1. 1. Hemodynamic disorder - 1 Dr. Bahoran Singh
2. 2. Normal body composition Water composes about 60% of total body mass 3 body compartments containing H2O: Intracellular = 70% Interstitial = 25% Plasma = 5%
3. 3. Edema it is increased fluid in interstitial tissue space. When the fluid is deposited in cavities it is called as effusion. Hydrothorax is edema in the thoracic cavity. Hydropericardium is edema in the pericardial cavity, and hydroperitoneum is edema in the peritoneum.
4. 4. Pathophysiology of Edema Two opposing major factors governing fluid movement between vascular and interstitial space:
5. 5. 1. Increase in hydrostatic pressure Caused due to impair venous return Localized- deep venous thrombosis Systemic- Congestive cardiac failure 2. Reduced Plasma Osmotic Pressure Mainly due to albumin causes- Reduced albumin synthesis- liver diseases and PEM Excess loss
6. 6. Pathophysiologic Categories of Edema Increased Hydrostatic Pressure Impaired Venous Return Congestive heart failure Constrictive pericarditis Ascites (liver cirrhosis) Venous obstruction or compression Thrombosis External pressure (e.g., mass) Lower extremity inactivity with prolonged dependency Arteriolar Dilation Heat Neurohumoral dysregulation
7. 7. ) 2. Reduced Plasma Osmotic Pressure (Hypoproteinemia Protein-losing glomerulopathies (nephrotic syndrome) Liver cirrhosis (ascites) Malnutrition Protein-losing gastroenteropathy 3. Lymphatic Obstruction Inflmmatory Neoplastic Postsurgical Postirradiation
8. 8. 4. Sodium Retention Excessive salt intake with renal insuffiiency Increased tubular reabsorption of sodium Renal hypoperfusion Increased renin-angiotensin-aldosterone secretion 5. Inflmmation Acute inflmmation Chronic inflmmation Angiogenesis
9. 9. Mechanisms of systemic edema in heart failure, renal failure, malnutrition, hepatic failure, and nephrotic syndrome.
10. 10. Types of edema Transudate: protein poor (1.020 results from endothelial damage and alteration of vascular permeability e.g. inflammatory and immunologic pathology
11. 11. MORPHOLOGY Easily recognized grossly and microscopically Gross- Subcutaneous edema- In region of high hydrostatic pressure, influenced by gravity so called dependent edema. Pitting edema Renal dysfunction- appears initially in parts of the body containing loose connective tissue eg Periorbital edema
12. 12. Pulmonary edema- lungs are often two to three times their normal weight, sectioning yields frothy, blood-tinged flida mixture of air, edema, and extravasated red cells. Brain edema- narrowed sulci and distended gyri
13. 13. Hyperemia & Congestion Hyperemia Active process resulting from increased tissue blood flow because of arteriolar dilation, e.g. skeletal muscle during exercise or at sites of inflammation. The affected tissue is redder because of the engorgement of vessels with oxygenated blood.
14. 14. Congestion Passive process resulting from impaired outflow from a tissue. It may be systemic e.g. cardiac failure, or local e.g. an isolated venous obstruction. The tissue has a blue-red color (cyanosis), due to accumulation of deoxygenated hemoglobin in the affected tissues
15. 15. CONGESTION Chronic congestion Raised venous pressure Anoxia Metabolite accumulation Enlarged interendothelial gap Base membrane degeneration Parenchymal Interstitial fibrosis Atrophy Reticular fiber collapsed Increase permeability Degeneration Collagen increased Necrosis Fibroblast proliferation Microscopic scarring Edema Hemorrhage Congestive sclerosis
16. 16. Liver with chronic passive congestion and hemorrhagic necrosis. A, Central areas are red and slightly depressed compared with the surrounding tan viable parenchyma, forming a nutmeg liver pattern (so-called because it resembles the cut surface of a nutmeg).
17. 17. Centrilobular necrosis with degenerating hepatocytes and hemorrhage and hemosiderin laden macrophages
18. 18. Lung: Acute pulmonary congestion Gross: Plump swollen lung with shining pleura, edematous fluid flowing out while cutting the lung LM: Alveolar capillaries highly dilated (rosary- like appearance) and engorged with blood Alveolar cavity filled with eosinophilic edema fluid Manifestation Pink colored foamy sputum
19. 19. CONGESTION Lung: Chronic pulmonary congestion Gross: Hard, with brown spots scattered Brown induration LM: Septa thickened and fibrosis Alveolar spaces containing heart failure cells hemosiderin-laden macrophages Manifestation Rusty sputum, dyspnea, etc.
20. 20. HEMOSTASIS Normal hemostasis comprises a series of regulated processes that maintain blood in a fluid, clot-free state in normal vessels while rapidly forming a localized hemostatic plug at the site of vascular injury. - Normal Hemostasis : Transient arteriolar vasoconstriction Primary haemostasis Tissue factor Secondary haemostasis Counter regulatory mechanisms
21. 21. Hemostasis Arteriolar vasoconstriction- occurs immediately and markedly reduces blood flow Mediated by reflex neurogenic mechanism Augmented by endothelin. It is transient.
22. 22. Primary hemostasis and platelets plug formation endothelium disruption exposes subendothelial von Willebrand factor(vWF) and collagen Promotes plateletes activation and adhesion
23. 23. Secondary hemostasis- deposition of fibrin exposure of tissue factor at the site of injury leads to activation factor VII and culminate in thrombin generation. Thrombin cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin meshwork
24. 24. Clot stabilization and resorption Permanent plug formation occur by contraction of polymerized fibrin platelets aggregates. Activation of counter regulatory mechanism (t-PA) that limit clotting and leads to clot resorption and tissue repair.
25. 25. Prothrombotic Properties : - Platelet effects : Endothelial injury brings platelets into contact with the subendothelial ECM, which includes among von Willebrand factor (vWF), a large multimeric protein that is synthesized by EC. vWF is held fast to the ECM through interactions with collagen and also binds tightly to Gp1b, a glycoprotein found on the surface of platelets. These interactions allow vWF to act as a sort of molecular glue that binds platelets tightly to denuded vessel walls .
26. 26. Platelets Have critical role in hemostasis by forming the primary plug and by providing a surface that binds and concentrates activated coagulation factors. their function depends on several glycoprotein receptors, a contractile cytoskeleton and granules. Two types of cytoplasmic granules are present in platelets 1. granules 2. Dense() granules
27. 27. granules- have Adhesion molecule P- selectin Proteins involved in coagulation such as fibrinogen, Factor V, and vWF. Protein involved in wound healing fibronectin platelet factor 4( a heparin-binding chemokines) PDGF TGF- Dense granules contain ADP, ATP, ionised calcium, serotonin and epinephrine.
28. 28. Platelets plug formation Platelet adhesion- Mediated via interaction with vWF vWF acts as bridge between GpIb( platelet surface receptor and exposed collagen. deficiencies of either vWF (von Willebrand disease) or GpIb (Bernard- Soulier syndrome) result in bleeding disorder.
29. 29. Change in platelets shape smooth disc to spiky sea urchins increase in surface area and alteration in GpIIb/IIIa that increase affinity for fibrinogen and by the translocation of negatively charged phospholipids ( phosphatidylserine) to the platelets surface
30. 30. Platelets secretion (release reaction ) of granule contents occurs along with changes in shape; often referred to together as platelet activation. Thrombin activate platelets through G-protein coupled receptor referred as protease -activated receptor (PAR) which is switched on by a proteolytic cleavage carried out by thrombin. ADP causes additional activation of platelets this is called recruitment. Activated platelets release thromboxane A2(TxA2) an inducer of platelets
31. 31. PLATELET AGGREGATION following activation there is conformational change in GpIIb/IIIa allow binding of fibrinogen form bridge between adjacent platelets Inherited deficiency og GpIIb/IIIa results in Glanzmann thromboasthenia. Initial aggregation is reversible. concurrent activation of thrombin stabilizes platelet plug by further platelet activation and aggregation and by promoting irreversible platelet contraction.
32. 32. Platelet adhesion and aggregation.
33. 33. Coagulation cascade The coagulation cascade is series of amplifying enzymatic reaction that leads to deposition of insoluble fibrin clot.
34. 34. Coagulation Cascade
35. 35. Role of thrombin in hemostasis and cellular activation
36. 36. Factors that limit Coagulation Fibrinolytic system
37. 37. Anticoagulant activities of normal endothelium
38. 38. The normal flow of liquid blood is maintained by endothelial antiplatelet, anticoagulant and fibrinolytic properties. After injury or activation, endothelium exhibits several procoagulant activities. Endothelial cells are central regulators of hemostasis; the balance between the anti- and prothrombotic activities of endothelium determines whether thrombus formation, propagation, or dissolution occurs.
39. 39. Antithrombotic properties : Antiplatelet effects : Intact endothelium prevents platelets (and plasma coagulation factors) from engaging the highly thrombogenic subendothelial ECM. Nonactivated platelets do not adhere to normal endothelium; even with activated platelets, prostacyclin (i.e., prostaglandin I2 [PGI2]) and nitric oxide produced by endothelium impede their adhesion.
40. 40. Even if platelets are activated after focal endothelial injury, they are inhibited from adhering to the surrounding uninjured endothelium by endothelial prostacyclin and nitric oxide. Endothelial cells also produce adenosine diphosphatase, which degrades adenosine diphosphate (ADP) and further inhibits platelet aggregation.
41. 41. 2. Anticoagulant effects : These actions are mediated by factors expressed on endothelial surfaces, particularly heparin-like molecules, thrombomodulin, endothelial protein C receptor and tissue factor pathway inhibitor . The heparin-like molecules act indirectly: They bind and activate antithrombin III , which then inhibit thrombin and factors IXa, Xa, XIa, and XIIa.
42. 42. Thrombomodulin also acts indirectly: It binds to thrombin, thereby modifying the substrate specificity of thrombin, so that instead of cleaving fibrinogen, it instead cleaves and activates protein C, an anticoagulant. Endothelium is also a major synthetic source for tissue factor pathway inhibitor, a cell-surface protein that complexes and inhibits activated tissue factor factor VIIa and factor Xa molecules.
43. 43. 3. Fibrinolytic effects : Endothelial cells synthesize tissue type plasminogen activator(t- PA) , promoting fibrinolytic activity to clear fibrin deposits from endothelial surfaces.
44. 44. Hemorrhagic Disorders Disorders associated with abnormal bleeding inevitably stem from primary or secondary defects in vessel walls, platelets, or coagulation factors. 1. Defects of primary hemostasis (platelet defects or von Willebrand disease) present with small bleeds in skin or mucosal membrane it may be petechiae(1-2 mm) or Purpura slightly larger( 3 mm)than peteciae
45. 45. Mucosal bleeding associated with defects in primary hemostasis may also take the form of epistaxis(nosebleeds), gastrointestinal bleeding, or excessive menstruation (menorrhagia). Or Intracerebral hemorrhage.
46. 46. Punctate petechial hemorrhages of the colonic mucosa Fatal intracerebral bleed
47. 47. Defects of secondary hemostasis (coagulation factor defects) present with bleeds into soft tissues (e.g., muscle) or joints (hemarthrosis). Hemarthrosis following minor trauma is the characteristic of hemophilia
48. 48. Generalized defects involving small vessels present with palpable purpura and ecchymoses . Ecchymoses (bruises) Hemorrhage of 1-2 cm in size There is formation of hematoma due to extravasation of blood. these are characteristic of systemic disorders that disrupt small blood vessels (vasculitis) or lead to blood vessel fragility ( Amyloidosis and scurvy