Use and safety of unfractionated heparin for anticoagulation during maintenance hemodialysis

Abstract

Anticoagulation is essential to hemodialysis, and unfractionated heparin (UFH) is the most commonly used anticoagulant in the United States. However, there is no universally accepted standard for its administration in long-term hemodialysis. Dosage schedules vary and include weight-based protocols and low-dose protocols for those at high risk of bleeding, as well as regional anticoagulation with heparin and heparin-coated dialyzers. Adjustments are based largely on clinical signs of under- and overanticoagulation. Risks of UFH use include bleeding, heparin-induced thrombocytopenia, hypertriglyceridemia, anaphylaxis, and possibly bone mineral disease, hyperkalemia, and catheter-associated sepsis. Alternative anticoagulants include low-molecular-weight heparin, direct thrombin inhibitors, heparinoids, and citrate. Anticoagulant-free hemodialysis and peritoneal dialysis also are potential substitutes. However, some of these alternative treatments are not as available as or are more costly than UFH, are dependent on country and health care system, and present dosing challenges. When properly monitored, UFH is a relatively safe and economical choice for anticoagulation in long-term hemodialysis for most patients.

Figure 1

Coagulation cascade. The dialyzer membrane activates the coagulation cascade primarily through the activation of leukocytes, which release tissue factor, triggering the extrinsic pathway. Exposure of the membrane to factor XII may also play a procoagulant role. Unfractionated heparin (UFH) binds to antithrombin, which then inhibits both factor Xa and thrombin, halting the coagulation cascade. Low-molecular-weight heparin (LMWH) primarily acts by inhibiting factor Xa because it generally is too short to link antithrombin and thrombin. Direct thrombin inhibitors (DTIs), as the name implies, stop the cascade by inhibiting thrombin. Heparinoids, similar to LMWH, inhibit factor Xa. Citrate stops coagulation by binding calcium (Ca²⁺).

Figure 2

Mechanism of thrombosis in heparin-induced thrombocytopenia. Several mechanisms contribute to thrombosis in heparin-induced thrombocytopenia. Platelet factor 4–heparin–immunoglobulin G (IgG) complexes bind to the Fcg receptor IIA on platelets, leading to platelet aggregation, acceleration of soluble clotting reactions (such as the conversion of factor II [prothrombin] to factor IIa [thrombin]), and activation of neighboring endothelial cells. IgG antibodies bind to heparin–platelet factor 4 complexes on the surface of endothelial cells, leading to additional endothelial-cell activation. Endothelial-cell activation in turn may lead to focal changes in the expression of endothelial-derived procoagulants and anticoagulants. Finally, platelet microparticles, which may be increased in heparin-induced thrombocytopenia, have increased procoagulant activity. Reproduced from Aird and Mark with the permission of the Massachusetts Medical Society.