Thrombin generation in plasma of patients with haemophilia A and B with inhibitors: Effects of bypassing agents and antithrombin reduction

Tami Livnat, Alfica Sehgal, Kun Qian, Huy Van Nguyen, Kate Madigan, Benny Sorensen, Gili Kenet*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Antithrombin (AT) reduction has been shown to improve thrombin generation (TG) in haemophilia with or without inhibitors. As treatment with bypassing agents (BPAs) may be required in patients with breakthrough bleeding while receiving AT-lowering therapy, we assessed TG in platelet-poor plasma samples from haemophilia patients in the presence of BPA (recombinant activated factor VII [rFVIIa; 1.25 or 2.5 μg mL−1] or activated prothrombin complex concentrate [aPCC; 0.5 or 1 U mL−1]) and AT reduction (anti-AT antibody). Mean ± SEM baseline peak thrombin height was 19.9 ± 4.3 nM in plasma from haemophilia patients (n = 12) and 230.5 ± 9.8 nM in healthy males (n = 24). Reduced AT improved mean peak thrombin height in haemophilia patient plasma to 75.4 ± 17.4 nM. Spiking of 90% AT-reduced haemophilia patient plasma with 2.5 μg mL−1 rFVIIa or 1 U mL−1 aPCC increased the mean peak thrombin height to 82.5 ± 12 nM and 134.8 ± 18.7 nM, respectively. Peak thrombin levels did not exceed the range for healthy volunteers when plasma samples from haemophilia patients with in vitro AT reduction were treated with BPAs, suggesting the potential use of BPAs in conjunction with AT reduction. Further clinical investigations are needed to confirm the safety of this approach.

Original languageEnglish
Article number102416
JournalBlood Cells, Molecules, and Diseases
Volume82
DOIs
StatePublished - May 2020

Funding

FundersFunder number
BPL
Alnylam Pharmaceuticals
Sanofi Genzyme

    Keywords

    • Activated prothrombin complex concentrate
    • Antithrombin
    • Bypassing agents
    • Haemophilia with inhibitors
    • Recombinant FVIIa
    • Thrombin

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