Heparins

Unfractionated heparin (UFH) has been used for the prevention and treatment of thrombosis since the 1930s. It is a mixture of sulphated glycosaminoglycans of variable lengths and weights. Anticoagulant efficacy and pharmacologic properties vary with the size of the molecules. Heparin is obtained from porcine intestine and bovine lung tissues.⁹⁶

Low-molecular-weight heparins (LMWHs), derived from UFH by depolymerisation, were introduced in Europe in the 1980s.^{96, 100} Because of several clinical advantages, LMWHs have gradually replaced UFH for most indications. However, UFH continues to be used during cardiovascular surgery and catheter-based interventional procedures.^{101, 102}

Heparins and heparinoids are parenteral agents, administered either intravenously or subcutaneously. UFH binds to plasma proteins, platelets (platelet factor 4), macrophages, and endothelial cells. This limits bioavailability and accounts for the highly variable anticoagulant response. LMWHs have reduced binding to plasma proteins, platelets, and other cells. As a result, LMWHs have a more predictable dose response.¹⁰¹ The need for parenteral administration makes these agents both inconvenient and costly for long-term use, especially outside the hospital setting.¹⁷

Each LMWH product has a specific molecular weight distribution. This distribution determines its anticoagulant activity and duration of action, so each agent is considered a unique drug. Indications for LMWHs vary — one product cannot always be substituted for another. LMWHs in current use globally include enoxaparin, dalteparin, nadroparin, tinzaparin, certoparin, reviparin, and bemiparin.¹⁰²

Danaparoid, available in several countries, is classified as a heparinoid. It is composed of sulphated glycosaminoglycans and can be used as an alternative to heparin in patients suffering from an antibody-mediated form of heparin-induced thrombocytopenia (HIT).^{7, 86}

Heparin and its derivatives bind to a plasma cofactor, antithrombin (AT), to inactivate several coagulation enzymes, including Factors IIa (thrombin), Xa, IXa, XIa, and XIIa. Thrombin and Factor Xa are most responsive to inhibition by the heparin-AT complex.¹⁰¹ The efficacy of heparin-based anticoagulants increases as selectivity for Factor Xa increases: LMWH is superior to unfractionated heparin, and fondaparinux is superior to LMWH.¹⁷

Bleeding is the most common adverse event with heparin therapy. Major bleeding occurs in 0.8% of patients receiving full-dose UFH, but it is less frequent with low-dose subcutaneous heparin. LMWH has been reported to cause bleeding less frequently, but this finding has not been consistent across trials. Major bleeding occurs in less than 3% of patients and varies with product, indication, patient population, and dose.⁸⁶

One area of special concern is the risk of epidural haematoma with spinal anaesthesia. This risk is greater with LMWH than with UFH. Careful timing of dosing is essential when epidural or spinal anaesthesia is used.¹⁰³

If a patient on heparin develops severe bleeding, the anticoagulant effect can be reversed with protamine administered intravenously. Protamine neutralises heparin by forming a stable salt. Because protamine binds preferentially to larger heparin molecules, it is not as effective in reversing the effect of LMWHs.¹⁰¹

There are two forms of thrombocytopenia seen in patients receiving heparin. Nonimmune heparin-associated thrombocytopenia is benign; platelet counts rarely drop below 100,000/mm³ and return to normal, even on continued heparin therapy. It is not necessary to discontinue therapy. In contrast, immune-allergic heparin-induced thrombocytopenia (HIT) is a serious condition requiring urgent treatment. In HIT, antibodies form against the heparin-platelet factor 4 complex, leading to widespread thrombosis. HIT usually occurs in the first three weeks of therapy, so platelet counts should be monitored in patients receiving heparin for more than a few days. Treatment involves immediate replacement of heparin with a parenteral direct thrombin inhibitor (either argatroban or lepirudin) or with danaparoid.^{96, 104}