Tài liệu THE MANAGEMENT OF SICKLE CELL DISEASE ppt

Division of Blood Diseases and Resources

THE MANAGEMENT
OF SICKLE
CELL DISEASE

N A T I O N A L
N A T I O N A L

I N S T I T U T E S

H E A R T,

L U N G ,

A N D

O F

B L O O D

H E A L T H
I N S T I T U T E



THE MANAGEMENT
OF

SICKLE

CELL DISEASE

N ATIONAL I NSTITUTES
OF H EALTH
National Heart, Lung,
and Blood Institute
Division of Blood Diseases
and Resources
NIH P UBLICATION
N O . 02-2117
O RIGINALLY P RINTED 1984
P REVIOUSLY R EVISED 1989, 1995
R EPRINTED J UNE 1999
R EVISED J UNE 2002
(F OURTH E DITION )


II


C ONTENTS

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

DIAGNOSIS AND COUNSELING
1.
2.
3.

4.

World Wide Web Resources. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Neonatal Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Sickle Cell Trait. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Genetic Counseling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

HEALTH MAINTENANCE
5.
6.
7.
8.
9.

Child Health Care Maintenance. . . . . . . . . . . . . . . . . .
Adolescent Health Care and Transitions . . . . . . . . . . .
Adult Health Care Maintenance . . . . . . . . . . . . . . . . .
Coordination of Care: Role of Mid-Level Practitioners
Psychosocial Management . . . . . . . . . . . . . . . . . . . . . .

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. . . . . . . . . . . . . . . 25
. . . . . . . . . . . . . . . 35
. . . . . . . . . . . . . . . 41
. . . . . . . . . . . . . . . 47
. . . . . . . . . . . . . . . 53

TREATMENT OF ACUTE AND CHRONIC COMPLICATIONS
10.
11.
12.
13.
14.
15.
16.
17.

Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Transient Red Cell Aplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Stroke and Central Nervous System Disease . . . . . . . . . . . . . . . . . . . . . . . . . 83
Sickle Cell Eye Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Cardiovascular Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Acute Chest Syndrome and Other Pulmonary Complications . . . . . . . . . . . 103
Gall Bladder and Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

III

18.
19.
20.
21.
22.

Splenic Sequestration. . . . . . . . . .
Renal Abnormalities in Sickle Cell
Priapism . . . . . . . . . . . . . . . . . . . .
Bones and Joints . . . . . . . . . . . . .
Leg Ulcers. . . . . . . . . . . . . . . . . . .

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Disease.
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119
123
129
133
139

SPECIAL TOPICS
23.
24.
25.
26.
27.

28.
29.

IV

Contraception and Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Anesthesia and Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Transfusion, Iron Overload, and Chelation . . . . . . . . . . . . . . . . . . . . . . . . . 153
Fetal Hemoglobin Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Hematopoietic Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
Genetic Modulation of Phenotype by Epistatic Genes . . . . . . . . . . . . . . . . 173
Highlights from Federally Funded Studies. . . . . . . . . . . . . . . . . . . . . . . . . . 181


P REFACE

Enclosed is the fourth edition of a book that
is dedicated to the medical and social issues of
individuals with sickle cell disease. This publication, which was developed by physicians,
nurses, psychologists, and social workers who
specialize in the care of children and adults
with sickle cell disease, describes the current
approach to counseling and also to management of many of the medical complications
of sickle cell disease.
Each chapter was prepared by one or more
experts and then reviewed by several others
in the field. Additional experts reviewed the
entire volume. This book is not the result of a
formalized consensus process but rather represents the efforts of those who have dedicated
their professional careers to the care of individuals with sickle cell disease. The names of

the authors, their affiliations, and their e-mail
addresses are listed in the front of the book.
Multiple new therapies are now available for
children and adults with sickle cell disease,
and often the options to be chosen present
a dilemma for both patients and physicians.
This book does not provide answers to many
of these newer questions but rather explains
the choices available. The book, which focuses
primarily on the basic management of indiv-

iduals with sickle cell disease and provides
relevant online resources at the end of the
chapters, is to serve as an adjunct to recent
textbooks that delve more deeply into all
aspects of the disorder.
The authors hope that this book will be used
by medical students, house staff, general practitioners, specialists, nurses, social workers, psychologists, and other professionals as well as
the families and patients who are coping with
the complexities of sickle cell disease on a daily
basis. The book, any part of which can be
copied freely, will be placed on the National
Heart, Lung, and Blood Institute (NHLBI)
Web site and will be updated as needed.
Research is essential to provide the knowledge
required to improve the care of individuals
with sickle cell disease, but it is the physicians
and other health care personnel who must
ensure that the very best care is actually
delivered to each child and adult who has

this disorder. We hope that this book will
help to achieve this goal.

Claude Lenfant, M.D.
Director, NHLBI

V


VI


C ONTRIBUTORS

Robert Adams, M.D.
Associate Professor, Department of Neurology
Room HB-2060
Medical College of Georgia
Augusta, GA 30912
Tel:
(706) 721-4670
Fax:
(706) 721-6757
E-mail:
Kenneth I. Ataga, M.D.
Division of Hematology/Oncology
CB# 7305, 3009 Old Clinic Building
University of North Carolina at Chapel Hill
Chapel Hill, NC 27599-7305
Tel:

(919) 843-7708
E-mail:
Harold Ballard, M.D.
Assistant Chief, Hematology Division
New York Veterans Administration
Medical Services, 12th Floor
New York, NY 10010
Tel:
(212) 951-3484
Fax:
(212) 951-5981
Lennette Benjamin, M.D.
Associate Professor of Medicine
Montefiore Hospital Medical Center
Comprehensive Sickle Cell Center
111 East 210th Street
Bronx, NY 10467-2490
Tel:
(718) 920-7375
Fax:
(718) 798-5095
E-mail:

Henny Billett, M.D.
Director, Clinical Hematology
Albert Einstein College of Medicine
Comprehensive Sickle Cell Center
Montefiore Hospital Medical Center
111 East 210th Street
Bronx, NY 10467

Tel:
(718) 920-7373
Fax:
(718) 920-5095
E-mail:
E-mail:
Carine Boehme, M.S.
Associate Professor
The Johns Hopkins University School of Medicine
CMSC Room 1004
600 North Wolfe Street
Baltimore, MD 21287-9278
Tel:
(410) 955-0483
Fax:
(410) 955-0484
E-mail:
Kenneth Bridges, M.D.
Associate Professor of Medicine
Director, Joint Center for Sickle Cell
and Thrombosis and Hemostasis Disorders
Brigham and Women’s Hospital
Harvard Medical School
75 Francis Street
Boston, MA 02115
Tel:
(617) 732-5842
Fax:
(617) 975-0876
E-mail:

VII


Oswaldo Castro, M.D.
Professor of Medicine/Pediatrics
Howard University School of Medicine
Comprehensive Sickle Cell Center
2121 Georgia Avenue, NW
Washington DC 20059
Tel:
(202) 806-7930
Fax:
(202) 806-4517
E-mail:

Joseph DeSimone, Ph.D.
Geneticist
VA West Side Medical Center
Hematology Research (151C)
820 South Damen Avenue
Chicago, IL 60612
Tel:
(312) 666-6500 x2683
Fax:
(312) 455-5877
E-mail:

Samuel Charache, M.D.
2006 South Road

Baltimore, MD 21209-4510
Tel:
(410) 466-6405
Fax:
(410) 466-4330
E-mail:

Ann Earles, R.N., P.N.P.
Research Nurse
Children’s Hospital of Oakland
747 52nd Street
Oakland, CA 94609-1809
Tel:
(510) 428-3453
Fax:
(510) 450-5635
E-mail:

Wesley Covitz, M.D.
Professor of Pediatrics
Wake Forest School of Medicine
Medical Center Boulevard
Winston-Salem, NC 27157-1081
Tel:
(336) 716-4267
Fax:
(336) 716-0533
E-mail:
Gary R. Cutter, Ph.D.
Professor of Medicine

Director, Center for Research Design
and Statistical Methods
UNR School of Medicine, Mail Stop 199
Reno, Nevada 89557
Tel:
(775) 784-1565
Fax:
(775) 784-1142
E-mail:
Carlton Dampier, M.D.
Director, Marian Anderson SCC
Hematology/Oncology
St. Christopher’s Hospital for Children
Erie Avenue at Front Street
Philadelphia, PA 19134
Tel:
(215) 427-5096
Fax:
(215) 427-6684
E-mail:

VIII

James Eckman, M.D.
Professor of Medicine
Emory University School of Medicine
69 Butler Street
Atlanta, GA 30303
Tel:
(404) 616-5982

Fax:
(404) 577-9107
E-mail:
Morton Goldberg, M.D.
Director, Department of Ophthalmology
The Johns Hopkins Hospital
The Wilmer Ophthamological Institute
Maumanee Building, Room 729
600 North Wolfe Street
Baltimore, MD 21287-9278
Tel:
(410) 955-6846
Fax:
(410) 955-0675
E-mail:
Harry E. Jergesen, M.D.
Department of Orthopaedic Surgery
University of California, San Francisco
500 Parnassus Avenue, MU-320W
San Francisco, CA 94143
Tel:
(415) 476-8938
Fax:
(415) 476-1301
E-mail:


Cage Johnson, M.D.
Professor of Medicine
University of Southern California

2025 Zonal Avenue
Los Angeles, CA 90033
Tel:
(323) 442-1259
Fax:
(323) 442-1255
E-mail:
Adrena Johnson-Telfair, P.A.C.
Associate Director for Clinical Services
University of Alabama at Birmingham
Comprehensive Sickle Cell Center
1900 University Boulevard
513 Tinsley Harrison
Birmingham, AL 35294-0006
Tel:
(205) 975-2281
Fax:
(205) 975-5264
E-mail:
Clinton Joiner, M.D., Ph.D.
Associate Professor of Pediatrics
Director, Comprehensive Sickle Cell Center
Children’s Hospital Medical Center
3333 Burnett Avenue, OSB 4
Cincinnati, OH 45229-3039
Tel:
(513) 636-4541
Fax:
(513) 636-5562
E-mail:

John Kark, M.D.
Professor, Hematology/Oncology
Howard University Hospital
5145 Tower Building
2041 Georgia Avenue, NW
Washington, DC 20060
Tel:
(202) 865-1511
Fax:
(202) 865-4607
E-mail:
Mabel Koshy, M.D.
University of Illinois
840 South Wood Street
MSC 787, Room 833
Chicago, IL 60612
Tel:
(312) 996-5680
Fax:
(312) 996-5984

Peter Lane, M.D.
Director, Colorado Sickle Cell Treatment
and Research Center
Campus Box C-222
University of Colorado Health Sciences Center
4200 East Ninth Avenue
Denver, CO 80262
Tel:
(303) 372-9070

Fax:
(303) 372-9161
E-mail:
Dimitris Loukopoulos, M.D., D.Sci.
First Department of Medicine
University of Athens School of Medicine
Laikon Hospital
Athens 11527 GREECE
Tel:
+30 1 7771 161
Fax:
+30 1 7295 065
E-mail:
Bertram Lubin, M.D.
Director of Medical Research
Children’s Hospital Oakland Research Institute
5700 Martin Luther King Junior Way
Oakland, CA 94609
Tel:
(510) 450-7601
Fax:
(510) 450-7910
E-mail:
Elysse Mandell, M.S.N.
Division of Hematology
Brigham and Women’s Hospital
75 Francis Street
Boston, MA 02115
Tel:
(617) 732-8485

Fax:
(617) 975-0876
E-mail:
Vipul Mankad, M.D.
Professor and Chairman
Kentucky Clinic, Room J406
University of Kentucky
Chandler Medical Center
Lexington, KY 40536-0284
Tel:
(859) 323-5481
Fax:
(859) 257-7706
E-mail:

IX


Marie Mann, M.D., M.P.H.
Deputy Chief, Genetic Services Branch
Maternal and Child Health Bureau
Health Resources and Services Administration
5600 Fishers Lane
Rockville, MD 20857
Tel:
(301) 443-4925
Fax:
(301) 443-8604
E-mail:

Orah Platt, M.D.
Director, Department of Laboratory Medicine
Enders Research Building, Room 761
Children’s Hospital Medical Center
320 Longwood Avenue
Boston, MA 02146
Tel:
(617) 355-6347
Fax:
(617) 713-4347
E-mail:

Ronald Nagel, M.D.
Head, Division of Hematology
Albert Einstein College of Medicine
1300 Morris Park Avenue
Bronx, NY 10461
Tel:
(718) 430-2186
Fax:
(718) 824-3153
E-mail:

Sonya Ross, B.S.
Director of Program Development
Sickle Cell Disease Association of America
P.O. Box 1956
Baltimore, MD 21203
Tel:
(410) 363-7711

Fax:
(410) 363-4052
E-mail:

Ms. Kathy Norcott
Sickle Cell Disease Association of the Piedmont
P.O. Box 20964
Greensboro, NC 27420
Tel:
(336) 274-1507 or (800) 733-8299
E-mail:

Frank Shafer, M.D.
St. Christopher’s Hospital for Children
Hematology/Oncology
Erie Avenue at Front Street
Philadelphia, PA 19134
Tel:
(215) 427-4399
Fax:
(215) 427-6684
E-mail:

Kwaku Ohene-Frempong, M.D.
Director, Comprehensive Sickle Cell Center
Children’s Hospital of Philadelphia
324 South 34th Street and Civic Center Boulevard
Philadelphia, PA 19104
Tel:
(215) 590-3423

Fax:
(215) 590-3992
E-mail:
Eugene Orringer, M.D.
Professor of Medicine
Director, Comprehensive Sickle Cell Program
University of North Carolina
125 MacNider Building
Chapel Hill, NC 27599-7000
Tel:
(919) 843-9485
Fax:
(919) 216-3602
E-mail:

X

Jeanne Smith, M.D.
Associate Professor of Clinical Research
Columbia University Comprehensive
Sickle Cell Center
Suite 6164
506 Lenox Avenue at 135th Street
New York, NY 10037
Tel:
(212) 939-1701
Fax:
(212) 939-1692
E-mail:
Kim Smith-Whitley, M.D.

Associate Director for Clinic Sickle Cell Program
Children’s Hospital of Philadelphia
324 South 34th Street
Philadelphia, PA 19104
Tel:
(215) 590-1662
Fax:
(215) 590-5992
E-mail:


Martin Steinberg, M.D.
Director, Center for Excellence in Sickle Cell Disease
Boston Medical Center
88 East Newton Street
Boston, MA 02118
Tel:
(617) 414-1020
Fax:
(617) 414-1021
E-mail:
Marie Stuart, M.D.
Professor of Pediatrics
Division of Pediatric Hematology
Thomas Jefferson University
1025 Walnut Street, Suite 727
Philadelphia, PA 19107
Tel:
(215) 955-9820
Fax:

(215) 955-8011
E-mail:
Paul Swerdlow, M.D.
Director of Red Cell Disorders
Associate Professor, Wayne State University
Harper Hospital, 4 Brush South
Barbara Ann Karmanos Cancer Institute
3990 John R St.
Detroit, MI 48201
Tel:
(313) 745-9669
Fax:
(313) 993-0307
E-mail:
Joseph Telfair, Dr.P.H., M.S.W., M.P.H.
Department of Maternal and Child Health
School of Public Health
University of Alabama at Birmingham
320 Royals Building
1665 University Boulevard
Birmingham, AL 35294-0022
Tel:
(205) 934-1371
Fax:
(205) 934-8248
E-mail:

Tim Townes, Ph.D.
Professor, Department of Biochemistry
and Molecular Genetics

Schools of Medicine and Dentistry
University of Alabama at Birmingham
BBRB 260
1530 3rd Avenue South
Birmingham, AL 35294-0022
Tel:
(205) 934-5294
Fax:
(205) 934-2889
E-mail:
Marsha Treadwell, Ph.D.
Hematology Behavioral Services Coordinator
Children’s Hospital Oakland
747 52nd Street
Oakland, CA 94609-1809
Tel:
(510) 428-3356
Fax:
(510) 428-3973
E-mail:
Elliott Vichinsky, M.D.
Division Head, Hematology/Oncology
Director, Comprehensive Sickle Cell Center
Children’s Hospital of Oakland
747 52nd Street
Oakland, CA 94609-1809
Tel:
(510) 420-3651
Fax:
(510) 450-5647

E-mail:
Mark Walters, M.D.
Fred Hutchinson Cancer Research Center
100 Fairview Avenue North, C1-169
P.O. Box 10924
Seattle, WA 98109-1024
Tel:
(206) 667-4103
Fax:
(206) 667-6084
E-mail:
Winfred Wang, M.D.
Department of Hematology/Oncology
St. Jude’s Children’s Research Center
P.O. Box 318
32 North Lauderdale
Memphis, TN 38101
Tel:
(901) 495-3497
Fax:
(901) 521-9005
E-mail:

XI


Russell Ware, M.D., Ph.D.
Professor of Pediatrics
Duke University Medical Center
Box 2916 DUMC

R-133 MSRB, Research Drive
Durham, NC 27710
Tel:
(919) 684-5665
Fax:
(919) 684-5752
E-mail:
Doris Wethers, M.D.
1201 Cabrini Boulevard
Apartment #57
New York, NY 10033
Tel:
(212) 928-2600
E-mail:
Charles Whitten, M.D.
President Emeritus, Sickle Cell Disease Association
of America
Distinguished Professor of Pediatrics and Associate Dean
Wayne State University School of Medicine
Scott Hall, Room 1201
540 East Canfield Street
Detroit, MI 48201
Tel:
(313) 577-1546
Fax:
(313) 577-1330
E-mail:
Wanda Whitten-Shurney, M.D.
Attending Pediatrician
Children’s Hospital of Michigan

3901 Beaubien Boulevard
Detroit, MI 48201
Tel:
(313) 745-5613
Fax:
(313) 745-5237
E-mail:
Nevada Winrow, Ph.D.
Postdoctoral Fellow
9624 Devedente Drive
Owings Mills, MD 21117
Tel:
(240) 601-8683
Fax:
(410) 902-3457
E-mail:

XII

Robert Yamashita, Ph.D.
Interdisciplinary Studies in Science and Society
Liberal Studies Department
California State University
San Marcos, CA 92096-0001
Tel:
(760) 750-4204
E-mail:
NATIONAL INSTITUTES OF HEALTH
Barbara Alving, M.D.
Deputy Director

National Heart, Lung, and Blood Institute
Building 31, Room 5A47, MSC 2490
31 Center Drive
Bethesda, MD 20892-2490
Tel:
(301) 594-5171
Fax:
(301) 402-0818
E-mail:
Griffin Rodgers, M.D.
Deputy Director
National Institute of Diabetes and Digestive
Kidney Diseases
Building 31, Room 9A52, MSC 1822
31 Center Drive
Bethesda, MD 20892-1822
Tel:
(301) 496-5741
Fax:
(301) 402-2125
E-mail:
Henry Chang, M.D.
Health Scientist Administrator
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7950
Bethesda, MD 20892-7950
Tel:
(301) 435-0065
Fax

(301) 480-0867
E-mail:
Charles Peterson, M.D.
Director, Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7950
Bethesda, MD 20892-7950
Tel:
(301) 435-0080
Fax:
(301) 480-0867
E-mail:


Duane Bonds, M.D.
Health Scientist Administrator
Sickle Cell Disease Scientific Research Group
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7950
Bethesda, MD 20892-7950
Tel:
(301) 435-0055
Fax:
(301) 480-0868
E-mail:
Greg Evans, Ph.D.
Health Scientist Administrator
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute

6701 Rockledge Drive, MSC 7950
Bethesda, MD 20892-7950
Tel:
(301) 435-0055
Fax:
(301) 480-0868
E-mail:

Petronella Barrow
Office Manager
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7950
Bethesda, MD 20892-7950
Tel:
(301) 435-0080
Fax:
(301) 480-0867
E-mail:
Kathy Brasier
Secretary
National Heart, Lung, and Blood Institute
Building 31, Room 5A47, MSC 2490
Bethesda, MD 20892-2490
Tel:
(301) 496-1078
Fax:
(301) 402-0818
E-mail:

David Bodine, Ph.D.
Chief, Hematopoiesis Section
Genetics and Molecular Biology Branch
National Human Genome Research Institute,
Building 49, Room 3W16, MSC 4442
Bethesda, MD 20892-4442
Tel:
(301) 402-0902
Fax:
(301) 402-4929
E-mail:
Jonelle Drugan, Ph.D.
Program Analyst
Office of Science and Technology
National Heart, Lung, and Blood Institute
Building 31, Room 5A06, MSC 2482
Bethesda, MD 20892-2482
Tel:
(301) 402-3423
Fax:
(301) 402-1056
E-mail:

XIII


XIV


I NTRODUCTION

This edition of The Management of Sickle
Cell Disease (SCD) is organized into four
parts: Diagnosis and Counseling, Health
Maintenance, Treatment of Acute and Chronic
Complications, and Special Topics. The original intent was to incorporate evidence-based
medicine into each chapter, but there was
variation among evidence-level scales, and
some authors felt recommendations could
be made, based on accepted practice, without
formal trials in this rare disorder.
The best evidence still is represented by randomized, controlled trials (RCTs), but variations exist in their design, conduct, endpoints,
and analyses. It should be emphasized that
selected people enter a trial, and results should
apply in practice specifically to populations
with the same characteristics as those in
the trial. Randomization is used to reduce
imbalances between groups, but unexpected
factors sometimes may confound analysis or
interpretation. In addition, a trial may last
only a short period of time, but long-term
clinical implications may exist. Another issue
is treatment variation, for example, a new

pneumococcal vaccine developed after the
trial, which has not been tested formally in
a sickle cell population. Earlier trial results
may be accepted, based on the assumption
that the change is small.
In some cases, RCTs cannot be done satisfactorily (e.g., for ethical reasons, an insufficient

number of patients, or a lack of objective
measures for sickle cell “crises”). Thus the
bulk of clinical experience in SCD still
remains in the moderately strong and weaker
categories of evidence.
Not everyone has an efficacious outcome in
a clinical trial, and the frequency of adverse
events, such as with long-term transfusion
programs or hematopoietic transplants, might
not be considered. Thus, an assessment of
benefit-to-risk ratio should enter into translation of evidence levels into practice recommendations. A final issue is that there may be two
alternative approaches that are competitive
(e.g., transfusions and hydroxyurea). In this
case the pros and cons of each course of treatment should be discussed with the patient.

1


Introduction

The practice guidelines best supported
by scientific evidence are:

■

■

■

In surgical settings, simple transfusions

to increase hemoglobin (Hb) levels to 10
g/dL are as good as or safer than aggressive
transfusions to reduce sickle hemoglobin
(Hb S) levels to below 30 percent.

Hydroxyurea decreases crises in patients
with severe sickle cell disease [evidence
from the Multicenter Study of Hydroxyurea
in Sickle Cell Anemia (MSH) trial].

Pneumococcal vaccine prevents
pneumococcal infection in children.

■

Transfusions to reduce Hb S levels to
below 30 percent prevent strokes in children with high central nervous system
blood flow [evidence from the Stroke
Prevention Trial in Sickle Cell Anemia
(STOP I)].

■

Penicillin prophylaxis prevents pneumococcal sepsis in children [evidence from
Prophylactic Penicillin Studies I and II
(PROPS I & II)].

■

Transfusions to maintain a hematocrit

of more than 36 percent do not reduce
complications of pregnancy.

The following nomenclature, derived from the Council of Regional Networks for Genetic Services
(CORN) guidelines for the U.S. newborn screening system [Pass KA, Lane PA, Fernhoff PM, et al.
U.S. newborn screening system guidelines II: Follow-up of children, diagnosis, management, and
evaluation. Statement of the Council of Regional Networks for Genetic Services (CORN). J Pediatr
2000;(4 Suppl):S1-46], is used throughout this book:

Genotype

Full Name

Abbreviation

βs

βs

Sickle cell disease-SS

SCD-SS

βs / βc

Sickle cell disease-SC

SCD-SC

βs

/

/

βo

thalassemia

βs / β+ thalassemia

2

thalassemia

SCD-S βo thal

Sickle cell disease-S β+ thalassemia

SCD-S β+ thal

Sickle cell disease-S

βo


DIAGNOSIS AND COUNSELING

3

4


1

W ORLD W IDE W EB R ESOURCES

SICKLE CELL AND GENETIC WEB SITES
Sickle Cell Disease Association of America (SCDAA)

A patient advocacy site with information for the public.
Center for Disease Control and Prevention: Hemoglobin S Allele and Sickle Cell Disease
/>An excellent article about sickle cell genetics and epidemiology.
The Comprehensive Sickle Cell Centers
/>A description of a major clinical research program supported by the NHLBI.
Harvard Sickle Cell Program

A comprehensive source for information for patients and health care providers.
The Sickle Cell Information Center
/>A broad range of information for the public and professionals.
National Organization for Rare Disorders, Inc.

A portal for all rare diseases.
ClinicalTrials.gov—Linking Patients to Medical Research

A search engine for clinical trials in different diseases.
The National Newborn Screening and Genetics Resource Center (NNSGRC)

Information and resources for health professionals, the public health community, consumers

and government officials.
Genetic Alliance

A support organization for different genetic problems.

5


Chapter 1: World Wide Web Resources

REGIONAL GENETIC NETWORKS
Mid-Atlantic Regional Human Genetics Network (MARHGN)
/>Genetic services for Delaware, Maryland, New Jersey, Pennsylvania, Virginia, West Virginia,
and the District of Columbia.
Mountain States Genetics Network

Genetic services for Arizona, Colorado, Montana, New Mexico, Utah, and Wyoming.
Pacific Northwest Regional Genetics Group (PacNoRGG)
/>Genetic services for Alaska, Idaho, Oregon, and Washington.
Southeastern Regional Genetics Group (SERGG)
/>Genetic services for the Southeastern region: Alabama, Florida, Georgia, Kentucky, Louisiana,
Mississippi, North Carolina, South Carolina, and Tennessee.
Texas Genetics Network (TEXGENE)
/>Genetic services for Texas.

6


2

N EONATAL S CREENING

The demonstration in 1986 that prophylactic
penicillin markedly reduces the incidence of
pneumococcal sepsis (1) provided a powerful
incentive for the widespread implementation
of neonatal screening for sickle cell disease
(SCD) (2). Neonatal screening, when linked
to timely diagnostic testing, parental education, and comprehensive care, markedly
reduces morbidity and mortality from
SCD in infancy and early childhood (2-11).
Approximately 2,000 infants with SCD are
identified annually by U.S. neonatal screening programs (12,13). Screening also identifies infants with other hemoglobinopathies,
hemoglobinopathy carriers, and in some
states, infants with α-thalassemia syndromes.

METHODS
Forty-four states, the District of Columbia,
Puerto Rico, and the Virgin Islands currently
provide universal screening for SCD.
Screening is available by request in the other
six states. The majority of screening programs
use isoelectric focusing (IEF) of an eluate from
the dried blood spots that also are used to
screen for hypothyroidism, phenylketonuria,
and other disorders (13-15). A few programs
use high-performance liquid chromatography
(HPLC) or cellulose acetate electrophoresis as
the initial screening method. Most programs
retest abnormal screening specimens using

a second, complementary electrophoretic
technique, HPLC, immunologic tests, or
DNA-based assays (13-15).

The sensitivity and specificity of current
screening methodology are excellent (11), but
neonatal screening systems are not foolproof.
A few infants, even in states with universal
screening, may not be screened. Other infants
with SCD may go undiscovered because of
extreme prematurity, blood transfusion prior
to screening, mislabeled specimens, clerical
errors in the laboratory, or the inability to
locate affected infants after discharge from
the nursery (5,14,16-20). It is imperative that
all infants, including those born at home, be
screened and that the initial screening test
always be obtained prior to any blood transfusion, regardless of gestational or postnatal age.
Information requested on screening forms
should be recorded accurately and completely
to facilitate the followup of positive screening
tests and interpretation of results. In states
that have not yet implemented universal
screening, neonatal screening for SCD should
be requested for all high-risk infants (those
of African, Mediterranean, Middle Eastern,
Indian, Caribbean, and South and Central
American ancestry). Any high-risk infant
not screened at birth, or for whom neonatal
screening results cannot be documented,

should be screened for hemoglobinopathies
prior to 2 months of age.
Hemoglobins (Hb) identified by neonatal
screening are generally reported in order of
quantity. Because more fetal hemoglobin (Hb
F) than normal adult hemoglobin (Hb A) is
present at birth, most normal infants show
Hb FA. Infants with hemoglobinopathies also

7


Chapter 2: Neonatal Screening

show a predominance of Hb F at birth. Those
with SCD show Hb S in absence of Hb A
(FS), Hb S with another hemoglobin variant
(e.g., FSC, FSDPunjab), or a quantity of Hb S
greater then Hb A (FSA). Hundreds of other
Hb variants may also be identified. Most of
these variants are associated with few or no
clinical consequences, but some are associated
with significant anemia or other problems.
Many screening programs also detect and
report Hb Bart’s, indicative of α-thalassemia.

SICKLE CELL DISEASE
As shown in table 1, a number of different
neonatal screening results may be indicative
of sickle cell disease (14,21). Hb FS in infancy

is associated with a variety of genotypes with
a wide range of clinical severity. Most infants
with screening results that show Hb FS have
SCD-SS, but other possible conditions include
sickle βo-thalassemia, sickle δβ-thalassemia,
and sickle HPFH. Some infants with sickle
β+-thalassemia also show FS screening results
when the quantity of Hb A at birth is insufficient for detection (22). The coinheritance of
α-thalassemia may complicate differentiation
of genotypes in some infants (23). For infants
with positive screening tests, confirmatory
testing of a second blood sample should be
accomplished by 2 months of age so that
parental education, prophylactic penicillin,
and comprehensive care can be promptly
implemented (11,14). In many states, confirmatory testing is provided by the screening
program using hemoglobin electrophoresis
(cellulose acetate and citrate agar), IEF,
HPLC, and/or DNA-based methods.
Solubility tests to detect Hb S are inappropriate screening or confirmatory tests, in part
because high levels of fetal hemoglobin (i.e.,
low concentrations of Hb S) give false-negative results in infants with SCD.

8

Hemolytic anemia and clinical signs and
symptoms of SCD are rare before 2 months
of age and develop variably thereafter as Hb F
levels decline (table 1). Thus for infants with
an FS phenotype, serial complete blood counts

(CBCs) and reticulocyte counts may not clarify the diagnosis during early infancy, and testing of parents or DNA analysis may be helpful
in selected cases (14). In all cases, infants with
Hb FS should be started on prophylactic penicillin by 2 months of age, and parents should
be educated about the importance of urgent
medical evaluation and treatment for febrile
illness and for signs and symptoms indicative
of splenic sequestration (11,14).
Achieving an optimal outcome for each
affected infant is a significant public health
challenge. State public health agencies should
have a responsibility to ensure the availability,
quality, and integration of all five components
of the neonatal screening system: screening,
follow-up, diagnostic testing, disease management and treatment, and evaluation of the
entire system (12-15). To be beneficial,
screening, follow-up, and diagnosis of sickle
cell disease must be followed by prompt referral to knowledgeable providers of comprehensive care (2,11). Comprehensive care includes
ongoing patient and family education about
disease complications and treatment, diseasespecific health maintenance services including
pneumococcal immunizations and prophylactic penicillin, access to timely and appropriate
treatment of acute illness, nondirective genetic counseling, and psychosocial support (14).
The extent to which these services are provided directly by public health agencies or by
other clinics and providers will vary among
states and communities. However, all states
should have the responsibility to ensure
that each infant and family with SCD
receive appropriate services and to conduct


Table 1. Sickle Hemoglobinopathies: Neonatal Screening and Diagnostic Test Results

Disorder

Approx.
% of U.S.
patients

Neonatal
screening
results1

Hb separation
by 2 months
of age1

Serial CBC,
reticulocytes

DNA
dot blot

Hematologic studies by 2 years

MCV2

Hb A23
(%)

Hb F
(%)

Hb F
distribution

SCD-SS

65

FS

FS

Hemolysis and anemia
by 6-12 months

N or ↑4

<3.64

<25

Heterocellular

βs

SCD-SC

25

FSC

FSC

Mild or no anemia
by 2 years

N or ↓

NA5

<15

Not applicable6

βs βc

SCD-S
β+ thal

8

FSA or FS7

FSA

Mild or no anemia
by 2 years

N or ↓

>3.6

<25

Not applicable6

βA βs

SCD-S
βo thal

2

FS

FS

Hemolysis and anemia
by 6-12 months

↓

>3.6

<25

Heterocellular

βA βs

SCD-S
δβ thal

<1

FS

FS

Mild anemia by
2 years

↓

<2.5

<25

Heterocellular

βs

S HPFH

<1

FS

FS

No hemolysis
or anemia

N or ↓

<2.5

<25

Pancellular

βs

Hb = hemoglobin, MCV = mean cell volume, thal = thalassemia, N = normal, ↑ = increased, ↓ = decreased, HPFH = hereditary persistance of Hb F.
Table shows typical results—exceptions occur. Some rare genotypes (eg. SDPunjab, SO Arab, SC Harlem, S Lepore, SE) not included.
1. Hemoglobins reported in order of quantity (e.g. FSA = F>S>A).
2. Normal MCV: >70 at 6-12 months, >72 at 1-2 years.
3. Hb A2 results vary somewhat depending on laboratory methodology.
4. Hb SS with co-existent α-thalassemia may show ↓MCV and Hb A2 >3.6 percent; however, neonatal screening results from such infants usually show Hb Bart’s.
5. Quantity of Hb A2 can not be measured by hemoglobin electrophoresis or column chromatography in presence of Hb C.
6. Test not indicated.
7. Quantity of Hb A at birth sometimes insufficient for detection.
9