Stevens SM, Woller SC, Bauer KA, et al. Guidance for the evaluation and treatment of hereditary and acquired thrombophilia. J Thromb Thrombolysis. 2016 Jan;41(1):154-64. doi: 10.1007/s11239-015-1316-1. PMID: 26780744; PMCID: PMC4715840.
Definition, Etiology, PathogenesisTop
Thrombophilia is a genetic or acquired tendency to the development of venous (VTE) or arterial thromboembolism.
1) Inherited thrombophilia: Factor V Leiden (majority of cases of resistance to activated protein C), the G20210A variant of the prothrombin gene, protein C deficiency (reduced concentration or activity), protein S deficiency (reduced concentration or activity), antithrombin (AT) deficiency (reduced concentration or activity), and a large number of rare abnormalities of various procoagulant (eg, dysfibrinogenemia) and anticoagulant proteins (eg, plasminogen deficiency). The most prevalent of thrombophilia—factor V Leiden—variably increases the risk of VTE and occurs in 5% of the European population, 20% of unselected patients with VTE, and 40% of patients with recurrent VTE or a strong family history of VTE.
2) Acquired thrombophilia: Procoagulant states are associated with antiphospholipid syndrome; increased activity of factor VIII (>150%), factor IX, or factor XI; acquired plasminogen deficiency; cancer; trauma; pregnancy; paroxysmal nocturnal hemoglobinuria; heparin-induced thrombocytopenia; JAK2 617VF mutation; immobilization; and a wide variety of other states.
In a third of cases, a thromboembolic event in a patient with thrombophilia develops in the presence of a concomitant acquired risk factor (see Deep Vein Thrombosis; eg, trauma, immobilization, pregnancy, oral contraceptive use, malignancy). Thrombophilia is usually associated with an increase in the production of thrombin or with its impaired inactivation.
Hereditary thrombophilia is associated with an increased risk of all forms of VTE, including cerebral sinus vein thrombosis, abdominal venous thrombosis (most frequently affecting the portal vein and hepatic veins), and upper extremity VTE. The risk of recurrent thrombosis varies with thrombophilias and is only slightly higher in patients heterozygous for factor V Leiden and the G20210A mutation than in the general population.
A rare complication of protein C or protein S deficiency is skin necrosis.
An increased risk of arterial thromboembolism, and particularly of ischemic stroke, is observed in patients with antiphospholipid syndrome and those with the JAK2 617VF mutation and associated thrombocytosis; a small increase in risk may also be attributable to other thrombophilias.
1. Indications for diagnostic workup of thrombophilia: There are few indications for routine thrombophilia screening. It might be considered in patients with a strong history of VTE in first-degree relatives, in patients with VTE in atypical locations (eg, abdominal veins), and in selected patients planning pregnancy or combined contraceptive use. Testing may be indicated in selected patients who are considering discontinuation of anticoagulation where the presence of the thrombophilia (particularly the lupus anticoagulant) may influence the discontinuation discussion. Experts also advise a focused workup in patients aged <50 years with arterial thrombosis despite no risk factors, such as young patients with myocardial infarction. Testing in these patients should include antiphospholipid antibody testing, homocysteine, and lipoprotein(a), as well as testing for more conventional risk factors for premature arterial thrombosis including lipids and a comprehensive assessment and treatment of other risk factors, such as diabetes and hypertension.
2. Investigations recommended in patients suspected of thrombophilia include resistance to activated protein C (mostly indicating the presence of factor V Leiden), the 20210A variant of the prothrombin gene, protein C activity, free protein S concentration, AT activity, the lupus anticoagulant, and IgG anticardiolipin antibodies. Additional testing might be considered, but only under the advice of a specialist in this area.
3. Investigations should be performed 3 to 6 months after a thromboembolic event, because it will both allow adequate counseling of patients, and because the thrombosis and its treatment may alter the results of functional assays. None of the functional assays should be performed in patients receiving any form of anticoagulation; if required, patients should temporarily interrupt anticoagulants to ensure they are tested after the anticoagulant effect has lapsed. In patients on warfarin, a switch to low-molecular-weight heparin is advised for 10 to 14 days; in patients on direct oral anticoagulants (DOACs), a delay of at least 24 hours since the last dose is recommended.
1. Treatment modalities and outcomes of acute VTE in patients with thrombophilia are the same as in patients with other forms of venous thrombosis. In patients with severe deficiency of natural anticoagulants, additional options (substitution) should be considered. The presence of a thrombophilia may influence the duration of treatment.
2. In patients with protein C or protein S deficiency avoid high loading doses of vitamin K antagonists (VKAs) and simultaneously administer heparin/low-molecular-weight heparin (LMWH) until the international normalized ratio (INR) has been in the range of 2 to 3 for 48 hours to reduce the risk of skin necrosis. DOACs may be preferred in such patients, as the agents do not reduce the levels of proteins C and S. In acute VTE associated with the use of VKAs in patients with protein C or S deficiency, vitamin K should be administered to increase anticoagulant levels and, in selected individuals, protein C concentrate may be considered.
3. In patients who would otherwise be discontinuing anticoagulants, lifelong secondary antithrombotic prevention with a VKA or DOAC could be considered after the first episode of VTE in patients with AT deficiency, homozygotes for factor V Leiden, or patients with the 20210A variant of the prothrombin gene, as well as patients with coexisting heterozygosity for these conditions, or in patients with antiphospholipid syndrome with an unprovoked VTE event. After the first episode of unprovoked thrombosis in patients with types of thrombophilia other than those mentioned above, anticoagulant treatment should be continued for ≥3 months. Consideration for extended-duration therapy in such patients (particularly men) is reasonable if the risk of bleeding is low to moderate.
Thrombophilia in a patient with no episodes of thrombosis requires no prophylactic treatment outside periods of a particularly high risk (eg, major surgery). It may be considered in patients—and particularly in pregnant women—with AT deficiency and a positive family history of thrombosis. All pregnant patients with the diagnosis of thrombophilia should be monitored for VTE on a regular basis; if there are additional thrombosis risk factors, preventative therapy may be administered (antithrombotic prevention in pregnant women with different types of thrombophilia: see Primary Prevention of Venous Thromboembolism). The highest risk of VTE is the 6 weeks after delivery; prophylaxis may be considered during this period even if it has not been used throughout pregnancy.