Thrombophilia causes
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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
Thrombophilia may be caused by either acquired, inherited, or, more commonly, a combination of both conditions.
Causes
- Hypercoagulability disorders are either acquired or inherited. However, actual thrombosis occurs due to the interplay of both genetic and environmental factors and follows the multiple hit hypothesis, thus explaining the inter-individual differences observed in patients with inherited mutations. Genetic factors can now be identified in up to 30% of patients with VTE and are mainly attributable to factor V Leiden and prothrombin G2021A mutation. These two thrombophilias implicate a weak thrombotic risk. Other inherited thrombophilias are rare such as antithrombin III, protein C and protein S deficiency (around 1% in the general population) but pose a higher risk for thrombosis. Acquired factors also influence the coagulation cascade and include surgery, pregnancy, hormonal replacement therapy, contraception, malignancy, inflammation, infection, and heparin-induced thrombocytopenia.
- The cause of thrombosis is multifactorial. As noted, thrombosis occurs when there is an imbalance in endogenous anticoagulation and hemostasis through a complex pathophysiologic mechanism. Historically, three common factors predispose to thrombosis: 1) damage to the endothelial lining of the vessel wall; 2) a hypercoagulable state, and 3) arterial or venous blood stasis. These three factors are known by the eponym "Virchow's triad." Rudolf Virchow proposed Virchow's triad in 1856, and he described how the presence of these three factors increases thrombosis. Endothelial wall damage is caused by different factors, which can include direct disruption of the vessel via catheter placement, trauma, or surgery. Hypercoagulability is a general hematologic concept that merely means an increased risk of thrombosis (i.e., thrombogenic) via enhanced levels of prothrombotic components in the bloodstream. This hypercoagulability is due to a variety of alterations in the coagulation and hemostatic system, which can result from inflammatory factors, variations in the viscosity of blood and blood components, increased cytokines, and prothrombotic proteins in circulation, or deficiencies of natural or endogenous anticoagulant factors.
- Hypercoagulable states can be acquired or inherited. Inherited forms are rare, but include examples such as antithrombin III deficiency, protein C and S deficiencies, factor V Leiden (activated protein C resistance), or prothrombin gene mutations (among many others). Acquired hypercoagulability is far more common and can result from medications (e.g., oral contraceptives, estrogen or other hormonal replacement), recent inflammatory conditions such as pregnancy, surgery, trauma, or infection, and chronic inflammatory conditions (e.g., morbid obesity, rheumatologic disease, ulcerative colitis, heavy smoking). Two specific types of acquired hypercoagulable states that can lead to both venous and arterial thrombus include the acquired antiphospholipid syndrome and heparin-induced thrombocytopenia & thrombosis (HITT);. However, beyond the scope of this review, clinicians must be aware of these conditions as potential contributors to acute thrombosis. Malignancy (occult or diagnosed) is also a well-known risk factor for hypercoagulability, as tumor cells can express a variety of procoagulant proteins, including increased expression tissue factor. Some malignancies, especially solid tumors, are known to significantly increase the risk of thrombosis (e.g., pancreatic cancer). The third aspect of Virchow's triad includes arterial or venous stasis of the blood, which could be due to immobility, pregnancy, or impaired blood flow resulting from previous thrombosis (e.g., residual blood clot, remodeling or fibrosis of blood vessels, or atherosclerosis). Long trips with limited mobility can also become a relative risk factor for thrombosis, especially if concurrent additional risk factors are present (as above).
- Typically, venous thrombosis is initiated by endothelial damage, while arterial thrombosis starts with atherosclerosis.
- Venous thromboembolism: When considering venous thromboembolism (VTE), an appreciation of the anatomy of the deep veins of the extremities and the pulmonary system is helpful. For example, the deep veins of the lower extremity include the femoral, iliac, and popliteal veins. Thrombosis can also occur in the veins of the upper extremity like in the subclavian, axillary, brachial veins. Other thrombosis sites include superior vena cava thrombosis, jugular vein thrombosis, cerebral venous sinus thrombosis, cavernous sinus thrombosis, retinal vein occlusion. The latter sites are less common, and with the identification of an isolated thrombus in one of these sites, one must consider the potential for other explanatory diagnoses or predisposing conditions (e.g., Budd-Chiari syndrome with hepatic thrombus or cirrhosis and associated splenic vein thrombus). Many myeloproliferative disorders or clonal disorders with acquired bone marrow failure have correlations with rare sites of venous or arterial thrombosis (e.g., paroxysmal nocturnal hemoglobinuria (PNH) may have cerebral venous or abdominal thrombosis as presenting feature). Thrombosis of superficial veins is also possible, especially with provoking factors such as intravenous catheterization or localized cellulitis; treatment of superficial vein thrombosis does not typically require any anticoagulation.
- Arterial thrombosis: It can present as an acute stroke, myocardial infarction, or acute on the chronic peripheral arterial disease. Other less common sites can include renal arteries, mesenteric arteries, and retinal arteries. In addition to acute management (not reviewed here), secondary prevention focuses on reducing cardiovascular risk factors such as obesity, high cholesterol, diabetes, high blood pressure, and encouraging lifestyle modification such as smoking cessation. The increased incidence of obesity, hypertension, and hypercholesterolemia all contribute to the risk of acquiring an arterial thrombosis. Other risk factors include underlying connective tissue or rheumatologic conditions (e.g., SLE, vasculitis), as well as the aforementioned rare HITT, antiphospholipid syndrome, myeloproliferative disorders, and PNH (all of these can predispose to both venous and arterial thrombosis).
Table 1: System wise causative factors of thrombophilia