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Hemostasis. The procedure by which draining is arrested.It is a progression of physiological and biochemical occasions which end in the arrangement of an insoluble fibrin clotHemostatic Sequence:Interaction between vessel divider and plateletsBlood coagulationFibrinolysis. Hemostatic Component Interactions.
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Hemostasis/Coagulation Gregory S. Travlos, DVM, DACVP National Institute of Environmental Health Sciences Research Triangle Park, NC 27709 919-541-0653 Travlos@niehs.nih.gov

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Hemostasis The procedure by which draining is captured. It is a progression of physiological and biochemical occasions which end in the arrangement of an insoluble fibrin clump Hemostatic Sequence: Interaction between vessel divider and platelets Blood coagulation Fibrinolysis

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Hemostatic Component Interactions Thompson & Harker, 1983

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Blood Vessels Intact endothelium frames a thromboresistant surface Required for the free stream of blood; does not advance platelet adherence or enact coagulation Passive instruments: Endothelial glycocalyx (negative charge - repulses like-charged particles, e.g.,platelets). Nearness of a 2-macroglobulin at cell surface (protease inhibitor). Dynamic systems: Endothelial cells expel platelet accumulation promoters from flow (e.g., PGF 1 , bradykinin, serotonin, adenine nucleotides). Emission of PGI 2 - intense inhibitor of platelet collection, initiates vasodilation. Proteoglycan grid of the vessel divider impacts thrombogenicity . Heparin, heparan sulfate and dermatan sulfate have anticoagulant movement; different glycosaminoglycans and hyaluronic corrosive don\'t. Veins have the most astounding fixation.

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Endothelium Besides their part in thromboresistance, endothelial cells have extra engineered capacities. Produce Von Willebrand\'s variable Absorbed by platelets; required for adherence to collagen Produce plasminogen activator (tPA) Mediates fibinolysis Injured cells discharge thromboplastin (element III) Activates the "outward" coagulation course Others (e.g., sort III and IV collagens, elastin, fibronectin, and so forth.)

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Blood Vessel Structure Thompson & Harker, 1983

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Platelets Adhere to uncovered collagen (platelet plug) Occurs in seconds; can control drain of moment wounds Secretory capacities; go betweens of coagulation and fibrinolysis Releases ADP; sticky and advances platelet adherence ADP initiates phospholipase A2 which fortifies thromboxane A2 combination Release of film fibrinogen, element V, component VIII and calcium Release of layer platelet phospholipid.

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microtublules OCS granules mitochodrion Platelet - TEM

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Ultrastructural and Functional Platelet Anatomy

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Platelets - cont. The part of platelets in hemostasis is as vital as the coagulation component. Thrombocytopenia, thrombasthenia or thromobopathia - weaken hemostasis Thrombocytosis or thrombocythemia - may impede, however for the most part advances coagulating (inclines to thrombosis). Platelets advance hemostasis by: Release of ADP and different agonists; advances adherence. ADP enacts phospholipase A 2 which fortifies thromboxane A 2 amalgamation Thromboxane A2 - empowers vasoconstriction and platelet conglomeration Release of film fibrinogen, variable V, element VIII and calcium Components of coagulation limited at site of damage Release of layer platelet phospholipid. Quickens the "inborn" and "common"pathways of coagulation

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Prostaglandin Metabolism Harlan & Harker, 1981

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Hemostatic Platelet Functions Thompson & Harker, 1983

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Platelet Response When a vessel is harmed or disjoined a brief, nearby, reflex vasoconstriction happens. Lessens blood stream at site. Kept up by vasoactive mixes (platelets, encompassing tissues). Passing platelets hold fast to uncovered collagen. Happens in seconds; at first follow in a solitary layer and get to be initiated. Extreme damage - collagen serves as an intense platelet activator. Less extreme harm - vWF and fibrinogen turn into the significant activators. The followed platelets experience a conformational change. From discoid to improvement of long filopodia. Actuation of GP receptors for fibrinogen and/or vWF (GPIIb/IIIa and GPIb/IX/V).

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Structure of the GPIb-IX-V receptor Tablin, 2000

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Platelet Response to Agonists Platelets - unstimulated Addition of ADP (mellow incitement) Addition of thrombin (solid incitement ) Characteristic discoid Shape change (stretching and bows) and filaform process arrangement (bolts) Increased spreading, filaform process augmentation (bolts) and total development (stars) SEM plates; Gentry, 2000

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Platelet Response cont. Enacted platelets discharge their a - granule and thick body substance initiating extra platelet enrollment. Thick granules - ADP, serotonin and epinephrine. alpha-granules - fibrinogen (and vWF in human and pig). Combination and arrival of PAF and TxA 2 . The agonists quicken the advancement of an irreversible platelet total (platelet plug). Reversible v. irreversible reactions. Thrombocytes of winged animals and reptiles don\'t react to ADP. Serotonin and epinephrine: Serotonin - shape change (rodent, g. pig and pooch); total (human, rabbit, bovine, horse, pig, sheep and feline). Epinephrine - just human, primate, feline and stallion platelets seem responsive. Either serotonin or epinephrine consolidated with another agonist - solid reaction in all species.

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Platelet Response cont. More about agonists. Platelet Activating Factor (PAF). Dairy animals, horse, sheep, primate, pooch, g. pig and rabbit react to PAF. Human less touchy and rodent and mouse are uncaring to this agonist. Thromboxane A 2 (TxA 2 ). Solid agonist - human, g. pig and rabbit. Powerless agonist - horse. Inhumane - rodent, cow, pig. All things considered, nonetheless, platelets are presented to different agonists from platelets and different cells (e.g., red cells, ADP; white cells, PAF).

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Platelet Aggregation to Thrombin Harlan & Harker, 1981

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Hemostatic Plug Formation Baumgartner & Muggli, 1980

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Coagulation System Consists of a falling arrangement of proteins Primarily beginning from liver (with the exception of variable III) Circulate in latent structure (aside from, potentially, figure VII) System incorporates: Enzymatic elements Non-enzymatic elements Tissue thromboplastin (element III) Calcium (element IV) Platelet phospholipid (PF 3) - basic segment; quickens element actuation Anticoagulant calculates The coagulation framework comprises of three pathways (inborn, extraneous and regular)

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Procoagulant Factors

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Coagulation Systems - cont. Enzymatic variables Circulate as non-dynamic zymogens - must be actuated to work Activated enzymatic components are not expended amid thickening (aside from elements II and XIII) Partial inadequacy brings about halfway loss of coagulating capacity Activated enzymatic elements hindered by antithrombin III (complexed with heparin) and some alpha-2-glycoproteins Enzymatic elements: XI and XII (contact elements) II, VII, IX and X (vitamin K-subordinate elements) XIII (cluster balancing out element or fibrin-settling element)

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Coagulation Systems - cont. Non-enzymatic variables Originate from liver however connect with platelet layers (likewise found in plasma) Normal thickening with halfway insufficiency; verging on aggregate nonattendance expected to influence hemostasis or coagulating Clotting devours these elements - truant in serum No known regular inhibitors Considered receptive proteins - expanded amid provocative and neoplastic procedures (aside from element III) Non-enzymatic elements: Fibrinogen (element I) Factor V Factor VIII:C (connected with Von Willebrand\'s element)

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Coagulation Cascade Interactions

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obviously, he does But, his feathered buddy does not Does this turkey have component XII?

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Coagulation Systems - cont. Clump adjustment Fibrin balancing out (element XIII) shapes fibrin strand cross-joins. Integrated by monocytes and hepatocytes. Zymogen is enacted by thrombin (in addition to calcium). A little measure of component XIII (2 - 10%) is sufficient for hemostasis. Changes over dissolvable fibrin monomers (flimsy) to a fibrin polymer (stable). Lead, silver, zinc and snake venoms are known inhibitors.

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Coagulation Inhibitors The action of coagulation framework must be weakened. Various inhibitors are found in blood. Coagulation is controlled by three sorts of activities. Restraint of changing over compounds (e.g., AT III, C1 esterase inhibitor, a 2 - macroglobulin, a 2 - antiplasmin, a 1 - antitrypsin, HC-II). Follow up on one or a greater amount of the changing over chemicals (actuated components). AT III-heparin pathway: significant framework - 80% of the thrombin inhibitory activity in plasma. Obliteration of protein cofactors (e.g., TM-PC-PS framework). TM-PC-PS framework corrupts cofactors V & VIII:C, restraining prothrombinase and tenase buildings, individually. Blocking receptor accessibility required for complex arrangement (e.g., Tissue element pathway inhibitor (TFPI) and annexin V).

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AT III Th H AT III Proposed Mechanism of AT III-Heparin System Lysine destinations H Serine site Arginine site Heparin Thrombin Antithrombin III Th

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Proposed Mechanism of Thrombomodulin, Protein C and Protein S (TM-PC-PS) System F-Xa Prothrombin Activated platelet F-Va PS Thrombin x Ca ++ Ca ++ Protein C Activated Protein C Thrombin Thrombomodulin

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Proposed Mechanism of Tissue Factor Pathway Inhibitor (TFPI) Activity F-Xa F-Xa TFPI F-Xa TFPI Tissue variable F-VIIa Endothelium

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Anticoagulant Factors

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Fibrinolytic System Method for evacuating clusters and support of a patent vascular framework and fibrin saved amid aggravation and tissue damage must be expelled. Plasmin (serine protease) fundamentally in charge of fibrinolysis. Created in the liver and kidney, it flows in an idle structure (plasminogen). Activators: tissue plasminogen activator (tPA), cytokinases-urokinases (pee, CSF, tears, salivation, milk, bile, synovial, prostatic and amniotic liquids), erythrocyte erythrokinase, neutropil activator and component XII-subordinate activator (XII-prekallikrien-hagem

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