Role of free protein S and C4b binding protein in regulating the coagulant response to Escherichia coli

Schultz

2013

171

Activation of coagulation frequently occurs in severe infection and sepsis and may contribute to the development of thrombosis. Coagulation abnormalities in sepsis range from a small decrease in platelet count and subclinical prolongation of global clotting times to fulminant disseminated intravascular coagulation (DIC), characterized by simultaneous widespread microvascular thrombosis and profuse bleeding from various sites. Septic patients with severe forms of DIC may present with manifest thromboembolic disease or clinically less apparent microvascular fibrin deposition, which predominantly presents as multiple organ dysfunction. Thrombophilia is associated with a prohemostatic state and consequently with an increased tendency to develop thrombosis. Hypothetically, patients with thrombophilia may suffer from more severe coagulopathy in case of severe infection or sepsis, which may result in a more serious clinical course and an unfavorable outcome. On the basis of the knowledge of the pathogenesis of thrombosis in severe inflammation and sepsis, strategies aimed at the inhibition of coagulation activation have been developed and have been found favorable in experimental and clinical studies.

Section: Prothrombotic Mechanisms In Sepsismentioning

confidence: 99%

Sepsis and Thrombosis

Schultz

2013

171

“…Although it has been shown that the b-chain of C4bBP (which mainly governs the binding to protein S) is not very much affected during the acute-phase response, 38 support for this hypothesis comes from studies showing that the infusion of C4bBP in combination with a sublethal dose of Escherichia coli into baboons resulted in a lethal response with severe organ damage due to DIC. 39 Finally, but importantly, in sepsis the EPCR has been shown to be downregulated, which may further negatively affect the function of the protein C system. 40 Apart from these effects, sepsis may cause a resistance toward APC by other mechanisms, which are partly dependent on a sharp increase in factor VIII levels (released from endothelial cells) but partly occur by yet unidentified mechanisms.…”

Section: Regulation Of Thrombin Generationmentioning

confidence: 99%

The Role of Natural Anticoagulants in the Pathogenesis and Management of Systemic Activation of Coagulation and Inflammation in Critically Ill Patients

2008

Critically ill patients often have systemic activation of both inflammatory systems and coagulation. Increasing evidence points to an extensive cross-talk between these two systems, whereby inflammation leads to activation of coagulation and coagulation considerably affects inflammatory activity. The intricate relationship between inflammation and coagulation may have major consequences for the pathogenesis of microvascular failure and subsequent multiple organ failure, as a result of severe infection and the associated systemic inflammatory response. Molecular pathways that contribute to inflammation-induced activation of coagulation have been precisely identified. Activation of the coagulation system and ensuing thrombin generation is dependent on an interleukin-6-induced expression of tissue factor on activated mononuclear cells and endothelial cells and is insufficiently counteracted by tissue factor pathway inhibitor. Simultaneously, endothelial-bound anticoagulant mechanisms, in particular the protein C system and the antithrombin system, are shut off by proinflammatory cytokines. Modulation of inflammatory activity by activation of coagulation also occurs by various mechanisms. Activated coagulation proteases, such as the tissue factor-factor VIIa complex, factor Xa, and thrombin, can bind to protease-activated receptors on various cells, and the ensuing intracellular signaling leads to increased production of proinflammatory cytokines and chemokines. Activated protein C can bind to the protein C receptor on endothelial cells and mononuclear cells, thereby affecting NF-kappaB nuclear translocation and subsequently influencing inflammatory gene expression and inhibition of tissue factor expression on mononuclear cells. Observations in experimental models of targeted disruption of the protein C gene and restoration of the downregulated protein C pathway by administration of recombinant activated protein C support this notion.

“…Blockade of the activity of protein C by infusion of C4 binding protein turns a sublethal model of E. coli in baboons into a lethal model. 34 Blockade of EPCR by a neutralizing monoclonal antibody also increased mortality in the E. coli baboon model. 35 Vice versa, infusion of PC in the same model protected against DIC and dying.…”

Section: Tissue Factormentioning

confidence: 99%

Disseminated Intravascular Coagulation in Infectious Disease

Schultz

2010

108

Severe infection and inflammation almost invariably lead to hemostatic abnormalities, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation. Systemic inflammation as a result of severe infection leads to activation of coagulation, due to tissue factor-mediated thrombin generation, downregulation of physiological anticoagulant mechanisms, and inhibition of fibrinolysis. Proinflammatory cytokines play a central role in the differential effects on the coagulation and fibrinolysis pathways. Vice versa, activation of the coagulation system may importantly affect inflammatory responses by direct and indirect mechanisms. Apart from the general coagulation response to inflammation associated with severe infection, specific infections may cause distinct features, such as hemorrhagic fever or thrombotic microangiopathy. The relevance of the cross-talk between inflammation and coagulation is underlined by the results of the treatment of severe systemic infection with modulators of coagulation and inflammation.