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HEMOSTASIS (2).pptttx slide presentation
- 1. NORMAL HAEMOSTASIS DR KASIMMUHAMMAD PINDIGA
- 2. BACKGROUND • Hemostasis isderived from a Greek word, which means stoppage of blood flow. • The process is a combination of cellular and biochemical events that function together to keep blood in the liquid state within the veins and arteries and prevent blood loss following injury through the formation of a blood clot.
- 3. • It consistsof a complex regulated system which is dependent on a delicate balance among several systems. • The systems involved in the hemostatic process include the vascular system, coagulation system, fibrinolytic system, platelets, kinin system, serine protease inhibitors, and the complement system.
- 4. • The systemswork together when the blood vessel endothelial lining is disrupted by mechanical trauma, physical agents, or chemical trauma to produce clots. • The clots stop bleeding and are eventually dissolved through the fibrinolytic process. • As a result, there is a delicate balance between the production and dissolution of clot during the hemostatic process.
- 5. • A disruptionof this balance may precipitate thrombosis or hemorrhage as a result of hypercoagulation or hypocoagulation, respectively.
- 6. • Hemostasis iscategorized as either a primary or secondary process. • Primary hemostasis involves the response of the vascular system and platelets to vessel injury. • It takes place when there are injuries to small vessels during which the affected vessels contract to seal off the wound and platelets are mobilized, aggregate, and adhere to components of the sub-endothelium of the vasculature.
- 7. • Platelet adhesionrequires the presence of various factors such as von Willebrand factor (vWF) and platelet receptors (IIb/IIIa and Ib/IX). • Additional platelets are attracted to the site of injury by the release of platelet granular contents, such as adenosine diphosphate (ADP).
- 8. • The plateletplug is stabilized by interaction with fibrinogen. • Thus a defect in platelet function or von Willebrand’s disease (vWD) may result in debilitating and sometimes fatal hemorrhage.
- 9. • Secondary hemostasisinvolves the response of the coagulation system to vessel injury. • It is required to control bleeding from large wounds and is a continuation of the primary hemostatic mechanisms
- 10. • Whereas theoutcome of primary hemostasis is the formation of the platelet plug, the outcome of secondary hemostasis is the formation of a thrombus.
- 11. COMPONENTS OF NORMALHEMOSTASIS • The Vascular System • Coagulation System • Fibrinolytic System • Platelets • Serine protease inhibitors
- 12. VASCULAR SYSTEM • Thevascular system has procoagulant, anticoagulant, and fibrinolytic properties and is made up of blood vessels. • The innermost lining of the blood vessels is made up of endothelial cells (ECs) which form a smooth, unbroken surface that promotes the fluid passage of blood and prevents turbulence that may trigger activation of platelets and plasma proteins.
- 13. • The ECsare supported by a collagen-rich basement membrane and surrounding layers of connective tissues. • A breakdown in the vascular system is rapidly repaired to maintain blood flow and the integrity of the vasculature
- 14. • The vascularsystem prevents bleeding through vessel contraction, diversion of blood flow from damaged vessels, initiation of contact activation of platelets with aggregation, and contact activation of the coagulation system.
- 15. • Platelets areactivated by collagen located in the basement membrane. • The ECs secrete vWF, which is needed for platelet adhesion to exposed sub-endothelial collagen in the arterioles. • The ECs produce a variety of other adhesion molecules, which include P-selectin, intercellular adhesion molecules (ICAMs), and platelet endothelial cell adhesion molecules (PECAMs).
- 16. • The smoothmuscle and fibroblast release tissue factor (TF), which activates factor VII (FVII). • The vascular system provides potent anticoagulant properties, which prevents the initiation and propagation of the coagulation process.
- 17. • Coagulation isinhibited through the expression of thrombomodulin (TM), which promotes activation of protein C and heparan sulfate (HS), which activates antithrombin III (AT-III) to accelerate thrombin inhibition.
- 18. • Endothelial cellsalso release tissue factor pathway inhibitor (TFPI), which blocks activated factor VIIa (FVIIa)-TF/factor Xa (FXa) complex and annexin V, which prevents binding of coagulation factors
- 19. COAGULATION SYSTEM • Thecoagulation system is where coagulation factors interact to form a fibrin clot. The coagulation system is involved in the conversion of soluble fibrinogen, a major component of the acute inflammatory exudates into fibrin.
- 20. • The fibrinclot reinforces the platelet plug formed during primary hemostasis. • Various protein factors present in the inactive state in the blood participate in the coagulation system. • The protein factors are designated by Roman numerals according to their sequence of discovery and not by their point of interaction in the coagulation cascade.
- 21. • Some ofthe coagulation factors such as fibrinogen and prothrombin are referred to by their common names, whereas others such as factors VIII and XI are referred to by their Roman numeral nomenclatures. • Activation of a factor is indicated by the addition of low case “a” next to the Roman numeral in the coagulation cascade such as VIIa, Xa, XIIa.
- 22. • Some ofthe common names were derived from the original patients in whom symptoms leading to the determination of the factor deficiency were found. Examples are the Christmas factor and Hageman factor.
- 23. • The coagulationfactors may be categorized into substrates, cofactors, and enzymes. • Fibrinogen is the main substrate. • The cofactors accelerate the activities of the enzymes, which are involved in the coagulation cascade. • Examples of cofactors include tissue factor, factor V, factor VIII, and Fitzgerald factor.
- 24. • With theexception of factor XIII, all the enzymes are serine proteases when activated. • The coagulation factors may also be categorized into 3 groups on the basis of their physical properties: • These groups are the contact proteins comprising of factors XII, XI, prekallikrein (PK), and high molecular weight kininogen (HMWK);
- 25. • the prothrombinproteins comprising of factors II, VII, IX, and X; and the fibrinogen or thrombin sensitive proteins comprising of factors I, V, VIII, and XIII.
- 27. FIBRINOLYTIC SYSTEM • Fibrinolysisis the physiological process that removes insoluble fibrin clots through enzymatic digestion of the cross-linked fibrin polymers. • Plasmin is responsible for the lysis of fibrin into fibrin degradation products, which may have local effects on vascular permeability. • Plasmin digests fibrin and fibrinogen through hydrolysis to produce smaller fragments.
- 28. • The gradualprocess occurs at the same time that healing is occurring, and eventually cells of the mononuclear phagocytic system phagocytize the particulate products of the hydrolytic digestion.
- 29. • Fibrinolysis iscontrolled by the plasminogen activator system. • The proteolytic activity of this system is mediated by plasmin, which is generated from plasminogen by 1 of 2 plasminogen activators. • Inactive plasminogen circulates in plasma until such a time that an injury occurs. • Then, plasminogen is activated by means of a number of proteolytic enzymes known as plasminogen activators.
- 30. • These activatorsare present at various sites such as the vascular endothelium. • Some of the activators include tissue-type plasminogen activator, urokinase, streptokinase, and acyl-plasminogen streptokinase activator complex. • Inhibitors of fibrinolysis include α2- plasmin inhibitor, tissue plasminogen activator inhibitor, and plasminogen activator inhibitor-1 (PAI-1).
- 32. • Individuals withreduced fibrinolytic activity are at increased risk for ischemic cardiovascular events, and reduced fibrinolysis may underlie some of the pathological consequences of reduced nitric oxide (NO) availability.
- 33. PLATELETS • Platelets areanuclear fragments derived from the bone marrow megakaryocytes. • They have a complex internal structure, which reflects their hemostatic function. • The 2 major intracellular granules present in the platelets are the α-granules and the dense bodies.
- 34. • The α-granulescontain platelet thrombospondin, fibrinogen, fibronectin, platelet factor 4, vWF, platelet derived growth factor, β-thromboglobulin,and coagulation factors V and VIII. • The dense granules contain ADP, adenosine triphosphate (ATP), and serotonin.
- 35. • When stimulated,platelets release both the α- granules and the dense bodies through the open canalicular system. • When platelets aggregate, they expend their stored energy sources, lose their membrane integrity, and form an unstructured mass called a syncytium.
- 36. • In additionto the plug formation, platelet aggregates release micro-platelet membrane particles rich in phospholipids and various coagulation proteins which provide localized environment that support plasma coagulation. • Platelets and ECs have biochemical pathways involving the metabolism of arachidonic acid (AA), which is released from membrane phospholipids by phospholipase A2.
- 37. • Subsequently, cyclooxygenaseconverts AA to cyclic endoperoxides. • The endoperoxides are then converted by thromboxane synthetase to thromboxane A2. Thromboxane A2 is a potent agonist that induces platelet aggregation. • Endothelial cells also contain AA and preferentially convert cyclic endoperoxides to prostacyclin, which is a potent inhibitor of platelet aggregation.
- 39. • During primaryhemostasis, platelets interact with elements of the damaged vessel wall leading to the initial formation of the platelet plug. • The platelet/injured vessel wall interaction involves a series of events that include platelet adhesion to components of the subendothelium, activation, shape change, release of platelet granules, formation of stabilized fibrin platelet aggregates, and clot retraction.
- 40. • In theprocess, activation of platelets with exposure of negatively charged phospholipids facilitates the assembly of coagulation factors on the activated platelet membrane, leading to the generation of thrombin and subsequent fibrin deposition.
- 41. KININ SYSTEM • Thekinins are peptides of 9 to 11 amino acids of which the most important vascular permeability factor is bradykinin (BK). • The kinin system is activated by coagulation factor XII. • Bradykinin is also a chemical mediator of pain, which is a cardinal feature of acute inflammation.
- 42. • Therefore, bradykininis capable of reproducing many of the characteristics of an inflammatory state, such as changes in local blood pressure, edema, and pain, resulting in vasodilation and increased microvessel permeability. • The docking of HMWK to platelet and EC membranes requires its binding by regions on both its heavy and light chains
- 43. CONCLUSSION • Hemostasis involvesthe stoppage of bleeding following an injury to the vasculature. • The various systems work together to maintain the integrity of this process and prevent what would otherwise be a traumatic reaction. • A delicate balance is maintained between all of the systems that are involved in the hemostatic process.
- 44.
Editor's Notes
- #3 Broadly= vascular system + platelets + plasma proteins (coagulation system, fibrinolytic system, kinin system, serine protease inhibitors, and the complement system)