Contaminated Heparin Associated with Adverse Clinical Events and Activation of the Contact System

Kishimoto, Takashi; Viswanathan, Karthik; Ganguly, Tanmoy; Elankumaran, Subbiah; Smith, Sean G.; Pelzer, Kevin D.; Lansing, Jonathan C.; Sriranganathan, Nammalwar; Zhao, Ganlin; Galcheva-Gargova, Zoya; Al-Hakim, Ali; Bailey, Gregory Scott; Fraser, Blair A.; Roy, Sucharita; Rogers-Cotrone, Thomas; Buhse, Lucinda F.; Whary, Mark T.; Fox, James G.; Nasr, Moheb; Pan, Gerald J. Dal; Shriver, Zachary; Langer, Robert; Venkataraman, Ganesh; Austen, K. Frank; Woodcock, Janet; Sasisekharan, Ram

doi:10.1056/nejmoa0803200

Cited by 580 publications

(465 citation statements)

References 14 publications

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“…OSCS has been suggested to be responsible for the adverse events by producing anaphylatoxins, complement C3a, C5a, and bradykinin, through contact system activation (9). Our data showed that all oversulfated forms of GAGs activated the contact system (Fig.…”

Section: Discussionsupporting

confidence: 53%

“…It was reported that negatively charged molecules can exert both activating and inhibitory effects on kallikrein-like activities in a time-dependent manner (35), and we measured the kinetics instead of a single time point used in previous studies (9). To this end, the human plasma was incubated with a series of negatively charged molecules at 37°C for 5 min.…”

Section: Chemically Oversulfated Gags Were More Sulfated Thanmentioning

confidence: 99%

“…OSCS has been suggested to be the cause of adverse reactions by inducing anaphylatoxins, bradykinin, C3a, and C5a, through contact system activation (9). The established contact system in human plasma consists of two serine protease prozymes as follows: prekallikrein and factor XII; a cofactor, high molecular weight kininogen; and a regulator, C1 inhibitor.…”

mentioning

confidence: 99%

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Chemically Oversulfated Glycosaminoglycans Are Potent Modulators of Contact System Activation and Different Cell Signaling Pathways

Pan

Qian

Zhou

et al. 2010

Journal of Biological Chemistry

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Contaminated heparin was associated with adverse reactions by activating the contact system. Chemically oversulfated/modified glycosaminoglycans (GAGs) consisting of heparan sulfate, dermatan sulfate, and chondroitin sulfate have been identified as heparin contaminants. Current studies demonstrated that each component of oversulfated GAGs was comparable with oversulfated chondroitin sulfate in activating the contact system. By testing a series of unrelated negatively charged compounds, we found that the contact system recognized negative charges rather than specific chemical structures. We further tested how oversulfated GAGs and contaminated heparins affect different cell signaling pathways. Our data showed that chemically oversulfated GAGs and contaminated heparin had higher activity than the parent compounds and authentic heparin, indicative of sulfation-dominant and GAG sequencedependent activities in BaF cell-based models of fibroblast growth factor/fibroblast growth factor receptor, glial cell linederived neurotrophic factor/c-Ret, and hepatocyte growth factor/c-Met signaling. In summary, these data indicate that contaminated heparins intended for blood anticoagulation not only activated the contact system but also modified different GAGdependent cell signaling pathways.

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Section: Discussionsupporting

confidence: 53%

Section: Chemically Oversulfated Gags Were More Sulfated Thanmentioning

confidence: 99%

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Chemically Oversulfated Glycosaminoglycans Are Potent Modulators of Contact System Activation and Different Cell Signaling Pathways

Pan

Qian

Zhou

et al. 2010

Journal of Biological Chemistry

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“…Although the inhibition of C5a generation has also been shown for heparin (35), other sulfated compounds like oversulfated chondroitin sulfate (OSCS) detected recently in batches of UFH have the adverse effect. By activating the kinin-kallikrein pathway, OSCS also induced the generation of the anaphylatoxins C3a and C5a (36). This clinical observation emphasizes the high demand for defined synthetic macromolecules for in vivo application.…”

Section: Discussionmentioning

confidence: 88%

Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation

Dernedde

Rausch

Weinhart

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

250

294

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Adhesive interactions of leukocytes and endothelial cells initiate leukocyte migration to inflamed tissue and are important for immune surveillance. Acute and chronic inflammatory diseases show a dysregulated immune response and result in a massive efflux of leukocytes that contributes to further tissue damage. Therefore, targeting leukocyte trafficking may provide a potent form of antiinflammatory therapy. Leukocyte migration is initiated by interactions of the cell adhesion molecules E-, L-, and P-selectin and their corresponding carbohydrate ligands. Compounds that efficiently address these interactions are therefore of high therapeutic interest. Based on this rationale we investigated synthetic dendritic polyglycerol sulfates (dPGS) as macromolecular inhibitors that operate via a multivalent binding mechanism mimicking naturally occurring ligands. dPGS inhibited both leukocytic L-selectin and endothelial P-selectin with high efficacy. Size and degree of sulfation of the polymer core determined selectin binding affinity. Administration of dPGS in a contact dermatitis mouse model dampened leukocyte extravasation as effectively as glucocorticoids did and edema formation was significantly reduced. In addition, dPGS interacted with the complement factors C3 and C5 as was shown in vitro and reduced C5a levels in a mouse model of complement activation. Thus, dPGS represent an innovative class of a fully synthetic polymer therapeutics that may be used for the treatment of inflammatory diseases.anti-inflammatory drug | complement inhibition | multiple target binding | multivalent selectin inhibitor | synthetic polymer

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“…The situation has been complicated recently due to the alarming discovery of heparin preparations that have been contaminated with oversulfated chondroitin sulfate (Guerrini et al, 2008). This contaminant induces hypotension associated with kallikrein release when administered by intravenous injection (Kishimoto et al, 2008). Fatal cases have been described.…”

Section: The Interaction Of Msps With Coagulation (Co)-factors: Stoppmentioning

confidence: 99%

Structure versus anticoagulant and antithrombotic actions of marine sulfated polysaccharides

Pomin¹,

Mourão²

2012

Rev. bras. farmacogn.

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Marine sulfated polysaccharides (MSP), such as sulfated fucans (SF), sulfated galactans (SG) and glycosaminoglycans (GAG) isolated from either algae or invertebrate animals, are highly anionic polysaccharides capable of interacting with certain cationic proteins, such as (co)-factors of the coagulation cascade during clotting-inhibition processes. These molecular complexes between MSP and coagulation-related proteins might, at first glance, be assumed to be driven mostly by electrostatic interactions. However, a systematic comparison using several novel sulfated polysaccharides composed of repetitive oligosaccharides with clear sulfation patterns has shown that these molecular interactions are regulated essentially by the stereochemistry of the glycans (which depends on a conjunction of anomericity, monosaccharide, conformational preference, and glycosylation and sulfation sites), rather than just a simple consequence of their negative charge density (mainly the number of sulfate groups). Here, we present an overview of the structure-function relationships of MSP, correlating their structures with their potential anticoagulant and antithrombotic actions, since pathologies related to the cardiovascular system are one of the major causes of illness and mortality in the world.

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Contaminated Heparin Associated with Adverse Clinical Events and Activation of the Contact System

Cited by 580 publications

References 14 publications

Chemically Oversulfated Glycosaminoglycans Are Potent Modulators of Contact System Activation and Different Cell Signaling Pathways

Chemically Oversulfated Glycosaminoglycans Are Potent Modulators of Contact System Activation and Different Cell Signaling Pathways

Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation

Structure versus anticoagulant and antithrombotic actions of marine sulfated polysaccharides

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