Haemostasis Lectures 2024-2025 PDF

Hemodynamic Disorders: Dr Adnan Anwer M.B.ch.B. – F.I.B.M.S. (Haematopath.)  Objectives The students should have adequate knowledge about: 1 – Haemostasis, A-How do endothelial cells promote and inhibit haemostasis? B-What is the role of platelets in haemostasis C- Formation of clo...

Hemodynamic Disorders: Dr Adnan Anwer M.B.ch.B. – F.I.B.M.S. (Haematopath.)  Objectives The students should have adequate knowledge about: 1 – Haemostasis, A-How do endothelial cells promote and inhibit haemostasis? B-What is the role of platelets in haemostasis C- Formation of clots (thrombosis), role of coagulation factors. D- What is the purpose of fibrinolysis? How can fibrinolysis be enhanced to treat patients? E- Anticoagulating therapy, Types and mode of actions, its uses.  Haemostasis Components Both hemostasis and thrombosis involve four components: 1. Vascular wall. Loading… 2. Platelets. 3. Coagulation cascade. 4. Fibrinolysis system Objective 1-A 1. Vascular wall. Objective 1-A  2- Platelets Platelets play a central role in normal hemostasis. Platelet Adhesion :Adhesion to ECM is Loading… mediated largely via interactions with vWF acting as a bridge between platelet surface receptors (e.g., GpIb) and exposed collagen. Objective 1-B Shape Change & spreading Fried Egg appearance Ultrastructural Shape Changes In platelets Objective 1-B  Secretion (Release Reaction) Platelet secretion plays a crucial role in various physiological and pathophysiological processes. It involves the release of bioactive molecules stored in platelet granules, impacting functions like hemostasis, thrombosis, inflammation, Objective 1-B Platelet Aggregation Platelet aggregation is a crucial process where platelets adhere to each other at sites of vascular injury. It involves multiple mechanisms dependent on shear conditions, with fibrinogen and integrin α IIbβ 3 playing a key role under low shear conditions. Platelet aggregation is mediated by the GPIIb/IIIa complex, which undergoes conformational changes upon activation, Objective 1-B allowing binding to fibrinogen or vWF. Role of platelet in haemostasis  Primary aggregation This primary aggregation is reversible. However, with activation of the coagulation cascade, the generation of thrombin that make an irreversible hemostatic plug. Concurrently, thrombin converts fibrinogen to fibrin within and about the platelet plug, contributing to the overall stability of the clot Objective 1-B Loading… Objective 1-B  3-Coagulation Cascade The coagulation cascade is essentially an amplifying series of enzymatic conversions; each step in the process proteolytically cleaves an inactive proenzyme into an activated enzyme, eventually culminating in thrombin. Thrombin converts the soluble plasma protein fibrinogen into fibrin monomers that polymerize into an insoluble gel; this gel encases platelets and other circulating cells in the definitive secondary hemostatic plug. Objective 1-C  Coagulation pathways vWF Objective 1-C  4-Fibrinolysis system Once activated, the coagulation cascade must be restricted to the local site of vascular injury to prevent runaway clotting of the entire vascular tree. Activation of the clotting cascade also sets into motion a fibrinolytic cascade that moderates the size of the ultimate clot. Fibrinolysis is largely accomplished by the enzymatic activity of plasmin, which breaks down fibrin and interferes with its Objective 1-D polymerization. Components of Fibrinolytic system (Simplified) α2-antiplasmin Inhibitors FVIII Plasminogen Plasmin FV Plasminogen activators Inhibitors Fibrin Fibrinogen Fibrinogen / fibrin Degredation products  Plasmin is generated by enzymatic degradation of the inactive circulating precursor plasminogen either by a factor XII-dependent pathway or by plasminogen activators. To prevent excess plasmin from lysing thrombi indiscriminately elsewhere in the body, free plasmin rapidly forms a complex with circulating α2-antiplasmin and is inactivated Objective 1-D  Anticoagulants are medicines that help Anticoagulant therapy prevent blood clots. They're given to people at a high risk of getting clots, to reduce their chances of developing serious conditions such as strokes and heart attacks Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood , As a class of medications, anticoagulants are used in therapy for thrombotic disorders.  Anticoagulants are closely related to anti- platelet drugs and thrombolytic drugs by manipulating the various pathways of blood coagulation. Specifically, antiplatelet drugs inhibit platelet aggregation (clumping together), whereas anticoagulants inhibit specific pathways of the coagulation cascade, which happens after the initial platelet aggregation and ultimately leads  to formation of fibrin and stable aggregated Heparins Heparin is a blood thinner that's used to treat and prevent blood clots and other clotting-related conditions. One of the anticlotting processes uses a type of blood protein called antithrombin. Heparin works by activating antithrombin, and then antithrombin keeps other parts of the clotting process from working normally  Haemodynamic disorders Tissue and cell activity depends on intact circulation to deliver oxygen to tissues and cells and on normal fluid homeostasis. Normal fluid homeostasis depends : Hydrostatic pressure Plasma osmotic pressure Endothelial integrity Lymphatic system Objective 2-A Under normal circumstance, there is a small net loss of fluid from the capillaries but this is drained by the lymphatics & thus edema does not accumulate. Objective 2-A Edema: refers to” increased fluid in the interstitial tissue spaces.” Objective 2-B  Mechanisms of edema: Either increased capillary pressure or diminished colloid osmotic pressure can result in increased interstitial fluid. Excess interstitial edema fluid is removed by lymphatic drainage, ultimately returning to the bloodstream via the thoracic duct; clearly, lymphatic obstruction (e.g., due to scarring or tumor) can also impair fluid drainage and cause edema. Finally, sodium retention (with its obligatory associated water) due to renal disease can also cause edema. Objective 2-B Causes of edema 1- Increased Hydrostatic Pressure: This is either A- localized edema or B- generalized (systemic) edema Objective 2-B  Increased Hydrostatic Pressure A- Localized (limited to an organ or limb) this is due to localized increase in intravascular pressure. Examples of localized edema are: Thrombosis of major veins of the lower extremity referred to as deep venous thrombosis (DVT); this can cause edema restricted to the distal portion of the affected Leg. Objective 2-B  Increased Hydrostatic Pressure B- Generalized edema: this is due to generalized increases in intravascular pressure, occurs most commonly in congestive heart failure, with involvement of the right ventricular cardiac function. Objective 2-B  Types of edema, according to cause Two types; Inflammatory oedema (called exudate) due to increased vascular permeability. It is a protein rich. Non-inflammatory oedema (called transudate). It is a protein poor. Objective 2-B  Differences between transudate & exudate edema Transudate: protein-poor Exudate: protein-rich edema edema fluid occurring in fluid secondary to increased hydrodynamic vascular permeability. disturbances. Specific gravity > 1.020 Specific gravity < 1.012. Protein rich (> 3 gm/dl). Protein poor (< 3 gm/ dl). High cellularity. Few cellularity. Results from increased capillary Results from increased capillary permeability in inflammation & pressure in cardiac failure, lymphatic obstruction reduced protein level in renal disorder. Objective 2-B  Thrombosis A thrombus, or blood clot, is the final product of the blood coagulation step in hemostasis, consisting of aggregated platelets, red Loading… blood cells that form a plug, and a mesh of cross-linked fibrin protein. Objective 3-A Types of thrombosis Thrombosis can occur anywhere in the body’s blood stream. There are two main types of thrombosis: Venous thrombosis, which is a blood clot that develops in a vein, and Arterial thrombosis, which is a blood clot that develops in an artery including chambers of the heart. Objective 3-A  Thrombosis Pathogenesis There are three primary influences on thrombus formation (called Virchow's triad): (1) endothelial injury, (2) stasis or turbulence of blood flow, and (3) blood hypercoagulability Objective 3-A  Endothelial injury (plays a major role in many arterial thrombi) Abnormal blood flow Turbulence of blood Hypercoagulability flow. Primary or a Reduction in blood genetic causes flow, stasis. Secondary (aquired) causes. Objective 3-A  Endothelial Injury It is particularly important for thrombus formation occurring in the heart or in the arterial circulation. It is important to note that endothelium need not be injured or physically disrupted to contribute to the development of thrombosis; any change in the dynamic balance of the prothrombotic and antithrombotic activities of endothelium can influence local clotting events Objective 3-A  Alterations in Normal Blood Flow Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction, as well as by forming countercurrents and local pockets of stasis; Stasis is a major contributor to the development of venous thrombi. Objective 3-A  Hypercoagulability It is loosely defined as any alteration of the coagulation pathways that predisposes to thrombosis, and it can be divided into: Primary (genetic) and Secondary (acquired) disorders Objective 3-A  Morphology Thrombi can develop anywhere in the cardiovascular system (e.g., in cardiac chambers, on valves, or in arteries, veins, or capillaries). The size and shape of a thrombus depend on the site of origin and the cause Thrombi in arteries and veins differ in composition, with arterial thrombi being platelet-rich and venous thrombi mainly composed of red blood cells and fibrin. Objective 3-A  Arterial Thrombi; Morphology Adherent masses of blood that demonstrate areas of pale alternating with areas of red – In large thrombi, lines of Zahn are seen grossly and microscopically: Platelet and fibrin layers (pale) alternating with layers of red blood cells (red). Objective 3-B  Venous Thrombi; Morphology – Almost occlusive because they are slow-moving in the vessel wall, they contain more RBC and called as a Red thrombi.  Fate of the Thrombus Propagation. Embolization.. Dissolution. Organization and recanalization. Objective 3-B Objective 3-B  Clinical Correlations: Venous versus Arterial Thrombosis The clinical difference between arterial and venous thrombosis lies in their pathophysiology, treatment, and associated risk factors. Arterial thrombosis primarily involves platelet activation and is treated with drugs targeting platelets, while venous thrombosis is more related to activation of the clotting system and is treated with drugs targeting proteins in the coagulation cascade Objective 3-B  Mural (cardiac) thrombosis A mural thrombus is an organizing blood clot attached to the wall of a blood vessel or the endocardium of the heart Mural thrombi can occur in large vessels like the heart and aorta, commonly due to conditions like atrial fibrillation, endocarditis, or post- myocardial infarction. Objective 3-C  Arterial (coronary) Mural (cardiac) thrombosis thrombosis Cardiac and Arterial Thrombosis Atherosclerosis is a major initiator of thromboses, because it is associated with loss of endothelial integrity and abnormal vascular flow. Cardiac mural thrombi can occur in the setting of myocardial infarction related to dyskinetic myocardial contraction as well as damage to the adjacent endocardium. Objective 3-B  Deep Vein Thrombosis (DVT) Deep vein thrombosis (DVT) is a condition characterized by a blood clot forming in a vein deep within the body, commonly in the legs. DVT can lead to serious complications if not treated promptly. Objective 3-C  DVT – Clinical Presentation Thrombosis often has few or no symptoms, ( silent condition (about 50% of patients. Therefore, it is important to be aware of the signs and risk factors of thrombosis. Objective 3-C Deep venous thrombosis: Clinical Deep Vein Thrombosis (DVT) Objective 3-C  Deep venous thrombosis can complicate: 1. Advanced age, bed rest, and immobilization 2. Cardiac failure is an obvious reason for stasis in the venous circulation. 3. Trauma, surgery, and burns usually result in reduced physical activity, injury to vessels. 4. Peripartum and postpartum states, late pregnancy and the postpartum period are associated with hypercoagulability. Objective 3-C Objective 4-A  A pulmonary embolism (PE) is a serious condition where one or more arteries in the lungs become blocked by a blood clot. This blockage can lead to decreased blood flow and oxygen levels in the lungs, potentially causing severe complications. In more than 95% of cases, venous emboli originate from deep leg vein thrombi above the level of the knee. Most pulmonary emboli (60% to 80%) are clinically silent because they are small. Objective 4-A Objective 4-A Objective 4-A Objective 4-A  Infarction This is defined as “localized area of ischemic cell necrosis in a living organ or tissue, resulting most often from sudden reduction or cessation of its arterial blood supply or occasionally its venous drainage” In 99% of cases, infarction results from thrombotic or embolic arterial occlusion. Objective 4-B  Gross features of infarction Infarcts are classified on the basis of their color (reflecting the amount of hemorrhage) :- Red (hemorrhagic) type: Organs with dual blood supply White (pale,anemic) type: Organ with single blood supply Objective 4-B  Red (Haemorrhagic) infaction In tissues with dual circulations such as small intestine, and lung permitting flow of blood from an unobstructed parallel supply into a necrotic area (such perfusion not being sufficient to rescue the ischemic tissues) White or anaemic infarcts occur in solid tissue with a single circulation and little collateral circulation, such as heart, kidney and spleen Renal white infarct Red (Hemorrhagic) infarcts of the lung Objective 4-B Objective 5-A Objective 5-A Objective 5-A Objective 5-A Objective 5-A Objective 5-B  Non Hemorrhagic causes hemorrhagic causes Gastrointestinal omiting DiarrheaBurns Trauma Post bleeding partum bleeding, Ectopic pregnancy Objective 5-B Objective 5-B Objective 5-B Objective 5-B Objective 5-B Objective 5-C Objective 5-C Objective 5-C