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61-552: The swelling may appear as a hard tumor, slow to develop, or as an inflammation. A traditional remedy, in the first case, involves splitting the skin along the breadth of the tumor, allowing the matter contained to escape, and stopping the hemorrhage by using an amadou or a hot iron. This kind of operation is best done by a veterinarian . If the tumor is inflammatory, one resorts to an oil of pompillion , an ointment made of buds of black poplar , lard and sheets of poppy, belladonna, etc. If it has formed an abscess , one first applies

122-774: A blood transfusion . The use of cyanoacrylate glue to prevent bleeding and seal battle wounds was designed and first used in the Vietnam War . Skin glue, a medical version of "super glue", is sometimes used instead of using traditional stitches used for small wounds that need to be closed at the skin level. The word "Haemorrhage" (or hæmorrhage ; using the æ ligature ) comes from Latin haemorrhagia, from Ancient Greek αἱμορραγία ( haimorrhagía , "a violent bleeding"), from αἱμορραγής ( haimorrhagḗs , "bleeding violently"), from αἷμα ( haîma , "blood") + -ραγία ( -ragía ), from ῥηγνύναι ( rhēgnúnai , "to break, burst"). Blood coagulation Coagulation , also known as clotting ,

183-473: A blood vessel . Exposure of blood to the subendothelial space initiates two processes: changes in platelets, and the exposure of subendothelial platelet tissue factor to coagulation factor VII , which ultimately leads to cross-linked fibrin formation. Platelets immediately form a plug at the site of injury; this is called primary hemostasis. Secondary hemostasis occurs simultaneously: additional coagulation factors beyond factor VII ( listed below ) respond in

244-412: 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

305-403: A bleeding disorder. Instead, contact activation system seems to be more involved in inflammation, and innate immunity. Despite this, interference with the pathway may confer protection against thrombosis without a significant bleeding risk. The division of coagulation in two pathways is arbitrary, originating from laboratory tests in which clotting times were measured either after the clotting

366-605: A cascade to form fibrin strands, which strengthen the platelet plug . Coagulation is highly conserved throughout biology. In all mammals , coagulation involves both cellular components (platelets) and proteinaceous components (coagulation or clotting factors). The pathway in humans has been the most extensively researched and is the best understood. Disorders of coagulation can result in problems with hemorrhage , bruising , or thrombosis . There are 13 traditional clotting factors, as named below, and other substances necessary for coagulation: Physiology of blood coagulation

427-484: 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. In acute or chronic liver failure , there

488-401: A platelet plug and thereby completing primary hemostasis). The coagulation cascade of secondary hemostasis has two initial pathways which lead to fibrin formation. These are the contact activation pathway (also known as the intrinsic pathway), and the tissue factor pathway (also known as the extrinsic pathway), which both lead to the same fundamental reactions that produce fibrin. It

549-420: A result of 3 basic patterns of injury: The underlying scientific basis for blood clotting and hemostasis is discussed in detail in the articles, coagulation , hemostasis and related articles. The discussion here is limited to the common practical aspects of blood clot formation which manifest as bleeding. Some medical conditions can also make patients susceptible to bleeding. These are conditions that affect

610-553: 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

671-430: A soft poultice . In pre- modern medicine , this was thought to be caused by a sanguine and bilious humour . The disease has also been erroneously attributed to the heart, whence it was called by Jacques de Solleysell a swelling of the pericardium , whereas it is really an inflammation in the gullet and throat . In humans , this is called Ludwig's angina , or squinancy. This equine-related article

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732-457: A standardized grading scale to measure the severity of bleeding. Acute bleeding from an injury to the skin is often treated by the application of direct pressure. For severely injured patients, tourniquets are helpful in preventing complications of shock . Anticoagulant medications may need to be discontinued and possibly reversed in patients with clinically significant bleeding. Patients that have lost excessive amounts of blood may require

793-522: 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

854-408: Is a stub . You can help Misplaced Pages by expanding it . This veterinary medicine –related article is a stub . You can help Misplaced Pages by expanding it . Hemorrhage Bleeding , hemorrhage , haemorrhage or blood loss is blood escaping from the circulatory system from damaged blood vessels . Bleeding can occur internally , or externally either through a natural opening such as

915-410: Is a transglutaminase . The coagulation factors circulate as inactive zymogens . The coagulation cascade is therefore classically divided into three pathways. The tissue factor and contact activation pathways both activate the "final common pathway" of factor X, thrombin and fibrin. The main role of the tissue factor (TF) pathway is to generate a "thrombin burst", a process by which thrombin ,

976-428: 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. Vitamin K is an essential factor to the hepatic gamma-glutamyl carboxylase that adds

1037-521: Is based on hemostasis , the normal bodily process that stops bleeding. Coagulation is a part of an integrated series of haemostatic reactions, involving plasma, platelet, and vascular components. Hemostasis consists of four main stages: After the fibrin clot is formed, clot retraction occurs and then clot resolution starts, and these two process are together called "tertiary hemostasis". Activated platelets contract their internal actin and myosin fibrils in their cytoskeleton, which leads to shrinkage of

1098-739: Is broken down into four classes by the American College of Surgeons' advanced trauma life support (ATLS). This system is basically the same as used in the staging of hypovolemic shock . Individuals in excellent physical and cardiovascular shape may have more effective compensatory mechanisms before experiencing cardiovascular collapse. These patients may look deceptively stable, with minimal derangements in vital signs, while having poor peripheral perfusion. Elderly patients or those with chronic medical conditions may have less tolerance to blood loss, less ability to compensate, and may take medications such as betablockers that can potentially blunt

1159-540: 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 . 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). Von Willebrand disease (which behaves more like

1220-404: Is converted to kallikrein and FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa. The minor role that the contact activation pathway has in initiating blood clot formation can be illustrated by the fact that individuals with severe deficiencies of FXII, HMWK, and prekallikrein do not have

1281-609: Is due to deficiency or abnormal function of von Willebrand factor , and leads to a similar bleeding pattern; its milder forms are relatively common. 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 ). An increase in platelet count

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1342-426: Is insufficient production of coagulation factors, possibly increasing risk of bleeding during surgery. 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

1403-537: 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 . 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

1464-408: Is regulated by plasmin activators and plasmin inhibitors . 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

1525-406: 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. Numerous medical tests are used to assess

1586-543: Is released from the endothelium and from platelets; vWF forms additional links between the platelets' glycoprotein Ib/IX/V and A1 domain. This localization of platelets to the extracellular matrix promotes collagen interaction with platelet glycoprotein VI . Binding of collagen to glycoprotein VI triggers a signaling cascade that results in activation of platelet integrins. Activated integrins mediate tight binding of platelets to

1647-727: Is taking antibiotics. The gut bacteria make vitamin K and are killed by antibiotics. This decreases vitamin K levels and therefore the production of these clotting factors. Deficiencies of platelet function may require platelet transfusion while deficiencies of clotting factors may require transfusion of either fresh frozen plasma or specific clotting factors, such as Factor VIII for patients with hemophilia. Infectious diseases such as Ebola , Marburg virus disease and yellow fever can cause bleeding. Dioxaborolane chemistry enables radioactive fluoride ( F ) labeling of red blood cells , which allows for positron emission tomography (PET) imaging of intracerebral hemorrhages. Hemorrhaging

1708-431: Is that related to the medication, warfarin ("Coumadin" and others). This medication needs to be closely monitored as the bleeding risk can be markedly increased by interactions with other medications. Warfarin acts by inhibiting the production of Vitamin K in the gut. Vitamin K is required for the production of the clotting factors, II, VII, IX, and X in the liver. One of the most common causes of warfarin-related bleeding

1769-491: 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 . Various substances are required for

1830-419: Is the process by which blood changes from a liquid to a gel , forming a blood clot . It results in hemostasis , the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation involves activation , adhesion and aggregation of platelets , as well as deposition and maturation of fibrin . Coagulation begins almost instantly after an injury to the endothelium that lines

1891-401: The mouth , nose , ear , urethra , vagina or anus , or through a puncture in the skin . Hypovolemia is a massive decrease in blood volume, and death by excessive loss of blood is referred to as exsanguination . Typically, a healthy person can endure a loss of 10–15% of the total blood volume without serious medical difficulties (by comparison, blood donation typically takes 8–10% of

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1952-647: The "Leiden" variant of Factor V or high levels of FVIII, also may lead to a thrombotic tendency. 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. Tissue factor pathway inhibitor (TFPI) limits

2013-676: The Factor VII and precipitate bleeding that is very difficult to control. This is a rare condition that is most likely to occur in older patients and in those with autoimmune diseases. Another common bleeding disorder is Von Willebrand disease . It is caused by a deficiency or abnormal function of the "Von Willebrand" factor, which is involved in platelet activation. Deficiencies in other factors, such as factor XIII or factor VII are occasionally seen, but may not be associated with severe bleeding and are not as commonly diagnosed. In addition to NSAID-related bleeding, another common cause of bleeding

2074-469: The action of tissue factor (TF). It also inhibits excessive TF-mediated activation of FVII and FX. 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. Prostacyclin (PGI 2 )

2135-621: 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

2196-499: The cardiovascular response. Care must be taken in the assessment. Although there is no universally accepted definition of massive hemorrhage, the following can be used to identify the condition: "(i) blood loss exceeding circulating blood volume within a 24-hour period, (ii) blood loss of 50% of circulating blood volume within a 3-hour period, (iii) blood loss exceeding 150 ml/min, or (iv) blood loss that necessitates plasma and platelet transfusion." The World Health Organization made

2257-410: 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. Eventually, blood clots are reorganized and resorbed by a process termed fibrinolysis . The main enzyme responsible for this process is plasmin , which

2318-404: The clot volume. Plasminogen activators , such as tissue plasminogen activator (t-PA), activate plasminogen into plasmin, which promotes lysis of the fibrin clot; this restores the flow of blood in the damaged/obstructed blood vessels. When there is an injury to a blood vessel, the endothelial cells can release various vasoconstrictor substances, such as endothelin and thromboxane, to induce

2379-465: The coagulation factors' ability to bind to phospholipid. Several mechanisms keep platelet activation and the coagulation cascade in check. Abnormalities can lead to an increased tendency toward thrombosis: 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

2440-471: The constriction of the smooth muscles in the vessel wall. This helps reduce blood flow to the site of injury and limits bleeding. When the endothelium is damaged, the normally isolated underlying collagen is exposed to circulating platelets, which bind directly to collagen with collagen-specific glycoprotein Ia/IIa surface receptors. This adhesion is strengthened further by von Willebrand factor (vWF), which

2501-457: The donor's blood volume). The stopping or controlling of bleeding is called hemostasis and is an important part of both first aid and surgery . Bleeding arises due to either traumatic injury, underlying medical condition, or a combination. Traumatic bleeding is caused by some type of injury. There are different types of wounds which may cause traumatic bleeding. These include: The pattern of injury, evaluation and treatment will vary with

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2562-478: The extracellular matrix. This process adheres platelets to the site of injury. Activated platelets release the contents of stored granules into the blood plasma. The granules include ADP , serotonin , platelet-activating factor (PAF), vWF , platelet factor 4 , and thromboxane A 2 (TXA 2 ), which, in turn, activate additional platelets. The granules' contents activate a G q -linked protein receptor cascade, resulting in increased calcium concentration in

2623-487: The fibrin network. The coagulation cascade is maintained in a prothrombotic state by the continued activation of FVIII and FIX to form the tenase complex until it is down-regulated by the anticoagulant pathways. A newer model of 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

2684-580: The function of the coagulation system: 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. 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. PT results are often reported as ratio ( INR value) to monitor dosing of oral anticoagulants such as warfarin . The quantitative and qualitative screening of fibrinogen

2745-410: The inherited state. 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. Desmopressin

2806-649: The inhibitory effect of aspirin is present until the platelets have been replaced (about ten days). Other NSAIDs, such as "ibuprofen" (Motrin) and related drugs, are reversible and therefore, the effect on platelets is not as long-lived. There are several named coagulation factors that interact in a complex way to form blood clots, as discussed in the article on coagulation . Deficiencies of coagulation factors are associated with clinical bleeding. For instance, deficiency of Factor VIII causes classic hemophilia A while deficiencies of Factor IX cause "Christmas disease"( hemophilia B ). Antibodies to Factor VIII can also inactivate

2867-401: The initiation of the platelet plug, which in turn promotes more platelet activation. Thrombin functions not only to convert fibrinogen to fibrin, it also activates Factors VIII and V and their inhibitor protein C (in the presence of thrombomodulin ). By activating Factor XIII, covalent bonds are formed that crosslink the fibrin polymers that form from activated monomers. This stabilizes

2928-497: The liver, kidney and spleen may bleed into the abdominal cavity. The only apparent signs may come with blood loss. Bleeding from a bodily orifice, such as the rectum, nose, or ears may signal internal bleeding, but cannot be relied upon. Bleeding from a medical procedure also falls into this category. "Medical bleeding" denotes hemorrhage as a result of an underlying medical condition (i.e. causes of bleeding that are not directly due to trauma). Blood can escape from blood vessels as

2989-482: The mechanism of the injury. Blunt trauma causes injury via a shock effect; delivering energy over an area. Wounds are often not straight and unbroken skin may hide significant injury. Penetrating trauma follows the course of the injurious device. As the energy is applied in a more focused fashion, it requires less energy to cause significant injury. Any body organ, including bone and brain, can be injured and bleed. Bleeding may not be readily apparent; internal organs such as

3050-451: The most important constituent of the coagulation cascade in terms of its feedback activation roles, is released very rapidly. FVIIa circulates in a higher amount than any other activated coagulation factor. The process includes the following steps: The contact activation pathway begins with formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein , and FXII (Hageman factor) . Prekallikrein

3111-474: The nature of the defect. 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

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3172-438: The next reaction in the cascade, ultimately resulting in cross-linked fibrin. Coagulation factors are generally indicated by Roman numerals , with a lowercase a appended to indicate an active form. The coagulation factors are generally enzymes called serine proteases , which act by cleaving downstream proteins. The exceptions are tissue factor, FV, FVIII, FXIII. Tissue factor, FV and FVIII are glycoproteins, and Factor XIII

3233-426: The normal hemostatic (bleeding-control) functions of the body. Such conditions either are, or cause, bleeding diatheses . Hemostasis involves several components. The main components of the hemostatic system include platelets and the coagulation system. Platelets are small blood components that form a plug in the blood vessel wall that stops bleeding. Platelets also produce a variety of substances that stimulate

3294-477: The platelets' cytosol. The calcium activates protein kinase C , which, in turn, activates phospholipase A 2 (PLA 2 ). PLA 2 then modifies the integrin membrane glycoprotein IIb/IIIa , increasing its affinity to bind fibrinogen . The activated platelets change shape from spherical to stellate, and the fibrinogen cross-links with glycoprotein IIb/IIIa aid in aggregation of adjacent platelets, forming

3355-427: The presence of two cell types for formation of coagulation complexes: cells that express tissue factor (usually extravascular) and platelets. 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

3416-403: The production of a blood clot. One of the most common causes of increased bleeding risk is exposure to nonsteroidal anti-inflammatory drugs (NSAIDs). The prototype for these drugs is aspirin, which inhibits the production of thromboxane. NSAIDs (for example Ibuprofen) inhibit the activation of platelets , and thereby increase the risk of bleeding. The effect of aspirin is irreversible; therefore,

3477-470: 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. 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 . Immunohemostasis

3538-443: The proper functioning of the coagulation cascade: Calcium and phospholipids (constituents of platelet membrane) are required for the tenase and prothrombinase complexes to function. 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. Calcium

3599-637: 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 . Coagulation defects may cause hemorrhage or thrombosis, and occasionally both, depending on

3660-401: Was initiated by glass, the intrinsic pathway; or clotting was initiated by thromboplastin (a mix of tissue factor and phospholipids), the extrinsic pathway. Further, the final common pathway scheme implies that prothrombin is converted to thrombin only when acted upon by the intrinsic or extrinsic pathways, which is an oversimplification. In fact, thrombin is generated by activated platelets at

3721-428: Was previously thought that the two pathways of coagulation cascade were of equal importance, but it is now known that the primary pathway for the initiation of blood coagulation is the tissue factor (extrinsic) pathway. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze

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