Kevin O’Connor, MD

Salehi Omran S, Hartman A, Zakai NA, Navi BB. Thrombophilia Testing After Ischemic Stroke: Why, When, and What? Stroke. 2021;52:1874-1884.

What are the indications for a thrombophilia evaluation in a patient who had an ischemic stroke? Salehi Omran et al. explore this in their topical review. They suggest that rather than obtaining thrombophilia studies in unselected patients who had an otherwise cryptogenic ischemic stroke, factors such as patient age, race, sex (i.e., pregnancy, estrogen-containing medication), presence of a patent foramen ovale (PFO), and personal or family history of thrombosis should guide testing. For example, younger patients may benefit from testing more than older patients. It is important to consider concomitant anticoagulant use, as well as the acuteness of the stroke when testing for thrombophilia. Repeat testing after 12 weeks validates positive results found in the acute setting and reduces the likelihood of false positives. Additionally, reference ranges derived from White European populations are important to consider when evaluating results from patients of different racial backgrounds.

Available studies find no association between ischemic stroke and inherited thrombophilias such as factor V Leiden (FVL) and prothrombin gene mutation (G20210A) in older adults. Fewer studies on protein C, protein S, and antithrombin deficiency in patients with ischemic stroke are available, but do not show associations between the respective deficiencies and stroke in older adults. Antiphospholipid syndrome (APLS; an acquired thrombophilia) is a risk factor for ischemic stroke, but the association is stronger in younger adults. Although studies show an association between ischemic stroke and FVL in younger adults, the association between ischemic stroke and prothrombin mutation is less evident. Studies in children who had a stroke find an association with inherited (except protein S and antithrombin deficiency) and acquired thrombophilias.

The relationship between PFO, thrombophilia, and stroke risk is unclear. Among patients with a PFO, some studies have shown associations between stroke and FVL and prothrombin mutations with other studies showing no association with deficiencies in protein C, protein S, or antithrombin. Similarly, the risk of recurrent stroke in patients with a PFO and thrombophilia is unclear. There are associations between thrombophilias and stroke in the setting of either pregnancy or the use of estrogen-containing medications, which can cause a prothrombotic state.

Data on the use of an antiplatelet versus an anticoagulant (or the type of anticoagulant) in patients who have an inherited thrombophilia and stroke is limited. Although more data are available for managing APLS with warfarin, typically used to prevent recurrent thrombotic events in patients with a history of venous thromboembolism (VTE), the optimal antithrombotic following an arterial ischemic event is unclear. Antithrombotic treatment for thrombophilia after an ischemic stroke is often guided by VTE literature and individualized according to the patient’s thrombophilia, history of thromboembolic events, comorbid conditions, and risk of hemorrhage.

Because deficiencies may occur along a continuum, the relationship between degree of deficiency and risk of ischemic stroke should be explored. Additionally, optimal antithrombotic strategies should be a focus of future investigations.