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Coagulation cascade & Fibrinolytic Mechanisms.PPTX
- 1. Coagulation cascade & Fibrinolytic Mechanisms Dr Tahir Hussain Soomro Assistant Professor of Cardiology GMMMC Sukkur
- 2. • Coagulation is the formation of a blood clot, and is essential to haemostasis. • Haemostasis is the body’s physiological response to damaged blood vessels, to slow down, minimize and eventually cease the bleeding. • The coagulation process is characterized by a cascade of events which lead to the formation of a blood clot. Proteins called clotting factors initiate reactions which activate more clotting factors
- 4. How bleeding is arrested? •When blood vessels are injured mechanically, chemically or physically, the first step is vasoconstriction platelets will adhere to endothelial cell membrane and forms the primary hemostatic plug and stop blood leakage from injured site. •Simultaneously activate the coagulation cascade (i.e extrinsic, intrinsic and common pathway) and form the fibrin mesh in clot which establish the plug and form secondary haemostatic plug (which is stable and irreversible) and arrest bleeding permanently.
- 6. Extrinsic Pathway • Agents extrinsic to blood and are widely distributed to all body tissues including vascular endothelium. • Damage to blood vessel + factor VII exits the circulation into surrounding tissues • Tissue factor (factor III) is released by damaged cells outside the circulation • Factor VII + factor III TF form TF-VIIa complex activates X into its active form, Xa. • Xa In conjunction with factor Va, this triggers the formation of thrombin. • Note that the extrinsic pathway is believed to be responsible for the initial generation of activated Factor X (Factor Xa), whereas the intrinsic pathway amplifies its production
- 7. Intrinsic Pathway •The intrinsic pathway is the longer and more intricate pathway: •Factor XII is activated once it comes into contact with negatively charged collagen on the damaged endothelium •e.g factors XIIa, XIa, Kallikrein
- 11. Plasminogen • Is a plasma glycoprotein i.e produced from liver • Plasminogen gene is located on chromosome#6 and having 19 exons • Is activated by specific enzyme called plasminogen activator • It degrades the fibrin into FDPs and D-Dimers • Lyse factor V and VIII
- 12. Mechanism of action of Thrombolytics / Fibrinolytics They all have common MOA By stimulation of plasminogen activation via converting Plasminogen (Pro- Enzyme) to plasmin (Active Enzyme) lysis of insoluble fibrin clots into soluble derivatives.
- 16. Extrinsic factors include 1.t-PA (tissue type plasminogen activator): • is a protein (serine protease) found on endothelial cells, the cells that line the blood vessels. • produced using recombinant biotechnology techniques therefore referred to as recombinant tissue plasminogen activator (rtPA). • Include alteplase, reteplase, and tenecteplase. • Has high affinity for fibrin • Gene is located at chromosome#8 and consist of 14 Exons • Physical exercise increases the t-PA
- 17. 2. u-PA (Urokinase plasminogen activator) •is a serine protease present in humans and other animals, was discovered in 1947. •Urokinase was originally isolated from human urine, and it is also present in the blood and in the extracellular matrix of many tissues. •3 types identified: 1. Single chain pro-urokinase 2. HMW urokinase 3. LMW urokinase
- 18. 3. Streptokinase • was discovered in 1933. Derived from beta-hemolytic streptococci • SK is non enzymatic polypeptide, which forms a stable 1:1 complex with plasminogen • Is a thrombolytic activating plasminogen by nonenzymatic mech. • It is used to break down clots in cases of STE Myocardial Infarction, pulmonary embolism, and arterial thromboembolism. • It is given by injection in vein. • Side effects include nausea, bleeding, low bp, and allergic reactions. • A second use in a person's lifetime is not recommended. While no harm has been found with use in pregnancy • It is no longer commercially available in the United States
- 19. Regulation of Clotting • To prevent excessive clotting and subsequent disease,mediators including Protein C and Protein S provide -ve feedback on the clotting cascade. • Protein C is activated following contact by thrombomodulin, which is itself activated by thrombin. Along with co-factors including protein S, activated protein C degrades Va and VIIIa, thus slowing the rate of clotting. • Calcium++ ions play a role through their interaction with an activation of several clotting factors. Low levels of calcium are therefore inhibitory to the clotting cascade. • Antithrombin is a protease inhibitor that degrades thrombin, IXa, Xa, XIa and XIIa. It is constantly active, but can be activated further by a group of common anticoagulants known as heparins.
- 20. How the blood is kept in fluid state in circulation? • Endothelial cell produces NO, PGI, ADPase act as anti-platelet agents. • ADP produced by platelets favors binding to endothelial cells but ADPase inactivates or digest ADP • Healthy endothelium does not tolerate activated clotting factors. • When anti-thrombin III binds with heparin sulfate. AT-III is activated and inhibit thrombin molecule and activated clotting IXa, Xa. • Normally thrombin helps in coagulation but when binds with thrombomodulin it modulates the function of thrombin which activates protein-C • Activated protein C digest Va and VIIIa • Endothelial cells not only prevents platelet aggregation but also inhibit proteins that involved in coagulation. They produce t-PA plasmin cleaves fibrin into FDPs which are then removed by macrophages and eosinophils • By this entire process the blood is kept in fluid state.