Cover
Preface to Second Edition
Preface to First Edition
List of Contributors
1 Hematological Assessment of a Patient with an Inherited Bleeding Disorder
1. 1.1 Introduction
2. 1.2 Normal Hemostasis
3. 1.3 Defects of Hemostasis
4. 1.4 Clinical Presentation of Bleeding
5. 1.5 Diagnosis
6. 1.6 Approach to a Female with a Bleeding History
7. 1.7 Summary
8. References
2 Bleeding Assessment Tools
1. 2.1 Introduction
2. 2.2 Evolution of Vicenza‐Based Bleeding Assessment Tools
3. 2.3 Women's Studies Using Vincenza‐Based Bleeding Tools
4. 2.4 Tools to Evaluate Menstrual Blood Loss
5. 2.5 Young Women's Hematology and Bleeding Assessment Tools
6. 2.6 Clinical Utility of Bleeding Assessment Tools
7. 2.7 Conclusion
8. References
3 Physiology of Menstruation
1. 3.1 Introduction
2. 3.2 Normal Menstruation
3. 3.3 Neuroendocrine Hormones
4. 3.4 Menarche
5. 3.5 Ovarian Follicle Development and Endocrine Function
6. 3.6 Endometrium
7. 3.7 Secretory Phase
8. 3.8 Menstruation
9. 3.9 Control of Bleeding
10. 3.10 Endometrial Repair
11. 3.11 Proliferative Phase
12. 3.12 Summary
13. References
4 Gynecology
1. 4.1 Introduction
2. 4.2 Heavy Menstrual Bleeding
3. 4.3 Management of Acute Episodes of Heavy Menstrual Bleeding
4. 4.4 Ovulation Bleeding
5. 4.5 Endometriosis
6. 4.6 Other Gynecological Conditions
7. 4.7 Conclusion
8. References
5 Carriers of Hemophilia A and Hemophilia B
1. 5.1 Inheritance
2. 5.2 Screening for the Genetic Status of Carriers of Hemophilia
3. 5.3 Confusion Between Genetic and Coagulation Testing
4. 5.4 When to Perform Genetic Testing
5. 5.5 What Reasons might Contribute to Delayed Genetic Diagnosis of Carriership?
6. 5.6 Bleeding Disorders in Carriers of Hemophilia
7. 5.7 Quality of Life of Carriers of Hemophilia
8. 5.8 Carriers of Hemophilia A and B and Pregnancy
9. 5.9 How to Improve Care for Carriers of Hemophilia
10. References
6 Von Willebrand Disease
1. 6.1 Introduction
2. 6.2 Structure and Function of Von Willebrand Factor
3. 6.3 Von Willebrand Factor Levels and Prevalence of Von Willebrand Disease
4. 6.4 VWF Levels, the Menstrual Cycle and Pregnancy
5. 6.5 Von Willebrand Disease Classification and Inheritance
6. 6.6 Clinical Presentation
7. 6.7 Menorrhagia and Postpartum Hemorrhage
8. 6.8 Diagnosis and Laboratory Testing
9. 6.9 Management of Von Willebrand Disease
10. 6.10 Management of Gynecological Bleeding
11. 6.11 Obstetric Management of Von Willebrand Disease
12. 6.12 Neonatal Management
13. 6.13 Cases
14. References
7 Factor XI Deficiency
1. 7.1 Factor XI Structure and Function in Coagulation
2. 7.2 Incidence and Inheritance of Factor XI Deficiency
3. 7.3 Bleeding Manifestations and Diagnosis of Factor XI Deficiency
4. 7.4 Factor XI Deficiency and Gynecological Issues
5. 7.5 Factor XI Deficiency and Pregnancy
6. 7.6 Neuroaxial Analgesia and Anesthesia
7. 7.7 Management of Postpartum Period
8. 7.8 Treatment Options
9. 7.9 Neonatal Bleeding
10. 7.10 Conclusions and Recommendations
11. References
8 Rare Bleeding Disorders
1. 8.1 Introduction
2. 8.2 Clinical Symptoms
3. 8.3 Gynecological and Obstetrical Manifestations in Women with Rare Bleeding Disorders
4. 8.4 Laboratory Diagnosis
5. 8.5 Differential Diagnosis in Women with Menorrhagia
6. 8.6 Treatment
7. 8.7 Conclusion
8. References
9 Inherited Platelet Defects
1. 9.1 Introduction
2. 9.2 Normal Platelet Function
3. 9.3 Presentation
4. 9.4 Investigation
5. 9.5 Syndromic and Non‐Syndromic Inherited Platelet Disorders with Recognized Causative Genes
6. 9.6 Prenatal Diagnosis
7. 9.7 Management
8. 9.8 Future Directions
9. 9.9 Case Histories
10. 9.10 Conclusion
11. References
10 Genetic and Laboratory Diagnosis
1. 10.1 Introduction
2. 10.2 Phenotypic Analysis of Hemophilia A
3. 10.3 Phenotypic Analysis of Hemophilia B
4. 10.4 Phenotypic Analysis of von Willebrand Disease
5. 10.5 Phenotypic Analysis of Inherited Bleeding Disorders
6. 10.6 Genetic Analysis of Hemophilia A
7. 10.7 Genetic Analysis of Hemophilia B
8. 10.8 Genetic Analysis of von Willebrand Disease
9. 10.9 Guidelines
10. 10.10 Summary
11. References
11 Antenatal Diagnosis
1. 11.1 Introduction
2. 11.2 Genetic Counseling
3. 11.3 Prenatal Diagnosis
4. 11.4 Prenatal Diagnosis of Hemophilia
5. 11.5 Prenatal Diagnosis of von Willebrand Disease
6. 11.6 Prenatal Diagnosis of Rare Bleeding Disorders
7. 11.7 Preimplantation Genetic Diagnosis
8. 11.8 Views about and Experiences of Prenatal Diagnosis of Women in Families Affected with Inherited Bleeding Disorders
9. 11.9 Termination of Pregnancy
10. References
12 Analgesia and Anesthesia for Pregnant Women with Inherited Bleeding Disorders
1. 12.1 Introduction
2. 12.2 Non‐Pharmacological Methods
3. 12.3 Pharmacological Methods
4. 12.4 Conclusion
5. References
13 The Newborn
1. 13.1 Introduction
2. 13.2 Developmental Hemostasis
3. 13.3 Laboratory Hemostatic Evaluation of the Neonate
4. 13.4 When to Suspect a Congenital Bleeding Disorder in a Newborn
5. 13.5 Congenital Bleeding Disorders and Their Presentation in Newborns
6. 13.6 Management of Bleeding in Neonates with Congenital Bleeding Disorders
7. 13.7 Conclusion
8. References
14 Women with Inherited Bleeding Disorders in Different Cultural Settings
1. 14.1 Introduction
2. 14.2 Pakistan
3. 14.3 Malaysia
4. 14.4 Lebanon
5. 14.5 Discussion
6. References
Index
End User License Agreement

List of Tables

Chapter 01
1. Table 1.1 Bleeding history and salient features indicating non‐trivial bleed.
2. Table 1.2 Laboratory assessment of hematological and coagulation system.
Chapter 02
1. Table 2.1 Comparison of the different scoring systems for the Vicenza‐based bleeding assessment tools.
Chapter 04
1. Table 4.1 Prevalence of heavy menstrual bleeding in women with IBD [14].
Chapter 06
1. Table 6.1 Laboratory findings, response to desmopressin, and inheritance patterns associated with different types of von Willebrand disease
2. Table 6.2 Case 1 test results.
3. Table 6.3 Case 2 test results.
Chapter 08
1. Table 8.1 Prevalence of menorrhagia and postpartum hemorrhage in women with RBDs.
2. Table 8.2 Recommended schedules for on‐demand treatment and long‐term prophylaxis in patients with RBDs.
3. Table 8.3 Classification as proposed by the European Network of Rare Bleeding Disorders (EN‐RBD) and trough levels (Peyvandi et al. [15]).
Chapter 09
1. Table 9.1 Inherited platelet disorders, causative genes, and associated features.
Chapter 10
1. Table 10.1 Numbers of hemophilia A and B carriers in 2016–2017.
2. Table 10.2 Females on the UKHCDO von Willebrand disease database.
3. Table 10.3 Variant types in in hemophilia A, B, and VWD.
Chapter 12
1. Table 12.1 Conditions for the use of regional block in women with inherited bleeding disorders during labor and delivery.
2. Table 12.2 Suggested hemostatic levels and therapeutic options for invasive procedures during pregnancy and management of delivery [29].
Chapter 13
1. Table 13.1 Genetics of rare coagulation factor deficiencies, listed in descending order of prevalence.
2. Table 13.2 Replacement products available for treatment of bleeds in coagulation disorders.

List of Illustrations

Chapter 01
1. Figure 1.1 Overview of hemostasis and key components. A vascular injury exposes collagen that allows platelets to adhere via VWF to the subendothelium. Activation of platelets occurs and platelets aggregate together via VWF and fibrinogen. Primary hemostasis results in the formation of the initial platelet plug. Tissue factor activates the coagulation pathway in parallel with platelet activation; both pathways enhance each other. Fibrinolysis prevents excessive thrombus formation, through the generation of plasmin followed by the digestion of fibrin.
2. Figure 1.2 Pathways of coagulation: the intrinsic (in vitro) pathway as measured by the activated partial thromboplastin time (APTT) and the extrinsic (in vivo) pathway as measured by the prothrombin time (PT). Both intrinsic and extrinsic pathways share a common final pathway.
3. Figure 1.3 Cell‐based model of hemostasis. The cell‐based model comprises three overlapping stages: (a) initiation, (b) amplification, and (c) propagation. (a) Initiation phase: this occurs on the TF‐expressing cell and is initiated when injury exposes the TF‐bearing cell to the flowing blood. A small amount of FIXa, Xa, and thrombin is formed. (b) Amplification phase: the small amount of thrombin generated from the initiation phase activates platelets, releases VWF, and leads to generation of activated forms of FV, FVIII, and FXI. (c) Propagation phase: activated coagulation factors from the previous phases aggregate on the platelet surface. FVIII complexes with FIX to form the tenase complex, resulting in FXa generation on the platelet surface. The prothrombinase complex forms and results in large amounts of thrombin generation. This thrombin burst leads to fibrin formation and also activates FXIII and TAFI. FXIIIa cross‐links fibrin strands to form a stable fibrin network, and TAFI protects the clot from plasmin‐mediated fibrinolysis.
Chapter 02
1. Figure 2.1 The evolution of the different Vicenza‐based bleeding scores from the original Vicenza bleeding score on the left and the subsequent versions. For each bleeding score, the year of publication of the original paper, scoring system used and the approximate administration time are shown [5–8, 11–13].
2. Figure 2.2 Pictorial blood assessment chart. (a) Menstrual pictorial chart. (b) An example of a completed chart. (c) Scoring system. The Pictorial Blood Assessment Chart (PBAC) (Figure 2.2a) consists of a series of diagrams representing lightly, moderately, and heavily soiled towels and tampons. The numbers at the top of the chart represent the day of menstruation. The women are instructed to insert a mark in the appropriate box at the time each towel and/or tampon is discarded and if sufficient, they are counted in groups of five. Passage of clots (size equated with the size of different coins) and episodes of flooding are also recorded. The woman is given the chart to complete with her next menstrual period, with clear instructions and explanation of how it should be used. An example of a completed chart is also provided (Figure 2.2b). The chart is scored using the scoring system devised by Higham et al. 1990 (Figure 2.2c). A baseline score is established, subsequent treatment cycles are then assessed, and success can be indicated by a decreasing score.
Chapter 03
1. Figure 3.1 Schematic diagram showing the hypothalamic‐pituitary‐ovarian axis. Kisspeptin signals directly to the GnRH neurons by acting on the kisspeptin receptor. This results in the pulsatile release of GnRH into the portal circulation. GnRH then stimulates the anterior pituitary to secrete FSH and LH. These gonadotrophins stimulate ovarian folliculogenesis and steroid hormone secretion. Activity of both the hypothalamus and pituitary is controlled by ovarian hormone (estradiol and progesterone) feedback loops.
2. Figure 3.2 The effect of vessel radius on blood flow. PGF_2α and endothelin‐1 (ET‐1) cause vasoconstriction of spiral arterioles at menstruation, resulting in reduced blood flow in women with normal menstrual bleeding (NMB). Studies have shown that women with heavy menstrual bleeding (HMB) have reduced FP receptors (the receptor for PGF_2α) [12], decreased endothelin‐1 [13], altered spiral arteriole maturation [14] and increased PGE₂ [15]. This results in less vasoconstriction and therefore increased blood loss (as per Poiseuille's equation).
Chapter 04
1. Figure 4.1 Screening for an underlying disorder of hemostasis in patients with heavy menstrual bleeding.
2. Figure 4.2 Algorithm of management of heavy menstrual bleeding.
3. Figure 4.3 Levonorgestrel‐IUS and PBAC scores: long‐term follow‐up ≱24 months after insertion.
Chapter 05
1. Figure 5.1 The inheritance of hemophilia.
Chapter 07
1. Figure 7.1 The structure of factor XI – a homodimer.
2. Figure 7.2 Coagulation cascade – extrinsic and intrinsic pathways.
3. Figure 7.3 Changes in factor XI level during pregnancy.
Chapter 08
1. Figure 8.1 Worldwide distribution of rare bleeding disorders derived from the WFH (www.wfh.org) and EN‐RBD (www.rbdd.org/en).
Chapter 09
1. Figure 9.1 (a) Process of platelet production from megakaryocytes in the bone marrow and key genes required by the steps involved in this process. (b) An individual platelet with many of the key components necessary for normal platelet function, and key genes required for each of these components to be present and to function correctly [3, 16, 35, 61].
2. Figure 9.2 Relationship between inherited thrombocytopenias, inherited platelet function defects, and disorders which encompass both such defects.
Chapter 11
1. Figure 11.1 Inheritance of hemophilia.
2. Figure 11.2 Chorionic villus sampling (transabdominal).
3. Figure 11.3 Amniocentesis.
4. Figure 11.4 Cordocentesis.
5. Figure 11.5 Algorithm for PND of hemophilia. CVS, chorionic villus sampling; TOP, termination of pregnancy; USS, ultrasound scan.
Chapter 13
1. Figure 13.1 (a) Diagnostic algorithm for use in neonates with suspected congenital bleeding disorders. (b) Platelet disorders characterized by platelet size. *FXII deficiency does not result in a bleeding disorder. aPTT, activated partial thromboplastin time; CBC, complete blood count; INR, international normalized ratio; ITP, immune thrombocytopenic purpura; PFA, platelet function analyzer; PT, prothrombin time.
2. Figure 13.2 Left‐sided ICH (arrows) causing occlusion of left ventricle and midline shift to the right in a male with severe hemophilia A.
3. Figure 13.3 Bleeding in the antecubital space of both arms after venepuncture in a male with severe hemophilia A.
4. Figure 13.4 Newborn with GT after venepuncture and holding of the child's left arm.

Copyright

This edition first published 2019

Edition History

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Library of Congress Cataloging‐in‐Publication Data

Names: Kadir, Rezan A., editor. | James, Paula D., editor. | Lee, Christine A., editor. | Preceded by (work): Lee, Christine A. Inherited bleeding disorders in women.

Title: Inherited bleeding disorders in women / edited by Rezan A. Kadir, Paula D. James, Professor Christine A. Lee.

Description: Second edition. | Hoboken, NJ : Wiley‐Blackwell, 2019. | Preceded by Inherited bleeding disorders in women / Christine A. Lee, Rezan A. Kadir, Peter A. Kouides. 2009. | Includes bibliographical references and index. |

Identifiers: LCCN 2018032345 (print) | LCCN 2018033046 (ebook) | ISBN 9781119426127 (Adobe PDF) | ISBN 9781119426066 (ePub) | ISBN 9781119426028 (hardback)

Subjects: | MESH: Blood Coagulation Disorders, Inherited | Women’s Health

Classification: LCC RC647.C55 (ebook) | LCC RC647.C55 (print) | NLM WH 322 | DDC 616.1/570082–dc23

LC record available at https://lccn.loc.gov/2018032345

Cover Design: Wiley

List of Contributors

Vanessa Bouskill, MN RN(EC)
- Department of Nursing
- Hospital for Sick Children
- Toronto
- Canada
Anne‐Sophie Bouthors, MD
- Department of Anesthesia and Intensive Care
- Maternité Jeanne de Flandre
- Academic Hospital
- Lille
- France
Manuel Carcao, MD FRCP(C) MSc
- Division of Haematology/Oncology
- Department of Paediatrics and Child Health Evaluative Sciences
- Research Institute
- Hospital for Sick Children
- Toronto
- Canada
Claudia Chi, MBBS MRCOG MD FAMS
- Department of Obstetrics and Gynaecology
- National University Hospital
- Singapore
Hilary O.D. Critchley, MD FRCOG FMedSci FRSE
- MRC Centre for Reproductive Health
- University of Edinburgh
- Edinburgh
- UK
Joanna S. Davies, MB ChB MD
- Department of Obstetrics and Gynaecology and Katharine Dormandy Haemophilia and Thrombosis Centre
- Royal Free Foundation Hospital
- London
- UK
Roseline d'Oiron, MD
- Reference Centre for Hemophilia and Rare Congenital Bleeding Disorders
- University Hospitals Paris Sud – Bicêtre Hospital – APHP
- Le Kremlin‐Bicêtre
- France
Adrian England, MBBS FRCA MD
- Department of Anaesthesia
- Royal Free Hospital
- London
- UK
Anne C. Goodeve, BSc PhD
- Department of Infection
- Immunity and Cardiovascular Disease
- University of Sheffield Medical School
- Sheffield
- UK
Irena Hudecova, PhD
- Cancer Research UK
- Cambridge Institute
- University of Cambridge
- Li Ka Shing Centre
- Cambridge
- UK
Paula D. James, MD FRCPC
- Department of Medicine
- Queen's University
- Kingston
- Canada
Rezan A. Kadir, MB ChB MRCOG FRCS(Ed) MD
- Department of Obstetrics and Gynaecology and Katharine Dormandy Haemophilia and Thrombosis Centre
- Royal Free Foundation Hospital
- London
- UK
and
Institute for Women's Health
University College London
London
UK
Christine A. Lee, MA MD DSc FRCP FRCPath FRCOG
- University College London
- London
- UK
Mike Makris, MA MBBS MD FRCP FRCPath
- Sheffield Haemophilia and Thrombosis Centre
- Royal Hallamshire Hospital
- Sheffield
- UK
Jackie A. Maybin, MB ChB MRCOG PhD
- MRC Centre for Reproductive Health
- University of Edinburgh
- Edinburgh
- UK
Marzia Menegatti, BSc PhD
- Luigi Villa Foundation and Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
- Milan
- Italy
Danijela Mikovic, MD PhD
- Haemostasis Department with Registry of Inherited Bleeding Disorders
- Blood Transfusion Institute of Serbia
- Belgrade
- Serbia
Carolyn M. Millar, MD FRCP FRCPath
- Centre for Haematology and Department of Experimental Medicine
- Imperial College Healthcare NHS Trust
- Imperial College London
- UK
Fadi G. Mirza, MD FACOG
- Faculty of Medicine and Medical Center
- American University of Beirut
- Beirut
- Lebanon
- and
- Columbia University
- New York
- USA
Bethan Myers, MA FRCP FRCPath
- Department of Haematology
- University Hospitals of Leicester NHS Trust and Lincoln County Hospital
- Lincoln
- UK
Sarah H. O'Brien, MD
- Division of Pediatric Hematology/Oncology
- Nationwide Children's Hospital/The Ohio State University College of Medicine
- Columbus
- USA
Sue Pavord, MB ChB FRCP FRCPath
- Department of Haematology
- Oxford University Hospitals NHS Foundation Trust
- Oxford
- UK
Flora Peyvandi, MD PhD
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation
- University of Milan
- Milan
- Italy
Jane Reavey, MA BMBCh MRCOG
- MRC Centre for Reproductive Health
- University of Edinburgh
- Edinburgh
- UK
Clare Samuelson, MB ChB MA
- Sheffield Haemophilia and Thrombosis Centre
- Royal Hallamshire Hospital
- Sheffield
- UK
Jameela Sathar, MD MRCP FRCPath
- Department of Haematology
- Ampang Hospital
- Malaysia
Ali T. Taher, MD PhD FRCP
- American University of Beirut Medical Center
- Beirut
- Lebanon
- and
- Emory School of Medicine
- Atlanta
- USA
Henna Wong, MBBS MRCP FRCPath
- Department of Haematology
- Oxford University Hospitals NHS Foundation Trust
- Oxford
- UK
Tahira Zafar, MB DCP FRCPath
- Haemophilia Treatment Centre
- Rawalpindi Islamabad
- Pakistan
- and
- Pakistan Haemophilia Patients Welfare Society
- Rawalpindi Islamabad
- Pakistan