The Role of Procoagulant Microparticles in Hemostasis - Essay Example

The role of procoagulant microparticles in hemostasis The role of procoagulant microparticles in hemostasis Healthy individuals contain microparticles (MPs), which increase with the occurrence of various diseases such as CVD, cancer, and diabetes. MPs are mall membrane vesicles emanating from activated cells. They act as mediators of cell to cell communication by transferring cell surface receptors from origin cells to target cells. Microparticles range in diameter from 100-1000 nm, but mostly have a diameter of 200 nm. Procoagulant MPs mostly appear as a result of apoptosis and vascular cell activation. Increased levels of circulating platelet, monocyte, or endothelial-derived MPs are associated with CVD risk factors and indicate poor clinical outcome. They indicate vascular cell damage and interfere with atherothrombosis by exerting effects on vascular and blood cells. Circulating MPs support cellular cross-talk under pathological conditions leading to vascular inflammation and tissue remodeling, leukocyte adhesion, endothelial dysfunction, and stimulation. Functional tissue factor and exposed membrane phosphatidyserine are procoagulant entities produced by circulating MPs. Platelet derived MPs contain anionic phospholipid PS, which makes them strongly procoagulant. The removal of MPs from the blood of normal human plasma prolongs the clotting time (Ahn, 2005). Platelet derived MPs support thrombin generation in plasma without platelets, which are important for blood clotting. Platelets form an important substrate for coagulation and their membranes provide a surface for the formation of prothrombinase complex. This enzyme is utilized in the conversion of fibrinogen to fibrin which combines with other factors to form a stable clot (Lawrie et al, 2009). The availability of platelet MPs at the site of vessel injury contributes to the clotting process by providing a large surface membrane necessary for enzymatic process. The exposure of phosphotidyserine during thrombin generation increases enzymatic catalytic effect. The large surface formed by MPs is necessary for activating the coagulation cascade leading to the formation of the fibrin clot. Circulating MPs harbor cytoplasmic effectors or functional membrane that promotes prothrombotic responses (Ay et al, 2009). They transfer their procoagulant potential to target when bearing appropriate counter ligands. They have the ability to bind to soluble and immobilized fibrinogen leading to the formation of aggregates that enables the delivery of procoagulant entities. In vitro, interaction between endothelial MPs and monocytes promotes tissue factor (TF) and TF-dependent procoagulant activity. TF is a constituent protein in minute amounts that switches the procoagulant properties of the endothelium towards the initiation of a clotting TF-driven process. Blood-borne TF can be trapped within the developing thrombus by means of CD15, CD18, and TF-dependent interactions. Blood-borne TF is mainly harbored by PMPs and monocyte-derived MPs provide the enzyme after lipopolysaccharide stimulation. Polunuclear leukocytes and endothelial-derived MPs also produce blood-borne TF under drastic endothelial activation. These MPs provide the required amount of TF and circulate the enzyme, which is necessary for maintaining a hemostatic balance. MPs, selectins and TF merge into a determining triad of thrombosis. P-selectin is an adhesion molecule found at platelet and endothelial cell surfaces (Hugel et al, 2005). The molecule is necessary for TF accumulation and leukocyte incorporation into the thrombus after endothelial injury. The accumulation of hematopeic cell-derived TF matches the kinetics of MPs accumulation before leukocyte-thrombus interaction. The shedding of leukocyte-derived TF-MPs that correct hemostasis is promoted by a soluble P-selectin. MPs plasma levels increase with age, which indicates the contribution of P-selectin pathway. P-selectin pathway also favors the transfer of PF into monocyte derived MPs that are delivered as a functional entity of platelets. TF-MPs emanating from P-selectin interaction stabilize the thrombus by inducing fibrin formation. P-selectin interactions mediate unstable rolling and additional cytoadhesins on leukocyte TF-MPs contribute to thrombus stabilization. The formation of stable platelet aggregates is enhanced by EMPs exposing unusually large von Willerbrandmultimers (Bonderman et al, 2002). The contribution of blood-borne TF to the thrombotic process is crucial in ischemia or stasis. The dilution of recruited MPs is limited by the occurrence of stasis making blood-borne TF determinant even at the sites of limited injury. High levels of leukocyte-derived MPs and ischemia regulate P-selectin at the endothelium surface increasing MPs recruitment. This leads to the formation of large thrombi observed in deep vein. Antibodies contribute to the release of procoagulant MPs in cases of immune-mediated thrombophilic disorders. High levels of EMPs are observed in anti-phospholipid syndrome detected in patients with systemic lupus erythematous (Flaumenhaft, 2006). Lupus anticoagulant is associated with thrombotic propensity. Cultured endothelial cells are treated by plasma samples from patients with antiphospholipid syndrome, which increases the release of EMPS. Immune mediated thrombocytopenia favors thrombotic diathesis. A common source of the drug-related condition is heparin-induced thrombocytopenia. Patients with heparin-induced thrombocytopenia develop antibodies against circulating heparin-platelet factor-4, which leads to platelet cross-linking and activation. PMPs released in the process expose GPIb, P-selectin and thrombospondin, and are highly thrombogenic with the ability to trigger the activation of the coagulation system. Additionally, the PMPs bind to the subendothelial matrix promoting the recruitment of more platelet complexes that constitute the PMPs reservoir. Platelet MPscontain several antigens such as GPIa, Von Willebrand factor and arachidonic acid which are important effectors of the clotting mechanism. According to Furie (2004) the molecular mechanisms of hemostasis describes coagulation as an interaction between P-selectin, TF thrombin and microparticles. P-selectin acts as an adhesion molecule at the platelet endothelial interface, which is critical for TF activity and leukocyte adhesion. Microparticles also facilitate the interaction of von Willebrand’s factor, platelets and endothelium. Platelet-derived MPs interact with protease ADAMTS-13, which regulates the activity of high molecular von Willebrand’s factor. High levels of circulating MPs compete in binding ADAMTS-13 reducing its interaction with the endothelium and causing multimer cleavage. This leads to the high rates of thrombosis observed in patients with thrombotic thrombocytopenic purpura (Mallat et al, 2000). Circulating blood has a wide range of MPs derived from platelets, leukocytes and endothelial cells. MPs activate endothelial cells and transfer chemokine to the endothelium. The stimulation of endothelial cells by PMPs releases cytokines and expresses adhesion molecules (VanWijk et al, 2003; Biro et al, 2003). PMPs have high amounts of RANTES, which is a pro-inflammatory cytokine deposited on activated endothelium. The delivery of RANTES promotes the recruitment of leukocyte to murine atherosclerotic carotid arteries. PMPs also have the ability to deliver arachidonic acid in a transcellular manner. PMPs are also capable of inducing cyclooxygenase-2 production by endothelial cells, which then activates platelets. Arachidonic acid is delivered to PMPs by endothelial cells, which is metabolized to thromboxane A2that induces artery contraction. Following endothelial injury, TF triggers the formation of intracoronary thrombi. The thrombus is rich in acelular lipids and forms the core of an atherosclerotic plaque which is enhanced by the activity of TF supported by TF-MP. Apoptotic macrophages are the main source of membrane-bound TF (Furie & Furie, 2006). The smooth muscle cells contribute to TF-MP accumulation in the lipid core. The MPs and the apoptotic cells are cleared by phagocytes to prevent tissue inflammatory responses. Under minimal apoptosis, human smooth muscle cells release TF-MPs while TF expression is up regulated by native low density lipoprotein (Robertson et al, 2006). Apoptotic bodies released in the process promote macrophage apoptosis and enhance MPs shedding. Apoptotic cells in the thrombogenic plaque create a reservoir for thrombogenic material and derived MPs. The presence of thrombomodulin, TF pathway inhibitor or protein C at the MP surface indicates possible contribution to anticoagulant activities (Garcia et al, 2010). After lipopolysaccharide treatment promoting TF expression, thrombomodulin activities at monocytes and MP surfaces is overwhelmed by the TF activities. A reduced TFPI expression experienced during fibrinolysis for myocardial infarction is associated with TF-driven coagulation. Reactive oxygen species in cell MP aggregates can contribute to TFPI inactivation and the de-encryption of TF activity. Therefore, TF activity expressed at the MP surface prevails due to insufficient anticoagulant counterbalance. Activated protein C is responsible for promoting shedding of endothelial and monocyte MPs through protease activated receptor mechanisms. These MPs harbor functional endothelial protein C receptor and display anticoagulant ability towards factor VA inactivation. MPs shed under pathological situations have multiple abilities in deregulating the vascular tone. Endothelial dysfunction and arterial stiffness are major determinants of cardiovascular risk, which are affected by circulating MPs (Diamant et al, 2002). PMPs produce thromboxane A2, which regulates vascular tone. MPs from apoptotic lymphocytes impair endothelium-dependent relaxation. The impairment is linked to endothelial nitric oxide synthetic down regulation and caveolin-1 overexpression. EMPs from renal microvasculature alter the endothelium dependent relaxation and the production of nitric oxide in the aorta. Patients suffering from end-stage renal failure have EMPs levels correlated to the loss of flow-mediated dilation and increased aortic pulse wave velocity (Horstman, et al, 2004). In conclusion, platelets are the main players in the hemostasis process. Microparticles produced in the platelets or endothelial cells aid in the process by enhancing the hemostatic process to seal injury sites to prevent blood loss. MPs aid in cell-cell communication by transferring biological information from the origin cell to the target cell. Endothelial damage and exposure of the tissue factor initiates platelet plug formation at the injury site. MPs together with the platelets activate a cascade of enzymes that form a fibrin clot. MPs influence plasma proteins such as von Willenbrand’s factor contained in the coagulation matrix. They form an important substrate in the coagulation process, which is responsible for speeding up the formation of the fibrin clot. 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