Turnover Study of Heparin Cofactor II in Healthy Man

Sié, P.; Dupouy, D.; Pichon, J.; Boneu, B

doi:10.1055/s-0038-1660087

Cited by 32 publications

(5 citation statements)

References 16 publications

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“…8 HCII circulates in human plasma at a concentration of Ϸ1 mol/L and has a half-life of 2 to 3 days. 9,10 The thrombin-HCII complex is cleared within minutes by the low-density lipoprotein receptor-related protein on hepatocytes. 11 Human HCII is a single-chain glycoprotein containing 480 amino acid residues.…”

Section: Biochemistry Of Hciimentioning

confidence: 99%

Heparin Cofactor II Modulates the Response to Vascular Injury

Tollefsen

2007

ATVB

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Abstract-Heparin cofactor II (HCII) has several biochemical properties that distinguish it from other serpins: (1) it specifically inhibits thrombin; (2) the mechanism of inhibition involves binding of an acidic domain in HCII to thrombin exosite I; and (3) the rate of inhibition increases dramatically in the presence of dermatan sulfate molecules having specific structures. Human studies suggest that high plasma HCII levels are protective against in-stent restenosis and atherosclerosis. Studies with HCII knockout mice directly support the hypothesis that HCII interacts with dermatan sulfate in the arterial wall after endothelial injury and thereby exerts an antithrombotic effect. In addition, HCII deficiency appears to promote neointima formation and atherogenesis in mice. These results suggest that HCII plays a unique and important role in vascular homeostasis. Key Words: heparin cofactor II Ⅲ thrombin Ⅲ thrombosis Ⅲ atherogenesis Ⅲ restenosis T hirty years have elapsed since Briginshaw and Shanberge demonstrated that human plasma contains 2 heparindependent inhibitors of thrombin. 1,2 They reported that the 2 inhibitors could be separated by gel filtration and ionexchange chromatography. One of the inhibitors resembled the known protein antithrombin (formerly called antithrombin III) because it inactivated both thrombin and factor Xa and had easily detectable progressive (ie, heparinindependent) antithrombin activity. The second inhibitor did not react with factor Xa and had comparatively weak progressive antithrombin activity, yet it appeared to comprise a significant fraction of the total heparin cofactor activity in plasma. A few years later, Tollefsen and Blank demonstrated that 125 I-thrombin forms 2 SDS-stable complexes in plasma containing heparin, 3 and other investigators noted that the heparin cofactor activity of plasma exceeds the amount predicted from the antithrombin antigen concentration. 4,5 The existence of a second heparin cofactor (now called heparin cofactor II or HCII) was firmly established when the inhibitor was purified to homogeneity from human plasma and was shown to be distinct from antithrombin. 6 Although much has been learned about the structure, mechanism of action, and genetics of HCII, relatively little is known about its physiological function. This review summarizes our current knowledge of the biochemistry of HCII and then focus on recent insights gained from clinical studies and experiments with knockout mice. Biochemistry of HCIIThe HCII gene (designated SERPIND1 in humans) has been identified in a variety of vertebrate species, including humans, chimpanzee, rhesus monkey, house mouse, Norway rat, rabbit, cow, chicken, African clawed frog, European flounder, and zebrafish (http://www.ncbi.nlm.nih.gov/ entrez/). HCII mRNA is highly expressed in the liver, which appears to be the major source of plasma HCII. 7 Low levels of HCII mRNA are also detectable in other tissues, but the significance of extrahepatic expression of HCII is unclear. 8 HCII circulates in human plasma at...

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Section: Biochemistry Of Hciimentioning

confidence: 99%

Heparin Cofactor II Modulates the Response to Vascular Injury

Tollefsen

2007

ATVB

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“…Whereas the half-life of HCII in the circulation is -2.5 days (44), thrombin-HCII complexes are cleared much more rapidly by a serpin-enzyme complex receptor on hepatocytes (45,46). Turnover studies of labeled HCII in man suggest that -40% of the protein equilibrates with an extravascular compart ment (44), but the tissue distribution of HCII has not yet been investi gated. Normal HCII levels are present during oral anticoagulant use, in the vast majority of patients with venous thrombosis, and in most patients with hereditary antithrombin deficiency (47,48).…”

Section: Physiologic Functionmentioning

confidence: 99%

Insight into the Mechanism of Action of Heparin Cofactor II

Tollefsen

1995

Thromb Haemost

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The anticoagulant activities of glycosammoglycans are mediated by antithrombin and heparin eofaetor II (H C II) (I). When antithronihin is bound to soluble heparin or to heparan sulfate in the vessel wall, it ra pidly inhibits thrombin, faetor Xa, and factor IXa. H C II inhibits throm bin, but not other eoagulation proteases, in the presence o f heparin or dermatan sulfate (2 ,3). This review will loeus on the biochemistry of H C II, with an emphasis on recent evidence that H C II and antithrombin inhibit thrombin by fundamentally different mechanisms. Structure H C II is a member of the a I-antitrypsin family of serine protease in hibitors (serpins). It is a single-chain glycoprotein with a mass of-6 6 kDa (2). The c D N A for human H C II encodes a polypeptide 480 amino acids in length preceded by a 19-residue signal peptide (4 ,5). The pro tein contains three N-linked glycosylation sites and three cysteine resi dues that apparently do not form disulfide bonds (6). H C II is-3 0 % identical in sequence to antithrombin and other serpins, the greatest similarity occurring in the C-terminal two-thirds of the protein. By contrast, the first 80 amino acid residues at the N-lerminal end o f H C II share no homology with other serpins. The N-terminal region includes a tandem repeat of two highly acidic sequences, each o f which contains a tyrosine residue that becomes O-sulfated during biosynthesis (Fig. I A) (7). As discussed below, the N-terminal acidic domain is required for rapid inhibition of thrombin in the presence o f a glycosaminoglycan. Murine plasma contains two forms o f H C II that appear to differ only in the composition of their N-linked oligosaccharides (8). H C II is also present in rabbit, rat, and dog (8-10), but it has not yet been identi fied in non-mammalian species. Human, murine, and rabbit H C II are 87% identical to one another in amino acid sequence. The sequences of the reactive site, the glycosaminoglycan-binding site, and the N-term i nal acidic domain (shown in Fig. IA for human H C II) are even more highly conserved. Some other human serpins, such as a I-antitrypsin and al-antichymotrypsin, are only-6 0 % identical to their murine homologues. The strong conservation of H C II implies that it serves the same physiologic function in different species.

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“…[29][30][31] Normal HCII human blood plasma concentration is 1.2 mM with a half-life of 2 to 3 days. 16,32,33 Clearance of HCII-thrombin complexes in vivo has been studied in mice 34 and rabbits [35][36][37] and shown to be specific for low-density lipoprotein receptorrelated protein 1. 38 Human HCII was cloned independently in 1988 by Blinder et al 25 and Ragg 24 from liver and localized to chromosome 22.…”

Section: Characteristics Of Heparin Cofactor Ii: Purification Cloninmentioning

confidence: 99%

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

Rau¹,

Mitchell²,

Fortenberry³

et al. 2011

Semin Thromb Hemost

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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.

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Turnover Study of Heparin Cofactor II in Healthy Man

Cited by 32 publications

References 16 publications

Heparin Cofactor II Modulates the Response to Vascular Injury

Heparin Cofactor II Modulates the Response to Vascular Injury

Insight into the Mechanism of Action of Heparin Cofactor II

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

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