Hemostais AMIR SAMADIAN M.D DEPARTMENT OF PHYSIOLOGY AUTUMN 2021 Learning objectives 1.Primary hemostasis & thrombocytes 2.Secondary hemostasis – Hemocoagulation (protein vs cell model) 3.Regulation of hemostasis 4.Basic Coagulation tests 5.Circulation and hemostasis 6. Hemostasis •Integrity of the blood vessel is necessary to carry blood to tissue. • Damage to wall is repaired by hemostasis (by formation of thrombus (clot) at injury site) • Prevention of blood loss require the interaction of blood vessels, platelets , coagulation factors , fibrinolytic agents 4 steps of Hemostasis • Hemostasis occurs in 4 steps : 1. Vascular phase (transiant vasoconstriction) 2. Platelet phase (Primary hemostasis) 3.Coagulation phase (Secondary hemostasis) 4.Fibrinolytic phase Hemostasis following injury to the vessel Platelets Platelet structure Primary hemostasis – 4 steps (results in formation of weak platelet plug) Transient vasoconstriction of damaged vessel i.Mediated by reflex neural stimulation and endothelin release from endothelial cells Platelet adhesion to the surface of disrupted vessel i.Von willbrand factor (vWF) binds exposed subendothelial collagen (SEC) ii.Platelets bind vWF using GP1b iii.Note : vWF is drived from Weibel-Palade bodies of endothelial cells and a-granules of plateles Platelet degranulation •Adhesion induces shape change in platelets and degranulation with release of multiple mediators ; i.ADP is released from platelet dense granules ; promotes exposure of GPIIb/IIIa receptors on platelets ii.TXA2 is synthesized by platelet cyclooxygenase (COX) and released ; promotes platelet aggregation Platelet aggregation i.Platelets aggregate at the site of injury via GPIIb/IIIa using fibrinogen (from plasma) as a linking molecule, results in formation of platelet plug ii.Platelet plug is weak ; coagulation cascade (secondary hemostasis) stabilizes it Platelet Adhesion, Activation & Agreggation (3A) Secondary hemostasis Secondary hemostasis : stabilizes the platelet plug and is mediated by the coagulation cascade § coagulation cascade generates thrombin (FIIa) which converts Fibrinogen in the platelet plug to fibrin §Fibrin is then cross-linked, yielding a stable platelet-fibrin thrombus. Ø Factors of the coagulation cascade are produced in the liver in an inactive state Activation requires : 1. Exposure to an activating substance Tissue Factor (TF) à F VII (extrinsic pathway) Subendothelial collagen (SEC) à F XII (intrinsic Pathway) 2. Phospholipid surface of the platelets 3. Calcium (derived from platelet dense granules) Coagulation cascade made easy (protein based model) Cell-model theory of coagulation https://www.youtube.com/watch?v=T4MG7bzQ2NI&t=58s&ab_channel=ThePhysiologyChannel Vitamin K dependent Coagulation factors Fibrinolytic phase a. Tissue plasminogen activator (tPA) activates plasminogen to release the enzyme plasmin. Plasmin à 1.Cleaves insoluble fibrin monomers and fibrinogen into fibrinogen degradation products (FDPs) (note : Fragments of cross-linked insoluble fibrin monomers are called d-dimers.) 2.Degrades factors V and VIII, and fibrinogen 3.3. α2-Antiplasmin, which is synthesized in the liver, inactivates plasmin. Fibrinolytics Coagulation tests (PT,INR,PTT) Platelet test antithrombotics Antiplatelets We influence function of thrombocytes, not number of throbocytes! 1.Inhibitors of cyklooxygenase/inhibitors of thromboxane A2 synthesis or antagonists of the receptors 2. Inhibitors of ADP receptors (P2Y12) 3.Antagonists of protease-activated receptors (PAR-1) 4.Antagonists of surface glycoproteins (GP IIb/IIa) 5.Blockage of serotonin pathway 6.Other mechanisms harr17_c112f003 Anticoagulant Role of Endothelial cells in hemostasis Endothelial cells prevent thrombosis by several mechanism ; 1.Block exposure of to Subendothelial collagen (SEC) and Tissue Factor (TF) 2.Produce Prostacyclin (PGI2) and NO à Vasodilation and inhibition of platelet aggregation 3.Expresses heparin-like molecules à augment antithrombin III à ATIII inactivates thrombin (FII) and other factors (XII,XI,IX,VIII,X) 4.Expresses Tissue Plasminogen aktivator (t-PA) à converts plasminogen to plasmin à cleaves fibrin and fibrinogen/destroys clotting factors & inhibit platelet aggregation 5.Expresses thrombomodulin à thrombin-thrombomodulin complex à activates Protein C (together with Protein S) à inactivates factor V and VIII 6.Plasminogen aktivator inhibitor (PAI) à inhibits activation of plasminogen to plasmin 7. Factors enhancing thrombus formation 1.Thromboxan A2 à Vasoconstrictor and enhances platelet aggregation 2.Von willbrand factor (vWF) à Platelet adhesion molecule 3.Tissue thromboplastin (Factor III) à activates factor VII (exterinsic pathway) 4. Endothelial function Thrombosis - Virchows triad Blood flow in the vessels • Blood flows in the vessels in continues and streameline (straight line) fashion à laminar flow • laminar flow keeps platelets and clotting factors dispersed and inactivated (anti-thrombotic) Stasis or Turbulance blood flow à increase risk of Clot formation (thrombosis) Výsledok vyhľadávania obrázkov pre dopyt turbulent blood flow https://d1j63owfs0b5j3.cloudfront.net/tutorial/finalImage/1222-1458567955050.gif LAMINAR VS. TURBULENT FLOW Laminar flow is streamlined (in a straight line), turbulent flow is not. Reynolds’ number predicts whether blood flow will be laminar or turbulent. When Reynolds’ number is increased, there is a greater tendency for turbulence, which causes audible vibrations called bruits. Courtesy of Prof.Babula Courtesy of Prof.Babula Courtesy of Prof.Babula Courtesy of Prof.Babula Courtesy of Prof.Babula Courtesy of Prof.Babula Courtesy of Prof.Babula Courtesy of Prof.Babula Remember , at the end of the day, patient can present with either bleeding disorder or sign & symptoms of formation of pathological clot. The fundamental knowladge of hemostasis and pharmacological approach helps you save them ! THANK YOU J 1. Le T, Bhushan V, Sochat M, et al., eds. First Aid for the USMLE Step 1 2021. McGraw Hill; 2021. 2. Sattar HA. Fundamentals of Pathology: Medical Course and Step 1 Review. Pathoma.com; 2011. Accessed December 26, 2021. 3. Boron WF, Boulpaep EL, eds. Medical Physiology. Third edition. Elsevier; 2017. 4. Wilson LB. USMLE Step 1 Lecture Notes 2017: Physiology.; 2017. References :