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In healthy people, homeostatic balance exists between procoagulant (clotting) forces and anticoagulant and fibrinolytic forces (see Hemostasis: Overview of Hemostasis). Numerous genetic, acquired, and environmental factors can tip the balance in favor of coagulation, leading to the pathologic formation of thrombi in veins (eg, deep venous thrombosis [DVT]), arteries (eg, MI, ischemic stroke), or cardiac chambers. Thrombi can obstruct blood flow at the site of formation or detach and embolize to block a distant blood vessel (eg, pulmonary embolism, embolic stroke).
Etiology
Genetic defects that increase the propensity for venous thromboembolism include
Acquired defects also predispose to venous and arterial thrombosis (see Table 1: Thrombotic Disorders: Acquired Causes of Thromboembolism ).
Other disorders and environmental factors can increase the risk of thrombosis, especially if a genetic abnormality is also present.
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Table 1
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| Acquired Causes of Thromboembolism |
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Condition
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Comments
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Antiphospholipid antibodies
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—
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Atherosclerosis
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Increases risk of arterial thrombi
Higher risk in patients with preexisting stenosis
When atherosclerotic plaques rupture, they release of tissue factor into the blood, activate coagulation, initiate local platelet adhesion and aggregation, and cause thrombosis
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Cancer (promyelocytic leukemia; lung, breast, prostate, pancreas, stomach, and colon tumors)
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May activate coagulation by secreting a factor X–activating protease, by expressing tissue factor on exposed membrane surfaces, or both
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Heparin-induced thrombocytopenia
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Associated with platelet aggregation and increased risk of thrombosis
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Hyperhomocysteinemia
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Possible cause
Due to folate, vitamin B12, or vitamin B6 deficiency
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Infection if severe (eg, sepsis)
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Increases risk of venous thrombosis
Increases expression of tissue factor by monocytes and macrophages
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Oral contraceptives that contain estrogen
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Low risk with low-dose regimens
More frequent in patients who have a predisposing genetic abnormality for venous thromboembolism
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Stasis
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Due to surgery, orthopedic or paralytic immobilization, heart failure, pregnancy, or obesity
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Tissue injury
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Due to trauma or surgery
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Diagnosis
Diagnoses are summarized elsewhere in The Manual specific to the location of the thrombus.
Predisposing factors:
Predisposing factors should always be considered. In some cases, the condition is clinically obvious (eg, recent surgery or trauma, prolonged immobilization, cancer, generalized atherosclerosis). If no predisposing factor is readily apparent, further evaluation should be conducted in patients with
As many as half of all patients with spontaneous DVT have a genetic predisposition.
Testing for predisposing congenital factors includes measurements of the quantity of activity of natural anticoagulant molecules in plasma and tests for specific gene defects. Testing begins with a group of screening tests, followed (if necessary) by specific assays.
Treatment
Treatment is summarized elsewhere in The Manual specific to the location of the thrombus.
Factor V Resistance to Activated Protein C (APC)
APC (in complex with protein S) degrades factors Va and VIIIa, thus inhibiting coagulation. Any of several mutations to factor V make it resistant to inactivation by APC, increasing the tendency for thrombosis. Factor V Leiden is the most common of these mutations. Homozygous mutations increase the risk of thrombosis more than do heterozygous mutations.
Factor V Leiden as a single gene defect in European populations is present in about 5%, but it rarely occurs in native Asian or African populations. It is present in 20 to 60% of patients with spontaneous venous thrombosis.
Diagnosis is based on a functional plasma coagulation assay (the failure of patient plasma PTT to become prolonged in the presence of snake venom–activated patient protein C) and on molecular analysis of the factor V gene.
Treatment, if necessary, involves anticoagulation with heparin followed by warfarin.
Protein C Deficiency
Protein C is a vitamin K–dependent protein, as are coagulation factors VII, IX, and X, prothrombin, and proteins S and Z. Because APC degrades factors Va and VIIIa, APC is a natural plasma anticoagulant. Decreased protein C from genetic or acquired causes promotes venous thrombosis. Heterozygous deficiency of plasma protein C has a prevalence of 0.2 to 0.5%; about 75% of people with this defect experience a venous thromboembolism (50% by age 50). Homozygous or doubly heterozygous deficiency causes neonatal purpura fulminans, ie, severe neonatal disseminated intravascular coagulation (DIC). Acquired decreases occur in patients with liver disease or DIC, during cancer chemotherapy (including l-asparaginase administration), and during warfarin therapy.
Diagnosis is based on antigenic and functional plasma assays.
Patients with symptomatic thrombosis require anticoagulation with heparin or low mol wt heparin, followed by warfarin; use of the vitamin K antagonist, warfarin, as initial therapy occasionally causes thrombotic skin infarction by lowering vitamin K–dependent protein C levels before a therapeutic decrease has occurred in most vitamin K–dependent clotting factors. Neonatal purpura fulminans is fatal without replacement of protein C (using normal plasma or purified concentrate) and anticoagulation with heparin.
Protein S Deficiency
Protein S, a vitamin K–dependent protein, is a cofactor for APC-mediated cleavage of factors Va and VIIIa. Heterozygous deficiency of plasma protein S predisposes to venous thrombosis and is similar to protein C deficiency in genetic transmission, prevalence, laboratory testing, treatment, and precautions. Homozygous deficiency of protein S can cause neonatal purpura fulminans that is clinically indistinguishable from that caused by homozygous deficiency of protein C. Acquired deficiencies of protein S (and protein C) occur during DIC and warfarin therapy and after l-asparaginase administration.
Diagnosis is based on antigenic assays of total or free plasma protein S. (Free protein S is the form unbound to C4 binding protein.)
Protein Z Deficiency
Protein Z, another vitamin K–dependent protein, functions as a cofactor to down-regulate coagulation by forming a complex with the plasma protein, Z-dependent protease inhibitor (ZPI). The complex inactivates factors Xa, XI, and IX on phospholipids surfaces. The consequence of either protein Z or ZPI deficiency in the pathophysiology of thrombosis and fetal loss is unresolved; however, either defect may make thrombosis more likely if an affected patient also has another congenital coagulation abnormality (eg, factor V Leiden). Quantification of protein Z and ZPI is done in research laboratories by plasma electrophoresis and immunoblotting. It is not yet known whether anticoagulant therapy or prophylaxis is indicated in protein Z or ZPI deficiency.
Antithrombin Deficiency
Antithrombin is a protein that inhibits thrombin and factors Xa, IXa, and XIa. Heterozygous deficiency of plasma antithrombin has a prevalence of about 0.2 to 0.4%; about half of those affected develop venous thromboses. Homozygous deficiencies are probably lethal to the fetus in utero. Acquired deficiencies occur in patients with DIC, liver disease, or nephrotic syndrome and during heparin or l-asparaginase therapy.
Laboratory testing involves quantification of plasma inhibition of thrombin in the presence of heparin.
Oral warfarin is used for prophylaxis against venous thromboembolism.
Prothrombin 20210 Gene Mutation
A mutation of the prothrombin 20210 gene results in increased plasma prothrombin levels and increases the risk of venous thromboembolism. Treatment, if necessary, involves anticoagulation with heparin followed by warfarin.
Antiphospholipid Antibody Syndrome
(Anti-Cardiolipin Antibodies; Lupus Anticoagulant)
The antiphospholipid antibody syndrome consists of thrombosis and (in pregnancy) fetal demise associated with various autoimmune antibodies directed against one or more phospholipid-binding proteins (eg, β2-glycoprotein I, prothrombin, annexin). These proteins normally bind to phospholipid membrane constituents and protect them from excessive coagulation activation. The autoantibodies displace the protective proteins and, thus, produce procoagulant endothelial cell surfaces and cause arterial or venous thromboses. In vitro clotting tests may paradoxically be prolonged because the antiprotein/phospholipid antibodies interfere with coagulation factor assembly and activation on the phospholipid components added to plasma to initiate the tests. The lupus anticoagulant is an antiphospholipid autoantibody that binds to protein-phospholipid complexes. It was initially recognized in patients with SLE, but these patients now account for a minority of patients with the autoantibody.
The lupus anticoagulant is suspected if the PTT is prolonged and does not correct immediately upon 1:1 mixing with normal plasma but does return to normal upon the addition of an excessive quantity of phospholipids (done by the hematology laboratory). Antiphospholipid antibodies in patient plasma are measured by immunoassays of IgG and IgM antibodies that bind to phospholipid-β2-glycoprotein I complexes on microtiter plates.
Heparin, warfarin, and aspirin have been used for prophylaxis and treatment.
Hyperhomocysteinemia
Hyperhomocysteinemia may predispose to arterial thrombosis and venous thromboembolism, possibly because of injury to vascular endothelial cells. Plasma homocysteine levels are elevated ≥ 10-fold in homozygous cystathionine β-synthase deficiency. Milder elevations occur in heterozygous deficiency and in other abnormalities of folate metabolism, including methyltetrahydrofolate dehydrogenase deficiency. However, by far the most common causes of hyperhomocysteinemia are acquired deficiencies of folate, vitamin B12, or vitamin B6.
The diagnosis is established by measuring plasma homocysteine levels.
Plasma homocysteine levels may be normalized by dietary supplementation with folic acid, vitamin B12, or vitamin B6 (pyridoxine) alone or in combination; however, it is not clear that this therapy reduces the risk of arterial or venous thrombosis.
Last full review/revision June 2009 by Joel L. Moake, MD
Content last modified February 2012
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