Dermatan Sulfate and LMW Heparin Enhance the Anticoagulant Action of Activated Protein C

José A. Fernández; Jari Petäjä; John H. Griffin

doi:10.1055/s-0037-1614856

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1999; 82(05): 1462-1468
DOI: 10.1055/s-0037-1614856

Rapid Communications

Schattauer GmbH

Dermatan Sulfate and LMW Heparin Enhance the Anticoagulant Action of Activated Protein C

José A. Fernández^*

¹From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA

,

Jari Petäjä^*

¹From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA

,

John H. Griffin

¹From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA

› Author Affiliations

Abstract

Summary

Unfractionated heparin potentiates the anticoagulant action of activated protein C (APC) through several mechanisms, including the recently described enhancement of proteolytic inactivation of factor V. Possible anticoagulant synergism between APC and physiologic glycosaminoglycans, pharmacologic low molecular weight heparins (LMWHs), and other heparin derivatives was studied. Dermatan sulfate showed potent APC-enhancing effect. Commercial LMWHs showed differing abilities to promote APC activity, and the molecular weight of LMWHs correlated with enhancement of APC activity. Degree of sulfation of the glycosaminoglycans influenced APC enhancement. However, because dextran sulfates did not potentiate APC action, the presence of sulfate groups per se on a polysaccharide is not sufficient for APC enhancement. As previously for unfractionated heparin, APC anticoagulant activity was enhanced by glycosaminoglycans when factor V but not factor Va was the substrate. Thus, dermatan sulfate and LMWHs exhibit APC enhancing activity in vitro that could be of physiologic and pharmacologic significance.

Keywords

Dermatan sulfate - heparin - activated protein C - factor V

Full Text

References

References
1 Schoen P, Lindhout T, Willems G, Hemker HC. Antithrombin III-dependent antiprothrombinase activity of heparin and heparin fragments. J Biol Chem 1989; 264: 10002-7.
2 Barrowcliffe TW, Thomas DP. Anticoagulant activities of heparin and fragments. Ann N Y Acad Sci 1989; 556: 132-45.
3 Baruch D, Lindhout T, Wagenvoord R, Hemker HC. Inhibition of thrombin-catalyzed reactions in blood coagulation and platelet activation by heparin fractions in the absence of Antithrombin III. Haemostasis 1986; 16: 71-81.
4 Nader HB, Dietrich CP. Natural occurrence, and possible biological role of heparin. In: Heparin. Chemical and Biological Properties and Clinical Applications. Lane DA, Lindahl U. eds. Boca Raton: CRC Press, Inc.; 1989: 81-96.
5 Verstraete M. Pharmacotherapeutic aspects of unfractionated and low molecular weight heparins. Drugs 1990; 40: 498-530.
6 Fareed J, Jeske W, Eschenfelder V, Iqbal O, Hoppensteadt D, Ashan A. Preclinical studies on a low molecular weight heparin. Thromb Res 1996; 81: 1-27.
7 Petäjä J, Fernández JA, Gruber A, Griffin JH. Anticoagulant synergism of heparin and activated protein C in vitro. Role of a novel anticoagulant mechanism of heparin, enhancement of degradation of factor V by activated protein C. J Clin Invest 1997; 99: 2655-63.
8 Fulcher CA, Gardiner JE, Griffin JH, Zimmerman TS. Proteolytic inactivation of activated human factor VIII procoagulant protein by activated protein C and its analogy to factor V. Blood 1984; 63: 486-9.
9 Esmon CT. The protein C anticoagulant pathway. Arterioscler Thromb 1992; 12: 135-45.
10 Naggi A, Torri G, Casu B, Pangrazzi J, Abbadini M. et al. “Supersulfated” heparin fragments, a new type of low molecular weight heparin. Biochem Pharmacol 1987; 36: 1895-1900.
11 Hackeng TM, van t’ Veer C, Meijers JCM, Bouma BN. Human protein S inhibits prothrombinase complex activity on endothelial cells and platelets via direct interactions with factors Va and Xa. J Biol Chem 1994; 269: 21051-8.
12 Gruber A, Harker LA, Hanson SR, Kelly AB, Griffin JH. Antithrombotic effects of combining activated protein C and urokinase in non-human primates. Circulation 1991; 84: 2454-62.
13 Fisher M, Fernández JA, Ameriso SF, Xie D, Gruber A. et al. Activated protein C resistance in ischemic stroke not due to factor V arginine⁵⁰⁶ glutamine mutation. Stroke 1996; 27: 1163-6.
14 Barrow RT, Parker ET, Krishnaswamy S, Lollar P. Inhibition by heparin of the human blood coagulation intrinsic pathway factor X activator. J Biol Chem 1994; 269: 26796-800.
15 Barrow RT, Healey JF, Lollar P. Inhibition by heparin of thrombin-catalyzed activation of the factor VIII-von Willebrand factor complex. J Biol Chem 1994; 269: 593-8.
16 Suzuki K, Nishioka J, Kusumoto H, Hashimoto S. Mechanism of inhibition of activated protein C by protein C inhibitor. J Biochem 1984; 95: 187-95.
17 España F, Berretini M, Griffin JH. Purification and characterization of plasma protein C inhibitor. Thromb Res 1989; 55: 369-84.
18 Atha DH, Stephens AW, Rosenberg RD. Evaluation of critical groups required for the binding of heparin to Antithrombin. Proc Natl Acad Sci USA 1984; 81: 1030-4.
19 Ofosu FA, Choay J, Anvari N, Smith LM, Blajchman MA. Inhibition of factor X and factor V activation by dermatan sulfate a pentasaccharide with high affinity for Antithrombin III in human plasma. Eur J Biochem 1990; 193: 485-93.
20 Gruber A, Griffin JH. Direct detection of activated protein C in blood from human subjects. Blood 1992; 79: 2340-8.
21 Fernández JA, Petäjä J, Gruber A, Griffin JH. Activated Protein C correlates inversely with thrombin levels in resting healthy individuals. Am J Hematol 1997; 56: 29-31.
22 Andrassy K, Eschenfelder V. Are the pharmacokinetic parameters of low molecular weight heparins predictive of their clinical efficacy?. Thromb Res 1996; 81: 29-38.
23 Cohen M, Demers C, Gurfinkel EP, Turpie AG, Fromell GJ. et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and safety of subcutaneous Enoxaparin in non-Q-wave coronary events study. N Engl J Med 1997; 337: 447-52.
24 Snow TR, Deal MT, Dickey DT, Esmon CT. Protein C activation following coronary artery occlusion in the in situ porcine heart. Circulation 1991; 84: 293-9.
25 Bianchini P, Bergonzini GL, Parma B, Osima B. Relationship between plasma antifactor Xa activity and the antithrombotic activity of heparins of different molecular mass. Haemostasis 1995; 25: 288-98.
26 Delorme MA, Tam ASK, Xu L. The effects of dermatan sulfate at submicrogram/ml concentrations on in vitro thrombin generation. Thromb Haemost 1996; 75: 747-51.
27 Andrew M, Mitchell L, Berry L, Paes B, Delorme M. et al. An anticoagulant dermatan sulfate proteoglycan circulates in the pregnant woman and her fetus. J Clin Invest 1992; 89: 321-6.