of private prac tices also recommended exchange transfusion to hct of 30% for the vignette Eighteen percent of pediatri c and 23% of adult practices recommended transfusion of two units of PRBCs for the scenario. In the fourth vignette, we queried recommenda tions for a twenty-one year old male who had undergone chronic transfusion for nine years for secondary stroke prevention. Continuation treatment options were (1) continue transfusions at four week interval s, (2) begin automated exchange transfusions at four week intervals, (3) discontinue transfusions and begin HU therapy or (4) discontinue transfusions. Overall for all respondents, both discontinuation of transfusions and beginning HU and continuation of transfusions at four week interv als were considered treatments of choice with 37% for each opti on and few indicating no further therapy or beginning automated exchange transfusion at four week intervals. The private and academic practices responses essentially mirrored the pediatric and adult practices for this vignette. Educational Resources Educational resources were also investigate d. Physicians were asked if information was readily available on transfusion of SCD patients. Eighty-two percen t of the pediatric and 64% of the adult practice respondents answered yes. Eighty-nine percent of academic and 62% of

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40 private practices answered yes. Physicians were also asked if they had attended at least one conference or presentati on on the management of SCD in the past two years. Twenty-eight percent of the pediatric and 18% of the adult pr actices answered yes. Sixty percent of the academic and 24% of the private practices responde d yes. In response to an open-ended question about materials that would be helpful, 35% of physicians that requested materials wanted specific transfusion guidelines fo r the management of SCD.

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41 Table 2-1. SCD patients according to practice type Number of SCD patients Pediat rics (%) Adult (%) P-value 0-15 2 94 16 or more 98 6 < 0.0001 Table 2-2. Clinical vignettes according to practice type Case 1: A 16 year old boy with sickle ce ll anemia (Hb SS) is scheduled for elective laparoscopic cholecystectomy. The baseline labs reveal Hct is 22% and Hb is 7.2. Responses Adult (%) Pediatric (%) Perform an exchange transfusion to reduce the Hb S to 30% 15 5 Transfuse RBCs to a Hct of 30% 56 92 Transfuse RBCs to a Hct of 36% 10 0 No pre-operative transf usion is indicated 17 3 Case 2: A 4 year old girl with known sickle cell anemia (Hb SS) presents to the Emergency Department with a 12 hour history of abdom inal pain, nausea, vomiting, and lethargy. Physical examination reveals an easily palp able and tender spleen. The CBC shows WBC 29,000/ L with 80% neutrophils and 12% bands, Hct 12%, platelets 88,000/ L. The physician in charge requests assist ance in transfusion recommendations. Responses Adult (%) Pediatric (%) Transfusion of packed RBCs 43 92 Transfusion of whole blood 3 0 Perform an exchange transfusion 35 5 Transfusion is not indicated 5 3 Case 3: A 28 year old woman with Hb SC dis ease has acute chest syndrome with progressive hypoxemia, despite oxygen supplementati on. Review of the CBC reveals WBC 22,000/ L, Hct 28%, platelets 530,000/ L. Responses Adult (%) Pediatric (%) Transfusion of 2 units packed RBCs 23 18 Exchange transfusion with target Hct 30% 64 69 Exchange transfusion with target Hct 38% 9 3 Transfusion is not indicated 4 3 Case 4: A 21 year old male with sickle cell an emia (Hb SS) would like to enter your practice. The patient has been undergoing transfusi ons of 2 units packed RBCs, every 4 weeks since a stroke at age 12 with a goal to mainta in his Hb S level at ~50%. He has been on deferoxamine therapy over the past 7 years. Responses Adult (%) Pediatric (%) Continue transfusion at 4 week intervals 36 39 Begin automated exchange transfusion at 4 week intervals 14 15 Discontinue transfusions a nd begin hydroxyurea therapy 40 28 Discontinue transfusions 8 0

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42 Figure 2-1. Use of practice spec ific guidelines and NIH monogr aph by respondents, p-values <0.0001 and <0.001 respectively. Figure 2-2. Frequency of RBC m odifications requested by res pondents. LR, leukocyte reduced.

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43 Figure 2-3. Importance of reasons for not using deferoxamine.

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44 CHAPTER 3 DISCUSSION The results support the hypothesis that there is variation in th e transfusion management of SCD among Florida hematologist s/oncologists. Although the private and adult practices are largest in number, the academic and pediatric pr actices have the most SCD patients and readily use the resources available for SCD management. As noted in a brief review of evidence-based approaches for the treatment of SCD, the application of evidence based medicine to the transfusion management of SCD patients is ba sed on a few RCTs. However, comparison of evidence-based recommendations and transfusion practices of respondents revealed variability between what is actually suggested based on the best evidence and what is actually practiced. In a survey of 1182 North American laboratorie s, the majority did not determine the red cell antigen phenotype of non-alloimmunized SCD patients beyond ABO and D, even with evidence to support phenotype matching for C, E a nd K to drastically prevent alloimmunization and delayed hemolytic transfusion reactions [46]. In our stud y, just as the study noted above, the majority of the respondents did not routin ely request phenotypically matched RBCs for SCD patients until the patient makes an antibody. The majority of respondents used leukocyte reduced products, consistent with current recommendations [45]. There was variability in the request of sickle negative product, which is consistent with the local blood ba nk practices [46]. The indications for washed and irradiated RBC product are limited to specific situations such as previous anaphylactic transfusion reactions or bo ne marrow transplant, respectively. Of note, we specified the request was for a SCD patient who had not had a bone marrow transplant. Even with this information provided, 15% of physicians responded they always request irradiated blood and six percent responded th at they always request washed blood, which is not necessary.

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45 Our study results are consistent with current literature on iron overload and chelation therapy. Most providers use multiple measures to assess iron levels as was the case in our study. Deferoxamine is an effective treatment of chel ation therapy. However, many factors contribute to the discrepancy between the number of SCD patients with indicati ons and the number of patients prescribed deferoxamine with patient co mpliance being the most frequently cited reason in our study as well as others [51]. Deferasirox s hows great promise as an oral iron chelator with less compliance issues since it is an once a day oral medication compared to deferoxamines nightly ritual of subcutaneous infusions. Deferasi rox has similar efficacy as deferoxamine in the treatment of iron overload in SC D patients [49]. The survey data may serve as a point of reference in future discussions comparing the us e of deferoxamine and de ferasirox in chelation therapy. A randomized clinical trial (RCT) demonstrat ed no benefit of prophyl actic transfusion in pregnancy in terms of maternal and perinatal complications [ 34]. In concordance with these findings, the majority of res pondents do not routinely transfus e for uncomplicated pregnancy. A RCT comparing conservative to aggressive transfusion in el ective surgery demonstrated equivalent efficacy [35]. Cholecystectomy is a commonly performed surgery for SCD patients [9]. The majority of adult and pediatric as well as private and academic practice respondents indicated conservative transfusi on management of laparoscopic cholecystectomy. However, this approach was more prevalent among pediatric practices. Randomized clinical trials s upport chronic transfusions fo r the primary prevention of stroke in high risk children [ 30-32]. There was variability in a dherence to this recommendation with only 41% of pediatric practice respondent s indicating they alwa ys transfuse and 22% indicating never transfusing fo r primary stroke prevention in children. A higher number of

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46 pediatric practice respondents we re expected to always use chronic transfusion for primary stroke prevention given the signi ficant reduction of strokes observ ed in the Cooperative Study of Sickle Cell Disease (CSSCD) group of participan ts with abnormal TCDs. However, in our study, the terms primary prevention of stroke do es not specify high risk children due to an abnormal TCD and may represent the source of such a low number for always and the high percentage for never. Observational data supports indefinite tran sfusion for secondary stroke prevention in children [27]. Ninety-five percent of pediatric prac tices always adhere to this recommendation, while only 26% of adult practices follow this re commendation. There are currently no standard of care guidelines or supportive studies for adults for secondary stroke prevention. So it is not unexpected that as many physicians opted to dis continue transfusions and begin HU as there were to continue transfusions. Clearly, there is no one option fo r the clinical vignette scenario especially in light of st udies such as the stroke with transf usions changing to HU (SWITCH) trial that is currently underway to compare treatments for the prevention of a recurrent stroke and the treatments of iron overload in children with sickle cell anemia [24]. The standard chronic transfusions for stroke prevention and iron chel ation for the prevention of iron overload will be compared with HU to prevent recurrent str oke and phlebotomy to treat iron overload. Limitations As a result of non-response bias, the complete d responses may not be a true representation of a larger sample. Although we attempted to specifically contact only hematologists/ oncologists prescribing transfusi ons to SCD patients, our sample size of 474 represents all physicians listed in the directories and not act ually the number of hematologists/oncologists managing SCD patients with transfusions. Therefor e, the response rate calculation based on our denominator is likely inaccura te. Florida Medicaid population data identified 265 unique

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47 providers that prescribed tr ansfusions for the management of SCD. Although primary care providers are included in the Medicaid data, the data suggest as we specu late that our sample requested is an overestimate of hematologists that actually prescrib e transfusions in the management of SCD. One solution to this pr oblem we are exploring is conducting follow-up phone calls to the non-respondents to find out if th ey actually care for SCD patients and if so, to ask if they have transfused a SCD patient in the past year. Therefore, non-respondents can be determined to be the same or different from the sampled population that completed the survey and conclusions drawn will be stronger. Generalization of the results is also limited by the fact that only one state (Florida) was sampled. It may be useful to survey physicians fr om other states and inve stigate if the practices observed are universal. Also, evidence-based medicine reco mmendations do not represent a definitive standard of care. Therefore, comparing results to evidence-based medicine recommendations may not be a true point of reference for interv ention. A few survey questions were specific for pediatric practice providers such as the questions about primary stroke prevention and splenic sequestration. Therefore, adult practices may not be as familiar with current recommendations as their pediatric practice colleagues. Conclusion The data indicate variability in the incorpor ation of evidence-based approaches, use of routine clinical guidelines, and av ailability of emergent excha nge transfusion when comparing pediatric and adult physician pr actices and academic and privat e practices. The high variation may relate to the fact that there are no standard of care guidelines establis hed and there is a lack of experience in managing SCD patients in ma ny provider populations. The differences in transfusion practices for stroke prevention in this study indicate a need to explore the challenges that exist in adequately providi ng these services. There exist oppor tunities to provide educational

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48 materials based on evidence-based medicine to all physicians caring for SCD patients. The differences in characteristics of pediatric and a dult practices in the stat e of Florida indicate a need for tailoring the available materials for individual practice needs. In a recent literature review of transfusion management of patients with SCD, Josephson et al. recommended a set of transfusion guidelines wh ich offer an excellent resource for physicians in the transfusion management of patients with SCD [47]. One of the most valuable lessons learned from this study was that many physicians who care for patients with SCD are not aware of the useful resources that are available to guide physicians in the management of SCD. A great starting point to reduce the variation in the tran sfusion management of the SCD is to come up with an efficient and effective way to dissemina te the current information to those caring for patients with SCD. Many points of reference fo r SCD treatments are considered controversial and therefore many different approa ches are acceptable. However, if there is less variation in the care of SCD, there will be less unnecessary transf usions and fewer complications from improper transfusions and therefore more effective treatment of SCD complications and ultimately better quality of care and life for individuals with SCD. Removing controversy surrounding treatments and having an agreed upon approach is extremel y important for future research and universal guidelines. Fortunately, many who care for patients with SC D recognize the need to provide universal transfusion guidelines not only in the literature but also among the Florida hematologist/oncologist who comp leted the survey. Given that there are so many acute and chronic complications associated with transfusions and that transfusions are so important in the treatment of almost every SCD complications, many studies are not only looking for effective alternatives to transf usion therapy, but also acceptable wa ys to improve the current use of transfusions.

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49 REFERENCES 1. Raphael RI, Vinchinsky EP. Pat hophysiology and treatment of sick le cell disease. Clin Adv in Hematol Oncol 2005;3:492-505. 2. Ginsburg D, Look AT, Nathan DG, Orkin SH. Nathan and Oskis hematology of infancy and childhood, sixth edition. Philadelphia, Pennsylvania: Saunders; 1974. p 790-841. 3. Knoll C, Redding-Lallinger R. Sickle cel l disease-pathophysiology and treatment. Curr Probl Pediatr Adolesc Health Care 2006;36:346-376. 4. Adams RJ, Hess DC, Nichols FT, Switzer JA. Pathophysiology and treatment of stroke in sickle-cell disease: present and future. Lancet Neurol 2006;5:501-512. 5. Bonds DR. Three decades of innovation in the ma nagement of sickle cell disease: the road to understanding the sickle ce ll phenotype. Blood Rev 2005;19:99-110. 6. Brambilla DJ, Platt OS, Rosse WF, et al. Mort ality in sickle cell disease: life expectancy and risk factors for early deat h. N Engl J Med 1994;330:1639-1644. 7. Gaston M, Rosse WF. The cooperative study of sickle cell disease: review of study design and objectives. Am J Pediatr Hematol Oncol 1982;4:197-201. 8. Buchanan GR, Quinn CT, Rogers ZR. Survival of children with sick le cell disease. Blood 2004;103:4023-4027. 9. National Institutes of Health, National Hear t, Lung and Blood Institute, Division of Blood Diseases and Resources. The management of sickle cell disease, 4th ed. Bethesda, Maryland: NIH publicati ons No. 04-2117; 2004. 10. Kahn MJ, Williams ME, editors. ASH-SAP American Society of Hematology selfassessment program, second edition. Malden, Massachusetts: Blackwell Publishing, Inc.; 2005. p 86-99. 11. Hassell KL, Lottenberg R. An evidence-based a pproach to the treatment of adults with sickle cell disease. Hematology (Am Soc Hematol Educ Program) 2005;58-65. 12. Serjeant BE, Serjeant GR, Th omas PW et al. Human parvovirus infection in homozygous sickle cell disease. Lancet 1993;341:1237-1240. 13. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. New Engl J Med 1986;314:1593-1599. 14. Faletta JM, Verter JI, Woods G, et al. Discontinuing penicillin prophylaxis in children with sickle cell anemia. Prophylactic peni cillin study II. J Pediatr 1995;127:685-690. 15. Butensky E, Harmatz P, Quirolo K, et al. Seve rity of iron overload in patients with sickle cell disease receiving chronic red ce ll transfusion therapy. Blood 2000;96:76-79.

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50 16. Clarkson JG. The ocular manifestations of si ckle cell disease: a prevalence and natural history study. Trans Opht halmol Soc 1992;90:481-504. 17. Ataga KI, Orringer EP. Renal abnormalities in sickle cell disease. Am J Hematol 2000;63:205-211. 18. Covitz W, Espeland N, Gallagher D, et al. Th e heart in sickle cell anemia: the cooperative study of sickle cell dis ease. Chest 1995;108:1214-1219. 19. Earles RN, Neumayr LD, Vinchinsky EP, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. N Engl J Med 2000;342:1855-1865. 20. Brambilla DJ, Castro O, Thori ngton B, et al. The acute chest s yndrome in sickle cell disease: incidence and risk f actors. Blood 1994;84:643-649. 21. Gladwin MT, Jison ML, Sachdev V, et al. Pulm onary Hypertension as a risk factor for death in patients with sickle cell di sease. N Engl J Med 2004;350:857-886-895. 22. Castro O, Gladwin MT. Pulmonary hypertensi on in sickle cell disease: mechanisms, diagnosis, and management. Hemato l Oncol Clin N Am 2005;19:881-896. 23. Ohene-Frempong K, Sleeper LA, Weiner SJ, et al. Cerebrovascular accid ents in sickle cell disease: rates and risk factors. Blood 1998;91:288-294. 24. Wang WC. The pathophysiology, pr evention, and treatment of str oke in sickle cell disease. Curr Opin Hematol 2007;14:191-197. 25. Goldberg HI, Hodson A, Russell MO, et al. Eff ect of transfusion ther apy on arteriographic abnormalities and on recurrence of stroke in sickle cell disease. Blood 1984;63:162-169. 26. Adams RJ, McKie V, Pegelow CH, et al. Risk of recurrent stroke in pa tients with sickle cell disease treated with erythrocyte transfusions. J Pediatr 1995;126:896-899. 27. Price C, Schwartz D, Scothorn DJ et al. Risk of recurrent stroke in children with sickle cell disease receiving blood transfusion therapy for at least five years af ter initial stroke. J Pediatr 2002;140:348-54. 28. Sylvestre PB, Ware RE, Zimmerman SA, et al. Prevention of s econdary stroke and resolution of transfusional iron overload in children with sickle cell anemia using hydroxyurea and phlebotomy. J Pediatr 2004;145:346-352. 29. Walters MC. Stem cell therapy and sickle cell disease: transplantati on and gene therapy. Hematology (Am Soc Hematol Educ Program) 2005;66-73. 30. Adams RJ, Hsu L, Mckie VC, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal resu lts on transcranial D oppler ultrasonography. N Engl J Med 1998;339:5-11.

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51 31. Adams RJ, Carl EM, Mckie VC, et al. Long-term stroke risk in children with sickle cell disease screened with transcranial Doppler. Ann Neurol 1997;42:699-704. 32. Adams RJ, Brambilla DJ. Discontinuing prophylact ic transfusions used to prevent stoke in sickle cell disease. N Engl J Med 2005;353:2769-2778. 33. Floyd RC, Morrison FS, Morrison JC, et al. Use of continuous flow erythrocytaphersis in pregnant patients with sickle ce ll disease. J Clin Apher 1991;6:224-229. 34. Burd L, Koshy M, Wallace D, et al. Prophylactic red-cell transfusions in pregnant patients with sickle cell disease. N Engl J Med 1998;319:1447-1452. 35. Haberkern CM, Neumayr L, Vinchinsky EP et al. A comparison of conservative and aggressive transfusion regimens in the periop erative management of sickle cell disease. N Engl J Med 1995;333:206-213. 36. Buchanan GR, Corrigan NJ, Fu T, et al. Mino r elective surgical proc edures using general anesthesia in children with sickle cell anemia without pr e-operative blood transfusion. Pediatr Blood Cancer 2005;45:43-47. 37. Buck J, Casbard A, Llewelyn C, et al. Preope rative transfusion in sickle cell disease: a survey of practice in Engla nd. Eur J Haematol 2005;75:14-21. 38. Atweh GF, Frenette PS. Sickle cell disease: old discoveries, new concepts, and future promise. J Clin Invest 2007;117:850-858. 39. Locatelli F, Reed W, Rocha V, et al. Related umbilical cord tr ansplantation in patients with thalassemia and sickle cell disease. Blood 2003;101:2137-2143. 40. Charache S, Moore R, Terrin ML et al. Effect of hydroxyurea on the frequency of painful crises in sickle anemia. Investigators of the multicenter study of hydroxyurea in sickle cell anemia. N Engl J Med 1995;332:1317-1332. 41. Zumberg MS, Reddy S, Boyette RL, Schwartz RJ et al. Hydroxyurea therapy for sickle cell disease in community-Based Practices: a survey of Florida and North Carolina Hematologist/Oncologists. Am J Hematol 2005;79:107-113. 42. Barton F, Castro O, Steinberg MH, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and bene fits up to nine years of treatment. JAMA 2003;289:1645-1651. 43. Vichinsky EP. Current issues with blood transf usions in sickle cell disease. Semin Hematol 2001;38(1suppl 1):14-22. 44. Telen MJ. Principles and problems of transf usion in sickle cell disease. Semin Hematol 2001;38:315-323.

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52 45. Luban NLC, Vinchinsky EP, Wright E, et al. Prospective RBC phe notype matching in a stroke-prevention trial in sickle cell anemia: a multicenter transfusion trial. Transfusion 2001;41:1086-1092. 46. Osby M, Shulman IA. Phenotype matchi ng of donor red bl ood cell units for nonalloimmunized sickle cell disease patients. Arch Pa thol Lab Med 2005;129:190-193. 47. Josephson CD, Su LL, Hillyer KL, Hillyer CD. Transfusion in the patient with sickle cell disease: a critical review of the literature and transfusi on guidelines. Transfus Med Rev 2007;21:118-33. 48. Cunningham MJ, Nathan DG. New developments in iron chelators. Curr Opin Hematol 2005;12:129-134. 49. Onyekwere O, Porter J, Vinchinsky EP, et al. A randomized comparison of deferasirox versus deferoxamine for the treatment of transf usional iron overload in sickle cell disease. Brit J hematol;136:501-508. 50. Ballas SK. Iron overload is a determinant of mo rbidity and mortality in adult patients with sickle cell disease. Semin Hematol 2001:38(1 suppl 1):30-36. 51. Treadwell MJ, Law AW, HackneyStephens E et al. Barriers to Adherence of Deferoxamine Usage in Sickle Cell Disease. Pediatr Blood Cancer 2005;44:500-507. 52. Wong E, Perez-Albuerne E, Moscow JA, Luba n NL. Transfusion management strategies: a survey of practicing pediatric hematol ogy/oncology specialists. Pediatr Blood Cancer 2005;44:119-127. 53. Smith B, Spivak J, Streif M. The diagnosis and management of polycythemia vera in the era since the polycythemia vera study group: a surv ey of the American society of hematology members practice patterns. Blood 2002;99:1144-1149. 54. Lindsey T, Southwood E, Watts-Tate N, et al. Chronic blood transfusi on therapy practices to treat strokes in children w ith sickle cell disease. J Am Acad Nurse Pract 2005;17:277-282. 55. Hinds PS, Stegenga KA, Ward-Smith P, et al. Quality of life among children with sickle cell disease receiving chronic transfusion th erapy. J Pediatr Oncol Nurs 2004;21:207-213.

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53 BIOGRAPHICAL SKETCH Levette Nicole Dunbar was born in Augusta, Georgia. She graduated from Augustus Richard Johnson High School and then pursued he r undergraduate degree at Tuskegee University (TU), in Tuskegee, Alabama. After completing her B.S. in biology at TU in 1991, she completed her Master of Public Health (MPH) at the Univer sity of Michigan School of Public Health in Ann Arbor, Michigan in 1993. Levette was an ei ghth grade science teacher after completing her MPH from the fall 1993 until spring 1994 at East A ugusta Middle School in Augusta, Georgia. After teaching for 1 year, Levette earned a certif icate of completion from the Southern Illinois University School of Medicine medical educatio n preparatory program in Carbondale, Illinois in 1997. Levette entered medical school in 1997 and earned her medical degree from the University of South Carolina Sc hool of Medicine in May 2001. After completing three years of a pediatric residency and thr ee years of a pediatric hemato logy/oncology fellowship at the University of Florida, Levette accepted a faculty position at the University of Florida Department of Pediatric Hematology/Oncology as a Clinical Lecturer in July 2007.


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