LAUSR

Cardiovascular diseases are major contributors to morbidity and mortality and pose a huge burden to the health care system. Thrombosis is the most common etiology for ischemic heart disease, ischemic stroke, and venous thromboembolism.1 Over the last 100 years, there has been tremendous progress in the treatment of thromboembolic diseases. Currently, several highly effective anticoagulant options are available for treatment of venous thromboembolism: heparin(s), vitamin K antagonists, or direct‐acting oral anticoagulants; however, all anticoagulants pose an increased risk of bleeding. A retrospective market scan study of data collected between 2008 and 2011 in the United States showed that 28% of venous thromboembolism‐affected patients experienced bleeding within 1 year after diagnosis, with half of the episodes being a major bleeding event.2 Even though direct‐acting oral anticoagulants are safer with regard to major, fatal, and intracranial bleeding than vitamin K antagonists,3 the annual rates of major bleeding in clinical practice are still as high as 3% to 4%, as found in a prospective German study of patients who were treated with rivaroxaban.4 Hence, although they are extremely effective, the safety of the currently used anticoagulant drugs needs to be improved. The ideal anticoagulant should only target the pathological and unwanted fibrin formation in thrombosis and leave the (thrombin and) fibrin formation in hemostasis unaffected. Over the last years, considerable efforts have been made to find a safe anticoagulant by targeting factors up‐ stream of the coagulation cascade such as factor XI or factor XII.5 The first human studies targeting factor XI are very promising,6‐8 and in the near‐future the potential of this approach will become clear. A completely different approach for potential safe anticoagu‐ lation was identified by chance in a patient who presented with a traumatic subdural hemorrhage and greatly prolonged global plasma coagulation test results (prothrombin time, activated partial thromboplastin time, and thrombin time) due to an anti‐thrombin immunoglobulin A paraprotein.9 Testing of the antibody revealed a specific and high‐affinity interaction with the fibrinogen recog‐ nition site (exosite I) of thrombin. Although the patient presented with a traumatic bleed, the presence of the paraprotein did not lead to previous or subsequent bleeding episodes. With its spec‐ ificity to exosite I, the antibody does not interfere with other im‐ portant interactions of thrombin via its active site or exosite II. The antibody was made recombinantly and changed to a human immu‐ noglobulin G4 (now called JNJ‐9375) with identical characteristics compared to the paraprotein.10 JNJ‐9375 inhibited thrombin‐in‐ duced platelet aggregation but not the aggregation induced by other agonists. There was a small increase in lag time in thrombin generation analyses, but hardly any effects on peak thrombin or the endogenous thrombin potential. This may have been expected from the mode of action of the antibody that interferes with the thrombin‐fibrinogen interaction, an interaction that is not tested in thrombin generation. In a rat arteriovenous shunt model of throm‐ bosis, pretreatment with JNJ‐9375 dose‐dependently reduced thrombus formation with a better safety profile than its compara‐ tor apixaban.10 The logical next step was therefore to test the anti‐ body for thrombosis prophylaxis during orthopedic surgery. In this issue of the Journal of Thrombosis and Haemostasis, Weitz et al11 tested the antibody in a double‐blind, double‐dummy phase 2 trial in patients undergoing knee arthroplasty in the Targeting Exosite‐1 Thrombin Inhibition‐Total Knee Replacement (TEXT‐TKR) study.