Hemostasis

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Hemostasis ↗ Stable identifier: R-HSA-109582
Hemostasis is a physiological response that culminates in the arrest of bleeding from an injured vessel.
Under normal conditions the vascular endothelium supports vasodilation, inhibits platelet adhesion and activation, suppresses coagulation, enhances fibrin cleavage and is anti-inflammatory in character. Under acute vascular trauma, vasoconstrictor mechanisms predominate and the endothelium becomes prothrombotic, procoagulatory and proinflammatory in nature. This is achieved by a reduction of endothelial dilating agents: adenosine, NO and prostacyclin; and by the direct action of ADP, serotonin and thromboxane on vascular smooth muscle cells to elicit their contraction (Becker et al. 2000).
The chief trigger for the change in endothelial function that leads to the formation of a haemostatic thrombus is the loss of the endothelial cell barrier between blood and extracellular matrix components (Ruggeri 2002). Circulating platelets identify and discriminate areas of endothelial lesions; here, they adhere to the exposed sub endothelium. Their interaction with the various thrombogenic substrates and locally generated or released agonists results in platelet activation. This process is described as possessing two stages, firstly, adhesion -the initial tethering to a surface, and secondly aggregation -the platelet-platelet cohesion (Savage & Cattaneo et al. 2001).
Three mechansism contribute to the loss of blood following vessel injury. The vessel constricts, reducing the loss of blood. Platelets adhere to the site of injury, become activated and aggregate with fibrinogen into a soft plug that limits blood loss, a process termed primary hemostasis. Proteins and small molecules are released from granules by activated platelets, stimulating the plug formation process. Fibrinogen from plasma forms bridges between activated platelets. These events initiate the clotting cascade (secondary hemostasis). Negatively-charged phospholipids exposed at the site of injury and on activated platelets interact with tissue factor, leading to a cascade of reactions that culminates with the formation of an insoluble fibrin clot.

Literature references
Colman, R., George, J., Clowes, A., Marder, V., Goldhaber, S. (2006) Under normal conditions the vascular endothelium supports vasodilation, inhibits platelet adhesion and activation, suppresses coagulation, enhances fibrin cleavage and is anti-inflammatory in character. Under acute vascular trauma, vasoconstrictor mechanisms predominate and the endothelium becomes prothrombotic, procoagulatory and proinflammatory in nature. This is achieved by a reduction of endothelial dilating agents: adenosine, NO and prostacyclin; and by the direct action of ADP, serotonin and thromboxane on vascular smooth muscle cells to elicit their contraction (Becker et al. 2000).
Cyclooxygenase-2 (COX-2) and endothelial nitric oxide synthase ( Compartments: extracellular region The formation of a fibrin clot at the site of an injury to the wall of a normal blood vessel is an essential part of the process to stop blood loss after vascular injury. The reactions that lead to fibrin clot formation are commonly described as a cascade, in which the product of each step is an enzyme or cofactor needed for following reactions to proceed efficiently. The entire clotting cascade can be divided into three portions, the extrinsic pathway, the intrinsic pathway, and the common pathway. The extrinsic pathway begins with the release of tissue factor at the site of vascular injury and leads to the activation of factor X. The intrinsic pathway provides an alternative mechanism for activation of factor X, starting from the activation of factor XII. The common pathway consists of the steps linking the activation of factor X to the formation of a multimeric, cross-linked fibrin clot. Each of these pathways includes not only a cascade of events that generate the catalytic activities needed for clot formation, but also numerous positive and negative regulatory events.

Dissolution of Fibrin Clot ↗ Location: Hemostasis
Stable identifier: R-HSA-75205 The crosslinked fibrin multimers in a clot are broken down to soluble polypeptides by plasmin, a serine protease. Plasmin can be generated from its inactive precursor plasminogen and recruited to the site of a fibrin clot in two ways, by interaction with tissue plasminogen activator at the surface of a fibrin clot, and by interaction with urokinase plasminogen activator at a cell surface. The first mechanism appears to be the major one responsible for the dissolution of clots within blood vessels. The second, although capable of mediating clot dissolution, may normally play a major role in tissue remodeling, cell migration, and inflammation (Chapman 1997;Lijnen 2001).
Clot dissolution is regulated in two ways. First, efficient plasmin activation and fibrinolysis occur only in complexes formed at the clot surface or on a cell membrane -proteins free in the blood are inefficient catalysts and are rapidly inactivated. Second, both plasminogen activators and plasmin itself are inactivated by specific serpins, proteins that bind to serine proteases to form stable, enzymatically inactive complexes (Kohler and Grant 2000).
These events are outlined in the drawing: black arrows connect the substrates (inputs) and products (outputs) of individual reactions, and blue lines connect output activated enzymes to the other reactions that they catalyze. This pathway describes some of the key interactions that assist in the process of platelet and leukocyte interaction with the endothelium, in response to injury.

Factors involved in megakaryocyte development and platelet production ↗ Location: Hemostasis
Stable identifier: R-HSA-983231 Megakaryocytes (MKs) give rise to circulating platelets (thrombocytes) through terminal differentiation of MKs which release cytoplasmic fragments as circulating platelets. As MKs mature they undergo endoreduplication (polyploidisation) and expansion of cytoplasmic mass to cell sizes larger than 50-100 microns, and ploidy ranges up to 128 N. As MKs mature, the polyploid nucleus becomes horseshoe-shaped, the cytoplasm expands, and platelet organelles and the demarcation membrane system are amplified. Platelet Adhesion to exposed collagen 6 Platelet activation, signaling and aggregation 8 Formation of Fibrin Clot (Clotting Cascade) 10

Dissolution of Fibrin Clot 11
Cell surface interactions at the vascular wall 13 Factors involved in megakaryocyte development and platelet production 15