Understanding of the pathophysiology of thrombosis, both venous
and arterial, has increased dramatically over the past 50 years.
A rapidly increasing number of inherited and acquired conditions
predisposing patients to venous thromboembolism and/or
arterial thrombosis or embolus are being discovered. Virchow’s
triad of hypercoagulability, venous stasis, and endothelial injury
continues to be a useful model for the interplay of genetic factors
and environmental triggers leading to inappropriate thrombosis.
Most patients develop venous thromboembolism after some inciting
event, such as trauma, surgery, or prolonged immobilization. However,
a patient with a disorder causing hypercoagulability can develop
a serious thrombotic event with little or no inciting factor. This
has led some researchers to postulate that risk from various factors
is additive; and when a patient’s risk reaches a “thrombosis threshold,” inappropriate
thrombus develops. In fact, some researchers believe that all patients
with thrombosis have a hypercoagulable tendency that is yet to be discovered. The initial
ED approach is similar for most common inherited and acquired conditions causing
hypercoagulable states (Table 229-1).
Table 229-1 Hypercoagulable
| Save Table
Table 229-1 Hypercoagulable
|Activated protein C resistance due to Factor
V Leiden mutation||Antiphospholipid syndrome|
|Prothrombin gene mutation 20210A||Oral contraceptives/hormone replacement
|Protein C deficiency|
|Protein S deficiency||Malignancy|
|Antithrombin deficiency||Heparin-induced thrombocytopenia|
|Hyperhomocysteinemia||Warfarin-induced skin necrosis|
Several physiologic systems are in place to ensure that blood
clots do not extend beyond the area in which they are needed. The
two most clinically important pathways involve protein C and antithrombin
(Figure 229-1 and Table
229-2). Antithrombin (previously known as antithrombin
III) is a plasma-based protein that inhibits the function
of several activated coagulation factors, primarily thrombin, Factor
Xa, and Factor IXa. Both unfractionated heparin and low-molecular-weight
heparin possess anticoagulant activity by increasing the rate by
which antithrombin inhibits these factors; approximately 2000- to
4000-fold for thrombin, about 500- to 1000-fold for Factor Xa, and
about a million-fold for Factor IXa. Protein C is a vitamin K–dependent
plasma protein that binds to the endothelial cell surface and is
activated by thrombin. Activated protein C cleaves both Factor Va
and Factor VIIIa, inhibiting both the common pathway and the intrinsic
pathway. Protein S, another vitamin K–dependent plasma
protein, is a cofactor that increases the inhibitory action of activated
protein C by about 20-fold.
Simplified depiction of the common pathway of coagulation
and the actions of antithrombin and activated protein C. Coagulation
is triggered by either the intrinsic and extrinsic pathways that
meet at the common pathway to activate Factor X. Factor Xa complexes
with Factor Va, phospholipid (PL) and calcium ion [Ca++] to
convert prothrombin (Factor II) to thrombin. One of thrombin’s
many actions is to convert fibrinogen into fibrin, which is a major
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