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

Abstract

Background Inherited 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 Results We 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%). Conclusions Inherited 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.

Keywords: hypercoagulopathy; stroke; stroke, ischemic; thrombosis.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta‐Analyses flow diagram. ATD indicates antithrombin deficiency; FVL, factor V Leiden; PCD, protein C deficiency; PSD, protein S deficiency; PTM, prothrombin G20210A mutation; TIA, transient ischemic attack.

Figure 2

Forest plot showing association between inherited thrombophilia and risk of arterial ischemic stroke. The forest plot shows the results from the meta‐analysis for each type of thrombophilia and its association with arterial ischemic stroke. The pooled odds ratio (OR) is represented by the square box. The whiskers represent 95% CIs. The I² statistic was used to evaluate study heterogeneity. FVL indicates factor V Leiden; PTM, prothrombin G20210A mutation.

Figure 3

Forest plot showing pooled odds ratio (OR) for each thrombophilia in specific subgroups of patients. The forest plot shows the results from the prespecified subgroup analyses for each type of thrombophilia. The pooled ORs are represented by the square boxes. The horizontal lines represent the 95% CIs. PFO indicates patent foramen ovale.