The use and limitations of unfractionated heparin

Despite the development of newer anticoagulants, unfractionated heparin remains an indispensible agent in the treatment of thrombotic disorders. Heparin exerts its major effect via antithrombin, converting antithrombin to a more efficient inhibitor of circulating thrombin (factor IIa), factor Xa, factor IXa, factor XIIa, and kallikrein. However, due to the multiple anticoagulant mechanisms of heparin, differential molecular weight-based clearance, issues of heparin resistance, and patient-specific characteristics (age, weight, gender, and tobacco), attaining therapeutic anticoagulation is complicated. As a result, a minority of patients in major clinical trials achieve an activated partial thromboplastin time within the target window in an appropriate time-frame despite the use of weight-based titration nomograms. The resultant under- or over-therapeutic anticoagulation is associated with increased risks of ischemic and bleeding complications, suggesting the importance of maintaining heparin anticoagulation within a relatively narrow therapeutic range. In this review we discuss the mechanisms of heparin action, clinical ramifications of incorrect dosing in major trials, and attempts to improve the achievement of therapeutic anticoagulation.