Andreas Czwalinna

Prevalence of a 23bp Insertion in Exon 3 of the Endothelial Cell Protein C Receptor Gene in Venous Thrombophilia

BACKGROUND The endothelial cell protein C receptor (EPCR) enhances protein C activation by the thrombin-thrombomodulin complex. As evidence is accumulating that EPCR is an important component of the protein C anticoagulant pathway, polymorphisms in the EPCR gene might be candidate risk factors predisposing to venous thromboembolism (VTE). Recently, a 23bp insertion in exon 3 of the EPCR gene has been identified, which duplicates the preceding 23 bases and results in a STOP codon downstream from the insertion point. However, the clinical significance of this mutation in VTE remains to be clarified. METHODS AND RESULTS In this study we evaluated the EPCR 23bp insertion in 889 patients with documented VTE and in 500 healthy controls. The prevalence of the EPCR insertion among patients was 0.1%, which was not significantly different compared to controls (0.6%, p = 0.1). CONCLUSIONS Our findings showed that the EPCR 23bp insertion is very rare in both patients with VTE and the general population and failed to support an association between the EPCR 23bp insertion and an increased risk of VTE.

Acquired haemophilia caused by non-haemophilic factor VIII gene variants

The aetiology of anti-factor VIII (FVIII) autoantibody formation in acquired haemophilia remains unknown. We hypothesised that encounter of antigenically different, allogeneic FVIII may challenge inhibitor formation after presentation on MHC class II. Eighteen consecutive cases with acquired haemophilia were enrolled (nine females, nine males). A control group comprised 50 male and 50 female healthy blood donors. The coding region of the FVIII gene and the HLA-DRB1 genotype were studied. The presentation of foreign FVIII variants on the patient’s MHC class II alleles was predicted using SYFPEITHI algorithm. A rare FVIII variant (E2004K) was found in one patient with acquired haemophilia after massive transfusion; the 2004 K allele was predicted to be presented on the patient’s HLA-DRB1*0101. Moreover, distribution of a polymorphism (D1241E) was significantly skewed comparing patients and controls. Three of three patients with transfusion-associated disease carried 1241D in homozygous or hemizygous form and were predicted to present 1241E (foreign), but not 1241D (self), on their HLA-DRB1*0301. Therefore, encounter of 1241E may result in the presentation of a new T cell epitope in these patients. The same conditions were not found in any patient with acquired haemophilia of other causes. The expected frequency in the general Caucasoid population undergoing transfusion is 3% to 4%. In conclusion, encounter of variant allogeneic FVIII presented on a suitable MHC background could be a risk factor for inhibitor formation.

Canine haemophilia A caused by a mutation leading to a stop codon

HAEMOPHILIA A is a mutationally heterogeneous coagulation disorder caused by defects in the large and complex coagulation factor VIII (FVIII) gene. It has been recorded in human beings and various animal species including dogs (Antonarakis 1995, Hough and others 2002, Oldenburg and El-Maarri 2006). The bleeding predisposition associated with haemophilia A results from a deficiency or dysfunction of FVIII, with the severity depending on the amount of residual FVIII activity. The human gene for FVIII is located on the X chromosome (Xq28) and the gene spans 186 kb across 26 exons, coding for approximately 9 kb mRNA. More than 40 per cent of all cases of severe haemophilia A in human beings are caused by gross rearrangements of the FVIII gene. In addition, sequence deletions, insertions and several hundred single-base substitutions or point mutations have been described of which approximately 100 lead …

Elevated Fibrinogen is a Risk Factor for Arterial Thrombosis in Children

Several authors reported about the role of an elevated fibrinogen level as a risk factor for arterial and venous thromboembolism in adults [1, 2, 3, 4, 5]. In children elevated fibrinogen levels also are discussed to be a risk factor for thrombus development, but no special pediatric studies exist, which confirm this hypothesis [6].

Analysis of the Fibrinogen Genes of 40 Patients with Suspicion of Dys-, Hypo- or Afibrinogenemia

Fibrinogen is a 340 kDa plasma glycoprotein mainly synthesized by liver parenchymal cells. It is secreted as a dimeric molecule composed of three different polypeptides, Aα, Bβ and γ [2]. Fibrinogen chains are encoded by separate, clustered genes located on chromosome 4q28 in a 50 kb region [5], organized in a γ, α and β sequence with the β gene in opposite transcriptional orientation.