Heparin Cofactor II

Tollefsen, Douglas M.

doi:10.1007/978-1-4615-5391-5_4

Cited by 52 publications

(36 citation statements)

References 69 publications

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“…HCII is present in plasma at similar levels to AT (Tollefsen, 1997), but HCII cannot substitute for AT in AT deficiency. HCII deficiency has no effect on plasma coagulation, but it does give rise to an increase in the formation of occlusive arterial thrombi after damage to the endothelium (He et al, 2002).…”

Section: Other Heparin-activated Serpinsmentioning

confidence: 99%

Pharmacology of Heparin and Related Drugs

et al. 2015

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Section: Other Heparin-activated Serpinsmentioning

confidence: 99%

Pharmacology of Heparin and Related Drugs

et al. 2015

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“…11 Third, thrombin is similarly inhibited by cleavage of L444 of the SERPIN heparin cofactor II in the presence of the glycosaminoglycan, heparan sulfate, or the galactosaminoglycan, dermatan sulfate. 12 The thrombin-thrombomodulin complex also activates a carboxypeptidase, thrombin-activated fibrinolysis inhibitor (TAFI) by proteolysis at R92, 13,14 at a rate approximately 1000 times greater than thrombin alone. Activated TAFI is then able to remove lysine residues from fibrin that form favored binding sites for fibrinolytic proteins.…”

Section: Introduction: Natural Hemostatic Substrates Of Thrombinmentioning

confidence: 99%

“…58,59 The mechanism is more complex than the heparin-accelerated inhibition of thrombin by antithrombin. 12 In addition to a template acceleration reaction mediated by exosite II, the polysaccharide releases a sequestered highly acidic N-terminal tail of heparin cofactor II, which is then able to bind to exosite I and position the thrombin for attempted cleavage of the Leu-Ser reactive center bond (Table 1). This mechanism is supported by crystallographic and mutagenesis studies.…”

mentioning

confidence: 99%

Directing thrombin

Lane

Philippou

Huntington

2005

Blood

319

279

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Following initiation of coagulation as part of the hemostatic response to injury, thrombin is generated from its inactive precursor prothrombin by factor Xa as part of the prothrombinase complex. Thrombin then has multiple roles. The way in which thrombin interacts with its many substrates has been carefully scrutinized in the past decades, but until recently there has been little consideration of how its many functions are coordinated or directed. Any understanding of how it is directed requires knowledge of its structure, how it interacts with its substrates, and the role of any cofactors for its interaction with substrates. Recently, many of the interactions of thrombin have been clarified by crystal structure and site-directed mutagenesis analyses. These analyses have revealed common residues used for recognition of some substrates and overlapping surface exosites used for recognition by cofactors. As many of its downstream reactions are cofactor driven, competition between cofactors for exosites must be a dominant mechanism that determines the fate of thrombin. This review draws together much recent work that has helped clarify structure function relationships of thrombin. It then attempts to provide a cogent proposal to explain how thrombin activity is directed during the hemostatic response. ( Introduction: natural hemostatic substrates of thrombinProteinases play crucial roles in biologic processes involved in organism homeostasis. Their actions require tight regulation and coordination. Failure of regulation and coordination leads to disease. The hemostasis system involves activation, regulation, and coordination of numerous proteinases. The complex reactions occur on activated or damaged cells, platelets, and endothelial cells. In normal physiologic conditions hemostasis is exquisitely initiated, controlled, and terminated. Genetic or physiologic perturbations, however, can lead to severe dysfunction, resulting in either hemorrhagic disorders or thromboembolic disease, illustrating the need for tight regulation of these proteolytic reactions.Central to the functioning of hemostasis are the roles of thrombin. Numerous potential substrates have been identified for thrombin, 1,2 suggesting diverse roles. Only those substrates related to hemostasis are considered here. A prime function of thrombin is the conversion of fibrinogen to fibrin. Two fibrinopeptides (FPs) are cleaved, FPA (the 16-residue N-terminal peptide from the A␣ chain) and FPB (the 14-residue peptide from the B␤ chain). Cleavage of FPA occurs first, and this forms a fibrin monomer (termed fibrin I) which spontaneously polymerizes to form protofibrils. Cleavage of FPB generates fibrin II protofibrils that undergo lateral aggregation. In the dynamic process of thrombin generation in blood, some of the early generated thrombin feeds back on the cascade system to activate factors V and VIII, enabling more sustained generation of thrombin. 3,4 Thrombin activates factors V and VIII by excision of their central B domains. In factor V, R709, R1018...

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“…The rate of thrombin inhibition by AT is enhanced by Ϸ1000-fold in the presence of heparin and heparan sulfates, 85,86 and inhibition by HCII is accelerated to a similar degree by either heparin or dermatan sulfate. 87,88 Mutagenesis studies have identified the heparin binding site of thrombin as exosite II and includes (in order of importance) arginine 93, lysine 236, lysine 240, arginine 101, and arginine 233. 89 -91 Biochemical work has also shown a minimal heparin binding site size of 6 monosaccharide residues, with binding strongly dependent on ionic strength, suggesting a nonspecific electrostatic association of 5 to 6 ionic interactions.…”

Section: Heparin and Other Glycosaminoglycansmentioning

confidence: 99%

Thrombin-Cofactor Interactions

Adams

Huntington

2006

ATVB

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Abstract-Precise modulation of thrombin activity throughout the hemostatic response is essential for efficient cessation of bleeding while preventing inappropriate clot growth or dissemination which causes thrombosis. Regulating thrombin activity is made difficult by its ability to diffuse from the surface on which it was generated and its ability to cleave at least 12 substrates. To overcome this challenge, thrombin recognition of substrates is largely controlled by cofactors that act by localizing thrombin to various surfaces, blocking substrate binding to critical exosites, engendering new exosites for substrate recognition and by allosterically modulating the properties of the active site of thrombin. Thrombin cofactors can be classified as either pro-or anticoagulants, depending on how substrate preference is altered. The procoagulant cofactors include glycoprotein Ib␣, fibrin, and Na ϩ , and the anticoagulants are heparin and thrombomodulin. Over the last few years, crystal structures have been reported for all of the thrombin-cofactor complexes. The purpose of this article is to summarize the features of these structures and to discuss the mechanisms and physiological relevance of cofactor binding in thrombin regulation.

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Heparin Cofactor II

Cited by 52 publications

References 69 publications

Pharmacology of Heparin and Related Drugs

Pharmacology of Heparin and Related Drugs

Directing thrombin

Thrombin-Cofactor Interactions

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