China
Africa
Explore chapters and articles related to this topic
Haemostasis and Thrombosis
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
In normal (resting) circumstances, the endothelium has an antithrombotic function:It secretes:Prostacyclin (vasodilator and platelet inhibition)Nitric oxide (vasodilator and platelet inhibition)Tissue-plasminogen activator (tPA: activates fibrinolysis)It expresses on its surface:ADPaseThrombomodulin (cofactor for activation of protein C)Endothelial protein C receptorHeparan sulphate (potentiates antithrombin)Tissue factor pathway inhibitor (TFPI)
Studies of the Primate Inflammatory Hemostatic Axis and Its Response to Inflammatory Mediators
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
In other conditions that are acute but are not influenced by hormonal factors, activation of the hemostatic system including consumption of terminal factors such as fibrinogen and development of thrombosis may not be critical in the chain of lethal events. This may be true even in cases where the classic picture of hemorrhagic adrenal glands is found at autopsy. Here the events driven by inflammatory mediators predominate over those involving the coagulation factors, as evidenced by a massive capillary leak and shock. In these cases there is undoubtedly expression and activation of proximal clotting factors, which may amplify the original inflammatory signal in a positive feedback. Receptors serving both the hemostatic mediator (tissue factor) and regulator (endothelial protein C receptor) arms of the hemostatic system can play such a role by altering the calcium flux in the course of forming complexes with their ligands. The intensity of these events involving inflammatory and proximal clotting factors and the efficiency of the fibrinolytic response are such that ocelusive microvascular thrombosis may not play as important a role in these acute cases of cardiovascular collapse, capillary leak, and shock as they do in the subacute and chronic cases described below.
Pulmonary Endothelium in Health and Viral Infections
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
Nikolaos Manitsopoulos, Frantzeska Frantzeskaki, Anastasia Kotanidou, Stylianos E. Orfanos
As mentioned before, the protein C system is considered an important regulator of the coagulant cascade through the anticoagulant activated protein C (APC) pathway. It also possesses cytoprotective properties through the cytoprotective protein C pathway in several cell types, including EC. Protein C is a vitamin K-dependent plasma glycoprotein present in the circulation as a biologically inactive, two-chain zymogen. It is activated on the EC surface by thrombin through a proteolytic reaction.6 This procedure can be enhanced more than 1000-fold by TM compared to thrombin-alone reaction. An even greater amplification (by an additional 20-fold) may be achieved if protein C is bound to endothelial protein C receptor (EPCR).6 The latter is also expressed in leukocytes and in its soluble form in vascular smooth muscle cells (SMCs).7 Apart from facilitating protein activation, EPCR also regulates EC leukocyte adhesion.6–8 APC downregulates the coagulation cascade by degrading the cofactors Va and VIIIa by limited proteolysis. The APC-mediated cleavage of these procoagulant cofactors shuts down thrombin generation, through both intrinsic and extrinsic pathways. In addition to promoting the activation of protein C in a Ca2+ depended way, TM also inhibits the activity of thrombin toward the procoagulant substrates fibrinogen, PAR-1, and cofactors V and VIII. TM can bind to a basic exosite on thrombin (exosite-1), thereby enabling the protease to recognize and rapidly activate protein C. The high-affinity interaction of TM with exosite-1 competitively inhibits the binding of procoagulant substrates to this site and, hence, the cofactor essentially converts thrombin from a procoagulant to a potent anticoagulant protease upon binding.6
Exploring the pathways of inflammation and coagulopathy in COVID-19: A narrative tour into a viral rabbit hole
Published in International Reviews of Immunology, 2022
Nitsan Landau, Yehuda Shoenfeld, Liat Negru, Gad Segal
Circulating protein C is activated by endothelial cell bound thrombomodulin, once this is activated by thrombin. Activated protein C (APC) acts with its cofactor protein S to degrade the essential coagulation cofactors Va and VIIIa. The endothelial protein C receptor (EPCR) not only accelerates the activation of protein C several-fold but also serves as a receptor for APC, and binding of APC to this receptor may amplify its anticoagulant and anti-inflammatory effects. In patients with severe inflammation, the protein C system is malfunctioning at virtually all levels (plasma levels of factors C and S are low and thrombomodulin is down regulated with resultant diminished protein C activation). Also, in sepsis the EPCR is down-regulated, negatively affecting the function of the protein C system [31]. Protein S also serves as a ligand for the immunosuppressive receptor tyrosine kinase (TK) MER, expressed by macrophages and other immune sentinels. Protein S depletion may silence MER signaling and activate sentinel cells to express and secrete pro-inflammatory cytokines [40]. In COVID-19, decreased factor C, S with concurrent rise in factors V, Va and VIII are documented [21–23]. It is suggested that a combined effect of both IL6 and hypoxia can further depress key anticoagulants such as protein S. Suggestions for treatments directed at augmenting such natural anticoagulants have not yet been tested [40, 41].
Venous thromboembolism prevention through the use of novel Factor Xa inhibitors
Published in Postgraduate Medicine, 2019
A. Al-Hillan, R. S. Bajwa, A. Cheema, A. Ezeume, S. Gor, H. Mahida, D. S. Kountz
Venous thrombosis tends to occur in areas where blood flow is decreased or altered mechanically. Valves function to help promote blood flow through the venous circulation, but they are also potential locations for venous stasis especially the area adjacent to valves that forms pockets in the deep veins of the leg [4]. Autopsy studies support the supposition of venous thrombus formation in sinuses adjacent to venous valves [5,6]. As blood flow slows in the venous system, oxygen concentration tends to decrease and the Hematocrit tends to rise [7]. As a result, antithrombotic proteins (thrombomodulin, endothelial protein C receptor EPCR) are preferentially expressed on venous valves [8]. Hypoxia also increases expression of certain procoagulants agents such as P-selectin which attracts immunologic cells containing tissue factor to the endothelium. Tissue factor and P-selectin trigger the first steps in thrombus formation [9,10]. As the ratio of procoagulants to anticoagulants increases, the risk of thrombosis increases. Conditions such as reduced mobility, polycythemia, congestive heart failure, and malignancy can precipitate these changes by increasing the key factor trigger which is stasis.
Disseminated intravascular coagulation: an update on pathogenesis and diagnosis
Published in Expert Review of Hematology, 2018
Marcel Levi, Suthesh Sivapalaratnam
Activated protein C is responsible for proteolytic degradation of the pivotal coagulation cofactors Va and VIIIa and is thereby another important regulator of thrombin generation. The conversion of protein C to activated protein C occurs after thrombin binds to endothelial thrombomodulin [43]. This process is importantly potentiated by binding of protein C to the endothelial protein C receptor (EPCR) [44]. In DIC, there is a significant cytokine-mediated downregulation of both thrombomodulin and EPCR, which causes reduced protein C activation. The downregulation of thrombomodulin also affects the clearance of thrombin, as thrombomodulin has a very high affinity for free thrombin. As activated protein C exerts also a series of anti-inflammatory effects, reduced formation of activated protein C may also seriously affect endogenous anti-inflammatory pathways. In observational clinical studies reduced plasma concentrations of protein C were associated with a higher risk of death [45]. Abrogation of protein C activation by various interventions increased mortality in baboons challenged with live bacteria [46,47]. In contrast, administration of activated protein C resolved the coagulopathy and improved survival in these experiments. Based on these findings, it seems that activated protein C is of pivotal relevance in the regulation of DIC.