Low Molecular Weight Heparin in Haemodialysis for Chronic Renal Failure: Dose Finding Study of CY222

Summary

A dose finding study of the very low molecular weight heparin CY222 (MW 2500) in patients (n = 8) with chronic renal failure undergoing dialysis has been carried out to (i) establish an effective dose and (ii) determine the relationship between ex vivo anti-factor Xa levels in plasma and the anticoagulant effect (in vivo suppression of FPA levels). Doses of CY222 were compared to a dose (5000 iu bolus + 1500 iu/hr) of unfractionated heparin (UFH) that has been shown to suppress FPA levels during prolonged (>5 hr) dialysis (Ireland et ah, J Lab Clin Med 103, 643, 1984). CY222 given iv in increasing doses produced a dose related increase in anti-factor Xa levels (measured as Institute Choay u/ml, with CY222 itself as standard) and suppression of FPA levels. When given in its highest dose, 20,000 Institute Choay u bolus + 1500 Institute Choay u/hr, there was little effect upon KCCT, FPA levels were statistically indistinguishable from those of the UFH regime (indicating comparable anticoagulant effect), but anti-factor Xa levels (expressed in Institute Choay u/ ml) were 2-3 times those of UFH (expressed in iu/ml). All samples were also assayed for anti-factor Xa level against the proposed low MW Heparin Standard. Plasma levels of CY222 were then found to be 2.78 times lower, so that the anti-factor Xa levels of CY222 required to produce comparable anticoagulant effect were then indistinguishable from those of UFH. Clinically, doses of CY222 exceeding 10,000 Institute Choay u bolus were effective, although increasing amounts of fibrin were visible in the drip chamber of the dialyser circuit with decreasing dose. These results indicate that CY222 is an effective anticoagulant for haemodialysis that can be monitored by its anti-factor Xa level in plasma (in conjunction with the appropriate standard). For prolonged dialysis a dose of 20,000 Institute Choay u bolus + 1500 Institute Choay u/hr is effective at suppressing fibrin formation, while the maintenance infusion may be unnecessary for short frequent dialyses.

Keywords

LMW heparin C - CY222 - Haemodialysis

• References

• 1 Andersson LO, Barrowclife TW, Holmer E, Johnson EA, Sims GE C. Anticoagulant properties of heparin fractionated by affinity chromatography on matrix bound antithrombin III and by gel filtration. Thromb Res 1976; 9: 575-583
• 2 Lane DA, MacGregor IR, Michalski R, Kakkar VV. Anticoagulant activities of four unfractionated and fractionated heparins. Thromb Res 1978; 12: 257-271
• 3 Lane DA, Denton J, Flynn AM, Thunberg L, Lindahl U. Anticoagulant activities of heparin oligosaccharides and their neutralization by platelet factor 4. Biochem J 1984; 218: 725-732
• 4 Johnson EA, Kirkwood TB L, Stirling Y, Perez-Requejo JL, Ingram GI C, Bangham DR, Brozovic M. Four heparin preparations: anti Xa potentiating effects of heparin after subcutaneous injection. Thromb Haemostas 1976; 35: 586-591
• 5 Lane DA, MacGregor IR, Van Ross M, Celia G, Kakkar VV. Molecular weight dependence of the anticoagulant properties ofheparin, intravenous and subcutaneous administration of fractionated heparins to man. Thromb Res 1979; 16: 651-662
• 6 Bergquist D, Hedner U, Sjorin E, Holmer E. Anticoagulant effects of two types of low molecular weight heparin administered subcutaneously. Thromb Res 1983; 32: 381-391
• 7 Bratt G, Tornebohm E, Lockner D, Bergstrom K. Pharmacokinetics of a low molecular weight heparin as compared to conventional heparin in humans. Thromb Haemostas 1983; 50: 184 Abstr
• 8 Carter CJ, Kelton JG, Hirsh J, Cerskus A, Santos AV, Gent M. The relationship between the haemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits. Blood 1982; 59: 1239-1245
• 9 Cade JF, Buchanan MR, Boneu B, Okelford P, Carter CJ, Cerskus AL, Hirsh J. A comparison of the antithrombotic and haemorrhagic effects of low molecular weight heparin fractions: the influence of the method of preparation. Thromb Res 1984; 35: 613-625
• 10 Holmer E, Mattsson C, Nilsson S. Anticoagulant and antithrombotic effects of heparin and low molecular weight heparin fragments in rabbits. Thromb Res 1982; 25: 475-485
• 11 Thomas DP, Merton RE, Barrowcliffe TW, Thunberg L, Lindahl U. Effects of heparin oligosaccharides with high affinity for antithrombin III in experimental venous thrombosis. Thromb Haemostas 1982; 47: 244-248
• 12 Kakkar VV, Djazaeri B, Fok J, Fletcher M, Scully MF, Westwick J. Low molecular weight heparin and prevention of postoperative deep vein thrombosis. Br Med J 1982; 284: 375-379
• 13 Turpie AG G, Levine MW, Hirsh J, Carter C, Jay RM, Powers PJ, Andrew M, Hull RD, Gent M. A randomized controlled trial of a low molecular weight heparin (Enoxaparin) to prevent deep vein thrombosis in patients undergoing elective surgery. New Engl J Med 1986; 315: 925-929
• 14 Ljunberg B. A low molecular weight fraction as an anticoagulant during haemodialysis. Clin Nephrol 1985; 24: 15-20
• 15 Borm JJ J, Krediet R, Sturk A, ten Cate JW. Heparin versus low molecular weight heparin K2165 in chronic haemodialysis patients: a randomized cross-over study. Haemostasis 1986; 16 suppl (Suppl. 02) 59-68
• 16 Schrader J, Rieger J, Muschen H, Stibbe W, Kostering H, Kramer P, Scheler F. Anwendung von niedermolekularem Heparin bei Haemodialysepatienten. Klin Wochenschr 1985; 63: 49-55
• 17 Lane DA, Ireland H, Flynn A, Anastassiades E, Curtis JR. Haemodialysis with low MW heparin: dosage requirements for the elimination of extracorporeal fibrin formation. Nephrology, Dialysis and Transplantation 1986; 1: 179-187
• 18 Anastassiades EG, Lane DA, Flynn A, Curtis JC. Preliminary evaluation of repeated use of a low MW heparin in haemodialysis for chronic renal failure. Proc Eur Dial Transpl 1985; 22: 329-333
• 19 Ireland H, Lane DA, Flynn A, Anastassiades E, Curtis JR. The anticoagulant effect of heparinoid Org 10172 during haemodialysis: an objective assessment. Thromb Haemostas 1986; 55: 271-275
• 20 Schrader J, Kandt M, Stibbe W, Armstrong VW, Schoel G, Kostering H, Seidel D, Scheler F. Low molecular weight heparin vs standard heparin in haemodialysis/haemofiltration patients: results of a multicentre long-term study. Submitted for publication
• 21 Ireland H, Lane DA, Curtis JR. Objective assessment of heparin requirements in humans. J Lab Clin Med 1984; 103: 643-652
• 22 Teien AN, Lie M, Abildgaard U. Assay of heparin in plasma using a chromogenic substrate for activatated factor X. Thromb Res 1976; 8: 413-416
• 23 Nossel HL, Yudelman I, Canfield RE, Butler VP, Spanondis K, Wilner GD, Qureshi GD. Measurement of fibrinopeptide A in human blood. J Clin Invest 1974; 54: 43-53
• 24 Ludlam CA, Moore S, Bolton AE, Pepper DS, Cash JD. The release of a human platelet specific protein measured by radioimmunoassay. Thromb Res 1975; 6: 543-548
• 25 Lane DA, Ireland H, Wolff S, Grant R, Jennings S, Allen Mersh T. Plasma concentration of fibrinopeptide A, fibrinogen fragment BB1- 42 and B thromboglobulin following total hip replacement. Thromb Res 1982; 26: 111-118
• 26 Ireland H, Lane DA, Wolff S, Foadi M. In vivo platelet release in myeloproliferative disorders. Thromb Haemostas 1982; 48: 41-45
• 27 Lane DA, Ireland KnightH, Wolff S, Kyle P, Curtis JR. The significance of fibrinogen derivatives in plasma in human renal failure. Br J Haematol 1984; 56: 251-260
• 28 Barrowcliffe TW, Curtis AD, Tomlinson TP, Hubbard AR, Johnson EA, Thomas DP. Standardization of low molecular heparins: a collaborative study. Thromb Haemostas 1985; 54: 675-679
• 29 Lane DA, Flynn AM, Ireland H. Unpublished observations
• 30 Bara L, Samama M. The need for standardization of low molecular weight heparins (LMWH). Thromb Haemostas 1986; 56: 418
• 31 Buchanan MR, Boneu B, Ofosu FA, Hirsh J. The relative importance of thrombin inhibition and factor Xa inhibition to the antithrombotic effects of heparin. Blood 1985; 65: 198-201
• 32 Ofosu FA, Blajchman MA, Modi GJ, Smith LW, Buchanan MR, Hirsh J. The importance of thrombin inhibition to the anticoagulant activities of heparin, dematan sulphate, low molecular weight heparin and pentosan polysulphate. Brit J Haematol 1985; 60: 695-704
• 33 Walenga JM, Fareed J, Petitou M, Samama M, Lormeau JC, Choay J. Intravenous antithrombotic activity of a synthetic heparin pentasaccharide in a human serum induced stasis thrombosis model. Thromb Res 1986; 43: 243-248
• 34 Walenga JM, Petitou M, Lormeau JC, Samama M, Fareed J, Choay J. Antithrombotic activity of a synthetic heparin pentasaccharide in a rabbit stasis thrombosis model using different thrombogenic challenges. Thromb Res 1987; 46: 187-198
• 35 Choay J, Petitou M, Lormeau JC, Sinay P, Casu B, Gatti G. Structure-activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity. Biochem Biophys Res Commun 1983; 116: 492-499