Research using thrombin generation

The thrombin generation assay as a method for monitoring hemophilia A/B patients using novel factor concentrates or non-factor products.

Background

Severe hemophilia A or B (SHA, SHB) are a bleeding disorders caused by the absence of factor VIII or FVIX. SHA or B-patients receive prophylactic treatment to prevent spontaneous bleeds. Traditionally, treatment consisted of intravenous administration of e.g. standard factor FVIII (SHL) replacement concentrates or extended half-life (EHL) FVIII products. Recently, a new non-factor product called emicizumab was introduced. This bi-specific antibody mimics factor VIII activity. Subcutaneous administration of this drug may clinically resemble a mild hemophilia. In case of bleeding, additional FVIII (SHL or EHL) is given, wich will interfere with emicizumab. Conventional laboratory tests are unreliable for monitoring of novel non-factor products such as emicizumab effect on coagulation, especially in case of co-administration with FVIII. Global coagulation assays, like thrombin generation (TG), may be promising as a laboratory test to monitor the effectiveness of non-FVIII replacement products and the combination with SHL or EHL FVIII. 

Aims

  • To investigate the performance of a commercially available thrombin generation assay (TGA, CAT-1)and new developed TG assays in assessing FVIII , FIX and emicizumab activity levels, using (1) FVIII or FIX deficient plasma spiked with FVIII or FIX products and/or non-FVIII replacement products and (2) plasma samples from SHA or SHB-patients treated with SHL or EHL products in presence or absence of emicizumab.
  • To investigate the relation between the different TGAs and the bleeding fenotypes of the patients.

Innovative use of global testing (test candidates)

  • For direct clinical use
    • Commercial TGA assays which are CE marked and/or FDA approved
  • For future clinical use and pathophysiological research
    • Newly developed Thrombin generation assays.

Patients

  • In vitro studies with factor deficient plasma or plasma from healthy volunteers
  • Hemophilia A or B patients on different medication and on different clinical timepoints (trough values, peak values, steady state emicizumab, in acute bleeding or surgery before and after suppletion)