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Individual thrombin generation and spontaneous bleeding rate during personalized prophylaxis with Nuwiq® (human-cl rhFVIII) in previously treated patients with severe haemophilia A.

  • Dargaud, Y1
  • Negrier, C1
  • Rusen, L2
  • Windyga, J3
  • Georgiev, P4
  • Bichler, J5
  • Solomon, C5, 6
  • Knaub, S5
  • Lissitchkov, T7
  • Klamroth, R8
  • 1 Hopital Cardiologique Louis Pradel, University of Lyon, Lyon, France. , (France)
  • 2 Sanador SRL, Bucharest, Romania. , (Oman)
  • 3 Department of Disorders of Haemostasis and Internal Medicine, Institute of Haematology and Transfusion Medicine, Warsaw, Poland. , (Poland)
  • 4 Clinic of Haematology, University Multiprofile Hospital for Active Treatment "Sveti Georgi" and Medical University, Plovdiv, Bulgaria. , (Bulgaria)
  • 5 Octapharma AG, Lachen, Switzerland. , (Switzerland)
  • 6 Department of Anesthesiology, Perioperative Care and General Intensive Care, Salzburg University Hospital, Paracelsus Medical University, Salzburg, Austria. , (Austria)
  • 7 Department of Clinical Haematology in Haemorrhagic Diathesis and Anaemia, Specialized Hospital for Active Treatment "Joan Pavel", Sofia, Bulgaria. , (Bulgaria)
  • 8 Vivantes Klinikum im Friedrichshain, Berlin, Germany. , (Germany)
Published Article
Haemophilia : the official journal of the World Federation of Hemophilia
Publication Date
Jul 01, 2018
DOI: 10.1111/hae.13493
PMID: 29855112


For individuals with haemophilia A, prophylaxis with factor VIII (FVIII) is typically directed towards trough activity >1 IU/dL; however, some patients still experience spontaneous bleeding events (sBEs). Aims were to evaluate relationships of endogenous thrombin potential (ETP) and FVIII:C with occurrence of clinical bleeding. GENA-21 was a prospective, open-label, phase IIIb study investigating the safety and efficacy of Nuwiq® (human-cl rhFVIII) in previously treated adults with severe haemophilia A. The study included a 72-hour pharmacokinetic (PK) evaluation phase and a 6-month personalized prophylaxis phase in which treatment was guided by PK parameters. This subanalysis assessed FVIII:C by one-stage assay and ETP by thrombin generation assay in blood samples. Baseline mean ETP was lower in the 7 patients who experienced sBEs during personalized prophylaxis versus 25 who did not (n = 32 with data from PK phase and prophylaxis phase; P = .0002). During personalized prophylaxis (n = 49), only patients with lower median trough ETP experienced sBEs (8/49 patients; ROC AUC = 0.9421; P < .0001); there was no significant relationship for FVIII:C in predicting sBEs (ROC AUC = 0.5838; P = .4750). Directly following infusion of human-cl rhFVIII, ETP was lower in patients who experienced sBEs versus those who did not (P = .0002), whereas FVIII:C did not differ significantly between these groups. In adults with severe haemophilia A and reduced thrombin generation, increased frequency of spontaneous bleeding was observed irrespective of trough FVIII levels. Thus, personalized prophylaxis should take into account variables other than FVIII:C. Large prospective trials are needed to verify ETP as a marker for spontaneous bleeding. © 2018 John Wiley & Sons Ltd.

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