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Brief Overview of the Coagulation

Cascade
Vandita Johari, MD, and Chandravathi Loke, MD
Introduction
The increasing number of indications for anticoagulation, as well as an
increase in the number of therapeutic anticoagulants being made avail-
able, makes it imperative for the modern-day practitioner to understand
currently available coagulation testing and drug monitoring. Clinical
testing includes a combination of clotting, immunologic, and chromo-
genic assays, which screen for disorders of coagulation, whether they be
genetic in origin or acquired because of either disease or anticoagulant
therapy. A brief review of the pathways of coagulation and clot lysis, and
the factors regulating them, will help in the understanding of how
anticoagulant drugs work and how they can be monitored or, if necessary,
their action reversed when toxicity is suspected.
Brief Overview of Coagulation
Thrombosis may be dened as the formation and propagation of a blood
clot within the vasculature. Clinical thrombosis involves the following:
1. Blood ow and the blood vessels
2. Plateletvessel interactions related to disruption of the endothelium
3. The coagulation system, in particular, the natural anticoagulants and
the brinolytic system.
1
Thrombin is the nal enzyme of the coagulation cascade and therefore
the target of most of the anticoagulants. Generation of thrombin following
vascular injury occurs in 2 waves of differing magnitude. During the
initiation phase, small amounts of thrombin are generated, which prepares
the coagulation cascade for the second larger thrombin burst.
1,2
Coagulation Cascade
Two pathways of anticoagulation have been describedextrinsic/tissue
factor pathway and the intrinsic/contact activation pathway (Fig 1). These
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2 pathways converge, forming the common pathway, which results in the
activation of factor X to Xa.
Coagulation is initiated by the interaction, in the extrinsic pathway, of
tissue factor (TF) exposed by vascular injury with plasma factor VIIa,
which, in turn, activates IX and X, which results in the formation of small
amounts of thrombin. Thrombin, in turn, primes the intrinsic pathway,
resulting in explosive generation of thrombin, which acts on brinogen to
form the brin clot. These reactions take place on phospholipid surfaces,
usually the activated platelet surface.
1,2
Antithrombotic Mechanisms
Several physiological antithrombotic mechanisms act in concert to keep
thrombosis in check under normal circumstances (Fig 1).
Antithrombin III (AT-III) is the plasma protease inhibitor that neutral-
izes thrombin and other coagulation factors, such as XIa, IXa, and Xa
AT-III, which is potentiated by heparin.
Protein C is a plasma glycoprotein that is activated by thrombin that in
turn inactivates factors Va and VIIIa. This reaction is accelerated by
protein S.
Tissue factor pathway inhibitor is a protease inhibitor that regulates
the extrinsic pathway by inhibiting TF/FVIIa initiation of coagula-
tion.
1,2
FIG 1. Physiological downregulation of coagulation. (Color version of gure is available
online.)
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The Fibrinolytic System
Any thrombin that escapes the inhibitory effects of the natural antico-
agulants described above converts soluble brinogen to insoluble brin
and activates factor XIII that stabilizes brin clot (Fig 2).
The endogenous brinolytic system is then activated to clear brin to
maintain patency of circulation. Plasmin is the major protease enzyme
that is activated to digest brin-to-brin degradation products. Physio-
logical regulation of brinolysis occurs primarily via plasminogen acti-
vator inhibitors and antiplasmin that inhibits plasmin.
1,2
REFERENCES
1. Hoffbrand AV, Pettit JE. Essential Hematology. 3rd edn. Oxford, UK: Blackwell
Scientic Publications, 1993.
2. Goodnight SH Jr, Hathaway WE. Disorders of Hemostasis and Thrombosis, A
Clinical Guide. 2nd edn. New York, NY: McGraw-Hill, 2001.
FIG 2. The brinolytic system. (Color version of gure is available online.)
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