**Indirect thrombin inhibitors**

*Heparin* 

Heparin is found in the liver and mast cell granules. Commercial heparin is extracted from bovine or porcine sources and is a mixture of acid mucopolysaccharides with molecular weights ranging from 3000 to 60,000 daltons. It is available in this unfractionated form and also as various low-molecular weight preparations. Heparin reversibly binds to antithrombin III, thereby enhancing inhibition of FIX, FX, FXI, FXII, FXIII, thrombin and also plasmin. At high concentrations heparin also inhibits platelet aggregation.

Unfractionated heparin is given intravenously or subcutaneously and is also used to anticoagulate the cardiopulmonary bypass circuit in cardiac surgery. Intravenous doses are titrated to a target range of ACT or APTT. The biological half-life is 1hr at physiological temperature but longer at lower temperatures during cardiopulmonary bypass. Heparin effects are reversed by protamine, a base that forms a stable, inactive salt complex with the acidic heparin.

Low-molecular weight heparin preparations have an average molecular weight below 8000 daltons. They are more effective at inhibiting factor Xa than unfractionated heparin, with less of an effect on thrombin. Their longer half-life and more predictable pharmacokinetic profile make them suitable for once-daily subcutaneous dosing without routine coagulation monitoring. APTT is not altered by LMWH so if monitoring is needed, anti-Xa levels are measured; this is useful for patients with renal impairment or at extremes of weight. LMWH effects cannot be reversed with protamine.

Side-effects of heparin can include hyperkalaemia and Heparin-induced Thrombocytopaenia (HIT). HIT has a frequency of 2.6% when unfractionated heparin is used, and 0.2% with LMWH (12). The most severe form of HIT is immune-mediated and can be complicated by thrombosis. Platelet counts should therefore be monitored in patients receiving heparin. If HIT occurs, heparin should be discontinued and an alternative anticoagulant used to reduce the risk of thrombosis. Warfarin should not be given to patients with HIT because of the high risk of warfarin necrosis, so alternatives such as lepirudin or danaparoid are chosen. A screening test for antibodies is the initial investigation when HIT is suspected. Patients testing positive proceed to the more specific serotonin release assay.

For post-CPB reversal of heparin, protamine sulphate is used. 1 mg of protamine neutralises the effect of 100 i.u of unfractionated heparin, by combining with heparin to form an inactive salt compound. Protamine acts within 5 minutes and can last for 2 hours. Effective protamine reversal is confirmed when the ACT returns to the baseline value.

Excess administration of protamine is undesirable, as it has its own intrinsic anticoagulant effect at high doses. It should be given slowly to minimise cardiovascular side-effects (systemic arterial vasodilatation and pulmonary arterial vasoconstriction), and the maximum administration rate in adults is 50mg per 10 minute period.

Protamine can only partially reverse the anticoagulant effect of LMWH.

#### **Other indirect thrombin inhibitors**

Warfarin reduces hepatic synthesis of FII. Factor Xa inhibitors will reduce activation of FII. These agents are considered by some sources to be indirect thrombin inhibitors and are covered elsewhere in this chapter.
