Thrombin Generation and Bleeding Phenotype during Personalized Prophylaxis with Recombinant Human FVIII in Previously Treated Patients with Severe Hemophilia A
Authors: Dargaud Yesim G. , Klamroth Robert , Rusen Luminita , Windyga Jerzy , Bichler Johann , Knaub Sigurd , Negrier Claude 
Published: November 2019

Abstract
Background and objectives
In apharmacokinetic (PK)-guided personalized prophylaxis study with human-cl rhFVIII(Nuwiq®), a factor VIII (FVIII) concentrate from a human cell line,58% of the previously treated adult patients (PTPs) with severe hemophilia A received 2 or fewer prophylactic infusions per weekwith a median dosing interval of3.5 days. Seventy-three percent (73%) of patients did not experience any bleeding and 83% had no spontaneous bleeding episodes during the 6-month personalized prophylaxis period. The objective of this analysis was to evaluate the relationship between endogenous thrombin generation (TG) as well as FVIII plasma concentrations with the bleeding phenotype.
Study design and methods
This prospective, open-label, multicenter study included 66 adult PTPs with severe hemophilia A. After the previously given FVIII concentrate was washed out, patients received human-cl rhFVIII(60 IU/kg) for PK evaluation. Individual PK data were analyzed to determine doses and injection intervals that would theoretically result in a trough FVIII plasma level of ≥1%. Individualized prophylaxis lasted 6 months. TG and FVIII:C plasma concentrations were measured before and during the PK assessment, and trough TG and FVIII:C levels were measured 2, 4 and 6 months after the start of personalized prophylaxis. For TG, blood was drawn in trisodium citrate tubes (0.106 M) containing 1.45 µM corn trypsin inhibitor, centrifuged twice to obtain platelet poor plasma, and stored frozen until central analysis. TG was initiated by adding tissue factor (1 pM), and endogenous thrombin potential (ETP) was measured using the calibrated, automated TG assay.FVIII:C was measured using one-stage (automated APTT, Trinity Biotech, Siemens BCX-XP) and chromogenic assays (Coatest SP FVIII Kit, Chromogenix, Siemes BCS-XP).
Results
Data on both baseline ETP and bleeding rate during PK-guided individualized prophylaxis were available for 32 patients. Twenty-one patients did not experience any bleeding episode, and 25 patients had no spontaneous bleeding episodes. The mean baseline ETP did not differ between patients with and without any bleeding (373 ± 334 vs 367 ± 168 nmol*min), but was considerably lower in patients who had spontaneous bleeding episodes compared with those without spontaneous bleeding episodes (164 ± 66 vs 426 ± 231 nmol*min). Data on trough ETPs and FVIII:C during personalized prophylaxis were available for 34 patients.Patients with low TG potential tended to experience more frequent spontaneous bleeding episodes during this phase of the protocol (Figure 1), while low FVIII:C levels seemed to be less related to spontaneous bleeding episodes.
Conclusions
Low TG capacity seems to be correlated with increased frequency of spontaneous bleeding episodes, irrespective of trough FVIII plasma levels. Further prospective studies should be carried out to evaluate the value of this global coagulation parameter in the personalization prophylactic treatment in patients with hemophilia A in comparison with trough FVIII coagulant activity.
Figure 1 Figure 1.

Disclosures
Klamroth: Biogen Idec: Other: honoraria for advisory boards and speaker fees; Baxalta: Other: honoraria for advisory boards and speaker fees ; Bayer: Other: honoraria for advisory boards and speaker fees; CSL Behring: Other: honoraria for advisory boards and speaker fees; NovoNordisk: Other: honoraria for advisory boards and speaker fees; SOBI: Other: honoraria for advisory boards and speaker fees; pfizer: Other: honoraria for advisory boards and speaker fees; Octapharma: Other: honoraria for advisory boards and speaker fees; uniqure: Other: honoraria for advisory boards and speaker fees. Windyga:Biogen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Aspen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Nordisk: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Alexion: Other: Speaker's honorarium; Sanofi: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Octapharma: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Baxalta, now part of Shire: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Patents & Royalties, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau. Bichler:Octapharma: Employment. Knaub:Octapharma: Employment. Negrier:NovoNordisk: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; LFB: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Pfizer: Research Funding; SOBI: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees.