Hirudin and its reversal

R. I. P. Dornan1, J. A. M. Anderson2 and E. L. Saenko2

1 Edinburgh, UK and 2 Belfast, UK

Editor—I read the informative editorial on heparin resistance by Anderson and Saenko1 with interest. However, experience forces me to point out a possible area for confusion. Currently, there is no drug reversal available for r-hirudin and reversal of its anticoagulant effect relies entirely on renal elimination (biological half-life of 1–1.5 h).2 In patients with poor renal function, r-hirudin has a prolonged half-life, which may lead to serious bleeding problems after cardiopulmonary bypass (CPB).3 Indeed, poor renal function can prolong the half-life of r-hirudin to 30 h, and end-stage renal failure can prolong it to more than 300 h. There may be little change with dialysis.4

Although haemofiltration used in conjunction with CPB is an established procedure and can be useful in accelerating the elimination of r-hirudin, some filter membranes will eliminate only 15–42% of the circulating drug.5 Given that r-hirudin has a molecular weight of less than 7000 Da and most filters have a pore size of 50 000 Da, this is unsurprising. R-hirudin will penetrate most filters in either direction—from plasma to ultrafiltrate and back again. The wide variation in membrane clearance rates presumably relates to the electrostatic charge on the membrane.

I was the anaesthetist responsible for a 71-year-old, 64-kg man with proven type II heparin-induced thrombocytopenia who required urgent coronary artery bypass grafting. Despite nearly normal preoperative serum creatinine (117 µmol litre–1), his preoperative glomerular filtration rate was only 41 ml min–1. A haemofiltration line was electively placed pre-bypass. In spite of careful monitoring of the hirudin level and ecarin clotting time, the measured r-hirudin level was 2.1 µg ml–1 (CPB therapeutic level 2.5–4 µg ml–1) after bypass. During the first four postoperative hours, blood loss was 1500 ml h–1. Haemofiltration (Baxter PSHF 1200) was instituted to little clinical effect. Samples taken from the circuit pre- and post-membrane showed a pre-filter hirudin level of 1.1 µg ml–1 and a post-filter level of 0.95 µg ml–1. In total, the patient required 41 units of packed red cells, six pools of platelets, 17 units of fresh frozen plasma and 32 units of cryoprecipitate. Over 16 h after it was last administered, the hirudin level finally fell to below 0.4 µg ml–1 and the patient produced clots. He went on to make an otherwise uneventful recovery.

In contrast to the above-described scenario, plasmapheresis filters (pore size 15 000 Da) can eliminate as much as 60–70% of circulating r-hirudin.6 Unfortunately, they will also remove large quantities of plasma proteins, including procoagulants, and this in turn may require the administration of quantities of fresh frozen plasma as a replacement.

R. I. P. Dornan

Edinburgh

UK

Editor—We read with interest the problems encountered in Dr Dornan’s patient who required emergency coronary bypass grafting, and in whom a diagnosis of type II heparin-induced thrombocytopenia had been made. With a preoperative reduced creatinine clearance, potential complications were clearly anticipated with the elective siting of a haemofiltration line, although subsequent haemodialysis (Baxter PSHF 1200) appeared to have little effect on the r-hirudin level. Although the r-hirudin level was within a therapeutic range for bypass, there was a clear need for reversal of the antithrombotic action of the drug, in view of bleeding complications.

Hirudin is a highly potent and specific inhibitor of thrombin which inactivates thrombin through the formation of an almost irreversible complex.7 Recombinant hirudin, available since 1997, exhibits tenfold less avid affinity for thrombin than leech-derived hirudin. Nevertheless, a potential weakness of r-hirudin remains the lack of an effective antidote in the event of bleeding. In such situations, r-hirudin can be eliminated by haemofiltration, and high-flux dialysis membranes appear to be the ‘treatment of choice’; the key to the successful removal of hirudin lies in choosing the correct membrane.5 Some low-flux membranes are only partially permeable to r-hirudin, while membranes made from polysulphone or regenerated cellulose have been shown to be impermeable to r-hirudin.8

Other direct thrombin inhibitors exist with some practical advantages over r-hirudin; bivalirudin, a hirulog, is a synthetic thrombin inhibitor that causes merely transient inhibition of thrombin. Its mechanism of action is unique and involves its conversion into a low affinity inhibitor after binding to the active site of thrombin.9 With only a small proportion of bivalirudin undergoing clearance by the kidneys, and with its shorter half-life, this drug may be a practical alternative to r-hirudin in the future, particularly in patients with renal impairment. Likewise, melagatran, a non-covalent inhibitor of the active site of thrombin, may also be a promising alternative.10

J. A. M. Anderson

E. L. Saenko

Belfast

UK

References

1 Anderson JAM, Saenko EL. Heparin resistance. Br J Anaesth 2002; 88: 467–9[Free Full Text]

2 Nowak G, Bucha E, Goock T, et al. Pharmacology of r-hirudin in renal impairment. Thromb Res 1992; 66: 707–15[ISI][Medline]

3 Koster A, Kuppe H, Hetzer R, Mertzlufft F. Bleeding complications associated with r-hirudin application for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II. Anesth Analg 1999; 88: SCA3

4 Vanholder R, Camez A, Veys N, et al. Pharmacokinetics of recombinant hirudin in haemodialyzed end-stage renal failure patients. Thromb Haemost 1997; 77: 650–5[ISI][Medline]

5 Frank RD, Farber H, Stefanidis I, Lanzmich R, Kierdorf HP. Hirudin elimination by haemofiltration: a comparative in vitro study of different membranes. Kidney Int Suppl 1999; 72: S41–5[Medline]

6 Koster A, Merkle F, Hansen R, et al. Elimination of recombinant hirudin by modified ultrafiltration during simulated cardiopulmonary bypass: assessment of different filter systems. Anesth Analg 2000; 91: 265–9[Abstract/Free Full Text]

7 Weitz JI, Hirsh J. New anticoagulant drugs. Chest 2001; 119: 95S–107S[Free Full Text]

8 Bucha E, Kreml R, Nowak G. In vitro study of r-hirudin permeability through membranes of different haemodialysers. Nephrol Dial Transplant 1999; 12: 2922–6

9 Marganore JM, Bourdon P, Jablonski J, Ramachandran KL, Fenton JW. Design and characterisation of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochemistry 1990; 29: 7095–7101[ISI][Medline]

10 Bredberg U, Eriksson U, Taure K, Johansson L, Frison L, Gustafsson D. Effects of melagatran, a novel direct thrombin inhibitor, in healthy volunteers following intravenous, subcutaneous and oral administration. Blood 1999; 94: Abstract 110 28a





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