title: Severe hemophilia with mild bleeding phenotype: molecular characterization and global coagulation profile.
abstract: BACKGROUND
  Patients with severe hemophilia may show very varied bleeding tendencies, and the reasons for this heterogeneous clinical expression are unclear. The factor VIII/FIX genotype is the main determinant of the residual factor activity; however, different bleeding phenotypes have also been reported in patients sharing the same mutation. Such global coagulation tests as thrombin generation assays are tools with which to investigate different coagulation profiles among severe hemophiliacs.
  
  
  OBJECTIVE
  This case-control study was aimed at comprehensively evaluating the role of genotype and endogenous thrombin potential (ETP) as predictors of the clinical phenotype in severe hemophiliacs with an extremely mild bleeding tendency (cases, n = 22), in comparison with those showing a typical bleeding tendency (controls, n = 50).
  
  
  RESULTS
  Cases were more frequently affected by hemophilia B than by hemophilia A, and showed a lower incidence of severe FVIII/FIX gene defects (referred to as null mutations), higher FVIII and FIX antigen levels and higher ETP values in platelet-rich plasma than controls (P < 0.05). By multivariate logistic regression, only non-null mutations were confirmed as an independent predictor of a mild clinical phenotype.
  
  
  CONCLUSIONS
  These results indicate that non-null mutations represent the main determinant of the bleeding tendency, and that ETP measurement in platelet-rich plasma is able to identify severe hemophiliacs with a mild clinical phenotype.
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Department of Medicine and Medical Specialties, IRCCS Ca' Granda Foundation, Policlinico Maggiore Hospital, Luigi Villa Foundation and University of Milan, Milan, Italy. e_santagostino@hotmail.com
authors.forename: E
authors.initials: E
authors.lastname: Santagostino
authors.forename: M E
authors.initials: ME
authors.lastname: Mancuso
authors.forename: A
authors.initials: A
authors.lastname: Tripodi
authors.forename: V
authors.initials: V
authors.lastname: Chantarangkul
authors.forename: M
authors.initials: M
authors.lastname: Clerici
authors.forename: I
authors.initials: I
authors.lastname: Garagiola
authors.forename: P M
authors.initials: PM
authors.lastname: Mannucci
mesh_terms: D000328:Adult; D001777:Blood Coagulation / Q000235:genetics; D001780:Blood Coagulation Tests; D016022:Case-Control Studies; D005164:Factor IX / Q000235:genetics / Q000378:metabolism; D005169:Factor VIII / Q000235:genetics / Q000378:metabolism; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006467:Hemophilia A / Q000097:blood / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D002836:Hemophilia B / Q000097:blood / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D006470:Hemorrhage / Q000097:blood / Q000209:etiology* / Q000235:genetics; D006801:Humans; D007558:Italy; D016015:Logistic Models; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013917:Thrombin / Q000378:metabolism
chemical_list: D005169:Factor VIII; D005164:Factor IX; D013917:Thrombin