L5 Hemostasis (1) PDF

# BLOOD PHYSIOLOGY ## L5: HEMOSTASIS Dr. ABDULRHMAN MUSTAFA MB, BS -MSc-MHPE, MHAE FAIMER FELLOWSHIP Crt ## OBJECTIVES - Define hemostasis and explain the mechanisms that help to achieve it. - Review the major steps in coagulation. - Explain how to prevent coagulation. - Define the abnormalities...

# BLOOD PHYSIOLOGY ## L5: HEMOSTASIS Dr. ABDULRHMAN MUSTAFA MB, BS -MSc-MHPE, MHAE FAIMER FELLOWSHIP Crt ## OBJECTIVES - Define hemostasis and explain the mechanisms that help to achieve it. - Review the major steps in coagulation. - Explain how to prevent coagulation. - Define the abnormalities and defects of coagulation. - List the laboratory tests for hemostasis. ## PLATELETS - Formed in bone marrow, 150-400,000/µl. - Sequestered in spleen (30%). - 2-4 µm in diameter. - Life span 8-12 days. - Active Cytoplasm! - **Membrane**: - Receptors: Thrombin, ADP, serotonin. - Adhesion proteins: VWF, fibronectin, collagen, fibrinogen. - Coat of glycoproteins: Adhesion to injured areas. - Phospholipids: Activation of intrinsic pathway. - Adenylate cyclase, cAMP: Activate other platelets. - **Enzyme synthesis** - **Storage of calcium** - **Synthesis of prostaglandins** - **Granules containing ADP, serotonin and ATP** - α-granules (fibrinogen, PDGF (Platelet-derived Growth Factor), VWF (Von Willebrand Factor), fibronectin) - **Fibrin stabilizing factor** ## HEMOSTASIS - Hemostasis refers to the stoppage of bleeding. - (hemo = blood; stasis = standing) - **Stages of hemostasis**: - Blood vessel spasm - Platelet plug formation - Blood coagulation ## HEMOSTASIS - Stage 1: Blood Vessel Spasm - **Triggered by**: - Pain receptors. - Local myogenic spasm. - Local release of Thromboxane A2 [TXA2], 5HT, serotonin. - **Results**: Smooth muscle in blood vessel contracts. - **Purpose**: To minimize the flow of blood from the wound site. ## HEMOSTASIS - Stage 2: Platelet Plug Formation - **Triggered by**: Exposure of platelets to collagen - **Result**: Platelets adhere to rough surface to form a plug - **Steps of Platelet Plug Formation**: - Platelet adhesion - Von Willebrand factor (VWF) - Platelet activation(secretion) - Ca++ release - Pseudopodia - Granule discharge - Thromboxane formation (TXA2) - Platelet aggregation ## HEMOSTASIS - Stage 3: Blood Coagulation - **Triggered by**: Cellular damage and blood contact with foreign surfaces - **Result**: A blood clot forms: - This is a hemostatic mechanism causes the formation of a clot via a series of reactions which activates the next in a cascade. - **Clotting Cascade**: - Occurs extrinsically (tissue factor pathway) or intrinsically (contact activation pathway) ## HEMOSTASIS - Clotting Cascade ### Intrinsic pathway - Involves seven separate steps. - Set off when factor XII (Hageman factor) - Activated by coming into contact with exposed collagen in injured vessel or foreign surface such as glass test tube. ### Extrinsic pathway - Requires contact with tissue factors external to the blood. - Tissue thromboplastic released from traumatized tissue directly activates factor X. ## HEMOSTASIS - Clotting Cascade - Diagram - **Intrinsic pathway** - Damaged vessel surface - Foreign surface such as test tube - Inactive factor XII - Active factor XII (Hageman factor) - Inactive factor XI - Active factor XI - Inactive factor IX - Active factor IX - Inactive factor X - Active factor X - Prothrombin (factor II) - Thrombin - Fibrinogen (factor I) - Fibrin (loose meshwork) - Factor XIII - Fibrin (stabilized meshwork) - Entrapment of blood cells - **Extrinsic pathway** - Tissue damage - Tissue thromboplastin (factor III) - Inactive factor VII - Factor VII - Inactive factor X - Active factor X - Prothrombin (factor II) - Thrombin - Fibrinogen (factor I) - Fibrin (loose meshwork) - Factor XIII - Fibrin (stabilized meshwork) - Entrapment of blood cells ## HEMOSTASIS - Clotting Cascade - Simplified Diagram - **Intrinsic pathway** - Damaged surface - Kininogen - Kallikrein - XII - XIIa - XI - XIa - IX - IXa - VIIIa - X - Xa - Va - Prothrombin (II) - Fibrinogen (I) - Thrombin (IIa) - Fibrin (Ia) - XIIIa - Cross-linked fibrin clot - **Extrinsic Pathway** - Trauma - Tissue factor - VIIa - VII - Trauma - Xa - X - Va - Prothrombin (II) - Fibrinogen (I) - Thrombin (IIa) - Fibrin (Ia) - XIIIa - Cross-linked fibrin clot - **Final common pathway** ## HEMOSTASIS - Fate of Blood Clot - **Plasmin** digests blood clots. ## HEMOSTASIS - Fibrinolytic System - The process of dissolution of clot is called fibrinolysis. - Plasminogen - t-PA - Endothelial cells - Plasmin - Fibrin - Fibrin degraded products ## HEMOSTASIS - Prevention of Blood Clotting within Normal Vascular System - The smooth lining of blood vessels discourages the accumulation of platelets and clotting factors. - Fibrin absorbs thrombin and prevents the clotting reaction from spreading. - Some cells such as basophils and mast cells secrete heparin (an anticoagulant) - The dynamic blood flow ## HEMOSTASIS - Natural Anticoagulant Mechanisms - Prostacyclin (PGI2) - Inhibits action of TXA2 - Antithrombin III: - Blocks the action of factors II, IX, X, XI, XII - Protein C: - Blocks the action of factors V & VIII - ↑ t-PA action - Heparan sulphate - Cofactor, enhances activity of antithrombin III ## HEMOSTASIS - Defects in Hemostatic Mechanism (I) - **Thrombus**: Abnormal intravascular clot attached to a vessel wall - **Emboli**: Freely floating clots - **Factors that can cause thromboembolism**: - Roughened vessel surfaces associated with atherosclerosis - Imbalances in the clotting-anticlotting systems - Slow-moving blood - Occasionally triggered by release of tissue thromboplastin into blood from large amounts of traumatized tissue ## HEMOSTASIS - Defects in Hemostatic Mechanism (II) 1. **Vitamin C deficiency**: Lack of stable collagen (elderly, alcoholics) 2. **Hepatic failure**: Almost all clotting factors are made in the liver. 3. **Vitamin K deficiency**: Required for II (prothrombin), VII, IX, and X. - Also fat malabsorption due to lack of bile secretion 4. **Hemophilia**: Excessive bleeding caused by deficiency of one of the factors in the clotting cascade. - Factor VIII (hemophilia A 1/10,000) - Factor IX (hemophilia B 1/100,000) 5. **Thrombocytopenia**: Bleeding small capillaries and blood vessels mucosal, skin. ## ANTIHEMOSTATIC DRUGS - **Heparin**: Potentiates antithrombin III. - **Aspirin**: Is an important inhibitor of platelet activation. By virtue of inhibiting the activity of cyclooxygenase (COX), aspirin reduces the production of Thromboxane A2 (TXA2) by platelets. - **Clopidogrel**: Is an irreversible inhibitor of the ADP receptor on platelet membranes. When ADP binds to platelets they are activated and aggregate leading to amplification of the coagulation response. - **Warfarin**: Decreases blood clotting by blocking an enzyme called vitamin K epoxide reductase that reactivates vitamin K₁. Without sufficient active vitamin K₁, clotting factors II, VII, IX, and X have decreased clotting ability. - **Streptokinase**: (An enzyme from the Streptococcibacterium) is another plasminogen activator. ## TESTS FOR HEMOSTASIS - **Platelet disorder** - Bleeding time - 2-6 min. - Increased in thrombocytopenia - **Coagulation disorders** - Clotting time - 5-11 min. - Increased in hemophilia - Partial thromboplastin time (PTT) - For intrinsic & common pathway - Normally less than 45 sec. - Prothrombin time (PT) - For extrinsic & common pathway ## Q1 A 60 years old diabetic man developed myocardial infarction due to occlusion of coronary arteries by thrombus. He was given tissue plasminogen activator in hospital. What is the expected result of action of tissue plasminogen activator? A. Lyse fibrin to fibrin degraded products B. Prevent platelet aggregation C. Stimulate prostacyclin release D. Stimulate tissue repair ## Q2 A person presented to the doctor with reddish-purple spots, more on the legs. Blood investigation showed thrombocytopenia. Which of the steps of hemostasis may be defective? A. Blood vessel spasm B. Platelet plug formation C. Blood coagulation D. Clot dissolution ## References - Human physiology by Lauralee Sherwood, 9th edition. - Text Book Of Physiology by Guyton & Hall, 12th edition. - Review of Medical Physiology by Ganong, 24th edition.