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
- Virchow's triad: The cause of thrombosis is multifactorial which causes an imbalance in endogenous anticoagulation and hemostasis through a complex pathophysiologic mechanism. Rudolf Virchow proposed Virchow's triad in 1856 and described the three common factors which predisposes to thrombosis as follows:
- Damage to the endothelial lining of the vessel wall: It can be caused by different factors which include direct disruption of the vessel via catheter placement, trauma, or surgery.
- Hypercoagulable state: It 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.
- Arterial or venous blood stasis: This third aspect could be due to immobility, pregnancy, or impaired blood flow resulting from previous thrombosis such as residual blood clot, remodeling or fibrosis of blood vessels, or atherosclerosis. Long trips with limited mobility in cases where concurrent additional risk factors are present can be considered as a relative risk factor for thrombosis.
- Hypercoagulable states: 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, thereby explaining the inter-individual differences observed in patients with inherited mutations.
- Inherited forms can be identified in up to 30% of patients with venous thromboembolism and are mainly attributable to factor V Leiden and prothrombin G2021A mutation. These two thrombophilias implicate a weak thrombotic risk. However, 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 are far more common and influence the coagulation cascade by multitude of factors including 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).
- Malignancy (occult or diagnosed) can predispose to hypercoagulability as tumor cells can express a variety of procoagulant proteins including increased expression tissue factor. Some solid tumors such as pancreatic cancer are known to significantly increase the risk of thrombosis.
- Typically, venous thrombosis is initiated by endothelial damage, while arterial thrombosis starts with atherosclerosis, and acquired hypercoagulable states leading to both venous and arterial thrombus include acquired antiphospholipid syndrome (APS) and heparin-induced thrombocytopenia & thrombosis (HITT).
- Venous thromboembolism (VTE): An anatomy of the deep veins of the extremities and the pulmonary system should be considered such as the deep veins of the lower extremity include the femoral, iliac, and popliteal veins; and the upper extremity veins include the subclavian, axillary, brachial veins. Other thrombosis sites include superior vena cava thrombosis, jugular vein thrombosis, cerebral venous sinus thrombosis, cavernous sinus thrombosis, and retinal vein occlusion. Thrombosis of superficial veins is possible with provoking factors such as intravenous catheterization or localized cellulitis; however, the 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. An increased incidence of obesity, hypertension, diabetes, and hypercholesterolemia all can contribute to the risk of an arterial thrombosis. Other risk factors include underlying connective tissue or rheumatologic conditions such as SLE, vasculitis; HITT, antiphospholipid syndrome, myeloproliferative disorders, and PNH.
Table 1: System wise causative factors of thrombophilia