Page 2360 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 142

VENOUS THROMBOEMBOLISM

Deborah Siegal and Wendy Lim

Venous thromboembolism (VTE), encompassing both deep venous intrinsic, extrinsic, and common pathways. Although these pathways
thrombosis (DVT) and pulmonary embolism (PE), remains a reflect the way coagulation is measured in the laboratory, they do not
common medical condition that is associated with significant mor- reflect how coagulation occurs in vivo. In vivo, coagulation is primar-
bidity and mortality. ily initiated via the tissue factor pathway. In this pathway, circulating
Although DVT can occur in any vein, it most commonly occurs activated factor VII (factor VIIa) binds to tissue factor at sites of
in the leg veins. Superficial venous thrombosis occurs most frequently vascular injury. The tissue factor–factor VIIa complex then activates
in varicosities and usually is self-limiting and benign. In contrast, factor IX and factor X. Levels of factor VIIa can be increased by factor
DVT is a more serious condition. Thrombi localized to the deep calf Xa; however, this reaction is rapidly downregulated by tissue factor
veins often are small and therefore less commonly associated with pathway inhibitor (TFPI). TFPI binds and inactivates factor Xa; the
clinically important PE or postthrombotic syndrome, but PE occurs TFPI–factor Xa complex then binds the factor VIIa–tissue factor
in about 60% of patients with proximal DVT involving the popliteal, complex and prevents further activation of factor X.
femoral, or iliac venous system. In the presence of calcium, factor Xa binds to factor Va on the
Increased clinical suspicion and availability of reliable, noninvasive surface of activated platelets to form the prothrombinase complex,
diagnostic tests have increased the frequency of diagnosis of acute which converts prothrombin to thrombin. Thrombin then converts
VTE. In hospitalized patients this condition is largely preventable fibrinogen to fibrin, and activates platelets and factor XIII. Factor
through the use of anticoagulant prophylaxis. In patients with estab- XIIIa, in the presence of calcium, cross-links fibrin, thereby stabiliz-
lished VTE advances in anticoagulant therapy have facilitated ing the clot. To ensure continuous generation of thrombin, thrombin
outpatient-based therapy. and, to a lesser extent, factor Xa activate factor VIII and factor V,
markedly accelerating the coagulation reactions involving these two
PATHOGENESIS OF VENOUS THROMBOEMBOLISM AND cofactors. Thrombin also activates factor XI, which in turn activates
additional factor IX, establishing a positive feedback loop.
CLINICAL RISK FACTORS Coagulation may be activated by contact of factor XII with col-
lagen on exposed subendothelium of damaged vessels, by contact
Venous thrombi are composed predominantly of fibrin and red cells, with prosthetic surfaces, by polyphosphates released from activated
and usually arise in the large venous sinuses in the calf, in valve cusp platelets, or by DNA or RNA released from damaged cells. There is
pockets in the deep veins of the calf, or at sites of vessel damage. mounting evidence that this pathway contributes to thrombosis.
Venous thrombosis occurs when activation of blood coagulation Thus mice deficient in factor XII or factor XI exhibit attenuated
exceeds the ability of the natural anticoagulant mechanisms and the thrombus formation at sites of injury and factor XI knockdown with
fibrinolytic system to prevent clot formation. The current under- an antisense oligonucleotide attenuated VTE after elective knee
standing of VTE pathogenesis was first described by Virchow more arthroplasty. Therefore the contact pathway appears to be important
than 150 years ago. He proposed that thrombotic disorders were for thrombus growth and stabilization.
associated with the triad of stasis, vascular injury, and hypercoagula- Under most situations coagulation is initiated by exposure of
bility. Stasis and vascular injury are the most frequent precipitants of blood to tissue factor made available locally as a result of vascular wall
VTE. In addition to activating coagulation, tissue damage and/or damage, by activation of endothelial cells, or by activated monocytes
vascular damage can also impair fibrinolysis by reducing synthesis of that migrate to areas of vascular injury. Factor X can be activated
tissue plasminogen activator (t-Pa) and by increasing endothelial cell directly by extracts of malignant cells that contain a cysteine protease,
production of plasminogen activator inhibitor type 1 (PAI-1), the which may be one of the mechanisms by which thrombosis is induced
major inhibitor of the fibrinolytic pathway. in patients with cancer. A factor elaborated by hypoxic endothelial
Under normal circumstances, activated coagulation factors are cells also can directly activate factor X, potentially leading to throm-
diluted in the flowing blood and are neutralized by inhibitors on the bosis in patients with severe venous stasis where hypoxia occurs in
surface of endothelial cells or by circulating proteinase inhibitors. the valve cusps.
Activated coagulation factors that escape regulation because of
reduced levels of inhibitors or because they are generated in over-
whelming amounts trigger the coagulation system and fibrin forma- Venous Stasis
tion. Homeostatic mechanisms, including activation of the fibrinolytic
system with release of t-PA and urokinase, are immediately invoked Venous stasis is produced by immobility, venous obstruction,
to reduce the likelihood of pathologic thrombus formation. increased venous pressure, venous dilation, and increased blood vis-
cosity. Venous return from the lower extremities is enhanced by
venous valves, which prevent blood from pooling in the lower legs,
THROMBOGENIC FACTORS and by contraction of the calf muscles, which propels blood upward
from the extremities. Venous stasis may contribute to thrombogenesis
Activation of Blood Coagulation by allowing stagnation of the blood with associated local hypoxia.

With the exception of small amounts of active factor VII, the coagula-
tion factors circulate as inactive protein precursors, or zymogens. Immobility
Each zymogen is converted into an active enzyme that then activates
the next zymogen in the coagulation pathway (see Chapter 122). Venous thrombosis can occur in immobilized persons because blood
Traditionally the coagulation system has been divided into the pools in the intramuscular sinuses of the calf, which are dilated during

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