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

Summary

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.

Introduction

The long-term use of oral anticoagulants and antithrombotic drugs for the prevention of thrombotic and thromboembolic vascular events is increasing.¹ Intracerebral bleeding is the most feared complication of these treatments. At symptom onset, about 20% of all patients with acute intracerebral haemorrhage are receiving anticoagulant treatment, and up to 30% take platelet inhibitors;2, 3 by contrast, only about 6% of a population with similar characteristics and without intracerebral haemorrhage were on anticoagulants and roughly 23% took platelet inhibitors, which suggests that symptomatic intracerebral haemorrhage is more common in patients using these drugs.⁴ Since these drugs interfere with haemostasis, the assumption that such medications are associated with larger haematoma volumes and, subsequently, a worse functional outcome seems intuitive.5, 6, 7 Consequently, the rapid reversal of anticoagulation with concentrated coagulation factors or recombinant factor VIIa and the transfusion of platelets are potential treatment options to promote haemostasis and to reduce haematoma growth.8, 9 In the past few years, several clinical case series and observational studies have addressed the pathophysiology of and treatment strategies in anticoagulation-associated intracerebral haemorrhage.³ All these studies were non-randomised and each only included a few patients, which precluded adequate control for confounding factors.¹⁰ However, such confounders seem to be crucial, since patients taking anticoagulants are unlikely to be identical in terms of clinical variables, such as concomitant diseases. Furthermore, large-scale randomised trials can rarely be performed because only a small proportion of patients qualify for study inclusion.¹¹ Thus, many questions remain unanswered, and clear clinical data with strong supportive evidence are unlikely to be available soon.

This area of research could benefit from being addressed in a translational “from-bedside-to-bench-to-bedside” approach, since a standardised and randomised experimental setting might overcome some of the limitations associated with non-randomised clinical trials.¹² This Review provides an overview of experimental studies in anticoagulation-associated intracerebral haemorrhage, and discusses their findings in the context of specific clinical questions.