Inherited Thrombophilia and the Risk of Arterial Ischemic Stroke: A Systematic Review and Meta‐Analysis

Abstract

BackgroundInherited thrombophilias are well‐established predisposing factors for venous thromboembolism, but their role in arterial thrombosis, such as arterial ischemic stroke, remains uncertain. We aimed to evaluate the association between inherited thrombophilia (factor V Leiden, prothrombin G20210A mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency) and risk of arterial ischemic stroke in adults.Methods and ResultsWe searched PubMed, EMBASE, and Cochrane Library Databases from inception to December 31, 2018. We included case‐control or cohort studies of adults reporting the prevalence of inherited thrombophilias in those with arterial ischemic stroke and subjects without arterial ischemic stroke. Two reviewers (T.C., E.D.) independently searched the literature and extracted data. Pooled odds ratios (ORs) and 95% CIs were calculated using random‐effects model. We identified 68 eligible studies, which collectively enrolled 11 916 stroke patients and 96 057 controls. The number of studies reporting factor V Leiden, prothrombin G20210A mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency were 56, 45, 15, 17, and 12, respectively. Compared with controls, patients with arterial ischemic stroke were significantly more likely to have the following inherited thrombophilias: factor V Leiden (OR, 1.25; 95% CI, 1.08–1.44; I2=0%), prothrombin G20210A mutation (OR, 1.48; 95% CI, 1.22–1.80; I2=0%), protein C deficiency (OR, 2.13; 95% CI, 1.16–3.90; I2=0%), and protein S deficiency (OR, 2.26; 95% CI, 1.34–3.80; I2=8.8%). Statistical significance was not reached for antithrombin deficiency (OR, 1.25; 95% CI, 0.58–2.67; I2=8.8%).ConclusionsInherited thrombophilias (factor V Leiden, prothrombin G20210A mutation, protein C deficiency, and protein S deficiency) are associated with an increased risk of arterial ischemic stroke in adults. The implications of these findings with respect to clinical management of patients with ischemic stroke require further investigation.

Protein C Deficiency as a Risk Factor for Stroke in Young Adults: A Review

“…A meta-analysis was performed in 2019 exploring 68 case-control and cohort studies in individuals older than 15 years of age. Out of the 68 cases, PC deficiency was reported in 15 studies, and patients with arterial ischemic stroke had a higher association with PC deficiency than the control group [4]. Mahmoodi et al in their cohort study also analyzed the risk of ATE in the setting of PC, PS, and antithrombin deficiency, as well as the significance of the positive history of VTE as a predisposing factor [22].…”

“…Anecdotal cases have reported an association between PC deficiency and ischemic cerebral vessel disease. Nevertheless, a definite association has not yet established or remains controversial [3,4]. In order to identify the etiology in arterial ischemic stroke, testing for inherited thrombophilia is often considered [4].…”

“…However, the benefit of screening in this regard has been controversial. Yet, the 2018 American Heart Association/American Stroke Association clinical practice guideline recommends thrombophilia workup in patients with ischemic stroke [4]. Although inherited procoagulant conditions have not been traditionally regarded as risk factors for arterial thrombosis, there are several mechanisms by which they can lead to arterial ischemic stroke.…”

“…Secondly, an imbalance between procoagulants and anticoagulants in individuals with inherited thrombophilias can unnecessarily aid the formation and progression of atherosclerotic plaques through different mechanisms, such as activation of platelets, endothelial and vascular smooth muscle cell dysregulation, and recruitment of monocytes and macrophages [4]. Keeping in view these mechanisms, a recent meta-analysis has demonstrated an association between multiple inherited thrombophilias and the subsequent risk of developing arterial ischemic stroke in adults [4]. Apart from being rare, the incidence of stroke secondary to PC deficiency has been reported in various case reports discussed further in the review.…”

Association of G20210A Prothrombin Gene Mutation and Cerebral Ischemic Stroke in Young Patients

“…However, De Stefano et al studied that homozygous prothrombin gene mutation is associated with a higher risk of ischemic stroke in young patients [27]. However, the other four studies failed to clearly show a more homozygous association than the heterozygous counterpart of prothrombin gene mutation [28][29][30][31].…”