Decision Making in Venous Thromboembolism

Hypercoagulable States In Specific Populations

Inherited Thrombophilias

Patients with a hereditary thrombophilia are at increased risk for incident VTE [99].These inherited mutations result in either a loss of normal anticoagulant function or gain of a prothrombotic state. Hereditary disorders associated with VTE include deficiency of antithrombin, protein C, or protein S, or the presence of factor V Leiden and/or prothrombin G20210A mutations. Although deficiency of protein C, protein S, or antithrombin is uncommon and affects only 0.5% of the population, these states have been associated with a 10-fold increased risk of thrombosis in comparison to the general population. Factor V Leiden and prothrombin gene mutation are less likely to be associated with incident thrombosis (2 to 5-fold increased risk of VTE) and are more prevalent in the Caucasian population [100].Though these hereditary thrombophilias increase risk of VTE, prophylactic anti-coagulation prior to a first VTE is not generally indicated.

Data regarding the impact of the inherited thrombophilias on risk of recurrent VTE is less well defined. While some data suggest that inherited thrombophilias are associated with increased risk of recurrent VTE, the degree of impact may be clinically modest especially in those with heterozygous factor V Leiden or prothrombin gene mutations [101].Ideally, a clinical trial would be designed to assess whether hereditary thrombophilia testing is beneficial for patients with VTE in decision-making regarding length of anticoagulation, type of anticoagulation, and risk of recurrence. If a patient with a low-risk inherited thrombophilia has a DVT in the setting of an additional provoking risk factor (surgery, pregnancy, etc), a 3-month course of anticoagulation followed by D-dimer assessment as above is reasonable. If a patient with an inherited thrombophilia experiences an idiopathic VTE, or if a patient with a “high-risk” thrombophilia as described above experiences any type of VTE, we generally recommend indefinite anticoagulation in the absence of high bleeding risk, though again this is a very patient-dependent choice.

Acquired Thrombophilias

Antiphospholipid Syndrome

Antibodies directed against proteins that bind phospho-lipids are associated with an acquired hypercoagulable state. The autoantibodies are categorized as antiphospho-lipid antibodies (APLAs), which include anticardiolipin antibodies (IgG and IgM), beta-2 glycoprotein 1 antibodies (anti-B2 GP), and lupus anticoagulant. These antibodies can form autonomously, as seen in primary disorders, or in association with autoimmune disease as a secondary disorder.

Criteria have been developed to distinguish antiphospholipid-associated clotting disorders from other forms of thrombophilia. The updated Sapporo criteria depend on both laboratory and clinical diagnostic criteria [102].The laboratory diagnosis of APLAs requires the presence of lupus anticoagulants, anticardiolipin antibodies, or anti-B2 GP on at least 2 assays at least 12 weeks apart with elevation above the 99th percentile of the testing laboratory’s normal distribution [103].Testing for lupus anticoagulant is based on 3 stages, the first of which is inhibition of phospholipid-dependent coagulation tests with prolonged clotting time (eg, aPTT or dilute Russell’s viper venom time). The diagnosis is confirmed by a secondary test in which excess hexagonal phase phospholipids are added to incubate with the patient’s plasma to absorb the APLA [104].The presence of anticardiolipin antibodies and anti beta-2 GP antibodies is determined using ELISA based immunoassays. Unlike most other thrombophilias, antiphospholipid syndrome is associated with both arterial and venous thromboembolic events and may be an indication for lifelong anticoagulation after a first thrombotic event. We generally recommend indefinite anticoagulation in the absence of significant bleeding risk.