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In a healthy person, a homeostatic balance exists between procoagulant (clotting) forces and anticoagulant and fibrinolytic forces (see 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 vein 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, stroke).
Etiology
Genetic defects that increase the propensity for venous thromboembolism include the factor V Leiden mutation, which causes resistance to activated protein C (APC); the prothrombin 20210 gene mutation; and a deficiency of protein C, protein S, protein Z, or antithrombin.
Acquired defects that predispose to venous and arterial thrombosis include heparin -induced thrombocytopenia/thrombosis, the presence of antiphospholipid antibodies, and (possibly) hyperhomocysteinemia as a result of folate, vitamin B12, or vitamin B6 deficiency.
Other disorders and environmental factors can increase the risk of thrombosis, especially if present in conjunction with one of the genetic abnormalities mentioned above.
Stasis associated with surgery or orthopedic or paralytic immobilization; heart failure; pregnancy; and obesity increase the risk of venous thrombosis. Tissue injury from trauma or surgery exposes tissue factor to blood and increases the risk of venous thrombosis.
Neoplastic cells, particularly from promyelocytic leukemia and tumors involving the lung, breast, prostate, and GI tract, predispose to venous thrombosis. They may activate coagulation by secreting a factor X–activating protease, by expressing tissue factor on exposed membrane surfaces, or both.
Sepsis and other severe infections associated with increased tissue factor exposure on monocytes and macrophages can increase the risk of venous thrombosis.
Oral contraceptives that contain estrogen increase the risk of arterial and venous thromboembolism; however, the risk with modern low-dose regimens is low. Patients who develop venous thromboembolism while taking these drugs often have a coexisting predisposing genetic abnormality.
Atherosclerosis predisposes to arterial thrombi, especially at sites of preexisting stenosis. Atherosclerotic plaques rupture and expose the contents of tissue factor–rich plaques to blood, which initiates local platelet adhesion/aggregation, coagulation factor activation, and thrombosis.
Diagnosis
and Treatment
Diagnosis and treatment of thrombi are summarized elsewhere in The Manual specific to their location. Predisposing factors should always be considered. In some cases, the condition is clinically obvious (eg, recent surgery or trauma, prolonged immobilization, malignancy, generalized atherosclerosis). If no predisposing factor is readily apparent, further evaluation should be conducted in patients with a family history of venous thrombosis, more than one episode of venous thrombosis, MI or ischemic stroke before age 50, or unusual sites of venous thrombosis (eg, cavernous sinus, mesenteric veins). As many as half of all patients with spontaneous DVT have a genetic predisposition.
Testing for predisposing congenital factors includes functional measurements of the 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.
Factor
V Resistance to Activated Protein C
APC 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. Its prevalence as a single gene defect in European populations is 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
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 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 coagulation assays (extent of prolongation of normal plasma PTT, using normal plasma depleted of protein C, as a result of the addition of patient plasma containing snake venom). 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 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. The complex inactivates factor Xa. The consequence of protein Z deficiency in the pathophysiology of thrombosis and fetal loss is unresolved.
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 gene results in increased plasma prothrombin levels and increases the risk of venous thromboembolism.
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 proteins (eg, β
2-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 those with the autoantibody. 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. 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 November 2005
Content last modified November 2005
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