Textbook of Hemophilia

Christine A. Lee, Erik E. Berntorp, W. Keith Hoots, Christine A. Lee, Erik E. Berntorp, W. Keith Hoots

• Publisher: Wiley-Blackwell
• Year: 2014
• Print ISBN: 9781118398241
• eBook ISBN: 9781118398289
• Edition: 3
• Topic: Medicine
• Subtopic: Hematology

Textbook of Hemophilia, 3rd edition

Edited by
Christine A. Lee, MA, MD, DSc, FRCP, FRCPath, FRCOG
Emeritus Professor of Haemophilia, University of London, London, UK

Erik E. Berntorp, MD, PhD
Professor of Coagulation Medicine, Lund University
Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Malmö, Sweden

W. Keith Hoots, MD
Director, Division of Blood Diseases and Resources, National Heart, Lung and Blood Institute
National Institutes of Health, Bethesda, MD;
Professor of Pediatrics and Internal Medicine, University of Texas Medical School at Houston, Houston, TX, USA

Without doubt, Textbook of Hemophilia, 3rd edition is the definitive reference source on all aspects of haemophilia including diagnosis, management and treatment. Edited by three, world-renowned experts on haemophilia, this completely revised resource features chapters written by over 60 international contributors with international expertise in caring for haemophilia patients.

Textbook of Hemophilia, 3rd edition

• Features eight new chapters, covering individualised dosing, vCJD and haemophilia, new drugs in the pipeline, and surgery in inhibitor patients
• Presents new developments, such as gene therapy
• Highlights controversial issues and provides advice for everyday clinical questions
• Represents essential reading for all healthcare professionals involved in the care of those with haemophilia

Titles of related interest

Hemophilia and Hemostasis: A Case-Based Approach to Management, 2nd Edition

http://eu.wiley.com/WileyCDA/Section/id-302479.html, ISBN: 9780470659762

Current and Future Issues in Hemophilia Care

http://eu.wiley.com/WileyCDA/Section/id-302479.html?query=E.+Carlos+Rodriguez-Merchan, ISBN: 9780470670576

http://www.wiley.com/go/hematology

PART I
Introduction

CHAPTER 1
Overview of Hemostasis

Kathleen Brummel Ziedins and Kenneth G. Mann

University of Vermont, College of Medicine, VT, USA

Introduction

The maintenance of blood fluidity and protection from blood leakage provide major biophysical challenges for the organism. Nature has evolved a highly complex, integrated, and dynamic system which balances the presentations of procoagulant, anticoagulant, and fibrinolytic systems. These systems function collectively to maintain blood within the vasculature in a fluid state while at the same time providing potent leak attenuating activity which can be elicited upon vascular perforation to provide the rapid assembly of a thrombus principally composed of platelets and fibrin to attenuate extravascular blood loss. The dynamic control of this system is such that the coagulation response is under the synergistic control of a variety of blood and vascular inhibitors, resulting in a process that is regionally restricted to the site of vascular damage and does not propagate throughout the vascular system. The rapid coagulation response is also tightly linked to the vascular repair process during which the thrombus is removed by the fibrinolytic system which is also activated regionally to provide clot removal coincident with vascular repair.

A list of important procoagulant, anticoagulant, and fibrinolytic proteins, inhibitors, and receptors can be seen in Table 1.1.

Table 1.1 Procoagulant, anticoagulant, and fibrinolytic proteins, inhibitors, and receptors.

Importance of Complex Assembly to Coagulation

Laboratory data combined with clinical pathology lead to the conclusion that the physiologically relevant hemostatic mechanism is primarily composed of three procoagulant vitamin K-dependent enzyme complexes (which utilize the proteases factor VIIa, factor IXa, and factor Xa) and one anticoagulant vitamin K-dependent complex (which utilizes the proteases thrombin, meizo, and α-thrombin) [1,2] (Figure 1.1). These complexes—extrinsic factor Xase (tissue factor–factor VIIa complex), intrinsic factor Xase (factor VIIIa–factor IXa complex) [3], and the protein Case complex (thrombin–thrombomodulin) [4]—are each composed of a vitamin K-dependent serine protease, a cofactor protein and a phospholipid membrane; the latter provided by an activated or damaged cell. The membrane-binding properties of the vitamin K-dependent proteins are a consequence of the post-translational γ-carboxylation of these macromolecules [5]. The cofactor proteins are either membrane binding (factor Va, factor VIIIa), recruited from plasma, or intrinsic membrane proteins (tissue factor, thrombomodulin). Cofactor–protease assembly on membrane surfaces yields enhancements in the rates of substrate processing ranging from 10⁵ to 10⁹-fold relative to rates observed when the same reactions are limited to solution-phase biomolecular interactions between the individual proteases (factor VIIa, factor IXa, and factor Xa) and their corresponding substrates [6–8] (Figure 1.2a). Membrane binding, intrinsic to complex assembly, also localizes catalysis to the region of vascular damage. Thus, a system selective for regulated, efficient activity presentation provides for a regionally limited, vigorous arrest of hemorrhage.

Figure 1.1 Overview of hemostasis. Coagulation is initiated through two pathways: the primary extrinsic pathway (shown on the right) and the intrinsic pathway (historically called the contact or accessory pathway, shown on the left). The components of these multistep processes are illustrated as follows: enzymes (circles), inhibitors (hatched circles), zymogens (boxes), or complexes (ovals). Fibrin formation is also shown as an oval. The intrinsic pathway has no known bleeding etiology associated with it, thus this path is considered accessory to hemostasis. Upon injury to the vessel wall, tissue factor, the cofactor for the extrinsic factor Xase complex, is exposed to circulating factor VIIa and forms the vitamin K-dependent complex, the extrinsic factor Xase. Factor IX and factor X are converted to their serine proteases factor IXa (FIXa) and factor Xa (FXa), which then form the intrinsic factor Xase and the prothrombinase complexes, respectively. The combined actions of the intrinsic and extrinsic factor Xase and the prothrombinase complexes lead to an explosive burst of the enzyme thrombin (IIa). In addition to its multiple procoagulant roles, thrombin also acts in an anticoagulant capacity when combined with the cofactor thrombomodulin in the protein Case complex. The product of the protein Case reaction, activated protein C (APC), inactivates the cofactors Va and VIIIa. The cleaved species, factors Va_i and VIIIa_i, no longer support the respective procoagulant activities of the prothrombinase and intrinsic Xase complexes. Once thrombin is generated through procoagulant mechanisms, thrombin cleaves fibrinogen, releasing fibrinopeptide A and B (FPA and FPB) and activate factor XIII to form a cross-linked fibrin clot. Thrombin–thrombomodulin also activates thrombin activatable fibrinolysis inhibitor (TAFIa) that slows down fibrin degradation by plasmin. The procoagulant response is downregulated by the stoichiometric inhibitors tissue factor pathway inhibitor (TFPI) and antithrombin (AT). TFPI serves to attenuate the activity of the extrinsic factor Xase trigger of coagulation. Antithrombin directly inhibits thrombin, factor IXa, and factor Xa. The intrinsic pathway provides an alternative route for the generation of factor IXa. Thrombin has also been shown to activate factor XI. The fibrin clot is eventually degraded by plasmin-yielding soluble fibrin peptides. α-AP, α-antiplasmin; HMW, high molecular weight; PAI-1, plasminogen activator inhibitor-1. Modified from [32].

Figure 1.2 Vitamin K-dependent complex assembly. (a) The factor Xa generated by the tissue factor–factor VIIa complex activates a small amount of thrombin which activates factor V and factor VIII leading to the presentation of the intrinsic factor Xase (factor VIIIa–factor IXa) and prothrombinase (factor Va–factor Xa) complexes. At this point in the reaction, factor IXa generation is cooperatively catalyzed by membrane-bound factor Xa and by the tissue factor–factor VIIa complex. The thick arrow representing factor Xa generation is cooperatively catalyzed by factor VIIIa-factor IXa and by the tissue factor-factor VIIa complex. (b) The tissue factor pathway inhibitor (TFPI) in...

Table of contents

• Cover
• Table of Contents
• Title page
• Copyright page
• Contributors
• Historical Introduction
• PART I: Introduction
• PART II: Hemophilia A
• PART III: Inhibitors to Factor VIII
• PART IV: Acquired Hemophilia
• PART V: Hemophilia B
• PART VI: Pharmacokinetics of Factors VIII and IX
• PART VII: Hemophilia: Birth to Old Age
• PART VIII: Products Used to Treat Hemophilia
• PART IX: Surgical Management
• PART X: Musculoskeletal
• PART XI: Transfusion-Transmitted Disease
• PART XII: Gene Therapy
• PART XIII: Laboratory
• PART XIV: Women and Bleeding Disorders
• PART XV: von Willebrand Disease
• PART XVI: Rare Bleeding Disorders
• PART XVII: Emergency Medicine
• PART XVIII: Evaluation of Hemophilia
• PART XIX: Comprehensive Care and Delivery of Care
• Supplemental Images
• Index
• End User License Agreement