Abstract
Prothrombin complex concentrates (PCC) are fractionated plasma protein drugs that reverse warfarin anticoagulation. PCC may control more general bleeding. We sought to identify the dominant procoagulant factor in PCC in vivo. We tested PCC or coagulation factor (F) treatment in CD1 mice made coagulopathic by exchange of whole blood for washed red cells. Anesthetized mice were transfused with murine fresh-frozen plasma (mFFP), PCC, mixtures of human vitamin K-dependent proteins (VKDP) (prothrombin, FVII, FIX, or FX), or purified single human VKDP, immediately prior to tail transection (TT), liver laceration (LL), or intravascular laser injury (ILI). Plasma donor mice were treated with vehicle or control antisense oligonucleotide (ASO-CON) or ASO specific for prothrombin (FII) (ASO-FII) to yield mFFP or ASO-CON mFFP or ASO-FII mFFP. Blood losses were determined spectrophotometrically (TT) or gravimetrically (LL). Thrombus formation was quantified by intravital microscopy of laser-injured arterioles. PCC or four factor- (4F-) VKDP or prothrombin significantly reduced bleeding from TT or LL. Omission of prothrombin from 4F-VKDP significantly reduced its ability to limit bleeding. Mice transfused with ASO-FII mFFP demonstrated inferior haemostasis versus those transfused with ASO-FII following TT, LL, or ILI. Prothrombin is the dominant procoagulant component of PCC and could limit bleeding in trauma.
Highlights
The restoration of haemostasis in the bleeding patient is challenging in coagulopathy, whether it arises from quantitative or qualitative deficiencies of clotting factors[1]
Our results suggest that prothrombin is the most important component of Prothrombin complex concentrates (PCC) formulations with respect to anti-hemorrhagic efficacy in vivo in mice, since purified prothrombin itself replicates the anti-hemorrhagic effects of PCC and antisense oligonucleotide-mediated depletion of prothrombin in donor mouse plasma eliminates its anti-hemorrhagic efficacy
We employed the Blood exchange-induced coagulopathy approach (BECA) mouse model in this study as a simplified model of coagulopathy with a bleeding diathesis, one that we had previously shown responded to plasma transfusion[18]
Summary
The restoration of haemostasis in the bleeding patient is challenging in coagulopathy, whether it arises from quantitative or qualitative deficiencies of clotting factors[1]. Limited clinical evidence suggests that PCC and/or fibrinogen concentrate administration may improve outcomes and reduce platelet and red cell transfusion requirements in patients with major blunt trauma[12]. We established a reductionist coagulopathic mouse model (Blood Exchange-induced Coagulopathy Approach, BECA) in which bleeding responds to plasma transfusion[18]. We hypothesized that administering PCC or one or more components of PCC would drive thrombin generation and fibrin formation in vivo, restoring haemostatic control and reducing bleeding. We tested this hypothesis in BECA mice subjected to tail transection, liver laceration, or intravascular laser injury. Our results suggest that prothrombin is the most important component of PCC formulations with respect to anti-hemorrhagic efficacy in vivo in mice, since purified prothrombin itself replicates the anti-hemorrhagic effects of PCC and antisense oligonucleotide-mediated depletion of prothrombin in donor mouse plasma eliminates its anti-hemorrhagic efficacy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
