+HDOWK3UHVV/WG ZZZ IDVWIDFWV FRP · mechanisms are promptly activated to limit bleeding by a complex series of interrelated reactions involving endothelial cells, plasma coagulation

© 2013 Health Press Ltd. www.fastfacts.com

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 IndependenceThis book is as balanced and as practical as we can make it. Ideas for improvement are always welcome: [email protected]


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)1235 523233 Fax: +44 (0)1235 523238

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)1752 202301 (UK, Europe and Asia–Pacific), 1 800 247 6553 (USA, toll free) or +1 419 281 1802 (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 978-1-908541-36-9

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.


Introduction 5

Abbreviations 4

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

Useful resources 144

Index 145

Perioperative bleeding 106

Disseminated intravascular coagulation 116

Anticoagulants and antithrombotic agents 124


4

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


5

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.


6

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.

• Primaryhemostasisoccursafterdamagetothevesselwall,andinvolves

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.

• Secondaryhemostasisinvolvesactivationofthecoagulationsystem,

leading to the generation of fibrin strands, which are laid down

between platelets and reinforce the platelet plug.

• Fibrinolysisentailsactivationoffibrin-boundplasminogen,resultingin

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.

Endothelial cellsBlood 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.

1 Normal hemostasis


7

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.

PlateletsEach bone marrow megakaryocyte produces 1000–2000 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

Open canalicular systemα-granulesMitochondrionGlycogen

MicrotubulesDense bodiesLysosome

Binding sitefor VWF

GpIbGpIX

Gp IIb/IIIacomplex

Bindingsite forfibrinogenand VWF

Figure 1.1 The structure of a platelet. VWF, von Willebrand factor;

Gp, glycoprotein.


8

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.

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.


9

Normal hemostasis

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.

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.

WBCs Activated byP-selectin

Activated WBCs and plateletsroll on the endothelium andrelease tissue-factor-bearingmicroparticles

Platelets adhere toconnective tissue andWBCs migrate into tissues

VWFInjury

Platelets

P-selectin

Subendothelial connective tissue

Endothelium


10

Fast Facts: Bleeding Disorders

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

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.

Tissue damage

TF

FVII

FVIII

FV

TF-FVIIa

FIX

FX

FXI

FXII

FXIII

FXIIIaThrombinProthrombin

Fibrinogen Fibrin Cross-linked fibrin

FXIIa

FXIa

Tenase

FIXa + platelets+ Ca2+ FVIIIa

Prothrombinase

FXa + platelets+ Ca2+ FVa


11

Normal hemostasis

the activated coagulation factors Va and VIIIa by proteolysis. Protein Z

binds to the Z-protease inhibitor and the complex inactivates FXa.

FibrinolysisSmall 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

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.

TM PC

PC

TM

FVaFVIIIa

FViFVIIIi

PS

PST T

T

Endothelial cell

APC


Documents

+HDOWK3UHVV/WG ZZZ IDVWIDFWV FRP · mechanisms are promptly activated to limit bleeding by a complex series of interrelated reactions involving endothelial cells, plasma coagulation