Thrombophilia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2]

Overview

The pathogenesis of thrombophilia is multi-factorial. It is characterized by hypercoagulability, which by itself or in synergy with endothelial injury or stasis (Virchow's Triad) can predispose to clot formation. Multiple genetic mutations and predisposing conditions have been associated with the increased risk of thrombosis due to abnormalities in the coagulation cascade. The most common genes involved in the pathogenesis of acquired thrombophilias are Factor V Leiden and prothrombin gene mutations.

• Coagulation is an inherent property of the hematologic system and under healthy conditions, normal blood flow is maintained by the balance between the pro-coagulant and anti-thrombotic factors. A hypercoagulable state and subsequent thromboembolism is a result of overactivity of pro-coagulant factors or a deficiency in anti-coagulants. The interplay of factors is complicated - coagulation activators and inhibitors and their production and degradation (quantitative) and functional properties (qualitative) all influence thrombosis. The triad of hypercoagulability, vascular stasis and vascular trauma as described by Virchow in 1856 still holds and remains the harbinger of vascular thrombosis. Arterial thrombosis results from atherosclerotic plaque rupture around which a platelet-rich white thrombus forms. Stasis behind venous valves contributes to venous thrombosis and red thrombus. Mutations influence coagulation depending on whether they are present in heterozygous or homozygous genotype.

Pathophysiology

• The primary mechanism for thrombus formation in common inherited thrombophilic states involves thrombin dysregulation.
• Anticoagulants that regulate thrombin include antithrombin, protein C, and protein S.
• Mutations in antithrombin can lead to increased thrombus formation.
• Protein C and S are natural anticoagulants which inhbit thrombin formation. Dysregulation in activated protein C (APC) can occur as either defects in the protein C or S molecule (Protein C and S deficiency) or as resistance to APC activity. APC resistance occurs when APC fails to inactivate downstream coagulation factors, specifically Factor V and Factor VIII.
• The most common inherited thrombophilia is Factor V Leiden, which is a polymorphism of Factor V that is resistant to APC inactivation.
• The second most common inherited thrombophilia involves a gain of function mutation of the prothrombin gene (Prothrombin G20210A) resulting in increased protein activity and thrombus formation.
• Dysfibrinogenemia is a disorder of fibrinogen formation or activity resulting in predisposition for bleeding, thrombosis or both.

Thrombus formation in inherited thrombophilia. In thrombophilia, procoagulant and anticoagulant factors are dysregulated, leading to thrombus formation

Figure: Thrombus formation in inherited thrombophilias. Adapted from: N Engl J Med. 2001 Apr 19;344(16):1222-31.

• Antithrombin III (ATIII) deficiency: Antithrombin III binds to heparin on endothelial cells and forms a complex with thrombin (thrombin-antithrombin (TAT) complex) thus inhibiting coagulation. The prevalence may be 1 in 500 in the general population. Its deficiency may present as early age thrombosis (less than 50 years old) and carries the highest risk for thrombotic events among the inherited thrombophilias. Antithrombin is synthesized in the liver but is not vitamin K-dependent. ATIII deficiency can occur as a consequence of reduced synthesis (liver damage) or increased loss (nephrotic syndrome, enteropathy, DIC, sepsis, burn, trauma, microangiopathy, and cardiopulmonary bypass surgery). Qualitative defects of ATIII (type II deficiency) describe mutations which either affect the heparin-binding site (HBS), the reactive site (RS) or result in pleiotropic effects (PE). Homozygous ATIII deficiency is incompatible with life unless affecting the heparin-binding site. Usually these patients present with venous thrombosis and less likely with arterial thrombosis.

• Protein C deficiency: It present as thrombosis in teenagers. Protein C and S deficiency may be inherited but is also inducable by liver dysfunction, vitamin k antagonists, renal failure, DIC, and active thrombosis. Protein S enhances the effect of activated protein C. Protein S deficiency can be classified as type I (reduced quantity of protein S), type II (low APC activity), and type III (low free protein S due to increased binding to the complement factor C4b). The interaction of protein S with C4, which is an active phase reactant exemplifies the relation of coagulation, inflammation, and autoimmunity. The half-life of protein C is shorter than the half-life of other vitamin K-dependent coagulation factors, hence the risk of increased coagulation with the initiation of vitamin K antagonists and need for bridging with parenteral heparin (warfarin-induced skin necrosis).

• Factor V Leiden mutation: Protein C interacts with thrombomodulin to become activated protein C (APC). APC has anticoagulant, anti-inflammatory, and cytoprotective properties and has been proposed for the treatment of sepsis. The signal cascade leading to APC can become distorted through many acquired or inherited mechanisms leading to APC resistance. Activated protein C inactivates coagulation factors V and VIII. The factor V Leiden mutation is a common cause for APC resistance and the most frequent genetic thrombophilia. The FV Leiden mutation is also suspected of increasing the risk of arterial thrombosis. Other FV mutations include factor V Cambridge and factor V Hong Kong. The most common genetic risk factor for thrombophilia is Factor V Leiden mutation. It increases the risk of thrombosis by enhanced thrombin production.

• Prothrombin G20210A mutation:Prothrombin is the precursor of thrombin, which is factor II. The prothrombin G20210A mutation is the second most common inherited risk factor for thrombosis and leads to increased levels of prothrombin which demonstrates a higher risk for arterial and venous thrombotic events. It is due to a single point mutation. It is seen commonly in Caucasians.

• Hyperhomocysteinemia: It is associated with premature atherosclerosis and thrombosis and caused by defects of the methionine metabolic pathway. Deficiencies of cofactors of this pathway such as vitamin B6, B12, and folate or defects of enzymes such as cystathionine beta-synthase (CBS) or methylenetetrahydrofolate reductase (MTHFR) decrease the efficiency of homocysteine metabolism. Furthermore renal failure, hypothyroidism, and drugs such as methotrexate, phenytoin, and carbamazepine increase homocysteine levels. On the other hand, lowering homocysteine levels has not been shown to reduce thrombotic risk.

• Elevated factor VIII (FVIII): It increases the risk of thrombosis. African-Americans appear to have higher levels whereas individuals with blood group O tend to have lower levels of FVIII. High levels of this factor also correlate with acute phase reactions, estrogen usage, pregnancy, and after aerobic exercise. A high FVIII level may cause APC resistance not due to FV mutation. In contrast, low levels of FVIII correlate with bleeding in hemophilia A patients.

• Dysfibrinolysis: plasminogen deficiency, dysfibrinogenemia, tissue plasminogen activator (tPA) deficiency, plasminogen activator inhibitor (PAI) increase, and factor XII deficiency, which is involved in plasmin generation. Deficient plasminogen clinically appears similar to protein c deficiency with thrombosis during the teenage years. PAI increase and deficient tPA has an association with diabetes mellitus, inflammatory bowel syndrome and coronary atherosclerosis. In patients with structural or functional changes to fibrinogen (dysfibrinogenemia) thrombosis or bleeding can occur.

• Antiphospholipid syndrome (APS): The most common acquired thrombophilia is the antiphospholipid syndrome (APS) in which antibodies are directed against natural constituents of cell membranes, the phospholipids. These antiphospholipid antibodies (APLA) occur in 3 to 5% of the population and may cause arterial or venous thrombosis and fetal loss. APLAs being tested for include lupus anticoagulant, anticardiolipin, anti-beta-2-glycoprotein. Lupus anticoagulant leads to prolongation of coagulation (aPTT) in vitro but thrombosis in vivo. Antiphospholipid antibodies may also occur secondary to other diseases (collagen vascular disease or infections) or drugs (phenytoin and cocaine among others). The most common thrombotic event is deep vein thrombosis. Any patient with stroke and rheumatological disorder should be screened for antiphospholipid antibody syndrome.

• Malignancy:he second most common acquired hypercoagulability and leads to a prothrombotic state through the production of procoagulant factors (tissue factor and cancer procoagulant) and the interaction of tumor cells with blood and vascular endothelium. Stasis from tumor compression, paraproteinemia, and cytokine release pose an additional risk. In 85% of cancer patients, cancer procoagulant (CP) is elevated. This enzyme actives factor X thus causing hypercoagulability in cancer patients. Polycythemia vera poses a thrombotic risk in addition to hyperviscosity. Migratory thrombophlebitis as a consequence of visceral malignancy is known as Trousseau syndrome. The interaction of malignancy and coagulation is of interest as not only malignancy favors thrombosis but the hemostatic system influences angiogenesis which support tumor growth and spread. Targeting the hemostatic system might offer treatment options for anticancer therapy.

• Smoking: Arterial bypass grafts fail prematurely in smokers. Smoking tobacco contains various toxins. Nicotine results in endothelial cell damage. The release of tissue plasminogen activator (tPA) and tissue factor pathway inhibitor (TFPI) get reduced. Carbon monoxide increases the permeability of endothelium to lipids thus leading to atheroma formation.