Inherited Bleeding Disorders in Women

198 Pages·2009·3.03 MB·English

by  Christine A. Lee

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Inherited Bleeding Disorders in Women
Inherited Bleeding Disorders in Women. Edited by Christine A Lee,
Rezan A Kadir and Peter A Kouides © 2009 Blackwell Publishing Ltd.
ISBN: 978-1-405-16915-8
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Inherited Bleeding
Disorders in Women
Christine A Lee
Oxford Haemophilia and Thrombosis Centre
Churchill Hospital
Old Road
Headington
Oxford
UK
Rezan A Kadir
Royal Free Hospital
Pond Street
London
UK
Peter A Kouides
Mary M Gooley Hemophilia Centre
Rochester General Hospital
Rochester
New York
USA
A John Wiley & Sons, Ltd., Publication
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This edition first published 2009, © 2009 by Blackwell Publishing Ltd
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Library of Congress Cataloging-in-Publication Data
Lee, Christine A.
Inherited bleeding disorders in women / Christine A. Lee, Rezan A. Kadir, Peter A. Kouides.
p. ; cm.
Includes bibliographical references.
ISBN 978-1-4051-6915-8
1. Blood coagulation disorders. 2. Women–Diseases. 3. Blood coagulation disorders in pregnancy.
I. Kadir, Rezan A. II. Kouides, Peter A. III. Title.
[DNLM: 1. Blood Coagulation Disorders, Inherited. 2. Women’s Health. WH 322 L477i 2009]
RC647.C55L44 2009
616.1′57–dc22
2008035471
A catalogue record for this book is available from the British Library.
Set in 9/11.5 Sabon by Graphicraft Limited, Hong Kong
Printed in Singapore by Fabulous Printers Pte Ltd
1 2009
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Contents
Contributors, vii
Preface, ix
1 Approach to the patient with an inherited bleeding disorder, 1
Peter A Kouides and Clare Philipp
2 Physiology of menstruation and menorrhagia, 12
Måns Edlund
3 Hemophilia A and hemophilia B, 34
Christine A Lee
4 von Willebrand disease, 42
Peter A Kouides
5 Rare bleeding disorders, 54
Flora Peyvandi
6 Platelet disorders, 65
Claire Philipp
7 Gynecology, 70
Rezan A Kadir
8 Genetic and laboratory diagnosis, 90
Edward Tuddenham
9 Antenatal diagnosis, 99
Claudia Chi and Rezan A Kadir
10 Obstetric management, 124
Claudia Chi and Rezan A Kadir
11 Analgesia and anesthesia for pregnant women with inherited bleeding disorders, 151
Claudia Chi, Adrian England, and Rezan A Kadir
12 The newborn, 163
H Marijke van den Berg and Rochelle Winikoff
13 Advocacy for women with bleeding disorders, 176
Rezan A Kadir, Ann-Marie Nazzaro, Rochelle Winikoff, Jane Mathesan,
and Peter A Kouides
Appendix i: Bleeding questionnaire, 184
Appendix ii: Pictorial blood assessment chart, 186
Index, 189
v
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Contributors
Claudia Chi
Department of Obstetrics and Gynaecology Jane Matheson
Royal Free Hospital Haemophilia Society
Pond Street Hatton Gardens
London, UK London, UK
H Marijke van den Berg Ann-Marie Nazzaro
Meander Medisch Centrum National Hemophilia Foundation US
Amersfoort, The Netherlands West 32nd Street
New York, New York, USA
Måns Edlund
Department of Obstetrics and Gynaecology Flora Peyvandi
Karolinska University Hospital Solna Fondazione Luigi Villa
Stockholm, Sweden Via Pace
Milan, Italy
Adrian England
Department of Anaesthetics Claire Philipp
Royal Free Hospital Division of Hematology
Pond Street University of Medicine and Dentistry of New Jersey
London, UK Robert Wood Johnson Medical School
New Brunswick, New Jersey, USA
Rezan A Kadir
Department of Obstetrics and Gynaecology Edward Tuddenham
Royal Free Hospital Haemophilia Centre and Thrombosis Unit
Pond Street Royal Free Hospital
London, UK Pond Street
London, UK
Peter Kouides
Mary M Gooley Hemophilia Center Rochelle Winikoff
Rochester General Hospital Division of Hematology
Portland Avenue CHU Sainte-Justine
Rochester, New York, USA Côte Ste-Catherine Road
Montreal, Quebec, Canada
Christine Lee
Oxford Haemophilia and Thrombosis Centre
Churchill Hospital
Old Road
Headington
Oxford, UK
vii
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Preface
In 1926 Erik von Willebrand described a large kindred tions are crucial to this endeavour. There also remains
from the Aland Islands, an archipelago in the Baltic the challenge of developing more effective, tolerable
sea, many of whom had a bleeding disorder. The index and widely available therapies in controlling menor-
case was a little girl called Hjordis, who presented with rhagia and post-partum haemorrhage.
severe epistaxis and died at the onset of her fourth This book is written by haematologists, obstetrician–
menstrual period. Her maternal grandmother died from gynaecologists, an anaesthetist and those involved in
haemorrhage after childbirth in her only pregnancy. patient advocacy. It covers the gynaecological and
von Willebrand wrote that the condition was parti- obstetric issues for carriers of haemophilia, women
cularly prevalent in women. This first description of with von Willebrand’s disease, rare bleeding disorders
von Willebrand disease underlined the haemostatic and inherited platelet disorders. We hope that this
challenges of menstruation and childbirth for those book is a modest step towards safe motherhood and
women with an inherited bleeding disorder. provision of quality of care for women with bleeding
Until recently, the predominant issue for men with disorders world-wide and that all those providing care
haemophilia has been safe and effective treatment, for these women, as well as the women themselves,
and most effort has been directed to the resolution of will find it useful.
transfusion-transmitted disease. Furthermore, since
haemophilia is a sex-linked disorder there has been a
failure to recognise that women have inherited bleed-
Acknowledgement
ing disorders. Thus, the substantial morbidity caused
in women with inherited bleeding disorders has only
recently been addressed in a comprehensive way. It is Cover image ‘Menorrhagia Healing’ © Barbara Bruch
important that collaboration in the care and research 1991
of bleeding disorders in women continue as many Christine A Lee
challenges remain. The main task now is to identify Rezan A Kadir
those women who do not realise they may have a Peter A Kouides
treatable condition. The patient advocacy organisa- December 2008
ix
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1
Approach to the patient with an
inherited bleeding disorder
Peter A Kouides and Claire Philipp
Introduction
Formation of the platelet “plug”
At the time of injury to the endothelium, the integrity The flowing blood is subjected to a high shear stress
of the high-pressure circulatory system is maintained rate upon exposure of subendothelial collagen follow-
through the hemostatic mechanism. In general terms, ing injury to the endothelium. The high shear stress
a “plug” of platelets is covered over by a “net” of fibrin, leads to “unfolding” of VWF with subsequent expo-
resulting in the formation of a clot (Fig. 1.1). The sure of the A1 and A3 domains [3]. The A1 domain
resultant clot normally leads to cessation of bleeding. primarily recognizes and binds to the glycoprotein
Bleeding occurs when there is a precipitant such as Ib /IX receptor on the platelet surface whereas the
α
direct traumatic injury to the endothelium or in the A3 domain primarily recognizes and binds to sub-
case of menstruation hormonal-induced shedding of endothelial type I and type III collagen [3]. In essence,
the endothelium, so “injuring” the endothelium. VWF localizes the platelets to the site of bleeding
The understanding of hemostasis can be simplified by binding to collagen and also to platelets that are
into two steps: first (step 1) the formation of the platelet traveling though the injured opening of the endothe-
“plug” at the initial site of injury and second (step 2) lium. The VWF protein is capable of binding to both
the formation of a “net” of fibrin covering the platelet platelets and collagen because it is a large, multimeric
plug. An evolving cell-based model of hemostasis aug- molecule. The binding of platelets to collagen by VWF
ments the historical description of coagulation focused leads to the subsequent aggregation and formation of
on enzymatic activation of a sequence of coagulant a platelet plug.
proteins as a “cascade.” The cell-based model includes
the crucial role of tissue factor (TF)-bearing cells at the
Formation of fibrin
site of bleeding [1, 2]. The two main components
within the blood exposed to the injured endothelium Adequate clot formation is necessary to fully stop
in step 1 are von Willebrand factor (VWF) and bleeding; thus, a patient with a clotting factor defici-
platelets. At the time of vessel injury, there is exposure ency, such as hemophilia, bleeds even though the
of free-flowing blood through the injured endothelium platelet count and function and VWF are normal. At
to two subendothelial constituents, collagen and TF, the time of injury factor VIIa (FVIIa) within the flow-
involved respectively in platelet plug formation and ing blood at the injured site is exposed to subendothelial
fibrin generation. TF. This imitates thrombin generation resulting in
fibrin formation. This leads to the formation of the
VIIa–TF complex on the surface of platelets which
Inherited Bleeding Disorders in Women. Edited by Christine A Lee, are acting as a “scaffold,” and then converts FX to
Rezan A Kadir and Peter A Kouides © 2009 Blackwell Publishing Ltd. activated FXa (termed the “extrinsic pathway” as
ISBN: 978-1-405-16915-8 depicted in Fig. 1.2). In turn, FXa is localized to the
1
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CHAPTER 1
Subendothelial
Injury to the vessel wall constituents
Blood vessel
The subendothelium C TF C TF C
Collagen
Tissue factor Platelets
Blood
The main constituents
von Willebrand factor VWF
Platelets
Clotting factors C C
“Step” 1
Formation of C platelet plug TF
via collagen + Platelets + VWF

“Step” 2 TF
Formation of fibrin clot on
“top” of the platelet plug Fig. 1.1 Steps in hemostasis. C,
via TF + factor X/V, collagen; TF, tissue factor; VWF, von
factor II then fibrinogen Willebrand factor.
XII →→ XIIa ProthroPmTbin time ToTfhh teish F eisI X cbo/eFacVgauuIIlsaIe tc isooumnc hpc lapesaxct aaiedcnteit vsba dyt eoFs n IXXo t t woh aiXtvhae , c aaomnfdapc iltsifio tcre arVmtiIoeIInd.
XI →→ XIa the propagation phase of coagulation.
VIIa + Tissue factor
”
A P T T “I IX →→ IXa way
ntrinsic c path Bvolene dWinilgle:b inrahnedri tdeidse paslaetelet disorders and
pathway” cofactor VXII I→a⊕→ Xa “Extrinsi Aas qinu atnhtei tcaatisvee odfe ifmecmt oufn ep ltahtreolemtsb (otchyrtoompbenoiccy tpouprepnuiraa)
⊕cofactor Va (ITP) or acute leukemia, or a qualitative defect (i.e.,
II →→→ →IIa dysfunction) of platelets (“thrombocytopathy”) as
(Prothrombin) (Thrombin) in the case of uremia or aspirin use can lead to bleed-
Fibrinogen→→→Fibrin ing. Another cause of bleeding related to step 1 of
hemostasis would be a quantitative or qualitative
deficiency of VWF termed von Willebrand disease
Fig. 1.2 The pathways of coagulation: the intrinsic (in vitro)
pathway as measured by the activated partial (VWD). von Willebrand disease is an inherited bleed-
thromboplastin time (APTT) and the extrinsic (in vivo) ing disorder. A mild to moderate (~15–50% VWF
pathway as measured by the prothrombin time. level) deficiency with normal multimer structure of
VWF is termed type 1; a qualitative deficiency with
dysfunctional VWF is type 2 [4]. In type 2, the qualit-
platelet surface by the cofactor, factor V (FV). This ative defect can be classified further as a loss of high
enzyme complex of FX+FV can then convert cir- and intermediate weight multimers (type 2A); a loss of
culating coagulation factor II (prothrombin) to IIa high molecular weight multimers (type 2B) usually
(thrombin). Thrombin is the main enzyme of the co- with associated thrombocytopenia; or normal VWF
agulation cascade, and cleaves circulating fibrinogen multimers (type 2M). Type 2N VWD involves a
to fibrin, which polymerizes to form a “net” of fibrin mutation leading to decreased binding of FVIII with
around the platelet plug. Patients with a deficiency resultant FVIII deficiency and this is often mis-
of FVIII (hemophilia A) or FIX (hemophilia B) bleed diagnosed as hemophilia A. Finally, a severe quantitat-
even though these patients should have an adequate ive deficiency of VWF with undetectable VWF protein
amount of FVII as well as FII, FV, FX, and fibrinogen. is termed type 3.
2
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APPROACH TO THE PATIENT WITH AN INHERITED BLEEDING DISORDER
The severe forms of VWD usually have a detect- Table 1.1 The prevalence of various bleeding symptoms
able genetic mutation whereas a third to a half of cases in the general population, adapted from Sadler [9] with
of type 1 VWD have a normal genotype implying permission
extragenetic factors in the pathogenesis of VWD in
Symptom Healthy controls (%)
these cases [5, 6]. Many of these cases (usually with
VWF levels ~30–50%) with a normal genotype are
Epistaxis 5–39
related to ABO blood group O [7]. In turn, 15%
Gum bleeding 7–51
of ABO blood group O patients have VWF levels
Bruising 12–24
<50% [8]. Consequently, given the ~40% prevalence
Bleeding from trivial wounds 0.2–2
of blood group O in the general population, ~5% of
Dental extraction related bleeding 1–13
the general population will have “subnormal” VWF
Post-tonsillectomy bleeding 2–11
levels.
Post-partum bleeding 6–23
Menorrhagia 23–44
Bleeding: inherited coagulation factor deficiencies
Bleeding may result from a deficiency of any of the The challenge for the clinician when encountering
clotting factors of the coagulation cascade from factor the bleeding patient is to determine whether the bleed-
I (fibrinogen) to factor XI. Inherited clotting factor ing symptom is due to an underlying disorder of
deficiencies are due to a mutation in the gene coding hemostasis. Many bleeding symptoms may be quite
for the respective coagulation protein resulting in a prevalent in the general “healthy” population with a
lower than normal level adequate for hemostasis. prevalence of bleeding symptoms reported ranging
from 0.2% (bleeding from trivial wounds) to 51%
(gingival bleeding) [9] as summarized in Table 1.1.
Clinical presentation of the However, only a relatively small proportion of these
bleeding patient patients will have a true underlying disorder of
hemostasis. Consequently, the discriminatory power
Inherited platelet disorders and VWD are associated of the various bleeding symptoms in predicting an
with “mucocutaneous” bleeding. Typical bleeding underlying disorder of hemostasis varies from poor
frequently involves nosebleeds (epistaxis), bleeding to excellent as depicted in Table 1.2, based on the
related to surgical invasive procedures including authors collective clinical experience and published
dental work, easy bruising and menorrhagia. In con- studies of bleeding risk [9–12].
trast, patients with an inherited coagulation factor These symptoms have been refined and incorpor-
deficiency such as hemophilia will have primarily ated into a scoring system (termed the bleeding score
deep tissue (ecchymoses) and muscle/joint bleeding. A assessment) by the International Society of Hemostasis
previously undiagnosed mild disorder such as mild and Thrombosis network [13] and then modified by the
hemophilia A with a low factor VIII level can be European Union VWD project [14] (Appendix i). The
“unmasked” in the setting of surgery. main principles underlying this bleeding assessment
Table 1.2 The relative discriminatory value of bleeding symptoms
Good Fair Poor
Family members with established bleeding disorder Bruising Family members with bleeding
symptoms
Profuse bleeding of small wounds Epistaxis Gum bleeds
Profuse surgical-related bleeding esp. T&A, dental Menorrhagia Hematuria
Muscle/joint-related bleeding Post-partum hemorrhage Bright blood per rectum
T&A, tonsillectomy and adenoidectomy.
3