Blood coagulation

Blood coagulation Conversion of fluid state of blood into semisolid state by activation and interaction of pro-coagulants in the blood Set in motion with formation of the platelet plug Many steps involving > 30 plasma factors Proteins (made in the liver), Vitamin K necessary for the synthesis of the liver proteins Ca++

Blood coagulation Starts earlier (15-20 seconds) if trauma is severe and late (1-2 minutes) if trauma is trivial The activating factors are Traumatized vessel wall or surrounding tissue Platelets Plasma proteins Clotting completes in 3-6 minutes Clot retracts after 20 minutes

Blood coagulation Last three phases of critical importance Prothrombin activator is formed Which converts prothrombin  thrombin Which converts fibrinogen  fibrin Fibrin threads form a meshwork which traps blood cells and seals the hole until permanent repair

Mechanism of blood coagulation - Pro coagulants- which promote clotting Anticoagulants- which inhibit coagulation In normal circulation anticoagulants dominate After trauma pro coagulants activated & dominate leading to coagulation.

Basic mechanism of clotting

Prothrombin A plasma protein α2 globulin M.W. 68700 15mg/dl Broken to thrombin MW 33700 Synthesized in liver Vit K required for synthesis ↓ Vit K or liver disease → ↓ prothrombin →↑Bleeding tendency

Fibrinogen Plasma protein 100 – 700 mg/dl M.W. 340,000 Formed in liver Liver diseases →↓fibrinogen → bleeding tendency Large molecule, does not leak into interstitial fluid which has very poor clotting property When it leaks into interstitial space in pathological conditions. Interstitial fluid clots

Thrombin & clot formation Thrombin → Breakdown of fibrinogen into fibrin monomer (4 small peptides removed) Fibrin molecules polymerize to fibrin threads Network of these fibers formed Thrombin → Activation of Fibrin stabilizing factor (FSF) → Covalent bond between fibrin molecules and cross linkages → more stable meshwork of fibrin threads FSF also formed from platelets entrapped in clot

Action of thrombin & clot formation Formed elements entrapped in fibrin meshwork Fibrin threads attached to damaged surface of blood vessels → rent sealed

Clot retraction The platelets attached to fibrin threads and bond different threads The platelet produce FSF which further strengthens the fibrin network Platelets activate thrombosthenin, actin and myosin → contraction of platelets → retraction of clot to smaller mass → extraction of serum The contraction is helped by Ca++ released from mitochondria, ER and Golgi complex of platelets Clot retraction → damaged ends of blood vessels closer to each other Serum extracted out of the clot Serum = Defibrinated plasma

Initiation of clotting Trauma to blood vessel Trauma to the surrounding tissue Trauma to the blood Contact of blood to Damaged endothelium Collagen Other water wettable surfaces Formation of prothrombin activator complex

Clotting Different clotting factors (Most important designated by Roman numerals I- XIII) Beta globulins plasma proteins Present in inactive form Cascade of different enzymatic action & activation of these procoagulants leads to clotting

Clotting factors Factor I Fibrinogen Factor II Prothrombin Factor III Tissue thromboplastin Factor IV Ca++ Factor V Proaccelerin, labile factor Factor VII Proconvertin, stable factor Factor VIII Antihemophilic factor

Clotting factors Factor IX Plasma thromboplastin component, Christmas factor Factor X Stuart Prower Factor Factor XI Plasma thromboplastin antecedent (PTA) Factor XII Hageman Factor Factor XIII Fibrin stabilizing factor (FSF) ----- Prekallikrein, fletcher factor ----- Fitzgerald factor High MW Kininogen ----- Platelets

Formation of prothrombin activator Two pathways Extrinsic pathway When there is injury to the tissues Starts with tissue thromboplastin or tissue factor Rapid clotting Intrinsic pathway When there is trauma to the blood itself Starts with platelet factor Relatively slow process

Extrinsic pathway

Intrinsic pathway

Ca++ are involved in almost all the steps after a few early steps of intrinsic pathway Removal or deionization of Ca++ prevent coagulation Extrinsic pathway is very fast and explosive mechanism After activation of Factor X both intrinsic and extrinsic pathways have common pathway

Prevention of Intravascular clotting

Prevention of Intravascular clotting Endothelial surface factors Smoothness Glycocalyx of endothelium repels clotting factors & platelets Thrombomodulin, a protein bound to endothelial membrane binds with thrombin (Thrombomodulin + thrombin) complex activates a plasma protein C → inactivate factor V and VIII

Intravascular anticoagulants Anticoagulants which remove thrombin Fibrin fibers Fibrin threads adsorb thrombin (85 -90 %) Prevention of excessive spread of clot Antithrombin III An alpha-globulin Combines with thrombin Inactivates thrombin

Intravascular anticoagulants Heparin A heteropolysaccharide Heparin is produced by Mast cells in the pericapillary CT, specially abundant in lungs and liver Basophilic Polymorphonuclear leucocytes in the blood Combines with antithrombin III → 100 – 1000 times increase in antithrombin activity of antithrombin III (Antithrombin + heparin) complex → inactivation or removal of factor IX, X, XI and XII

Plasmin Plasminogen, a plasma protein Tissue plasminogen activator (t PA) produced very slowly from the damaged tissues Coverts plasminogen into Plasmin Plasmin a proteolytic enzyme, causes digestion of fibrin, Fibrinolysis Removes extra or unwanted minute clots in the blood vessels Plasmin also causes lysis of other clotting factors like prothrombin, factor V, VIII & XII So it acts as anticoagulant as well

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