title: Antithrombin heparin binding site deficiency: A challenging diagnosis of a not so benign thrombophilia.
abstract: BACKGROUND
  Hereditary antithrombin (AT) deficiency is a rare autosomal dominant disorder characterised by decreased AT activity in plasma and predisposition to recurrent venous thromboembolism (VTE). Thrombotic risk is thought to vary according to the subtype of deficiency, with Heparin Binding Site (HBS) deficiencies being the less thrombogenic.
  
  
  OBJECTIVE
  The study population consisted of 82 genetically confirmed HBS deficient patients sharing six different mutations. Plasma samples of 35 of them, including one homozygous patient, were used for the evaluation of 4 commercial activity assays in their ability to diagnose HBS deficiency. We assessed mutation-specific prevalence of venous and arterial thrombosis and the contribution of additional thrombophilic risk factors.
  
  
  CONCLUSIONS
  Only one assay showed 100% sensitivity for all HBS mutations. The other ones failed mainly in the cases with p.Pro73Leu and p.Arg79His mutations. Shortening of incubation time resulted in an increase in sensitivity. In one patient, a novel HBS mutation, p.Asn77His, was identified, a quite exceptional and important finding given the restricted number of causal mutations reported so far in AT HBS deficiency. The overall prevalence of VTE in our study population (35%) was higher than previously reported (6-8%) in these patients. The presence of additional thrombophilic risk factors such as Factor V Leiden or prothrombin gene mutation G20210A contributed to a higher risk of VTE. Interestingly, the p.Pro73Leu and p.Arg79His mutations were associated with a high prevalence of arterial thrombosis. Our data suggest that AT HBS deficiencies are probably more prevalent and less benign than previously assumed.
authors.affiliation: Department of Haematology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090 Brussels, Belgium. Electronic address: christelle.orlando@uzbrussel.be.
authors.forename: Christelle
authors.initials: C
authors.lastname: Orlando
authors.affiliation: Department of Haematology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090 Brussels, Belgium. Electronic address: olivierheylen@gmail.com.
authors.forename: Olivier
authors.initials: O
authors.lastname: Heylen
authors.affiliation: Centre for Medical Genetics, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090 Brussels, Belgium. Electronic address: willy.lissens@telenet.be.
authors.forename: Willy
authors.initials: W
authors.lastname: Lissens
authors.affiliation: Department of Haematology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090 Brussels, Belgium. Electronic address: kristin.jochmans@uzbrussel.be.
authors.forename: Kristin
authors.initials: K
authors.lastname: Jochmans
mesh_terms: D000293:Adolescent; D000328:Adult; D000990:Antithrombin III / Q000235:genetics*; D020152:Antithrombin III Deficiency / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D000991:Antithrombins / Q000097:blood / Q000737:chemistry*; D001158:Arteries / Q000503:physiopathology; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D005165:Factor V / Q000235:genetics; D005260:Female; D006493:Heparin / Q000737:chemistry*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D015995:Prevalence; D015203:Reproducibility of Results; D012306:Risk; D012307:Risk Factors; D012680:Sensitivity and Specificity; D019851:Thrombophilia / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D013927:Thrombosis / Q000503:physiopathology; D055815:Young Adult
chemical_list: D000991:Antithrombins; C542513:SERPINC1 protein, human; C095381:factor V Leiden; D000990:Antithrombin III; D005165:Factor V; D006493:Heparin
keywords: Antithrombin deficiency; Arterial Thrombosis; Mutation; Thrombophilia; Venous thromboembolism