Hemostasis and inflammation: two of a kind?

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Abstract

Hemostasis is a defense mechanism to stop bleeding. Activated by vessel wall injury, it consists of intertwined activation of platelets and the coagulation cascade, tightly controlled by natural anticoagulants and the fibrinolytic system.

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Inflammation, endothelium, and coagulation in sepsis.

Marcel Levi, Tom van der Poll, Willem Wiersinga … (2008)

Sepsis is a systemic response to infection, and symptoms are produced by host defense systems rather than by the invading pathogens. Amongst the most prominent features of sepsis, contributing significantly to its outcome, is activation of coagulation with concurrent down-regulation of anticoagulant systems and fibrinolysis. Inflammation-induced coagulation on its turn contributes to inflammation. Another important feature of sepsis, associated with key symptoms such as hypovolemia and hypotension, is endothelial dysfunction. Under normal conditions, the endothelium provides for an anticoagulant surface, a property that is lost in sepsis. In this review, data about the interplay between inflammation and coagulation in sepsis are summarized with a special focus on the influence of the endothelium on inflammation-induced coagulation and vice versa. Possible procoagulant properties of the endothelium are described, such as expression of tissue factor (TF) and von Willebrand factor and interaction with platelets. Possible procoagulant roles of microparticles, circulating endothelial cells and endothelial apoptosis, are also discussed. Moreover, the important roles of the endothelium in down-regulating the anticoagulants TF pathway inhibitor, antithrombin, and the protein C (PC) system and inhibition of fibrinolysis are discussed. The influence of coagulation on its turn on inflammation and the endothelium is described with a special focus on protease-activated receptors (PARs). We conclude that the relationship between endothelium and coagulation in sepsis is tight and that further research is needed, for example, to better understand the role of activated PC signaling via PAR-1, the role of the endothelial PC receptor herein, and the role of the glycocalyx.

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Thrombomodulin mutations in atypical hemolytic-uremic syndrome.

Mieke Delvaeye, Marina Noris, Astrid De Vriese … (2009)

The hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. The common form of the syndrome is triggered by infection with Shiga toxin-producing bacteria and has a favorable outcome. The less common form of the syndrome, called atypical hemolytic-uremic syndrome, accounts for about 10% of cases, and patients with this form of the syndrome have a poor prognosis. Approximately half of the patients with atypical hemolytic-uremic syndrome have mutations in genes that regulate the complement system. Genetic factors in the remaining cases are unknown. We studied the role of thrombomodulin, an endothelial glycoprotein with anticoagulant, antiinflammatory, and cytoprotective properties, in atypical hemolytic-uremic syndrome. We sequenced the entire thrombomodulin gene (THBD) in 152 patients with atypical hemolytic-uremic syndrome and in 380 controls. Using purified proteins and cell-expression systems, we investigated whether thrombomodulin regulates the complement system, and we characterized the mechanisms. We evaluated the effects of thrombomodulin missense mutations associated with atypical hemolytic-uremic syndrome on complement activation by expressing thrombomodulin variants in cultured cells. Of 152 patients with atypical hemolytic-uremic syndrome, 7 unrelated patients had six different heterozygous missense THBD mutations. In vitro, thrombomodulin binds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor I-mediated inactivation of C3b in the presence of cofactors, CFH or C4b binding protein. By promoting activation of the plasma procarboxypeptidase B, thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulin variants associated with atypical hemolytic-uremic syndrome had diminished capacity to inactivate C3b and to activate procarboxypeptidase B and were thus less protected from activated complement. Mutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic-uremic syndrome. 2009 Massachusetts Medical Society

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Cell membrane microparticles in blood and blood products: potentially pathogenic agents and diagnostic markers.

Jan Šimák, Monique P Gelderman (2006)

Cell membrane microparticles (MPs) circulate in the blood of healthy donors, and their elevated counts have been documented in various pathologies. Microparticles are phospholipid microvesicles of 0.05 to 1.5 microm in size, containing certain membrane proteins of their parental cells. Thus, different phenotypes of MPs derived from platelets, blood cells, endothelial cells, and some other cell types have been identified in plasma. Microparticles are released by various stimuli including shear stress, complement attack, or proapoptotic stimulation. Microparticle release is a highly controlled process and likely independent from metabolic energy. Elevated MPs in various diseases indicate their diagnostic importance, particularly in vascular pathologies. Moreover, MPs in blood possess a broad spectrum of biologic activities. Microparticles may facilitate cell-to-cell interactions, induce cell signaling, or even transfer receptors between different cell types. The physiological roles of MPs in various tissue defense processes have been suggested and the pathophysiologic implications of MPs in thrombosis, inflammation, cancer metastasis, or response to pathogens have been proposed. This is important for transfusion medicine because MPs are present in both plasma and cellular blood products. Thus, the investigation of potentially pathogenic effects of MPs in blood products and of MP release associated with blood product processing and storage have yet to come.

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Author and article information

Journal

Journal ID (nlm-ta): Thromb J

Title: Thrombosis Journal

Publisher: BioMed Central

ISSN (Electronic): 1477-9560

Publication date Collection: 2009

Publication date (Electronic): 18 November 2009

Volume: 7

Page: 15

Affiliations

[1 ]Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium

Article

Publisher ID: 1477-9560-7-15

DOI: 10.1186/1477-9560-7-15

PMC ID: 2784434

PubMed ID: 19922636

SO-VID: f4ded923-33e6-4e0c-9a9f-0d5b59dd56be

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Hemostasis and inflammation: two of a kind?

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Cardiovascular Innovations and Applications

Most cited references 9

Inflammation, endothelium, and coagulation in sepsis.

Thrombomodulin mutations in atypical hemolytic-uremic syndrome.

Cell membrane microparticles in blood and blood products: potentially pathogenic agents and diagnostic markers.

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