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Learning Objectives: Understand how and why Hemostasis occurs Determinates of hemostasis Review the coagulation cascade and anticoagulation Understand fibrinolysis and anticoagulation http://www.mhhe.com/biosci/esp/2002_general/Esp/folder_structure/tr/m1/s7/trm1s7_3.ht m Normal hemostasis is a process that involves a cascade of events which either maintains the blood in a fluid state or induces the formation of a fibrin clot at a site of vascular injury. In pathologic conditions, when the hemostatic process is inappropriately activated, thrombosis occurs. Both hemostasis and thrombosis are processes that involve platelets, the endothelium (vessels) and the coagulation cascade. When there is endothelial injury with exposure of the basement membrane and extracellular matrix (ECM). The ECM is highly thrombogenic and provides a surface for platelets to adhere to. However, initially there is a reflex (neurogenic) vasoconstriction. This vasoconstriction is very brief and not sufficient for stopping the flow. This vasoconstriction is also augmented by endothelin, a potent vasoconstrictor secreted by the endothelium. Then platelet adhesion, activation and aggregation occur. Platelets are formed and released into the bloodstream by precursor cells called megakaryocytes that reside within the bone marrow. Platelets are anuclear and discoid; and they measure 1.5 3.0 m in diameter. They have several different types of granules, the contents of which are released upon activation of the platelet. Platelets contain - lysosomes containing acid hydrolases - Dense bodies containing ADP, ATP, serotonin and calcium - alpha granules containing fibrinogen, factor V, vitronectin, thrombospondin and von Willebrand factor. On the surface of platelets there are glycoprotein receptors to adhere to the endothelium via von Willebrand factor (vWF); Glycoprotein 1b adheres to vWF; vWF bridges platelets to collagen for Adhesion to the disrupted underlying ECM. Once adhered, platelet activation occurs with shape change and degranulation. Degranulation involves the release of granules. The components of the granules are as above and also calcium: require for Coagulation cascade; Dense body: ADP: causes platelet aggregation Aggregation is defined as the recruitment of more platelets to form the platelet plug. Another granule component is thromboxane A2 (TXA2)- augments aggregation and
COAGULATION CASCADE http://www. The end result is the formation of Thrombin (soluble) and subsequently Fibrin (insoluble). These two pathways overlap in the common pathway with the generation of factor X and ultimately fibrin.vasoconstriction (potent). The gpIIb-IIIa receptor on the surface of platelets links fibrinogen and platelets together and promotes aggregation and stabilization.swf The Coagulation cascade is a series of step-wise enzymatic conversions where inactive proenzymes are converted to activated enzymes (a). the intrinsic and extrinsic pathway. further promoting aggregation and leading to clotting). the next step is the coagulation cascade to form a fibrin clot.org/hematology/Coagulation. WHAT WOULD HAPPEN IF THE PLATLETS COULDN T ADHERE TO THE UNDERLYING BASEMENT MEMBRANE? WHAT CLINICAL FEATURES MAY THIS PATIENTS DEMONSTRATE? Clotting can't be initiated (they won't aggregate and degranulate. This pathway is inhibited by Aspirin. The intrinsic pathway begins in the blood utilizing the major clotting factors. There are two arms to the coagulation cascade. activation and aggregation occurs.hopkinsmedicine. The platelets are adherent to each other via glycoprotein IIb-IIIa complex. . TXA2 is produced via the arachadonic acid pathway via platelet phospholipases and COX pathway. Patients may demonstrate hemophilia (they may bleed excessively). After this process of platelet adherence. The Extrinsic pathway begins at the site of injury usually and begins with the generation of tissue factor by the endothelium. The fibrin clot is assembled on a platelet phospholipid membrane via shape change of the platelets and the complex is held together by Calcium.
pl) Va IIa (Thrombin) XIIIa crosslinks Fibrinogen Fibrin Common Pathway . pl) VIIa : Tissue Factor Ca++ VIII a Xa (Ca++.Intrinsic Pathway Negatively Charged Surface Kallekrein XIIa XIa Extrinsic Pathway IXa (Ca++.
Other Vitamin K dependant factors are Factors 2. thereby preventing coagulation. Plasmin is the main contributor to the process and causes the splitting of fibrin into fibrin split products. It is Vitamin K dependant. Tissue factor pathway inhibitor is produced by the endothelium and inhibits Tissue Factor. Fibrinolysis is a process that occurs simultaneously with thrombosis and results in clot lysis. a blood clot can't be formed. This step depends on platelets adhering to exposed collagen and platelet degranulation (releasing serotonin. Activated Protein C cleaves Factors Va and VIIIa. and ADP). Protein C is also an anticoagulant and is activated by thrombin via thrombomodulin and Protein S. Factor IXa and Xa thereby preventing the formation of a fibrin clot. Antithrombin III inactivates thrombin. Platelets have Factor XII which activates Factor XI. Prostacyclin I2 is produced by the endothelium and prevents platelet aggregation. Plasmin is activated by Urokinase-like Plasminogen activator which is present in plasma and Tissue-type Plasmingen activator (tPA). Without Factor VIII. WILL THESE PATIENTS BE ABLE TO FORM A PLATLET PLUG? HOW WILL THERE DISORDER AFFECT THERE ABILITY TO CLOT? Factor VIII converts factor X to Factor Xa (when in the presence of Ca++ and phospholipids). ANTICOAGULATION AND FIBRINOLYSIS Our body provides some natural anticoagulation in order to prevent a fibrin clot from forming. which ultimately forms a dense aggregation that catches rbc's and platelets and creates a blood clot. TXA. and active when attached to fibrin (so at the site of the clot) . There is also heparin-like molecules produced by endothelial cells activate antithrombin III. This is mainly in the form of Antithrombin III. which generates fibrin. 7.HEMOPHILIA A IS A RARE INHERITED BLEEDING DISORDER CHARACTERIZED BY A DEFECT IN CLOTTING FACTOR VIII. which activates (?) Factor X. tPA is synthesized by endothelial cells. Factor X is important for the activation of prothrombin activator which generates thrombin. both of which are produced by the endothelium. but a platelet plug can form. Other anticoagulants are tissue factor pathway inhibitor and prostacyclin I2. 9 and 10. These patients will be able to form a platelet plug.
a protein complex that participates in the formation of "bridges" between platelets by binding fibrinogen and vWF. BLEEDING DISORDERS von Willebrand disease: frequency of 1% . excessive bleeding from wounds. This glycoprotein is a receptor for vWF and is essential for normal platelet adhesion to the extracellular matrix. chunks of clot may break off and resettle at a different part of the body. menorrhagia. Because vWF stabilizes factor VIII by binding to it. If you just treated them with a fibrolytic. Bernard-Soulier disease: autosomal recessive disorder caused by an inherited deficiency of the platelet membrane glycoprotein complex Ib-IX. it is characterized by spontaneous bleeding from mucous membranes.IN A PATIENT WHO HAS A CLOTTING DEFECT CHARACTERIZED BY THE INCREASED TENDENCY TO CLOT WOULD YOU WANT TO ANTICOAGULATE THEM OR TREAT THEN WITH A FIBRINOLYTIC? You would want to anticoagulate them. interfering with blood flow. Glanzmann thrombasthenia: autosomal recessive disorder caused by the failure of platelets to aggregate owing to a deficiency or dysfunction of glycoprotein IIb-IIIa. Autosomal dominant disorder. . a deficiency of vWF gives rise to a secondary decrease in factor VIII levels.
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