HEMOSTASIS AND BLOOD COAGULATION a e Hemostasis is a sequence of responses that stops bleeding and can prevent hemorrhage from smaller blood vessels. + Hemostasis plays an important part in maintaining homeostasis ¢ Stages of hemostasis: When a blood vessel is injured, the i of reactions, resulting in hemostasis, which is occurs in three ) Vasoconstriction ) Platelet aggregation - ) Coagulation, Ai.initiryto\biodd|vessalland|damagele/endethellrn Exposure of estiagen won Waobrana factor >] Adherence of platelets to collagen ‘Sceretion of ADP and Formauon of ‘Sccretion of serotonin thramboxane Ay prothrombin oetvater [eo Par Aggregation of platetets Tecan | [RR wie Fioure 4: Slates of hemostasis. ADP = Adenosine dipho rian ‘Scanned with CamSeanner 1 activating faciorPlatelets © Cell membrane is covered by an exterior glycocalyx coat made up of glycoproteins * Negative charge on the surface due to presence of sialic acid residues that prevents the resting platelets to attach to each other and to the negatively charged endothelial cells * Platelet membrane glycoproteins -Gp la : Mediates platelet adhesion to exposed collagen independent of vWF -Gp Ib: Active receptor mediates vWF dependent platelet adhesion to subendothelial collagen -Gp lib: Mediates aggregation between platelets ‘Scanned with CamSeanner° Platelet granules -c granules: Adhesive proteins like fibrinogen, vWF, Fibronectin, thrombospondin Growth factors like PDGF, PAF Coagulation factors like fibrinogen, factor V, Factor IX -Dense granules: ADP, ATP, Serotonin, calcium ‘Scanned with CamSeanner| COAGULATION OF BLOOD Blood coagulation is an important process to maintain homeostasis Blood clotis defined as the mass of coagulated blood which contains RBCs, WBCs and platelets entrapped in fibrin meshwork. RBCs and WBCs are not necessary for clotting process. These cells ate trapped with platelets when clot is formed The trapped RBCs are responsible for the red color of the clot The external blood clot is also called scab. |t adheres (sticks) (o the opening of damaged blood vessel and prevents blood loss. During this process, the fibrinogen is converted into fibrin Fibrin thr attached to the loose platelet plug, which blocks the ruptured part of blood vessels and prevents further blood loss completely. ‘Scanned with CamSeannerTHE BLOOD COAGULATION MECHANISM e The clotting mechanism is a series of reactions involving chemicals that normally circulate in the blood and others that are released when a vessel is damaged. ¢ A blood clot is formed when the plasma protein fibrinogen is cleaved by proteolytic enzyme to produce fibrin. « If blood vessel damage is so extensive that platelet aggregation and vasoconstriction cannot stop the bleeding. ¢ The complicated process of coagulation (blood clotting) required the aid of clotting factors. ‘Scanned with CamSeannereee Clotting factors Factor |: Fibrinogen Factor Il; Prothrombin Factor Ill; Tissue thromboplastin Factor IV: Catcium ion Factor V : Proaccclerin Factor VI does not exist Factor VII: proconvertin Factor Vill; Antihaemophilicfactor A Factor IX : Christmas Factor Factor X ; Stuart Prower factor Factor Xl: Antihaemophilic factor C FactorXll : Hageman factor, contact factor + Factor XII : Fibrin stabilizing factor ( Laki lorand factor) “Scanned with CamSeannerScanned with CamSeannerThe three pathways that makeup the classical blood coagulation pathway Intrinsic Xi ~ Hageman factor, a serine protease a Xt —Plasma thromboplastin, antecedent serine proteas surface contact IX. Christmas factor, serine protease VII -Stable factor, serine protease Xt — Fibrin stabilising factor, a transglutaminase PL — Platelet membrane phospholipid ———— Sox aw . Ca*—Calciumions | TF — Tissue Factor (,, =active form) Xe Ale nace | Extrinsic 1 tissue damage x ——> kk, (vn, PL, |.ca) mon X ———> x, ——— x Commo! (v, PL.) Ca™>) a prothrombin» thrombin. _.| (serine protease) Xi, fibrinogen > fibrin ———} stable fibrin clot ‘Scanned with CamScannerFormation of fibrin from fibrinogen « It occurs in three steps -Proteolysis of soluble fibrinogen : Thrombin bind with central domain of fibrinogen and releases peripheral fibrinopeptides. Release of fibrinopeptides leads to formation of fibrin monomer -Polymerization of fibrin monomer: Fibrin monomers jain to form protofibrils. 15-20 protofibrils join together to form fibrin thread. Thrombin activates the process of polymerization and simultaneously activates factor XIII. Factor XIII completes the process of polymerization r: Calcium acts as a cofactor. Covalent cross Stabilization of fibrin polyme' dequate strength to fibrin polymer linking of fibrin polymers provides ai "Scanned with camSeannerAnticlotting factors ° Thrombomodulin with thrombin has anticoagulant activity ° Protein C inactivates factor Va and Villa ° ProteinS acts as a cofactor for protein C that inactivates Va and Villa ° ProteinZ acts as cofactor * Tissue factor pathway inhibitor ° Antithrombin II inhibits thrombin, Xa and |Xa ‘Scanned with CamSeannerPlasminogen t-PA =>" < = Urokinase activator inhibitor | i Plasminogen | | Y \ | Plasmin g,-Amtiplasmin | Noo | ; > | Fibrin ———=> Fibr Fibrinolytic System ‘Scanned with CamSeannerHEPARIN © Heparin is a naturally produced anticoagulant in the body. tis produced by mast cells which are abundant in liver and lungs e Basophils also secrete heparin. © Heparin is a conjugated polysaccharide. Mechanism of Action of Heparin + Prevents blood clotting by its anti-thrombin activity. It directly suppresses the activity of thrombin > Combines with anti-thrombin Ill and removes thrombin from circulation > Activates anti-thrombin Ill. > Inactivates the active form of other clotting factors like IX, X, Xf and Xl. ‘Scanned with CamSeannerSynthetic Anticoagulants + Vitamin K antagonists: -Coumarin derivatives €.8 Dicoumarol -Warfarin -Phenindione -Nicoumalone They act by c! competitive inhibition of vitamin K receptor liver and prevent vitamin K to carry out its physiological ‘Scanned with CamSeannerHaemorrhagic Disorders * Haemorrhagic disorders are classified as -Defective blood clotting due to deficiency of clotting factors (1, Il, V, VII, IX, X) Deficiency of Vitamin K Anticoagulant overdose -Defective capillary contractility: Purpura -Combined defects ‘Scanned with CamScannerHemophilia * X-linked recessive disorder © Deficiency of factor VIII ° Females are carriers and males are affected « Increased Clotting time with normal bleeding time * Blood collected from hemophilic patients takes 1-12 hours to clot ‘Scanned with CamSeannerVitamin K deficiency * Vitamin K is required for the synthesis of factor Il, Vil, IX, and X in the liver * Vitamin K derived from green leafy vegetables, cereals, synthesized by bacteria present in the intestine * Causes of Vitamin K deficiency -Obstructive jaundice -Chronic diarrhoeas -liver disease haemorrhagic diseases in absence of vitamin K haemormasic ciseeses dre -Treated with Vit K Injections ‘Scanned with CamSeannerDefective capillary contractility ¢ Purpura haemorrhagic spots beneath the skin, mucus membrane and internal organs due to spontaneous hge called as purpura haemorrhagica ° Two types -Primary (Idiopathic): Congenital or hereditary, usually occurs in children -Secondary (Symptomatic): Due to allergies and infections like subacute bacterial endocarditis, "Scanned with CamSeannes* Bleeding time increases and clotting time remains normal * Increased capillary fragility © Skin microscopy will show altered anatomy of blood vessels in primary purpura and in secondary purpura blood vessels will have normal morphology but altered capillary contractility * Platelet count may be normal or altered Thrombocytopenic purpura Athrombocytopenic purpura Thrombosthenic purpura ‘Scanned with CamSeannerEffects of calcium deficiency on coagulation * Calcium acts as a catalyst in many reactions of hemostasis but is required in very small amount. So calcium deficiency does not produce coagulation disorders * Evenin case of severe calcium deficiency it may produce other symptoms like tetany before coagulation disorders ‘Scanned with CamSeannerWhy blood does not clot in circulation * Endothelial factors -Smoothness of endothelial lining prevents platelet adhesion and extension of clot into blood vessel -Negatively charged particles such as glycocalyx present over endothelial lining repel the clotting factors * Velocity of circulation if decreases leads to clotting * Presence of natural anticoagulants like heparin and protein Cin blood + Simultaneous activation of fibrinolytic system along with clotting mechanism * In the event of spontaneous clot formation liver removes the activated clotting factors from the circulation ‘Scanned with CamSeanner