Heparin Cofactor II: Discovery, Properties, and Role in Controlling Vascular Homeostasis

Jill C Rau; Jennifer W Mitchell; Yolanda M Fortenberry; Frank C Church

doi:10.1055/s-0031-1276582

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2011; 37(4): 339-348
DOI: 10.1055/s-0031-1276582

Heparin Cofactor II: Discovery, Properties, and Role in Controlling Vascular Homeostasis

Jill C. Rau¹ ^, ⁵ , Jennifer W. Mitchell¹ , Yolanda M. Fortenberry¹ ^, ⁶ , Frank C. Church¹ ^, ² ^, ³ ^, ⁴

¹Department of Pathology and Laboratory Medicine, Chapel Hill, North Carolina
²Department of Pharmacology, Chapel Hill, North Carolina
³Department of Medicine, Chapel Hill, North Carolina
⁴Department of UNC McAllister Heart Institute, The University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina
⁵Present address for Dr. Rau is Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada
⁶Present address for Dr. Fortenberry is Department of Pediatric-Hematology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Abstract

ABSTRACT

Heparin cofactor II (HCII) is a serine protease inhibitor (serpin) found in high concentrations in human plasma. Despite its discovery >30 years ago, its physiological function is still poorly understood. It is known to inhibit thrombin, the predominant coagulation protease, and HCII-thrombin complexes have been found in plasma, yet it is thought to contribute little to normal hemostasis. However, thrombin has several other physiological functions, and therefore many biological roles for HCII need consideration. The unique structure and mechanism of action of HCII have helped guide our understanding of HCII. In particular, HCII binds many glycosaminoglycans (GAGs) such as heparin and heparin sulfate as well as several different polyanions to enhance its inhibition of thrombin. Distinctly, HCII is able to use the GAG dermatan sulfate for accelerated thrombin inhibition. Dermatan sulfate is found in high concentrations in the walls of blood vessels as well as in placental tissue. This knowledge has led to research indicating that HCII may play a protective role in atherosclerosis and placental thrombosis. Additionally, pharmaceuticals are being developed that use the dermatan sulfate activation of HCII for anticoagulation. Although much research is still needed to fully understand HCII, this humble protein may have significant impact in our medical future. This article reviews the laboratory history, protein characteristics, structure–activity relationships, protease inhibition, physiological function, and medical relevance of HCII in hopes of regenerating interest in this sometimes forgotten serpin.

KEYWORDS

Heparin cofactor II - serpin - thrombin - dermatan sulfate - heparin

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REFERENCES

1 Rosenberg R D, Aird W C. Vascular-bed—specific hemostasis and hypercoagulable states. N Engl J Med. 1999; 340 (20) 1555-1564
2 Colman R W, Hirsh J, Marder V J, Clowes A W, George J N. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, PA: Lippincott, Williams and Wilkins; 2001
3 Mackman N. Role of tissue factor in hemostasis, thrombosis, and vascular development. Arterioscler Thromb Vasc Biol. 2004; 24 (6) 1015-1022
4 Monroe D M, Hoffman M. What does it take to make the perfect clot?. Arterioscler Thromb Vasc Biol. 2006; 26 (1) 41-48
5 Wakefield T W, Myers D D, Henke P K. Mechanisms of venous thrombosis and resolution. Arterioscler Thromb Vasc Biol. 2008; 28 (3) 387-391
6 Heit J A. Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost. 2005; 3 (8) 1611-1617
7 Silverman G A, Bird P I, Carrell R W et al.. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J Biol Chem. 2001; 276 (36) 33293-33296
8 Huntington J A. Mechanisms of glycosaminoglycan activation of the serpins in hemostasis. J Thromb Haemost. 2003; 1 (7) 1535-1549
9 Rau J C, Beaulieu L M, Huntington J A, Church F C. Serpins in thrombosis, hemostasis and fibrinolysis. J Thromb Haemost. 2007; 5 (Suppl 1) 102-115
10 Brinkhous K M, Smith H P, Warner E D, Seegers W H. The inhibition of blood clotting: an unidentified substance which acts in conjunction with heparin to prevent the conversion of prothrombin into thrombin. Am J Physiol. 1939; 125 683-687
11 Briginshaw G F, Shanberge J N. Identification of two distinct heparin cofactors in human plasma. II. Inhibition of thrombin and activated factor X. Thromb Res. 1974; 4 (3) 463-477
12 Briginshaw G F, Shanberge J N. Identification of two distinct heparin cofactors in human plasma. Separation and partial purification. Arch Biochem Biophys. 1974; 161 (2) 683-690
13 Tollefsen D M, Blank M K. Detection of a new heparin-dependent inhibitor of thrombin in human plasma. J Clin Invest. 1981; 68 (3) 589-596
14 Tollefsen D M, Majerus D W, Blank M K. Heparin cofactor II. Purification and properties of a heparin-dependent inhibitor of thrombin in human plasma. J Biol Chem. 1982; 257 (5) 2162-2169
15 Wunderwald P, Schrenk W J, Port H. Antithrombin BM from human plasma: an antithrombin binding moderately to heparin. Thromb Res. 1982; 25 (3) 177-191
16 Griffith M J, Carraway T, White G C, Dombrose F A. Heparin cofactor activities in a family with hereditary antithrombin III deficiency: evidence for a second heparin cofactor in human plasma. Blood. 1983; 61 (1) 111-118
17 Griffith M J, Noyes C M, Church F C. Reactive site peptide structural similarity between heparin cofactor II and antithrombin III. J Biol Chem. 1985; 260 (4) 2218-2225
18 Griffith M J, Marbet G A. Dermatan sulfate and heparin can be fractionated by affinity for heparin cofactor II. Biochem Biophys Res Commun. 1983; 112 (2) 663-670
19 Church F C, Griffith M J. Evidence for essential lysines in heparin cofactor II. Biochem Biophys Res Commun. 1984; 124 (3) 745-751
20 Tollefsen D M, Pestka C A, Monafo W J. Activation of heparin cofactor II by dermatan sulfate. J Biol Chem. 1983; 258 (11) 6713-6716
21 Hortin G, Tollefsen D M, Strauss A W. Identification of two sites of sulfation of human heparin cofactor II. J Biol Chem. 1986; 261 (34) 15827-15830
22 Church F C, Meade J B, Pratt C W. Structure-function relationships in heparin cofactor II: spectral analysis of aromatic residues and absence of a role for sulfhydryl groups in thrombin inhibition. Arch Biochem Biophys. 1987; 259 (2) 331-340
23 Griffith M J, Noyes C M, Tyndall J A, Church F C. Structural evidence for leucine at the reactive site of heparin cofactor II. Biochemistry. 1985; 24 (24) 6777-6782
24 Ragg H. A new member of the plasma protease inhibitor gene family. Nucleic Acids Res. 1986; 14 (2) 1073-1088
25 Blinder M A, Marasa J C, Reynolds C H, Deaven L L, Tollefsen D M. Heparin cofactor II: cDNA sequence, chromosome localization, restriction fragment length polymorphism, and expression in Escherichia coli . Biochemistry. 1988; 27 (2) 752-759
26 Tollefsen D M. Heparin cofactor II modulates the response to vascular injury. Arterioscler Thromb Vasc Biol. 2007; 27 (3) 454-460
27 Law R H, Zhang Q, McGowan S et al.. An overview of the serpin superfamily. Genome Biol. 2006; 7 (5) 216
28 Silverman G A, Bird P I, Carrell R W et al.. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J Biol Chem. 2001; 276 (36) 33293-33296
29 Zhang G S, Mehringer J H, Van Deerlin V MD, Kozak C A, Tollefsen D M. Murine heparin cofactor II: purification, cDNA sequence, expression, and gene structure. Biochemistry. 1994; 33 (12) 3632-3642
30 Kamp P, Strathmann A, Ragg H. Heparin cofactor II, antithrombin-beta and their complexes with thrombin in human tissues. Thromb Res. 2001; 101 (6) 483-491
31 Hoffman M, Loh K L, Bond V K, Palmieri D, Ryan J L, Church F C. Localization of heparin cofactor II in injured human skin: a potential role in wound healing. Exp Mol Pathol. 2003; 75 (2) 109-118
32 Sié P, Dupouy D, Pichon J, Boneu B. Turnover study of heparin cofactor II in healthy man. Thromb Haemost. 1985; 54 (3) 635-638
33 Tollefsen D M, Pestka C A. Heparin cofactor II activity in patients with disseminated intravascular coagulation and hepatic failure. Blood. 1985; 66 (4) 769-774
34 Pratt C W, Church F C, Pizzo S V. In vivo catabolism of heparin cofactor II and its complex with thrombin: evidence for a common receptor-mediated clearance pathway for three serine proteinase inhibitors. Arch Biochem Biophys. 1988; 262 (1) 111-117
35 Hatton M W, Ross B, Southward S M et al.. Uptake of heparin cofactor II and antithrombin into the aorta wall after a deendothelializing injury in vivo: comparison with the behaviors of prothrombin and fibrinogen. J Lab Clin Med. 1999; 133 (1) 81-87
36 Hatton M W, Hoogendoorn H, Southward S M, Ross B, Blajchman M A. Comparative metabolism and distribution of rabbit heparin cofactor II and rabbit antithrombin in rabbits. Am J Physiol. 1997; 272 (5 Pt 1) E824-E831
37 Buchanan M R, Brister S J. Anticoagulant and antithrombin effects of intimatan, a heparin cofactor II agonist. Thromb Res. 2000; 99 (6) 603-612
38 Kounnas M Z, Church F C, Argraves W S, Strickland D K. Cellular internalization and degradation of antithrombin III-thrombin, heparin cofactor II-thrombin, and alpha 1-antitrypsin-trypsin complexes is mediated by the low density lipoprotein receptor-related protein. J Biol Chem. 1996; 271 (11) 6523-6529
39 Blinder M A, Andersson T R, Abildgaard U, Tollefsen D M. Heparin cofactor IIOslo. Mutation of Arg-189 to His decreases the affinity for dermatan sulfate. J Biol Chem. 1989; 264 (9) 5128-5133
40 Filion M L, Bhakta V, Nguyen L H, Liaw P S, Sheffield W P. Full or partial substitution of the reactive center loop of alpha-1-proteinase inhibitor by that of heparin cofactor II: P1 Arg is required for maximal thrombin inhibition. Biochemistry. 2004; 43 (46) 14864-14872
41 Kanagawa Y, Shigekiyo T, Aihara K, Akaike M, Azuma H, Matsumoto T. Molecular mechanism of type I congenital heparin cofactor (HC) II deficiency caused by a missense mutation at reactive P2 site: HC II Tokushima. Thromb Haemost. 2001; 85 (1) 101-107
42 Ragg H, Ulshöfer T, Gerewitz J. On the activation of human leuserpin-2, a thrombin inhibitor, by glycosaminoglycans. J Biol Chem. 1990; 265 (9) 5211-5218
43 Bhakta V, Begbie M E, Gupta A, Sandhu V, Sheffield W P. Heparin cofactor II is more sensitive than antithrombin to secretory impairment arising from mutations introduced into its carboxy-terminal region. Thromb Res. 2004; 113 (2) 163-173
44 Liaw P CY, Austin R C, Fredenburgh J C, Stafford A R, Weitz J I. Comparison of heparin- and dermatan sulfate-mediated catalysis of thrombin inactivation by heparin cofactor II. J Biol Chem. 1999; 274 (39) 27597-27604
45 Ciaccia A V, Cunningham E L, Church F C. Characterization of recombinant heparin cofactor II expressed in insect cells. Protein Expr Purif. 1995; 6 (6) 806-812
46 Huntington J A, Read R J, Carrell R W. Structure of a serpin-protease complex shows inhibition by deformation. Nature. 2000; 407 (6806) 923-926
47 Gettins P G. Serpin structure, mechanism, and function. Chem Rev. 2002; 102 (12) 4751-4804
48 Pike R N, Buckle A M, le Bonniec B F, Church F C. Control of the coagulation system by serpins. Getting by with a little help from glycosaminoglycans. FEBS J. 2005; 272 (19) 4842-4851
49 Patston P A, Church F C, Olson S T. Serpin-ligand interactions. Methods. 2004; 32 (2) 93-109
50 Baglin T P, Carrell R W, Church F C, Esmon C T, Huntington J A. Crystal structures of native and thrombin-complexed heparin cofactor II reveal a multistep allosteric mechanism. Proc Natl Acad Sci U S A. 2002; 99 (17) 11079-11084
51 Kresse H, Hausser H, Schönherr E. Small proteoglycans. EXS. 1994; 70 73-100
52 Tollefsen D M. The interaction of glycosaminoglycans with heparin cofactor II: structure and activity of a high-affinity dermatan sulfate hexasaccharide. Adv Exp Med Biol. 1992; 313 167-176
53 Cardin A D, Demeter D A, Weintraub H JR, Jackson R L. Molecular design and modeling of protein-heparin interactions. Methods Enzymol. 1991; 203 556-583
54 Casu B. Structure and biological activity of heparin and other glycosaminoglycans. Pharmacol Res Commun. 1979; 11 (1) 1-18
55 Höök M, Kjellén L, Johansson S. Cell-surface glycosaminoglycans. Annu Rev Biochem. 1984; 53 847-869
56 Church F C, Meade J B, Treanor R E, Whinna H C. Antithrombin activity of fucoidan. The interaction of fucoidan with heparin cofactor II, antithrombin III, and thrombin. J Biol Chem. 1989; 264 (6) 3618-3623
57 Church F C, Pratt C W, Treanor R E, Whinna H C. Antithrombin action of phosvitin and other phosphate-containing polyanions is mediated by heparin cofactor II. FEBS Lett. 1988; 237 (1–2) 26-30
58 Church F C, Treanor R E, Sherrill G B, Whinna H C. Carboxylate polyanions accelerate inhibition of thrombin by heparin cofactor II. Biochem Biophys Res Commun. 1987; 148 (1) 362-368
59 Pratt C W, Whinna H C, Meade J B, Treanor R E, Church F C. Physicochemical aspects of heparin cofactor II. Ann N Y Acad Sci. 1989; 556 104-115
60 Maimone M M, Tollefsen D M. Structure of a dermatan sulfate hexasaccharide that binds to heparin cofactor II with high affinity. J Biol Chem. 1990; 265 (30) 18263-18271
61 Tovar A M, de Mattos D A, Stelling M P, Sarcinelli-Luz B S, Nazareth R A, Mourão P A. Dermatan sulfate is the predominant antithrombotic glycosaminoglycan in vessel walls: implications for a possible physiological function of heparin cofactor II. Biochim Biophys Acta. 2005; 1740 (1) 45-53
62 McGuire E A, Tollefsen D M. Activation of heparin cofactor II by fibroblasts and vascular smooth muscle cells. J Biol Chem. 1987; 262 (1) 169-175
63 Hiramoto S A, Cunningham D D. Effects of fibroblasts and endothelial cells on inactivation of target proteases by protease nexin-1, heparin cofactor II, and C1-inhibitor. J Cell Biochem. 1988; 36 (3) 199-207
64 Whinna H C, Choi H U, Rosenberg L C, Church F C. Interaction of heparin cofactor II with biglycan and decorin. J Biol Chem. 1993; 268 (6) 3920-3924
65 Shirk R A, Church F C, Wagner W D. Arterial smooth muscle cell heparan sulfate proteoglycans accelerate thrombin inhibition by heparin cofactor II. Arterioscler Thromb Vasc Biol. 1996; 16 (9) 1138-1146
66 Shirk R A, Parthasarathy N, San Antonio J D, Church F C, Wagner W D. Altered dermatan sulfate structure and reduced heparin cofactor II-stimulating activity of biglycan and decorin from human atherosclerotic plaque. J Biol Chem. 2000; 275 (24) 18085-18092
67 Tollefsen D M. The interaction of glycosaminoglycans with heparin cofactor II. Ann N Y Acad Sci. 1994; 714 21-31
68 Tollefsen D M. Heparin cofactor II. In: Church F C, Cunningham D D, Ginsburg D, et al, eds. Advances in Experimental Medicine and Biology: Chemistry and Biology of Serpins. New York, NY: Plenum Press; 1997: 35-44
69 Mungall D. Desmin 370 (Opocrin SpA/Alfa Wassermann). IDrugs. 1999; 2 (6) 579-583
70 Pavão M S, Aiello K R, Werneck C C et al.. Highly sulfated dermatan sulfates from Ascidians. Structure versus anticoagulant activity of these glycosaminoglycans. J Biol Chem. 1998; 273 (43) 27848-27857
71 Suwan J, Zhang Z, Li B et al.. Sulfonation of papain-treated chitosan and its mechanism for anticoagulant activity. Carbohydr Res. 2009; 344 (10) 1190-1196
72 Zhu Z, Zhang Q, Chen L et al.. Higher specificity of the activity of low molecular weight fucoidan for thrombin-induced platelet aggregation. Thromb Res. 2010; 125 (5) 419-426
73 Volpi N, Maccari F. Structural characterization and antithrombin activity of dermatan sulfate purified from marine clam Scapharca inaequivalvis . Glycobiology. 2009; 19 (4) 356-367
74 Majdoub H, Ben Mansour M, Chaubet F, Roudesli M S, Maaroufi R M. Anticoagulant activity of a sulfated polysaccharide from the green alga Arthrospira platensis . Biochim Biophys Acta. 2009; 1790 (10) 1377-1381
75 Fonseca R J, Mourão P A. Fucosylated chondroitin sulfate as a new oral antithrombotic agent. Thromb Haemost. 2006; 96 (6) 822-829
76 Sarilla S, Habib S Y, Kravtsov D V, Matafonov A, Gailani D, Verhamme I M. Sucrose octasulfate selectively accelerates thrombin inactivation by heparin cofactor II. J Biol Chem. 2010; 285 (11) 8278-8289
77 Li B, Suwan J, Martin J G et al.. Oversulfated chondroitin sulfate interaction with heparin-binding proteins: new insights into adverse reactions from contaminated heparins. Biochem Pharmacol. 2009; 78 (3) 292-300
78 Whinna H C, Blinder M A, Szewczyk M, Tollefsen D M, Church F C. Role of lysine 173 in heparin binding to heparin cofactor II. J Biol Chem. 1991; 266 (13) 8129-8135
79 Blinder M A, Tollefsen D M. Site-directed mutagenesis of arginine 103 and lysine 185 in the proposed glycosaminoglycan-binding site of heparin cofactor II. J Biol Chem. 1990; 265 (1) 286-291
80 Ragg H, Ulshöfer T, Gerewitz J. Glycosaminoglycan-mediated leuserpin-2/thrombin interaction. Structure-function relationships. J Biol Chem. 1990; 265 (36) 22386-22391
81 Johnson D J, Li W, Adams T E, Huntington J A. Antithrombin-S195A factor Xa-heparin structure reveals the allosteric mechanism of antithrombin activation. EMBO J. 2006; 25 (9) 2029-2037
82 Sheehan J P, Tollefsen D M, Sadler J E. Heparin cofactor II is regulated allosterically and not primarily by template effects. Studies with mutant thrombins and glycosaminoglycans. J Biol Chem. 1994; 269 (52) 32747-32751
83 Verhamme I M, Bock P E, Jackson C M. The preferred pathway of glycosaminoglycan-accelerated inactivation of thrombin by heparin cofactor II. J Biol Chem. 2004; 279 (11) 9785-9795
84 Van Deerlin V MD, Tollefsen D M. The N-terminal acidic domain of heparin cofactor II mediates the inhibition of alpha-thrombin in the presence of glycosaminoglycans. J Biol Chem. 1991; 266 (30) 20223-20231
85 Mitchell J W, Church F C. Aspartic acid residues 72 and 75 and tyrosine-sulfate 73 of heparin cofactor II promote intramolecular interactions during glycosaminoglycan binding and thrombin inhibition. J Biol Chem. 2002; 277 (22) 19823-19830
86 Sutherland J S, Bhakta V, Sheffield W P. The appended tail region of heparin cofactor II and additional reactive centre loop mutations combine to increase the reactivity and specificity of alpha1-proteinase inhibitor M358R for thrombin. Thromb Haemost. 2007; 98 (5) 1014-1023
87 Sutherland J S, Bhakta V, Filion M L, Sheffield W P. The transferable tail: fusion of the N-terminal acidic extension of heparin cofactor II to alpha1-proteinase inhibitor M358R specifically increases the rate of thrombin inhibition. Biochemistry. 2006; 45 (38) 11444-11452
88 Tollefsen D M. Insight into the mechanism of action of heparin cofactor II. Thromb Haemost. 1995; 74 (5) 1209-1214
89 O'Keeffe D, Olson S T, Gasiunas N, Gallagher J, Baglin T P, Huntington J A. The heparin binding properties of heparin cofactor II suggest an antithrombin-like activation mechanism. J Biol Chem. 2004; 279 (48) 50267-50273
90 Fortenberry Y M, Whinna H C, Gentry H R, Myles T, Leung L L, Church F C. Molecular mapping of the thrombin-heparin cofactor II complex. J Biol Chem. 2004; 279 (41) 43237-43244
91 Myles T, Church F C, Whinna H C, Monard D, Stone S R. Role of thrombin anion-binding exosite-I in the formation of thrombin-serpin complexes. J Biol Chem. 1998; 273 (47) 31203-31208
92 Liaw P CY, Becker D L, Stafford A R, Fredenburgh J C, Weitz J I. Molecular basis for the susceptibility of fibrin-bound thrombin to inactivation by heparin cofactor ii in the presence of dermatan sulfate but not heparin. J Biol Chem. 2001; 276 (24) 20959-20965
93 Church F C, Noyes C M, Griffith M J. Inhibition of chymotrypsin by heparin cofactor II. Proc Natl Acad Sci U S A. 1985; 82 (19) 6431-6434
94 Parker K A, Tollefsen D M. The protease specificity of heparin cofactor II. Inhibition of thrombin generated during coagulation. J Biol Chem. 1985; 260 (6) 3501-3505
95 Toulon P, Chadeuf G, Bouillot J L et al.. Involvement of heparin cofactor II in chymotrypsin neutralization and in the pancreatic proteinase-antiproteinase interaction during acute pancreatitis in man. Eur J Clin Invest. 1991; 21 (3) 303-309
96 Derechin V M, Blinder M A, Tollefsen D M. Substitution of arginine for Leu444 in the reactive site of heparin cofactor II enhances the rate of thrombin inhibition. J Biol Chem. 1990; 265 (10) 5623-5628
97 Liu L, Dewar L, Song Y et al.. Inhibition of thrombin by antithrombin III and heparin cofactor II in vivo. Thromb Haemost. 1995; 73 (3) 405-412
98 Tollefsen D M. Heparin cofactor II deficiency. Arch Pathol Lab Med. 2002; 126 (11) 1394-1400
99 Villa P, Aznar J, Vaya A et al.. Hereditary homozygous heparin cofactor II deficiency and the risk of developing venous thrombosis. Thromb Haemost. 1999; 82 (3) 1011-1014
100 Corral J, Aznar J, Gonzalez-Conejero R et al.. Homozygous deficiency of heparin cofactor II: relevance of P17 glutamate residue in serpins, relationship with conformational diseases, and role in thrombosis. Circulation. 2004; 110 (10) 1303-1307
101 Tanaka K A, Szlam F, Vinten-Johansen J, Cardin A D, Levy J H. Effects of antithrombin and heparin cofactor II levels on anticoagulation with Intimatan. Thromb Haemost. 2005; 94 (4) 808-813
102 Giri T K, Tollefsen D M. Placental dermatan sulfate: isolation, anticoagulant activity, and association with heparin cofactor II. Blood. 2006; 107 (7) 2753-2758
103 Massouh M, Jatoi A, Gordon E M, Ratnoff O D. Heparin cofactor II activity in plasma during pregnancy and oral contraceptive use. J Lab Clin Med. 1989; 114 (6) 697-699
104 Andersson T, Lorentzen B, Hogdahl H, Clausen T, Mowinckel M C, Abildgaard U. Thrombin-inhibitor complexes in the blood during and after delivery. Thromb Res. 1996; 82 (2) 109-117
105 Andrew M, Mitchell L, Berry L et al.. An anticoagulant dermatan sulfate proteoglycan circulates in the pregnant woman and her fetus. J Clin Invest. 1992; 89 (1) 321-326
106 Bellart J, Gilabert R, Cabero L, Fontcuberta J, Monasterio J, Miralles R M. Heparin cofactor II: a new marker for pre-eclampsia. Blood Coagul Fibrinolysis. 1998; 9 (2) 205-208
107 He I, Tollefsen D M. Heparin cofactor II-deficient mice are viable and fertile. Blood. 2000; 45 (Abst)
108 He L, Vicente C P, Westrick R J, Eitzman D T, Tollefsen D M. Heparin cofactor II inhibits arterial thrombosis after endothelial injury. J Clin Invest. 2002; 109 (2) 213-219
109 Aihara K, Azuma H, Akaike M et al.. Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II-deficient mice. J Clin Invest. 2007; 117 (6) 1514-1526
110 Ishiguro K, Kojima T, Kadomatsu K et al.. Complete antithrombin deficiency in mice results in embryonic lethality. J Clin Invest. 2000; 106 (7) 873-878
111 Aihara K, Azuma H, Takamori N et al.. Heparin cofactor II is a novel protective factor against carotid atherosclerosis in elderly individuals. Circulation. 2004; 109 (22) 2761-2765
112 Huang P H, Leu H B, Chen J W et al.. Decreased heparin cofactor II activity is associated with impaired endothelial function determined by brachial ultrasonography and predicts cardiovascular events. Int J Cardiol. 2007; 114 (2) 152-158
113 Giri T K, Ahn C W, Wu K K, Tollefsen D M. Heparin cofactor II levels do not predict the development of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. Arterioscler Thromb Vasc Biol. 2005; 25 (12) 2689-2690
114 Rau J C, Deans C, Hoffman M R et al.. Heparin cofactor II in atherosclerotic lesions from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. Exp Mol Pathol. 2009; 87 (3) 178-183
115 Schillinger M, Exner M, Sabeti S et al.. High plasma heparin cofactor II activity protects from restenosis after femoropopliteal stenting. Thromb Haemost. 2004; 92 (5) 1108-1113
116 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 (4) 481-486
117 Vicente C P, He L, Tollefsen D M. Accelerated atherogenesis and neointima formation in heparin cofactor II deficient mice. Blood. 2007; 110 (13) 4261-4267
118 He L, Giri T K, Vicente C P, Tollefsen D M. Vascular dermatan sulfate regulates the antithrombotic activity of heparin cofactor II. Blood. 2008; 111 (8) 4118-4125
119 Randall D R, Sinclair G B, Colobong K E, Hetty E, Clarke L A. Heparin cofactor II-thrombin complex in MPS I: a biomarker of MPS disease. Mol Genet Metab. 2006; 88 (3) 235-243
120 Randall D R, Colobong K E, Hemmelgarn H et al.. Heparin cofactor II-thrombin complex: a biomarker of MPS disease. Mol Genet Metab. 2008; 94 (4) 456-461
121 Langford-Smith K, Arasaradnam M, Wraith J E, Wynn R, Bigger B W. Evaluation of heparin cofactor II-thrombin complex as a biomarker on blood spots from mucopolysaccharidosis I, IIIA and IIIB mice. Mol Genet Metab. 2010; 99 (3) 269-274

Frank C ChurchPh.D.

Department of Pathology and Laboratory Medicine, Campus Box 7035, 932 Mary Ellen Jones Building

The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7035

eMail: fchurch@email.unc.edu