Inherited Thrombophilia and the Risk of Arterial Ischemic Stroke: A Systematic Review and Meta-Analysis
Authors: Chiasakul Thita , De Jesus Elizabeth , Tong Jiayi , Chen Yong , Crowther Mark , Garcia David A. , Chai-Adisaksopha Chatree , Messé Steven R. , Cuker Adam 
Published: October 2019

Abstract
Introduction:The inherited thrombophilias Factor V Leiden (FVL), the Prothrombin G20210A mutation (PTM), Protein C deficiency (PCD), Protein S deficiency (PSD), and Antithrombin deficiency (ATD) are well-established predisposing factors for venous thromboembolism, but their role in arterial thrombosis such as arterial ischemic stroke remains uncertain. The 2018 American Heart Association/American Stroke Association clinical practice guideline recommends against thrombophilia testing in patients with ischemic stroke, though such testing remains common in clinical practice. We conducted a systematic review and meta-analysis to evaluate the association of inherited thrombophilias and risk of arterial ischemic stroke in adults.
Methods:A systematic literature search was performed using MEDLINE, EMBASE, and Cochrane Library Databases from inception to December 31, 2017 without language restrictions. Manual reviews of conference abstracts and bibliographies of included studies were performed to identify additional eligible studies. We included case-control studies of adults age ≥15 years that reported the prevalence of at least one of the inherited thrombophilias of interest (FVL, PTM, PCD, PSD, ATD) in both subjects with a history of arterial ischemic stroke (cases) and subjects without arterial ischemic stroke (controls). Studies were required to have ≥10 subjects in each group. Studies that enrolled patients with transient ischemic attack, hemorrhagic stroke, cerebral venous sinus thrombosis, and other arterial thromboses were excluded. Two reviewers (T.C. and E.D.) independently searched the literature and extracted data from eligible studies. Disagreements were resolved by consensus or a third reviewer (A.C.) when necessary. Methodological quality of included studies was appraised using the NIH Quality Assessment of Case-Control Studies assessment tool. Data analysis was performed using R version 3.4.4. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Inter-study heterogeneity was evaluated using Cochran's Q test and I2statistics. Prespecified subgroup analyses were performed in young patients (<65 years), patients with a patent foramen ovale (PFO), and patients with cryptogenic stroke. Funnel plots and Egger's test were used to assess for the presence of publication bias. The study protocol is available on PROSPERO (CRD42018090020).
Results:A total of 1,730 records were retrieved from the literature search. After screening by title and abstract, 1527 records were excluded. The remaining 203 references underwent full text review, 71 of which met eligibility criteria and were included in the analysis. These 71 studies collectively enrolled 13,347 stroke patients and 31,676 controls. The number of studies that reported on FVL, PTM, PCD, PSD, and ATD were 59, 47, 14, 15, and 11, respectively. Heterogeneity among studies was low. Compared with controls, inherited thrombophilia was significantly more common in patients with arterial ischemic stroke for the following defects: homozygous FVL (OR 2.24; 95%CI, 1.24-4.07; I2=0%), heterozygous FVL (OR 1.32; 95%CI, 1.11-1.57; I2=33%), homozygous PTM (OR 7.19; 95%CI 2.47-20.95; I2=0%), heterozygous PTM (OR 1.53; 95%CI, 1.27-1.84; I2=2%), PCD (OR 2.70; 95%CI, 1.44-5.04; I2=0%), and PSD (OR 2.75; 95%CI, 1.56-4.85; I2=34%) (Figure 1). Statistical significance was not reached for ATD (OR 1.84; 95%CI, 0.92-3.71; I2=11%). Subgroup analyses showed a higher magnitude of stroke risk in young patients across all thrombophilias. The associations were non-significant for patients with PFO and cryptogenic stroke (Table 1). Funnel plots were symmetrical and Egger's test was non-significant (p>0.05), suggesting absence of publication bias, for all thrombophilias except heterozygous FVL (p=0.003).
Conclusions: Our results suggest that inherited thrombophilias including FVL, PTM, PCD, and PSD are associated with an increased risk of arterial ischemic stroke, particularly in young patients. The association with FVL and PTM is stronger in the homozygous than in the heterozygous state, suggesting a potential dose-response relationship and causal role for inherited thrombophilias. The implications of these findings with respect to the evaluation and management of patients with ischemic stroke require further investigation.

Disclosures
Crowther: Alnylam: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Shinogi: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Speakers Bureau. Garcia:Bristol Meyers Squibb: Consultancy; Daiichi Sankyo: Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy; Portola: Research Funding; Incyte: Research Funding; Retham Technologies LLC: Consultancy; Shingoi: Consultancy; Boehringer Ingelheim: Consultancy. Cuker:Kedrion: Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Research Funding; Synergy: Consultancy; Genzyme: Consultancy.