Heparin cofactor II

Danaparoid (Orgaran mean MW, 6,000 Da) is a mixture of nonheparin glycosaminoglycans derived from pig gut (dermatan sulfate, heparan sulfate, chondroitin sulfate). Die anti-Xa/anti-IIa ratio (22 1) is even greater than seen with LMWH. Die anti-IIa effect may be mediated in part by dermatan sulfate, which catalyzes thrombin inhibition by heparin cofactor II. 

Besides AT, heparin cofactor II (HCII) is an antic-oagulatory protein enhanced by heparin. HCII inactivates thrombin and the nonclotting enzymes cathepsin-G and chymotrypsin. 

Four naturally occurring thrombin inhibitors exist in normal plasma. The most important is antithrombin III (often called simply antithrombin), which contributes approximately 75% of the antithrombin activity. Antithrombin III can also inhibit the activities of factors IXa, Xa, XIa, Xlla, and Vila complexed with tissue factor. a2-Macroglobulin contributes most of the remainder of the antithrombin activity, with heparin cofactor II and aj-antitrypsin acting as minor inhibitors under physiologic conditions. 

FIGURE 7-4. Coagulation cascade. AT, antithrombin HCII, heparin cofactor II TFPI, tissue factor pathway inhibitor. (Reproduced from Haines ST, Zeolla M, Witt DM. Venous thromboembolism. In ... 

Heparin cofactor II, when activated by binding to glycosaminoglycans (dermatan sulfate, heparins, and heparin), inhibits thrombin (24). The 43-kDa serpin, proteinase nexin 1, possesses 30% sequence homology with ATIII and can be activated by binding to heparin to inhibit several serine proteinases including thrombin (25). Proteinase nexin 2 is found within the platelet a-granule and is released when platelets are activated (26). It is able to inhibit factor XIa. 

PC Liaw, RC Austin, JC Fredenburgh, AR Stafford, JI Weitz. Comparison of heparin- and dermatan sulfate-mediated catalysis of thrombin inactivation by heparin cofactor II. J Biol Chem 274 27597-27604, 1999. 

Heparin binds to antithrombin III and induces a conformational change that accelerates the interaction of antithrombin III with the coagulation factors. Heparin also catalyzes the inhibition of thrombin by heparin cofactor II, a circulating inhibitor. Smaller amounts of heparin are needed to prevent the formation of free thrombin than are needed to inhibit the protease activity of clot-bound thrombin. Inhibition of free thrombin is the basis of low-dose prophylactic therapy. 

Another serine protease inhibitor of the al-antitrypsin family (serpin) is heparin cofactor II (HCII), which also forms a 1 1 complex with thrombin, but does not react with factor Xa [4,10]. The rate of inhibition of thrombin is not only increased by heparinoids but also by the related glycosaminoglycan dermatan sulfate. The identification of an inhibitor variant and site-directed mutagenesis studies on HC II cDNA led to the understanding that the binding sites for heparin and dermatan sulfate may be overlapping but not identical. Further proteinase inhibitors interacting with heparinoids are tissue factor pathway inhibitor and protease nexin-1. 

Micromedex, lepirudin directly inhibits all actions of thrombin. It inhibits free and clot-bound thrombin without requiring endogenous cofactors. Lepirudin is not inhibited by platelet factor 4 and acts independently of antithrombin III and heparin cofactor II. It has no direct effect on platelet function, except inhibition of thrombin-induced platelet activation. No physiological inhibitor of lepirudin is known. 

Scully, M. F., Ellis, V., Seno, N., and Kakkar, V. V. (1988). Effect of oversulphated chondroitin and dermatan sulphate upon thrombin and factor Xa inactivation by antithrombin III or heparin cofactor II. Biochem. J. 254,547-551. 

TABLE 12.1 Anticoagulant activities of MSPs measured by APTT° and by IC50 for thrombin (lla) and factor Xa inhibition in the presence of antithrombin (AT) or heparin cofactor II (HCII) (Fonseca et al., 2008 Mourao, 2004 Mourao and Pereira, 1999 Pavao et al., 1998 Pereira et al., 2005)... 

Heparin cofactor II is a second plasma SERPIN which has resemblance to antithrombin in that it is activatable by glycosaminoglycan binding. This protein has also been called antithrombin BM, dermatan sulfate cofactor, and human leuserpin 2 (88). The existence of this second inhibitor and heparin cofactor was first shown by Briginshaw in 1974 (89). Whereas antithrombin is observed to have progressive antithrombin activity and to also inhibit factor Xa, the second... 

Like antithrombin, heparin cofactor II inhibits proteases by forming a I I stoichiometric complex with the enzyme. The protease attacks the reactive site of heparin cofactor II located on the C-terminus, resulting in the formation of a covalent bond. Heparin cofactor II has higher protease specificity than antithrombin. Of the coagulation enzymes, heparin cofactor II is known only to inhibit thrombin (92). Additionally heparin cofactor II has been shown to inhibit chymotrypsin (93) and leukocyte cathepsin G (94), This protease specificity appears to be due to the active site bond present in heparin cofactor II. Whereas antithrombin contains an Arg-Ser bond as its active site, heparin cofactor II is unique in containing a Leu-Ser bond. This suggests than another portion of the heparin cofactor II molecular may be required for protease binding,... 

The normal plasma level of heparin cofactor II is approximately 1.2 0.2 jlM (90). Two patients to date have been described as having thrombosis related to heparin cofactor II deficiency (95). 

Olson ST, Bjork I. Regulation of thrombin by antithrombin and heparin cofactor II. In Berliner LJ, ed. Thrombin Structure and Function. New York Plenum Press, 1992 159-217. 

Church FC, Noyes CM, Griffith MJ. Inhibition of chymotrypsin by heparin cofactor II. Proc Natl Acad Sci USA 1985 82 6431-6434. 

Parker KA, Tollefsen DM. The protease specificity of heparin cofactor II. Inhibition of thrombin generated during coagulation. J Biol Chem 1987 260 3501-3503. 

Sie R DuPouy D, Pichon J, Boneu B. Constitutional heparin cofactor II deficiency associated with recurrent thrombosis. Lancet 1985 2 414-416. 

Matsuo T, Kario K, Sakamoto S, et al. Hereditary heparin cofactor II deficiency and coronary artery disease. Thromb Res 1992 65 495-505. 

A synthetic hypersulfeted lactobionic acid amide (Aprosulate) has been developed for prophylactic antithrombotic use. This agent produces its action via heparin cofactor II and by inhibiting protease generation. The bioavailability of this agent is better than that of dermatan and heparan sulfetes. However, this product exhibits heparin-induced ftirombocytopenic effects and some teratogenetic potential. Thus, its use in clinical trials has been stopped. 

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