Mechanism of the anticoagulant action of heparin

@article{Bjork2004MechanismOT,
  title={Mechanism of the anticoagulant action of heparin},
  author={Ingemar Björk and Ulf Lindahl},
  journal={Molecular and Cellular Biochemistry},
  year={2004},
  volume={48},
  pages={161-182}
}
SummaryThe anticoagulant effect of heparin, a sulfated glycosaminoglycan produced by mast cells, requires the participation of the plasma protease inhibitor antithrombin, also called heparin cofactor. Antithrombin inhibits coagulation proteases by forming equimolar, stable complexes with the enzymes. The formation of these complexes involves the attack by the enzyme of a specific Arg-Ser bond in the carboxy-terminal region of the inhibitor. The complexes so formed are not dissociated by… Expand
Structure of activated thrombin-activatable fibrinolysis inhibitor, a molecular link between coagulation and fibrinolysis.
TLDR
It is shown that purified bovine TAFI activated in the presence of a proteinaceous inhibitor renders a stable enzyme-inhibitor complex, contributing to high inhibitory efficiency. Expand
Interaction of designed sulfated flavanoids with antithrombin: lessons on the design of organic activators.
TLDR
Competitive binding experiments indicate that activator CS does not compete with a saccharide ligand that binds antithrombin in the pentasaccharide binding site, while it competes with full-length low-affinity heparin. Expand
Interactions of antithrombin and proteins in the plasma contact activation system with immobilized functional heparin.
TLDR
The interactions of antithrombin (AT) and the contact phase clotting factors with two commercially available heparinized surfaces are reported and determined that the CBAS surface adsorbed about 4 times as much AT as the Corline surface. Expand
Quantitative analysis of antithrombin III binding site in low molecular weight heparins by exhausetive heparinases digestion and capillary electrophoresis.
TLDR
A capillary electrophoresis method in combination with heparinase digestion and affinity chromatography for the measurement of molar percentage of ATIII-binding site of LMWHs demonstrated that it provides more precise data for assessing the anti-FXa activity than that of the biochemical assay method. Expand
Effect of thrombin inhibitors on positive feedback in the coagulation cascade
TLDR
It is found that argatroban slows the appearance of thrombin and lowers its amount, whereas for bivalirudin they lower its inhibitory activity, and it seems that PLMs stabilize protein complexes mediating positive feedback in the coagulation cascade. Expand
Thrombin generation and its inhibition: a review of the scientific basis and mechanism of action of anticoagulant therapies.
This review concentrates on discussing the various therapeutic agents available to prevent or inhibit clot formation. Particular emphasis is placed on therapies associated with modi®cation toExpand
Novel anticoagulant polyethylenimine: inhibition of thrombin-catalyzed fibrin formation.
TLDR
Although PEI upregulated TF-dependent FVII activation under the low-salt condition, the effective downstream inhibition of fibrin formation readily abolished and overrode the upstream enhancement, demonstrating the overall anticoagulation. Expand
Hydropathic interaction analyses of small organic activators binding to antithrombin.
TLDR
This investigation indicates that HINT is a useful tool in understanding interactions of antithrombin with small sulfated organic ligands at a molecular level, has some good predictive properties, and is likely to be useful for rational design purposes. Expand
Pharmacology of Heparin and Related Drugs
TLDR
A “state of the art” review of the current understanding of the pharmacology of heparin and related drugs and an overview of the status of development of such drugs are provided. Expand
Interaction of heparin and heparin-derived oligosaccharides with synthetic peptide analogues of the heparin-binding domain of heparin/heparan sulfate-interacting protein.
TLDR
The site-specific binding of protonated histidine side chains to heparin provides a molecular-level explanation for the pH-dependent binding of beta-amyloid peptides by he parin and heparan sulfate proteoglycan and may have implications for amyloid formation. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 160 REFERENCES
Slow, spontaneous dissociation of the antithrombin—thrombin complex produces a proteolytically modified form of the inhibitor
TLDR
It is demonstrated that purified antithrombin-thrombin complex slowly dissociates also under physiological conditions, i.e., in the absence of any denaturing or dissociating agents. Expand
Anticoagulant Action of Heparin
TLDR
It is proposed that heparin acts to accelerate inhibitor function by binding to antithrombin and inducing an allosteric modification in it, which renders the arginine in its reactive site more accessible to the serine in the active centre of thrombin4. Expand
The heparin binding site of antithrombin III. Evidence for a critical tryptophan residue.
TLDR
Results indicate that the integrity of a specific tryptophan residue is critical to the binding of heparin to antithrombin III. Expand
The purification and mechanism of action of human antithrombin-heparin cofactor.
TLDR
It is suggested that heparin binds to the inhibitor and causes a conformational change which results in a more favorable exposure of the arginine reactive site, allowing a rapid interaction with thrombin. Expand
The kinetics of hemostatic enzyme-antithrombin interactions in the presence of low molecular weight heparin.
TLDR
It is demonstrated that binding of heparin to antithrombin is required for the mucopolysaccharide-dependent enhancement in the rates of neutralization of thrombin, factor IXa, factor Xa, or plasmin by the protease inhibitor. Expand
Inhibition of activated factor XII by antithrombin-heparin cofactor.
TLDR
Sodium dodecyl sulfate gel electrophoresis of reduced proteins has indicated that antithrombin-heparin cofactor functions by forming an undissociable complex with either species of the enzyme, which represents a 1:1 stoichiometric combination of activated Factor XII and inhibitor. Expand
The production of an inactive form of antithrombin through limited proteolysis by thrombin
TLDR
This report deals with the ~~~Iirnin~ ~ha~~c~e~ation and with various conditions for the formation of such a proteolytic modified form of ~~t~ro~~b~, which is rapidly formed in considerable amounts in the presence of ~r~~bIn, which has lost the ability to inhibit thrombin and has reduced affinity for heparin. Expand
Role of heparin in the inactivation of thrombin, factor Xa, and plasmin by antithrombin III.
TLDR
Hemparin is believed to act as an activator of the enzymes that makes them more susceptible to antithrombin III because of enzyme-heparin interactions. Expand
Anticoagulant activity of heparin: Isolation of antithrombin‐binding sites
TLDR
Findings suggest that binding of heparin to antithrombin may require a specific sequence of variously substituted sugar residues, which is in contrast to previous reports which suggested that it does not require such a sequence. Expand
The inhibition of human plasmin by human antithrombin-heparin cofactor.
TLDR
Sodium dodecyl sulfate gel electrophoresis of reduced and nonreduced proteins indicates that antithrombin functions as a potent antiplasmin by forming an undissociable complex which is stable in the presence of denaturing or reducing agents (or both). Expand
...
1
2
3
4
5
...