Thrombophilia

Thrombophilia


I’m Mya Mae Tho, registrar from the Department of Hematology, Singapore General Hospital. Thrombophilia is a hypercoagulable state, which may lead to pathogenic thromboembolism. It can be due to heredity or acquired conditions resulting in loss of balance between natural coagulants and anticoagulant proteins. Some of the thrombophilic conditions can lead to occurrence of recurrent and extensive venous thromboembolism or severe arterial events. The resulting morbidity and mortality can be high. These are the commonly listed inherited and acquired thrombophilic conditions. Factor V Leiden mutation, protein C and S deficiencies, antithrombin III deficiency and prothrombin gene mutation, are commonest inherited thrombophilic conditions. Acquired thrombophilia can be due to malignancy, surgery, trauma, pregnancy, drugs like oral contraceptive pills, antiphospholipid syndrome, and so on. Antithrombin III proteins C and S are major natural anticoagulants. Antithrombin III primarily inhibits thrombin and factor Xa. Complete deficiency is not compatible with life. Activated protein C in the presence of its cofactor protein S, inactivates active Factor V and VIII and controls the formation of thrombin. Therefore, antithrombin III, protein C, or S deficiency can enhance thrombin formation leading to hypercoagulability. Protein C and S deficiencies are more common in Asians compared to Caucasians. Factor V Leiden results from single-point mutation replacing arginine by glutamine at position 506. It renders Factor V and active Factor V to be partially resistant to inactivation by activated protein C. It is commonest thrombophilia in Caucasians and rare in Asians and Africans. Prothrombin gene mutation at base 20210 results in increased basal levels of functionally normal prothrombin providing greater availability of prothrombin for conversion to thrombin. It is found in 5% to 10% of patients presenting with venous thrombosis and about 15% of patients being investigated for thrombophilia. The condition is rare in patients of African or Asian descent. Antiphospholipid syndrome is an acquired prothrombotic condition, which is characterized by venous or arterial thrombosis, recurrent miscarriages, and other clinical features like livido reticularis, pulmonary hypertension, valvular heart disease, or neurological disorders. The diagnostic criteria includes the presence of clinical thrombosis associated with positive lupus anticoagulant, anticardiolipin antibodies, or anti-beta2-glycoprotein 1 antibody. The positive results must be persistent when tested 12 weeks apart. It can occur as primary antiphospholipid syndrome or can be associated with underlying autoimmune conditions. In general, hereditary thrombophilic conditions alone will not lead to thrombosis. Venous thrombosis can be viewed as a multigene disorder in which susceptible persons would have one or more genetic mutations, and clinical events occur when they are exposed to exogenous prothrombotic stimuli. So to do or not to do thrombophilia screening in a patient with VTE or in an asymptomatic relative of a patient with VTE is a much debated topic. Comprehensive thrombophilia testing is recommended if the results will have much influence on subsequent therapy. Identifying affected family members for prophylaxis may benefit young relatives as aggressive prophylactic measures can be taken timely, especially in the setting of strong or positive family history. Exclusion of malignancy and other medical disorders or screening for antiphospholipid syndrome should also be appropriately carried out in the correct setting. In patients with provoked VTEs, say secondary to immobilization or surgery, it is not advisable to screen for inherited prothrombotic conditions. As the incidence is usually low, there is no cost effectiveness and positivity will not have any impact on initiation and duration of treatment with anticoagulation. For the patients with a first unprovoked VTE, the main risk factor for recurring VTE is the previous VTE itself and not the presence or absence of inherited thromobophilia. It is not routinely recommend to do screening for thrombophilia unless there is clinical indication, such as justification of extended anticoagulation therapy or positive family history. However, since there is no safe long-term anticoagulation, it is not recommended for the individuals with inherited thrombophilic conditions to be placed on long-term anticoagulation without any other additional risk factors. There are some points to take note in carrying out screening for thrombophilic conditions. One should know that the current list of tests is not complete. Acquired risk factors are far more common and important than inheritable thrombophilia. Thromobophila testing does not affect initial duration of treatment nor predict occurrences. Cost effectiveness of patient care and reliability of the coagulation in the laboratory should also be taken into consideration. Thromobophila tests should be interpreted in the correct setting to avoid potential errors. For example, low protein C and S levels can be due to acute thrombosis itself or vitamin K antagonist therapy. These are the various tests for the workup of thrombophilia. Again, I would like to emphasize that it should be guided by the positive findings from history and physical examinations and done selectively to get the most relevant diagnosis. Anticoagulation therapy for symptomatic DVT should be based on the presence or absence of risk factors. The recommended duration for anticoagulation for provoked DVT is up to three months after the risk factor has been removed. As for the idiopathic first, deep vein thrombosis, extended anticoagulation therapy can be considered regardless of the status of the screening test for thrombophilia, especially in a high risk patient for recurrence and low risk for bleeding. Antiplatelet therapy should be considered for arterial events, especially in case of antiphospholipid syndrome. The underlying risk factors should be addressed as soon as possible as it is the only safe and effective way to prevent recurrent VTEs or clot extension. In case of failure to do so, anticoagulation should be continued as long as the risk factor is present.

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