1. Introduction to Haemostasis Ahmad Sh. Silmi Hematologist Msc,FIBMS

2. Course Objectives Identify the factors that influence the effectiveness of hemostatic processes. Describe the mechanisms that are involved in the arrest of blood flow from a damaged vessel. Identify key aspects associated with primary and secondary hemostasis. Explain the role of various coagulation components in hemostatic processes. Define the extrinsic, intrinsic, and common pathways that are part of the coagulation cascade, identifying the coagulation factors that are associated with each pathway. Describe the function of various laboratory tests in evaluating hemostasis. Identify common coagulation disorders, their symptomology, and subsequent treatment. Explain the role of the prothrombin time and activated partial thromboplastin time in monitoring anticoagulation therapy.

3. Course outline Part one An Introduction to the Fundamentals of Coagulation Introduction to the Fundamentals of Coagulation Which of the following would NOT impact the effectiveness of hemostatic processes? – Primary Hemostasis Introduction to Hemostatic Mechanisms Primary Hemostasis: The Vascular System and Platelet Involvement Primary Hemostasis: Platelet Production Primary Hemostasis: Characteristics of the Platelet Primary Hemostasis: Platelet Function Summary of Primary Hemostasis Which of the following processes does NOT occur during primary hemostasis?

4. Course outline Part one Cont. – Overview of Secondary Hemostasis Overview of Secondary Hemostasis Secondary Hemostasis: Fibrin Formation via the Coagulation Cascade Consequences Linked to Deficiencies in Coagulation Factors What is the ultimate goal of secondary hemostasis? Coagulation Factors in the Coagulation Cascade Secondary Hemostasis: The Extrinsic Pathway Secondary Hemostasis: The Intrinsic Pathway Secondary Hemostasis: The Common Pathway Secondary Hemostasis: Coagulation Factor Characteristics Factor VII is part of which coagulation pathway? – The Fibrinolytic System The Fibrinolytic System Regulation of hemostatic mechanisms

5. Course outline Part Two – Coagulation Disorders Coagulation Disorders: Inherited Coagulation Disorders: Acquired Coagulation Disorders: Platelet Disorders Coagulation Disorders and Liver Disease – Anticoagulation Therapy Anticoagulation Therapy Heparin Therapy Oral Anticoagulant Therapy Other

6. Let us Begin……

7. 7 HEMOSTASIS  Haemostasis or Hemostasis (Greek: aimóstasis, from aíma "blood" + stásis "stagnation") is a complex process which continually ensures:Greek  prevention of spontaneous blood loss and  stops hemorrhage caused by damage of vascular system  Most times this includes the changing of blood from a fluid to a solid state and then to fluid state.

8. 8 Function of Haemostasis  Arrests bleeding  Keeps blood in fluid state  Repair and reestablish the blood flow through the injured vessels  Remove haemostatic plug If any of the above functions is exaggerated or impaired it will cause either thrombosis or hemorrhage respectively; so hemostasis is a balance between thrombosis and hemorrhage

9. asilmi Without this balance, the individual may experience either excessive bleeding (poor clot formation or excessive Fibrinolysis) Vaso-occlusion (uncontrolled formation of thrombin in vascular system, occluding vessels and depriving organs of blood).

10. asilmi HEMOSTASIS There are certain conditions associated with excessive bleeding are referred to as: Hypo-coagulable states. Such as, Hemophilia or deficiency in one of the plasma coagulation proteins such as factors VIII. Acquired conditions such as DIC, Liver and Kidney diseases. In addition to Coagulation promotion, vessel injury initiates Fibrinolysis through endothelial cell release of tissue Plasminogen activators (tPAS). This is to ensure that excessive coagulation does not occur.

11. asilmi HEMOSTASIS Role of Coagulation in Hemostasis Coagulation: Is the process where by on vessel injury, Plasma protein, Tissue factors and Calcium interact on the surface of the platelets to form a Fibrin clot. Platelets provide a surface for the coagulation reaction, and interact with fibrin to form a stable platelet fibrin clot.

12. asilmi HEMOSTASIS Tissue factors (except Ca and Tissue Thromboplastin) normally circulate in the plasma as inactive proteins. On activation some factors form enzymatic proteins known as Seiren Proteases that activate other specific factors in the coagulation sequence. Other conditions are related to uncontrolled thrombosis are called Hyper-coagulable state. This is related to an appropriate formation of thrombi in the vascular vessels that occlude normal blood flow.

13. 13 Mechanism of Hemostasis Haemostasis involves a series of delicately balanced physical and biochemical changes following an injury to a blood vessel. As the most immediate response, the blood vessel constrict Then platelets adhere and aggregate at the site of the injury and form a plug

14. 14 Mechanism of Hemostasis These activated platelets secretes substances that initiate the coagulation factors which interact serially, forming a fibrin network or clot in which white cells, red cells and platelets are trapped and form a solid plug of blood ( coagulation) which seals off the injury vessel completely. Finally slow lysis of the clot, fibrinolysis, begins and the site of the injury is repaired.

15. 15 Components of normal hemostasis vessels Tissue Tissular coagulation factor Platelets Thrombocytic Platelet Coagulation factors Coagulation (activator & inhibitors) Humoral ( plasma factors) Fibrinolysis (activater & inhibitors)

16. The effectiveness or failure of haemostatic mechanism to control bleeding depends on : – The type & degree of injury. – The size & ability of injured vessel to contract. – The pressure within the vessel & surrounding tissues. – The availability & activity of the platelets. – The quantity & functional ability of blood clotting factors. – The absence of inhibitors.

17. Hemostasis The hemostatic components remain inert in the presence of intact vascular tissue or endothelium Following injury, each component must function optimally.

18. asilmi Vessel wall, Blood flow & Coagulation Substances

19. asilmi In Case if there is an Endothelial Injury (Bleeding must be prevented at site of injury)

20. asilmi Flow must be Maintained

21. Virchow Law There are three haemostatic components: 1- The extra-vascular (The tissues surrounding blood vessels) involved in Hemostasis when local vessel is injured. It plays a part in Hemostasis by providing back-pressure on the injured vessel through swelling and trapping of escaped blood. asilmi

22. HEMOSTASIS The three haemostatic components 2- The vascular (The blood vessels through which blood flow) it depends on the size, amount, of smooth muscle within their walls and integrity of the endothelial cell lining. 3- The intra-vascular (The platelets and plasma proteins that circulate within the blood vessels). These components are involved in Coagulation (clot or thrombus formation) or Fibrinolysis (clot or thrombus dissolution).

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24. Phases Three –phase process I. Primary hemostasis II. Coagulation (secondary hemostasis) III. Fibrinolysis (Tertiary hemostasis)

25. Phases cont’d I. Primary hemostasis  Involves  Blood vessels (vascular vasoconstriction phase and release of tissue or exogenous factors)  Thrombocytes (platelate or endothelial –thrombocyte phase, platelate aggregation and release of platelate factors).  After 3 to 5 minutes, blood flow is arrested with the formation of a platelate plug.

26. Phases cont’d II. Coagulation  Involves  Plasma coagulation factors (plasma phase)  Platelate factor 3  provides for definitive hemostasis  Takes 5 to 10 minutes by formation of fibrin  Reinforces the platelate plug.

27. 27 Phases cont’d III Fibrinolysis  Essential final step in any hemostasis mechanism,  Enabling in 48 to 72 hours, and a  Return to normal by destroying fibrin and healing the injured vessel.

28. I. Primary hemostasis  Is a result of a three –way interaction between:  Vascular wall  Platelets  plasma coagulation factors  Triggered by  Small injuries to blood vessels  The plasma coagulation factors desquamation (damaging of epithelial cells in pinpricks)

29. 29 Primary hemostasis  Involves:  Vasoconstriction  Platelet adhesion  Platelet aggregation  Platelet secretion

30. asilmi HEMOSTASIS Role of Blood Vessels in Hemostasis Blood flows through the vascular system to and from all parts of the body. The vascular system consists of capillaries, arteries, and veins. Blood normally carried within vessels whose physical capabilities include Contraction (narrowing) and Dilation, which are controlled by the smooth muscle of the vessel media.

31. asilmi HEMOSTASIS Vasoconstriction and Vasodilatation provide the means for control blood flow rate and blood pressure. Substances released from the endothelial cells and sub- endothelial smooth muscles also contribute to normal blood flow and prevent abnormal formation of clot.

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43. Arachidonic acid ENDOTHELIAL CELL PLATELET Thromboxane synthetase Prostacyclin synthetase Cyclo-oxygenase Prostacyclin (PGI 2 ) Thromboxane (TxA 2 ) Inhibits plt aggregation Vasodilator Enhances plt aggregation Vasoconstrictor Cyclic Endoperoxides

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46. Summary of Important Vascular Function asilmi

47. 47 Vascular Endothelium Function Prostacyclin Thromboxane A 2 ELAMs, ICAMs von Willebrand factor Vasodilation, inhibition of platelet aggregation From platelets, constrict muscular arteries Cytokines induce synthesis to promote leukocyte adhesion Promote platelet-collagen adhesion to exposed sub- endothelium

48. 48 Vascular Endothelium Function Tissue factor pathway inhibitor Thrombomodulin Tissue plasminogen activator Heparan sulfate proteoglycans Tissue factor Anticoagulant- Inhibits coagulation extrinsic pathway Anticoagulant- Inhibits coagulation by activating protein C system Anticoagulant- Inhibits coagulation by activating fibrinolysis Anticoagulant- Inhibits coagulation by activating antithrombin Procoagulant- Inflammatory cytokines (IL-1, TNF) induce expression

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51. Upon conclusion one can aske the following question 51