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

Abstract

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.

Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation

“…This approach has recently been tested in a study that showed an increased frequency of spontaneous bleeding in HA patients with reduced TG regardless of FVIII trough levels when patients were on personalized prophylaxis with human-cl rhFVIII (Nuwiq). 9 A follow-up study postulated a PK/PD non-linear relationship between FVIII and ETP, thereby creating a dosing tool for this FVIII product to even further personalize FVIII prophylaxis. 40 Our goal is to use our PD data to develop a uniform model to individualize FVIII replacement therapy based on PK/PD data for a range of FVIII products.…”

“…However, some patients still experience bleeding episodes despite adequate FVIII trough levels 6 . In general, severity of bleeding phenotype is roughly correlated with measured FVIII activity level but can vary between individual patients with an equal FVIII activity level 7‐9 . The underlying difference in bleeding phenotype and response to replacement therapy is yet to be determined, with individual variations in the hemostatic balance as a potential leading cause.…”

A new paradigm for personalized prophylaxis for patients with severe haemophilia A

“…For PK data, plasma FVIII:C was measured at a central laboratory (LabCorp) using a one‐stage assay (automated activated partial thromboplastin time [APTT] from Trinity Biotech, Siemens BCS‐XP). For PD data, TGA was performed using platelet‐poor plasma samples prepared according to a standardized protocol . Blood samples were drawn in tubes containing 1.45 μmol/L corn trypsin inhibitor (Haematologic Technologies).…”

“…For PD data, TGA was performed using platelet-poor plasma samples prepared according to a standardized protocol. 8 Blood samples were drawn in tubes containing 1.45 μmol/L corn trypsin inhibitor (Haematologic Technologies). Thrombin generation was measured using the calibrated automated thrombin generation test (CAT).…”

“…In an analysis of a sub-set of patients from GENA-21, a prospective phase IIIb study investigating the safety and efficacy of human-cl rhFVIII (Nuwiq ® , Octapharma AG) in patients with severe haemophilia A, we recently showed this PD endpoint to be a better marker of spontaneous bleeding than FVIII activity, with low ETP predicting patients at high risk for spontaneous bleeds during prophylaxis. 8 Here, we used a joint PK-PD model to describe a new tool to help physicians personalize prophylaxis for patients with severe haemophilia A. By incorporating both FVIII activity (FVIII:C) and ETP into the model, prediction of the correct dosage and frequency of FVIII infusions is improved.…”