Heparin Response and Clearance in Acute and Chronic Liver Disease

Summary

Patients with liver disease are at risk of bleeding due to abnormalities of the clotting system although they must be anticoagulated if they require haemodialysis or haemoperfusion. The anticoagulant of choice is heparin.

In this study we have investigated heparin kinetics in patients with fulminant hepatic failure (FHF) after a single intravenous dose of heparin (2,500 units) and found there was an increased clearance of heparin whether measured by its anti-Xa effect (t_1/2 = 27.8 ± 2.9 min compared to t_1/2 = 50.2 ± 2.7 min in normal controls p <0.001) or by the whole blood activated clotting time (t_1/2 = 23.7 ± 2.2 min compared to t_1/2 = 37.0 ± 2.0 min p <0.001). There was a decreased peak level of heparin measured by anti-Xa effect (peak level in FHF = 0.48 ± 0.05 u/ml and in controls = 0.69 ± 0.04 u/ml, p <0.02), but an increased sensitivity to heparin (sensitivity in FHF = 0.072 ± 0.011 sec/unit, in controls 0.033 ± 0.003 sec/unit, p <0.001). Patients with FHF had very low levels of antithrombin III (AT III), but there was no correlation between this and any parameters of heparin effect or clearance. In a group of patients with chronic liver disease heparin kinetics did not differ from controls despite low levels of AT III.

The changes in heparin kinetics in FHF are likely to be complex with the balance between the proteins that act as cofactors, (e.g. AT III) and the proteins that have heparin neutralising activity, controlling the response of added heparin.

Keywords

Heparin - Fulminant hepatic failure - Anticoagulation

• References

• 1 Lechner K, Niessnere H, Thaler E. Coagulation abnormalities in liver disease. Semin Thromb Haemostas 1977; 4: 40-56
• 2 Roberts HR, Cederbaum AL. The liver and blood coagulation physiology and pathology. Gastroenterology 1972; 63: 297-320
• 3 Bloom AL. Intravascular coagulation and the liver. Br J Haematol 1975; 30: 1-7
• 4 Duckert F. Behaviour of antithrombin III in liver disease. Scand J. Gastroenterology 1973; 8 (Suppl. 19) 109-12
• 5 Rosenberg RD, Damus PS. The purification and mechanism of action of human antithrombin-heparin cofactor. J Biol Chem 1973; 248: 6490-505
• 6 Rosenberg RD. The heparin-antithrombin mechanism. Triangle 1984; 23: 43-8
• 7 De Swart CAM, Nijmeyer B, Roelofs JM M, Sixma JJ. Kinetics of intravenously administered heparin in normal humans. Blood 1982; 60: 1251-8
• 8 Stenbjerg S, Berg E, Albrechsten OK. Evaluation of the activated whole blood clotting time (ACT) in vitro. Scand J Haematol 1979; 23: 239-44
• 9 Hill JD, Doutigny L, Leval MD, Mielke CH. A simple method of heparin management during prolonged extracorporeal circulation. Ann Thorac Surgery 1974; 17: 129-34
• 10 Stenbjerg S, Berg E, Albrechsten OK. Heparin levels and activated clotting time (ACT) during open heart surgery. Scand J Haematol 1981; 26: 281-4
• 11 Estes JW. The kinetics of heparin. New York Acad Sci 1971; 179: 187-204
• 12 Estes JW. The heterogeneity of the anticoagulant response to heparin. J Clin Pathol 1972; 25: 45-8
• 13 McAvoy TT. The biological half-life of heparin. Clin Pharmacol Ther 1979; 25: 372-9
• 14 Teien AN. Heparin elimination in patients with liver disease. Thromb Haemostas 1977; 38: 701-6
• 15 Simon TL, Hyers TM, Gaston JP, Harker LA. Heparin pharmacokinetics: Increased requirements in pulmonary embolism. Br J Haematol 1978; 39: 111-20
• 16 Ceustermans R, Hoylaerts M, De Mol M, Collen D. Preparation, characterization and turnover properties of heparin-antithrombin III complexes stabilized by covalent bonds. J Biol Chem 1982; 257: 3401-8
• 17 Glimelius B, Busch C, Hook M. Binding of heparin on the surface of cultured human endothelial cells. Thromb Res 1978; 12: 773-82
• 18 Mahadoo J, Hiebert L, Jaques LB. Vascular sequestration of heparin. Thromb Res 1977; 12: 79-90
• 19 Hughes RD, Lane DA, Ireland H, Langley PG, Gimson AES, Williams R. Fibrinogen derivatives and platelet activation products in acute and chronic liver disease. Clin Sci 1985; 68: 701-7
• 20 Schrader J, Kostering H, Kramer P, Scheler F. Antithrombin-III-Substitution bei dialysepflichtiger Niereninsuffizienz. Dtsche Med Wochenschr 1982; 107: 1847-50
• 21 Vogel GE. Early treatment with AT III in acute liver failure. Behring Inst Mitt 1983; 73: 79-93
• 22 Lijnen HR, Hoylaerts M, Collen D. Heparin binding properties of human histidine-rich glycoprotein: Mechanism and role in the neutralisation of heparin in plasma. J Biol Chem 1983; 258: 3803-8
• 24 Levine SP, Sorensin RR, Harris MA, Knierin LK. The effect of platelet factor 4 (PF4) on assays of plasma heparin. Br J Haematol 1984; 57: 585-96
• 24 O’Brien JR, Etherington MD, Pashley M. Intra-platelet platelet factor 4 (IP.PF4) and the heparin-mobilisable pool of PF4 in health and atherosclerosis. Thromb Haemostas 1984; 51: 354-7