Hemostatic Therapy in Experimental Intracerebral Hemorrhage Associated With the Direct Thrombin Inhibitor Dabigatran

Abstract

Background and Purpose-Dabigatran-etexilate (DE) recently has been approved for stroke prevention in atrial fibrillation. However, lack of effective antagonists represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with dabigatran, and to test the efficacy of different hemostatic factors in preventing hematoma growth. Methods-In C57BL/6 mice receiving DE (4.5 or 9.0 mg/kg), in vivo and in vitro coagulation assays and dabigatran plasma levels were measured repeatedly. Thirty minutes after inducing ICH by striatal collagenase injection, mice received an intravenous injection of saline, prothrombin complex concentrate (PCC; 100 U/kg), murine fresh-frozen plasma (200 L), or recombinant human factor VIIa (8.0 mg/kg). ICH volume was quantified on brain cryosections 24 hours later. Results-DE substantially prolonged tail vein bleeding time and ecarin clotting time for 4 hours corresponding to dabigatran plasma levels. Intracerebral hematoma expansion was observed mainly during the first 3 hours on serial T2* MRI. Anticoagulation with high doses of DE increased the hematoma volume significantly. PCC and, less consistently, fresh-frozen plasma prevented excess hematoma expansion caused by DE, whereas recombinant human factor VIIa was ineffective. Prevention of hematoma growth and reversal of tail vein bleeding time by PCC were dose-dependent. Conclusions-The study provides strong evidence that PCC and, less consistently, fresh-frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with dabigatran. The efficacy and safety of this strategy must be further evaluated in clinical studies. Key Words: anticoagulation Ⅲ factor VIIa Ⅲ fresh-frozen plasma Ⅲ prothrombin complex concentrate Ⅲ stroke I mproving treatment strategies to prevent stroke in atrial fibrillation (AF) represents a key medical challenge worldwide. Oral anticoagulation (OAC) with vitamin K antagonists reduces the relative stroke risk by Ͼ60%, 1 but vitamin K antagonist have multiple undesirable properties that have resulted in undertreatment of patients at risk. 2 Consequently, new oral anticoagulants have been developed that directly inhibit the key coagulation factors thrombin or factor Xa, respectively. 3 The direct thrombin inhibitor dabigatranetexilate (DE) was recently approved for stroke prevention in AF after the RE-LY trial had shown that DE is not inferior or even superior to warfarin in preventing stroke without compromising bleeding. 4 -6 Although the benefits of OAC outweigh the risk in AF by several fold, 7 intracerebral hemorrhage (ICH) remains the most serious and lethal complication of long-term use of OAC. 8 The mortality for oral anticoagulant-associated ICH (OAC-ICH) is substantially higher than that of spontaneous ICH. 9,10 A major goal of ICH management is to prevent secondary hematoma growth because hematoma size affects outcome after ICH substantially. 11 Current guidelines for managing OAC-IC...

Translational Insights into Traumatic Brain Injury Occurring during Dabigatran or Warfarin Anticoagulation

“…In experimental studies, diminished bleeding times have been observed in the absence of measurable parameter changes after PCC administration. 12,25 In our third experimental series, the application of PCC 30 minutes after TBI for anticoagulation reversal did not prevent the development of larger bleeding volumes in some of the mice with excess dabigatran levels as compared with saline injections. Apart from an incomplete anticoagulation reversal, another explanation might be that the PCC injection occurred at a time that was too late to substantially change the hemorrhage volume after 24 hours.…”

“…Zhou et al 12 showed in the aforementioned study that PCC reduced bleeding expansion in mice with high levels of dabigatran. We investigated whether a similar effect could be achieved in the event of TBI.…”

“…12 For anticoagulation reversal, either 200 U/kg of four-factor PCC (Beriplex, CSL Behring, Marburg, Germany) or an equal amount of saline (200 mL) was injected into the tail vein 30 minutes after TBI in a masked fashion.…”

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

“…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],…”

Anticoagulant update

“…If reversal of NOACs is essential, haemodialysis has been recommended to eliminate dabigatran and there is some evidence that coagulation factor concentrates may be effective. [5][6][7] Now there is new evidence that an antibody fragment which binds dabigatran (aDabi-Fab) can reverse its anticoagulant effects 8 …”