The Coagulation-Cancer Interaction in Situ
Róza Ádány in Tumor Matrix Biology, 2017
Tumor cell procoagulants lead to thrombin formation that can promote cancer growth in several ways.16–18 The procoagulant activity of certain tumor cell lines has been correlated with their metastatic potential and drugs that limit thrombin formation or activity block tumor progression in vivo. Thrombin may contribute to tumor stroma formation by converting fibrinogen to fibrin, which may enhance tumor angiogenesis or block invasion by host inflammatory cells. Thrombin may also increase tumor cell proliferation through its growth factor activity.46–56 Studies in cell culture systems have shown that thrombin51 and thrombin-antithrombin III complex52 can bind to the surface of certain cell types. Thrombin binding may also be mediated by thrombomodulin.53 Thrombin-initiated signal transduction is mediated by protein kinase C-mediated enhancement of phosphoinositide turnover and calcium mobilization54–57 that is associated with reduced intracellular cyclic adenosine monophosphate (cAMP) levels.58 Thrombin-induced cell activation may lead to a variety of changes in various cell types, including increased expression of plasminogen activator inhibitor,59 tissue factor,60 and the cMyc protooncogenes;61 increased cell motility;62,63 and increased DNA synthesis and mitosis.,54,61,64–66
Physiology and Basic Investigation of Blood Coagulation
Hau C. Kwaan, Meyer M. Samama in Clinical Thrombosis, 2019
Antithrombin I activity is attributed to the fibrin clot which possesses a great affinity for thrombin. The excess of thrombin formed during coagulation is adsorbed on the fibrin surface; antithrombin II is the heparin cofactor and seems to be identical to antithrombin III (AT-III). ATIII is a physiologic agent which is by far the most important inhibitor. It inhibits in a progressive reaction, not only thrombin, but also several other factors in their activated forms, especially activated Stuart factor or Factor Xa and activated antihemophilic B factor (Factor IXa). In contrast, ATIII is immediately active in the presence of heparin. A constitutional deficiency of ATIII may be accompanied by a recurrent venous thrombosis; this is discussed in Chapter 6. Antithrombin IV is poorly recognized. α1-Antitrypsin and α2-macroglobulin also exhibit antithrombin activity. In addition, thrombomodulin released from blood vessel wall by thrombin binds thrombin with great affinity and removes it effectively from further clotting action.
Thrombosis, heparin and laboratory monitoring of heparin therapy
John Edward Boland, David W. M. Muller in Interventional Cardiology and Cardiac Catheterisation, 2019
The common antithrombotic and prothrombotic properties of normal vascular endothelium are listed in Table 5.1. Normal endothelium inhibits thrombus formation by a number of mechanisms. Prostacyclin (Prostaglandin I2) is produced by endothelial cells and released into the blood stream, causing inhibition of platelet activation and inducing vasodilation via an increase of cyclic AMP. Endothelium-derived relaxing factor (EDRF, nitric oxide) is another molecule produced and secreted by endothelium, and inhibits platelet activation and induces vasodilation by increasing cyclic GMP. Other antithrombotic agents such as Ecto-ADPase and thrombomodulin are not released into the blood but are expressed on the surface membrane of the endothelial cell. Thrombomodulin is a protein that, in response to binding with thrombin, activates the naturally occurring anticoagulant Protein C. Heparin sulfate glycosaminoglycans are expressed on the cell surface and catalyse binding of antithrombin III and heparin cofactor II to thrombin and other coagulation proteins, inactivating them and arresting propagation of the coagulation response. Plasminogen activators such as tissue plasminogen activator (tPA) and urokinase (uPA) are produced and released by endothelium in response to a range of stimuli. These molecules bind to fibrin, which allows them to form complexes with circulating or membrane-bound plasminogen. Formation of plasmin results, facilitating fibrinolysis. Tissue factor pathway inhibitor (TFPI) is a membrane-bound protein that inactivates factors VIIa and Xa.
Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF): an overview of current and future therapeutic strategies
Published in Expert Review of Respiratory Medicine, 2020
Davide Biondini, Elisabetta Balestro, Nicola Sverzellati, Elisabetta Cocconcelli, Nicol Bernardinello, Christopher J. Ryerson, Paolo Spagnolo
Thrombomodulin (TM) is a transmembrane glycoprotein expressed mainly on the surface of endothelial cells that exerts antinflammatory, anticoagulant, and anti-fibrinolytic properties [67]. Based on the hypothesis that altered coagulation and fibrinolysis contribute to the pathogenesis of AE-IPF, a number of mostly retrospective studies have assessed the efficacy of recombinant human soluble TM (rhTM) in this setting. Tsushima and colleagues compared the outcome of 20 AE-IPF patients treated with rhTM 0.06 mg/kg/day for 6 days added to methylprednisolone with that of six historical patients treated with pulse methylprednisolone alone who served as controls [68]. The 28-day survival was significantly higher in the rhTM group (65% vs. 17%, respectively; p = 0.048), and rhTM treatment was also associated with improved SpO2/FiO2 ratio. Similarly, two retrospective studies reported a 90-day survival of almost 90% among AE-IPF patients treated with rhTM, but in both studies most patients received also cyclosporine A [69,70]. More recently, Sakamoto and colleagues reported on a retrospective study of 80 patients with AE-IPF, 45 of whom had been treated with rhTM [71]. Compared with patients who did not receive rhTM (control group), those treated with rhTM had a significantly higher 3-month survival (37.1% vs. 66.6%; p = 0.003); overall survival was also significantly better in the rhTM group than in the control group (p = 0.003).
New data on FII, FV, FIX and thrombomodulin defects: blood keeps clotting in normal and in peculiar ways
Published in Hematology, 2019
Antonio Girolami, Silvia Ferrari, Bruno Girolami, Maria Luigia Randi
Thrombomodulin (TM) is a transmembrane glycoprotein composed of 557 aminoacids. It has a great affinity for binding to thrombin and to transform it from a coagulant to an anticoagulant compound [9,32]. The complex thrombin-thrombomodulin (T-TM) has two main actions: 1) it activates Protein C which by its turn, once activated, downregulates FVa and FVIIIa namely it behaves as an anticoagulant. and 2) it activates also the thrombin activable fibrinolysis inhibitor (TAFI) [9,32]. Activated TAFI inhibits the adherence of plasminogen to the surface of a fibrin clot thereby decreasing the effect of plasmin-induced fibrinolysis. As a consequence, TM plays an important role in regulating the structure and resistance of the fibrin clot [32]. Congenital TM deficiency has never been described. In 2014 and 2015 two families with a mild bleeding tendency but normal coagulation tests were reported [7,8]. Extensive and elegant investigations demonstrated that the defect was due to greatly elevated levels of soluble TM. Genetic analysis of the TM gene showed the presence of the same mutation, namely Cys537Stop in both families [7,8]. Such mutation is responsible for the gain of function effect of TM. It has to be remembered that another TM mutation (Asp468Tyr) has been associated with venous thrombosis. This observation has not been confirmed yet. Should it be, TM defect should be included, together with FII, FV and FIX, among the coagulation defects that may cause both bleeding and thrombosis.
Disseminated intravascular coagulation: an update on pathogenesis and diagnosis
Published in Expert Review of Hematology, 2018
Marcel Levi, Suthesh Sivapalaratnam
A lot of attention has been given to replacement of deficient natural anticoagulant factors in DIC. In view of the central role of the activated protein C system in controlling the coagulopathy and because of its anti-inflammatory properties (at least in vitro), administration of recombinant human activated protein C was exhaustively studied, mostly in patients with sepsis. Eventually, the clinical results of these studies were disappointing, although subgroups of patients with the most severe coagulopathy consistently showed a benefit of this intervention on secondary outcome measures. A more recent intervention that is also aimed at the activated protein C pathway consists of the administration of recombinant human thrombomodulin. Initial phase II/III studies in patients with sepsis and DIC showed a beneficial effect of this intervention, including a significant reduction in mortality and ongoing randomized controlled trials are focused on confirming these findings. Thrombomodulin has distinctive properties targeting both coagulation and inflammation, most of which are different from activated protein C. In addition, thrombomodulin has a very high affinity for thrombin and may act as a scavenger for free circulating thrombin. Another new option that is worth exploring is recombinant ADAMTS13, in particular in DIC patients with low levels of this protease and that may therefore exhibit excessive platelet thrombi in the microvasculature.
Related Knowledge Centers
- Cluster of Differentiation
- Coagulation
- Enzyme
- Integral Membrane Protein
- Mesothelium
- Endothelium
- Dendritic Cell
- Monocyte
- Cluster of Differentiation
- Thrombin
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