Effects of antithrombin and heparin cofactor II levels on anticoagulation with Intimatan

Summary

Heparin is the current mainstay drug for anticoagulation during cardiac surgery, but it requires normal levels of antithrombin (AT) for optimal anticoagulation. Heparin anticoagulation may be less effective in cardiac surgical patients because of decreased AT levels due to the prolonged heparin therapy. Therefore, other anticoagulants that would work well in AT deficient patients may be more desirable. One such agent currently being evaluated is Intimatan, which catalyzes heparin cofactor II (HCII) dependent inhibition of thrombin. In the current in vitro study we examined the effects of Intimatan (20 μg/ml), heparin (0.25 U/ml), or both drugs in combination on thrombin generation in plasma with decreasing levels of AT, HCII or both cofactors, using a novel method based on the continuous measure-ment of thrombin generation. For the study, we collected blood samples from healthy volunteers, isolated platelet poor plasma by centrifugation and mixed it withAT, HCII, orAT-HCII deficient plasma samples to achieve different levels of AT, HCII and AT-HCII. Thrombin generation was inhibited equally well with heparin or Intimatan when the level of their respective cofactors was within the normal range. With decreasing levels of AT or HCII, heparin and Intimatan became less effective in thrombin inhibition, respectively. With the absence of both cofactors, neither agent alone or in combination had any effect on thrombin generation. We conclude that Intimatan may be an effective adjunct to heparin therapy under low AT conditions.

The study was presented in part at the annual meeting of the Society of Cardiovascular Anesthesiologists, Honolulu, HI on April 26, 2004

Keywords

Intimatan - heparin cofactor II - antithrombin

• References

• 1 Hemker HC, Giesen P, Al Dieri R. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4-15.
• 2 Buchanan MR, Brister SJ. Anticoagulant and antithrombin effects of intimatan, a heparin cofactor II agonist. Thromb Res 2000; 99: 603-12.
• 3 Hennan JK, Hong TT, Shergill A K. et al. Intimatan prevents arterial and venous thrombosis in a canine model of deep vessel wall injury. J Pharmacol Exp Thera 2002; 301: 1151-6.
• 4 Rand MD, Lock JB, van’t Veer C. et al. Blood clotting in minimally altered whole blood. Blood 1996; 88: 3432-45.
• 5 Matthai Jr. WH, Kurnik PB, Groh W C. et al. Antithrombin activity during the period of percutaneous coronary revascularization: Relation to heparin use, thrombotic complications and restenosis. J Am Col Cardiol 1999; 33: 1248-56.
• 6 Tanaka KA, Szlam F, Katori N. et al. The effects of argatroban on thrombin generation and hemostatic activation in vitro. Anesth Anlag 2004; 99: 1283-9.
• 7 Matsuo T, Yamada T, Yamanashi T, Kodama K. Choice of anticoagulant in a congenital antithrombin III (AT III)-deficient patient with chronic renal failure undergoing regular haemodialysis. Clin Lab Haematol 1989; 11: 213-9.
• 8 Murano G, Williams L, Miller-Andersson M. et al. Some properties of antithrombin-III and its concentration in human plasma. Thromb Res 1980; 18: 259-62.
• 9 Vicente CP, He L, Pavao MS, Tollefsen DM. Antithrombotic activity of dermatan sulfate in heparin cofactor II-deficient mice. Blood 2004; 104: 3965-70.
• 10 Andersson TR. Consumption of heparin cofactor II (dermatan sulfate cofactor) and antithrombin during coagulation. Thromb Res 1987; 46: 355-62.
• 11 Bertina RM, van der Linden IK, Engesser L. et al. Hereditary heparin cofactor II deficiency and the risk of development of thrombosis. Thromb Haemost 1987; 57: 196-200.
• 12 Kondo S, Tokunaga F, Kario K. et al. Molecular and cellular basis for type I heparin cofactor II deficiency (heparin cofactor II Awaji). Blood 1996; 87: 1006-12.
• 13 Ishiguro K, Kojima T, Kadomatsu K. et al. Complete antithrombin deficiency in mice results in embryonic lethality. J Clin Invest 2000; 106: 873-8.
• 14 He L, Vicente CP, Westrick R J. et al. Heparin cofactor II inhibits arterial thrombosis after endothelial injury. J Clin Invest 2002; 109: 213-9.
• 15 Andersson TR, Sie P, Pelzer H. et al. Elevated levels of thrombin-heparin cofactor II complex in plasma from patients with disseminated intravascular coagulation. Thromb Res 1992; 66: 591-8.
• 16 Duboscq C, Quintana I, Barros J, Kordich L. Heparin cofactor II in diabetic patients. Blood Coag Fibrinolysis 1994; 5: 201-4.
• 17 Andersson TR, Berner NS, Larsen M L. et al. Plasma heparin cofactor II, protein C and antithrombin in elective surgery. Acta Chir Scand 1987; 153: 291-6.
• 18 Shirk RA, Parthasarathy N, San Antonio JD. et al. Altered dermatan sulfate structure and reduced heparin cofactor II-stimulating activity of biglycan and decorin from human atherosclerotic plaque. J Biol Chem 2000; 275: 18085-92.
• 19 Takamori N, Azuma H, Kato M. et al. High plasma heparin cofactor II activity is associated with reduced incidence of in-stent restenosis after percutaneous coronary intervention. Circulation 2004; 109: 481-6.
• 20 Toulon P, Jacquot C, Capron L. et al. Antithrombin III and heparin cofactor II in patients with chronic renal failure undergoing regular hemodialysis. Thromb Haemost 1987; 57: 263-8.
• 21 Toulon P, Gandrille S, Remy P. et al. Significance of high levels of heparin cofactor II in the plasma and urine of adult patients with nephrotic syndrome. Nephron 1992; 60: 176-80.
• 22 Hara T, Jojima K, Takeuchi K. et al. Intraoperative management of a congenital antithrombin deficient patient on chronic hemodialysis. Thromb Haemost 2004; 92: 208-10.
• 23 Ryan KE, Lane DA, Flynn A. et al. Antithrombotic properties of dermatan sulphate (MF 701) in haemodialysis for chronic renal failure. Thromb Haemost 1992; 68: 563-9.
• 24 Taliani MR, Agnelli G, Nenci GG, Gianese F. Dermatan sulphate in patients with heparin-induced thrombocytopenia. Brit J Haematol 1999; 104: 87-9.
• 25 Tollefsen DM. Heparin cofactor II deficiency. Arch Pathol Lab Med 2002; 126: 1394-400.