The Study On Roles Of The Plasminogen Activator And Its Inhibitor-1 In The Pathogenesis Of Acute Pulmonary Thromboembolism And Deep Vein Thrombosis

Background For their strong associations and similarities in both clinical and post-mortem study between pulmonary embolism (PE) and deep vein thrombosis (DVT), they should be regarded as a single clinico-pathological entity, i.e. venous thromboembolism. With the progress of investigation in recent years, scientific researchers have discovered that the disease not only afflicts a wide scope of people and involves much more disciplines, but also threatens the patients severely with high morbidity and mortality. It has been known that increased levels of plasminogen activator inhibitor-l(PAI-l) and decreased levels of tissue type plasminogen activator(t-PA) in circulation can impaired fibrinolysis system. The 4G/5G PAI-1 polymorphism has been shown to be associated with plasma PAI-1 levels in several groups of patients: after myocardial infarction, in non-insulin-dependent diabetes mellitus and in cerebrovascular disease. Therefor, it can be deduced that plasminogen activator, plasminogen activator inhibitor-1 and PAI-1 promoter 4G/5G gene polymorphism might play important roles in the pathogenesis of PE and DVT. But there has been no such report in China up to now.Objective To reveal the relationships of plasminogen activator, plasminogen activator inhibitor-1 or PAI-1 promoter 4G/5G gene polymorphism to the incidence of PE and/or DVT in Chinese Han ethnic group; To provide an objective evidence in the prophylaxis and management of venous thromboembolism.Methods The subjects of the study consist of four groups: (1) PE group(24 men and 20 women; mean age 55 13 years); (2) DVT group (72 men and 48 woman; mean age 58 16 years);(3) normal-control group of PE (31 men and25 woman; mean age 53 14 years).(4) normal-control group of DVT (76men and 44 woman; mean age 57 16 years). The t-PA activity assay was measured by chromophorous substrate method ; the antigen of t-PA or PAI-1 was quantified by a commercially available enzyme-linked immunosorbent assay (ELISA) respectively; the PAI-1 promoter 4G/5G gene polymorphism was evaluated by polymerase chain reaction (PCR). The relationship of PAI-1 levels to some anthropometric and metabolic factors was also investigated.Results (1) Comparing with health-control group, PE patients have higher levels of PAI-1 antigen (82.32 (66.18-102.38) ng/ml vs 62.87 (56.27-70.25) ng/ml) and t-PA antigen (19.12 (14.25-25.66) ng/ml vs 10.50 (8.15-13.50) ng/ml), but lower levels of t-PA activity (0.16 0.01 RJ/ml vs 0.20 0.01IU/ml). (2) The distribution of the PAI-1 promoter 4G/5G gene polymorphism in the DVT and its control group was 4G/4G genotype: 38.33% (46/120) vs 35.00% (42/ 120); 4G /5Ggenetype: 45.83% (55/120) vs 42.50% (51/120); 5G/5Ggenotype: 15.83 % (19/120) vs 22.50% (27/120), respectively. The 4G and 5G allele frequences were 0.62/0.38 in DVT patients and 0.56/0.44 in controls respectively. Neither in the distribution of PAI-1 promoter 4G/5G gene polymorphism nor in the frequences of 4G and 5G allele is there a difference between the two groups. (3) The levels of PAI-1 or t-PA in the carriers of the 4G/4G genotype were significantly higher than those either in the 4G/5G genotype or in the 5G/5G genotype; The levels of TG differ significantly between any two 4G/5G genotypes in the whole sample, with the highest in 4G/4G genotype, intermediate in 4G/5G genotype, and the lowest in 5G/5G genotype. Other factors such as BMI, Glu, Hct, TC and t-PA activity are observed to be similar statistically among the threegenotypes. (4) In all of samples, the levels of PAI-1 were influenced by smoking, drinking, blood pressure, Fib, Glu, TG and PAI-1 promoter 4G/5G gene polymorphism. Multiple regression analysis disclosed that the plasma PAI-1 levels were independently determined by smoking, Glu, TG and the genotype of the PAI-1 promoter gene.Conclusions The present outcome suggest that (1) both increased levels of PAI-1 and decreased levels of t-PA in circulation are risk factors for PE and DVT. (2) The possession of 4G/4G genotype may contribute to defective fibr...