College of American Pathologists Conference XXXI on Laboratory Monitoring of Anticoagulant Therapy

Abstract

Thromboembolism is a common clinical problem that is associated with serious morbidity and mortality if not appropriately treated. For nearly 50 years, the therapy of venous thromboembolism has centered around the use of heparin and warfarin. Use of these agents has always presented a double-edged sword; too little anticoagulation is associated with a higher risk of recurrent thrombosis, while too much anticoagulation is associated with a higher risk of bleeding. Thus, laboratory tests were introduced at an early point to monitor the therapy of these 2 agents; indeed, laboratory monitoring of anticoagulant therapy is one of the oldest forms of therapeutic drug monitoring. Heparin and warfarin have traditionally been monitored with global assays of coagulation, such as the prothrombin time, the Lee-White clotting time, and the activated partial thromboplastin time (aPTT). These tests were introduced before the pharmacology of these agents and the nature of the tests were fully understood, in part because it was felt that the degree of prolongation of these global tests reflected the degree of antithrombotic activity of the drugs. Since their introduction into clinical usage, considerable progress has been made in our understanding of the pharmacology of these agents. During this time, new insights into the laboratory tests used to monitor these agents have also been gained. Comparison of clinical trials of oral anticoagulant therapy conducted in the United States and Europe during the 1970s and early 1980s demonstrated that oral anticoagulant therapy in the United States was associated with a higher rate of bleeding. This was ultimately linked to differences in the average dosage of oral anticoagulants administered, with the dosage being related to the prothrombin time used to monitor these patients. 1 It became apparent that there were significant discrepancies between the prothrombin times obtained using American versus European reagents. A method was devised to calibrate the response of prothrombin time reagents so that a uniform measure of anticoagulation could be reported by all laboratories; thus was born the international normalized ratio (INR). 2 Although first recommended in 1983, the INR was not widely adopted in the United States