A modified thrombin generation assay to evaluate the plasma coagulation potential in the presence of emicizumab, the bispecific antibody to factors IXa/X

Int J Hematol. 2020 Nov;112(5):621-630. doi: 10.1007/s12185-020-02959-x. Epub 2020 Aug 3.

Abstract

Emicizumab shortens activated partial thromboplastin time (aPTT) greater than Factor (F)VIII. Clot waveform analysis triggered by ellagic acid and tissue factor trigger (Elg/TF) provided a useful means of assessing emicizumab activity. Thrombin generation assays (TGA) using this trigger reagent might also overcome the difficulties associated with aPTT by emicizumab. To compare TGA triggered by Elg/TF and other reagents (FXIa, TF) for evaluating emicizumab activity. Emicizumab, FVIII, or FVIII-bypassing agents (BPAs) were incubated with FVIII-deficient plasmas prior to TGA initiated by Elg/TF (0.2 μM/0.5 pM), FXIa (5.21 pM), or TF (PPP-Reagent LOW®). Emicizumab, FVIII, or BPAs increased peak thrombin generation (peak-Th) dose-dependently using Elg/TF-trigger and the other triggers. Low responses were evident with FXIa-trigger and the enhanced effects remained below normal levels with Elg/TF-trigger. Experiments using FVIII with emicizumab demonstrated an additive effect on peak-Th using Elg/TF-trigger, and this effect appeared to be less at FVIII ≥ 40 IU/dl. BPAs with emicizumab appeared to mediate additive effects, although its effects were variable. Parameters of thrombin generation from BPAs and emicizumab with Elg/TF-trigger were improved to normal level compared to low TF-trigger. Elg/TF-TGA could evaluate global coagulation potential during emicizumab prophylaxis including concomitant therapy with FVIII or BPAs.

Keywords: Bispecific antibodies; Blood coagulation tests; Factor VIII; Hemophilia A; Treatment.

MeSH terms

  • Antibodies, Bispecific / pharmacology*
  • Antibodies, Bispecific / therapeutic use*
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Blood Coagulation Tests / methods*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Drug Therapy, Combination
  • Factor VIII / pharmacology
  • Factor VIII / therapeutic use*
  • Factor X / immunology*
  • Hemophilia A / blood
  • Hemophilia A / complications
  • Hemophilia A / drug therapy*
  • Hemorrhage / etiology
  • Hemorrhage / prevention & control*
  • Humans
  • Partial Thromboplastin Time*
  • Thrombin / metabolism*

Substances

  • Antibodies, Bispecific
  • Antibodies, Monoclonal, Humanized
  • emicizumab
  • Factor VIII
  • Factor X
  • Thrombin