Comparative effectiveness of hemostatic therapy in experimental warfarin-associated intracerebral hemorrhage.
OBJECTIVE
intracerebral hemorrhage associated with oral anticoagulants has a poor prognosis. Current treatment guidelines are based on case series and plausibility only, and a common consensus on effective hemostatic therapy is missing. We compared the effectiveness of diverse hemostatic approaches in a mouse model of warfarin-associated intracerebral hemorrhage.


METHODS
male C57BL/6 mice received anticoagulant treatment with warfarin (0.4 mg/kg for 3 days). Intracerebral hemorrhage was induced by striatal injection of collagenase, and 30 minutes later, mice received an intravenous injection of saline (200 μL n=15), prothrombin complex concentrate (100 U/kg, n=10), fresh-frozen plasma (200 μL, n=13), recombinant human Factor VII activated (3.5 mg/kg, n=8 and 10 mg/kg, n=8), or tranhexamic acid (400 mg/kg, n=12). Intracerebral hemorrhage volume was quantified on T2-weighted images after 24 hours.


RESULTS
mean hematoma volumes were 7.4 ± 1.8 mm(3) in the nonwarfarin controls and 21.9 ± 5.0 mm(3) in the warfarin group receiving saline. Prothrombin complex concentrate (7.5 ± 2.3 mm(3)) and fresh-frozen plasma (8.7 ± 2.1) treatment resulted in significantly smaller hematoma volume compared with saline. Recombinant human Factor VII activated (10 mg/kg: 14.7 ± 3.4; 3.5 mg/kg: 15.0 ± 6.8 mm(3)) and tranexamic acid (16.2 ± 4.1 mm(3)) were less effective. Water content in the hemorrhagic hemisphere was similar in all groups except for tranexamic acid in which it was significantly increased.


CONCLUSIONS
prothrombin complex concentrate and fresh-frozen plasma effectively prevent hematoma growth in murine warfarin-associated intracerebral hemorrhage, whereas Factor VIIa was less effective. Tranexamic acid exacerbates perihematoma edema in this mouse warfarin-associated intracerebral hemorrhage model.
Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, Heidelberg 69120, Germany.
Sergio
S
Illanes
Wei
W
Zhou
Sönke
S
Schwarting
Sabine
S
Heiland
Roland
R
Veltkamp
D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects* / Q000494:pharmacology; D001779:Blood Coagulation Factors / Q000494:pharmacology*; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D017364:Collagenases / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D015942:Factor VIIa / Q000494:pharmacology*; D006406:Hematoma / Q000473:pathology / Q000517:prevention & control; D006487:Hemostasis; D006801:Humans; D008297:Male; D051379:Mice; D010949:Plasma; D011994:Recombinant Proteins / Q000494:pharmacology; D014148:Tranexamic Acid / Q000009:adverse effects / Q000494:pharmacology; D014859:Warfarin / Q000009:adverse effects* / Q000494:pharmacology
D000925:Anticoagulants; D001779:Blood Coagulation Factors; D011994:Recombinant Proteins; C025667:prothrombin complex concentrates; D014859:Warfarin; D014148:Tranexamic Acid; C103587:recombinant FVIIa; D015942:Factor VIIa; D017364:Collagenases