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In vitro studies show synergistic effects of a procoagulant bispecific antibody and bypassing agents
Author(s): ,
R. Hartmann
Affiliations:
Shire, Vienna, Austria
,
T. Feenstra
Affiliations:
Shire, Vienna, Austria
,
L. Valentino
Affiliations:
Shire, Bannockburn, USA
,
M. Dockal
Affiliations:
Shire, Vienna, Austria
F. Scheiflinger
Affiliations:
Shire, Vienna, Austria
Correspondence: Friedrich Scheiflinger, Shire, Donau‐City‐Strasse 7, 1220 Vienna, Austria|Tel.: +43 1 20 100 247 3410|E‐mail: fritz.scheiflinger@shire.com
ISTH Academy. Scheiflinger F.
Aug 2, 2018; 227419
Friedrich Scheiflinger
Friedrich Scheiflinger

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Journal Abstract
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Background
Investigational non‐factor products such as emicizumab offer a treatment option for patients with hemophilia and inhibitors. However, their mechanism of action raises questions regarding safety when they are combined with treatments for breakthrough bleeding.
Objectives
To evaluate in vitro thrombin generation (TG) and clot formation for combinations of activated prothrombin complex concentrate (aPCC), recombinant activated factor VII (rFVIIa), and a sequence‐identical analog of emicizumab (SIA).
Methods
Therapeutic concentrations of SIA (20–600 nm) alone or with aPCC (0.05–1 U mL), isolated aPCC components or rFVIIa (0.88–5.25 μg mL) were tested for TG and compared with reference ranges for healthy donor plasma. Coagulation of FVIII‐inhibited blood was determined with a widely established method, i.e. rotational thromboelastometry (ROTEM), and confirmed with the Total Thrombus‐formation Analysis System.
Results and conclusions
SIA (600 nm) or aPCC (0.5 U mL) alone resulted in peak thrombin levels of 21.4 nm and 38.6 nm, respectively, both of which are lower than normal (83.7 ± 29.8 nm). SIA plus aPCC (0.5 U mL) increased the peak thrombin level 17‐fold over SIA alone, exceeding the reference plasma value by 4.2‐fold. This hypercoagulable effect occurred with 600 nmSIA combined with as little as 0.25 U mL aPCC, confirmed by ROTEM. FIX was the main driver for enhanced TG. SIA plus rFVIIa (1.75 μg mL) induced a 1.8‐fold increase in the peak thrombin level in platelet‐rich plasma, but it did not reach the normal range. These in vitro experiments demonstrate excessive TG after administration of a combination of aPCC and SIA at clinically relevant doses. Careful judgement may be required when breakthrough bleeding is treated in patients receiving emicizumab.
Keyword(s)
activated partial thromboplastin time, emicizumab, FEIBA , hemophilia A, thrombotic microangiopathies
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