The Coagulation Consult A Case Based Guide

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Alan Lichtin • John Bartholomew
Editors

The Coagulation Consult

A Case-Based Guide
Editors
Alan Lichtin, MD, FACP John Bartholomew, MD, FACC, MSVM
Hematologic Oncology Cardiovascular Medicine
and Blood Disorders and Hematology
Cleveland Clinic Cleveland Clinic
Cleveland, OH, USA Cleveland, OH, USA

ISBN 978-1-4614-9559-8 ISBN 978-1-4614-9560-4 (eBook)

DOI 10.1007/978-1-4614-9560-4
Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 2013956817

© Springer Science+Business Media New York 2014

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For J. Leon and Beverly Lichtin
—Alan Lichtin

For Kathleen Bartholomew

—John Bartholomew
Preface

The reader might ask, “Why does the world need another coagulation textbook?”
In this time of instant access to medical information on the Internet, indeed,
one might ask what is the worth of any textbook, with its inherent publication
delay.
Many texts in the field of coagulation lean toward an emphasis on basic
science. This text does not do that. The goal of this book is to describe clinical
scenarios for which the practicing hematologist or vascular medicine expert
(either vascular medicine doctor or vascular surgeon) is consulted for bleed-
ing or clotting issue.
Many of us are very comfortable dealing with the spectrum of bleeding
and clotting disorders, and yet, these days, many of us feel more comfortable
dealing with one or the other. In fact, at many institutions, there are separate
departments of hematology (often overly weighted to the malignant hematol-
ogy side) and vascular medicine/vascular surgery. The bleeding patients tend
to be seen by the hematologists, and the thrombotic patients are more fre-
quently evaluated and treated by the vascular medicine doctors.
There are several disorders that present challenges such that both teams
are called to the bedside, and cooperation between these two services leads to
the best results. This is especially true for the heparin-associated thrombocy-
topenia (HIT) patients, who do not recover their platelet counts as one might
expect. They may remain on a direct thrombin inhibitor, and day after day, the
platelets remain frustratingly low. The vascular medicine doctors will call the
hematologists to make sure that there is not some other reason for the throm-
bocytopenia. Likewise, the severely affected antiphospholipid patient may
present with thrombocytopenia and be seen by the hematologists first, and the
thrombotic aspect of the disorder will be of more paramount importance, and
the hematologist may call the vascular medicine colleague to help. Another
common scenario where one service calls the other is when there is a patient
with a thrombosis in an unusual location and is first seen by the vascular
medicine doctor and work-up suggests a primary hematologic reason for the
thrombosis, such as a myeloproliferative disorder or paroxysmal nocturnal
hemoglobinuria. That is when the hematologist might be called.
This book is divided into chapters whose titles are the typical reasons we
are consulted to see patients. Our non-hematologic colleagues will call us for
a patient with a prolonged PT, a prolonged PTT, bleeding with surgery, easy
bruising, etc. The reader should look over the chapter headings and realize

vii
viii Preface

that many of the reasons we are consulted are listed there. Also, chapters are
devoted to special categories of patients, such as the patient with postopera-
tive bleeding, the patient with thrombosis around catheters, the individual
with heparin-induced thrombocytopenia, and the pregnant woman.
We wish to acknowledge many individuals who have made this text pos-
sible. The team of editors at Springer, especially Michael Wilt, have been
most helpful. The photography in the chapter on Easy Bruising was made
possible by Janine Sot. This book obviously could not have been written
without the help of our authors, and we appreciate their efforts. Also, we have
been blessed to have an exceptional secretary, Marge Dvorsack, to prepare
the manuscripts for the publisher. She has done a phenomenal job.

Cleveland, OH Alan Lichtin

John R. Bartholomew
Contents

1 Laboratory Analysis of Coagulation ........................................... 1

Heesun J. Rogers, Suzanne Bakdash,
Megan O. Nakashima, and Kandice Kottke-Marchant
2 Easy Bruisability ........................................................................... 39
Alan Lichtin and Anthony P. Fernandez
3 Prolonged PT ................................................................................. 51
Alan Lichtin
4 Prolonged PTT .............................................................................. 57
Kenneth D. Friedman and Jenny H. Petkova
5 Prolongation of Both PT and aPTT............................................. 71
Bernard J. Silver
6 Excessive Bleeding with Normal Prothrombin Time,
Partial Thromboplastin Time, and Platelet Count .................... 87
Senthilkumar Damodaran and Spero R. Cataland
7 Diagnosing Thrombocytopenia in the Clinic .............................. 99
Samir M. Dalia and Benjamin Djulbegovic
8 Thrombocytopenia in the Intensive Care Unit
and After Solid Organ Transplantation ...................................... 115
Suvasini Lakshmanan and Adam Cuker
9 Thrombocytosis ............................................................................. 133
Stephan Lindsey and Ramon V. Tiu
10 Prolonged Bleeding After Surgery............................................... 151
Sam Schulman
11 The Excessively Clotting Cancer Patient .................................... 161
Marcelo P. Villa-Forte Gomes
12 Thrombotic Risk Factors.............................................................. 185
Erika Leemann Price and Tracy Minichiello
13 Clotting Around Catheters and Devices...................................... 203
Natalie S. Evans, Manoj K. Dhariwal, and Lee Joseph

ix
x Contents

14 Heparin-Induced Thrombocytopenia ......................................... 215

John R. Bartholomew
15 Surgery on Patients on Antiplatelet Agents ................................ 231
Michael A. Militello
16 Newer Oral Anticoagulants .......................................................... 237
Douglas E. Joseph
17 Pregnancy ...................................................................................... 249
Alan Lichtin and Elliot H. Philipson

Index ....................................................................................................... 271

Contributors

Suzanne Bakdash, MD, MPH Department of Clinical Pathology, Cleveland

Clinic, Cleveland, OH, USA
John R. Bartholomew, MD, FACC, MSVM Cleveland Clinic Lerner
College of Medicine, Cleveland, OH, USA
Departments of Cardiovascular Medicine and Hematology/Oncology,
Cleveland Clinic Foundation, Cleveland, OH, USA
Spero R. Cataland, MD Division of Hematology and Oncology, Department
of Internal Medicine, Ohio State University, Columbus, OH, USA
Adam Cuker, MD, MS Department of Medicine, University of Pennsylvania,
Philadelphia, PA, USA
Department of Pathology and Laboratory Medicine, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, PA, USA
Samir M. Dalia, MD Department of Hematology and Oncology, University
of South Florida & H. Lee Moffitt Cancer Center & Research Institute, Tampa,
FL, USA
Senthilkumar Damodaran, MD, PhD Division of Hematology and Oncology,
Department of Internal Medicine, Ohio State University, Columbus, OH, USA
Manoj K. Dhariwal, MD Department of Family Medicine, Indiana University,
Indianapolis, Indiana
Benjamin Djulbegovic, MD, PhD Division of Evidence Based Medicine,
Department of Internal Medicine, University of South Florida, Tampa,
FL, USA
Department of Hematology & Health Outcomes & Behavior, H. Lee Moffitt
Cancer Center & Research Institute, USF Health Clinical Research, Tampa,
FL, USA
Natalie S. Evans, MD Section of Vascular Medicine, Department of
Cardiology, Cleveland Clinic Foundation, Cleveland, OH, USA
Anthony P. Fernandez, MD, PhD Department of Dermatology and
Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA

xi
xii Contributors

Kenneth D. Friedman, MD Medical Sciences Institute, Blood Center of

Wisconsin, Milwaukee, WI, USA
Departments of Internal Medicine and Pathology, Medical College of
Wisconsin, Milwaukee, WI, USA
Marcelo P. Villa-Forte Gomes, MD Section of Vascular Medicine,
Cleveland Clinic, Cleveland, OH, USA
Douglas E. Joseph, DO Cardiovascular Medicine, Cleveland Clinic,
Cleveland, OH, USA
Lee Joseph, MD Division of Cardiology, Department of Internal Medicine,
University of Iowa, Iowa City, Iowa
Kandice Kottke-Marchant, MD, PhD Department of Clinical Pathology,
Cleveland Clinic, Cleveland, OH, USA
Suvasini Lakshmanan, MD Department of Medicine, University of
Pennsylvania, Philadelphia, PA, USA
Alan Lichtin, MD, FACP Hematologic Oncology and Blood Disorders,
Cleveland Clinic, Cleveland, OH, USA
Stephan Lindsey, PhD Nemours Center for Childhood Cancer Research,
A.I. DuPont Hospital for Children, Wilmington, DE, USA
Michael A. Militello, PharmD, BCPS Department of Pharmacy, Cleveland
Clinic, Cleveland, OH, USA
Tracy Minichiello, MD San Francisco Veterans’ Affairs Medical Center,
San Francisco, CA, USA
Megan O. Nakashima, MD Department of Clinical Pathology, Cleveland
Clinic, Cleveland, OH, USA
Jenny H. Petkova, MD Department of Internal Medicine, Medical
University of South Carolina, Charleston, SC, USA
Elliot H. Philipson, MD, MBA Department of Obstetrics and Gynecology,
Women’s Health Institute, Hillcrest Hospital, Mayfield Heights, OH, USA
Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA
Erika Leemann Price, MD San Francisco Veterans’ Affairs Medical
Center, San Francisco, CA, USA
Heesun J. Rogers, MD, PhD Department of Clinical Pathology, Cleveland
Clinic, Cleveland, OH, USA
Sam Schulman, MD, PhD Department of Medicine, McMaster University
and Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
Thrombosis Service, HHS-General Hospital, Hamilton, ON, Canada
Bernard J. Silver, MD Department of Hematologic Oncology and Blood
Disorders, Cleveland Clinic, Cleveland, OH, USA
Ramon V. Tiu, MD Taussig Cancer Institute, Cleveland Clinic, Cleveland,
OH, USA
 Laboratory Analysis
of Coagulation 1
Heesun J. Rogers, Suzanne Bakdash,
Megan O. Nakashima,
and Kandice Kottke-Marchant

List of Abbreviations BT Bleeding time

BU Bethesda unit
AA Arachidonic acid C4bBP C4b-binding protein
ACA Anticardiolipin antibody CAP College of American Pathologists
ADP Adenosine diphosphate CLIA Clinical Laboratory Improvement
APA Antiphospholipid antibody Amendments
APC Activated protein C COX1 Cyclooxygenase 1
APC-R APC resistance CT Closure time
APS Antiphospholipid syndrome DIC Disseminated intravascular coagulation
aPTT Activated partial thromboplastin time DRVVT Dilute Russell’s viper venom test
AR Autosomal recessive DTI Direct thrombin inhibitor
AS Allele-specific DVT Deep vein thrombosis
ASA Aspirin (acetyl salicylic acid) ELISA Enzyme-linked immunosorbent assay
AT Antithrombin ELT Euglobulin lysis time
ATP Adenosine triphosphate EM Electron microscopy
B2GPI Beta2 glycoprotein 1 ET Essential thrombocythemia
FDP Fibrin degradation product
FII Prothrombin
H.J. Rogers, M.D., Ph.D. (*) FIIa Thrombin
Department of Clinical Pathology, Cleveland Clinic, FVIIa Activated factor VII
9500 Euclid Avenue (L-11), Cleveland, FVIII Factor VIII
OH 44195, USA FVL Factor V Leiden
e-mail: [email protected]
FRET Fluorescence resonance energy
S. Bakdash, M.D., M.P.H. transfer
Department of Clinical Pathology, Cleveland Clinic,
9500 Euclid Avenue (Q6-2), Cleveland, GP Glycoprotein
OH 44195, USA HMWK High-molecular-weight kininogen
e-mail: [email protected] INR International normalized ratio
M.O. Nakashima, M.D. ISI International sensitivity index
Department of Clinical Pathology, Cleveland Clinic, ISTH International Society for Thrombosis
9500 Euclid Ave (L-11), Cleveland, OH 44195, USA and Haemostasis
e-mail: [email protected]
LA Lupus anticoagulant
K. Kottke-Marchant, M.D., Ph.D. LMW Low molecular weight
Department of Clinical Pathology, Cleveland Clinic,
9500 Euclid Avenue (L21), Cleveland, OH 44195, USA MPN Myeloproliferative neoplasms
e-mail: [email protected] MPV Mean platelet volume

A. Lichtin and J. Bartholomew (eds.), The Coagulation Consult: A Case-Based Guide, 1

DOI 10.1007/978-1-4614-9560-4_1, © Springer Science+Business Media New York 2014
2 H.J. Rogers et al.

MTHFR Methylenetetrahydrofolate reductase does not accurately depict in vivo events, it remains
NSAIDs Nonsteroidal anti-inflammatory drugs particularly relevant with regard to understanding
PAI Plasminogen activator inhibitor the in vitro process of hemostasis reflected by
PCR Polymerase chain reaction widely used coagulation screening tests such as
PDW Platelet distribution width the prothrombin time (PT) and activated partial
PE Pulmonary embolism thromboplastin time (aPTT).
PFA Platelet function analyzer
PK Prekallikrein
PRP Platelet rich plasma Physiology of Hemostasis
PT Prothrombin time
RFLP Restriction fragment length Following an insult to the vascular wall, hemo-
polymorphism stasis is initiated by platelet adhesion at the site
RIPA Ristocetin-induced platelet aggregation of injury. This is followed by platelet aggrega-
RT Reptilase time tion and degranulation, with release of multiple
SLE Systemic lupus erythematosus mediators and procoagulant factors by the acti-
SNP Single nucleotide polymorphism vated platelets. At the same time, tissue factor
TAFI Thrombin-activatable fibrinolysis expressed at the site of injury initiates serial
inhibitor activation of coagulation factors. These events
TAR Thrombocytopenia with absent radii culminate in the formation of a fibrin thrombus
TF Tissue factor which incorporates the activated platelets into
TFPI Tissue factor pathway inhibitor its structure. In order to prevent the clot from
TM Thrombomodulin growing uncontrollably, antithrombotic mecha-
tPA Tissue plasminogen activator nisms are activated to maintain the balance of
TT Thrombin time pro- and anticoagulant processes. Clot remodel-
TxA2 Thromboxane A2 ing by fibrinolysis occurs over time, while cellu-
uPA Urokinase plasminogen activators lar elements move in to repair the underlying
VTE Venous thromboembolism tissue damage. The remainder of the clot is
VWD von Willebrand disease eventually eliminated and vascular patency and
VWF von Willebrand factor integrity restored. Thrombin plays a key role in
XR X-linked recessive virtually every step of the hemostatic process.
Derangements of one or more pro- or anticoagu-
lant elements of hemostasis may result in an
Introduction of Hemostasis increased risk of bleeding, an increased risk of
and Thrombosis clotting, or, rarely, both.

The goal of physiologic hemostasis is to stop any Initiation of Hemostasis by Platelet

bleeding that occurs and, ultimately, to return the Plug Formation
vessel wall back to its original state. This is achieved The role of platelets in hemostasis and laboratory
through a dynamic interaction of pro- and antico- evaluation of platelet function are discussed in
agulant elements. Early studies of hemostasis section of this chapter.
focused primarily on the process of clot formation.
Originally described as a coagulation “cascade,” the Initiation and Propagation of Clotting
model for in vivo hemostasis subsequently evolved Through Activation of Coagulation
to incorporate the more complex contributions of Factors
elements beyond the traditional coagulation factors Clotting factors are proenzymes or inactive pre-
(Roberts et al. 1998; Hoffman and Monroe 2001; cursor proteins (zymogens), enzyme cofactors,
Schmaier and Miller 2011). Although it is now well and substrates that are sequentially activated to
established that the classic coagulation cascade form a fibrin clot. All of these factors are made
1 Laboratory Analysis of Coagulation 3

Fig. 1.1 Classic coagulation cascade. This model of coagula- of this process (Reprinted with permission, Cleveland Clinic
tion depicts extrinsic, intrinsic, and common pathways of Center for Medical Art & Photography © 2013. All Rights
coagulation. Calcium ions and phospholipids, which are not Reserved). aPTT activated partial thromboplastin time, PT
depicted for simplicity, are necessary cofactors in several steps prothrombin time, TT thrombin time, RT reptilase time

in the liver by hepatocytes, except for factor tion of FVII by tissue factor (TF), followed by
VIII (FVIII) which may be made by the reticu- direct activation of the common pathway by
loendothelial system (Shovlin et al. 2010; activated factor VII (FVIIa). The intrinsic path-
Schmaier and Miller 2011). Some of the proco- way, which is assessed by the aPTT, starts with
agulant factors (II, VII, IX, and X) undergo vita- activation of the contact factor XII, followed by
min K-dependent gamma-carboxylation, which a cascading activation of factors XI then IX.
allows them to bind to the phospholipid surfaces Activated factor VIII serves as a cofactor for
where they are activated. Nutritional vitamin K activation of the common pathway by FIXa.
deficiency and oral anticoagulation with warfa- Once the common pathway is initiated by acti-
rin, a vitamin K antagonist, anticoagulate by vation of FX by either FVIIa or FIXa, activated
disrupting this process (Ageno et al. 2012; factor V serves as a cofactor for FXa to activate
Schmaier and Miller 2011). prothrombin (FII) to thrombin (FIIa), which in
turn cleaves fibrinogen (factor I) to fibrin.
Classic Coagulation Cascade Calcium is a necessary cofactor for nearly all of
The classic coagulation cascade (Fig. 1.1) illus- the above steps, while phospholipid is required
trates intrinsic and extrinsic pathways of clot- for activation events in the intrinsic pathway
ting which converge in a common pathway and for activation of FII (Mann 2003; Hoffman
ending in clot formation. The extrinsic pathway, and Monroe 2007; Schmaier and Miller 2011;
which is assessed by the PT, starts with activa- Leung 2013).
4 H.J. Rogers et al.

Fig. 1.2 Cell-based model of coagulation. This model of complex and FXIa. Together with its cofactor FVIIIa,
coagulation incorporates some of the cellular elements FIXa activates FX on the surface of activated platelets.
involved in coagulation and better reflects the complex- FXa, together with its cofactor FVa, activates prothrom-
ity and interdependence of the elements of in vivo coag- bin (FII) to thrombin (FIIa). The thrombin (FIIa) gener-
ulation. Calcium ions, which are not depicted for ated at this point converts fibrinogen (FI) to fibrin (FIa)
simplicity, are necessary cofactors in several steps of and factor XIII to the clot-stabilizing FXIIIa. The end
this process. In the cell-based model of coagulation, result of this process is a stable, cross-linked polymer-
FVII is activated to FVIIa by tissue factor (TF). The TF– ized fibrin clot. Black arrows indicate transition of inac-
FVIIa complex activates FX to FXa, which together with tivated factors to their activated forms. Red arrows
its cofactor FVa activates prothrombin (FII) to thrombin indicate an activating effect, with cofactor contribution
(FIIa). In addition to activating factors V, VIII, and XI, by the factors tangential to the red arrows (Reprinted
the FIIa generated by this mechanism also activates with permission, Cleveland Clinic Center for Medical
platelets. Factor IX is activated by both the TF–FVIIa Art & Photography © 2013. All Rights Reserved)

Cell-Based Model of Coagulation damage or disruption, expression of TF is

Activation of circulating FVII to FVIIa by tissue increased and TF-bearing cells are exposed to
factor is the primary initiator of the coagulation circulating blood. TF activates FVII to FVIIa
cascade in both the classic and cell-based models (Rapaport and Rao 1995; Hoffman and Monroe
of coagulation. However, the cell-based model of 2007; Breitenstein et al. 2009; Leung 2013).
coagulation better reflects the complexity and The TF–FVIIa complex activates FX to FXa.
interdependence of the in vivo events resulting in Activated factor V acts as a cofactor for FXa to
clot formation (Fig. 1.2). activate prothrombin (FII) to thrombin (FIIa).
Tissue factor (TF) is a transmembrane glyco- The FVa needed for this process may be released
protein expressed in a variety of cells which are directly from activated platelets or activated by
not typically in direct contact with the blood flow, FXa or non-coagulation proteases. The small
including vascular smooth muscle cells, adventi- amount of thrombin generated by TF–FVIIa
tial fibroblasts, and pericytes. Endothelial cells activation stimulates upregulation of TF expres-
do not normally express TF. In the event of an sion and activates platelets, resulting in expo-
injury to a vascular wall resulting in endothelial sure of the platelet phospholipid surfaces needed
1 Laboratory Analysis of Coagulation 5

for assembly of intrinsic factor activating com- rapid lysis by plasmin (Hoffman and Monroe
plexes. Thrombin also directly activates factors 2007; Schmaier and Miller 2011; Leung 2013).
V, VIII, and XI, which, together with activation In summary, although the classic coagulation
of factor IX to FIXa by the TF–FVIIa complex, cascade might imply that the extrinsic and intrin-
facilitates clotting through the intrinsic path- sic pathways are redundant, the cell-based coagu-
way. The hemostatic response is markedly lation model makes it clear that they are not.
amplified at this point given the ability of FIXa Extrinsic pathway activities are limited to
to diffuse to adjacent platelet surfaces, as TF-expressing surfaces and result in initiation of
opposed to the FXa generated by the TF–FVIIa clotting and activation of the platelets and coagu-
complex which is localized to TF-expressing lation factors needed for amplification of the
cell due to inhibition of FXa by antithrombin hemostatic response. On the other hand, intrinsic
(AT) and tissue factor pathway inhibitor (TFPI) pathway activities take place on the phospholipid
(Mann 2003; Hoffman and Monroe 2007; surface of the activated platelets and generate the
Schmaier and Miller 2011; Leung 2013). thrombin burst which facilitates formation and
Once activated, FVIIIa and FIXa quickly stabilization of the fibrin clot. Thus, the intrinsic
become localized to the surface of activated and extrinsic coagulation pathways each play a
platelets and activate FX. The prothrombinase unique and vital role in achieving hemostasis
complex, consisting of FXa and its cofactor FVa, (Hoffman and Monroe 2007).
is a very potent thrombin generator in the com-
mon pathway. The enhanced thrombin genera- Termination of Clotting by
tion by this mechanism results in conversion of Antithrombotic Mechanisms
fibrinogen to fibrin. The fibrin monomers undergo The three main antithrombotic mechanisms
polymerization and the clot is then cross-linked involved in terminating clotting are tissue factor
and stabilized by FXIII, which is also activated pathway inhibitor (TFPI), antithrombin (AT), and
by thrombin (Mann 2003; Hoffman and Monroe activated protein C (APC). Deficiencies of these
2007; Schmaier and Miller 2011; Leung 2013). natural anticoagulants, or their cofactors, can result
FXII (Hageman factor) autoactivates in associa- in an increased risk of thrombosis. The function of
tion with negatively charged surfaces, such as natural anticoagulants is not captured by coagula-
exposed collagen at the site of a vascular injury and tion screening tests such as the PT and aPTT.
polysomes released by activated platelets. FXII, TFPI is the most potent inhibitor of TF–FVIIa
prekallikrein (PK or Fletcher factor), and high- complex and inhibits TF–FVIIa by forming a
molecular-weight kininogen (HMWK, Fitzgerald, quaternary complex with FVIIa, TF, and FXa
or Williams factor) comprise the contact system (Breitenstein et al. 2009; Leung 2013). Although
which can also activate FIX. The contact system AT inhibits most of the activated coagulation fac-
factors are redundant in vivo; deficiencies in these tors, including thrombin (FIIa) and factors IXa,
factors are not associated with bleeding but may Xa, XIa, and XIIa, it exerts its primary effect
instead be associated with an increased risk of through inhibition of factors IIa and Xa.
thrombosis (Gallimore et al. 2004; Girolami et al. Endogenous and exogenous heparin and heparin-
2011; Schmaier and Miller 2011). like substances can significantly potentiate the
Binding of thrombin to thrombomodulin (TM) anticoagulant effect of AT, in some cases by
induces a conformational change in thrombin 1,000-fold or greater (Schmaier and Miller 2011;
whereby it ceases to activate platelets and cleave Leung 2013). The structure of the different types
fibrinogen. The thrombin–TM complex activates of heparin plays a role in determining their effect
protein C to decelerate the clotting process. In through interaction with AT; for example, unfrac-
addition to its role in slowing down the clotting tionated heparin exerts its primary anticoagulant
process, the thrombin–TM complex also activates effect through AT-mediated inactivation of FIIa,
thrombin-activatable fibrinolysis inhibitor (TAFI) whereas low molecular weight (LMW) heparins
to further stabilize the clot and protect it from exert their primary anticoagulant effect through
6 H.J. Rogers et al.

AT-mediated inactivation of FXa (Garcia et al.

2012). The thrombin–TM complex activates pro- Laboratory Assays for Evaluation
tein C, which, in association with its cofactor of Coagulation Disorders
protein S, inactivates factors Va and VIIIa.
Activated protein C (APC) has also been found to Commonly Used Laboratory Assays
play a role in other associated processes includ- Related to Hemostasis
ing inflammation and stimulating fibrinolysis
(Schmaier and Miller 2011; Griffin et al. 2012; The most widely used screening tests of coagula-
Leung 2013). tion function are the prothrombin time (PT), the
international normalized ratio (INR), and the
Clot Lysis activated partial thromboplastin time (aPTT).
After hemostasis is achieved, it is important to Unless otherwise specified, samples used for
remove the clot and restore the patency of the coagulation testing are collected in 3.2 % sodium
blood vessel as part of the wound healing process. citrate (light blue top) test tubes. The anticoagu-
Tissue plasminogen activator (tPA) converts fibrin- lant effect of citrate is exerted by chelating cal-
bound plasminogen to plasmin which cleaves the cium, which is a required cofactor for most steps
fibrin strands releasing fibrin degradation products in the hemostatic process (Adcock et al. 1998).
(FDPs). D-dimer is a major FDP consisting of two
D domains from adjacent fibrin monomers that Prothrombin Time (PT) and
had been cross-linked by FXIIIa. tPA is primarily International Normalized Ratio (INR)
responsible for initiating intravascular fibrinolysis, The PT assesses the extrinsic and common path-
while urokinase plasminogen activators (uPA) per- ways (factors VII, X, V, II, and I) (Fig. 1.1).
form this function in the extravascular compart- Patient plasma is incubated for a short time with
ment. Plasminogen activator inhibitors (PAI-1 and thromboplastin, a source of phospholipid and tis-
PAI-2) inhibit tPA and uPA, while alpha-2-anti- sue factor, and then recalcified. The PT is the
plasmin inhibits plasmin (Hoffman and Monroe time (in seconds) that it takes to form a fibrin clot
2007; Schmaier and Miller 2011; Leung 2013). To after adding the calcium.
further maintain the balance of pro- and antifibri- Variable prolongation of the PT was noted in
nolytic processes, thrombin, plasmin, and the patients on warfarin therapy depending on the
thrombin–TM complex may all activate thrombin- thromboplastin reagent and test system used
activatable fibrinolysis inhibitor (TAFI) to TAFIa, (Bailey et al. 1971). The INR was conceived to
which inhibits fibrinolysis and protects the clot provide a standardized approach to therapeutic
from premature degradation by plasmin (Hoffman monitoring of warfarin, whereby an international
and Monroe 2007; Schmaier and Miller 2011; sensitivity index (ISI) is determined by the manu-
Colucci and Semeraro 2012; Leung 2013). facturer for each reagent/test system combination
The activity of pro- and antifibrinolytic relative to the international standard for thrombo-
factors is not captured by coagulation screen- plastin. The INR is then calculated as follows:
ing tests such as the PT and aPTT, or even by INR = (Patient PT/Mean normal PT for the
the thrombin time. The euglobulin lysis time laboratory)ISI
(ELT) can be used as a screening test to assess (Ageno et al. 2012). The INR has only been
global fibrinolytic function; assays for indi- validated for patients on oral anticoagulant ther-
vidual factors may also be performed. The apy with a vitamin K antagonist, in other words,
ELT is expected to be shortened in hyperfibri- those in whom only the vitamin K-dependent fac-
nolysis and may be prolonged with hypofibri- tors are expected to be decreased (Loeliger et al.
nolysis. However, the usefulness of ELT is 1985). The widespread adoption of the INR as a
limited by its relative insensitivity and a broad general indicator of coagulation function, and its
variation in results among normal individuals incorporation into the model for end-stage liver
(Glassman et al. 1993). disease (MELD) scoring system for prioritization