Novel insights and developments in thrombosis and haemostasis

The first part of this thesis focuses on direct oral anticoagulants (DOACs), a new class of antithrombotic agents which can be prescribed in a stable dosage, unlike their predecessors the Vitamin K antagonists (VKA). In healthy volunteers, prothrombin complex concentrate completely reversed the anticoagulant effect of DOAC rivaroxaban as assessed by coagulation assays, but not of dabigatran. Also, a post-hoc analysis showed evidence that major bleeding under treatment with rivaroxaban had a milder clinical presentation versus VKA associated bleeding. Suitable drug-specific antidotes for DOACs therefore do not appear to be necessary.
The second part of this thesis focuses on (the role of ADAMTS13 in) no-reflow.
Percutaneous coronary interventions (PCI) are known to be life-saving for treating acute myocardial infarctions (AMI), but nevertheless approximately 50% of all PCI are followed by no-reflow: a lack of reperfusion of the myocardium. No-reflow is associated with increased mortality and morbidity. Few therapies have shown success in substantially decreasing no-reflow. Unlike common belief that no-reflow is caused by microvascular obstruction of the pericardium, intramyocardial haemorrhage was detected by cardiac MRIs performed on pigs and patients, and using histopathologic findings from pigs with no-reflow. Metalloprotease ADAMTS13 diminishes the thrombotic properties of coagulation protein Von Willebrand Factor (VWF). In a prospective study following patients with AMI, ADAMTS13 levels were lower and VWF levels higher in case of no-reflow. In a porcine AMI model however, recombinant ADAMTS did not decrease damage caused by no-reflow. The alterations of ADAMTS13/VWF levels seem therefore to be compensatory and necessary.