1. BLOOD AND BODY DEFENCE Dr. Amel Eassawi Dr. Abdelrahman Mustafa 1

2. HMIM 224 L 6: HEMOSTASIS 2

3. OBJECTIVES The student should be able to:  Define hemostasis and explain the mechanisms that help to achieve it.  Review the major steps in coagulation.  Explain how to prevent coagulation. 3

4. PLATELETS Formed in bone marrow, 150-400,000 /µl The hormone thrombopoietin, produced by the liver stimulate the bone marrow for production of thrombocytes. 2-4 µm in diameter, life span 8-12 days, no nucleus Active Cytoplasm:  Actin + myosin  Enzyme synthesis + storage of calcium  Synthesis of prostaglandins  Dense granules containing ADP, serotonin and ATP  Alpha granules (fibrinogen, PDGF (Platelet-derived Growth Factor), VWF (Von Willbrand Factor), fibronectin)  Fibrin stabilizing factor 4

5. 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 PLATELETS 5

6. 6 HEMOSTASIS Hemostasis refers to the stoppage of bleeding Stages of hemostasis: Blood vessel spasm Platelet plug formation Blood coagulation

7. 7 HEMOSTASIS 1. Blood Vessel Spasm: Triggered by pain receptors, platelet release, or serotonin. Smooth muscle in blood vessel contracts. 2. Platelet plug formation Triggered by exposure of platelets to collagen Platelets adhere to rough surface to form a plug

8. HEMOSTASIS Stages of Platelet Plug Formation: 1.Platelet adhesion Von Willebrand factor (VWF) 2.Platelet activation Ca ++ releaase Granule discharge Integrin on surface Thromboxane formation (TX A2 ) 3.Platelet aggregation 8

9. HEMOSTASIS 9

10. 10 HEMOSTASIS 3.Blood Coagulation: Triggered by cellular damage and blood contact with foreign surfaces A hemostatic mechanism causes the formation of a blot clot via a series of reactions which activates the next in a cascade. Occurs extrinsically (tissue factor pathway) or intrinsically (contact activation pathway).

11. CLOTTING FACTORS 11

12. CLOTTING CASCADE Series of steps involving 12 plasma clotting factors that lead to final conversion of fibrinogen into a stabilized fibrin mesh. May be triggered by  Intrinsic pathway Involves seven separate steps Factor XII (Hageman factor) is activated by coming into contact with exposed collagen in injured vessel or foreign surface such as glass test tube. 12

13. Intrinsic Pathway Figure 36-4; Guyton & Hall 13

14. CLOTTING CASCADE  Extrinsic pathway Requires only 4 steps Requires contact with tissue factors external to the blood. Tissue thromboplastin released from traumatized tissue directly activates factor X. 14

15. Extrinsic Pathway Figure 36-3; Guyton & Hall 15

16. Clot Pathways 16

17. 17

18. 18 FATE OF BLOOD CLOTS After a blood clot forms it retracts and pulls the edges of a broken blood vessel together while squeezing the fluid from the clot. Platelet-derived growth factor stimulates smooth muscle cells and fibroblasts to repair damaged blood vessel walls. Plasmin digests the blood clots. Plasmin is a plasma protein produced by the liver, present in the plasma as inactive form plasminogen. Plasmin is activated in a cascade of reaction involve many factors.

19. 19 PREVENTION OF COAGULATION The smooth lining of blood vessels discourages the accumulation of platelets and clotting factors. As a clot forms fibrin absorbs thrombin and prevents the clotting reaction from spreading Anti-thrombin inactivates additional thrombin by binding to it and blocking its action on fibrinogen. Some cells such as basophils and mast cells secrete heparin (an anticoagulant).

20. 20

21. ABNORMAL BLOOD CLOTTING Thrombus –Abnormal intravasculaar 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-anti-clotting systems –Slow-moving blood –Occasionally triggered by release of tissue thromboplastin into blood from large amounts of traumatized tissue. Hemophilia –Excessive bleeding caused by deficiency of one of the factors in the clotting cascade. 21

22. I. 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 factor II (prothrombin), VII, IX, and X 4. Hemophilia COAGULATION DEFECTS 22

23. HEMOPHILIA Hemophilia A is classic hemophilia (a disease referring to the inability to clot blood). About 80% is Hemophilia A. It is due to deficiency in factor VIII. Symptoms include: –Joint and muscle hemorrhage –Easy bruising –Prolonged bleeding from wounds. Treatment of hemophilia A is accomplished by infusion of factor VIII concentrates prepared from either human plasma or by recombinant DNA technology. Hemophilia B results from deficiencies in IX. Hemophilia C results from deficiencies in XI. 23

24. ITP (Idiopathic thrombocytopenic purpura (ITP) is the condition of having an abnormally low platelet count (thrombocytopenia) of unknown cause (idiopathic). autoimmune (common). Characterize by bleeding of small capillaries in the skin. COAGULATION DEFECTS 24

25. ANTIHEMOSTATIC DRUGS Heparin: Activate antithrombin III. Antithrombin III inactivates various coagulation factors including thrombin. Used in prevention of Deep vein thrombosis (DVT) & Pulmonary embolism (PE). During heart surgery and hemodialysis. 25

26. ANTIHEMOSTATIC DRUGS Aspirin: - An important inhibitor of platelet activation. -By inhibiting the activity of cyclooxygenase (COX) prostaglandin-endoperoxide synthase (PTGS), -Cyclooxygenase responsible for formation of prostaglandins, prostacyclin and thromboxane. prostaglandinsprostacyclinthromboxane 26

27. ANTIHEMOSTATIC DRUGS The drug clopidogrel: Plavix is an irreversible inhibitor of the ADP receptor on platelet membranes., thus Plavix interferes with the process of platelet aggregation. Tissue plasminogen activator (tPA) is highly selective for the degradation of fibrin in a clot. Used particular during the short period following myocardial infarct. Streptokinase (an enzyme from the Streptococci bacterium) is another plasminogen activator. 27

28. TESTS 1. PLATELET DISORDER: Bleeding Time : The time it takes for the bleeding to stop. Normally 2-6 min. Increased bleeding time in thrombocytopenia 2. COAGULATION DISORDERS: 1.Clotting Time: The time required for a sample of blood to coagulate in vitro under standard conditions. Normally 5-11 min. Increased clotting time in hemophilia 2. Partial Thromboplastin Time (PTT) For intrinsic & common pathway Normally less than 45 sec. 3. Prothrombin Time (PT) For extrinsic & common pathway. Usually around 12–13 seconds 28

29. SUMMARY 29

30. REFERENCES  Human Physiology, Lauralee Sherwood, seventh edition.  Text book Physiology by Guyton &Hall,11 th edition.  Text book of Physiology by Linda S. Contanzo, third edition.  Physiology by Berne and Levy, sixth edition. 30