title: Association of genotypes of thrombin-activatable fibrinolysis inhibitors with thrombotic microangiopathies--a pilot study.
abstract: 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.
  
  
  METHODS
  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.
authors.affiliation: Department of Haemostasis and Transfusion Medicine, Heinrich Heine University Medical Center, Moorenstrasse 5, 40221 Duesseldorf, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Sucker
authors.forename: Gerd Ruediger
authors.initials: GR
authors.lastname: Hetzel
authors.forename: Firuseh
authors.initials: F
authors.lastname: Farokhzad
authors.forename: Fieras
authors.initials: F
authors.lastname: Dahhan
authors.forename: Michael
authors.initials: M
authors.lastname: Schmitz
authors.forename: Christine
authors.initials: C
authors.lastname: Kurschat
authors.forename: Bernd
authors.initials: B
authors.lastname: Grabensee
authors.forename: Beate
authors.initials: B
authors.lastname: Maruhn-Debowski
authors.forename: Rainer
authors.initials: R
authors.lastname: Zotz
authors.forename: Ruediger
authors.initials: R
authors.lastname: Scharf
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D025901:Carboxypeptidase B2 / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006463:Hemolytic-Uremic Syndrome / Q000097:blood / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D011697:Purpura, Thrombotic Thrombocytopenic / Q000097:blood / Q000235:genetics; D012307:Risk Factors; D013927:Thrombosis / Q000097:blood / Q000235:genetics*; D014652:Vascular Diseases / Q000097:blood / Q000235:genetics*
chemical_list: D025901:Carboxypeptidase B2