Glycosaminoglycans affect the interaction of human plasma kallikrein with plasminogen, factor XII and inhibitors

Gozzo, Andrezza Justino; Nunes, Viviane Abreu; Nader, Helena B.; Dietrich, Carl P.; Carmona, Adriana K.; Sampaio, Misako U.; Sampaio, Cláudio Hoffmann; Araújo, Magali

doi:10.1590/s0100-879x2003000800011

Cited by 14 publications

(12 citation statements)

References 20 publications

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“…In one study [21], chondroitin-4-sulphate and chondroitin-6-sulphate were not shown to have anticoagulant properties, but the concentrations used were 10-fold less than in the present study. The effect on coagulation of chondroitin sulphate at its highest concentration was not mediated by an increase in anti-FXa activity.…”

Section: Discussioncontrasting

confidence: 74%

The effects of glycosaminoglycans on coagulation: a thromboelastographic study

Senzolo¹,

Coppell²,

Cholongitas³

et al. 2007

Blood Coagulation &Amp; Fibrinolysis

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Endogenous heparinoids impair coagulation, evidenced by thrombelastography in cirrhotic patients with bacterial infection, but it is not clear which glycosaminoglycans can be detected by native and heparinase-modified thrombelastography. To assess the effects of different glycosaminoglycans on thrombelastography parameters and the reversibility of these effects by heparinase-I-modified thrombelastography. Twenty volunteers were enrolled. Solutions of heparan sulphate, dermatan sulphate, and chondroitin-4-sulphate were prepared at 'equivalent' concentrations, based on the composition and anticoagulant activity of danaparoid. Serial dilutions of each glycosaminoglycan were prepared to achieve 1.0, 0.5, 0.1, and 0.05 U/ml. Native and heparinase-modified thrombelastography, anti-activated factor X activity and heparin cofactor II activity were evaluated at each concentration. A statistically significant heparin-like effect was seen with 1 and 0.5 U/ml heparan sulphate, and 1 and 0.5 U/ml dermatan sulphate, which was completely reversed by heparinase-modified thrombelastography. Anti-activated factor X activity was significantly increased in samples containing heparan and dermatan sulphates. The heparin cofactor II activity decreased with 1.0 and 0.5 U/ml dermatan sulphate and chondroitin-4-sulphate, but not with heparan sulphate. Heparan and dermatan sulphates affect haemostasis when added to whole blood in vitro, detectable by native thrombelastography and completely reversed by heparinase-I-modified thrombelastography. They may therefore be responsible for the heparin-like effect seen by thrombelastography in patients with cirrhosis and bacterial infection.

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Section: Discussioncontrasting

confidence: 74%

The effects of glycosaminoglycans on coagulation: a thromboelastographic study

Senzolo¹,

Coppell²,

Cholongitas³

et al. 2007

Blood Coagulation &Amp; Fibrinolysis

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“…The properties of C1inh are not limited to the complement and contact systems (Zeerleder, 2011). Heparin potentiates the activity of C1inh (Gozzo et al, 2003), and the crystal structure of C1inh (Beinrohr et al, 2007) indicates a different mode of action toward the protease and a wholly different heparin binding site to AT.…”

Section: Other Heparin-activated Serpinsmentioning

confidence: 99%

Pharmacology of Heparin and Related Drugs

et al. 2015

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“…C1s, plasma kallikrein, fXIa, and fXIIa were included in the study, since independent experimental data were available in the literature. Polyanions increase inhibitory capacity against fXIa the most (60 -115-fold potentiation) (45,46), followed by C1s (15-60-fold) (47,48), and a minor effect is observed on plasma kallikrein (ϳ2-fold increase) (49). In contrast, the reaction against fXIIa is hindered 2-4-fold (45).…”

Section: Charge Distribution Of Target Proteinases Suggests a Neutralmentioning

confidence: 99%

C1 Inhibitor Serpin Domain Structure Reveals the Likely Mechanism of Heparin Potentiation and Conformational Disease

Beinrohr

Harmat

Dobó

et al. 2007

Journal of Biological Chemistry

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C1 inhibitor, a member of the serpin family, is a major downregulator of inflammatory processes in blood. Genetic deficiency of C1 inhibitor results in hereditary angioedema, a dominantly inheritable, potentially lethal disease. Here we report the first crystal structure of the serpin domain of human C1 inhibitor, representing a previously unreported latent form, which explains functional consequences of several naturally occurring mutations, two of which are discussed in detail. The presented structure displays a novel conformation with a seven-stranded ␤-sheet A. The unique conformation of the C-terminal six residues suggests its potential role as a barrier in the active-latent transition. On the basis of surface charge pattern, heparin affinity measurements, and docking of a heparin disaccharide, a heparin binding site is proposed in the contact area of the serpinproteinase encounter complex. We show how polyanions change the activity of the C1 inhibitor by a novel "sandwich" mechanism, explaining earlier reaction kinetic and mutagenesis studies. These results may help to improve therapeutic C1 inhibitor preparations used in the treatment of hereditary angioedema, organ transplant rejection, and heart attack.C1 inhibitor belongs to the group of serpin-type proteinase inhibitors in blood plasma. Serpins act as pseudosubstrates of serine and cysteine proteinases (although there are noninhibitory serpins as well) (1). A conformational change is triggered in the serpin upon peptide bond cleavage, which distorts the active site of proteinase and traps it in an inactive, covalently linked serpin-enzyme complex (2, 3). Serpins are vital downregulator components of proteolytic signal amplification cascades. Human C1 inhibitor (C1-inh) 4 is the only inhibitor that acts on early components of the classical pathway (C1r and C1s) and on that of the lectin pathway (MASP-1 and MASP-2) of the complement system (4). Complement mediates host defense against pathogens and altered host cells, but its uncontrolled activation could be harmful. Other physiologically crucial targets include plasma kallikrein and activated factor XII (fXIIa) of the contact activation and activated factor XI (fXIa) of the intrinsic coagulation systems (4). Apart from proteinase inhibition, it was recently discovered that C1-inh binds the central component C3b of complement (5), endotoxins from bacteria (6) and E-, P-selectin adhesion proteins on endothelial cells (7). C1-inh is a single-chain glycoprotein that has atypical two-domain architecture (8) with the C-terminal serpin and the unique N-terminal domains (9). C1-inh is extensively modified post-translationally, bearing six N-linked carbohydrates. Sequencing analysis revealed 14 potential O-glycosylation sites (9), seven of which had been verified by carbohydrate analysis (10). Most of the sugars are present in the N-terminal domain and do not affect proteinase inhibition (11, 12), but affinity to endotoxins and selectins depends on the N-glycans.The importance of C1-inh is underlined by its def...

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Glycosaminoglycans affect the interaction of human plasma kallikrein with plasminogen, factor XII and inhibitors

Cited by 14 publications

References 20 publications

The effects of glycosaminoglycans on coagulation: a thromboelastographic study

The effects of glycosaminoglycans on coagulation: a thromboelastographic study

Pharmacology of Heparin and Related Drugs

C1 Inhibitor Serpin Domain Structure Reveals the Likely Mechanism of Heparin Potentiation and Conformational Disease

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