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, functional protein C deficiency, functional protein S deficiency, functional antithrombin (AT) deficiency, and a large number of rare abnormalities. The most prevalent of thrombophilia in the Caucasian population—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 (HIT); thrombosis with thrombocytopenia syndrome (TTS) after adenoviral vector–based coronavirus disease 2019 (COVID-19) vaccines; JAK2 617VF mutation; immobilization; and a wide variety of other states.
In many 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).
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 severe protein C or protein S deficiency is vitamin K antagonist (VKA)–induced skin necrosis. An increased risk of arterial thromboembolism, and particularly of ischemic stroke, is observed in patients with TTS, 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.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of intervention). Quality of Evidence lowered due to imprecision and observational data. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. NICE guideline [NG158]. Published: 26 March 2020. www.nice.org.uk/guidance/ng158 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 recent COVID-19 adenoviral vector-based vaccination, diabetes, hypertension, and illicit drug use.
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 for "routine" thrombophilias 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. Selected thrombophilias, such as HIT, TTS, and paroxysmal nocturnal hemoglobinuria (PNH), must be tested for at the time they are suspected to allow for timely treatment.
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 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.
3. Patients with suspected TTS should have diagnostic testing performed before treatment with high-dose IV immunoglobulins and nonheparin anticoagulants is initiated, but likely without waiting for results.
Thrombophilia in a patient with no episodes of thrombosis requires no prophylactic treatment outside periods of a particularly high risk (eg, major surgery). All patients with a known thrombophilia who are in high-risk situations, including those with cancer and pregnant patients, should be regularly monitored for VTE; if there are additional thrombosis risk factors, preventative therapy may be administered (eg, antithrombotic prevention in patients with cancer or selected pregnant women: 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.