title: The fibrinogen but not the Factor VIII content of transfused plasma determines its effectiveness at reducing bleeding in coagulopathic mice.
abstract: BACKGROUND
  The evidence supporting plasma transfusion as a means to restore hemostatic control and prevent or treat bleeding is weak, leading to uncertainties as to which proteins affect the therapeutic quality of plasma. Some regulators focus on coagulation Factor (F)VIII activity, but whether this measure reflects overall transfusable plasma efficacy is questionable. We developed a mouse model of coagulopathy in which bleeding outcomes were responsive to plasma transfusion and addressed the relative contributions of FVIII and fibrinogen (Fg) to plasma quality.
  
  
  METHODS
  Anesthetized mice were rendered coagulopathic by four rounds of exchange of whole blood for washed red blood cells (RBCs) in 5% human albumin solution (HAS), which reduced RBCs, platelets, and plasma protein levels by 55, 66, and 80% of starting levels, in a blood exchange-induced coagulopathy approach (BECA). Before tail vein transection, BECA mice were transfused with HAS, wild-type murine fresh-frozen plasma (WT mFFP), or mFFP from FVIII-/- or Fg-/- knockout mice. BECA mice were also subjected to laser-induced arteriolar injury and thrombus formation quantified by intravital microscopy.
  
  
  RESULTS
  Transfusion of WT or FVIII-/- mFFP reduced blood loss by fourfold in BECA mice relative to HAS; Fg-/- mFFP had no effect. WT or FVIII-/- mFFP transfusion, but not that of Fg-/- mFFP, increased thrombus size in laser-injured BECA mice arterioles. Extended refrigerated storage of mFFP did not reduce its antihemorrhagic effects.
  
  
  CONCLUSIONS
  The content of Fg, but not FVIII, determined the efficacy of plasma transfusion in coagulopathic mice.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Eltringham-Smith
authors.affiliation: Centre for Innovation, Canadian Blood Services, Hamilton, Ontario, Canada.|Toronto, Ontario, Canada.|Vancouver, British Columbia, Canada.|Department of Laboratory Medicine, University of Toronto, Keenan Research Centre for Biomedical Science of St Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Xi
authors.initials: X
authors.lastname: Lei
authors.affiliation: Department of Laboratory Medicine, University of Toronto, Keenan Research Centre for Biomedical Science of St Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Adili
authors.initials: A
authors.lastname: Reheman
authors.affiliation: Centre for Innovation, Canadian Blood Services, Hamilton, Ontario, Canada.|Toronto, Ontario, Canada.|Vancouver, British Columbia, Canada.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Lambourne
authors.affiliation: Centre for Innovation, Canadian Blood Services, Hamilton, Ontario, Canada.|Toronto, Ontario, Canada.|Vancouver, British Columbia, Canada.|Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Pryzdial
authors.affiliation: Centre for Innovation, Canadian Blood Services, Hamilton, Ontario, Canada.|Toronto, Ontario, Canada.|Vancouver, British Columbia, Canada.|Department of Laboratory Medicine, University of Toronto, Keenan Research Centre for Biomedical Science of St Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Heyu
authors.initials: H
authors.lastname: Ni
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.|Centre for Innovation, Canadian Blood Services, Hamilton, Ontario, Canada.|Toronto, Ontario, Canada.|Vancouver, British Columbia, Canada.
authors.forename: William P
authors.initials: WP
authors.lastname: Sheffield
mesh_terms: D000818:Animals; D004912:Erythrocytes; D005169:Factor VIII / Q000378:metabolism*; D005260:Female; D005340:Fibrinogen / Q000378:metabolism*; D006461:Hemolysis; D006470:Hemorrhage / Q000628:therapy*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010951:Plasma Exchange / Q000379:methods*
chemical_list: D005169:Factor VIII; D005340:Fibrinogen