Blood Coagulation PDF

Blood Coagulation Fadi Khasawneh, Ph.D. (361) 221-0755 [email protected] 1 Learning Outcomes At the end of these lectures, you should be able to: Explain hemostasis, the physiology of coagulation fac...

Blood Coagulation Fadi Khasawneh, Ph.D. (361) 221-0755 [email protected] 1 Learning Outcomes At the end of these lectures, you should be able to: Explain hemostasis, the physiology of coagulation factors, thrombolysis and physiological prevention of coagulation Explain the pathophysiological relevance of coagulation abnormalities, and thrombosis development. List the body’s endogenous inhibitors of coagulation. Describe how coagulation is measured both in vitro and in vivo Identify the theoretical strategies for producing anticoagulant, and thrombolytic agents 2 1  Clot Formation √ 3 The Role of the Coagulation Factors in Fibrin Formation Factor Name - Zymogens: Proenzymes: e.g. factor X I Fibrinogen II Prothrombin Infanta Thrombinwhencleared III Tissue factor or thromboplastin - Proteases: IV Calcium notzymogen Activated enzymes: e.g. factor Xa V Proaccelerin (Labile factor) VII Proconvertin (Stable factor) Elif - Factor VI? VIII Antihemophilic factor A, Antihemophilic globulin a IX Antihemophilic factor B, Plasma thromboplastin Old name for factor Va component, Christmas factor X Stuart-Prower factor Factors2 II, VII,9 10 7 IX, and X contain 1972glutamate Giamodification theseundergo amino acids that are converted to  - mate XI Plasma thromboplastin antecedent, Hemophilia C, Rosenthal syndrome carboxyglutamate (Gla) residues during a XII Hageman factor biosynthesis in the liver. The Gla residues bind Ca2+ and are necessary for the XIII Fibrin stabilizing factor, Laki-Lorand factor coagulant activities of these proteins. PL Platelet Phospholipid 4 Don'tneed to memorise all clottingfactors knowones in Red 2  Factoria Pick 5 up lectureOct8 6 10 Coagulation Cascade - Coagulation is also known as secondary hemostasis, and it involves two pathways: Contact with surfaces (e.g. subendothelial cells) activates Contact Activation pathway (Intrinsic). This pathway does not require external coagulation factors. Tissue Factor (TF) produced by vascular injury activates the Tissue Factor pathway (Extrinsic). This pathway requires extrinsic factors. 6 3  Coagulation Cascade 7 Coagulation Cascade (2) The intrinsic pathway is activated in vitro by factor XII, while the extrinsic pathway is initiated in vivo by tissue factor. Although these two pathways converge at the activation of factor X, there also exists much interconnection between the two pathways. Because factor VII (activated by the extrinsic pathway) can proteolytically activate factor IX (in the intrinsic pathway), the extrinsic pathway is regarded as the primary pathway for the initiation of coagulation in vivo. Both the intrinsic and extrinsic coagulation pathways lead to the activation of factor X. In an important reaction that requires factor V, activated factor X proteolytically cleaves prothrombin (factor II) to thrombin (factor IIa). Thrombin is a multifunctional enzyme that acts in several important ways: (1) it converts the soluble plasma protein fibrinogen into fibrin, which then forms long, insoluble polymer fibers; (2) it activates factor XIII, which crosslinks the fibrin polymers into a highly stable meshwork or clot; and (3) it strongly activates platelets. 8 4  Coagulation Pathways XII XI Va Xa Thrombin Platelet Activation Fibrinogen, FIBRIN Jean AMIRAL – May 2007 9 Coagulation Factor Activation on Phospholipid Surfaces Surface catalysis is critical for a number of the activation reactions in the coagulation cascade. Each activation reaction consists of an enzyme (e.g., factor IXa), a substrate (e.g., factor X), and a cofactor or reaction accelerator (e.g., factor VIIIa), all of which are assembled on the phospholipid surface of activated platelets. Ca2+ allows the enzyme and substrate to adopt the proper conformation. In the example shown, factor VIIIa and Ca2+ act as cofactors in the factor IXa-mediated cleavage of factor X to factor Xa. Factor Va and Ca2+ then act as cofactors in the factor Xa-mediated cleavage of prothrombin to thrombin. 10 5  Coagulation Cascade Contact Vascular injury 11 (factor I) Fibrin forms the mesh for clot formation 12 6  Clot Formation At the end, the clot will solidify 13 How Coagulation is Prevented in the Body? Protein C and the cofactor protein S – Activated to APC (or PCa) by thrombin – APC cleaves and thereby inhibits Va and VIIIa Endothelium – NO  vasodilation, reduce platelet aggregation ?? – PGI2 (made by endothelial cells) reduces platelet aggregation – Heparans (made by endothelial cells) prevents coagulation Antithrombin III – A plasma protein that inactivates thrombin Plasmin (lysis) – Palsminogen converted to plasmin by tissue plasminogen activator (tPA) – Plasmin  lyses fibrin 14 7  Measures of Coagulation PT (Prothrombin Time): – In vitro test – Indicator of extrinsic and common pathways – In this test, the patient's citrated plasma is added to a crude preparation of tissue factor and phospholipids (called thromboplastin), and the time for formation of a fibrin clot is measured – Expressed as Prothrombin Ratio (PR): ratio of patient PT to normal control PT (pooled plasma from normal human). – 12 – 15 seconds – Mainly monitor effects of warfarin, liver abnormalities (prolong) 15 Coagulation Cascade 16 8  Measures of Coagulation INR (International Normalized Ratio) – Worldwide Standardized measure of PT – PT in patient’s sample compared to normal sample, normalized for the International Sensitivity Index (ISI) of the laboratory's thromboplastin preparation compared to the World Health Organization's reference thromboplastin preparation. – 0.8 – 1.2 INR = (PTpatient/PTnormal/control)ISI aPTT (activated Partial Thromboplastin Time) – Indicator of intrinsic and common pathways – Time taken for clotting of citrated plasma after addition of Ca++, phospholipid and kaolin or silica. – Mainly monitor effects of heparin, hemophilia (prolonged) – 24 – 38 seconds Bleeding Time – In vivo – Indicator of blood vessels and platelet function – Small incision made on forearm and blood wiped every 30 seconds with a blotting paper. Should clot within 8-10 minutes 17 Coagulation Disorders 18 9 19 Common Causes of Thrombosis Stasis (lack of blood movement) Secondary to venous thrombosis (VT) Atherosclerosis Atrial fibrillation Smoking, diabetes, contraceptive pills 20 10  Angina, Myocardial Infarction 21 Deep Vein Thrombosis (DVT) Occurs in deep vein Due to stasis of blood – Long-term immobility – Surgery Leads to embolism Emboli: a fragment of the thrombi that can travel in blood vessel  known as thromboembolism Deep veins 22 11  Pulmonary Embolism Caused mainly by blockade of an artery or one of its branches in the lung by a blood clot (due to DVT), clumped tumor cells, or air bubbles. How embolus from periphery gets into the lung? 23 Hemophilia Hemophilia A – Most common hemophilia – Deficiency or reduced activity of clotting factor VIII  hypocoagulability – Defective gene located on X chromosome – Currently treated with infusions of factor VIII Hemophilia B (“Christmas disease”) – Deficiency or reduced clotting factor IX – Defective gene located on X chromosome Von Willebrand's Disease – Very common – Deficiency of von Willebrand Factor (vWF) – vWF normally involved in platelet adhesion 24 12  Pharmacological Intervention Why should we interfere with blood coagulation? How can we do it? 25 Clot Formation 26 13  Blood Coagulation Modulators Antiplatelet Drugs – prevent platelet activation Anticoagulants – prevent fibrin formation Thrombolytics – cause fibrinolysis Procoagulants – enhance coagulation 27 Any questions? The End 28 14