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Chapter 142 Venous Thromboembolism 2103

recumbency. Many clinical examples highlight the role of stasis in the coagulation, and vessel wall generation of prostacyclin and nitric
pathogenesis of VTE. For example, the prevalence of VTE at autopsy oxide and synthesis of plasminogen activators limit platelet aggrega-
is markedly increased in persons who were confined to bed for more tion and fibrin deposition.
than 1 week before death. Preoperative immobility is associated with Heparan sulfate, thrombomodulin, and EPCR present on the
a higher frequency of perioperative VTE, and postoperative immobil- luminal surface of endothelial cells are important modulators of
ity contributes to the high incidence of postoperative VTE in patients thrombin activity. Heparan sulfate, a glycosaminoglycan similar to
who have undergone hysterectomy, transabdominal prostatectomy, heparin, catalyzes the inhibition of thrombin and factor Xa by anti-
hip or knee arthroplasty, or surgery for fractures of the lower limb. thrombin. Thrombomodulin serves as a surface-bound receptor for
The effect of immobility on thrombus formation is well illustrated thrombin. Once bound to thrombomodulin, thrombin undergoes a
by comparing the location of thrombosis in patients with paraplegia change in substrate specificity that renders it incapable of activating
with that in patients who have had a stroke. Whereas thrombosis platelets, of converting fibrinogen to fibrin, or of activating factors
occurs with equal frequency in both legs in patients with paraplegia, V, VIII, and XIII. Instead, once bound to thrombomodulin, throm-
it occurs more frequently in the paralyzed limb in patients with a bin becomes a potent activator of protein C. Activated protein C,
stroke. together with protein S, its cofactor, downregulates coagulation by,
proteolytically inactivating factors Va and VIIIa. EPCR enhances
protein C activation by binding protein C and presenting it to the
Venous Obstruction and Increased Venous Pressure thrombin–thrombomodulin complex for activation.
Generation of plasminogen activators by vascular endothelium
Venous obstruction contributes to the risk of VTE in patients with limits fibrin deposition, and platelet aggregation is inhibited by the
pelvic tumors and to recurrent venous thrombosis in patients with release of prostacyclin (prostaglandin I 2) and endothelium-derived
persistent obstruction because of residual proximal vein thrombosis. nitric oxide. Plasminogen binds to the cell surface, where it can be
Raised central venous pressure produces venous stasis in the extremi- activated to plasmin by t-PA, thereby promoting local fibrinolytic
ties, which may explain the high prevalence of venous thrombosis in activity.
patients with congestive heart failure. A similar mechanism may
underlie the propensity for thrombosis in the left leg during preg-
nancy, presumably from obstruction of the left common iliac vein by Inhibitors of Blood Coagulation
the right common iliac artery, which is accentuated by the gravid
uterus. Activated coagulation factors are serine proteases and their activity is
modulated by several naturally occurring plasma inhibitors. The most
important inhibitors of the blood coagulation system are antithrom-
Increased Blood Viscosity and Venous Dilation bin, protein C, and protein S. Congenital deficiency in one of these
three proteins was found in 11% of patients enrolled in a prospective
Venous stasis can be caused by increased blood viscosity or venous study of 2132 consecutive patients presenting with VTE. Abnormali-
dilation. The blood viscosity can be increased by polycythemia, ties in the fibrinolytic system including congenital dysfibrinogenemias
hypergammaglobulinemia, dysproteinemias, or increased fibrinogen and deficiency of plasminogen can also predispose the affected person
levels. Stasis because of venous dilation may contribute to the to thromboembolism.
increased risk of thromboembolism in patients with varicose veins
and in elderly patients, particularly if they are bedridden. The capac-
ity of estrogens to cause venous dilation may contribute to the HYPERCOAGULABLE STATES
increased prevalence of thrombosis during pregnancy, in women
taking estrogen-containing oral contraceptive pills or estrogen In addition to deficiencies of antithrombin and proteins C and S,
replacement therapy. other hypercoagulable states associated with VTE include factor V
Leiden (activated protein C resistance) and prothrombin G20210A
mutations, hyperhomocysteinemia, antiphospholipid syndrome,
Vessel Wall Damage pregnancy, and malignancy. Hypercoagulable states are the subject of
Chapter 140.
Damage or injury to the vascular endothelium exposes tissue factor,
which triggers coagulation. Furthermore, the exposure of blood to
the subendothelium leads to platelet adhesion, activation, and NATURAL HISTORY OF VENOUS THROMBOEMBOLISM
aggregation.
The vascular endothelium can be damaged by direct trauma, or Most DVTs are asymptomatic and confined to the intramuscular
it can be perturbed by exposure to endotoxin, inflammatory cytokines veins of the calf. These distal thrombi often undergo spontaneous
such as interleukin-1 and tumor necrosis factor, thrombin, or low lysis and rarely produce long-term sequelae. In contrast, complete
oxygen tension. Perturbed endothelial cells synthesize tissue factor lysis of proximal vein thrombosis is uncommon even when antico-
and PAI-1 and internalize thrombomodulin, promoting thrombo- agulant treatment is given.
genesis. Furthermore, damaged endothelial cells may produce less The symptoms and signs of VTE are caused by obstruction to
t-PA, the principal activator of intravascular fibrinolysis. venous outflow, inflammation of the vessel wall or perivascular
Direct venous damage may lead to venous thrombosis in patients tissues, and embolization of thrombus into the pulmonary circula-
undergoing hip surgery, knee surgery, or varicose vein stripping, and tion. Asymptomatic PE is detected by perfusion lung scanning in
in patients with severe burns, lower limb trauma, or central venous approximately 50% of patients with documented proximal vein
catheters. thrombosis. Most clinically significant and fatal PEs arise from DVT
in the proximal veins of the legs. PE occurs less commonly and tends
to be less extensive in patients with calf DVT than in those with
PROTECTIVE MECHANISMS proximal DVT. Asymptomatic DVT is found in 70% of patients who
present with confirmed PE. The DVT in such patients tends to be
Endothelial Protective Mechanisms extensive and involves the proximal veins.
Extensive DVT can lead to venous valvular damage, which is a
Normal vascular endothelium is nonthrombogenic to flowing blood. hallmark of postthrombotic syndrome. Patients with a previous
Endothelial cell surface glycosaminoglycans, thrombomodulin, and history of DVT are at increased risk of recurrence, particularly when
endothelial protein C receptor (EPCR) are potent inhibitors of patients are exposed to high-risk situations.