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TRANSCRIPT
© 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]
© 2013 Health Press Ltd. www.fastfacts.com
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
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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.
© 2013 Health Press Ltd. www.fastfacts.com
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
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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
© 2013 Health Press Ltd. www.fastfacts.com
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.
© 2013 Health Press Ltd. www.fastfacts.com
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
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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.
© 2013 Health Press Ltd. www.fastfacts.com
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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.
© 2013 Health Press Ltd. www.fastfacts.com
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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
© 2013 Health Press Ltd. www.fastfacts.com
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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
© 2013 Health Press Ltd. www.fastfacts.com
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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
© 2013 Health Press Ltd. www.fastfacts.com