Association of elevated levels of prothrombin fragment 1+2 and Arg506 to Gln mutation in patients with a history of ischemic stroke.
BACKGROUND: Recent findings have indicated the association between APC-resistance and cerebrovascular disease. These reports prompted us to investigate whether resistance to APC could be found in patients suffering from stroke. METHODS: Therefore, we studied APC-resistance in 50 young adults (< or =45 yrs) with a history of ischemic stroke. Eleven out of fifty cerebrovascular subjects showed APC-resistance, while 2 had PC deficiency and 3 PS deficiency. No deficiencies in the anticoagulant protein AT III and in fibrinolytic proteins were found. The family history demonstrated a distribution of APC-resistance compatible with dominant autosomal inheritance. The plasma concentration of prothrombin fragment 1+2 (F1+2), which is a marker of hypercoagulable states, was also measured in patients and family members of resistant subjects (n = 38). RESULTS: DNA analysis showed factor V R506Q mutation (Leiden mutation) in 11 patients and their relatives with poor response to activated protein C detected by APTT tests. Of 11 investigated subjects with APC-resistance, 9 were heterozygotes and 2, with the lowest APC-ratio values, were homozygotes for factor V mutation. Among 38 relatives, 22 showed a poor response to APC and according to the APC-ratio values, 18 were heterozygotes and 4 homozygotes for FV Leiden mutation. The mutation, in heterozygous form, was also found in 2% of our normal population (n = 100). The plasma concentration of F1+2 was significantly higher both in 11 individuals carrying the FV:Q506 mutation and in 39 patients without APC-resistance compared to that found in the control group. However, the patients with FV:Q506 mutation showed the highest values in F1+2. In the studied family members F1+2 plasma levels were within normal values. CONCLUSIONS: Our findings indicate a possible involvement of APC-resistance in the pathogenesis of cerebral thrombosis in young adults and agree with the hypothesis that individuals with APC-resistance have an imbalance between pro-and anti-coagulant forces leading to increased thrombin generation and a hypercoagulable state.