Intracerebral haemorrhage associated with antithrombotic treatment: translational insights from experimental studies

Abstract

Little is known about the pathophysiology of intracerebral haemorrhage that occurs during anticoagulant treatment. In observational studies, investigators have reported larger haematoma volumes and worse functional outcome in these patients than in those with intracerebral haemorrhage and a normal coagulation status. The need to prevent extensive haematoma enlargement by rapid reversal of the anticoagulation seems intuitive, although no evidence is available from randomised clinical trials. New oral anticoagulants, such as the direct thrombin inhibitor dabigatran and the factor Xa inhibitor rivaroxaban, have been approved recently; however, intracerebral haemorrhage during dabigatran or rivaroxaban anticoagulation has not been characterised, and whether anticoagulation reversal can be beneficial in this scenario is unknown. In a translational approach, new experimental models have been developed to study anticoagulation-associated intracerebral haemorrhage in more detail and to test treatment strategies. Vitamin k antagonists enlarge haematoma volumes and worsen functional outcome in animal models. Rapid reversal of anticoagulation in the experimental setting prevents prolonged haematoma expansion and improves outcome. The new oral anticoagulants increase intracerbral haemorrhage volumes less than does warfarin. Haemostatic approaches that have been used for vitamin k-associated intracerebral haemorrhage also seem to be effective in intracerebral haemorrhage associated with the new anticoagulants. These experimental studies are valuable for filling gaps in knowledge, but the results need careful translation into routine clinical practice.

Figure 1. Representative CT scans of intracerebral haemorrhage

(A) This patient presented without medical history of anticoagulants. (B) This patient had raised international normalised ratio values and a positive history of vitamin K antagonist treatment at presentation. A fluid blood level is seen as a result of non-coagulated blood within the haematoma. (B) Reproduced from reference , by permission of the American Heart Association.

Figure 2. Collagenase-induced intracerebral haemorrhage in a murine model

(A) Schematic experimental study protocol. After a defined period of anticoagulation, intracerebral haemorrhage is induced by stereotactic administration of collagenase into the right striatum. After the follow-up period, functional outcome and haematoma volume are measured. (B) Similar study design, but with reversal of anticoagulation after intracerebral haemorrhage induction to assess the effects of haemostatic agents. (C) Representative brain sections obtained 24 h after intracerebral haemorrhage induction in anticoagulation-naive (control) and warfarin-treated (warfarin) animals. Note larger haematoma size, higher clot density, and spots of non-coagulated blood in the warfarin-treated animal.

Figure 3. In-vivo femtosecond laser-induced microhaemorrhage formation

(A) In-vivo two-photon excited fluorescence (2PEF) image frames showing rapid expansion of the microhaemorrhage after irradiation of a penetrating arteriole about 100 μm beneath the cortical surface with a single, 800 nm wavelength, 100 fs duration, roughly 1 μJ energy laser pulse. Laser energy is only absorbed in the focal volume, leading to damage to and rupture of the vessel wall, but with no direct laser damage to surrounding tissue, thus producing a model of cortical microhaemorrhage. Fluorescently labelled blood plasma is red. The blood plasma and red blood cells (seen as dark shadows in the sea of fluorescent plasma) are pushed into the brain parenchyma. Neurons and astrocytes are labelled green with Oregon green BAPTA. (B) In-vivo 2PEF image stacks of fluorescently labelled blood plasma spanning a 20 μm depth centred at the microhaemorrhage origin in warfarin-treated animals and controls. Extravasated plasma is detected as diffuse fluorescence, in a halo surrounding the target vessel. The dark core immediately adjacent to the target vessel is filled with red blood cells. The warfarin-treated animal has a larger haematoma volume than the control. Image (A) reproduced from reference , by permission of OSA, the Optical Society.