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coagulation mechanism explains the intricate combination of cellular and biochemical events that occur during the coagulation process in vivo along with the procoagulant and anticoagulant plasma proteins normal physiologic coagulation requires the presence of two cell types for formation of coagulation complexes cells that express tissue factor usually extravascular and platelets 36 the coagulation process occurs in two phases first is the initiation phase which occurs in tissue factor expressing cells this is followed by the propagation phase which occurs on activated platelets the initiation phase mediated by the tissue factor exposure proceeds via the classic extrinsic pathway and contributes to about 5 of thrombin production the amplified production of thrombin occurs via the classic intrinsic pathway in the propagation phase about 95 of thrombin generated will be during this second phase 37 fibrinolysis edit main article fibrinolysis eventually blood clots are reorganized and resorbed by a process termed fibrinolysis the main enzyme responsible for this process is plasmin which is regulated by plasmin activators and plasmin inhibitors 38 role in immune system edit the coagulation system overlaps with the immune system coagulation can physically trap invading microbes in blood clots also some products of the coagulation system can contribute to the innate immune system by their ability to increase vascular permeability and act as chemotactic agents for phagocytic cells in addition some of the products of the coagulation system are directly antimicrobial for example beta lysine an amino acid produced by platelets during coagulation can cause lysis of many gram positive bacteria by acting as a cationic detergent 39 many acute phase proteins of inflammation are involved in the coagulation system in addition pathogenic bacteria may secrete agents that alter the coagulation system e g coagulase and streptokinase 40 immunohemostasis is the integration of immune activation into adaptive clot formation immunothrombosis is the pathological result of crosstalk between immunity inflammation and coagulation mediators of this process include damage associated molecular patterns and pathogen associated molecular patterns which are recognized by toll like receptors triggering procoagulant and proinflammatory responses such as formation of neutrophil extracellular traps 41 cofactors edit various substances are required for the proper functioning of the coagulation cascade calcium and phospholipids edit calcium and phospholipids constituents of platelet membrane are required for the tenase and prothrombinase complexes to function 42 calcium mediates the binding of the complexes via the terminal gamma carboxy residues on factor xa and factor ixa to the phospholipid surfaces expressed by platelets as well as procoagulant microparticles or microvesicles shed from them 43 calcium is also required at other points in the coagulation cascade calcium ions play a major role in the regulation of coagulation cascade that is paramount in the maintenance of hemostasis other than platelet activation calcium ions are responsible for complete activation of several coagulation factors including coagulation factor xiii 44 vitamin k edit vitamin k is an essential factor to the hepatic gamma glutamyl carboxylase that adds a carboxyl group to glutamic acid residues on factors ii vii ix and x as well as protein s protein c and protein z in adding the gamma carboxyl group to glutamate residues on the immature clotting factors vitamin k is itself oxidized another enzyme vitamin k epoxide reductase vkorc reduces vitamin k back to its active form vitamin k epoxide reductase is pharmacologically important as a target of anticoagulant drugs warfarin and related coumarins such as acenocoumarol phenprocoumon and dicumarol these drugs create a deficiency of reduced vitamin k by blocking vkorc thereby inhibiting maturation of clotting factors vitamin k deficiency from other causes e g in malabsorption or impaired vitamin k metabolism in disease e g in liver failure lead to the formation of pivkas proteins formed in vitamin k absence which are partially or totally non gamma carboxylated affecting the coagulation factors ability to bind to phospholipid 45 regulators edit coagulation with arrows for negative and positive feedback several mechanisms keep platelet activation and the coagulation cascade in check 46 abnormalities can lead to an increased tendency toward thrombosis protein c and protein s edit protein c is a major physiological anticoagulant it is a vitamin k dependent serine protease enzyme that is activated by thrombin into activated protein c apc protein c is activated in a sequence that starts with protein c and thrombin binding to a cell surface protein thrombomodulin thrombomodulin binds these proteins in such a way that it activates protein c the activated form along with protein s and a phospholipid as cofactors degrades fva and fviiia quantitative or qualitative deficiency of either protein c or protein s may lead to thrombophilia a tendency to develop thrombosis impaired action of protein c activated protein c resistance for example by having the leiden variant of factor v or high levels of fviii also may lead to a thrombotic tendency 46 antithrombin edit antithrombin is a serine protease inhibitor serpin that degrades the serine proteases thrombin fixa fxa fxia and fxiia it is constantly active but its adhesion to these factors is increased by the presence of heparan sulfate a glycosaminoglycan or the administration of heparins different heparinoids increase affinity to fxa thrombin or both quantitative or qualitative deficiency of antithrombin inborn or acquired e g in proteinuria leads to thrombophilia 46 tissue factor pathway inhibitor tfpi edit tissue factor pathway inhibitor tfpi limits the action of tissue factor tf it also inhibits excessive tf mediated activation of fvii and fx 47 plasmin edit plasmin is generated by proteolytic cleavage of plasminogen a plasma protein synthesized in the liver this cleavage is catalyzed by tissue plasminogen activator t pa which is synthesized and secreted by endothelium plasmin proteolytically cleaves fibrin into fibrin degradation products that inhibit excessive fibrin formation citation needed prostacyclin edit prostacyclin pgi 2 is released by endothelium and activates platelet g s protein linked receptors this in turn activates adenylyl cyclase which synthesizes camp camp inhibits platelet activation by decreasing cytosolic levels of calcium and by doing so inhibits the release of granules that would lead to activation of additional platelets and the coagulation cascade 38 medical assessment edit numerous medical tests are used to assess the function of the coagulation system 3 48 common aptt pt also used to determine inr fibrinogen testing often by the clauss fibrinogen assay 49 platelet count platelet function testing often by pfa 100 thrombodynamics test other tct bleeding time mixing test whether an abnormality corrects if the patient s plasma is mixed with normal plasma coagulation factor assays antiphospholipid antibodies d dimer genetic tests e g factor v leiden prothrombin mutation g20210a dilute russell s viper venom time drvvt miscellaneous platelet function tests thromboelastography teg or sonoclot euglobulin lysis time elt the contact activation intrinsic pathway is initiated by activation of the contact activation system and can be measured by the activated partial thromboplastin time aptt test 50 the tissue factor extrinsic pathway is initiated by release of tissue factor a specific cellular lipoprotein and can be measured by the prothrombin time pt test 51 pt results are often reported as ratio inr value to monitor dosing of oral anticoagulants such as warfarin 52 the quantitative and qualitative screening of fibrinogen is measured by the thrombin clotting time tct measurement of the exact amount of fibrinogen present in the blood is generally done using the clauss fibrinogen assay 49 many analysers are capable of measuring a derived fibrinogen level from the graph of the prothrombin time clot if a coagulation factor is part of the contact activation or tissue factor pathway a deficiency of that factor will affect only one of the tests thus hemophilia a a deficiency of factor viii which is part of the contact activation pathway results in an abnormally prolonged aptt test but a normal pt test deficiencies of common pathway factors prothrombin fibrinogen fx and fv will prolong both aptt and pt if an abnormal pt or aptt is present additional testing will occur to determine which if any factor is present as aberrant concentrations deficiencies of fibrinogen quantitative or qualitative will prolong pt aptt thrombin time and reptilase time role in disease edit coagulation defects may cause hemorrhage or thrombosis and occasionally both depending on the nature of the defect 53 the gp1b ix receptor complex this protein receptor complex is found on the surface of platelets and in conjunction with gpv allows for platelets to adhere to the site of injury mutations in the genes associated with the glycoprotein ib ix v complex are characteristic of bernard soulier syndrome platelet disorders edit platelet disorders are either congenital or acquired examples of congenital platelet disorders are glanzmann s thrombasthenia bernard soulier syndrome abnormal glycoprotein ib ix v complex gray platelet syndrome deficient alpha granules and delta storage pool deficiency deficient dense granules most are rare they predispose to hemorrhage von willebrand disease is due to deficiency or abnormal function of von willebrand factor and leads to a similar bleeding pattern its milder forms are relatively common citation needed decreased platelet numbers thrombocytopenia is due to insufficient production e g myelodysplastic syndrome or other bone marrow disorders destruction by the immune system immune thrombocytopenic purpura or consumption e g thrombotic thrombocytopenic purpura hemolytic uremic syndrome paroxysmal nocturnal hemoglobinuria disseminated intravascular coagulation heparin induced thrombocytopenia 54 an increase in platelet count is called thrombocytosis which may lead to formation of thromboembolisms however thrombocytosis may be associated with increased risk of either thrombosis or hemorrhage in patients with myeloproliferative neoplasm 55 coagulation factor disorders edit the best known coagulation factor disorders are the hemophilias the three main forms are hemophilia a factor viii deficiency hemophilia b factor ix deficiency or christmas disease and hemophilia c factor xi deficiency mild bleeding tendency 56 von willebrand disease which behaves more like a platelet disorder except in severe cases is the most common hereditary bleeding disorder and is characterized as being inherited autosomal recessive or dominant in this disease there is a defect in von willebrand factor vwf which mediates the binding of glycoprotein ib gpib to collagen this binding helps mediate the activation of platelets and formation of primary hemostasis medical citation needed in acute or chronic liver failure there is insufficient production of coagulation factors possibly increasing risk of bleeding during surgery 57 thrombosis is the pathological development of blood clots these clots may break free and become mobile forming an embolus or grow to such a size that occludes the vessel in which it developed an embolism is said to occur when the thrombus blood clot becomes a mobile embolus and migrates to another part of the body interfering with blood circulation and hence impairing organ function downstream of the occlusion this causes ischemia and often leads to ischemic necrosis of tissue most cases of venous thrombosis are due to acquired states older age surgery cancer immobility unprovoked venous thrombosis may be related to inherited thrombophilias e g factor v leiden antithrombin deficiency and various other genetic deficiencies or variants particularly in younger patients with family history of thrombosis however thrombotic events are more likely when acquired risk factors are superimposed on the inherited state 58 pharmacology edit procoagulants edit the use of adsorbent chemicals such as zeolites and other hemostatic agents are also used for sealing severe injuries quickly such as in traumatic bleeding secondary to gunshot wounds thrombin and fibrin glue are used surgically to treat bleeding and to thrombose aneurysms hemostatic powder spray tc 325 is used to treated gastrointestinal bleeding citation needed desmopressin is used to improve platelet function by activating arginine vasopressin receptor 1a 59 coagulation factor concentrates are used to treat hemophilia to reverse the effects of anticoagulants and to treat bleeding in people with impaired coagulation factor synthesis or increased consumption prothrombin complex concentrate cryoprecipitate and fresh frozen plasma are commonly used coagulation factor products recombinant activated human factor vii is sometimes used in the treatment of major bleeding tranexamic acid and aminocaproic acid inhibit fibrinolysis and lead to a de facto reduced bleeding rate before its withdrawal aprotinin was used in some forms of major surgery to decrease bleeding risk and the need for blood products rivaroxaban drug bound to the coagulation factor xa the drug prevents this protein from activating the coagulation pathway by inhibiting its enzymatic activity anticoagulants edit main articles antiplatelet drug and anticoagulant anticoagulants and anti platelet agents together antithrombotics are amongst the most commonly used medications anti platelet agents include aspirin dipyridamole ticlopidine clopidogrel ticagrelor and prasugrel the parenteral glycoprotein iib iiia inhibitors are used during angioplasty of the anticoagulants warfarin and related coumarins and heparin are the most commonly used warfarin affects the vitamin k dependent clotting factors ii vii ix x and protein c and protein s 60 whereas heparin and related compounds increase the action of antithrombin on thrombin and factor xa a newer class of drugs the direct thrombin inhibitors is under development some members are already in clinical use such as lepirudin argatroban bivalirudin and dabigatran also in clinical use are other small molecular compounds that interfere directly with the enzymatic action of particular coagulation factors the directly acting oral anticoagulants dabigatran rivaroxaban apixaban and edoxaban 61 history edit initial discoveries edit theories on the coagulation of blood have existed since antiquity physiologist johannes müller 1801 1858 described fibrin the substance of a thrombus its soluble precursor fibrinogen was thus named by rudolf virchow 1821 1902 and isolated chemically by prosper sylvain denis 1799 1863 alexander schmidt suggested that the 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