Association of genotypes of thrombin-activatable fibrinolysis inhibitors with thrombotic microangiopathies--a pilot study.

Background: Thrombotic microangiopathies are characterized by microvascular thrombosis, consequently leading to microangiopathic haemolytic anaemia, thrombocytopenia and organ dysfunction. Although recent research has elucidated the pathogenesis of these rare thrombotic disorders to some extent, the determinants contributing to the manifestation remain rather unclear in the majority of affected patients.

Method: In the present pilot study, we used a case-control design, enrolling 40 patients [mean age (+/-SD) 35+/-11 years] with a history of thrombotic microangiopathy and 689 control subjects to evaluate the association of gene polymorphisms of the thrombin-activatable fibrinolysis inhibitor (TAFI) with the manifestation of these rare thrombotic disorders. These polymorphisms are major determinants of TAFI plasma levels that were found to modulate the onset of venous and arterial thrombosis.

Results: As a result of our study, the prevalence of the GG genotype (adjusted OR 2.58; 95% CI 0.9-6.1, P=0.044) and the G allele (adjusted OR 2.2; 95% CI 1.2-4.2, P=0.017) of the C1542G polymorphism was significantly higher in patients with a history of thrombotic microangiopathy compared with controls. A higher prevalence of the GG genotype of the TAFI G505A polymorphism was also observed, but this association was not statistically significant (adjusted OR 4.97, CI 0.7-36.7, P=0.12). Considering the established genotype-phenotype associations, our observation suggests that lower TAFI plasma levels are associated with an increased risk for the manifestation of thrombotic microangiopathies. A diminished inactivation of C3a and C5a-also known from haemolytic uraemic syndrome (HUS) associated with factor H deficiency-might be the most likely explanation.

Conclusions: The results of our pilot study indicate that the GG genotype of the C1542G polymorphism of TAFI displays risk factors for the manifestation of thrombotic microangiopathies. Our observation provides a rationale to assess genotype-phenotype relations by determination of TAFI plasma levels in various stages of disease in patients suffering from these rare thrombotic disorders.