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 Clotting 2297733e@student.gla.ac.ukY our Intended Learning Outcomes Clotting • Outline the three phases of haemostasis. • Differentiate between the intrinsic and extrinsic clotting mechanisms. • Explain what an Activated Partial Thromboplastin Time (APTT) Assay is and its clinical relevance. • Design and interpret experiments based on the APTT Assay that investigate the effects of reagents on blood coagulation. • Outline the process of fibrinolysis. Clotting factors Factor Number Factor Name Activated by Vitamin K dependent? I Fibrinogen Thrombin (factor II) II Prothrombin Factor Xa/Va complex * III Tissue Thromboplastin/ Tissue Factor Endothelial injury IV Calcium V Labile factor Thrombin (factor II) VII Stable Factor Tissue Factor (Factor III) * VIII Anti-haemophillic Factor Thrombin (factor III) IX Christmas Factor Factor XIa * X Stuart-Prower Factor III and VIIa complex * and VIIIa and IXa complex XI Plasma Thromboplastin Factor XII Thrombin (factor II) XII Hageman factor Exposed collagen Plasma proteins: kallikrein, high molecular weight kininogen XIII Fibrin-Stabilising Factor Fibrin (factor II)Physiology • The vascular endothelium secrete: • NO and PGI2 – which inactivate platelets and prevents binding to the cell surface A proteoglycan called heparin sulphate, also bound to the • endothelial surface binds antithrombin III • Antithrombin III inactivates clotting factors, II, IX and X • Thrombomodulin, binds thrombin (factor II), which binds and activates protein C • Protein C degrades factor V and VIII Haemostasis • A five step process: HAEMOSTASIS: Vascular spasm Platelet plug formation SECONDARY Clot retraction HAEMOSTASIS: and repair Coagulation Fibrinolysis Haemostasis • Vascular spasm • Damaged endothelial cells secrete endothelin • Endothelin causes activation of smooth muscle contraction within the vascular wall • Decreases the surface area • Decreases blood leakage through the damaged tissue • Direct injury or contact with the smooth muscle causes myogenic mechanism ▯ contraction Activation of nociceptors leads to reflex • contraction of the smooth muscle • (enhancing vascular spasm)Haemostasis • PRIMARY HAEMOSTASIS: Platelet plug formation • Damage to the endothelium, smooth muscle cells, or collagen causes release of von Willebrand factor (VWF) • VWF release (and the absence of NO and PGI2) allows binding of platelets to the damage area via glycoprotein 1B This causes activation and degranulation of the platelet. They change shape (undergo • morphological change) and start releasing ADP, thromboxane A2 and serotonin • ADP and thromboxane A2 activate and cause aggregation of the platelets • Platelets bind to one another via the glycoprotein IIB/IIIA receptors on their cell surfaces and fibrin – AGGREGATION ▯ platelet plug Thromboxane A2 and serotonin bind the smooth muscle, and cause contraction (enhancing vascular • spasm)Coagulation cascade Coagulation cascade Intrinsic pathway Extrinsic pathway: 12 3 11 + 10 missing 7 9 = 8 10 10Coagulation cascade Common pathway: 10/5 (Xa-Va complex ) = 2x1 (factor II cleaves factor I) 10/5 = 2x1Other important mnemonics Activated partial thrombin time Remember, you Play Table Tennis INSIDE; and the APTT tells you about the functioning of the INTRINSIC pathway (normal 27-41 seconds) Prothrombin time You Play Tennis OUTSIDE; the PT tells you about the functional status of the EXTRINSIC pathway (normal: 12-14.8 seconds)Clot retraction and repair 1) Platelet contraction – activation of ACTIN and MYOSIN within the protein clot brings the edges of the clot together 2) PLATELET DERIVED GROWTH FACTOR triggers/stimulates repair of smooth muscle cells and collagen 3) VGEF , stimulates repair of the endotheliumFibrinolysis • Tissue injury leads to the release and activation of plasminogen activators, which convert plasminogen to active  plasmin. • Tissue plasminogen activator (tPA) • Urokinase (see fibrinolytics) • Plasmin breaks down and deactivates fibrin and fibrinogen → release of fibrin degradation products (e.g, D-dimers)  My recommendations for resources: https://www.osmosis.org/invite/L5Lhttps://www.youtube.com/c/NinjaNerdScience