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

Abstract

Summary. 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.

Reversal Agents: What We Have and What We Can Expect

“…PCCs are the preferred nonspecific hemostatic agent for NOAC reversal; they are plasma-derived products that contain three (factors II, IX, and X) or four (factors II, IX, X, and VII) clotting factors, in addition to variable amounts of heparin and the natural coagulation inhibitors protein C and protein S. Animal studies have demonstrated that PPCs have a variable ability to normalize anticoagulation parameters and to prevent or attenuate bleeding seen with NOAC usage. 14,[19][20][21][22][23][24][25] The limited data available in humans are restricted to healthy volunteers only. In three small, randomized, placebo-controlled studies involving between 12 and 93 patients, PCC use reversed the anticoagulant effects of rivaroxaban and edoxaban, but not of dabigatran.…”

Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents

“…Use of dabigatran was associated with a reduced risk of intracranial hemorrhage (hazard ratio [HR] = 0.34, 95 % CI 0.26-0.46) and death (HR = 0.86, 95 % CI 0.77-0.96) and an increased risk of major gastrointestinal bleeding (HR = 1.28, 95 % CI 1.14-1. 44) [4].…”

“…Human studies (dabigatrantreated healthy volunteers) PCC No reduction in blood loss after tail transection in mice [44] Reduced intracranial hematoma expansion and 24-hr mortality in mice [45] Reduced blood loss following kidney incision in rabbits [46] Reduced bleeding time, but not coagulation tests in rat tail transection model [18] Corrected some TG indices [25] Corrected PT, aPTT, TT and some TG indices [13] No correction of Hemoclot assay [13] No correction of aPTT, ECT, TT [9] aPCC No reduction in blood loss after tail transection in mice [44] Reduced bleeding time, but not coagulation tests in rat tail transection model [18] Corrected some TG indices [25] Corrected PT, aPTT and some TG indices [13] [23],…”

“…No correction of Hemoclot assay [13] rVIIa No reduction in blood loss after tail transection in mice [44] No reduction intracranial hematoma expansion and 24-h mortality in mice [4] [5]…”

Reversing targeted oral anticoagulants

“…31,32 In general, fewer studies found FVIIa to be effective than PCC or aPCC, and some studies found both PCC and FVIIa to be without benefit. 33 The reason for the inconsistent findings with FVIIa might be explained by the fact that in vitro studies suggest that FVIIa can reverse the effect of dabigatran at therapeutic levels, but the effectiveness of FVIIa declines as the dabigatran levels increase. 34 The animal models for studying reversal used a range of NOAC doses, with those using extremely high levels of dabigatran being less likely to show effective reversal.…”