Hemostatic effect of activated factor VII without promotion of thrombus growth in melagatran-anticoagulated primates.
BACKGROUND
Pharmacological enhancement of coagulation using activated prothrombin complex concentrate (APCC) or activated factor VII (FVIIa) might be useful hemostatic approaches to bleeding emergencies during anticoagulant therapy. However, any such intervention should not increase thrombotic risk. We therefore investigated their hemostatic and prothrombotic potential during propagation of large arterial-type thrombin in anticoagulated baboons.


METHODS
High dose melagatran, a competitive inhibitor of thrombin (0.6 mg/kg/h), or inactivated FVIIa (FVIIai), a competitive inhibitor of FVIIa (2 mg/kg) were used for anticoagulation. APCC or FVIIa were administered to melagatran-anticoagulated animals only. Primary hemostasis was assessed as template bleeding time (BT). Thrombus formation was quantified as fibrin deposition (FD) and platelet deposition (PLD) in synthetic vascular grafts that were deployed for 40 min into arteriovenous shunts.


RESULTS
Melagatran (n=11) prolonged BT to 279% (95% CI +/-140%; P<0.019), reduced FD to 33% [+/-8%; P<0.001]; and PLD to 39% [+/-11%; P<0.001] of untreated controls. FVIIai (n=3) prolonged BT (222% [+/-51%; P<0.010]) without inhibiting thrombus propagation. APCC (n=10) reduced the antithrombotic effect of melagatran (FD 52% [+/-9%; P<0.002], PLD 61% [+/-17%; P=0.028] versus melagatran alone) at a dose (250 U/kg) that had no effect on the BT (327% [+/-150%; P=0.607]. Meanwhile, FVIIa (n=12) normalized the BT to 115% (+/-32%; P<0.05) at a dose (270 microg/kg) that was not yet prothrombotic (FD 26% [+/-4%; P<0.001], PLD 39% [+/-9%; P=0.970]).


CONCLUSIONS
Administration of FVIIa during antithrombotic treatment with direct thrombin inhibitors might support hemostasis before promoting the intraluminal expansion of thrombi.
Gruber
András
A
Department of Biomedical Engineering, OGI School of Science and Engineering, Oregon Health and Science University, 20000 N.W. Walker Road, Beaverton, OR 97006-8921, USA. gruber@ohsu.edu
Carlsson
Stefan
S
Kotzé
Harry F
HF
Marzec
Ulla
U
Sarich
Troy C
TC
Hanson
Stephen R
SR
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D016022:Case-Control Studies; D015942:Factor VIIa / Q000378:metabolism*; D006487:Hemostasis; D006801:Humans; D008297:Male; D010215:Papio; D011486:Protein C / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D013927:Thrombosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D011486:Protein C; D011994:Recombinant Proteins; C109573:melagatran; D015942:Factor VIIa