A diagnostic challenge: mild hemophilia B with normal activated partial thromboplastin time

Hemophilia B is a hereditary bleeding disorder from the deficiency of factor IX (FIX) activity. Hemophilia B is caused by a mutation in the F9 gene on Xq27.1 encoding FIX and, thus, has an X-linked inheritance. The diagnosis of hemophilia B is typically suspected by significantly prolonged activated partial thromboplastin time (aPTT) on screening tests, but aPTT may be normal or minimally prolonged in mild hemophilia B. We herein describe the cases of two Korean brothers with mild hemophilia B. The proband was a 26-year-old male patient with a mild bleeding history. He had a younger brother and a male cousin of maternal side with a similar bleeding tendency. Coagulation screening tests revealed no remarkable findings, including normal aPTT at 40.0 s (STA-PTT Automate, local reference range, 29.1-41.9 s). However, factor assays revealed a significantly decreased FIX activity at 27% (67-154%). The younger brother also had mildly prolonged aPTT at 45.1 s, which was corrected on mixing test. His FIX activity was 34%. Molecular genetic analysis of F9 revealed that the brothers were both hemizygous for a missense mutation, c.280G>A (p.Gly94Arg or Gly48Arg by conventional numbering based on the mature protein). Gly94Arg (Gly48Arg) is a mutation previously described in mild hemophilia B. This report shows that aPTT can be normal even with a reagent reported to be sensitive in detecting mild hemophilia B. It is important to pay attention to the clinical and family history and perform factor assays, and molecular genetic analysis can confirm the diagnosis and reveal genotype-phenotype correlations. Blood Coagul Fibrinolysis 21:368-371 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.