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2 Fast Facts Fast Facts: Bleeding Disorders Second edition David Green MD PhD Professor of Medicine Emeritus Feinberg School of Medicine Northwestern University Chicago, Illinois, USA Christopher A Ludlam PhD FRCP FRCPath Emeritus Professor of Haematology and Coagulation Medicine University of Edinburgh and Former Director of the Haemophilia and Thrombosis Centre Royal Infirmary, Edinburgh, UK Declaration of Independence This book is as balanced and as practical as we can make it. Ideas for improvement are always welcome: feedback@fastfacts.com

3 Fast Facts: Bleeding Disorders First edition 2004 Second edition March 2013 Text 2013 David Green, Christopher A Ludlam 2013 in this edition Health Press Limited Health Press Limited, Elizabeth House, Queen Street, Abingdon, Oxford OX14 3LN, UK Tel: +44 (0) Fax: +44 (0) Book orders can be placed by telephone or via the website. For regional distributors or to order via the website, please go to: fastfacts.com For telephone orders, please call +44 (0) (UK, Europe and Asia Pacific), (USA, toll free) or (Americas). Fast Facts is a trademark of Health Press Limited. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the express permission of the publisher. The rights of David Green and Christopher A Ludlam to be identified as the authors of this work have been asserted in accordance with the Copyright, Designs & Patents Act 1988 Sections 77 and 78. The publisher and the authors have made every effort to ensure the accuracy of this book, but cannot accept responsibility for any errors or omissions. The authors therapeutic recommendations may not accord with licensed indications worldwide. For all drugs, please consult the product labeling approved in your country for prescribing information. Registered names, trademarks, etc. used in this book, even when not marked as such, are not to be considered unprotected by law. A CIP record for this title is available from the British Library. ISBN Green D (David) Fast Facts: Bleeding Disorders/ David Green, Christopher A Ludlam Cover image: Scanning electron micrograph of a blood clot, showing erythrocytes (red), platelets (green) and a white blood cell (yellow) enmeshed in a web of fibrin threads. Medical illustrations by Dee McLean, London, UK and Annamaria Dutto, Withernsea, UK. Typesetting and page layout by Health Press Limited. Printed by Latimer Trend and Company, Plymouth, UK. Text printed on biodegradable and recyclable paper manufactured using elemental chorine free (ECF) wood pulp from well-managed forests.

4 Abbreviations 4 Introduction 5 Normal hemostasis 6 Assessment of bleeding symptoms 14 Vascular purpuras 23 Platelet disorders 33 Pharmacological hemostatic products 51 Hemophilia 58 Von Willebrand disease 69 Uncommon congenital coagulation disorders 77 Liver and kidney disorders 87 Pregnancy 98 Perioperative bleeding 106 Disseminated intravascular coagulation 116 Anticoagulants and antithrombotic agents 124 Useful resources 144 Index 145

5 Abbreviations ADAMTS13: a disintegrin and metalloprotease with thrombospondin type 1 motif, 13 ADP: adenosine diphosphate ALK (1, 2): activin receptor-like kinase-(1, 2) AMP: adenosine monophosphate aptt: activated partial thromboplastin time ASA: acetylsalicylic acid ATP: adenosine triphosphate camp: cyclic adenosine monophosphate cgmp: cyclic guanosine monophosphate CNS: central nervous system DIC: disseminated intravascular coagulation EACA: ε-aminocaproic acid EDTA: ethylenediamine tetra-acetic acid F: factor HCV: hepatitis C virus HELLP: hemolytic anemia with elevated liver enzymes and low platelet count (syndrome) HHT: hereditary hemorrhagic telangiectasia HLA: human leukocyte antigen HPA (-1A): human platelet antigen (-1A) Ig: immunoglobulin IL-2: interleukin-2 INR: international normalized ratio LDH: lactate dehydrogenase LMWH: low-molecular-weight heparin NSAID: non-steroidal anti-inflammatory drug PAI (-1, -2): plasminogen activator inhibitor (-1, -2) PCR: polymerase chain reaction PFA-100: platelet function analyzer 100 PT: prothrombin time TAFI: thrombin activatable fibrinolysis inhibitor TNFα: tumor necrosis factor α tpa: tissue plasminogen activator VCAM1: vascular cell adhesion molecule 1 VWF: von Willebrand factor 4

6 Introduction Most hemorrhagic problems are emergencies, and rapid action is necessary to stop bleeding. Waiting for the results of laboratory tests and specialist consultations delays treatment and permits expansion of hematomas. To rapidly and effectively control bleeding, the clinician needs a ready and reliable source of information about a variety of hemorrhagic conditions. Fast Facts: Bleeding Disorders provides such a resource. Since the publication of the first edition there have been major advances in the diagnosis and treatment of bleeding disorders, and we have made numerous updates to this handbook to ensure it remains a comprehensive up-to-date reference that reflects the latest research and clinical guidelines. These include a description of the bleeding score that enables clinicians to make a quantitative estimate of bleeding severity, objective criteria for diagnosing hereditary hemorrhagic telangiectasia, discussions on the benefits of prophylaxis in patients with hemophilia, updated methods for evaluation and treatment of bleeding problems in pregnancy, and an overview of the scoring system for overt disseminated intravascular coagulation. The book contains many useful alerts for readers, such as the potential thrombogenicity of factor VIII-containing VWF concentrates, the caution required when prescribing clotting factor concentrates for bleeding in patients with liver disease, and the bleeding risk associated with currently administered antithrombotic agents. We have revised the final chapter on anticoagulants and antithrombotic agents with respect to the new drugs available, including tables that display bleeding risks and strategies to control bleeding. Fast Facts: Bleeding Disorders provides concise, evidence-based reviews of the diagnosis and treatment of a large number of diseases in an easily accessible format. It will assist physicians, physician assistants, nurse practitioners and pharmacists as they confront the challenges of controlling bleeding in patients with hemophilia, von Willebrand disease, platelet disorders and thrombosis, or as a result of antithrombotic or anticoagulant therapy. It is our hope that this new edition will enable readers to better cope with the protean problems presented by patients with hemorrhagic disorders. 5

7 1 Normal hemostasis In health, hemostasis ensures that blood remains fluid and contained within the vasculature. If a vessel wall is damaged, a number of mechanisms are promptly activated to limit bleeding by a complex series of interrelated reactions involving endothelial cells, plasma coagulation factors, platelets and fibrinolytic proteins. The activities of these components are finely balanced between keeping the blood fluid and preventing excessive activation of the procoagulants, which would lead to intravascular thrombosis. It is helpful to consider the hemostatic process as three distinct phases. Primary hemostasis occurs after damage to the vessel wall, and involves vasoconstriction and adhesion of platelets in a monolayer on exposed subendothelial fibrils. Subsequently, further platelets aggregate to form a platelet plug, which stems the flow of blood. Secondary hemostasis involves activation of the coagulation system, leading to the generation of fibrin strands, which are laid down between platelets and reinforce the platelet plug. Fibrinolysis entails activation of fibrin-bound plasminogen, resulting in clot lysis. Lysis is modulated by inhibitors of fibrinolysis, which are activated by thrombin or released by platelets. In reality, these processes tend to merge, with the activated platelet and endothelial cell membranes providing the foundation on which the clotting factors can become activated, and fibrin formed and lysed. 6 Endothelial cells Blood vessels are lined with endothelial cells, which promote hemostasis and keep the blood fluid by preventing excessive deposition of fibrin through the synthesis and secretion of various antithrombotic agents. Proteins that directly promote hemostasis von Willebrand factor (VWF) and P-selectin are stored in specialized organelles called Weibel Palade bodies. Other endothelial constituents are plasminogen activator inhibitor-1 (PAI-1) and cell adhesion molecules (e.g. vascular cell adhesion molecule 1 [VCAM1]), which promote the accumulation of white cells.

8 Normal hemostasis Antithrombotic agents secreted by endothelial cells include: heparan sulfate, which inhibits activated clotting factors; prostacyclin and nitric oxide, which inhibit platelet aggregation and induce vasodilatation; and tissue plasminogen activator (tpa), which promotes the dissolution of fibrin that is deposited within the vasculature. This prevents excessive fibrin deposition and thrombosis. Platelets Each bone marrow megakaryocyte produces platelets, which remain in the circulation for about 10 days. These highly specialized anucleate cells (Figure 1.1) take part in a series of complex reactions to prevent blood loss. Trauma induces neurally mediated vasoconstriction and increases the shear rate of the flowing blood. Platelets leave the axial column of blood and move to the periphery, where they are activated by P-selectin exposed on the injured endothelium. The platelet membrane glycoprotein 1b-IX-V becomes the receptor for high-molecular-weight strings of VWF, released from Weibel Palade bodies in the endothelial cells (see above). The VWF tethers platelets to the endothelium, and glycoprotein VI binds platelets to subendothelial collagen. Platelet activation exposes the fibrinogen receptor glycoprotein αiibβ3, and there are also receptors for thrombin and thromboxane. Binding of these ligands to their receptors induces platelet activation and aggregation. Hemostatic proteins, such as VWF and fibrinogen, are released from α-granules (one of two unique types of granule found in platelets) and Binding site for VWF GpIX GpIb Open canalicular system α-granules Mitochondrion Glycogen Binding site for fibrinogen and VWF Gp IIb/IIIa complex Lysosome Dense bodies Microtubules Figure 1.1 The structure of a platelet. VWF, von Willebrand factor; Gp, glycoprotein. 7

9 Fast Facts: Bleeding Disorders promote cross-linking between platelets to help the development of a platelet plug to stem hemorrhage. In addition, adenosine diphosphate (ADP) is released from the second type of granule (called platelet dense granules because of their calcium content), and promotes further aggregation of platelets by binding to platelet P2Y1 and P2Y12 receptors. The platelet membrane also has receptors for plasma coagulation factors (e.g. prothrombin and factors V, X and XI). Thus, the activated platelet membrane provides a surface on which the components of coagulation can gather very rapidly, leading to the development of a fibrin-reinforced stable platelet plug. Inhibitors. The participation of platelets and endothelial cells in the formation of the platelet plug is mediated by inhibitors: ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, 13) cleaves the high-molecular-weight strings of VWF, ADP is converted to adenosine monophosphate (AMP) by ADPase, and platelet aggregation is inhibited by nitric oxide and prostacyclin, which also are vasodilators. Coagulation system The coagulation factors are a series of plasma proteins synthesized by the liver that, when activated, generate thrombin and convert fibrinogen to fibrin via a sequence of complex reactions. Although originally conceived as a simple cascade, it is now viewed as an interrelated network of reactions, consisting of three phases: initiation, propagation and termination. 8 Initiation phase. When the endothelium is damaged the subendothelial vessel wall components become exposed, and circulating VWF promotes adhesion of platelets to the exposed subendothelial connective tissue. P-selectin is exposed on activated endothelial cells and binds to P-selectin glycoprotein ligand on leukocytes and platelets, initiating the rolling of these cells on the endothelium toward the site of injury and the release of membrane microparticles (Figure 1.2). Tissue factor (TF), a transmembrane glycolipoprotein, is expressed by injured endothelium, subendothelial connective tissue and microparticles. At the site of injury, TF forms a complex with factor (F)VII (TF FVIIa) on the surface of activated platelets. The TF FVIIa complex activates FIX and FX, and the activated FX cleaves prothrombin to form small amounts of thrombin.

10 Normal hemostasis WBCs Platelets Activated by P-selectin Activated WBCs and platelets roll on the endothelium and release tissue-factor-bearing microparticles Platelets adhere to connective tissue and WBCs migrate into tissues P-selectin Injury VWF Endothelium Subendothelial connective tissue Figure 1.2 Initiation of hemostasis. Injury to the endothelium provokes exposure of P-selectin, which binds to P-selectin glycoprotein ligand on platelets and leukocytes, and to von Willebrand factor (VWF), which is required for platelet adhesion to subendothelial connective tissue. Binding of P-selectin activates platelets and leukocytes, which roll on the endothelium toward the site of injury. The activated cells shed tissue-factor-bearing membrane microparticles, which accumulate at the site of injury and initiate the coagulation cascade (see Figure 1.3). WBC, white blood cell. Thrombin is a potent activator of platelets, which provide an enhanced catalytic surface on which further coagulation is promoted. The activated platelets release hemostatic factors (e.g. fibrinogen and VWF) and polyphosphate, which accelerate the activation of FXI by thrombin. Polyphosphate is also capable of activating FV, further enhancing thrombin formation. Propagation phase. The small amounts of thrombin that are formed during the initiation phase activate FV, FVIII and FXI, leading to the formation of sufficient thrombin to overcome inhibitors and generate fibrin from fibrinogen, as well as activate FXIII to cross-link the fibrin and form a stable clot (Figure 1.3). Termination phase. This occurs when protein C is activated and, together with protein S, inhibits activated FV and FVIII, as described below. 9

11 Fast Facts: Bleeding Disorders Tissue damage TF FVII TF-FVIIa FXII FIX FXIIa FXI FXIa Tenase FIXa + platelets + Ca 2+ FVIIIa FVIII FX Prothrombinase FXa + platelets + Ca 2+ FVa FV Prothrombin FXIII Thrombin FXIIIa Fibrinogen Fibrin Cross-linked fibrin Figure 1.3 The coagulation system. Clotting is initiated by tissue factor (TF) expressed on microparticles (see Figure 1.2). The enzyme complexes tenase and prothrombinase form on the platelet surface. The blue lines represent the positive-feedback effects (propagation) of small amounts of thrombin, which greatly enhance the activity of the coagulation network and result in large amounts of thrombin and thus fibrin (clot) formation. The clotting factors (Fs) are represented by Roman numerals. 10 Inhibitors of coagulation. The plasma contains a series of proteins that inhibit activated procoagulant enzymes and prevent excessive intravascular coagulation. Raised levels of these inhibitors are usually not associated with a bleeding state, but a reduced concentration may predispose to thrombosis. Tissue factor pathway inhibitor binds FXa, forming a complex that rapidly inhibits the TF FVIIa complex. Antithrombin is a potent and clinically very important inhibitor of thrombin, FXa, FXIa and the TF FVIIa complex. It limits the overall activation of the coagulation mechanism, preventing excessive fibrin deposition and thrombosis. Protein C. The protein C pathway is a further mechanism by which intravascular coagulation is limited (Figure 1.4). This pathway is initiated by thrombin when it binds to thrombomodulin on the endothelial surface and activates protein C bound to its receptor on the cell membrane. Activated protein C along with its cofactor, free protein S inactivates

12 Normal hemostasis T PC FVa FVIIIa FVi FVIIIi T T PS TM PC TM APC PS Endothelial cell Figure 1.4 The protein C pathway. Thrombin (T), generated by the coagulation network, binds to thrombomodulin (TM) on the endothelial cell membrane. Protein C (PC) binds to the endothelial protein C receptor and is converted by thrombomodulin-bound thrombin to activated protein C (APC). When the plasma cofactor protein S (PS) binds to APC, it can inactivate activated factors V (FVa) and VIII (FVIIIa) to inactive molecules FVi and FVIIIi. Thus, a deficiency in the protein C/S pathway leads to persistence of FVa and FVIIIa, which predispose to thrombosis and may modify the severity of inherited bleeding disorders. the activated coagulation factors Va and VIIIa by proteolysis. Protein Z binds to the Z-protease inhibitor and the complex inactivates FXa. Fibrinolysis Small amounts of fibrin are constantly being deposited within the vasculature and are removed by the fibrinolytic system (Figure 1.5). This pathway consists of an initiator, tpa, which is synthesized and released from endothelial cells. tpa converts its substrate plasminogen (bound within the clot to fibrin) to plasmin. In turn, plasmin lyses intravascular fibrin to soluble fibrin-degradation products. These consist of fragments of cross-linked fibrin known as D-dimers, levels of which can be measured in the laboratory and reflect the amount of fibrin degradation. The small amount of plasmin escaping from the clot is neutralized by circulating antiplasmin. Inhibitors of fibrinolysis. Fibrinolysis is inhibited by the following factors. Plasminogen activator inhibitor-1 and antiplasmin inhibit tpa and plasmin, respectively. Raised levels of PAI-1 are associated with atheroma, though it is unclear whether a high plasma level predisposes to, or is a consequence of, atherothrombosis. Raised antiplasmin levels do not 11