**Direct thrombin inhibitors**

186 Perioperative Considerations in Cardiac Surgery

Thrombin (FIIa) is central to the coagulation process. It usually converts soluble fibrinogen to fibrin, stimulates platelets and activates FV, FVIII, FXI and FXIII. Thrombin inhibitors can

Heparin is long-established as an anticoagulant, which facilitates endogenous antithrombin to decrease activation of FII. The indirect mechanism has limited activity against thrombin that is bound to fibrin or fibrin degradation products (FDPs). In contrast, direct-acting

Heparin remains the most widely used drug in this class, but other agents are being investigated that may offer increased efficacy or a more favourable side-effect profile. Thrombin inhibitors may also have administrative advantages over heparin if they can be

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

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

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

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

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

work directly on FIIa, or indirectly by preventing activation of FII.

thrombin inhibitors (DTIs) inhibit bound, as well as free, FIIa.

given orally and if anticoagulation monitoring is unnecessary.

plasmin. At high concentrations heparin also inhibits platelet aggregation.

**10. Thrombin inhibitors** 

**Indirect thrombin inhibitors** 

*Heparin* 

acidic heparin.

serotonin release assay.

effects cannot be reversed with protamine.

This class includes Dabigatran, Argatroban, Bivalirudin, the recombinant Hirudins (eg lepirudin and desirudin) and also Melagatran and its prodrug Ximelagatran.

**Dabigatran** is a direct thrombin inhibitor, taken orally, which is being increasingly used in prevention of thromboembolism following lower limb joint replacement surgery. Dabigatran is also gaining a role in prevention of embolic stroke in patients with atrial fibrillation. The predictable pharmacokinetic profile allows a fixed-dose regimen to be used without routine coagulation monitoring. Dabigatran cannot be reversed. It should be discontinued at least 24hrs before elective surgery. In the event of life-threatening haemorrhage, non-specific prohaemostatic agents such as recombinant factor VIIa and prothrombin concentrate complexes could be considered; accelerated clearance using haemofiltration or charcoal filtration has also been suggested (13).

**Argatroban** is given intravenously and has a role in prevention/treatment of thrombosis and during Percutaneous Coronoary Interventions (PCI) in patients with HIT. It is metabolised hepatically so may be more appropriate than Lepirudin for patients with renal impairment. Its effect can be monitored by APTT.

**Hirudins** are direct thrombin (FIIa) inhibitors derived from chemicals found in leech saliva. Lepirudin and Desirudin are recombinant agents. Lepirudin is used to anticoagulate patients with HIT. It is given intravenously, titrated according to APTT(14), and cleared renally. Desirudin can be given subcutaneously to prevent thromboembolism.

Bivalirudin is a hirudin analogue, and can be used in combination with antiplatelet agents for patients undergoing percutaneous coronary intervention (PCI). It can be titrated according to ACT(14). Thrombin function recovers to normal approximately 1hr after Bivalirudin infusion is discontinued.

**Melagatran** and its prodrug **Ximelagatran** were withdrawn from the market after the EXTEND trial found potential risk of severe liver injury (15).
