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.Coagulation is a complex process by which blood forms clots.^ Blood coagulation cascade Blood coagulation cascade The clotting cascades.
  • Coagulation Pages for Hoslink 10 February 2010 13:34 UTC www.hoslink.com [Source type: Academic]

^ There are two descriptions of what may be referred to using the term “coagulation cascade.” The first is the physiological coagulation cascade , which is used to describe a very complex step-by-step process that occurs in the body ( in vivo ) when a blood vessel is injured.

^ The role of factor VIII in this process is to act as a receptor, in the form of factor VIIIa, for factors IXa and X. Factor VIIIa is termed a cofactor in the clotting cascade.

.It is an important part of hemostasis (the cessation of blood loss from a damaged vessel), wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel.^ The formation of a clot prevents blood loss from a ruptured blood vessel.
  • Coagulation Pages for Hoslink 10 February 2010 13:34 UTC www.hoslink.com [Source type: Academic]

^ Then, platelet plug is reinforced by fibrin clot .

^ Initial step is formation of platelet plug to stop bleeding from damaged vessel .

.Disorders of coagulation can lead to an increased risk of bleeding (hemorrhage) or clotting (thrombosis).^ Hypercoagulability is the increased risk of thrombosis or blood clot formation in blood vessels.

^ Increased risk of venous & arterial clots.

^ Different TEG patterns have been identified in a variety of hemostatic disorders, including coagulation factor deficiencies, thrombocytopenia, increased fibrolysis, and hypercoagulability.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

.Coagulation is highly conserved throughout biology; in all mammals, coagulation involves both a cellular (platelet) and a protein (coagulation factor) component.^ All of the following statements describe a method by which platelets aid coagulation EXCEPT: .
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ F5 (Gene Symbol) FVL OTTHUMP00000032547 PCCF Activated protein C cofactor Proaccelerin, labile factor coagulation factor V coagulation factor V (proaccelerin, labile factor) coagulation factor V jinjiang A2 domain factor V Leiden .
  • F5 Gene - GeneCards | FA5 Protein | FA5 Antibody 10 February 2010 13:34 UTC www.genecards.org [Source type: Academic]

^ The activated protein is a cofactor that participates with activated coagulation factor X to activate prothrombin to thrombin.
  • F5 Gene - GeneCards | FA5 Protein | FA5 Antibody 10 February 2010 13:34 UTC www.genecards.org [Source type: Academic]

The system in humans has been the most extensively researched and is therefore the best understood.
.Coagulation begins almost instantly after an injury to the blood vessel has damaged the endothelium (lining of the vessel).^ A sample of blood is tested by adding substances that begin the coagulation process, and the time that it takes for the sample to begin to clot is measured.

^ The design of the vasculature, or blood vessels, is such that the walls of the vessels are chemically inert to both coagulation factors and platelets under normal conditions.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ It involves an interaction between blood vessels, platelets, and coagulation.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

.Exposure of the blood to proteins such as tissue factor initiates changes to blood platelets and the plasma protein fibrinogen, a clotting factor.^ Formal name: see table Related tests: PT , aPTT or PTT , fibrinogen , proteins C and S , von Willebrand factor .

^ NovoSeven Coagulation VIIa Recombinant for Hemophilia URL: http://www.novoseven.com/ NovoSeven is a genetically engineered blood clotting protein for treatment of bleeding episodes in hemophilia A or B patients with inhibitors (antibodies) to coagulation Factor VIII or Factor IX. Miscellaneous .
  • Coagulation Pages for Hoslink 10 February 2010 13:34 UTC www.hoslink.com [Source type: Academic]

^ For factor IX, double the initial dosage because factor IX distributes to tissue fluid.
  • UAB Coagulation Service 10 February 2010 13:34 UTC coag.path.uab.edu [Source type: Academic]

.Platelets immediately form a plug at the site of injury; this is called primary hemostasis.^ Once woven into the platelet plug, and further stabilized with covalent cross-linking, a fibrin clot (the end goal of secondary hemostasis) is achieved.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ When injury to a blood vessel occurs, platelets aggregate forming a plug which helps to stop the flow of blood.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ This process continues until a platelet "plug" is formed.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

.Secondary hemostasis occurs simultaneously: Proteins in the blood plasma, called coagulation factors or clotting factors, respond in a complex cascade to form fibrin strands, which strengthen the platelet plug.^ To insure stability of the initially loose platelet plug, a fibrin mesh (also called the clot ) forms and entraps the plug.

^ This platelet plug then serves as a matrix upon which blood clotting or coagulation proceeds.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ The tissue factor-VIIa complex then serves to activate thrombin, which, in turn, cleaves fibrinogen to fibrin while simultaneously causing platelet aggregation.
  • Disseminated Intravascular Coagulation: eMedicine Emergency Medicine 10 February 2010 13:34 UTC emedicine.medscape.com [Source type: Academic]

[1]

Contents

Physiology

Platelet activation

.Damage to blood vessel walls exposes subendothelium proteins, most notably von Willebrand factor (vWF), present under the endothelium.^ Platelet Activation and von Willebrand Factor (vWF) .

^ Willebrand factor antigen assay (vWF) .

^ Diagrams: binding of von Willebrand factor .

vWF is a protein secreted by healthy endothelium, forming a layer between the endothelium and underlying basement membrane. .When the endothelium is damaged, the normally-isolated, underlying vWF is exposed to blood and recruits Factor VIII, collagen, and other clotting factors.^ These include: Coagulation proteins (blood clotting factors), which, if activated, will form a blood clot , and Serum proteins, which are left dispersed in liquid after the clot is formed.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Type 2N: mutation in N-terminis (factor VIII binding site), leading to decreased binding of vWF to factor VIII .

^ Normally, activated protein C degrades activated factors V and VIII by cleaving specific arginine residues .

.Circulating platelets bind to collagen with surface collagen-specific glycoprotein Ia/IIa receptors.^ The function of vWF is to act as a bridge between a specific glycoprotein complex on the surface of platelets (GPIb-GPIX-GPV) and collagen fibrils.

^ Intrinsic membrane glycoprotein on luminal surface of endothelial cells that binds thrombomodulin and facilitates the activation of protein C .

^ Surface expression and functional characterization of alpha-granule factor V in human platelets: effects of ionophore A23187, thrombin, collagen, and convulxin.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

.This adhesion is strengthened further by additional circulating proteins vWF, which forms additional links between the platelets glycoprotein Ib/IX/V and the collagen fibrils.^ The function of vWF is to act as a bridge between a specific glycoprotein complex on the surface of platelets (GPIb-GPIX-GPV) and collagen fibrils.

^ In addition to its role as a bridge between platelets and exposed collagen on endothelial surfaces, vWF binds to and stabilizes coagulation factor VIII. Binding of factor VIII by vWF is required for normal survival of factor VIII in the circulation.

^ Once woven into the platelet plug, and further stabilized with covalent cross-linking, a fibrin clot (the end goal of secondary hemostasis) is achieved.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

.These adhesions activate the platelets.^ The thrombin-induced signaling also leads to increased platelet activation and leukocyte adhesion.

.Activated platelets release the contents of stored granules into the blood plasma.^ WF is synthesized by (a) endothelial cells, stored in Weibel-Palade bodies, secreted into plasma and subendothelium and (b) megakaryocytes, present in platelets in alpha granules .

^ Activated factor X converts prothrombin to thrombin, with activated factor V, anionic phospholipids (from activated platelets) and calcium as cofactors; prothrombin factor 1.2 is released (see common pathway, below ) .

^ In vivo, platelets flow through the blood vessels in an inactivated state because the blood vessel lining, the endothelium, prevents activation of platelets.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

.The granules include ADP, serotonin, platelet-activating factor (PAF), vWF, platelet factor 4, and thromboxane A2 (TXA2), which, in turn, activate additional platelets.^ Platelet Activation and von Willebrand Factor (vWF) .

^ Additional platelets then adhere to the activated platelets and also become activated.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ The tissue factor-VIIa complex then serves to activate thrombin, which, in turn, cleaves fibrinogen to fibrin while simultaneously causing platelet aggregation.
  • Disseminated Intravascular Coagulation: eMedicine Emergency Medicine 10 February 2010 13:34 UTC emedicine.medscape.com [Source type: Academic]

.The granules' contents activate a Gq-linked protein receptor cascade, resulting in increased calcium concentration in the platelets' cytosol.^ This activated protein induces the release of platelet granule contents; one of which is ADP. ADP further stimulates platelets increasing the overall activation cascade.

^ Such a deficiency, and the resulting post-operative bleeding risk, could be remedied by a transfusion of platelet concentrate.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ The prostate stromal/epithelial signaling may be accomplished through activation of the ECM-receptor interaction, Complement and coagulation cascades , focal adhesion and cell adhesion pathways.
  • View Pathway: Complement and coagulation cascades 10 February 2010 13:34 UTC apropos.mcw.edu [Source type: Academic]

.The calcium activates protein kinase C, which, in turn, activates phospholipase A2 (PLA2).^ The collagen to which platelets adhere as well as the release of intracellular Ca 2+ leads to the activation of phospholipase A 2 (PLA 2 ), which then hydrolyzes membrane phospholipids, leading to liberation of arachidonic acid.

^ Inhibition of coagulation, fibrinolysis, and endothelial cell activation by a p38 mitogen-activated protein kinase inhibitor during human endotoxemia.
  • Disseminated Intravascular Coagulation: eMedicine Emergency Medicine 10 February 2010 13:34 UTC emedicine.medscape.com [Source type: Academic]

^ IP 3 induces the release of intracellular Ca 2+ stores, and DAG activates protein kinase C (PKC).

.PLA2 then modifies the integrin membrane glycoprotein IIb/IIIa, increasing its affinity to bind fibrinogen.^ WF binds glycoproteins Ib, IIb, and IIIa.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Intrinsic membrane glycoprotein on luminal surface of endothelial cells that binds thrombomodulin and facilitates the activation of protein C .

^ Reduced clot formation: Glanzmann thrombasthenia (reduced glycoprotein IIb/IIIa causes reduced platelet aggregation and clot retraction); DIC, hypofibrinogenemia, dysfibrinogenemia (small clot with increased red blood cell fall-out) .

.The activated platelets change shape from spherical to stellate, and the fibrinogen cross-links with glycoprotein IIb/IIIa aid in aggregation of adjacent platelets.^ Assays for fibrinogen, platelet aggregation or platelet function assay (e.g.

^ Note: aggregation of platelets implies linkage via fibrinogen and GP IIb/IIIa; ristocetin links platelets through vWF and GP Ib, and appropriate term is actually agglutination .

^ Once woven into the platelet plug, and further stabilized with covalent cross-linking, a fibrin clot (the end goal of secondary hemostasis) is achieved.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

The coagulation cascade

The coagulation cascade.
.The coagulation cascade of secondary hemostasis has two pathways, the contact activation pathway (formerly known as the intrinsic pathway), and the tissue factor pathway (formerly known as the extrinsic pathway), which lead to fibrin formation.^ This process is the result of the activation of the extrinsic pathway .

^ Secondary Hemostasis – The Extrinsic Pathway It should be noted that this pathway is sometimes referred to as the Tissue Factor Pathway.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Two pathways lead to the formation of a fibrin clot: the intrinsic and extrinsic pathway.

.It was previously thought that the coagulation cascade consisted of two pathways of equal importance joined to a common pathway.^ Mouse proteins in Complement and coagulation cascades pathway There are 55 IPI Records from this pathway found in Mus musculus .
  • View Pathway: Complement and coagulation cascades 10 February 2010 13:34 UTC apropos.mcw.edu [Source type: Academic]

^ The prostate stromal/epithelial signaling may be accomplished through activation of the ECM-receptor interaction, Complement and coagulation cascades , focal adhesion and cell adhesion pathways.
  • View Pathway: Complement and coagulation cascades 10 February 2010 13:34 UTC apropos.mcw.edu [Source type: Academic]

^ Pathway analysis revealed the over-representation of the Complement and coagulation cascades , the hematopoietic cell lineage and the arachidonic acid metabolism pathways.
  • View Pathway: Complement and coagulation cascades 10 February 2010 13:34 UTC apropos.mcw.edu [Source type: Academic]

.It is now known that the primary pathway for the initiation of blood coagulation is the tissue factor pathway.^ Tissue factor activates coagulation by the extrinsic pathway involving factor VIIa.
  • Disseminated Intravascular Coagulation: eMedicine Emergency Medicine 10 February 2010 13:34 UTC emedicine.medscape.com [Source type: Academic]

^ The primary mechanism of the coagulation pathway in vivo is tissue factor binding to activated factor VII (factor VIIa) .

^ The prothrombin time (PT) is an assay designed to screen for defects in fibrinogen, prothrombin, and factors V, VII, and X and thus measures activities of the extrinsic pathway of coagulation.

.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 the next reaction in the cascade, ultimately resulting in cross-linked fibrin.^ Prothrombin is the precursor of the serine protease thrombin.

^ As clotting proceeds, polymerization and cross-linking of fibrin results in the permanent clot.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ Then, fibrin clot is stabilized by activated factor XIII, which cross-links fibrin strands .

.Coagulation factors are generally indicated by Roman numerals, with a lowercase a appended to indicate an active form.^ Platelet Factor 3 catalyzes the coagulation reaction whereby a fibrin clot is formed, completing the seal.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ There are severe, moderate and mild forms of hemophilia A that reflect the level of active factor VIII in the plasma.

^ To elucidate the mechanisms involved, the effects of various coagulation factors on Complement activation and generation of anaphylatoxins were investigated and summarized in the light of the latest literature.
  • View Pathway: Complement and coagulation cascades 10 February 2010 13:34 UTC apropos.mcw.edu [Source type: Academic]

.The coagulation factors are generally serine proteases (enzymes).^ Factor IX is a proenzyme that contains vitamin K-dependent γ-carboxyglutamate ( gla ) residues, whose serine protease activity is activated following Ca 2+ binding to these gla residues.

^ These findings suggest that various serine proteases belonging to the coagulation system are able to activate the Complement cascade independently of the established pathways.
  • View Pathway: Complement and coagulation cascades 10 February 2010 13:34 UTC apropos.mcw.edu [Source type: Academic]

^ Blocks protein families ( see all 6 ): IPB000001 Kringle IPB000294 Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain IPB001254 Serine protease IPB001314 Chymotrypsin serine protease family (S1) signature IPB002383 Coagulation factor GLA domain signature .
  • F2 Gene - GeneCards | THRB Protein | THRB Antibody 10 February 2010 13:34 UTC www.genecards.org [Source type: Academic]

There are some exceptions. .For example, FVIII and FV are glycoproteins, and Factor XIII is a transglutaminase.^ Factor XIII is the proenzyme form of plasma transglutaminase and is activated by thrombin in the presence of calcium ions.

^ The sea squirt genome has a transglutaminase, but there was no evidence of the signal peptide required for a circulating factor XIII, and it is likely an ordinary tissue transglutaminase.
  • The evolution of vertebrate blood coagulation as viewed from a comparison of puffer fish and sea squirt genomes — PNAS 10 February 2010 13:34 UTC www.pnas.org [Source type: Academic]

.Serine proteases act by cleaving other proteins at specific sites.^ Thrombin also binds to a class of G-protein-coupled receptors called protease activated receptors ( PARs ), specifically PAR-1, -3 and -4.

^ Less likely to bind to acute phase reactant proteins, platelets, platelet factor 4, macrophages and other sites, due to its shorter length .

^ The activity of antithrombin III is potentiated in the presence of heparin by the following means: heparin binds to a specific site on antithrombin III, producing an altered conformation of the protein, and the new conformation has a higher affinity for thrombin as well as its other substrates.

.The coagulation factors circulate as inactive zymogens.^ During this excessive intravascular coagulation phase, platelets and coagulation factors are consumed, resulting in thrombocytopenia, thrombocytopathy, and depletion and inactivation of coagulation factors.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

^ The predominant form of thrombin in the circulation is the inactive prothrombin, whose activation requires the pathways of proenzyme activation described above for the coagulation cascade.

.The coagulation cascade is classically divided into three pathways.^ A diagram is provided of the testing coagulation cascade that shows the factors that make up the intrinsic, extrinsic, and common pathways.

^ The predominant form of thrombin in the circulation is the inactive prothrombin, whose activation requires the pathways of proenzyme activation described above for the coagulation cascade.

.The tissue factor and contact activation pathways both activate the "final common pathway" of factor X, thrombin and fibrin.^ Tissue factor activates coagulation by the extrinsic pathway involving factor VIIa.
  • Disseminated Intravascular Coagulation: eMedicine Emergency Medicine 10 February 2010 13:34 UTC emedicine.medscape.com [Source type: Academic]

^ The common point in both pathways is the activation of factor X to factor Xa.

^ The tissue factor-VIIa complex then serves to activate thrombin, which, in turn, cleaves fibrinogen to fibrin while simultaneously causing platelet aggregation.
  • Disseminated Intravascular Coagulation: eMedicine Emergency Medicine 10 February 2010 13:34 UTC emedicine.medscape.com [Source type: Academic]

Tissue factor pathway (extrinsic)

.The main role of the tissue factor pathway is to generate a "thrombin burst," a process by which thrombin, the most important constituent of the coagulation cascade in terms of its feedback activation roles, is released instantaneously.^ Thrombin can then activate factors XI, VIII and V furthering the cascade.

^ Tissue factor activates coagulation by the extrinsic pathway involving factor VIIa.
  • Disseminated Intravascular Coagulation: eMedicine Emergency Medicine 10 February 2010 13:34 UTC emedicine.medscape.com [Source type: Academic]

^ The tissue factor-VIIa complex then serves to activate thrombin, which, in turn, cleaves fibrinogen to fibrin while simultaneously causing platelet aggregation.
  • Disseminated Intravascular Coagulation: eMedicine Emergency Medicine 10 February 2010 13:34 UTC emedicine.medscape.com [Source type: Academic]

.FVIIa circulates in a higher amount than any other activated coagulation factor.^ These include: Coagulation proteins (blood clotting factors), which, if activated, will form a blood clot , and Serum proteins, which are left dispersed in liquid after the clot is formed.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ The primary mechanism of the coagulation pathway in vivo is tissue factor binding to activated factor VII (factor VIIa) .

^ However, it is less selective than tPA, being able to activate circulating plasminogen as well as that bound to a fibrin clot.

.
  • Following damage to the blood vessel, FVII leaves the circulation and comes into contact with tissue factor (TF) expressed on tissue-factor-bearing cells (stromal fibroblasts and leukocytes), forming an activated complex (TF-FVIIa).
  • TF-FVIIa activates FIX and FX.
  • FVII is itself activated by thrombin, FXIa, plasmin, FXII and FXa.
  • The activation of FXa by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor (TFPI).
  • FXa and its co-factor FVa form the prothrombinase complex, which activates prothrombin to thrombin.
  • Thrombin then activates other components of the coagulation cascade, including FV and FVIII (which activates FXI, which, in turn, activates FIX), and activates and releases FVIII from being bound to vWF.
  • FVIIIa is the co-factor of FIXa, and together they form the "tenase" complex, which activates FX; and so the cycle continues.^ Thrombin can then activate factors XI, VIII and V furthering the cascade.

    ^ Which of the following coagulation factor(s) are found only in the extrinsic pathway.
    • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

    ^ The intrinsic pathway can also be activated by vessel wall contact with bacteria.

    ("Tenase" is a contraction of "ten" and the suffix "-ase" used for enzymes.)

Contact activation pathway (intrinsic)

.The contact activation pathway begins with formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein, and FXII (Hageman factor).^ Factor XII is activated by high molecular weight kininogen and prekallikrein .

^ HMWK = high molecular weight kininogen.

^ Involves factors VIII, IX, XI, XII (Hageman factor), prekallikrein, high molecular weight kininogen .

.Prekallikrein is converted to kallikrein and FXII becomes FXIIa.^ Activated factor XII converts prekallikrein to kallikrein, which activates more factor XII .

^ Factor XIIa also converts prekallikrein to kallikrein, which activates more factor XIIa; both require high molecular weight kininogen as cofactors .

FXIIa converts FXI into FXIa. .Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa.^ Factor XIIa then activates factor XI to factor XIa.

^ The tissue factor-VIIa complex then serves to activate thrombin, which, in turn, cleaves fibrinogen to fibrin while simultaneously causing platelet aggregation.
  • Disseminated Intravascular Coagulation: eMedicine Emergency Medicine 10 February 2010 13:34 UTC emedicine.medscape.com [Source type: Academic]

^ These include: Coagulation proteins (blood clotting factors), which, if activated, will form a blood clot , and Serum proteins, which are left dispersed in liquid after the clot is formed.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

.The minor role that the contact activation pathway has in initiating clot formation can be illustrated by the fact that patients with severe deficiencies of FXII, HMWK, and prekallikrein do not have a bleeding disorder.^ Severe hereditary bleeding disorder .

^ The intrinsic pathway requires the clotting factors VIII, IX, X, XI, and XII. Also required are the proteins prekallikrein (PK) and high-molecular-weight kininogen (HK or HMWK), as well as calcium ions and phospholipids secreted from platelets.

^ The assemblage of contact phase components results in conversion of prekallikrein to kallikrein, which in turn activates factor XII to factor XIIa.

Final common pathway

Thrombin has a large array of functions. .Its primary role is the conversion of fibrinogen to fibrin, the building block of a hemostatic plug.^ Also inhibits fibrinogen conversion to fibrin, causing prolongation of thrombin time and reptilase time .

^ Liver failure is a common complication in DIC due to a combination of microthrombosis, anemia, bleeding, and hypoxia; conversely, patients with primary hepatic failure are prone to develop DIC due to the liver’s main role in the production of hemostatic proteins.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

^ Plays a role in platelet plug and fibrin clot, both essential to hemostasis at site of endothelial injury, particularly in high flow vessels .

.In addition, it activates Factors VIII and V and their inhibitor protein C (in the presence of thrombomodulin), and it activates Factor XIII, which forms covalent bonds that crosslink the fibrin polymers that form from activated monomers.^ Factor VIII inhibitor .

^ Factor VIII inhibitor assay / Bethesda assay .

^ Active factor XIII catalyzes the cross-linking of fibrin monomers.

.Following activation by the contact factor or tissue factor pathways, 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.^ Which of the following coagulation factor(s) are found only in the extrinsic pathway.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Secondary Hemostasis – The Extrinsic Pathway The shortest, and least complex of the three pathways, the extrinsic pathway primarily focuses on the interaction of tissue factor with factor VII, leading to the activation of factor VII. Tissue factor, a substance expressed on the surface of cells such as fibroblasts and macrophages found outside the vasculature, initiates coagulation when plasma contained within the vessel walls leaks outside the broken vessel, and comes into contact with these cells.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ After initial activation, pathway is inhibited by the binding of tissue factor pathway inhibitor (TFPI) to factor Xa, which inhibits TF-Factor VIIa complex, and further coagulation is dependent on the intrinsic pathway .

Cofactors

Various substances are required for the proper functioning of the coagulation cascade:
.
  • Calcium and phospholipid (a platelet membrane constituent) are required for the tenase and prothrombinase complexes to function.^ The intrinsic pathway requires the clotting factors VIII, IX, X, XI, and XII. Also required are the proteins prekallikrein (PK) and high-molecular-weight kininogen (HK or HMWK), as well as calcium ions and phospholipids secreted from platelets.

    ^ Factor V is a cofactor in the formation of the prothrombinase complex, similar to the role of factor VIII in tenase complex formation.

    ^ The exposure of these phospholipids allows the tenase complex to form.

    .Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on FXa and FIXa to the phospholipid surfaces expressed by platelets, as well as procoagulant microparticles or microvesicles shed from them.^ Factor Va binds to specific receptors on the surfaces of activated platelets and forms a complex with prothrombin and factor Xa.

    ^ Activated factor X converts prothrombin to thrombin, with activated factor V, anionic phospholipids (from activated platelets) and calcium as cofactors; prothrombin factor 1.2 is released (see common pathway, below ) .

    ^ The intrinsic pathway requires the clotting factors VIII, IX, X, XI, and XII. Also required are the proteins prekallikrein (PK) and high-molecular-weight kininogen (HK or HMWK), as well as calcium ions and phospholipids secreted from platelets.

    .Calcium is also required at other points in the coagulation cascade.
  • Vitamin K is an essential factor to a 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.^ Combined factors II, VII, IX and X deficiency: due to mutation in gamma-glutamyl carboxylase gene, whose protein carboxylates glutamate residues in vitamin K-dependent coagulation factors .

    ^ Vitamin K: cofactor in carboxylation of glutamic acid residues of factors II, VII, IX and X and protein S and C .

    ^ Vitamin K is a cofactor in reactions that carboxylate glutamic acid residues in factors II, VII, IX, X, protein C, protein S .

    .In adding the gamma-carboxyl group to glutamate residues on the immature clotting factors Vitamin K is itself oxidized.^ Combined factors II, VII, IX and X deficiency: due to mutation in gamma-glutamyl carboxylase gene, whose protein carboxylates glutamate residues in vitamin K-dependent coagulation factors .

    ^ Vitamin K: cofactor in carboxylation of glutamic acid residues of factors II, VII, IX and X and protein S and C .

    ^ In earlier discussions, it was mentioned that certain clotting factors are considered to be vitamin K dependant.
    • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

    .Another enzyme, Vitamin K epoxide reductase, (VKORC) reduces vitamin K back to its active form.^ Warfarin (coumadin): therapeutic anticoagulant to reduce risk of thromboembolism; impairs regeneration of active vitamin K .

    .Vitamin K epoxide reductase is pharmacologically important as a target for anticoagulant drugs warfarin and related coumarins such as acenocoumarol, phenprocoumon, and dicumarol.^ Coumarin drugs (based on the chemical benzopyrone), such as warfarin (trade name Coumadin®) as well as the glycosaminoglycans , heparin and heparan sulfate, are useful as anticoagulants.

    ^ Warfarin, a dicumarol derivative, is one of the most popular oral anticoagulants used today.
    • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

    ^ For this reason, heparin is normally administered first followed by warfarin or warfarin-related drugs.

    .These drugs create a deficiency of reduced vitamin K by blocking VKORC, thereby inhibiting maturation of clotting factors.^ When any of these factors is deficient then the PT is prolonged.

    ^ In earlier discussions, it was mentioned that certain clotting factors are considered to be vitamin K dependant.
    • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

    ^ Hemophilia B results from deficiencies in factor IX. The prevalence of hemophilia B is approximately one-tenth that of hemophilia A. All patients with hemophilia B have prolonged coagulation time and decreased factor IX clotting activity.

    Other deficiencies of vitamin K (e.g., in malabsorption), or disease (hepatocellular carcinoma) impairs the function of the enzyme and leads to the formation of PIVKAs (proteins formed in vitamin K absence); this causes partial or non-gamma carboxylation, and affects the coagulation factors' ability to bind to expressed phospholipid.

Regulators

.Five mechanisms keep platelet activation and the coagulation cascade in check.^ The primary mechanism of the coagulation pathway in vivo is tissue factor binding to activated factor VII (factor VIIa) .

^ The prostate stromal/epithelial signaling may be accomplished through activation of the ECM-receptor interaction, Complement and coagulation cascades , focal adhesion and cell adhesion pathways.
  • View Pathway: Complement and coagulation cascades 10 February 2010 13:34 UTC apropos.mcw.edu [Source type: Academic]

^ Coagulation factors in intrinsic or extrinsic pathway assemble on surface of activated platelets, which are usually at site of vascular injury .

Abnormalities can lead to an increased tendency toward thrombosis:
.
  • Protein C is a major physiological anticoagulant.^ Major anticoagulant systems are protein C and protein S, antithrombin and tissue factor pathway inhibitor (TFPI, see Extrinsic pathway above) .

    .It is a vitamin K-dependent serine protease enzyme that is activated by thrombin into activated protein C (APC).^ Prothrombin is the precursor of the serine protease thrombin.

    ^ These findings suggest that various serine proteases belonging to the coagulation system are able to activate the Complement cascade independently of the established pathways.
    • View Pathway: Complement and coagulation cascades 10 February 2010 13:34 UTC apropos.mcw.edu [Source type: Academic]

    ^ Orthologous genes were identified for each of the five vitamin K-dependent serine proteases (prothrombin, factors VII, IX, and X, and protein C).
    • The evolution of vertebrate blood coagulation as viewed from a comparison of puffer fish and sea squirt genomes — PNAS 10 February 2010 13:34 UTC www.pnas.org [Source type: Academic]

    .Protein C is activated in a sequence that starts with Protein C and thrombin binding to a cell surface protein thrombomodulin.^ Intrinsic membrane glycoprotein on luminal surface of endothelial cells that binds thrombomodulin and facilitates the activation of protein C .

    ^ Drawings: thrombomodulin protein , flowchart of protein C activation .

    ^ Thrombin combines with thrombomodulin present on endothelial cell surfaces forming a complex that converts protein C to protein Ca.

    .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.^ Activation: endothelial cell protein C receptor binds thrombin-thrombomodulin complex, which activates protein C, which binds to free protein S on endothelial or platelet phospholipids surfaces; this protein C / protein S complex degrades factors Va and VIIIa, which reduces fibrin formation .

    ^ It is an endothelial cell–based protein activated by thrombomodulin-bound thrombin and through binding to the cofactor protein S. APC prevents amplification of procoagulant activity by inactivating factors Va and VIIIa and enhances fibrinolysis through inhibition of plasminogen activator inhibitor.
    • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

    ^ These include: Coagulation proteins (blood clotting factors), which, if activated, will form a blood clot , and Serum proteins, which are left dispersed in liquid after the clot is formed.
    • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

    .Quantitative or qualitative deficiency of either may lead to thrombophilia (a tendency to develop thrombosis).^ Dysfibrinogenemia: qualitative fibrinogen deficiency with production of dysfunctional fibrinogen; usually heterozygous; usually either no symptoms or mild bleeding; may paradoxically be associated with thrombosis, with or without bleeding; often prolonged thrombin time and reptilase time, PT and PTT .

    ^ Hereditary deficiencies occur in 0.07 to 0.17% of general population; many mutations exist (qualitative or quantitative); usually autosomal dominant .

    ^ Type 2 (15-20%): qualitative deficiency of vWF, variable quantitative deficiency, usually mild/moderate bleeding disorder, but may be severe .

    .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.
  • Antithrombin is a serine protease inhibitor (serpin) that degrades the serine proteases: thrombin, FIXa, FXa, FXIa, and FXIIa.^ The activation of factor VII occurs through the action of thrombin or factor Xa.

    ^ Resistance to activated protein C .

    ^ Prothrombin is the precursor of the serine protease thrombin.

    .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).^ Antithrombin, heparin, and heparan sulfate.
    • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

    ^ Moreover, the presence of endotoxin or inflammatory mediators reduces the endothelial expression of glycosaminoglycans, such as heparan sulfate, that normally augment the activity of AT, leading to reduced AT activity and endothelial antithrombotic function 22–26 ( Figure 2 ).
    • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

    ^ Heparin and heparan sulfates increase the activity of antithrombin at least 1000 fold.

    .Quantitative or qualitative deficiency of antithrombin (inborn or acquired, e.g., in proteinuria) leads to thrombophilia.
  • Tissue factor pathway inhibitor (TFPI) limits the action of tissue factor (TF).^ Abbreviations: t-PA, tissue plasminogen activator; u-PA, urokinase-type plasminogen activator; EGF, epidermal growth factor; FN, fibronectin; GLA, γ-carboxy-glutamate; TFI, tissue factor inhibitor.
    • The evolution of vertebrate blood coagulation as viewed from a comparison of puffer fish and sea squirt genomes — PNAS 10 February 2010 13:34 UTC www.pnas.org [Source type: Academic]

    ^ Deficiency leads to neonatal umbilical cord bleeding, intracranial hemorrhage and soft tissue hematomas.

    ^ Each of these pathway constituents leads to the conversion of factor X (inactive) to factor Xa.

    .It also inhibits excessive TF-mediated activation of FIX and FX.
  • Plasmin is generated by proteolytic cleavage of plasminogen, a plasma protein synthesized in the liver.^ Poorly stimulated tPA-Fx is often accompanied by high plasminogen activator inhibitor activity (PAI-Fx), the major inhibitor of fibrinolysis.

    ^ This vitamin K-dependent protein is synthesized in the liver and is a co-factor for protein C, helping to suppress factor Va activity.

    ^ Tissue plasminogen activator (tPA) and, to a lesser degree, urokinase are serine proteases which convert plasminogen to plasmin.

    .This cleavage is catalyzed by tissue plasminogen activator (t-PA), which is synthesized and secreted by endothelium.^ Orthologous genes for plasminogen, t-PA (tissue plasminogen activator) and u-PA (urokinase-type plasminogen activator), were readily identified.
    • The evolution of vertebrate blood coagulation as viewed from a comparison of puffer fish and sea squirt genomes — PNAS 10 February 2010 13:34 UTC www.pnas.org [Source type: Academic]

    ^ Abbreviations: t-PA, tissue plasminogen activator; u-PA, urokinase-type plasminogen activator; EGF, epidermal growth factor; FN, fibronectin; GLA, γ-carboxy-glutamate; TFI, tissue factor inhibitor.
    • The evolution of vertebrate blood coagulation as viewed from a comparison of puffer fish and sea squirt genomes — PNAS 10 February 2010 13:34 UTC www.pnas.org [Source type: Academic]

    ^ Tissue plasminogen activator (tPA) and, to a lesser degree, urokinase are serine proteases which convert plasminogen to plasmin.

    .Plasmin proteolytically cleaves fibrin into fibrin degradation products that inhibit excessive fibrin formation.
  • Prostacyclin (PGI2) is released by endothelium and activates platelet Gs protein-linked receptors.^ D-dimers are products of cross-linked fibrin degradation.
    • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

    ^ The tissue factor-VIIa complex then serves to activate thrombin, which, in turn, cleaves fibrinogen to fibrin while simultaneously causing platelet aggregation.
    • Disseminated Intravascular Coagulation: eMedicine Emergency Medicine 10 February 2010 13:34 UTC emedicine.medscape.com [Source type: Academic]

    ^ They are prothrombotic via several mechanisms, including inhibition of prostacyclin synthesis, impairment of the thrombomodulin-protein C-protein S anticoagulant system, action as anti-endothelial cell antibodies, or interaction with platelet membrane phospholipids.

    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.

Fibrinolysis

.Eventually, blood clots are reorganised and resorbed by a process termed fibrinolysis.^ The role of factor VIII in this process is to act as a receptor, in the form of factor VIIIa, for factors IXa and X. Factor VIIIa is termed a cofactor in the clotting cascade.

^ The washer may eventually stop moving as a clot forms about it, and no additional information can be obtained on the coagulation process in the sample.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ In accordance with one simplified conceptual view, the whole blood coagulation process can be generally viewed as three activities: platelet adhesion, platelet aggregation, and formation of a fibrin clot.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

.The main enzyme responsible for this process (plasmin) is regulated by various activators and inhibitors.^ When ADP binds to platelets they are activated and aggregate leading to amplification of the coagulation response, thus Plavix interferes with this process.

^ The initial response to inflammation appears to be augmentation of fibrinolytic action; however, this response soon reverses as inhibitors (plasminogen activator inhibitor-1 [PAI-1], TAFI) of fibrinolysis are released.
  • Disseminated Intravascular Coagulation: eMedicine Emergency Medicine 10 February 2010 13:34 UTC emedicine.medscape.com [Source type: Academic]

^ The activation of thrombin is also regulated by 4 specific thrombin inhibitors Antithrombin III is the most important since it can also inhibit the activities of factors IXa, Xa, XIa and XIIa.

Testing of coagulation

Numerous tests are used to assess the function of the coagulation system:
.
.The contact activation pathway is initiated by activation of the "contact factors" of plasma, and can be measured by the activated partial thromboplastin time (aPTT) test.^ Also called activated partial thromboplastin time (aPTT) .

^ PTT - Partial thromboplastin time .

^ Among these tests are platelet count (PLT), thrombin time (TT), prothrombin time (PT), partial thromboplastin time (aPTT), activated clotting time (ACT), fibrinogen level (FIB), fibrinogen degradation product concentrations, and general purpose clotting (GPC) time.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

.The tissue factor pathway is initiated by release of tissue factor (a specific cellular lipoprotein), and can be measured by the prothrombin time (PT) test.^ PT - Prothrombin time .

^ Among these tests are platelet count (PLT), thrombin time (TT), prothrombin time (PT), partial thromboplastin time (aPTT), activated clotting time (ACT), fibrinogen level (FIB), fibrinogen degradation product concentrations, and general purpose clotting (GPC) time.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ The primary mechanism of the coagulation pathway in vivo is tissue factor binding to activated factor VII (factor VIIa) .

.PT results are often reported as ratio (INR value) to monitor dosing of oral anticoagulants such as warfarin.^ Note: Warfarin is monitored using INR (international normalized ratio), which standardizes PT results for patients on oral anticoagulants; goal is INR of 2-3; calculated as patient PT divided by mean normal PT; PT/INR should be checked daily at onset of warfarin use until dose and INR are stable (usually at least a week since half life of factors II and X are long), then decreased gradually to every 4 weeks .

^ Note: test is necessary for high-dose heparin monitoring because PTT is often unclottable at very high heparin levels .

^ Such a value may also be achieved through replacement and supportive therapy alone and should be maintained through laboratory monitoring and heparin administration as needed.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

.The quantitative and qualitative screening of fibrinogen is measured by the thrombin clotting time (TCT).^ Among these tests are platelet count (PLT), thrombin time (TT), prothrombin time (PT), partial thromboplastin time (aPTT), activated clotting time (ACT), fibrinogen level (FIB), fibrinogen degradation product concentrations, and general purpose clotting (GPC) time.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ Measures rate of fibrin clot formation after addition of standard concentration of thrombin to citrated plasma; thrombin cleaves fibrinogen, releasing fibrinopeptides A and B, and converting fibrinogen to fibrin .

^ A sample of blood is tested by adding substances that begin the coagulation process, and the time that it takes for the sample to begin to clot is measured.

.Measurement of the exact amount of fibrinogen present in the blood is generally done using the Clauss method for fibrinogen testing.^ Often need to repeat tests, because von Willebrand factor and factor VIII are elevated during acute phase reactions, pregnancy, estrogen use and in newborns - can measure fibrinogen (acute phase reactant) to determine if acute phase condition exists .

^ A first embodiment of a test cartridge 50 used with the test instrument depicted in FIG. 1 in accordance with the method of FIG. 14 is depicted in FIGS. 2-9.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ Tests of Hemostatic Function – Fibrinogen Assay The fibrinogen assay performed in the clinical laboratory is a quantitative measure of factor I. This assay is used to determine whether there is enough fibrinogen present to allow for normal clotting.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

.Many analysers are capable of measuring a "derived fibrinogen" level from the graph of the Prothrombin time clot.^ Among these tests are platelet count (PLT), thrombin time (TT), prothrombin time (PT), partial thromboplastin time (aPTT), activated clotting time (ACT), fibrinogen level (FIB), fibrinogen degradation product concentrations, and general purpose clotting (GPC) time.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ Measures clotting time from factor VII activation through fibrin formation (i.e.

^ Measures rate of fibrin clot formation after addition of standard concentration of thrombin to citrated plasma; thrombin cleaves fibrinogen, releasing fibrinopeptides A and B, and converting fibrinogen to fibrin .

.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.^ Which of the following coagulation factor(s) are found only in the extrinsic pathway.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Homozygous deficient patients have <30% of normal values of affected factors .

^ When any of these factors is deficient then the PT is prolonged.

.The exceptions are prothrombin, fibrinogen, and some variants of FX that can be detected only by either aPTT or PT. If an abnormal PT or aPTT is present, additional testing will occur to determine which (if any) factor is present as aberrant concentrations.^ Among these tests are platelet count (PLT), thrombin time (TT), prothrombin time (PT), partial thromboplastin time (aPTT), activated clotting time (ACT), fibrinogen level (FIB), fibrinogen degradation product concentrations, and general purpose clotting (GPC) time.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ The effectiveness and presence of all the coagulation factors are assayed by this diagnostic test with the exception of factors VII and XIII. The results of the activated partial thromboplastin time are used in conjunction with other diagnostic tests, as well as the clinical picture of the patient, to determine hemostatic abnormalities which may be present.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ The results of the prothrombin time are used in conjunction with other diagnostic tests, as well as the clinical picture of the patient, to determine any hemostatic abnormalities which may be present.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

.Deficiencies of fibrinogen (quantitative or qualitative) will affect all screening tests.^ Hereditary deficiencies occur in 0.07 to 0.17% of general population; many mutations exist (qualitative or quantitative); usually autosomal dominant .

^ Type 2 (15-20%): qualitative deficiency of vWF, variable quantitative deficiency, usually mild/moderate bleeding disorder, but may be severe .

^ Afibrinogenemia: homozygous form; causes severe quantitative deficiency of fibrinogen and increased risk of bleeding; associated with intracranial hemorrhages .

Role in disease

.Problems with coagulation may dispose to hemorrhage, thrombosis, and occasionally both, depending on the nature of the pathology.^ However, the clinical signs may be highly variable, depending on the underlying primary disease and the phase of DIC (i.e., the balance between thrombosis and hemorrhage).
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

^ Impaired hemostatic mechanisms, be it acquired in cases of disease or inherent, may result in situations of either hemorrhage or thrombosis.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Val134Leu polymorphism, which may protect against deep venous thrombosis, but predispose to intracranial hemorrhage .

Platelet disorders

Platelet conditions may be inborn or acquired. .Some inborn platelet pathologies 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).^ Reduced clot formation: Glanzmann thrombasthenia (reduced glycoprotein IIb/IIIa causes reduced platelet aggregation and clot retraction); DIC, hypofibrinogenemia, dysfibrinogenemia (small clot with increased red blood cell fall-out) .

^ Hereditary disorders: consider in patients with bleeding histories, no obvious acquired cause, but abnormal platelet aggregation study repeated at least once, same abnormality in family members; may be a platelet storage pool disorder (deficiency in alpha or dense platelet granules), Glanzmann thombasthenia (deficiency of platelet glycoprotein IIb/IIIa, reduced aggregation by all agonists except ristocetin), Bernard-Soulier disease (deficiency of platelet glycoprotein Ib, causes decreased ristocetin-induced aggregation only) .

^ Disorders that are commonly associated with an increased bleeding time include thrombocytopenia, disseminated intravascular coagulation (DIC), Bernard-Soulier syndrome and Glanzmann thrombasthenia .

Most are rare conditions. Most inborn platelet pathologies 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.^ Willebrand disease (vWD) is due to inherited deficiency in von Willebrand factor (vWF).

^ Acquired von Willebrands disease .

^ Molecular basis of von Willebrands disease .

.Decreased platelet numbers may be due to various causes, including insufficient production (e.g., in myelodysplastic syndrome or other bone marrow disorders), destruction by the immune system (immune thrombocytopenic purpura/ITP), and consumption due to various causes (thrombotic thrombocytopenic purpura/TTP, hemolytic-uremic syndrome/HUS, paroxysmal nocturnal hemoglobinuria/PNH, disseminated intravascular coagulation/DIC, heparin-induced thrombocytopenia/HIT).^ Disorders that are associated with immune mechanisms of destruction include: Idiopathic (or immune) thrombocytopenic purpura (ITP) Heparin-induced thrombocytopenia (HIT) Neonatal alloimmune thrombocytopenia (NAIT)Increased destruction of platelets is not always caused by the immune system.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Disseminated intravascular coagulation.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

^ Mammen EF. Disseminated intravascular coagulation (DIC).
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

.Most consumptive conditions lead to platelet activation, and some are associated with thrombosis.^ This leads to platelet activation and consumption.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ The conditions that lead to DIC are the same as those associated with systemic inflammatory response syndrome and are characterized by activation of cytokine production.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

^ When ADP binds to platelets they are activated and aggregate leading to amplification of the coagulation response, thus Plavix interferes with this process.

Disease and clinical significance of thrombosis

.The best-known coagulation factor disorders are the hemophilias.^ Hemophilia A is associated with a deficiency in which coagulation factor: .
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Hemophilia A is a deficiency of coagulation factor VIII. It is the most commonly encountered hereditary based coagulation disorder.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Coagulation Disorders - Inherited Hemophilia B is a deficiency of coagulation factor IX. Found almost exclusively in males, its pattern of inheritance is sex-linked recessive.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

.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).^ Also assays for factors VIII, IX or XI, even with normal PTT .

^ Factor XI deficiency .

^ Deficiency in factor XI confers an injury-related bleeding tendency.

.Hemophilia A and B are X-linked recessive disorders, whereas Hemophilia C is much more rare autosomal recessive disorder most commonly seen in Ashkenazi Jews.^ The disorder is inherited in an autosomal recessive manner.

^ X linked recessive disorder; (gene is on X chromosome) .

^ This deficiency was identified in 1953 and originally termed hemophilia C. Factor XI deficiency is very common in Ashkenazic Jews and is inherited as an autosomal disorder with either homozygosity or compound heterozygosity.

.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.^ Algorithm for workup of hereditary bleeding disorders .

^ The disorder is inherited in an autosomal recessive manner.

^ Indications: familial bleeding disorder, after ruling out more common bleeding disorders such as von Willebrand disease .

.In this disease, there is a defect in von Willebrand factor (vWF), which mediates the binding of glycoprotein Ib (GPIb) to collagen.^ Willebrand disease (vWD) is due to inherited deficiency in von Willebrand factor (vWF).

^ Acquired von Willebrands disease .

^ Molecular basis of von Willebrands disease .

.This binding helps mediate the activation of platelets and formation of primary hemostasis.^ The primary mechanism of the coagulation pathway in vivo is tissue factor binding to activated factor VII (factor VIIa) .

^ When ADP binds to platelets they are activated and aggregate leading to amplification of the coagulation response, thus Plavix interferes with this process.

^ WF mediates platelet adhesion to endothelium (and formation of platelet plug) by serving as a bridge between them - binds to GPIb glycoprotein on platelet surface and to exposed subendothelium at site of endothelial injury .

.Bernard-Soulier syndrome is a defect or deficiency in GPIb.^ Disorders that are commonly associated with an increased bleeding time include thrombocytopenia, disseminated intravascular coagulation (DIC), Bernard-Soulier syndrome and Glanzmann thrombasthenia .

^ The importance of this interaction between vWF and the GPIb-GPIX-GPV complex of platelets is demonstrated by the inheritance of bleeding disorders caused by defects in three of the four proteins of the complex, the most common of which is Bernard-Soulier syndrome (also called giant platelet syndrome).

^ Coagulation Disorders - Platelet Disorders Bernard-Soulier Syndrome is a genetic platelet disorder characterized by abnormal platelet function tests, unusually large platelets, and a moderate decrease in platelet count.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

.GPIb, the receptor for vWF, can be defective and lead to lack of primary clot formation (primary hemostasis) and increased bleeding tendency.^ Factor XIII deficiency causes delayed bleeding after clot formation due to deficient crosslinking of the fibrin clot .

^ Two pathways lead to the formation of a fibrin clot: the intrinsic and extrinsic pathway.

^ However, treatment with APC also caused an increased bleeding tendency.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

.This is an autosomal recessive inherited disorder.^ The disorder is inherited in an autosomal recessive manner.

^ Coagulation Disorders - Inherited Hemophilia B is a deficiency of coagulation factor IX. Found almost exclusively in males, its pattern of inheritance is sex-linked recessive.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Homozygous deficiencies are rare, autosomal recessive; cause very long PTT but no bleeding disorders and no definite association with hypercoagulability .

Thrombasthenia of Glanzman and Naegeli (Glanzmann thrombasthenia) is extremely rare. .It is characterized by a defect in GPIIb/IIIa fibrinogen receptor complex.^ GPIIb-GPIIIa constitutes a receptor for vWF and fibrinogen, resulting in fibrinogen-induced platelet aggregation.

^ The GPIIb-GPIIIa complex is a member of the integrin family of cell-surface receptors that interact with the extracellular matrix .

^ The most commonly inherited platelet dysfunction is Glanzmann thrombasthenia which results from defects in the GPIIb protein of this complex.

.When GPIIb/IIIa receptor is dysfunctional, fibrinogen cannot cross-link platelets, which inhibits primary hemostasis.^ The most commonly inherited platelet dysfunction is Glanzmann thrombasthenia which results from defects in the GPIIb protein of this complex.

^ Bleeding disorders are often classified as defects of primary hemostasis (platelets, vessels, etc.

^ GPIIb-GPIIIa constitutes a receptor for vWF and fibrinogen, resulting in fibrinogen-induced platelet aggregation.

.This is an autosomal recessive inherited disorder.^ The disorder is inherited in an autosomal recessive manner.

^ Coagulation Disorders - Inherited Hemophilia B is a deficiency of coagulation factor IX. Found almost exclusively in males, its pattern of inheritance is sex-linked recessive.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Homozygous deficiencies are rare, autosomal recessive; cause very long PTT but no bleeding disorders and no definite association with hypercoagulability .

.In liver failure (acute and chronic forms), there is insufficient production of coagulation factors by the liver; this may increase bleeding risk.^ Factor VII: high levels or certain genetic polymorphisms are associated with increased risk for myocardial infarction, but not an independent risk factor; levels are associated with triglyceride and cholesterol levels .

^ Antibodies may be formed against bovine thrombin, also against bovine factors V, VII, X ( Archives 1998;122:887 ) .

^ Platelet Factor 3 catalyzes the coagulation reaction whereby a fibrin clot is formed, completing the seal.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

Deficiency of Vitamin K may also contribute to bleeding disorders because clotting factor maturation depends on Vitamin K.
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 Introduction to the Fundamentals of Coagulation Vessel size as related to time required for clotting to occur, amount of products used (platelets and clotting factors), and size of the corresponding bleed.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ The washer may eventually stop moving as a clot forms about it, and no additional information can be obtained on the coagulation process in the sample.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ These include: Coagulation proteins (blood clotting factors), which, if activated, will form a blood clot , and Serum proteins, which are left dispersed in liquid after the clot is formed.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

.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.^ Thromboelastography (TEG) characterizes the coagulation function by recording a tracing that represents blood clot creation and breakdown.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

^ Preoperatively, the assessment of the clotting function of the patient's blood is utilized as a predictor of risk of patient bleeding, allowing advanced preparation of blood components.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ During heart bypass surgery, the platelets of blood circulated in an extracorporeal circuit may become activated by contact with the materials present in the extracorporeal circuit.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

.This causes ischemia and often leads to ischemic necrosis of tissue.^ Fibrin deposition forms multiple microthrombi within small blood vessels, leading to tissue ischemia and necrosis in vital organs.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

^ Anticoagulant and fibrinolytic systems are activated simultaneously and overwhelmed, leading to disseminated microthrombi and tissue ischemia, consumption of platelets, coagulation factors and natural anticoagulants, and variable bleeding .

.Most cases of thrombosis are due to acquired extrinsic problems (surgery, cancer, immobility, obesity, economy class syndrome), but a small proportion of people harbor predisposing conditions known collectively as thrombophilia (e.g., antiphospholipid syndrome, factor V Leiden, and various other rarer genetic disorders).^ The management of thrombosis in the antiphospholipid-antibody syndrome.

^ THR-APCR is a hemostatic disorder due to defective degradation of factor Va by activated protein C. It is characterized by a poor anticoagulant response to activated protein C resulting in tendency to thrombosis Defects in F5 are a cause of susceptibility to Budd-Chiari syndrome [MIM:600880].
  • F5 Gene - GeneCards | FA5 Protein | FA5 Antibody 10 February 2010 13:34 UTC www.genecards.org [Source type: Academic]

^ Presence of second risk factor (genetic or acquired) is often necessary to produce thrombosis; acquired risk factors are malignancy, trauma, surgery, oral contraceptive use, estrogen replacement therapy, antiphospholipid antibody, heterozygosity for prothrombin G20210A, elevated serum homocysteine .

.Mutations in factor XII have been associated with an asymptomatic prolongation in the clotting time and possibly a tendency toward thrombophlebitis.^ The time required for a clot to form is prolonged.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Mutation in blood coagulation Factor V associated with resistance to activated protein C. Nature 1994 ; 369:64-67.

^ Measures clotting time from factor VII activation through fibrin formation (i.e.

Other mutations have been linked with a rare form of hereditary angioedema (type III).

Pharmacology

Procoagulants

.The use of adsorbent chemicals, such as zeolites, and other hemostatic agents are also used for use in sealing severe injuries quickly (such as in traumatic bleeding secondary to gunshot wounds).^ Coumarin drugs (based on the chemical benzopyrone), such as warfarin (trade name Coumadin®) as well as the glycosaminoglycans , heparin and heparan sulfate, are useful as anticoagulants.

^ The results of the prothrombin time are used in conjunction with other diagnostic tests, as well as the clinical picture of the patient, to determine any hemostatic abnormalities which may be present.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

.Thrombin and fibrin glue are used surgically to treat bleeding and to thrombose aneurysms.^ After use of bovine fibrin glue to achieve hemostasis, 1.7% develop a clinically significant inhibitor .

^ Some fibrin glue contains bovine thrombin and cryoprecipitate (containing human fibrinogen) .

.Desmopressin is used to improve platelet function by activating arginine vasopressin receptor 1A.^ Once platelets are irreversibly activated, they lose their ability to function further.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ The important role of ADP in platelet activation can be appreciated from the use of the ADP receptor antagonist, Plavix® (clopidogrel), in the control of thrombosis (see below).

^ Used to assess platelet function if a familiar bleeding disorder is suspected, but the PT, PTT, platelet count and von Willebrand tests are normal (which is unusual) .

.Coagulation factor concentrates are used to treat hemophilia, to reverse the effects of anticoagulants, and to treat bleeding in patients with impaired coagulation factor synthesis or increased consumption.^ Hemophilia A is associated with a deficiency in which coagulation factor: .
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Hemophilia A is a deficiency of coagulation factor VIII. It is the most commonly encountered hereditary based coagulation disorder.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Patients with this disorder present with significantly increased bleeding times.

.Prothrombin complex concentrate, cryoprecipitate and fresh frozen plasma are commonly-used coagulation factor products.^ Fresh plasma (FP) or fresh frozen plasma (FFP) is administered to replace the consumed coagulation factors.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

^ Elevated coagulation factor levels in plasma .

^ Treatment: recombinant factor VIIa, alternatively 10-20 ml fresh frozen plasma/kg, then 3 ml/kg every 12-24 hours as necessary; prothrombin complex concentrates may be used for serious bleeding .

.Recombinant activated human factor VII is increasingly popular in the treatment of major bleeding.^ The primary mechanism of the coagulation pathway in vivo is tissue factor binding to activated factor VII (factor VIIa) .

^ The activation of factor VII occurs through the action of thrombin or factor Xa.

^ Treatment with recombinant factor concentrates appears to lead to more inhibitors than plasma-derived concentrates .

.Tranexamic acid and aminocaproic acid inhibit fibrinolysis, and lead to a de facto reduced bleeding rate.^ Specimen: plasma in citrate tube, without epsilon-aminocaproic acid, aprotinin, heparin or other fibrinolysis inhibitors .

^ This leads to an impairment of plasminogen activation, thereby reducing the rate of fibrin clot dissolution (i.e.

.Before its withdrawal, aprotinin was used in some forms of major surgery to decrease bleeding risk and need for blood products.^ Need 50-80% of normal levels for surgical hemostasis with major surgery or major bleeding, 40% postoperatively, 30-50% to prevent minor bleeding .

^ Even though the PTT may be decreased by deficiencies of contact factors, this does not necessarily correlate with increased bleeding risk .

^ The Ivy method for determining the bleeding time involves the use of a blood pressure cuff (sphygmomanometer) which is placed on the forearm and inflated to 40mmHg.

Anticoagulants

.Anticoagulants and anti-platelet agents are amongst the most commonly used medicines.^ Choose the anticoagulant most commonly used for hemostasis testing: .
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ The table below lists the most commonly used blood collection tubes.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Warfarin, a dicumarol derivative, is one of the most popular oral anticoagulants used today.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

.Anti-platelet agents include aspirin, clopidogrel, dipyridamole and ticlopidine; the parenteral glycoprotein IIb/IIIa inhibitors are used during angioplasty.^ Aspirin is an important inhibitor of platelet activation.

^ Fujita M, Izutani W, Takahashi K. Protein C inhibitor as an anti-disseminated intravascular coagulation agent—mechanism and modification.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

^ WF binds glycoproteins Ib, IIb, and IIIa.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

.Of the anticoagulants, warfarin (and related coumarins) and heparin are the most commonly used.^ Anticoagulation Therapy - Heparin Therapy The use of heparin is prophylactic.
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Choose the anticoagulant most commonly used for hemostasis testing: .
  • Coagulation Information and Courses from MediaLab, Inc. 10 February 2010 13:34 UTC www.medialabinc.net [Source type: Academic]

^ Heparin is useful as an anticoagulant because it binds to, and activates, antithrombin III which then inhibits the serine proteases of the coagulation cascade.

.Warfarin affects the vitamin K-dependent clotting factors (II, VII, IX,X) , whereas heparin and related compounds increase the action of antithrombin on thrombin and factor Xa.^ The activation of factor VII occurs through the action of thrombin or factor Xa.

^ Factor Xa activates prothrombin (factor II) to thrombin (factor IIa).

^ Chromogenic factor X assays: used to monitor warfarin in the presence of a lupus anticoagulant, hirudin or argatroban (which prolong the PT and increase the INR), because warfarin decreases factor X (also factors II, VII, IX), and the chromogenic assay has no interference from lupus anticoagulant, hirudin or argatroban; patient plasma is added to a known amount of excess factor Xa with excess antithrombin; anticoagulant binds to antithrombin and inhibits factor Xa; residual factor Xa is inversely proportional to anticoagulant in plasma, cleaves a chromogenic substrate, and colored compound is detected by spectrophotometer; results reported in antifactor Xa units/mL .

.A newer class of drugs, the direct thrombin inhibitors, is under development; some members are already in clinical use (such as lepirudin).^ Nowak G. Clinical monitoring of hirudin and direct thrombin inhibitors.
  • Pharmacokinetics and Pharmacodynamics of the Direct Oral Thr... : Clinical Pharmacokinetics 10 February 2010 13:34 UTC adisonline.com [Source type: Academic]

^ The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans.
  • Pharmacokinetics and Pharmacodynamics of the Direct Oral Thr... : Clinical Pharmacokinetics 10 February 2010 13:34 UTC adisonline.com [Source type: Academic]

^ Coadministration of the oral direct thrombin inhibitor dabigatran etexilate and diclofenac has little impact on the pharmacokinetics of either drug [poster no.
  • Pharmacokinetics and Pharmacodynamics of the Direct Oral Thr... : Clinical Pharmacokinetics 10 February 2010 13:34 UTC adisonline.com [Source type: Academic]

.Also under development are other small molecular compounds that interfere directly with the enzymatic action of particular coagulation factors (e.g., rivaroxaban).^ V deficient plasma (dilutes the effect of other factor deficiencies or elevations) and add polybrene (neutralizes unfractionated heparin or low molecular weight heparin) .

^ Thus, the presence of D-dimers is evidence of the combined actions of thrombin, factor XIIIa, and plasmin and is specific for the combined presence of coagulation and fibrinolysis (physiologic or pathologic).
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

^ The bleeding time is affected (prolonged) by any defect in platelet function, by vascular disorders, and in von Willebrand disease but is not affected by other coagulation factors.

Coagulation factors

Coagulation factors and related substances
Number and/or name Function
I (fibrinogen) Forms clot (fibrin)
II (prothrombin) Its active form (IIa) activates I, V, VII, VIII, XI, XIII, protein C, platelets
Tissue factor Co-factor of VIIa (formerly known as factor III)
Calcium Required for coagulation factors to bind to phospholipid (formerly known as factor IV)
V (proaccelerin, labile factor) Co-factor of X with which it forms the prothrombinase complex
VI Unassigned – old name of Factor Va
VII (stable factor) Pro Convertin - Activates IX, X
VIII (Anti Hemophilic factor A) Co-factor of IX with which it forms the tenase complex
IX (Anti Hemophilic Factor B or Christmas factor) Activates X: forms tenase complex with factor VIII
X (Stuart-Prower factor) Activates II: forms prothrombinase complex with factor V
XI (plasma thromboplastin antecedent) Activates IX
XII (Hageman factor) Activates factor XI, VII and prekallikrein
XIII (fibrin-stabilizing factor) Crosslinks fibrin
von Willebrand factor Binds to VIII, mediates platelet adhesion
prekallikrein Activates XII and prekallikrein; cleaves HMWK
high-molecular-weight kininogen (HMWK) Supports reciprocal activation of XII, XI, and prekallikrein
fibronectin Mediates cell adhesion
antithrombin III Inhibits IIa, Xa, and other proteases;
heparin cofactor II Inhibits IIa, cofactor for heparin and dermatan sulfate ("minor antithrombin")
protein C Inactivates Va and VIIIa
protein S Cofactor for activated protein C (APC, inactive when bound to C4b-binding protein)
protein Z Mediates thrombin adhesion to phospholipids and stimulates degradation of factor X by ZPI
Protein Z-related protease inhibitor (ZPI) Degrades factors X (in presence of protein Z) and XI (independently)
plasminogen Converts to plasmin, lyses fibrin and other proteins
alpha 2-antiplasmin Inhibits plasmin
tissue plasminogen activator (tPA) Activates plasminogen
urokinase Activates plasminogen
plasminogen activator inhibitor-1 (PAI1) Inactivates tPA & urokinase (endothelial PAI)
plasminogen activator inhibitor-2 (PAI2) Inactivates tPA & urokinase (placental PAI)
cancer procoagulant Pathological factor X activator linked to thrombosis in cancer

History

Initial discoveries

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 conversion from fibrinogen to fibrin is the result of an enzymatic process, and labeled the hypothetical enzyme "thrombin" and its precursor "prothrombin".[2][3] Arthus discovered in 1890 that calcium was essential in coagulation.^ Measures rate of fibrin clot formation after addition of standard concentration of thrombin to citrated plasma; thrombin cleaves fibrinogen, releasing fibrinopeptides A and B, and converting fibrinogen to fibrin .

^ Also inhibits fibrinogen conversion to fibrin, causing prolongation of thrombin time and reptilase time .

^ Laboratory: presence of fibrin degradation products and D-dimers, decreased fibrinogen and plasminogen, prolonged thrombin time, PT and PTT .

[4][5] Platelets were identified in 1865, and their function was elucidated by Giulio Bizzozero in 1882.[6]
.The theory that thrombin is generated by the presence of tissue factor was consolidated by Paul Morawitz in 1905.[7] At this stage, it was known that thrombokinase/thromboplastin (factor III) is released by damaged tissues, reacting with prothrombin (II), which, together with calcium (IV), forms thrombin, which converts fibrinogen into fibrin (I).^ Factor IV: ionized calcium .

^ Factor II: prothrombin .

^ Factor II (prothrombin) deficiency .

[8]

Coagulation factors

.The remainder of the biochemical factors in the process of coagulation were largely discovered in the 20th century.^ FP/FFP administration is aimed at halting the consumption of platelets, coagulation factors, and inhibitors (e.g., AT, α 2 -macroglobulin) by arresting the ongoing hemorrhagic and coagulation processes.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

.A first clue as to the actual complexity of the system of coagulation was the discovery of proaccelerin (initially and later called Factor V) by Paul Owren (1905-1990) in 1947. He also postulated its function to be the generation of accelerin (Factor VI), which later turned out to be the activated form of V (or Va); hence, VI is not now in active use.^ Factor V: occasionally called labile factor or proaccelerin .

^ Normal coagulation factor activity usually means normal clotting function.

^ The clinician activates the Mix switch 20 when an initial mixing phase is to be included in the coagulation time test.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

[8]
.Factor VII (also known as serum prothrombin conversion accelerator or proconvertin, precipitated by barium sulfate) was discovered in a young female patient in 1949 and 1951 by different groups.^ Sometimes factor testing may be done on a patient with a known deficiency to monitor the factor deficiency and to evaluate the effectiveness of treatment.

^ Factor VII: occasionally called stable factor or proconvertin .

^ PT prolonged, PTT normal: deficiency of extrinsic pathway factor VII; occasionally due to deficiency of common pathway factors fibrinogen, prothrombin, factors V or X .

Factor VIII turned out to be deficient in the clinically recognised but etiologically elusive hemophilia A; it was identified in the 1950s and is alternatively called antihemophilic globulin due to its capability to correct hemophilia A.[8]
.Factor IX was discovered in 1952 in a young patient with hemophilia B named Stephen Christmas (1947-1993).^ Factor IX deficiency (hemophilia B) .

^ In patients with hemophilia A and factor VIII inhibitor, titer of inhibitor often increases after treatment with factor VIII containing products - this does not happen with autoimmune factor VIII inhibitor .

^ Develops in 2-12% of patients with severe hemophilia B after transfusion of factor IX containing products, less commonly with mild/moderate disease .

His deficiency was described by Dr. Rosemary Biggs and Professor R.G. MacFarlane in Oxford, UK. The factor is, hence, called Christmas Factor. .Christmas lived in Canada, and campaigned for blood transfusion safety until succumbing to transfusion-related AIDS at age 46. An alternative name for the factor is plasma thromboplastin component, given by an independent group in California.^ Factor IX: plasma thromboplastin component, Christmas factor .

^ Factor XI: occasionally called plasma thromboplastin antecedent .

^ Alternatively, fresh whole blood can be administered as a source of coagulation factors and inhibitors and platelets.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

[8]
.Hageman factor, now known as factor XII, was identified in 1955 in an asymptomatic patient with a prolonged bleeding time named of John Hageman.^ Factor XII: Hageman factor .

^ Patients with nephrotic syndrome may have decreased factors XI and XII .

^ Prolonged PTT remains prolonged after mixing study: indicates inhibitor; most common is lupus anticoagulant; also therapeutic anticoagulant; rarely due to inhibitors to factors IX, XI or XII .

Factor X, or Stuart-Prower factor, followed, in 1956. This protein was identified in a Ms. Audrey Prower of London, who had a lifelong bleeding tendency. In 1957, an American group identified the same factor in a Mr. Rufus Stuart. .Factors XI and XIII were identified in 1953 and 1961, respectively.^ Thrombin may also activate factor XI (part of intrinsic pathway), factors V, VIII, XIII, XI and platelets .

^ However, factor I (hypofibrinogenemia or dysfibrinogenemia), X, XI or XIII deficient heterozygotes may have bleeding symptoms .

[8]
.The view that the coagulation process is a "cascade" or "waterfall" was enunciated almost simultaneously by MacFarlane[9] in the UK and by Davie and Ratnoff[10] in the USA, respectively.^ FIG. 1 is perspective view of the simplified automatic coagulation time test instrument 10 that can advantageously be used in the practice of the present invention.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ In accordance with one simplified conceptual view, the whole blood coagulation process can be generally viewed as three activities: platelet adhesion, platelet aggregation, and formation of a fibrin clot.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ Several tests of coagulation are routinely utilized to assess the complicated cascade of events leading to blood clot formation and test for the presence of abnormalities or inhibitors of this process.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

Nomenclature

The usage of Roman numerals rather than eponyms or systematic names was agreed upon during annual conferences (starting in 1955) of hemostasis experts. In 1962, consensus was achieved on the numbering of factors I-XII.[11] This committee evolved into the present-day International Committee on Thrombosis and Hemostasis (ICTH). .Assignment of numerals ceased in 1963 after the naming of Factor XIII. The names Fletcher Factor and Fitzgerald Factor were given to further coagulation-related proteins, namely prekallikrein and high-molecular-weight kininogen, respectively.^ Includes factor XII (Hageman factor), prekallikrein (PK; Fletcher factor), high molecular weight kininogen (Williams, Flaujeac or Fitzgerald factor); some authors include factor XI .

^ Factor XII is activated by high molecular weight kininogen and prekallikrein .

^ Involves factors VIII, IX, XI, XII (Hageman factor), prekallikrein, high molecular weight kininogen .

[8]
Factors III and VI are unassigned, as thromboplastin was never identified, and actually turned out to consist of ten further factors, and accelerin was found to be activated Factor V.

Other species

.All mammals have an extremely closely related blood coagulation process, using a combined cellular and serine protease process.^ Replacement therapy is the mainstay for the treatment of DIC. 93 A dual approach of blood component therapy and heparin administration is used to halt intravascular coagulation.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

^ Blocks protein families ( see all 6 ): IPB000001 Kringle IPB000294 Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain IPB001254 Serine protease IPB001314 Chymotrypsin serine protease family (S1) signature IPB002383 Coagulation factor GLA domain signature .
  • F2 Gene - GeneCards | THRB Protein | THRB Antibody 10 February 2010 13:34 UTC www.genecards.org [Source type: Academic]

^ All results normal (considering ABO blood type) - unlikely to have vWD if no acute phase reaction, pregnancy, estrogen use, newborn .

In fact, it is possible for any mammalian coagulation factor to "cleave" its equivalent target in any other mammal. .The only nonmammalian animal known to use serine proteases for blood coagulation is the horseshoe crab.^ In healthy animals, the normal mechanisms of clot formation and fibrinolysis are well balanced so that coagulation and clot formation occur only on demand.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

^ Blood "coagulation" and "clotting" are used interchangeably herein unless specifically distinguished from one another.
  • BLOOD COAGULATION TEST CARTRIDGE, SYSTEM, AND METHOD - Patent application 10 February 2010 13:34 UTC www.faqs.org [Source type: Reference]

^ Replacement therapy is the mainstay for the treatment of DIC. 93 A dual approach of blood component therapy and heparin administration is used to halt intravascular coagulation.
  • Disseminated Intravascular Coagulation | Articles and Archives | Compendium 10 February 2010 13:34 UTC www.compendiumvet.com [Source type: Academic]

References

  1. ^ Furie B, Furie BC (2005). "Thrombus formation in vivo". J. Clin. Invest. 115 (12): 3355–62. doi:10.1172/JCI26987. PMID 16322780. http://www.jci.org/cgi/content/full/115/12/3355.  Full text at PMC: 1297262
  2. ^ Schmidt A (1872). "Neue Untersuchungen ueber die Fasserstoffesgerinnung". Pflüger's Archiv für die gesamte Physiologie 6: 413–538. doi:10.1007/BF01612263. 
  3. ^ Schmidt A. Zur Blutlehre. Leipzig: Vogel, 1892.
  4. ^ Arthus M, Pagès C (1890). "Nouvelle theorie chimique de la coagulation du sang". Arch Physiol Norm Pathol 5: 739–46. 
  5. ^ Shapiro SS (2003). "Treating thrombosis in the 21st century". N. Engl. J. Med. 349 (18): 1762–4. doi:10.1056/NEJMe038152. PMID 14585945. 
  6. ^ Brewer DB (2006). "Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet". Br. J. Haematol. 133 (3): 251–8. doi:10.1111/j.1365-2141.2006.06036.x. PMID 16643426. 
  7. ^ Morawitz P (1905). "Die Chemie der Blutgerinnung". Ergebn Physiol 4: 307–422. 
  8. ^ a b c d e f Giangrande PL (2003). "Six characters in search of an author: the history of the nomenclature of coagulation factors". Br. J. Haematol. 121 (5): 703–12. doi:10.1046/j.1365-2141.2003.04333.x. PMID 12780784. 
  9. ^ MacFarlane RG (1964). "An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier". Nature 202: 498–9. doi:10.1038/202498a0. PMID 14167839. 
  10. ^ Davie EW, Ratnoff OD (1964). "Waterfall sequence for intrinsic blood clotting". Science 145: 1310–2. doi:10.1126/science.145.3638.1310. PMID 14173416. 
  11. ^ Wright IS (1962). "The nomenclature of blood clotting factors". Can Med Assoc J 86: 373–4. PMID 14008442.  Full text at PMC: 1848865

External links

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