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Inflammation and Thrombosis – Brothers in Arms


most abundant chemokines secreted by platelets and are the first chemokines to be purified. Their elevated concentration and ready availability on platelet activation are associated with their role in early host defence. Contrary to other, similar chemokines, PF-4 does not promote cell migration but rather firmly positions neutrophils at the vascular endothelium. It favours release of metalloproteinases from secondary neutrophil granules, thus predisposing to extravasation. Furthermore, PF-4 can induce oxygen radical formation in monocytes. Beta-thromboglobulins are in fact several proteins differing in their N-terminuses. They result from proteolytic processing of the precursor platelet basic protein. One beta-thromboglobulin, neutrophil-activating peptide 2, is a potent chemotactic for neutrophils and stimulates the release of lysosomal and secondary granules.


Inflammation, Coagulation, Naturally Occurring Anticoagulants and the Endothelium For more than two decades experimental results obtained in vitro, in animal models and in humans have shown that inflammation favours a procoagulant phenotype and, reciprocally, that coagulation factors have pro-inflammatory activities. Physiologically, the endothelium is an anti-inflammatory anticoagulant surface. It exposes glycosaminoglycans that enhance antithrombin function and it expresses thrombomodulin, which binds thrombin and activates the protein C pathway with the aid of the endothelial protein C receptor. The endothelium also synthesises the tissue factor pathway inhibitor, which binds and inhibits the tissue factor-activated factor VII-activated factor X complex.22 Cytokines derived from activated leukocytes during inflammation downregulate the endothelial receptors and upregulate leukocyte adhesion molecules, while proteases from leukocytes cleave thrombomodulin and glycosaminoglycans from the endothelial surface.23


The net result is that the endothelium is tipped towards being a procoagulant, pro-inflammatory surface. At the same time, cytokines such as TNF-α and interleukin-1 (IL-1) induce tissue factor expression on monocytes and the endothelium, favouring unopposed thrombin formation.23


Figure 1: Interactions Between Inflammation, Immunity and Haemostasis in Chronic Disease Leading to Thrombosis


Infection


(Auto) immune response


Platelet activation Coagulation activation Loss of anticoagulant protection


Persistent


pro-inflammatory stimulus


(i.e. smoke, hyperglycaemia, hyperlipidemia, etc.)


Inflammation Thrombosis


Atherosclerosis


endothelial growth factor, hypoxia determines a complex procoagulant response mediated by several cellular mechanisms.30


Oxidative stress,


mediated by leukocytes and bacteria, also shifts the haemostatic balance. One specific and well-described mechanism, for example, is the oxidation of methionine 388 in thrombomodulin. This is known to slow the rate at which the thrombomodulin–thrombin complex activates protein C. It has been shown to be a potential mechanism of hypercoagulability in patients with diabetes and in those who smoke.31


Haemostasis and Immunity – An Evolutionary Perspective


Thrombin in turn has several pro-inflammatory activities. It induces the expression of P-selectin and the secretion of platelet- activating factor by the endothelium. It is chemotactic for leukocytes. It also stimulates the production of monocyte chemotactic protein-1, IL-6 and IL-8.24


The inflamed endothelium loses its barrier function so leukocytes can extravasate in the extraluminal space. This is an initial step that occurs in chronic inflammatory diseases of vessel walls, such as atherosclerosis or vasculitis.25


In vasculitis, immune complexes that


bind to the endothelium and trigger an upregulation of leukocyte adhesion molecules may be a source of arterial injury, initiating endothelial inflammation and atherosclerosis.26


Downregulation of thrombomodulin and endothelial protein C receptor was reported in the mucosal microvessels of patients suffering from inflammatory bowel disease.27


necrosis of the intestinal mucosa.27


It might contribute to ischaemia and Patients with inflammatory


bowel disease also develop thrombosis in vessels that are far from the gut. They have a more than three-fold higher risk of venous thrombosis than the control population or patients with other chronic bowel diseases, such as coeliac disease.28


The proposed mechanism


is that tissue-factor-carrying microparticles or cells generated by inflammatory stimuli in the intestinal circulation eventually reach the systemic circulation and are the trigger for thrombosis.29


Another important effector of inflammation is tissue hypoxia. Besides exerting a proangiogenic effect through upregulation of vascular


EUROPEAN ONCOLOGY & HAEMATOLOGY


The amebocyte degranulates on activation, releasing proteins that react to form an insoluble clot. At this point it releases a substance with antibacterial properties – a vestigial form of innate immunity. The result is the ‘clotting out’ and destruction of the disturbing agent.32


That haemostasis, inflammation and innate immunity are tightly linked is not so surprising. These defense mechanisms have developed together and were a single entity before vertebrates evolved. In the horseshoe crab, an invertebrate model for the study of the evolution of coagulation, external ‘agents’ disrupting its integrity activate a cell, called the amebocyte, which functions as both a platelet and a macrophage.32


Vertebrates have evolved separate clotting and inflammatory immune systems that can co-operate and interact. Most of the inflammatory signals responsible for immune activation will also precipitate procoagulant signals.


Conversely, the coagulation system rapidly feeds back and upregulates the innate immune response.33,34


Anticoagulants possess several


anti-inflammatory properties, which have been exploited therapeutically in settings such as severe sepsis.35–37


Their anti-inflammatory properties


are independent of their antithrombotic action, as shown in the case of protein C by results obtained in animal sepsis models after separating the anticoagulant from the anti-inflammatory function.38


The interaction


between inflammation, haemostasis and immunity is schematically represented in Figure 1.


Inflammation, Ageing and Thrombosis In recent years it has become clear that ageing is associated with a low-grade persistent inflammatory response that has been termed inflamm-ageing.39,40


Coagulation factors and pro-inflammatory cytokines 83


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