Prothrombin G20210A Mutation, but Not Factor V Leiden, Is a Risk Factor in Patients with Persistent Foramen ovale and Otherwise Unexplained Cerebral Ischemia

Abstract

Background: Paradoxical embolism via persistent foramen ovale (PFO) is suspected to be a frequent cause of stroke in younger patients. We investigated whether the prevalence of the risk factors for venous thrombosis factor V Leiden (FVL) and prothrombin G20210A mutation (PT G20210A) is increased in this group of patients. Methods: We examined FVL and PT G20210A mutation in 220 patients (group 1) with cerebral ischemia associated with a PFO and without other etiology, in 196 patients with cerebral ischemia of an etiology other than PFO (group 2), and in 362 healthy subjects (group 3) from the same region in Germany. Results: Heterozygosity for the PT G20210A mutation was more common in group 1 (5.0%) than in group 3 (1.4%; sex- and age-adjusted odds ratio 3.66; 95% CI 1.25–10.75; p = 0.01). By contrast, the mutation was not more common in group 2 (2.6%; odds ratio 1.50; 95% CI 0.42–5.41; p = 0.5). Prevalences of FVL were not different between groups. Conclusions: We identified PT G20210A but not FVL – the strongest genetic risk factor for deep venous thrombosis – to be significantly associated with stroke attributed to PFO. These findings rise doubts about the concept of paradoxical brain embolism as the dominating mechanism in stroke associated with PFO.

Prothrombotic Mutations as Risk Factors for Cryptogenic Ischemic Cerebrovascular Events in Young Subjects With Patent Foramen Ovale

“…The present data are consistent with previous reports [11][12][13] and have important clinical implications. From a clinical viewpoint, it is critical to define in which cases PFO per se constitutes a risk high enough to warrant percutaneous closure and then define the best treatment.…”

“…Accordingly, the G20210A variant in the PT gene was confirmed to be significantly associated with cerebral ischemia in patients with PFO. [11][12][13] Recently, a case-control study demonstrated that only "major" venous-to-arterial circulation shunts, usually due to PFO, were associated with stroke in young adults, but no relation was found between thrombophilia and ischemic stroke. 20 However, major venous-to-arterial circulation shunts were identified by transcranial Doppler after intravenous microbubble ultrasound contrast in only 24 (25%) patients compared with 12 (12%) control subjects.…”

“…8 Recently, prothrombotic mutations have been suggested as genetic risk factors for "cryptogenic" ischemic cerebrovascular disease in young adults, 9,10 and a relation between the prothrombotic mutation and cerebral ischemia risk in younger PFO patients has also been reported. [11][12][13] However, the prevalence of coagulation mutations in patients with a PFO has not been consistently studied. Furthermore, the question of whether it is beneficial to recommend laboratory testing for inherited coagulopathies in patients with PFO-related strokes remains an unresolved issue.…”

Testing for Inherited Thrombophilias in Arterial Stroke

“…Without limitation to the number of subjects, we identified 9 case-control studies examining the relationship of the inherited thrombophilias, patent foramen ovale (PFO), and stroke 21,24,[37][38][39][40][41][42][43] (Table 3). Sastry et al 9 collected data on both PFO and thrombophilia in ischemic stroke but did not evaluate them in relation to each other.…”

“…Sastry et al 9 collected data on both PFO and thrombophilia in ischemic stroke but did not evaluate them in relation to each other. These studies also produced conflicting results, with some studies suggesting an association between PTM or FVL and PFO, 24,[41][42][43] and others finding no relation. 21,[37][38][39][40] None of the studies that examined PC, PS, or AT found any association of these deficiencies with PFO and stroke.…”