Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate

• Published in: Journal of thrombosis and haemostasis Vol. 10; no. 9; pp. 1830 - 1840
• Main Authors: LAMBOURNE, M. D., ELTRINGHAM‐SMITH, L. J., GATAIANCE, S., ARNOLD, D. M., CROWTHER, M. A., SHEFFIELD, W. P.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-09-2012
• Subjects: Animals; Anticoagulants - adverse effects; Antithrombin Proteins - adverse effects; Benzimidazoles - adverse effects; bleeding; Blood Coagulation Disorders - chemically induced; Blood Coagulation Disorders - physiopathology; Blood Coagulation Disorders - therapy; Dabigatran; dabigatran etexilate; fresh‐frozen plasma (FFP); Mice; Prothrombin - administration & dosage; prothrombin complex concentrates (PCCs); Pyridines - adverse effects; warfarin; Warfarin - adverse effects
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2012.04863.x

Background:  Both established oral anticoagulants such as warfarin and newer agents such as dabigatran etexilate (DE) effectively prevent thromboembolic disease, but may provoke bleeding. Limited clinical data exist linking oral anticoagulant reversal and bleeding tendency, as opposed to surrogate laboratory markers.
Objective:  To quantify bleeding in warfarin‐anticoagulated and DE‐anticoagulated mice by tail transection with or without pretreatment with potential reversal agents: prothrombin complex concentrate (PCC); activated PCC (APCC); recombinant factor VIIa (rFVIIa); or murine fresh‐frozen plasma (FFP).
Methods:  CD1 mice were given warfarin or DE by gavage, and the effects on in vitro coagulation assays, volume of blood loss and the bleeding time following tail transection injury were evaluated with different reversal agents.
Results:  PCC (14.3 IU kg−1), but not rFVIIa (3 mg kg−1) or FFP (12 mL kg−1), normalized blood loss and bleeding time in mice with warfarin‐induced elevations of mean prothrombin time at two intensities (prothrombin time ratios of either 4.3 or 24). Neither separate nor combined PCC and/or rFVIIa treatment nor APCC (100 U kg−1) treatment significantly reduced blood loss in mice anticoagulated with 60 mg kg−1 DE 75 min prior to tail transection. Both combined PCC plus rFVIIa treatment and APCC treatment significantly reduced bleeding time in the DE‐treated mice.
Conclusions:  Our data suggest that PCC treatment prevents excess bleeding much more effectively in warfarin‐induced coagulopathy than in DE‐induced coagulopathy.