All of the nonhemorrhagic limitations are caused by the AT-independent, charge-dependent binding properties of heparin to proteins and surfaces. Pharmacokinetic limitations are caused by the AT-independent binding of heparin to plasma proteins, to proteins released from platelets, and possibly to endothelial cells, which result in the variable anticoagulant response to heparin and to the phenomenon of heparin resistance; AT-independent binding to macrophages and endothelial cells also result in the dose-dependent mechanism of clearance.
The biophysical limitations occur because the hepa-rin/AT complex is unable to inactivate factor Xa in the prothrombinase complex and thrombin bound to fibrin or to subendothelial surfaces. The biological limitations of heparin include osteopenia and HIT. Osteopenia is caused by the binding of heparin to osteoblasts, which then release factors that activate osteoclasts, whereas HIT results from heparin binding to platelet factor (PF) 4, forming an epitope to which the HIT antibody binds. The pharmacokinetic and non-anticoagulant biological limitations of heparin are less evident with LMWH, while the limited affinity of the heparin/AT complex to fibrin-bound thrombin and factor Xa has been overcome by several new classes of AT-independent thrombin and factor Xa inhibitors.
The anticoagulant effect of heparin is modified by platelets, fibrin, vascular surfaces, and plasma proteins. Platelets reduce the anticoagulant effect of heparin by protecting surface factor Xa from inhibition by heparin/AT complex and by secreting PF4, a heparin-neutralizing protein. Fibrin protects thrombin bound to its surface from inhibition by heparin/AT complex because heparin binds to fibrin, and bridges between fibrin and the heparin-binding site on thrombin. As a result, heparin increases the affinity of thrombin for fibrin and, by occupying the heparin-binding site on thrombin, protects fibrin-bound thrombin from inactivation by the hepa-rin/AT complex. Thrombin also binds to subendothelial matrix proteins, where it is protected from inhibition by heparin. These observations explain why heparin is less effective than the AT-independent thrombin and factor Xa inhibitors for preventing thrombosis at sites of deep arterial injury in experimental animals, and may explain why hirudin is more effective than heparin in patients with unstable angina and non-Q-wave MI.
The treatment of clinically severe bleeding in the course of heparin therapy includes antiheparin therapy in addition to supportive care and transfusion therapy. The effects of UFH can be rapidly antagonized by an IV bolus of protamine. Protamine is a basic protein derived from fish sperm that binds to heparin to form a stable salt. One milligram of protamine will neutralize approximately 100 U UFH.