Fluid & Hemodynamic Disorders Past Paper 2024-2025 PDF

CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. CH. I. FLUID AND HEMODYNAMIC DISORDERS Learning objectives/Subjects for the theoretical exam: 1. Define and classify, know the etiology of hyperemia 2. Enumerate the forms of active hyperemia, know the evolution of...

CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. CH. I. FLUID AND HEMODYNAMIC DISORDERS Learning objectives/Subjects for the theoretical exam: 1. Define and classify, know the etiology of hyperemia 2. Enumerate the forms of active hyperemia, know the evolution of hyperemia 3. Correlate the macroscopic aspects of active hyperemia with the microscopy 4. Enumerate and gives examples of passive hyperemia (congestion) in different organs 5. Explain the etiology and the consequences of the portal hypertension 6. Know the etiology and correlate the macroscopic changes with microscopy of passive congestion in the lung and liver 7. Define ischemia and enumerate the causes of the ischemia based of the type of blood vessel 8. Enumerate and explain the factors that determine the consequences of the ischemia 9. Enumerate and explain the effects of the ischemia 10. Define hemorrhage, classify, and give examples of hemorrhage based on pathogenesis 11. Classify the hemorrhage based on the topography and gives examples 12. Know the consequences of hemorrhage 13. Define thrombosis, enumerate, and explain the favoring factors of thrombosis 14. Enumerate and describe the morphological types of thrombi 15. Classify thrombosis by topography and make clinicopathologic correlations of thrombosis based on topography 16. Enumerate and describe the fate of thrombi 17. Define and classify embolism 18. Classify the embolism according to the direction of the emboli with examples 19. Give examples of embolism according to the nature of emboli 20. Define, classify, and explain the consequences of thromboembolism 21. Define the infarction and describe the morphology of infarction 22. Describe the morphology of the brain infarction 23. Describe the morphology of the lung and intestinal infarction 24. Describe the morphology of the lesions in disseminated intravascular coagulation 25. Describe the morphology of the lesions in shock 26. Define edema, enumerate the causes and describe the morphology of the lung and brain edema 27. Classify the forms of lymphedema based on the etiology 28. Describe the pathology of the lymphedema BLOOD FLOW DISORDERS HYPEREMIA Definition: the increase of blood flow to different tissues in the body Classification: - Active (arterial) hyperemia - Passive (venous) hyperemia Active (arterial) hyperemia Definition: increased blood inflow (arterial blood) to different tissues in the body Pathogenesis: - Mechanisms: produced by neurogenic stimuli or vasoactive substances - Effects: Arteriolar and capillary dilation, opening of inactive capillaries 1  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. Classification of arterial hyperemia: - Physiologic hyperemia: - Uterus and breast: premenstrual period (active hyperemia is responsible for the pelvic discomfort and breast tenderness) - Skeletal muscle during exercise (the blood flow increases 50 times) - Gastrointestinal blood vessels: after meal (more blood is necessary for the digestion) - Cerebral blood vessels associated with increased neuronal activity in the brain (blood flow increases 2 times) - Hot flushes in menopause (redness of the skin of the face and heat sensation due to age-related hormonal disturbance) - Blushing: reddening of the skin of the face, neck, anterior aspect of the thorax; triggered by emotional stress, especially in women - Pathologic hyperemia: - Systemic pathologic hyperemia: - Etiology: - Increased cardiac output: hypoxia (anemia, pulmonary diseases) - Increased metabolic activity: hyperthyroidism, fever - Localized pathologic hyperemia: crucial event in inflammation - Etiology: - The same etiological factors as for inflammation: - Physical agents: heat, cold, radiations, mechanical factors (stroking) - Biological agents: bacteria, viruses, parasites, fungi - Chemical agents: acids, bases, drugs, chemical mediators - Lumbar sympathectomy for Raynaud’s phenomenon or for peripheral arterial disease (by surgery or chemically): improves the blood flow in the lower limb Pathology of active hyperemia: Macroscopy: the tissue/organ/region: - Red color (erythema). Differential diagnosis with hemorrhage: hyperemia disappears on vitropressure (blanching test), hemorrhage not - Warm (arterial blood) - Swollen (because of edema) - The cut surface is hemorrhagic and wet Microscopy: - Dilation of precapillary arterioles (filled with blood) - High velocity of the blood (examined in vivo by capillaroscopy) - Edema Clinical features: pulsating pain Evolution: it is transient phenomenon → without sequelae Passive (venous) hyperemia Synonyms: venous hyperemia, stasis, passive congestion Definition: increased amount of venous blood in a tissue, organ, region of the body Pathogenesis: diminished or blocked venous drainage (impaired outflow) - Mechanism: an obstacle which impairs the blood outflow - Effects: dilation of veins, venules, and capillaries Classification: local, regional and systemic passive congestion Etiology: - Cardiac failure: systemic effects - Venous obstruction: local or regional effects - Luminal obstruction: thrombosis, embolism - Parietal causes: inflammation (phlebitis) - Compression: tumors; enlarged lymph nodes (because of metastases, lymphoma, inflammation: tuberculosis, sarcoidosis); casts; wounds, tourniquet 2  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. Components of passive congestion: - Edema (venous hyperemia and edema commonly occur together): - Mechanism of edema: - Increased fluid transudation because of increased intravascular pressure - Vascular hyperpermeability because of the lesions of the blood vessel wall due to chronic hypoxia - Cell degeneration or death (chronic hypoxia) → replaced by fibrosis (scarring) - Small foci of hemorrhage (injury of the capillaries) → breakdown of the red cells, phagocytosis of the hemosiderin by macrophages (siderophages) Pathology of passive congestion Macroscopy: - Acute congestion: - Organs are larger and heavier than normal, with rounded borders, distended capsule, increased consistency, blue-red colored (cyanosis) - The cut surface: hemorrhagic and wet, with venous blood - The skin is cold - Chronic congestion: - Firm consistency (fibrosis) - On cut section: dry appearance, brown color (hemosiderin) Microscopy: - Acute congestion - Dilated veins, venules and capillaries, filled with blood - Edema - Small foci of hemorrhage - Chronic congestion - Fibrosis - Hemosiderin: in macrophages (siderophages) or extracellular Local passive congestion Definition: involves one vein → one limb or organ (i.e., spleen) Etiology: see above (intraluminal obstacles, parietal causes, compression) Effects: edema and cyanosis in the affected territory Regional passive congestion Definition: involves a venous trunk → it affects more organs Examples: superior vena cava, inferior vena cava, portal vein Clinical effects: superior vena cava syndrome, inferior vena cava syndrome, portal hypertension Superior vena cava syndrome (SVCS, Passive congestion of the superior vena cava) Etiology: - Compression: mediastinal tumors, mediastinal adenopathy (tuberculosis, sarcoidosis, metastases) - Thrombosis (complication of venous catheterism), embolism Effects: edema and cyanosis of the head, neck, shoulders, upper chest 3  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. Portal hypertension (Passive congestion of the portal vein, portal stasis) Etiology: Presinusoidal causes: - Extrahepatic: - Portal vein: portal vein thrombosis, portal vein phlebitis, neoplastic invasion, compression (adenopathy at the hepatic hilum) - Thrombosis of other veins: superior mesenteric, - Intrahepatic: congenital liver fibrosis, primary biliary cirrhosis, sarcoidosis, schistosomiasis, Wilson’s disease, malaria, toxic substances: arsenic, PVC fumes Sinusoidal causes: 90% of cases of portal congestion - Liver cirrhosis - Sclerosing cholangitis Postsinusoidal causes: - Venooclusive disease - Congestive heart failure - Budd Chiari syndrome (thrombosis of the hepatic veins) - Constrictive pericarditis The main causes of the portal congestion are: - Liver cirrhosis - Lesions of the portal vein: neoplastic invasion (hepatocellular carcinoma), thrombosis, phlebitis, compression Effects: increased pressure within the portal vein → portal hypertension Consequences of the portal hypertension = portal hypertension syndrome - Splenomegaly: because of chronic congestion (impaired splenic vein blood flow) - Collateral circulation (collateral pathways): connections between the portal vein system and the inferior vena cava system (portosystemic or portocaval shunts): - Esophageal varices: - Dilation of the submucosal veins - Located in the lower third of the esophagus - Risk of spontaneous rupture after vomiting → life-threatening hemorrhage - Rectal varices/Hemorrhoids - Caput medusae: distended and engorged paraumbilical veins - Ascites: edema fluid in the peritoneal cavity Systemic (generalized) passive congestion Etiology: right-sided heart failure, congestive heart failure Pathophysiology: increased blood pressure in the following territories: - Superior vena cava → dilation of jugular veins - Inferior vena cava → visceral congestion - Microcirculation → peripheral (cutaneous) edema, transudates 4  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. PULMONARY PASSIVE CONGESTION (PULMONARY STASIS) Pathogenesis: the inability of the left heart to evacuate the pulmonary venous blood → increased pressure in the left atrium → initially increased pressure in the pulmonary veins, and then increased pulmonary capillary pressure. Etiology: Acute passive congestion: - Acute left-sided heart failure, more commonly related to myocardial infarction of the left ventricle. The histology is dominated by the edema (changes develop rapidly) Chronic passive congestion: - Mitral stenosis - Chronic left-sided heart failure Pathology: Acute congestion Macroscopy: - Increased weight and volume of the lungs, rounded borders, bluish color - Cut section: wet appearance, large amount of venous blood Microscopy: - Alveolar walls are dilated: capillaries filled with blood ± edema, microhemorrhage (few red blood cells leave the capillaries because of the hyperpermeability that follows the increased intravascular pressure) - Alveolar spaces: edema fluid, red blood cells Chronic congestion: “brown induration of the lung” Macroscopy: - Lungs have firm consistency - Dry aspect on cut section - Brown color Microscopy: - Pulmonary capillaries are distended, with blood - Within the interstitium: hemosiderin, fibrosis - Within the alveoli: hemosiderin-laden macrophages (siderophages) !!! Hemosiderin, a brown pigment, originates from the degradation of extravasated red blood cells. Its presence in the interstitium determines the proliferation of fibrous connective tissue (fibrosis). The association between hemosiderin and fibrosis explains the brown color and firm consistency of the lung with chronic stasis ("brown induration"). Hemosiderin is phagocytized by the alveolar macrophages, which become siderophages; they are eliminated in the airways and can be identified in the sputum of the patients as "heart failure cells" Effects of lung congestion: - Impairment of gas diffusion across the alveolar-capillary membrane (because of edema or of fibrosis) - Decrease of pulmonary excursions (because of fibrosis) → ventilatory restriction - Pulmonary artery hypertension → cor pulmonale: right-sided heart failure → congestive heart failure. The most frequent etiology of the right-sided heart failure is the left-sided heart failure (pulmonary congestion) !!! 5  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. LIVER PASSIVE CONGESTION (PASSIVE HEPATIC CONGESTION) Etiology: right-sided heart failure, congestive heart failure Pathogenesis: increased pressure in the right atrium → inferior vena cava → hepatic veins → pathological consequences mainly in the liver The pathology of liver passive congestion Acute congestion Macroscopy: - The liver is enlarged (hepatomegaly), heavy, with rounded borders, the capsule is distended - After cutting: blue-red color of the blood, the capsule becomes wrinkled - Wet, hemorrhagic appearance on the cut section, homogenous Microscopy: - The centrilobular venules are distended, with blood - When the stasis is severe, there may be central hepatocyte degeneration/death (central hemorrhagic necrosis) – it can be fatal Chronic congestion Macroscopy: “nutmeg liver” - Mottled appearance on cut section (“nutmeg liver”): dark-red spots surrounded by a paler or yellowish area ± normal liver at the periphery - In advanced stages, the liver is contracted, firm, brown, with granular surface - “cardiac fibrosis of liver” (suggesting the cardiac etiology of the liver disease) or “cardiac cirrhosis” (a misnomer, while this is not a real cirrhosis) Microscopy: - One can see three regions with different histological aspects - Centrilobular zone: - The centrilobular venules and surrounding sinusoids are dilated, full of red blood cells (correspond to the dark-red points described macroscopically) - Hepatocytes around centrilobular venule are atrophied (due to the compression exerted by the enlarged sinusoids and to hypoxia) - Midlobular zone: - Hepatocytes loaded with fats (triglycerides) = fatty change (steatosis), due to chronic hypoxia related to blood stagnation in sinusoids. With hematoxylin-eosin (HE) staining, clear vacuoles are observed in the cytoplasm of the hepatocytes (this area corresponds to the macroscopically described yellow area) - Periportal zone (the periphery of the lobule): normal-looking hepatocytes (the blood coming through the hepatic artery provides the oxygen necessary to maintain cell integrity) - In advanced stages: fibrotic proliferation disrupting hepatic parenchyma, starting from the centrilobular region (replaces missing hepatocytes due to prolonged hypoxia). It differs from hepatic cirrhosis, where fibrosis delineates liver regenerative nodules. CONGESTIVE SPLENOMEGALY Etiology: heart failure, portal obstruction (liver cirrhosis – the most common etiology), splenic vein thrombosis Pathology: Macroscopy: long-standing congestion produces marked enlargement of the spleen (1000 gm →5000 gm). The spleen is firm, the capsule is usually thickened and fibrous. On cross section it has a meaty appearance and varies from deep red to gray-red, depending on the amount of fibrosis. Often the white pulp is indistinct Microscopy: the red pulp initially is congested, and then becomes more fibrous and cellular, with deposition of collagen in the basement membrane of the sinusoids. There may be seen foci of recent hemorrhage or old hemorrhage foci, which become organized, with fibrosis, hemosiderin and calcium salts deposits, forming Gamna-Gandy nodules (Gamna-Gandy bodies, siderotic nodules) Effects of the splenic congestion: fibrosis of sinusoids → rigidity of their walls → slowing of blood flow from the cords to the sinusoids → prolongs the exposure of the blood cells to the cordal macrophages → excessive destruction (hypersplenism) → therapeutic splenectomy may be considered in these patients. 6  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. ISCHEMIA Definition: decreased blood flow to an area of the body Etiology: 1. Arterial obstruction - Functional: vasospasm - Raynaud’s phenomenon - Chemical agents: nicotine, ergotamine - Organic: - Lesions of the wall: atherosclerosis, arteritis, Mönckeberg medial sclerosis - Obstruction: thrombus, embolus - Extrinsic compression: tumor, lymph nodes, tourniquet, scar, cast 2. Capillary obstruction - Endothelial lesions: frostbite - Occlusion: - Abnormal red cells (sickle cell disease) - Fibrin (DIC - disseminated intravascular coagulation) - Emboli: fat embolism, gas embolism - Extrinsic compression: decubitus ulcers (“pressure ulcer”, “bed sore”). Pressure ulcers are areas of ischemic necrosis of the skin produced by the compression of the dermal capillaries between the bed and the bone prominences. They occur in individuals who are bedridden or confined to a wheelchair, because of severe heart failure, cancer, fractures, comatose. The ulcers are located on the skin over the bony prominences: sacrum, coccyx, heels or the hips, elbows, knees, ankles, back of shoulders, or the back of the cranium. 3. Venous obstruction – main venous trunks Pathophysiology: venous occlusion and engorgement, with subsequent arterial ischemia causing infarction Examples: - Mesenteric veins, strangled hernias → intestinal infarction - Spermatic cord (testicular torsion) → the most frequent cause of testicle loss in male adolescent - Thrombosis of the superior longitudinal (sagittal) sinus → hemorrhagic necrosis of the cerebral cortex Factors that determine the consequences of the ischemia 1. Previous blood or cardiovascular diseases: - Anemia, chronic hypoxia (because of chronic pulmonary diseases) - Heart failure, shock Effects of ischemia are more severe in these situations. 2. Tissue resistance during hypoxia: - CNS: neurons: 3-5 min; glial cells are more resistant - Myocardium: 20-30 min. - Liver: 20-30 min. - Kidney: 30-50 min. - Gut mucosa: 6 h - Skeletal muscles: 6-12 h skin: 6-12 h - Fibrous tissue: the most resistant à → ensures the repair of cells/tissues damaged by ischemia (scar formation) 3.The pattern of arterial supply: - *Double systems: lung, liver - *Parallel systems: forearm - *Large anastomoses: intestinal arterial arcades - Terminal arteries: kidney, spleen, brain, retina 7  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. !!! The effects of ischemia are less severe in the first three cases (*): no infarct. Ischemia in organs with terminal arteries leads to infarct. The heart has a particular situation: the coronary arteries have small branches with reduced anastomoses → ischemia has dramatic consequences: infarct 4. The type of the ischemia: - Slow, partial obstruction allows the development of collaterals → scleroatrophy - Sudden, complete obstruction → infarct. The effects of ischemia Functional manifestations Pathogenesis: - At rest, there is enough blood (oxygen)in tissues and organs - With increasing demand of blood, the patients develop functional manifestations (without morphological changes): pain Examples: - Angina pectoris: chest pain in individuals with ischemic heart disease (affectation of the coronary arteries) - Intermittent claudication: pain affecting the calf that is induced by exercise (walking) in individuals with peripheral arterial disease of the lower extremities Tissue lesions - Long standing (chronic) ischemia affects isolated cells: because of hypoxia, initially there will be the atrophy then the death of the cells, which will be replaced by fibrosis → scleroatrophy - Heart: diffuse cardiosclerosis in individuals with chronic ischemic heart disease - Lower extremities: PAD (peripheral arterial disease) → atrophy of calf muscles, the skin is thin and dry, without hair, cold - Sudden (acute) ischemia or complete obstruction of an artery determine ischemic necrosis: - Infarction: myocardium, brain, kidney, spleen - Gangrene: leg HEMORRHAGE Definition: the loss of blood from the circulatory system (blood extravasation) Source: - Arterial: bright red, the blood "spurts" from the wound - Venous: dark red, the blood flows in a steady stream - Capillary: slow, oozing - Cardiac: massive Pathogenesis (mechanisms): - Rupture of the wall (“per rhexin”): blood vessels (tear of the vessel wall in trauma, open fractures); heart (trauma, myocardial infarct, aortic dissection) - Erosion of the wall (“per diabrosin”) – ulcer (stomach, duodenum), malignant tumors of the gastrointestinal tract, tuberculosis or cancer of the lung - Diapedesis (“per diapedesin”) - increased blood vessel permeability - leakage) - Lesions of the vascular wall: vasculitis, hypovitaminosis C - Platelets disorders - Coagulation disorders Topographic classification of hemorrhage External hemorrhage Definition: visible on the outside of the body Etiology: trauma (open fractures, sectioning of an artery) 8  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. Externalized hemorrhage Definition: blood flowing from natural orifices → ears, nose, mouth, urethra, vagina, anus Source of bleeding: hollow organs (bronchi, esophagus, etc.) Examples of externalized hemorrhages: - Epistaxis: acute hemorrhage from the nostril, nasal cavity, or nasopharynx - Hemoptysis: expectoration (coughing up) of blood or of blood-stained sputum from the upper airways or lungs (tuberculosis, cancer) - Otorrhagia: bleeding from the external auditory canal of the ear (fractures of the skull base) - Gingivorrhagia: bleeding from the gums - Stomatorrhagia: bleeding from the oral mucosa - Hematemesis: vomiting of blood. Significance: upper digestive hemorrhage (UDH) – esophagus, stomach, duodenum. The blood may be bright-red or brown or black, looking like coffee grounds (digested). - Melena: black, "tarry" feces, associated with gastrointestinal hemorrhage (UDH). The black color is caused by oxidation of the iron in hemoglobin during its passage through the ileum and colon - Rectorrhagia: bright-red bleeding (fresh blood) through the anus not related to defecation. It occurs in lower digestive hemorrhage (LDH) – may be from rectal cancer or cancer of the anus - Hematochezia: passage of fresh blood through the anus while defecating; the most common causes are diverticulitis, hemorrhoids (LDH) - Menorrhagia: abnormally heavy and prolonged menstrual period at regular intervals - Metrorrhagia: uterine bleeding at irregular intervals, particularly between the expected menstrual periods (not synchronized with the menstrual period) - Hematuria: the presence of red blood cells (erythrocytes) in the urine (tumors or lithiasis of the urinary tract) Internal hemorrhage Definition: hemorrhage inside the body, that does not communicate with the exterior of the body Classification: interstitial hemorrhage; hemorrhage in the body cavities Interstitial hemorrhage Sites: skin, mucous membranes, serosal surfaces, parenchymatous organs Subclassified based on the size: - Petechia: minute 1- to 2-mm, red - Purpura: ≥ 3 mm, initially red, then brown - Ecchymosis: ≥ 1 cm, color is variable, depending on the age of the lesion (blue, green, yellow), irregular border - Hematoma: collection of blood, generally well demarcated Petechia, purpura, and ecchymosis are usually located on the surfaces (skin, mucous membranes, serous membranes), but may be found in parenchymal organs (petechia on the surface of the kidney, cerebral purpura). Hematoma may be in parenchymal organs (liver, spleen, brain), muscles, subcutaneous tissue. Hemorrhage in body cavities - Hemothorax: hemorrhage in the pleural cavity (trauma, tumors of the lung) - Hemopericardium: hemorrhage in the pericardial cavity (rupture of a myocardial infarction, aortic dissection, trauma) - Hemoperitoneum: hemorrhage in the peritoneal cavity (trauma, rupture of the liver or spleen, ruptured tubal pregnanacy) - Hemarthrosis: hemorrhage in the joints (trauma, hemophilia) - Hematocele: hemorrhage in the vaginala testis - Hematosalpinx: hemorrhage in the fallopian tube (ectopic pregnancy) 9  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. Evolution of hemorrhagic focus - Complete resorption: small hematomas, subcutaneous (15-20 days) - Neutrophils, macrophages intervene and remove the debris - Organization: - Medium-sized hematomas - Granulation tissue → scar ± siderotic nodules - Encapsulation: large hematomas, deep seated are transformed into cysts (pseudocyst) - Macroscopy: - Fibrous capsule - greysh-white - Fluid content (cyst-like): xanthochromic, reddish, brownish - Microscopy: fibrous tissue at the periphery - Hemosiderin-laden macrophages extracellular hemosiderin hematoidin crystals - Calcium salts - Treatment: surgery - Complication: infection → abscess - Differential diagnosis: cyst, tumor Consequences of hemorrhage Systemic effects: - Single small or medium-sized hemorrhages → no effects - Repeated (chronic) small or medium-sized → chronic anemia (iron-deficiency anemia) - Acute massive hemorrhages → hemorrhagic shock, death - Extensive hemorrhage → jaundice (massive breakdown of red blood cells and systemic release of bilirubin) Local effect: - Compression - Subdural hematoma → compression atrophy of the brain - Hemopericardium → cardiac tamponade - Hemothorax → dyspnea, pulmonary collapse - Other - Small cerebral hemorrhage: focal irritation → seizures - Retina hemorrhage → blindness - Liver, splenic hemorrhage → rupture of the organs THROMBOSIS Definition: is the formation of a clot (thrombus) inside a blood vessel or inside the heart in living individuals Thrombus: is a solid mass of blood constituents Pathogenesis of thrombosis (Virchow’s triad) 1. Endothelial injury 2. Alterations in normal blood flow 3. Hypercoagulability 1. Endothelial injury Observations: The intact endothelial cells serve primarily to inhibit platelet adherence and blood clotting. Injury or activation of endothelial cells results in a procoagulant phenotype that augments local clot formation Types of endothelial injury: - Lesions → expose the highly thrombogenic subendothelial ECM - Functional disturbances: ↑ the production of procoagulant factors; ↓ the production of anticoagulant factors Etiology of endothelial injury - In the blood vessels: - Arteries: atherosclerosis, hemodynamic stress (hypertension), arteritis, chemical agents (nicotine) - Veins: sclerosing substances, mechanical agents (catheters), hypoxia, neoplastic invasion - Capillaries: physical agents (frostbite) 10  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. - In the heart: - Mural (parietal) endocardium: infarct, endocarditis, surgery - Valvular endocardium: infectious endocarditis, rheumatic endocarditis 2. Alterations in normal blood flow - Stasis and turbulences: effects - Disrupt the laminar flow and bring platelets into contact with the endothelium - Prevent dilution of activated clotting factors by fresh flowing blood - Retard the inflow of clotting factor inhibitors → permit the build-up of thrombi - Promote endothelial cell activation, predisposing to local thrombosis Examples Stasis: - Systemic: heart failure, hyperviscosity syndromes (e.g., polycythemia) - Localized: - Veins: prolonged immobilization, varices - Arteries: aneurysms - Heart: - Ventricles: dilated cardiomyopathy, myocardial infarction (MI), post-infarction aneurysm - Left atrium: mitral stenosis, atrial fibrillation Turbulence: aneurysms, bifurcation points, atherosclerosis, valvular vegetations 3. Hypercoagulability Hypercoagulable States Primary (Genetic) - Thrombophilia Common: mutation in factor V gene (factor V Leiden); mutation in prothrombin gene; mutation in methyltetrahydrofolate gene Rare: antithrombin III deficiency; protein C deficiency; protein S deficiency Very rare: fibrinolysis defects Secondary (Acquired) High risk for thrombosis Prolonged bed rest or immobilization, Myocardial infarction, Atrial fibrillation, Tissue damage (surgery, fracture, burns), Cancer, Prosthetic cardiac valves, Disseminated intravascular coagulation, Heparin-induced thrombocytopenia, Antiphospholipid antibody syndrome (lupus anticoagulant syndrome) Lower risk for thrombosis Cardiomyopathy, Nephrotic syndrome, Hyperestrogenic states (pregnancy), Oral contraceptive use, Sickle cell anemia, Smoking Morphology of thrombi !!! General features - Thrombi may develop anywhere in the cardiovascular system - An area of attachment to the underlying vessel or heart wall is characteristic of all thrombi - Thrombi often have macroscopically and microscopically apparent laminations called lines of Zahn, which are pale platelet and fibrin deposits alternating with darker red cell–rich layers. The lines of Zahn signify that a thrombus has formed in flowing blood; their presence can therefore distinguish antemortem clots from the bland nonlaminated clots that occur postmortem - Microscopy: all thrombi are formed by platelets + fibrin network Classification: 1. Relationship to the lumen: - Occlusive: blood vessels (small, medium-sized, veins) - Parietal (partial): heart chambers, aorta, large aneurysms 2. Size, shape: are variable, depending on site of origin (usually thrombi adopt the shape of the lumen) 3. Color, structure: white, red, mixed, hyaline thrombi 11  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. White thrombi: appear in regions with rapid blood flow: arteries, cardiac valves - Grow slowly - Macroscopy: - White - Dull, dry surface, friable - Firm - Microscopy: platelets + fibrin network (the platelets predominate) - Platelets cannot be seen with light microscopy - The fibrin is a meshwork of eosinophilic filaments Evolution: they become laminated (alternating pale and red areas – lines of Zahn), after new waves of platelets are added (in the chambers of the heart, in the aorta) Red thrombi: in regions with slow blood flow (stasis): veins, cardiac aneurysm, LA, behind an occlusive white thrombus, varicose veins - Formed rapidly by the coagulation of stagnating blood - Macroscopy: - Dark red color - Surface: lines of Zahn, dull - Firm consistency - Because of the contraction of the fibrin, they can be partially detached from the wall (seem to float in the lumen of the blood vessel) - Microscopy: platelets + fibrin network + blood cells (red blood cells predominate) - Difficult to be differentiated from blood clots during autopsies (see table) Mixed thrombi: veins - Macroscopy: - Head: white, adherent to the endothelium - Body: laminated (alternating white and red layers) → lines of Zahn - Tail: red - Microscopy: - Head: like white thrombus - Body: alternating white-red thrombus - Like red thrombus Hyaline thrombi: in capillaries, in disseminated intravascular coagulation, formed by fibrin and disintegrated platelets Differential diagnosis between red thrombus and postmortem blood clot Thrombus Blood clot In blood vessels or in the chambers of the Outside blopd vessels or heart chambers, in heart, in living individuals living individuals or inside, postmortem Attached to the underlying endothelium or Not attached to the wall endocardium Friable Elastic Firm Gelatinous Undeformable Deformable Dull Shiny Presence of the lines of Zahn Lines of Zahn are absent. Postmortem clots have a dark red dependent portion where red cells have settled by gravity and a yellow “chicken fat” upper portion. Topography of thrombosis Classification: - Cardiac thrombosis - Arterial thrombosis - Venous thrombosis 12  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. Clinicopathological correlations of thrombosis Cardiac thrombosis - Parietal (mural) endocardium: red thrombi - LA (left atrium): mitral stenosis, atrial fibrillation - LV (left ventricle): MI (myocardial infarction), myocarditis, cardiomyopathy - Valvular endocardium: white thrombi - Rheumatic endocarditis: verrucous endocarditis (verrucae - warty-like) - Infective endocarditis: vegetant endocarditis (vegetations) - Complications: systemic embolism → infarction Arterial thrombosis - Morphology: commonly white thrombi - Sites: - Aorta and large branches (iliac, common carotid): parietal, laminated thrombi - Medium-sized arteries (coronaries, cerebral, femoral, mesenteric): occlusive thrombi - Aneurysms: usually parietal - Risk factors: atherosclerosis, arteritis, severe HBP (high blood pressure) - Tend to grow in a retrograde direction from the point of attachment - Complications: - Obstruction → ischemia - Thromboembolism → infarction Venous thrombosis (phlebothrombosis) Deep vein thrombosis - Almost invariably occlusive - The thrombus often creates a long cast of the vein lumen - Red (or stasis) thrombi 1. Deep veins of the lower limbs (90%) - Risk factors - Recent surgery or hospitalization (40% of the patients did not receive heparin prophylaxis) - Prolonged immobilization, bed rest - Advanced age, obesity, infection, female sex - Hormonal contraception - Air travel: "economy class syndrome“: immobility and relative dehydration (!!! compression socks) - Thrombophilia - Sites - Usually develop first in the calf veins – supravavular sinuses - Extend in the direction of blood flow (i.e., toward the heart): iliac vein, inferior vena cava - Complications: occlusion of the vein - Acute effects: edema, cyanosis - Chronic effects: - Postthrombotic syndrome (skin pigmentation, dermatitis, ulceration) - Embolism: pulmonary embolism: may be lethal!! 2. Pelvic veins: surgery, inflammations, neoplasia, delivery, abortion 3. Portal vein and branches: inflammation, neoplasia 4. Superior longitudinal sinus of dura mater - Aseptic thrombosis: - Infants: severe dehydration - Marantic patients: cancer, tuberculosis, AIDS - Septic thrombosis: infections in the tributary veins territory - sepsis 5. Migratory thrombophlebitis: Trousseau sign – recurrent deep and superficial thrombosis in patients with cancers (pancreas, prostate, colon) 13  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. Superficial vein thrombosis - Lower limbs - In the saphenous system (frequently associated with varicosities) - It is not life threatening - Favors local infections, varicose ulcers Capillary thrombosis Example: in disseminated intravascular coagulation (DIC) Fate of thrombi 1. Dissolution (autolysis): the thrombus may be removed by fibrinolytic activity - Mechanism: activation of the plasminogen - plasmin (fibrinolytic) system - Effects: - Small thrombi: complete lysis - Large thrombi: partial lysis - Remarks: - More effective in early stages - Usually in the case of venous thrombi 2. Embolization: thrombi may dislodge and travel to other sites in the vasculature → thromboembolism 3. Propagation: the thrombus may accumulate more platelets and fibrin (propagates), eventually leading to vessel obstruction. Arterial thrombi tend to grow retrograde, while venous thrombi extend in the direction of blood flow; thus, both propagate toward the heart. The propagating portion of a thrombus is often poorly attached and therefore prone to fragmentation and embolization. 4. Softening: the center of large aneurysmal or cardiac thrombi - Aseptic softening: produced by the neutrophil enzymes - Septic: bacterial enzymes - Result: fragmentation → embolization - Aseptic fragments → infarction - Septic fragments → septic infarction, abscess 5. Organization: thrombus is replaced by granulation tissue and transformed into a fibrous scar - Phases of the organization of the thrombus: - Ingrowths of endothelial cells, smooth muscle cells, and fibroblasts into the fibrin-rich thrombus = granulation tissue - Formation of capillary channels (new capillaries): they convert the thrombus into a vascularized mass of connective tissue - With time blood vessels close, the fibroblasts proliferate (maturation)→ the thrombus is transformed into a fibrous scar - Effects: - Stabilization of the thrombus and avoiding embolism - Because the contraction of the mesenchymal cells (particularly for smaller thrombi), the connective tissue may be incorporated as a subendothelial swelling of the vessel wall - Larger thrombi remain as permanent internal obstacle Particularities: - New capillaries may anastomose to create conduits from one end of the thrombus to the other, re-establishing, to a limited extent, the continuity of the original lumen: recanalization - Calcification: calcium salts deposits within an organized thrombus. Mainly on the cardiac valves or in venous thrombi, which are transformed into phleboliths (venous “stones”). Sometimes the calcified thrombi my contain areas of bone tissue with medullary spaces (osseous metaplasia) 14  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. EMBOLISM Definition: traveling of a foreign material (i.e., blood clot, air bubble, etc.), named embolus, through the bloodstream Classification: - Based on the traveling direction of the embolus - Based on the nature of the embolus A. Forms of embolism based on the direction of the embolus 1. Anterograde (direct) embolism: emboli move in the direction of blood flow - The most frequent form - Examples: - From the deep vein thrombosis of the leg → femoral vein → iliac vein → inferior vena cava - From the right atrium → right ventricle → pulmonary artery - From the left atrium → left ventricle → aorta → branches → various organs 2. Paradoxical embolism: emboli from the venous system reach the systemic arterial circulation Pathogenesis: Emboli passing through an abnormal communication: - Between the chambers of the heart: ASD, VSD - Patent ductus arteriosus - Pulmonary arteriovenous malformation Origin: mainly the deep vein thrombosis (lower limbs) Importance: - The major cause of cerebral ischemic events in young patients - Can be presumed in the presence of arterial embolism with no evidence of left-sided circulation thrombus Minute emboli passing through the capillary bed of the lungs (fat, air embolism) 3. Retrograde embolism: the emboli move in opposition to the blood flow direction - Significant in blood vessels with low pressure (veins) or with emboli of high weight - Examples: - A thromboembolus from the inferior vena cava into renal vein - Tumoral emboli from the paravertebral venous plexus of Batson to vertebral body → vertebral metastases in lung, renal cell, and prostatic cancers B. Forms of embolism based on the nature of the embolus 1. Thromboembolism Definition: the embolus is a thrombus Incidence: the most common form (90%) Classification: arterial thromboembolism; venous thromboembolism a) Arterial thromboembolism = systemic thromboembolism Sources: - Cardiac thrombosis (80%): - Parietal thrombus: left ventricle (myocardial infarction); left atrium (mitral stenosis, fibrillation) - Valvular thrombus: fragmented vegetations (endocarditis) - Arterial thrombosis: aorta and its branches (aneurysms, atherosclerosis) Effects: ischemia in the distal territories - lower extremities, brain, intestine, kidney, spleen, heart, retina b) Venous thromboembolism = pulmonary thromboembolism (PE) Sources: deep vein thrombosis anywhere in the body - Deep veins of lower extremities - Pelvic veins - Deep veins of upper extremities: axillary vein, subclavian vein - Right atrium 15  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. Effects: thromboemboli reach the pulmonary circulation = pulmonary thromboembolism → effects depend on the size of the embolus: - Large thromboemboli (massive pulmonary thromboembolism) occlude the main pulmonary artery or impact across the bifurcation (saddle embolus) → sudden death because of: - Acute right heart failure (acute cor pulmonale) - Cardiovascular collapse (if 60% or more of the pulmonary circulation is obstructed with emboli) - Reflex coronary spasm - Medium-sized emboli: - Occlude the of medium-sized arteries → pulmonary hemorrhage. Usually, they do not produce pulmonary infarction (dual blood flow into the area from the bronchial circulation). With time, the blood is reabsorbed, and the lung returns to normal. - Infarction is possible in the setting of left-sided cardiac failure or pulmonary diseases that compromise the bronchial circulation. - Small emboli occlude the small end-arteriolar pulmonary branches → infarction or hemorrhage - Multiple recurrent small emboli determine pulmonary hypertension → right heart failure Remarks: PE is an often-fatal complication of underlying venous thrombosis. Most pulmonary emboli are clinically silent because they are small. Pulmonary embolism may be produced by other types of emboli (fats, gas, amniotic fluid etc.) 2. Fat embolism Pathogenesis: fat droplets are deposited in the pulmonary capillary beds and travel through arteriovenous shunts to the brain Etiology: - Fractures of long bones (which have fatty marrow) - Soft tissue trauma (rarely) e.g., liposuction - Joint reconstruction - Severe burns Incidence: 90% from individuals with severe skeletal injuries Effects: Fat embolism syndrome - Incidence: 10% of individuals with severe skeletal trauma - Pathogenesis: microvascular lodging of droplets produces local ischemia and inflammation, with concomitant release of inflammatory mediators, platelet aggregation, and vasoactive amines - Clinical manifestations: sudden onset, 1-3 days after injury - Pulmonary insufficiency: tachypnea, dyspnea, tachycardia - Neurologic symptoms: irritability, restlessness, delirium, coma - Anemia (consequence of erythrocyte aggregation and hemolysis) - A diffuse petechial rash in nondependent areas: because of the thrombocytopenia (presumably caused by platelets adhering to the myriad fat globules and being removed from the circulation) - Prognosis: fatal in up to 10% of cases Pathology Microscopy: autopsy - Frozen sections and fat stains (e.g., Scharlach rot, Oil red, Sudan III) - Fat microglobules (i.e., in the absence of accompanying marrow): within the capillaries of lung, brain 3. Gas embolism: Pathogenesis: the bubbles act like physical obstructions and may coalesce to form frothy masses sufficiently large to occlude major vessels. 16  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. a) Air embolism Etiology: - In the brain: surgery in the head and neck region - In coronary arteries: interventions for coronary artery bypass grafting - In the lungs (venous route): infusions, births, abortions (air is sucked into the uterine veins), insufflation of the fallopian tubes, hemodialysis, laparoscopy, thoracic trauma Effects: - In the right heart: a foam forms in the right ventricle, which blocks the pulmonary artery - In the systemic arterial circulation: air blocks the cerebral arteries Pathology Macroscopy: the heart and pulmonary arteries open under water (highlighting air bubbles) Microscopy: air bubbles in capillaries (lung, brain) → differential diagnosis with fatty embolism b) Decompression sickness Etiology: because of diving accidents or may be an occupational disease (caisson disease) Pathogenesis: at great depths, when air is breathed at high pressure, much of the gas (especially nitrogen) is dissolved in the blood and tissues; upon sudden transition to low atmospheric pressure (rapid rise), nitrogen enters the gas phase and blocks the lumen of the vessels Classification: - Acute illness: - Gas bubbles in muscles, joints, periarticular tissues → pain - Focal ischemia in the brain, heart - Respiratory distress - Chronic disease: caisson disease - Multiple foci of ischemic necrosis in the bones: femoral head, tibia, humerus 4. Amniotic fluid embolism Important cause of maternal mortality Pathogenesis: the infusion of amniotic fluid or fetal tissue into the maternal circulation via a tear in the placental membranes or rupture of uterine veins Clinical features: - Sudden onset: severe dyspnea, cyanosis, hypotensive shock, seizures, coma - Up to 50% of patients die within the first hour after the onset of the symptoms - If the patient survives the initial crisis → pulmonary edema, DIC (50% of patients) Pathology Microscopy: - In the pulmonary maternal microcirculation - Squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa - Mucin derived from the fetal respiratory or GI tracts - Marked pulmonary edema - Diffuse alveolar damage - Systemic fibrin thrombi (indicative of DIC) 5. Cholesterol embolism (CE) Pathogenesis: cholesterol crystals (atherosclerotic debris) spontaneously break off from severely atherosclerotic plaques and shower into downstream organs, occluding arterioles of 100-200 micrometers diameter Clinical features: cutaneous manifestations are the most common findings in patients with CE (35% of patients): - Livedo reticularis - the most common dermatologic manifestation of CE - Gangrene (35%) - Acrocyanosis or blue toe syndrome (28%) - Ulceration (17%) is typically unilateral, on the toes and the feet - Nodules or indurated papules (10%), firm, violaceous, and painful - on the legs, the thighs, the toes, or the feet because of an inflammatory reaction surrounding cholesterol crystals - Purpura (9%) and petechiae (4%) 17  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. 6. Bone marrow embolism Etiology: fractures of long bones, re-animation procedures, bone surgery Effects: pulmonary embolism 7. Tumoral embolism: the emboli are represented by malignant cells → formation of metastases 8. Septic embolism: associated with septic conditions (osteomyelitis, endocarditis); emboli contain bacteria 9. Parasitic embolism: echinococcosis, filariasis 10. Foreign body embolism: talc, fragments of catheters, bullets INFARCTION Definition: an area of ischemic necrosis Etiology: vascular occlusion - Arteries – frequently: thrombosis, embolism - Rarely: vasospasm, expansion of an atherosclerotic plaque, compression, torsion, rupture - Veins: torsion of a pedicle (testicle, bowel), compression Classification: - White infarctions (anemic): brain, myocardium, kidney, spleen - Red infarctions (hemorrhagic): lung, intestine, brain (rarely) Pathology: - Initially: there is an infiltration of the necrotic area with blood derived from the anastomotic vessels or from the local injured microvessels (diapedesis) → at the beginning all infarcts are swollen and red - With time: - White infarcts typically become progressively paler and sharply defined - Red infarcts become firm and brown (due to the hemosiderin pigment) THE WHITE INFARCT Sites: - Organs with terminal arterial circulation (brain, kidneys, spleen) and myocardium - Organs with a dense texture, rich in proteins: kidneys, spleen, myocardium Pathology Macroscopy: - Initially: poorly defined, red - After 24 hours (recent, typical infarction): - Shape: according to the pattern of arterial vascularization: - Wedge-shaped, the base to the periphery of the organ and the apex to the occluded blood vessel: spleen, kidney - Spherical (rounded on cut section): brain - Irregular, map-like: myocardium - Color: yellowish, pale - Limits: well delineated, with a red frame at the periphery. Initially this is formed by dilated blood vessels; after 7 days it consists of the granulation tissue that develops at the periphery of the infarct - Consistency: firm (coagulation necrosis), except for brain infarction, which is soft (liquefaction necrosis) - The overlying serosa (if this is the case): is covered by fibrinous exudate - After 4-6 weeks (old infarction): - Transformed into a white-greyish fibrous scar, firm, contracted - Exception: cerebral infarction is transformed into a cyst with a fluid content 18  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. Microscopy: - 6-12 hours: without major changes - 24 hours: coagulative necrosis (acellular, amorphous, acidophilic); except for cerebral infarction (liquefaction necrosis) - 2-3 days: infiltration with neutrophils (PMNs) from the periphery to the center (produce the lysis of the dead cells) - 5-7 days: infiltration with macrophages (remove cell debris) - 1-3 weeks: from the periphery develops a granulation tissue that gradually replaces the necrotic area - except for cerebral infarction - 4-6 weeks: fibrous scar (maturation of granulation tissue) - except for cerebral infarction Brain infarct Etiology: - Thrombosis (superposed on atherosclerosis): - Sites: carotid bifurcation, vertebrobasilar system - Embolism: middle cerebral artery Morphologic forms: - Nonhemorrhagic: most commonly - Hemorrhagic Nonhemorrhagic brain infarct Pathology Macroscopy: - During the first 6 hours: no/subtle modifications - After 24 hours: the gray-white matter junction becomes indistinct - After 4 days: - The tissue becomes pale, soft, and swollen, then it liquefies (liquefactive necrosis): the necrotic area is transformed into a fluid-filled cavity - Weeks to months: the lesion is converted into a cyst: filled with xanthochromic (yellow), and then clear fluid, with a thin capsule at the periphery Microscopy: - 4 to 6 hours: ischemic change of the neurons (red neurons: cytoplasm is intensely eosinophilic) - 24 -48 hours: tumefaction of the axons, disintegration of myelin, influx of neutrophils - 48 hours to 2-3 weeks: liquefaction and phagocytosis - Phagocytic cells: - Derive from circulating monocytes and activated microglia - Macrophages remove products of myelin breakdown or blood and transform into foam cells → may persist in the lesion for months to years - After 1 week: astrocytosis - reactive astrocytes at the edges of the lesion (large, develop a prominent network of protoplasmic extensions) - After several months: gliosis: a dense network of glial fibers admixed with new capillaries and a few connective tissue fibers → form the capsule (the wall of the cavity) Hemorrhagic brain infarct Pathogenesis: - Secondary to the perfusion of the infarcted territory from collateral vessels or after the dissolution of the occlusive material (thrombus, embolus) - Secondary to venous occlusion Microscopy: like nonhemorrhagic infarct but blood extravasations and resorption predominate 19  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. Red (hemorrhagic) infarct Lung infarct (pulmonary infarct) Etiology: - Pulmonary thromboembolism - Small emboli - only about 10% of them cause infarction - Middle-sized emboli: only when the circulation is already inadequate (in patients with heart or lung disease) → pulmonary infarcts tend are uncommon in the young Pathology Macroscopy - Site: lower lobes: 75% of all cases - Number: multiple > 50% of cases - Size: variable, from barely visible to the naked eye to massive involvement of large parts of an entire lobe - Location: they extend to the periphery of the lung substance - Recent infarct: - Often, the pleural surface is covered by a fibrinous exudate - Shape: wedge-like, with the apex pointing toward the lung hilus. An occluded vessel can be identified near the apex of the infarct - Firm, swollen, well delineated - Color: hemorrhagic; red-blue in the early stages, then red-brown (hemosiderin) - Old infarct: transformed into a white contracted scar Microscopy: - Recent infarct: complete hemorrhagic necrosis - Ischemic necrosis of the alveolar walls, bronchioles, vessels - Large area of hemorrhage - Old infarct: replaced by fibrosis (fibrous scar) Ischemic bowel disease Affects small bowel, large bowel or both Pathogenesis: - Ischemia of the superior mesenteric artery - Occlusive ischemia: thrombosis (atherosclerosis, dehydration, etc.), embolism - Nonocclusive ischemia: decreased cardiac output (shock, hypotension) - Venous occlusion (thrombosis) Classification: - Transmural infarct: all the layers of the wall are affected - Mucosal and mural infarct - Chronic ischemia Transmural intestinal infarct Sites: - Small intestine: a short/long segment involved - Colon: any portion may be affected, but the splenic flexure is at greatest risk of ischemic injury (it is the watershed between the distribution of the superior and inferior mesenteric arteries) Pathology Macroscopy: - In the early stages: - Intensely congested and dusky to purple-red - Foci of subserosal and submucosal red discoloration (ecchymoses) - With time: - The wall becomes edematous, thickened, rubbery, and hemorrhagic - The correspondent serosa is covered by fibrin - The lumen commonly contains hemorrhagic mucus or blood 20  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. - Demarcation from normal bowel: - In arterial occlusions: sharply defined - In venous occlusions: ill-delineated Microscopy: - Edema - Interstitial hemorrhage - Transmural necrosis (necrosis of all layers): - Sloughing of the mucosa - Mural musculature loss nuclei - Fibrinous exudate on the serosa - A little inflammatory response Evolution: gangrene within 1 to 4 days (intestinal bacteria develops within the necrotic wall) → may determine perforation of the bowel → peritonitis (may be lethal) DISSEMINATED INTRAVASCULAR COAGULATION (DIC) Definition: acute, subacute, or chronic thrombo-hemorrhagic condition DIC: - Is not a primary disease - Is a potential complication of any condition associated with widespread activation of thrombin Pathogenesis: DIC could result from: - Pathologic activation of the extrinsic and/or intrinsic pathways of coagulation (frequently) - Or impairment of clot-inhibiting influences Two major mechanisms trigger DIC: - Release of tissue factor or thromboplastic substances into the circulation (placenta, mucus released from adenocarcinomas, bacterial endotoxins) - Widespread injury to the endothelial cells - The sudden or insidious onset of widespread fibrin thrombi in the microcirculation can cause diffuse circulatory insufficiency (brain, lungs, heart, and kidneys) and microangiopathic hemolytic anemia - With the development of the multiple thrombi, there is a rapid concurrent consumption of - Platelets and coagulation proteins (consumption coagulopathy) - At the same time, fibrinolytic mechanisms are activated → an initially thrombotic disorder can evolve into a serious bleeding disorder Major disorders associated with disseminated intravascular coagulation Obstetric complications: Abruptio placentae, retained dead fetus, septic abortion, amniotic fluid embolism, toxemia Infections: Gram-negative sepsis, meningococcemia, Rocky Mountain spotted fever, histoplasmosis, aspergillosis, malari Neoplasms: Carcinomas of pancreas, prostate, lung, and stomach; acute promyelocytic leukemia Massive Tissue Injury: Trauma, burns, extensive surgery Miscellaneous: Acute intravascular hemolysis, snakebite, giant hemangioma, shock, heat stroke, vasculitis, aortic aneurysm, liver disease The most important causes of DIC: - Obstetric complications - Malignant neoplasia - Sepsis - Major trauma 21  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. PATHOGENESIS Etiological agents ↓ Clotting activation (intrinsic- extrinsic) ↓ DIC ↓ Consumption of coagulation factors (V,VIII, X, Fbg, Thrombin) → hemorrhage Fibrin thrombi → - Capillary occlusion → ischemia → micronecroses - Microangiopathic hemolitic anemia - Plasmin activation → fibrinolysis → fibrin degradating products → - Inhibition of coagulation → hemorrhage - Proteolysis of coagulation factors → hemorrhage Pathology of DIC General microscopic findings: - Microthromboses - Micronecroses - Microhemorrages Thrombi: - Sites, in the order of frequency: brain, heart, lungs, kidneys, adrenals, spleen, and liver - No tissue is spared - Are occasionally found in only one or several organs Ischemic manifestations: Brain: - Fibrin thrombi can cause microinfarcts - Occasionally simultaneous hemorrhage → seizures, coma Lungs: - Numerous fibrin thrombi in alveolar capillaries - Pulmonary edema and fibrin exudation → “hyaline membranes”: like in the acute respiratory distress syndrome Kidneys: - Small thrombi in the glomeruli - In severe cases: microinfarcts, bilateral renal cortical necrosis → acute renal failure Gastrointestinal tract: acute ulcers Endocrine glands: - Pituitary: postpartum necrosis → Sheehan’s syndrome: hypopituitarism (multiple endocrine organ insufficiency) - Adrenal gland: Waterhouse-Friderichsen syndrome in meningococcemia: - Fibrin thrombi within the microcirculation of the adrenal cortex → massive adrenal hemorrhage Hemorrhagic diathesis: - Cutaneous petechiae, ecchymoses - Cerebral hemorrhage - Waterhouse-Friderichsen syndrome - Hematuria SHOCK Definition: a condition of profound hemodynamic and metabolic disturbance characterized by failure of circulatory system to maintain adequate perfusion of vital organs, which leads to a severe hypoxia, with reversible/irreversible cell injury Synonym: cardiovascular collapse 22  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. Pathogenesis The final common pathway for different potentially lethal clinical events Regardless of the underlying pathology, shock gives rise to systemic hypoperfusion caused by reduction either in cardiac output or in the effective circulating blood volume The end results are hypotension, followed by impaired tissue perfusion and cellular hypoxia Classification: Cardiogenic shock: results from myocardial pump failure: MI, ventricular arrhythmias Extrinsic compression: cardiac tamponade outflow Obstruction: pulmonary embolism Hypovolemic shock: results from loss of blood or plasma volume: hemorrhage, fluid loss from severe burns, or trauma Septic shock: is caused by systemic microbial infection: Most commonly with gram-negative infections (endotoxic shock) it can also occur With gram-positive and fungal infections Less commonly: - Neurogenic shock: in the setting of anesthetic accident or spinal cord injury - Anaphylactic shock: initiated by a generalized IgE-mediated hypersensitivity response Pathology: - The cellular and tissue changes induced by shock are essentially those of hypoxic injury - The cellular changes may appear in any tissue, but they are particularly evident in brain, heart, lungs, kidneys, adrenals, and gastrointestinal tract Microscopy: like in DIC: - Microthromboses - Micronecroses - Microhemorrages Brain: ischemic encephalopathy Heart: - Focal or widespread coagulation necrosis: subendocardial infarction - Or subendocardial hemorrhage (petechiae) Lungs: - Rarely affected in pure hypovolemic shock (they are resistant to hypoxia) - Diffuse alveolar damage (shock lung): shock caused by bacterial sepsis or trauma Kidneys: typically: extensive tubular ischemic injury → acute tubular necrosis → oliguria, anuria, electrolyte disturbances Gastrointestinal tract: patchy mucosal hemorrhages and necroses: hemorrhagic enteropathy Liver: - Fatty change - Central hemorrhagic necrosis Pancreas: acute hemorrhagic pancreatitis Endocrine glands: - Pituitary: necrosis, hemorrhage → Sheehan’s syndrome - Adrenal glands: - Cortical cell lipid depletion - Waterhouse-Friderichsen syndrome EDEMA Definition: increased fluid in the interstitial tissue spaces Approximately 60% of lean body weight is water. Two thirds of this water is intracellular. The remainder is found in the extracellular space: mostly as interstitial fluid; blood plasma: only 5% of total body water Terminology: - Edema - Fluid collections in body cavities: hydrothorax, hydropericardium, ascites -Anasarca: a severe and generalized edema with profound subcutaneous tissue swelling Pathogenesis: - Increased hydrostatic pressure - Reduced plasma osmotic pressure (hypoproteinemia) 23  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. - Lymphatic obstruction - Sodium retention - Inflammation 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., tumor mass) Lower extremity inactivity with prolonged dependency Arteriolar dilation Heat Neurohumoral dysregulation Reduced Plasma Osmotic Pressure (Hypoproteinemia) Protein-losing glomerulopathies (nephrotic syndrome) Liver cirrhosis (ascites) Malnutrition, protein-losing gastroenteropathy Lymphatic Obstruction Inflammatory, neoplastic, postsurgical, postirradiation Sodium Retention Excessive salt intake with renal insufficiency Increased tubular reabsorption of sodium Renal hypoperfusion Increased renin-angiotensin-aldosterone secretion Inflammation Acute inflammation Chronic inflammation Angiogenesis Classification: - Based on the etiology - Based on the extension Etiological classification of edema: - Inflammatory: the interstitial liquid is an exudate - Noninflammatory: the interstitial liquid is an transudate Exudate vs Transudate Properties Exudate Transudate Color Yellowish Yellowish (paler) Fluid proteins/Plasma >0,5 0,6 < 0,6 LDH > 2/3 normal plasma values Total proteins > (3)4 g% < (3)4 g% Specific density > 1018 < 1015 Protein pattern Plasma-like Albumins Fibrinogen ++ (coagulation) Absent (no coagulation) Cells ++ Rare (mesothelial) Classification of edema based on the extension: - Local edema - Generalized (systemic) edema: visceral, body cavities, subcutaneous tissue Local edema - Acute inflammatory - Venous - Lymphedema - Immune reactions: urticaria, angioedema (angioneurotic, Quincke’s disease) 24  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. Generalized edema: 1. Cardiac edema - Etiology: right-sided heart failure, congestive heart failure - The nature of the fluid: transudate - Edema of the dependent parts of the body (e.g., the legs when standing, the sacrum when recumbent) 2. Renal edema: transudate - Nephritic edema. Pathogenesis: decreased glomerular filtration - Nephritic edema. Pathogenesis: proteinuria, sodium retention 3. Hepatic edema: transudate. Pathogenesis: hypoalbuminemia 4. Nutritional edema: transudate. Pathogenesis: hypoalbuminemia General pathology of edema: most easily recognized macroscopically - Microscopy: - Subtle cell swelling - Clearing and separation of the extracellular matrix elements Main sites: subcutaneous, lungs, brain Subcutaneous edema: - May have different distributions depending on the cause: diffuse or at the sites of highest hydrostatic pressures - The edema distribution is typically influenced by gravity (dependent) - Finger pressure over substantially edematous subcutaneous tissue displaces the interstitial fluid and leaves a finger-shaped depression: pitting edema PULMONARY EDEMA Etiopathogenesis (see table): - Hemodynamic disturbances (hemodynamic or cardiogenic pulmonary edema): increased hydrostatic pressure (increased pulmonary venous pressure): Most common: Left-sided heart failure – myocardial infarction!! (acute) Mitral stenosis (chronic congestion) Volume overload Hypoalbuminemia - Increases in capillary permeability, owing to microvascular injury: Infections: pneumonia, septicemia Inhaled gases: oxygen, smoke Liquid aspiration: gastric contents, near-drowning Etiology of pulmonary edema Hemodynamic Edema Left-sided heart failure (common), volume overload, pulmonary vein obstruction Decreased oncotic pressure (less common) - hypoalbuminemia, nephrotic syndrome, liver disease, protein-losing enteropathies. Lymphatic obstruction (rare) Edema Due to Microvascular Injury (Alveolar Injury) Infections: pneumonia, septicemia. Inhaled gases: oxygen, smoke. Liquid aspiration: gastric contents, near-drowning Drugs and chemicals: chemotherapeutic agents (bleomycin), other medications (amphotericin B), heroin, kerosene, paraquat. Shock, trauma, radiation, transfusion related Edema of Undetermined Origin: High altitude, neurogenic (central nervous system trauma) 25  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. Pathology of pulmonary edema Pathology: Macroscopy: - Dependent edema: accumulates initially in the basal regions of the lower lobes (high hydrostatic pressure) - Heavy, wet lungs: two to three times their normal weight - On section: frothy, blood-tinged fluid - A mixture of air, edema fluid, and extravasated red blood cells Microscopy: - Alveolar walls: dilated capillaries, edema, fibrosis (in mitral valve stenosis) - Alveolar spaces: - Granular pink precipitate (transudate) + air-bubbles - Microhemorrhages and hemosiderin-laden macrophages: "heart failure" cells (in mitral stenosis) Clinical features (in all forms of edema): - Anxiety, dyspnea at rest, orthopnea and paroxysmal nocturnal dyspnea - Cough productive of pink, frothy sputum – moist rales with or without wheezing Chest X-ray films: - Interstitial edema (early signs of pulmonary edema): the Kerley B lines: horizontal lines seen laterally in the lower zones, ≥ 2 cm long that reach the lung edge - Alveolar edema: "butterfly" pattern: central shadows with a clear zone at periphery Acute pulmonary edema is one of the most common medical emergencies and very life threatening! Edema caused by microvascular injury Morphology: - Leakage of fluids and proteins first into the interstitial space and into the alveoli - When localized (i.e., in pneumonia), edema is overshadowed by the manifestations of infection - When diffuse, alveolar edema is an important contributor to the acute respiratory distress syndrome CEREBRAL EDEMA (BRAIN EDEMA) Definition: the presence of excess fluid within either the cells or the extracellular tissues of the brain Pathogenetic classification: Vasogenic edema: disruption of the integrity of the normal blood-brain barrier, followed by increased vascular permeability → fluid escapes from the intravascular compartment into the extracellular spaces of the brain - The paucity of conventional lymphatics and the close apposition of cell processes of neurons and glia in the brain greatly impairs the resorption of excess extracellular fluid - Mainly in the white matter – 2 forms of vasogenic edema: - Localized: adjacent to an abscess, neoplasm, infarction, cerebral hemorrhage - Generalized: encephalitis, hypertensive crises, obstruction to the brain's venous outflow Trauma may result in local or generalized edema depending on the nature and extent of the injury!!! Cytotoxic edema: Increase in intracellular fluid secondary to neuronal, glial or endothelial cell membrane injury: generalized hypoxic/ischemic insult, intoxications - Mainly in the grey matter In practice, conditions associated with generalized edema often have elements of both vasogenic and cytotoxic edema Interstitial edema (hydrocephalic edema) - occurs especially around the lateral ventricles Pathology of cerebral edema: Macroscopy: - The brain is softer than normal, often appears to "overfill" the cranial vault - Wet appearance on cut section - In generalized edema: - The gyri are flattened - The intervening sulci are narrowed - The ventricular cavities are compressed - As the brain expands, herniation may occur (because of the raised intracranial pressure) 26  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. Microscopy: - Loose aspect of the white matter - Clear pericellular/perinuclear halo - Enlarged blood-brain barrier Complications: herniations of the parenchyma: - Subfalcine (cingulate) herniation → compression of branches of the anterior cerebral artery owing to brain infarct - Transtentorial (uncinate, mesial temporal) herniation → affects the third cranial nerve (oculomotor nerve) or posterior cerebral artery may be compressed - Tonsillar herniation: displacement of the cerebellar tonsils through the foramen magnum → life- threatening: determines brainstem compression → compromises vital respiratory and cardiac centers in the medulla oblongata LYMPH FLOW DISORDERS LYMPHEDEMA Definition: localized fluid retention caused by a compromised lymphatic system (normally, lymphatics collect and filters the interstitial fluid of the body) Pathogenesis: lymphedema increases the hydrostatic pressure in the lymphatics distal to the obstruction and causes increased interstitial fluid accumulation Pathology: persistance of the edema leads to increased subcutaneous interstitial fibrous tissue → - Enlargement of the affected part - Brawny induration (skin is firm, due to fibrosis) - "Peau d'orange" (orange peel) appearance of the skin - Skin ulcers - Initially, lymphedema is a pitting edema, but in chronic states, because of fibrosis, it becomes non-pitting edema Classification of lymphedema: - Secondary (obstructive lymphedema) - Primary lymphedema Secondary lymphedema (obstructive or acquired lymphedema) Types of obstructive lymphedema based on etiology: 1. Spread of malignant tumors obstructing either the lymphatic channels or the regional lymph nodes → the “peau d’orange” aspect of the skin in breast cancer 2. Radical surgical procedures with removal of regional groups of lymph nodes (e.g., the axillary dissection of radical mastectomy) → arm lymphedema: it may be complicated by an angiosarcoma (in long-standing cases) and this association is called Stewart-Treves syndrome 3. Postirradiation fibrosis 4. Filariasis Etiology: nematode worms (Wuchereria bancrofti, Brugia malayi, Brugia timori ) – transmitted by mosquitoes – endemic in tropical regions of Asia, Africa, Central and South America Pathogenesis: nematodes block lymphatic channels → fluid accumulates in the tissues Clinical feature: In filariasis, external genitalia and legs are affected - Legs: most affected. - Lymphedema typically begins in the ankle and progresses to the foot and leg - At first the swollen leg may feel soft to the touch but eventually becomes hard and thick - The skin may appear darkened or warty and may even crack, allowing bacteria to infect the leg and complicate the disease. Due to the appearance of the skin and to the enlargement of the limb, the disease is also called elephantiasis. Potential consequences: - Disability (owing to the size of the limb) - Superimposed infection, chronic ulcerations 5. Postinflammatory thrombosis and scarring 27  CH. I. FLUID AND HEMODYNAMIC DISORDERS. MGE III, 2024-2025. Primary lymphedema Pathogenesis: - An isolated congenital defect of lymph vessels (simple congenital lymphedema) - Familial Milroy disease (heredofamilial congenital lymphedema) - Lymphedema praecox: - Females, between 10 and 25 years - Begins in the feet and slowly accumulates throughout life - The involved extremity may swell to many times its normal size, and the process may extend upward to affect the trunk 28