TY - JOUR
T1 - Thrombin generation in plasma of patients with haemophilia A and B with inhibitors
T2 - Effects of bypassing agents and antithrombin reduction
AU - Livnat, Tami
AU - Sehgal, Alfica
AU - Qian, Kun
AU - Van Nguyen, Huy
AU - Madigan, Kate
AU - Sorensen, Benny
AU - Kenet, Gili
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/5
Y1 - 2020/5
N2 - 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.
AB - 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.
KW - Activated prothrombin complex concentrate
KW - Antithrombin
KW - Bypassing agents
KW - Haemophilia with inhibitors
KW - Recombinant FVIIa
KW - Thrombin
UR - http://www.scopus.com/inward/record.url?scp=85079380917&partnerID=8YFLogxK
U2 - 10.1016/j.bcmd.2020.102416
DO - 10.1016/j.bcmd.2020.102416
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C2 - 32066048
AN - SCOPUS:85079380917
SN - 1079-9796
VL - 82
JO - Blood Cells, Molecules, and Diseases
JF - Blood Cells, Molecules, and Diseases
M1 - 102416
ER -