Fibrinogen Thr312Ala polymorphism increased incidence of chronic thromboembolic pulmonary hypertension other than pulmonary thromboembolism through increasing its fibrin's resistance to plasmin

摘要

Objective:Find out polymorphisms associated with CTEPH and/or PTE.Ascertain whether fibrin resistance to lysis occurs in CTEPH and/or PTE.Find out the influence of fibrinogen Aa Thr312Ala polymorphism to fibrin's resistance to lysis.Methods:Genomic DNA was isolated from 101 CTEPH subjects, 102 PTE subjects and 108 control. Polymorphisms were analyzed by Massarray or restriction fragment length polymorphism (RFLP).Fibrinogen was purified from 69 subjects (29 with CTEPH, 21 with PTE and 19 control) and exposed to thrombin to obtain fibrin clots.Plasmin-mediated cleavage of fibrin was assessed at intervals over a 12-hour period by SDS-polyacrylamide gel electrophoresis (SDS-PAGE}. Fibrinband intensity was measured by densitometry of stained gels. Data were normalized to the bandintensity of the undigested protein.Results :Among the common polymorphisms of the haemostatic factors and factors of fibrinolyticsystem, only fibrinogen Thr312A1a genotype frequencies and allele frequencies are significantlydifferent between CTEPH subjects and control, the similar result exist between CTEPH subjectsand PTE subjects, but not between PTE and control. The OR and 95% CI before (OR=1.763,95%CI 1.185-2.623) and after adjustment (OR=2.037, 95%CI 1.262-3.289) both showed thatThr312A1a polymorphism is a risk factor of CTEPH.Fibrin is more resistant to lysis in CTEPH subjects than that both in PTE subjects and in control(p=0.013 between CTEPH subjects and control; p=0.00 between CTEPH subjects and PTEsubjects).And, fibrin's resistance to lysis is significantly different between Aa Thr312A1a (AIG) genotypeswithin CTEPH subjects (p<0.001 between CTEPH subjects and control; p<0.001 between CTEPHsubjects and PTE subjects).Conclusion :Fibrinogen Thr312A1a polymorphism increased incidence of chronicthromboembolic pulmonary hypertension other than pulmonary thromboembolism throughincreasing its fibrin's resistance to plasmin.