Morphology of cells and tissues reversible and irreversible injury. Intracellular and extracellular accumulation (uptake) of proteins, hydrocarbons and lipids.

(Parenchimatous and mesenchimal dystrophies)

Cells and tissue reversible changes occurs in the result of tissue or cell metabolism disturbance and are accompanied with these substances (proteins, fats, hydrocarbons) which exists as norm intracellular or tissue uptakes and appearance of those pathological which do not exist in the norm. These changes are named metabolic products pathologic uptakes or dystrophies (from Lat. dys – disturbance, trophe – nutrition). Intracellular uptake of substances causes parenhymatous degenerations development. Parenhymatous degenerations occurs mostly in highly specialized cells of parenhymatous organs (kidneys, liver, heart, cerebrum, etc.). Acquired or congenital fermentopathies underlie parenhymatous degenerations development. These fermentopathies make a big group of storage diseases or thesaurismoses. Latter contain a big group of storage diseases or thesaurismoses.

Causes of metabolism products abnormal uptake

1 Cell pathology. Cells are not able to utilize substances as energy or plastic material or release them. This is caused mostly by cells structure injury with various factors, sometimes by congenital or acquired ferments pathology, which participate in metabolism (fermentopathies).

2 Function disturbance of transport systems, providing both substances supply to tissues and cells and metabolism products excretion. It is often observed under cardiovascular collapse and pulmonary insufficiency.

3 Endocrine and nervous regulation of trophism disorders.

Mechanisms of metabolism products abnormal uptake Infiltration is excessive penetration of metabolism products from blood into cells and intercellular substance with their subsequent uptake due to ferment system, providing their metabolism, insufficiency. Substances metabolism products abnormal uptake by way of infiltration is observed in liver, kidneys, aorta wall.

Decomposition (phanerosis) occurs under cell and intercellular substance ultrastructures destruction due to intoxication, hypoxia or other reasons. Ultrastructures membranes are made of proteins, fats and hydrocarbons, so under their destruction these substances are accumulated and stored in cells.

Distored synthesis is synthesis of those substances in cells and tissues which are not observed in them as a norm. As an example, it’s glycogen synthesis in nephron tubules epithelium under diabetes mellitus, alcohol hyaline synthesis in hepatocytes.

Transformation is the creation of one kind of metabolism products from intermediate disintegration products, which should be utilized for proteins, fats and hydrocarbons synthesis. For example, it’s fats and hydrocarbons components transformation into proteins under starvation, fats and hydrocarbons components transformation

into glycogen under diabetes mellitus.

Metabolism products abnormal uptake classification

Classification by the kind of metabolism disturbance prevail:

a) protein, b) fat, c) hydrocarbon, d) mineral

By pathologic process localization:

a) parenchymatous (modifications in the organs parenchymatous cells - cardiomyocytes, hepatocytes, ganglionic cells of cerebrum, etc.);

b) stromal-vascular (modifications in organs stroma);

c) mixed (changes in parenchyma and stroma).

Depending on genetic factors influence:

a) congenital, b) acquired.

By process spread:

a) general, b) local.

Morphology of proteins abnormal uptake (proteinosis)

Occurs under proteins metabolism disturbance. Tissues proteins form cells as plastic materials (capsule, nucleus, cytoplasm, intracellular organelles) as well as intercellular stroma – collagen, elastic, reticulin fibers, basic intercellular substance, vessels, nerves. By proteins metabolism disturbance development location proteinosises are divided into parenchymatous, stromal-vascular and mixed. .

Under parenchymatous proteinosis physical-chemical features of intracellular proteins are violated. At the beginning grain effect occurs in cytoplasm at the cost of protein inclusions, which is manifestation of cell ultrastructures overstrain (hyper function). This process is reversible. Quite often proteins disbolism is combined with Na-K-pump operation faults, which is accompanied with natrium ions uptake and cells hydration. In case intoxication, hypoxia, inflammation or other reasons of proteinosis increase this cause cells destructive changes intensification. The following kinds of parenchymatous proteinaceous degenerations (proteinosis) are recognized: hyaline-drop, hydropic (vacuolar), keratinization.

At hyaline-drop proteinosis proteins compacts and become similar to hyaline cartilage. Big hyalinoid drops of protein occur in cells cytoplasm. Sometimes coagulation necrosis develops and cells die, organ function decreases, but macroscopic changes are not found. This kind dystrophy is often observed in hepatocytes under alcoholic hepatitis (Mellori bodies), in renal tubules epithelium under nephrotic syndrome, etc.

Cytoplasmic organelle damage leads to a variety of injury patterns, most of which are best seen by electron microscopy. Acute injuries tend to damage an entire cell, so specific organelle damage is beside the point. However, in some cases the damage can be cumulative over many years. Here are Mallory bodies (the red globular material) composed of cytoskeletal filaments in liver cells chronically damaged from alcoholism. These are a type of "intermediate" filament between the size of actin (thin) and myosin (thick).

Intracellular accumulations of a variety of materials can occur in response to cellular injury. Here is fatty metamorphosis (fatty change) of the liver in which deranged lipoprotein transport from injury (most often alcoholism) leads to accumulation of lipid in the cytoplasm of hepatocytes.

Hydropic or dropsy proteinosis is characterized by intracellular fluid increase, in which cytoplasm proteins are dissolved due to hydrolytic pigments action. Vacuoles full of cytoplasm fluid occur in cells. Further on cells cytoplasm transforms into blisters full with fluid, intracellular organelles destroy, cell dies off and coliquation necrosis develops. Organs also didn’t change macroscopically. Hydropic proteinosis often develops in liver under viral hepatitis, in kidneys under glomerulonephritis, etc.

Sometimes cellular injury can lead to accumulation of a specific product. Here, the red globules seen in this PAS stained section of liver are accumulations of alpha-1-antitrypsin in a patient with a congenital defect involving cellular metabolism and release of this substance.

Many inherited disorders of metabolism involving enzymes in degradation pathways can lead to accumulation of storage products in cells, as seen here with Gaucher disease involving spleen. The large pale cells contain an accumulated storage product from lack of the glucocerebrosidase enzyme.

The yellow-brown granular pigment seen in the hepatocytes here is lipochrome (lipofuscin) which accumulates over time in cells (particularly liver and heart) as a result of "wear and tear" with aging. It is of no major consequence, but illustrates the end result of the process of autophagocytosis in which intracellular debris is sequestered and turned into these residual bodies of lipochrome within the cell cytoplasm.

Keratinization proteinosis is characterized with excessive keratin generation on the surface of plane keratinized epithelium – hyperkeratosis, ichthyosis. The causes of keratinization development is chronic inflammation, avitaminosis, skin development abnormalities. Leukoplakia which is mucous tunics epithelium pathologic keratinization, also belongs to this process and can become a source of malignant growth.

Extracellular uptakes

Extracellular uptakes occur in the result of metabolism disturbance in organs stroma or in vessels walls, so they are named stromal-vascular or mesenchymal proteinosis. Important attention is paid to proteinosis developing in the result of proteins metabolism in conjunctive tissue and are found in stroma and vessels walls. Primary pathologic changes are developed on histion level, consisting of microcirculation channel: basic substance, fibers (collagen, reticulum, elastic), cells (fibroblasts, fibrocytes, lymphocytes, labrocytes, histiocytes), nerves. Basic substance is connecting, cementing, fiber and cells are situated in it. By chemical composition it is polymer of composite protein-hydrocarbon molecules – mucopolysaccharides (glycosamineglycanes). The following relates to stromal-vascular proteinosis: mucoid swelling, fibrinoid swelling (fibrinoid), hyalinosis, which are considered to be consequent stages of conjunctive tissue destruction.

Mucoid swelling – is primary disorganization of conjunctive tissue. Causes: hypoxia, allergy, endocrine pathologies. It often occurs under rheumatic and infection diseases, atherosclerosis, it is found in artery walls, cardiac valves, endocardium, heart. Basic substance depolymerization underlies its development. As a consequence it becomes hydrophilic, attracts liquid, vessel wall penetrability increases. Basic substance hydration, collagen fibers swelling occurs. With vascular-tissue penetrability growth conjunctive tissue saturates with blood plasm proteins, in first turn with albumines and globulins. Macroscopically organ or tissue mostly doesn’t change. Microscopically phenomenon of metachromasia is observed: glycosamineglycanes are painted with toluidine blue in red color. Described changes in conjunctive tissue provided that the reason was eliminated are reversible and tissue structure is rehabilitated.

This Congo red stain reveals orange-red deposits of amyloid, which is an abnormal accumulation of breakdown products of proteinaceous material that can collect within cells and tissues.

Fibrinoid swelling is following stage of conjunctive tissue disorganization. Under substantial growth of vascular-tissue penetrability fibrinogen sweats in stroma from vessels clearance, which rather quickly precipitates in strings of fibrin, collagen fibers are destroyed (broken, fragment), conjunctive tissue basic substance chemical composition is changed. Under fibrinoid swelling deep and irreversible disorganization of conjunctive tissue is observed, which is accompanied with basic substance and fibers destruction against the background of considerable increase of balls vascular permeability. Macroscopically organ doesn’t change, microscopically collagen fibers become homogenous, eosinophilic, becomes yelow when painted with picrofuchsin, pyroninophil and argyrophil. Consequence Fibrinoid necrosis is developed in the final of the process. Significance – organ function disturbance under heart disease formation, joints immobility, luminal narrowing and vessel wall elasticity decrease, organ function termination under renal insufficiency at malignant hypertension, when fibrinoid changes as well as arterioles and cappilars necrosis develops.

Hyalinosis is the final stage of tissue disorganization and is characterized with uptake of collagen destruction products, plasm proteins, polysaccharides, which merge into homogenous mass which consolidates as time passes, becomes semi-transparent similar to hyaline cartilage, so it is called hyaline. This is complex fibrillar protein. Hyalinosis occurs as a consequence of fibrinoid swelling, plasmorrhagia, sclerosis, necrosis. It develops as the result of peculiar completion of sclerosis in scarring, cardiac valves under rheumatism (local conjunctive tissue hyalinosis). Macroscopically fibrous conjunctive tissue becomes dense, cartilaginous, whitish, semi-transparent. Microscopically collagen fibers loss fibrillarity and merge into homogenous dense cartilaginous mass, cells squeeze and atrophy.

Heart in such cases is enlarged, ventricular cavities are dilated, mitral valve flappers are dense, whitish color, conjoint in between each other, considerably deformed. This kind of hyalinosis is peculiarly expressed in rough vicious cicatrix after burns (keloid). Consequences are unfavorable because of considerable deterioration of organ or injured tissue function.

Systemic hyalinosis develops in vessels walls under hypertension disease, diabetes mellitus (vascular hyalinosis) and is mostly expressed in kidneys, cerebrum, eye retina, pancreas. Considering occurrence pathogenesis three kinds of vascular hyaline are recognized: simple is observed under hypertension disease, atherosclerosis; lipohyaline is developed under diabetes mellitus; complex hyaline occurs in the result of immunopathologic disturbances and vessel wall fibrinoid disorganization at collagenosis.

Morphology of lipids pathological uptake (lipidosis)

Occurs as the result of fats metabolism disturbance.

Lipidosis are divided into parenchymatous and stromal-vascular (mesenchymal) fatty (adipose) degenerations. To reveal fats frozen sections are colored with sudan ІІІ or ІV.

Parenchymatous lipidosis are manifested with neutral lipids (triglycerides) drops uptake in cells cytoplasm and are the results of cytoplasm fats metabolism disturbance. Mostly they are found in myocardium, lever, kidneys.

Myocardium lipidosis is characterized with lipoproteids drops uptake in cardiac hystiocytes. As a rule it is observed under intoxications (diphtherial, alcohol, with phosphoric compounds, arsenic, diseases of liver, kidneys, thyrotoxicosis, etc.), long time general hypoxia (anemia, chronic pulmonary and cardiovascular insufficiency), Under oxygen deficiency process of oxidative phosphorylation and ATP synthesis in cardiomyocytes decreases, fatty acids beta-oxidation violates. So fats coming into cell are not completely utilized as plastic and power material and they accumulate in cytoplasm. Besides that under hypoxia membrane lipoprotein complexes destruction is observed (decomposition or phanerosis). Macroscopically heart at this process enlarges in size, its chambers stretch, myocardium becomes flaccis, of clay-yellow color, retraction ability of cardial muscle decreases. From myocardium side especially on papillary muscles surface, trabeculas, it is observed yellow-grey striation– “ tiger heart”, which is caused by dystrophy. Microscopically fat uptakes in muscular cells groups, situated downstream cappilars venous elbow and small veins where hypoxia factor is mostly expressed.

Liver lipidosis is characterized with fat content increase in hepatocytes. Quite often it is the result of imbalance between increased fats supply under hyper lipidemia (alcoholism, diabetes mellitus, general obesity), their decreased assimilation (fatty acids oxidation in mitochondrions under hypoxia or toxic influences) and lipids excretion decrease by liver cells under apoprotein production decrease which transports fats in the form of lipoproteins. This is observed in case protein insufficiency in food or under gastrointestinal disturbances, poisoning with ethanol, phosphor, etc., congenital defects of ferments metabolizing fats. Microscopically first occurs saw type, then small drop and large drop degeneration. Three stages of liver lipidosis are distinguished:

1- fat uptake in hepatocytes, 2- fat uptake with mesenchymal reaction development, 3- fat uptake with liver fibrosis and cirrhosis development. Fat fills all cytoplasm and gradually pushes nucleus aside to periphery and modified hepatocytes becomes similar to adipocytes. Fatty degeneration prevalence in peripheral portions of liver part confirms infiltration mechanism of its development, which is observed under hyperlipidemia. Fatty degeneration development prevalence in central portions of liver part is connected with decompensation mechanism and is observed under hypoxia or intoxication. Macroscopically liver is enlarged, loose (of pastry consistency), yellow or clay color.

Kidneys lipidosis is often observed under nephrotic syndrome, chronic renal insufficiency when hyperlipidemia and lipiduria occur. Fat excess is excreted from organism with kidneys and constipates them. Microscopically fat occurs in proximal, distal or convoluted renal tubules epithelium in cells basal portions. Nephrocytes lipidosis often joins hyaline-drop degeneration and hydropic proteinosis. Macroscopically kidney is enlarged, flaccid, cortical layer is dilated with signs of swelling, of grey color with yellow specks.

Congenital lipid metabolism disturbances are manifested with systemic lipidosis and pertain to fermentopathies (diseases of storage or uptake). The following diseases are marked out: cerebrosine lipidosis (Gaucher's disease), sphingomyelin lipidosis (Niemann-Pick disease), generalized gangliosidosis (Tay-Sachs disease), generalized gangliosidosis (Norman-Landig disease), which are accompanied with liver, spleen, marrow, nervous system and other organs and tissues damage.

Stromal-vascular lipidosis include neutral fat metabolism disturbance in adipose tissue and adipose depot as well as cholesterol and its ethers in arteries walls under atherosclerosis.

General disturbance of neutral fats metabolism is manifested with neutral fat stocks increase or decrease in hypodermic fat tissue, mesentery, pericardium, marrow, etc. General uptake of neutral fat in fat depots is called obesity. The following is recognized: primary or idiopathic obesity the cause of which is unknown and secondary obesity which occurs under endocrine, cerebral and hereditary diseases. By external signs obesity kinds are as follows: upper, mid, lower and universal symmetric. By morphologic signs hyper plastic type is marked out characterized with fat cells (adipocytes) quantity increase in organism as well as hypertrophic (malignant) type the basis of which is adipose cells size increase several times and triglycerides content increase in cytoplasm several times.

Under general obesity the important clinical attention is paid to heart injury. In this case adipose tissue grows under pericardium, surrounding organ like case. Lipocytes uptake in myocardium stroma between cardiac hystiocytes, squeezing the latter ones which causes their atrophy. Right portion of the heart is the most injured one. Sometimes the whole thickness of right ventricle myocardium is changed with adipose tissue, that can cause cardiac rupture or accelerate decompensation process.

Neutral fat local uptake is observed under Madelung's syndrome, Dercum's disease and Weber-Krischen’s desease, as well as vacant obesity when organ atrophied portion is substituted. The essence of Dercum's disease is in painful lipomas occurrence in subcutaneous adipose tissue of extremities and trunk. Weber-Krischen’s disease is characterized with recurrent nonpurulent cellulites with productive granulomatous inflammation development around sphacelous adipose tissue.

General decrease of adipose tissue occurs under emaciation (cachexia). Tissue becomes loose, flabby, is saturated with liquid, sliming.

Cholesterol and its ethers’ metabolism imbalance is a basis of atherosclerosis development. Uptake of cholesterol fractions, lipoproteins of various density, proteins in arteries’ walls causes formation of fat detritus (atheroma) and conjunctive tissue enlargement (sclerosis). Hereditary cholesterol metabolism disturbance is observed under family hypercholesterolemic xanthomatosis, manifested with xanthalasms formation (cholesterol deposition in skin, big vessels’ walls, heart valves and other organs).

Carbohydrates pathologic uptake (glycogenosis) morphology

The most valuable in carbohydrates metabolism disturbance is glycogen, glycosamineglycanes and glycoproteins. The most important in this pathology is glycogen metabolism disturbance occurring under diabetes mellitus. In case insulin deficiency in blood the tissues utilize sugar insufficiently causing sugar level increase in blood (hyperglycemia), and glycogen quantity in tissues decreases. Kidneys remove sugar excess with urine (glucosuria). In the result of glucose polymerization under its resorption from plasma ultrafiltrate glycogen is accumulated in tubules epithelium, mesangium and membranes of glomerule vessels. The most of it is in epithelial cells and in Henle’s loop lumens (narrow segment). Epithelium in these sections of nephron becomes high, with light and foamy cytoplasm. Changes in kidneys under diabetes mellitus are finalized with sclerosis development called diabetic glomerulosclerosis.

Hereditary (glycogenosis) occurs under deficiency of ferment which splits glycogen and the latter accumulates in cells. These includes hepatorenal glygenosis, Pompe disease, MacArdles and Gerce’s under which glycogen structure is not damaged, as well as Forbes-Cori (type 3 glycogenosis) and Anderson’s disease (type 4 glycogenosis) under which this structure is changed.

Under glycoproteins metabolism disturbance (mucins and mucoids which are the base of mucus) mucus degeneration develops. The typical manifestation of it is mucoviscidosis which is systemic disease, charactristic of which is high viscosity of mucus, causing development of retention cysts and sclerosis in pancreas, bronchi, digestive and other glands. Besides that this degeneration is often observed under catarrhal inflammation of nose mucous tunic (rhinitis), mucous tunic of larynx (laryngitis), bronchi (bronchitis), stomach (gastritis), etc. Macroscopically excess of mucus is seen on mucous tunic, and this mucous trickles down from the surface. Microscopically wine glass like cells appear in mucous tunic and release mucus. Also desquamation or cells necrosis is observed, glands’ excretory ducts are clogged with mucus which is accompanied with cysts formation.

Glycoproteins and glycosamineglycanes uptake in organs’ stroma is accompanied with collagen fiber as well as cartilage and adipose tissue substitute with mucus-like mass. Damaged tissues cells have star-like shape. This process is called tissue sliming and it is observed under cachexias and myxedema. Carbohydrates uptake consequence can be reversible and under process progress they become semi-transparent, looks like mucus, colliquative necrosis develops.

Metabolic disease. Morphology of pathologic accumulation of endogenous and exogenous pigments.

Morphology of mineral metabolism disease

Importance of the topic: metabolic disease rather often occurs in practice of clinicians and should be considered as a manifestation of general pathologic processes. Often it occurs at endocrine diseases, as well as at pathology of gastrointestinal tract and hepatobiliary system and it reveals through structural morphologic changes. Knowledge of issues of this topic enlarges the minds of would-be clinicians concerning the kind of changes that underlie various pathologic processes at one or another disease.

Purpose: to study causes, development mechanism, morphologic manifestations and consequences of accumulation of endogenous and exogenous pigments, as well as mineral metabolism disease.

Specific goals: 1 To learn varieties of metabolic diseases and their development mechanisms.

2 To study causes, development mechanism, pathogenesis and morphogenesis, morphologic presentations and consequences of accumulation of endogenous and exogenous pigments, as well as mineral metabolism disease.

3 To learn to differentiate various kinds of pigment metabolic diseases and mineral metabolism diseases according to morphologic signs.

4 To evaluate functional importance and consequences of accumulation of endogenous and exogenous pigments, as well as mineral metabolism diseases, to know how to diagnose their morphologic manifestations in cells and tissues.

Iron metabolic disease and metabolic disorder of hematogenous pigments. Metabolism and pathogenic action of iron, formation of anabolic and catabolic ferritin. Classification of hematogenous pigments. Toxic forms of ferritin: causes and consequences of their formation.

Hemosiderosis (topical and extensive): causes, pathogenesis, morphologic characteristics and consequences. Acquired and congenital hemochromatosis: morphologic characteristics and consequences.

Hematoidin, hematin, porphyrin: features and area of formation, morphologic characteristics and consequences of their accumulation.

Bilirubin metabolic disease: causes, pathogenesis and anatomical pathology of hemolytic jaundice, hepatic jaundice, obstructive jaundice. Pathogenic effect of increased bilirubin, complications and causes of death at jaundice.

Melanin formation disorder. Causes, pathogenesis, morphologic characteristics of hypopigmentation (leukoderma, vitiligo, albinism) and hyperpigmentation (common melanoderma, local melanosis, pigmented nevus).

Nucleoprotein metabolic disease. Podagra and gouty arthritis: classification, aetiology, pathogenesis, stage of disease and morphologic characteristics of joints’ changes, clinical presentations, complications and consequences. Podagric nephropathy. Clinicopathologic characteristics.

Copper metabolic disease. Hepatolenticular degeneration (Wilson's disease).

Potassium metabolic disease. Periodic paralysis.

Calcium metabolic disease. Acute hypocalcemia and hypercalcemia: definition, pathogenesis, consequences and their role in thanatogenesis. Calcinosis (calcification): definition, classification, morphogenesis of metastatic calcification, dystrophic calcification and metabolic calcinosis; consequences, the role of calcification of organs in thanatogenesis.

Stone formation: localization, causes, pathogenesis, types of stones, consequences and complications of stone formation.

Auxiliary materials for self-training to practical lesson

Pathologic accumulation of endogenous pigments rather often is represented in metabolic disease of complex proteins – chromoproteins, nucleoproteins, glucoproteins and lipoproteins. Chromoproteins, or colored proteins, are endogenous pigments, to which hematogenous, proteinogenous and lipidogenous pigments are referred. Metabolic disease of complex proteins is observed in parenchyma, as well as in stroma of tissues and organs.

Iron metabolic disease and metabolic disorder of hematogenous pigments

Ferritin, hemosiderin, bilirubin are referred to hematogenous pigments. There are pigments which may be accumulated in organism at physiological conditions and at some diseases; hematoidin, hematin, porphyrin are pigments which are formed only at pathologic processes. They are generated from hemoglobin at destruction (hemolysis) of erythrocytes.

Ferritin is generated from hemoglobin at intensive intravascular hemolysis of erythrocytes – catabolic form. Anabolic form is generated from iron absorbed in bowels . At conditions of hypoxia ferritin is restored into an active form (SH-ferritin) which is an adrenalin antagonist, that’s why it acts vasoparesically, i.e. as vasodilator. An active ferritin is accumulated at incompatible blood transfusion and collapse of vessels is observed, then a syncope takes place.

Hemosiderin is generated from hemoglobin only in macrophages (intracellularily). It appears outside the cell only after cell destruction. It looks like small brown seeds; tissue acquires brown coloration at evident hemosiderosis. One can distinguish common and topical hemosiderosis. Common hemosiderosis is developed at intensive intravascular hemolysis of erythrocytes (incompatible blood transfusion, hemolytic poisoning). Unconjugated hemoglobin is captured by macrophages of unitary mononuclear phagocyte system of liver, spleen, lymph nodes, bone marrow, thymus gland in which hemoglobin turns into hemosiderin. Listed organs acquire brown coloring.

Topical hemosiderosis arises at areas of extravasation. Erythrocytes are absorbed outside the vessels by macrophages, in which hemoglobin turns into hemosiderin. An example of topical hemosiderosis is pulmonary hemosiderosis which is developed at venous plethora of lungs accompanied by diapedetic extravasations.

Hemochromatosis is a peculiar disease closely related to common hemosiderosis. There could be primary and secondary one. Primary (hereditary) hemochromatosis is referred to storage diseases, caused by a hereditary defect of small intestine ferments. A secondary one is conditioned by acquired enzymatic deficiency of systems providing food iron metabolism.

A Prussian blue reaction is seen in this iron stain of the liver to demonstrate large amounts of hemosiderin that are present within the cytoplasm of the hepatocytes and Kupffer cells. Ordinarily, only a small amount of hemosiderin would be present in the fixed macrophage-like cells in liver, the Kupffer cells, as part of iron recycling.

The brown coarsely granular material in macrophages in this alveolus is hemosiderin that has accumulated as a result of the breakdown of RBC's and release of the iron in heme. The macrophages clear up this debris, which is eventually recycled.

Bilirubin is a bile pigment generated at destruction of hemoglobin and detachment of haem in reticulum- endothelial (mononuclear) system. Increased bilirubin (bilirubinhemia) is evidence of jaundice. One can distinguish hemolytic jaundice, hepatocellular jaundice and obstructive (mechanical) jaundice. Hemolytic jaundice arises at infectious diseases, intoxications, isoimmune and autoimmune conflicts, massive hemorrhage, as well as erythrocytopathy and hemoglobinopathy.

Hepatocellular jaundice arises at liver diseases of various aetiology, in case defective hepatocytes are not able to capture bilirubin, its conjugation to glucuronic acid and excretion are disturbed. Obstructive (mechanical) jaundice arises at retention of bile outflow from liver.

These renal tubules contain large amounts of hemosiderin, as demonstrated by the Prussian blue iron stain. This patient had chronic hematuria.

Hematoidin is a pigment which doesn’t contain iron. It is accumulated in central areas of hemorrhage in the distance of living tissues.

Hematin – is an oxidized form of haem. The following pigments are referred to: malarial pigment which is generated from hemoglobin under influence of malarial plasmodia, muriatic hematin which is generated at hemoglobin interaction with intestinal juice ferments and hydrochloric acid (it colours erosions and bottom of bleeding ulcer into black and brown), as well as formalin pigment which occurs in histologic specimen fixed by acid formalin.

The yellow-green globular material seen in small bile ductules in the liver here is bilirubin pigment. This is hepatic cholestasis.

The black streaks seen between lobules of lung beneath the pleural surface are due to accumulation of anthracotic pigment. This anthracosis of the lung is not harmful and comes from the carbonaceous material breathed in from dirty air typical of industrialized regions of the planet. Persons who smoke would have even more of this pigment.

Hematoporphyrin is a pigment which is melanin antagonist. Its small quantity is contained in blood, urine and stool, it heightens light sensibility of skin. Excess accumulation of this pigment is called porphyria. It could be caused by congenital defect of porphyrin metabolism or acquired one: lead or barbiturate poisoning, avitaminosis PP, etc. Such patients are UV hypersensitive which causes burns, ulcers, skin atrophy and depigmentation. Bones and teeth are coloured into brown.

Metabolic disorder of proteinogenous pigments.

Melanin chromogenesis disorder.

Melanin, as well as adrenochrome and pigment of enterochromaffin cell granules are referred to proteinogenous (tyrosinogenous) pigments which are tyrosine and tryptophan metabolic derivatives.

Melanin is a brown-black pigment which determines color of skin, hair and eyes. Melanin chromogenesis disorder could appear in increase or decrease of this pigment in skin. There could be local or extensive process. There could be congenital or acquired pathology. Extensive hypopigmentation or hypomelanosis (albinism) appears as a result of hereditary deficiency of tyrosinase. Local hypomelanosis (vitiligo, leukoderma) appears as a result of disorder of neuroendocrine control of melanogenesis at leprosy, diabetes mellitus, hyperparathyroidism, Hashimoto's thyroiditis, syphilitic skin affection. Extensive acquired hypermelanosis declares itself in excessive accumulation of melanin in skin (melanoderma) and is observed at emaciation, Addison's disease, endocrine disorders, pellagra, scurvy. Extensive congenital hypermelanosis declares itself in spotted skin pigmentation, hyperkeratosis and edema – pigmentary xeroderma. Local congenital hypermelanosis is represented by birthmarks or nevus, acquired one is observed at pregnancy, pituitary adenoma, lentigo, melanosis coli at constipation.

Adrenochrome is an adrenalin oxidation product. It occurs in the form of granules in cells of medullary substance of adrenal glands.

Pigment of enterochromaffin cell granules occurs in cells of diffuse endocrine system: enterochromaffin cells of stomach, bowels, B and C cells of thyroid gland, cells of juxtaglomerular apparatus of kidney, cells of Langans’s islands of pancreas. It is considered to be a serotonin analog. Carcinoids or tumors made of above mentioned cells possess a significant serotonin activity. In such cases patients get carcinoid syndrome.

Here is anthracotic pigment in macrophages in a hilar lymph node. Anthracosis is nothing more than accumulation of carbon pigment from breathing dirty air. Smokers have the most pronounced anthracosis. The anthracotic pigment looks bad, but it causes no major organ dysfunction.

Metabolic disorder of lipidogenous pigments

Lipofuscin and lipochromes are referred to lipidogenous pigments.

Lipofuscin is a pigment of goldish colour. Its perinuclear location is an evidence of active metabolic processes. Its accumulation (lipofuscinosis) at the periphery of a cell is an evidence of activity decrease of respiratory ferments in a cell. Lipofuscinosis is occurred at aging, cachexy. The organs are colored into brown – brown atrophy of myocardium, liver.

Lipochrome colours lipocytes, adrenal gland cortex, blood serum, yellow body of ovary into yellow. At pathologic conditions the quantity of lipochromes is increased in fatty tissue at diabetes mellitus, lipidic-vitaminous metabolic disorder, drastic emaciation.

Metabolic disorder of nucleoproteids

It could be often observed at excessive formation of uric acid and its salts which determines development of podagra, urolithiasis, uric acid infarct. At most cases pathology is determined by congenital purine metabolic disorder. Over-use of animal proteins, kidney diseases are of a significant importance for disease pathogenesis. Uric acid sodium deposits in joints (synovial membrane, articular cartilages of hands and feet), synovial membranes of tendon with necrosis areas developed, granulomatosis giant-cell reaction, painful arthroliths, deformation of joints are typical for podagra and gouty arthritis. Podagric nephropathy – uric acid salt deposits in ducts and gathering tubes with obstruction of their lumens and inflammatory, sclerotic and atrophic changes – arises as complication.

Copper metabolic disorder

It could be most often observed at hereditary hepatolenticular degeneration or Wilson's disease. Copper accumulation is observed in liver, brain, kidneys, pancreas,

Potassium metabolic disorder cornea – typical green-brown Kaiser- Fleischer ring at the periphery of cornea. Dystrophic and sclerotic changes are the result of copper accumulation in organs.

It could declare itself in increase of potassium in blood and tissues which is observed at Addison’s disease as result of affection of adrenal glands. Decrease of potassium causes periodic paralysis – fit of weakness and motor paralysis development.

Calcium metabolic disorder

It could declare itself in increase or decrease of calcium concentration in blood (hypocalcemia and hypercalcemia). Calcium metabolic disorder results in development of calcifications (calcinosis) – calcium salts deposits in intercellular substance or cells, that’s why calcifications are divided into intercellular and extracellular ones. According to development mechanism there are metastatic, dystrophic, metabolic calcifications. Calcifications also could be systemic or local.

Metastatic calcifications are more often systemic and appear at hypercalcemia caused by the following:

- disorder of endocrine control of calcium metabolism (hyperproduction of parathyroid hormone, calcitonin deficiency), excessive vitamin D content;

- intensive calcium excretion from bones (multiple fractures, myelomatosis, tumor deposits of bones, osteomalacia, hyperparathyroidic osteodystrophy);

- disorder of calcium excretion from organism (colonic involvement, chronic dysentery, mercuric chloride poisoning, kidney diseases: polycystic renal disease, chronic nephritis).

Most often there are calcium salts deposits in lungs, mucous coat of stomach, kidneys, miocard, walls of arteries.

This is dystrophic calcification in the wall of the stomach. At the far left is an artery with calcification in its wall. There are also irregular bluish-purple deposits of calcium in the submucosa. Calcium is more likely to be deposited in tissues that are damaged.

Here is so-called "metastatic calcification" in the lung of a patient with a very high serum calcium level (hypercalcemia).

Dystrophic calcifications or petrifications are of local character and result in calcium salts deposits formation in necrosis areas or areas of severe dystrophic changes of tissues (tuberculosis, gumma, infarction, atherosclerosis of vessel wall, mitral valve at endocarditis, dead parasites).

Change of physicochemical composition of tissues and local increase in phosphatase activity determine their development, there is no hypercalcemia observed at the same time.

Metabolic calcinosis appears at instability of buffer systems of organism (calcium gout, interstitial calcinosis). Consequences of calcifications are unfavorable in most cases.

Stone formation is appearance of solid concrements in caval organs or excretory ducts of glands. Stones appear in biliary and urinary tracts, excretory ducts of pancreas and salivary glands, bronchi and bronchiectasis, as well as in vessels and bowels. Stone formation is caused by acquired or hereditary metabolic diseases (metabolic disorders of carbohydrates, fats, nucleoproteins, minerals). Among local factors there are secretion disorder, secretion congestion, inflammation. Depending on localization and form of organ in which stones appear there are solitary, multiple, round, oval stones, stones with processes, cylindrical, smooth and shaggy stones. Cholelithic disease and urolithiasis, pressure bedsore, perforation of organs, fistulas, inflammation of walls of caval organs, jaundice, hydronephrosis are the consequences of stone formation.

Cells and tissues damage and death. Necrosis and apoptosis. Pathologic anatomy of organ deficiency. Fundamentals of thanatology.

Death, definition, signs of death

Critical alteration of specialized cells. Definition, etiology and consequences.

Molecular mechanisms of cells critical alteration. Concepts of endogenous metabolic catastrophe: cells biological combustion insufficiency, cell acidotic alteration, plasma membrane transportaion mechanisms injury, activation of cytoplasm lipid peroxidation and cell membranes, injury with free radicals and nitrogen oxide excess, catastrophic increase of free calcium in cell, cell injury with transmitters excess, abnormal proteins accumulation in cell. Critical injury of cell with external factors: external physics-chemical factors, pathogenic infects (ultramicrobs, Rickettsias, bacteria, fungi).

Kinds of specialized cells death in organism.

Cell necrosis: definition, terms and phases of development, morphologic characteristic of coagulation necrosis and cells necrosis, their consequences.

Pathogenic inductive apoptosis: definition, molecular mechanisms, term of development, microscopic manifestation, consequences.

Immune destruction of cells. Immune destruction of cells in organism conditions and designation. Phagocytosis: definition, main cells-phagocytes, phagocytosis mechanisms and microscopic manifestation. Immune cells killing: definition, cytotoxical cells, mechanisms and microscopic manifestations, consequences. Cells destruction with activated complement: definition, mechanisms and microscopic manifestations.

Pathological anatomy of organ insufficiency.

Autoimmune (lymphocytic) destruction of all specialized structures of organ: definition, stages of development, clinical-morphological characteristics, consequences.

Postishemic-markfusional organs injury: definitions, morphogenesis peculiarities, clinical-morphologic characteristics, consequences.

Necrosis of organ or its portion. Morphologic types of tissues necrosis (colliquative, coagulative): definition, causes, pathological anatomy. Organ necrosis: definition, causes, development stages (ore-necrotic, necrosis and tissues destruction). Post necrotic transformation of organ’s sphacelus (necrosis demarcation and encapsulation, regeneration, infection and inflammation, formation of ulcer, cyst, sequester, sclerosis/gliosis foci, calcinosis foci).

Clinical-morphological classification of organ necrosis basic kinds.

Infarction: definition, morphogenesis, pathological anatomy of main types, consequences. Gangrene: definition, morphogenesis, pathological anatomy of dry, wet and anaerobic, consequences. Morphologic characteristics of infarction, gangrene. Decubitus: definition, trophoneurotic necrosis morphogenesis, consequences. Noma: definition, morphogenesis, pathological anatomy, consequences. Morphogenesis, pathological anatomy of liver toxic necrosis and enzymatic pancreatonecrosis. Sequester: definition, morphogenesis, pathological anatomy, consequences.

Fundamentals of thanatology.

Human being birth and death. Organism death from biological, social and medical positions: idea of natural, violent death and death from diseases (untimely and sudden). Intrauterine death definition.

Thanatogenesis. Cause, molecular-metabolic and structural mechanisms of vital parts activity cessation under natural course of disease. Immidiate consequences of heart, lungs, cerebrum, kidneys and liver work cessation.

Clinical-pathological characteristics of the main periods of thanatogenesis. Modern acknowledged periods of thanatogenesis: critical period, apparent death, post reanimation period, natural death. Consequences of vital parts activity cessation.

Critical and agonal periods of disease: definition, clinical-pathological features, consequences.

Clinical death: definition, features and terms of development, idea of cardiopulmonary reanimation and its consequences.

Post reanimation period: definition, molecular and clinical-pathological anatomy features of vital parts injury and their functions recovery.

Natural death: definition, immediate (main) causes and development terms under natural clinical course and under sudden death of a person. Precursory and delayed signs of natural death and resuscitated patient. Morphological characteristic of cadaveric changes. Basic reasons and morphological signs of intrauterine fetal death and neonate death.

Critical alteration of specialized cells is manifested with their death being the final result of their damage. The most often cell’s death is caused by acute hypoxia or ischemia; physical factors (mechanical trauma, burns, frostbites, radiation, electric shock); chemical substances and medicines; infections, intoxications, immune reactions and other conditions.

Mechanisms of cells damage

Mechanisms of cells damage are extremely various. Under ischemia damage develops in the result of oxygen scarcity in tissues and its free radicals creation causing lipids peroxidation and cellular breakdown. Critical damage can develop under calcium homeostasis disturbance. Under cytolemma hyperpermeability free calcium ions concentration grows causing activation of numerous ferments’ damaging cell: phospholipase, protease, ATPase, endonuclease. ATP content decrease causes cytolemmas damage and induces cell death.

Types of specialized cells death.

Three basic types of specialized cells death in organism are recognized: ischemic or hypoxic, toxic and damage with oxygen free radicals. Hypoxic and ischemic damage occurs in the result of arterial flow cessation. Herewith oxidative phosphorilation is ceased and ATP formation is terminated, anaerobic glycolysis enhances, lactic acid, inorganic phosphate accumulates, intracellular pH decreases, chromatin consenses, cell becomes dropsical, membrane structures destruct. Cell damage by free radicals is caused by membranes lipids peroxidation, autocatalytic reactions development, oxic proteopepsis, DNA damage. Toxic damage occurs under chemical substances action on cell membrane or intracellular organelles.

Two types of local death exists: necrosis and apoptosis. Necrosis (from Greek nekros – dead) which is local death, death is characterized with cells death in living body. Specific cells, a group of cells, the portion of the organ, organ in full can be subject to death.

Cells necrosis

Cell necrosis is cell death under the influence of extreme negative exogenic and endogenic factors and it is manifested with considerable cells edema or cellular breakdown, cytoplasmic proteins denaturation and coagulation, cell organelles breakdown. Three stages are differentiated in necrosis development: pre-necrotic, necrotic and post necrotic. Pre-necrotic stage is characterized with severe degenerative changed which are ended with necrosis. At necrosis stage the following is broken-down and decomposed (kariorrhexis, kariolysis), cellular cytoplasm (plasmorrhexis, plasmolysis) and intercellular substance – fibrinoid necrosis.

In the post necrotic stage necrosis products are subject to autolysis, meaning dilation or dispersion or organization. Macroscopically necrosis region differs from surrounding living tissues. Its of dirty black color in skin and bowels and whitish yellow in the other organs (myocardium, liver, kidneys, spleen).

By etio-pathogenetic principle the following direct necrosis is differentiated: traumatic, toxic and the following indirect ones: trophoneurotic, allergic, vascular.

Microscopic signs of necrosis:

Cell nucleus change: karyopyknosis, karyorrhexis, kariolysis.

Cell cytoplasm chang: plasma coagulation, plasmorrhesis, plasmolysis.

Intracellular substance change: mucoid swelling, fibrinoid swelling, fibers disintegration.

Necrosis classification by etiology: trophoneurotic, toxic, traumatic, vascular, allergic.

Trophoneurotic necrosis occurs under central nervous system and peripheral nerves injury. Traumatic necrosis occurs in the result of physical, electrical, chemical, thermal trauma direct action. Toxic necrosis occurs in the result of toxins, mostly of bacterial origin influence on tissues. Allergic necrosis develops on condition of tissues hypersensitivity (sensibilization). Vascular (ischemic) necrosis occurs in the result of tissues blood supply significant decrease or termination.

Clinicopathologic classification of the main types of organs’ and tissues’ necrosis

The following types of necrosis are differentiated: coagulation, colliquative, infarction, gangrene, decubitus, sequester.

Coagulation (dry) necrosis is characterized with sphacelus portion deaquation and induration. It includes cheesy (caseation) necrosis under tuberculosis, lues, lymphogranulomatosis as well as cereous myonecrosis under abdominal and flea-borne typhus, cholera, fibrinoid necrosis under allergic and lymphocytic diseases, malignant hypertension as well as adiponecrosis which is distributed into ferment, which occurs under pancreatitis and non-ferment caused by trauma.

Colliquative (wet) necrosis is characterized with necrotic tissue rarefication and fusion in the result of hydrolytic processes activation. It is developed in tissues rich with moisture, for example in cerebrum.

Infarction is necrosis caused by blood supply deficiency. Occurs in the result of thrombosis, embolism, long term arteriostenosis and long term, functional overexertion of organ in hypoxia conditions. By its shape infarction could be wedge-like (spleen, lung, kidneys) and irregular shape (heart, cerebrum). By its appearance it is distributed into white (ischemic), which the most often is found in cerebrum, spleen; red (hemorrhagic) which occurs in lungs, bowel, amphiblestrodes; white with hemorrhagic crown – in heart, kidneys. Infarction form and appearance depends on the features of organ’s vascular system, types of vessels branching, anastomosis development, structural-functional features of the organ (for detail see the theme of circulatory disturbances).

Gangrene is death of tissues contacting with air (bowel, extremities). Under the influence of air ferric sulphide is formed from hemoglobin, and this ferric sulphide colors necrotic portion in black. Dry and wet gangrenes are differentiated. Dry occurs mostly in the result of insufficient arterial blood supply. Necrotic portion dries up, densifies, mummifies. Wet gangrene occurs in the cases when lymph and black blood outflow is disrupted or when necrosis portion is subject to putrefactive mycronychia action. Necrotic portion is hydropic, diluted, of dirty black color with very unpleasant smell. Anaerobic gangrene development is based also on blood outflow disrupted. It is caused by a group of anaerobic activators. During that gases squeeze microvasculature structures.

Decubitus is a kind of gangrene. It is caused by blood supply and nervous trophism disturbance of subiculum in the place of squeezing (sacral bone, bladebones, calx) under seriously ill patient long term decubitus, for example, cerebrovascular accident.

Sequestrum is sphacelus which is not subject for autolysis for a long time. As a rule sequestra are observed in bones under osteomyelitis.

Demarcation line of red color with a tinge of yellow occurs surrounding necrotic portion. This is reactive inflammation characterized with vascular distention in living tissue, edema, leukocytic infiltration, macrophages incipiency. Lytic ferments of heterophilic leukocytes expedite dead zymolyte maceration and resolution similar to the one observed under wet necrosis, for example in cerebrum with cisterns formation and cyst buildup or rejection (autoamputation) of external necrotic body parts. In favorable cases mesenhymal origin cells proliferation starts around necrotic portion, spacelous aggregate either grow with conjunctive tissue (organization) or encrust with it (encapsulation) or are subject to calcification (petrification). Sometimes necrotic portion purulence is observed with abscess formation.

Apoptosis

Apoptosis is genetically programmed death of unnecessary or defective cells in living body and the following causes these cells destruction in the process of embryogenesis and physiologic involution: cutaneous epithelium, white and red corpuscles extinction. Herewith chromatin condensation and fragmentation in cells is observed. In case apoptosis decrease neoplastic process is developed and in case apoptosis increase – atrophy. Apoptosis differs from necrosis in:

- inflammation absence,

- only several cells or their groups are involved in the process,

- cell membrane is saved,

- cellular breakdown is done not by activated hydrolytic ferments, but in participation of special calcium-magnesium dependent endonucleases which cut nucleus into numerous fragments,

- formed cells fragments (apoptosis corpuscles) phagocytized by parenchymatous or stromal cells which are situated nearby.

Apoptosis morphogenesis develops in several stages:

- chromatin condensation and margination, nucleus becomes fragmented,

- intracellular organelles condensation and cells shrinkage,

- apoptosis corpuscles formation,

- apoptosis corpuscles phagocytosis with parenchymatous cells or macrophages .

Under histological investigation apoptosis cells are round or oval particles with intensively colored cytoplasm and dark fragments of nucleus chromatin.

Fundamentals of thanatology

Thanatology is doctrine of organism dying starting from initial signs up to full corruption of the body. In the course of dying organism stays in terminal (critical) condition and is capable for reversible development occur prior to death coming. Herewith progressive functions decrement of various organism’s systems is observed, first of all respiratory depression as well as blood flow organs depression occurs, organism’s homeostatic systems incoordination has place: pulmonary edema, arrhythmia, paroxysm, respiration disturbance, constrictors paralyses, etc. Hypoxia and blood circulation disturbance cause pathologic changes in organs and tissues, which are called moribund state. Blood circulation directed to support functions of cerebrum causes microcirculation disturbance on periphery resulting in parenhymal organs structure and functions failure. Energy metabolism switches to anaerobic glycolysis causing lactic acid accumulation, acidosis, hypoxia intensifies. Biologically active substances come into blood causing microcirculation channel paresis and paralysis, increase of vascular permeability, blood clotting, stasis occurrence, clots formation. Terminal condition development and signs depend on pathological process caused death agony. In case dying is going on, terminal condition can be divided into several stages: pre-agony, terminal pause, agony, apparent death, natural death. During pre-agony stage arterial tension gradually decreases, inhibition of sensorium and electric activity of cerebrum. Tachycardia passes into bradycardia, trunkal reflex disturbance occur. In terminal phase temporary breath holding is observed, and periodic asystolia changes bradycardia. Agony is characterized with sudden activation of bulbar centers on the background of cerebral cortex full shutdown. Such disintegration of vegetal centers is accompanied with temporary and short time arterial tension increase, sinus automatism initiation and respiratory movements intensification. Apparent death is characterized with the deepest inhibition of central nervous system which expands also on spinal bulb with blood circulation termination and apnea.

Death, types, signs, postmortem changes

Depending on the causes the following types of death are recognized: natural (physiologic) death from age and organism depreciation, violent death from trauma or other negative influence on organism which ends with death and from diseases. Depending on reversible or irreversible changes in organism apparent death and natural death are specified. Apparent death is characterized with apnea, blood circulation termination and lasts for 5-6 minutes until cerebral cells death. Apparent death is reversible process of dying. Reversibility depends on the stage of hypoxic changes in cerebrum. Natural death is manifested with irreversible changes development and autolytic processes beginning in all the organs. It has characteristic signs and postmortem changes in tissues: dead body cooling, postmortem rigidity, mummification, blood relocation, postmortem lividity, cadaveric disintegration. In case death process in fast, it is observed liquid blood in the heart and vessels caused by fibrinolysis, postmortem face lividity, ecchymosis in conjunctiva, intensive and wide spread cadaveric lividity, urine, fecal matter discharge as well as red mucus presence in respiratory passages, considerable venous plethora of internal organs, hemicardia engorgement, punctuate hemorrhage on heart, lungs surface.

In case agony comes prior to death dense blood clots are observed in the heart and vessels – red in case of short term agony and yellowish-white or white under long term agony. Following basic vital functions of organism termination, early and late signs of natural death gradually develop in organism. Early signs are as follows: cadaveric lividity (occur in 30 –60 minutes post mortem), cadaveric rigidity (occurs in 2-4 hours), cooling (every hour of death gives 1 degree dead body temperature decrease, desiccation of specific parts of skin and mucous coats (the most clearly it can be seen on opened eye sclera – Lyarshe spots) and autolysis. Late signs of natural death occur on 2-3 day port mortem. They are ruining (putrefaction, dead body damage by plants, animals) and preserving (grave wax, mummification, turfy tannage, etc.). Putrefaction occurs with microorganisms participation and is characterized with dead body organic substances destruction. This is accompanied with gases formation, tissues mollities and dilution. First signs of putrefaction occur in large bowel in 24-36 hours, abdominal wall derma turns green because of sulfgemoglobin accumulation.

Autopsy.

Autopsy procedure and methods in medical and preventive treatment facilities

Dead body stays in the ward for two hours after the fact of natural death is established by in-patient hospital’s physician. Surname, name, father’s name, date and time of death, department are to be written on the hip with brilliant green. Usually rubber-coated label on which above mentioned passport data is written is fixed to the arm. The latter method is better to use in those medical and preventive treatment facilities in which sporadic death cases occur.

Under body lift and its further examination it’s necessary to keep all moral-ethical and professional requirements. Ethical requirements include medical secrecy keeping regarding everything revealed at autopsy (thanatopsy). It’s also should be taken in mind that dead body serving for science has relatives and family. For example, Professor V.Gruberg required from students and those working in autopsy room to take off hats, as "hats wearing does not correspond the credit of the room". It’s advised to warn junior health professionals of the fact that cadaveric hypostasis can disfeature the face in case body stays dorsum upwards. It should be kept in mind that after natural death fact is etsbalished it’s necessary to close eyes, fasten up lower jaw, to cover the body with clean linen, etc. Simultaneously with diseased body completely filled-in medical records should be submitted to mortuary.

Prior to deceased body autopsy anatomist studies all the data regarding patient’s life, disease and death which can be found in medical card of hospital patient, asks attending doctor missed facts relating to course of disease and dying. Sometimes it’s useful to clarify some data from relatives, especially in case patient’s short term stay in the hospital. The following should be carefully investigated: laboratory, tolls and other methods of investigations, methods of treatment, medicines potions taken by patient, diagnosis written on title page of medical records as well as all working diagnosis written in log books. All this circumstances study pursues one more important aim – to exclude or to find out medicolegal aspect.

It’s desirable that anatomist examining all necessary data independently formulated diagnosis which can differ of attending doctor diagnosis. Doing this, as P.Kalitiyevskyi mentions, anatomist in a certain manner puts her/himself in the position of attending doctor, which is really important for mutual understanding between anatomist and clinician.

There is certain algorithm in autopsy fulfillment:

1 To carry out autopsy in day light as artificial lighting changes color transfer.

2 To put on gown and rubberized apron and oversleeves. It’s advisable to use anatomical gloves. This will ensure contagious diseases prevention, as well as cadaveric alkaloid penetration through possible defects of skin.

3 External examination of diseased body. The following should be established: sex, body-type, nutrition, state of integumentum, existence of death signs, eruptions, hematomas, wounds, ulcerations, edema, etc. It’s desirable that attending doctor could confirm passport data of diseased.

4 Main incision. It’s necessary to watch to prevent it coming through after surgical sections, cicatrix and other defects.

5 Detailed examination of cavities establishing the position and interlocation of organs, presence of joints, exudates, transudate, foreign objects, etc.

6 Organs’ withdrawal from the cavities and their investigations (size, weight, color, consistency, shape, etc.) with simultaneous necropsy taking and, depending on tasks set for anatomist, material for bacteriologic, serologic, biochemical and virology investigations. Sometimes X-ray examination of bones is done.

7 Short summary incorporating paragnosis, the cause of death, possible discrepancies between clinical diagnosis and paragnosis, accessory matters clarification which are of interest for clinicians.

8 Cadaver toilette.

9 Autopsy records keeping.

First autopsy methods were described in details by R.Virhov. Later on it was improved by Kiary, L’Etule, O.Abrykosov, G.Shore. methods of two last ones are the most widely used in anatomists’ practice.

O.Abrikosov offers to investigate organs by cavities. First organs of cervix and thoracic cavity are removed in totality. Then separately intestinal tract, liver, stomach and dodecadactylon in one set, urinary tracts and genital organs in totality.

G.Shore suggested organs full evisceration method, which means removal of cervix, thoracic cavity, abdominal cavity and small pelvis as single total complex. This method is rather convenient to be used under investigation of those deceased bodies who died of after surgery complications. In this cases it’s reasonable to search in details field of operation area, namely state of surgical sutures, vessels, exudates presence and character, correctness of surgery fulfillment.

Autopsy recording

Autopsy recoding should be done in autopsy document – records of post mortem examination (autopsy). It consists of the following parts: passport, descriptive, paragnosis and clinical autopsy epicrisis. Passport portion includes data regarding deceased’ surname, name and father’s name, his/her age, address, number of in-patent’s observation records, profession and specialty, the date of admission to the hospital and date of death, diagnosis. Autopsy records should contain also brief extract from observation records regarding features of etiology, clinical implications, tools and laboratory results, methods of treatment. Take into consideration that it’s advisable to indicate specialty instead of writing “retired”, as well as characteristic features of disease which made it possible to make diagnosis mentioned in clinics.

There are various procedures to fill-in descriptive part. At present there is a tendency to simplify it, to go apart from classical form of presentation. It’s unacceptable to use general terms, for example "atherosclerosis", "adenoma", "pneumosclerosis", etc. instead of pathologic signs or to compare the size of pathologic changes with such objects as English walnut, pea, egg instead of accurate statement of dimensions. It should be remembered that autopsy records is legal document in which minor changes, which, to the opinion of anatomist, are not critical could be of first priority under further examination. Moreover it’s not feasible to use autopsy records in which the character of pathologic changes is only emphasized. This way often causes mistakes, which are hard to correct. Making pictures and audio tape recording are also considered to be ancillary methods of recording. The basic requirement imposed to descriptive part of records is sufficient completeness and distinctness combined in case possible with briefness of presentation.

The following forms of pathologicoanatomic changes registration are widely used in autopsy practice:

Ø by anatomic systems of organism;

Ø by the way of autopsy fulfillment;

Ø by preliminary defined place of system injury in conformance with peculiarities of the case, and further on - by the way of other systems examination.

It’s always recommended to start descriptive part from body appearance description, registration of nutrition, status of skin integuments, mucus tunic, eyes, hair, nails, character of edema, etc. These features are sometimes sufficient to assume this or that pathology presence. It’s advisable to make records immediately following autopsy and do not defer that on the next day, it’s better to make records at dictation by stages of autopsy carrying out or using voice recorder.

Pathologoanatomic diagnosis formulation follows descriptive part of records, based on macroscopic diagnostics and in case necessary using express-methods. Diagnosis formulation is advised to be done in attending doctors presence prior to the body toilette.

Hemodynamic Disorders, Thromboembolic Disease, and Shock

The health of cells and organs critically depends on an unbroken circulation to deliver oxygen and nutrients and to remove wastes. However, the well-being of tissues also requires normal fluid balance; abnormalities in vascular permeability or hemostasis can result in injury even in the setting of an intact blood supply. This chapter will describe major disturbances involving hemodynamics and the maintenance of blood flow, including edema, hemorrhage, thrombosis, embolism, infarction, and shock. Normal fluid homeostasis encompasses maintenance of vessel wall integrity as well as intravascular pressure and osmolarity within certain physiologic ranges. Changes in vascular volume, pressure, or protein content, or alterations in endothelial function, all affect the net movement of water across the vascular wall. Such water extravasation into the interstitial spaces is called edema and has different manifestations depending on its location. In the lower extremities, edema mainly causes swelling; in the lungs, edema causes water to fill alveoli, leading to difficulty in breathing. Normal fluid homeostasis also means maintaining blood as a liquid until such time as injury necessitates clot formation. Clotting at inappropriate sites (thrombosis) or migration of clots (embolism) obstructs blood flow to tissues and leads to cell death (infarction). Conversely, inability to clot after vascular injury results in hemorrhage; local bleeding can compromise regional tissue perfusion, while more extensive hemorrhage can result in hypotension (shock) and death.

Some of the failures of fluid homeostasis reflect a primary pathology in a discrete vascular bed (e.g., hemorrhage due to local trauma) or in systemic coagulation (thrombosis due to hypercoagulability disorders); others may represent a secondary manifestation of some other disease process. Thus, pulmonary edema due to increased hydrostatic pressure may be a terminal complication of ischemic or valvular heart disease. Similarly, shock may be the fatal sequela of infection. Overall, disturbances in normal blood flow are major sources of human morbidity and mortality; thrombosis, embolism, and infarction underlie three of the most important causes of pathology in Western society-myocardial infarction, pulmonary embolism, and cerebrovascular accident (stroke). Thus, the hemodynamic disorders described in this chapter are important in a wide spectrum of human disease.

Edema

Approximately 60% of lean body weight is water; two thirds of this water is intracellular, and the remainder is found in the extracellular space, mostly as interstitial fluid (only about 5% of total body water is in blood plasma). The term edema signifies increased fluid in the interstitial tissue spaces. In addition, depending on the site, fluid collections in the different body cavities are variously designated hydrothorax, hydropericardium, and hydroperitoneum (the last is more commonly called ascites). Anasarca is a severe and generalized edema with profound subcutaneous tissue swelling

Inflammation

Acute inflammation

Chronic inflammation

Angiogenesis

In general, the opposing effects of vascular hydrostatic pressure and plasma colloid osmotic pressure are the major factors that govern movement of fluid between vascular and interstitial spaces. Normally the exit of fluid into the interstitium from the arteriolar end of the microcirculation is nearly balanced by inflow at the venular end; a small residuum of excess interstitial fluid is drained by the lymphatics. Either increased capillary pressure or diminished colloid osmotic pressure can result in increased interstitial fluid. As extravascular fluid accumulates, the increased tissue hydrostatic pressure and plasma colloid osmotic pressure eventually achieve a new equilibrium, and water reenters the venules. Any excess interstitial edema fluid is typically removed by lymphatic drainage, ultimately returning to the bloodstream via the thoracic duct .clearly, lymphatic obstruction (e.g., due to scarring or tumor) will also impair fluid drainage and result in edema. Finally, a primary retention of sodium (and its obligatory associated water) in renal disease also leads to edema.

Increased Hydrostatic Pressure. Local increases in hydrostatic pressure may result from impaired venous outflow. For example, deep venous thrombosis in the lower extremities leads to edema, which is restricted to the affected leg. Generalized increases in venous pressure, with resulting systemic edema, occur most commonly in congestive heart failure affecting right ventricular cardiac function.

Although increased venous hydrostatic pressure is important, the pathogenesis of cardiac edema is more complex Congestive heart failure is associated with reduced cardiac output and, therefore, reduced renal perfusion. Renal hypoperfusion, in turn, triggers the renin-angiotensin-aldosterone axis, inducing sodium and water retention by the kidneys (secondary aldosteronism). This process is putatively designed to increase intravascular volume and thereby improve cardiac output (via the Frank-Starling law) with restoration of normal renal perfusion. If the failing heart cannot increase cardiac output, however, the extra fluid load results only in increased venous pressure and eventually edema.¹ Unless cardiac output is restored or renal water retention is reduced (e.g., by salt restriction, diuretics, or aldosterone antagonists), a cycle of renal fluid retention and worsening edema ensues. Although discussed here in the context of edema in congestive heart failure, salt restriction, diuretics, and aldosterone antagonists may also be used to manage generalized edema arising from a variety of other causes

Reduced Plasma Osmotic Pressure. Reduced plasma osmotic pressure can result from excessive loss or reduced synthesis of albumin, the serum protein most responsible for maintaining colloid osmotic pressure. An important cause of albumin loss is the nephrotic syndrome characterized by a leaky glomerular capillary wall and generalized edema. Reduced albumin synthesis occurs in the setting of diffuse liver pathology (e.g., cirrhosis, or as a consequence of protein malnutrition (In each case, reduced plasma osmotic pressure leads to a net movement of fluid into the interstitial tissues and a resultant plasma volume contraction. Predictably, with reduced intravascular volume, renal hypoperfusion with secondary aldosteronism follows. The retained salt and water cannot correct the plasma volume deficit because the primary defect of low serum proteins persists. As with congestive heart failure, edema precipitated by hypoproteinemia is exacerbated by secondary salt and fluid retention.

Lymphatic Obstruction. Impaired lymphatic drainage and consequent lymphedema is usually localized; it can result from inflammatory or neoplastic obstruction. For example, the parasitic infection filariasis often causes massive lymphatic and lymph node fibrosis in the inguinal region. The resulting edema of the external genitalia and lower limbs is so extreme that it is called elephantiasis. Cancer of the breast may be treated by removal or irradiation (or both) of the breast and the associated axillary lymph nodes. The resection of the lymphatic channels as well as scarring related to the surgery and radiation can result in severe edema of the arm. In carcinoma of the breast, infiltration and obstruction of superficial lymphatics can cause edema of the overlying skin, giving rise to the so-called peau d'orange (orange peel) appearance. Such a finely pitted appearance results from an accentuation of depressions in the skin at the site of hair follicles.

Sodium and Water Retention. Sodium and water retention are clearly contributory factors in several forms of edema; however, salt retention may also be a primary cause of edema. Increased salt, with the obligate accompanying water, causes both increased hydrostatic pressure (owing to expansion of the intravascular fluid volume) and diminished vascular colloid osmotic pressure. Salt (and water) retention may occur with any acute reduction of renal function, including glomerulonephritis and acute renal failure

Morphology. Edema is most easily recognized grossly; microscopically, edema fluid generally manifests only as subtle cell swelling, with clearing and separation of the extracellular matrix elements. Although any organ or tissue in the body may be involved, edema is most commonly encountered in subcutaneous tissues, the lungs, and the brain. Severe, generalized edema is called anasarca

Pulmonary edema is a common clinical problem most typically seen in the setting of left ventricular failure but also occurring in renal failure, acute respiratory distress syndrome , pulmonary infections, and hypersensitivity reactions. The lungs are two to three times their normal weight, and sectioning reveals frothy, blood-tinged fluid representing a mixture of air, edema fluid, and extravasated red blood cells.

Edema of the brain may be localized (e.g., owing to abscess or neoplasm) or may be generalized, as in encephalitis, hypertensive crises, or obstruction to the brain's venous outflow. Trauma may result in local or generalized edema depending on the nature and extent of the injury. With generalized edema, the brain is grossly swollen, with narrowed sulci and distended gyri, showing signs of flattening against the unyielding skull

Hyperemia and Congestion

The terms hyperemia and congestion both indicate a local increased volume of blood in a particular tissue. Hyperemia is an active process resulting from augmented tissue inflow because of arteriolar dilation, as in skeletal muscle during exercise or at sites of inflammation. The affected tissue is redder because of the engorgement of vessels with oxygenated blood. Congestion is a passive process resulting from impaired outflow from a tissue. It may occur systemically, as in cardiac failure, or it may be local, resulting from an isolated venous obstruction. The tissue has a blue-red color (cyanosis), particularly as worsening congestion

leads to accumulation of deoxygenated hemoglobin in the affected tissues

Congestion and edema commonly occur together, primarily since capillary bed congestion can result in edema due to increased fluid transudation. In long-standing congestion, called chronic passive congestion, the stasis of poorly oxygenated blood also causes chronic hypoxia, which can result in parenchymal cell degeneration or death, sometimes with microscopic scarring. Capillary rupture at these sites of chronic congestion may also cause small foci of hemorrhage; breakdown and phagocytosis of the red cell debris can eventually result in small clusters of hemosiderin-laden macrophages

Morphology. The cut surfaces of hyperemic or congested tissues are hemorrhagic and wet. Microscopically, acute pulmonary congestion is characterized by alveolar capillaries engorged with blood; there may be associated alveolar septal edema and/or focal intra-alveolar hemorrhage. In chronic pulmonary congestion, the septa are thickened and fibrotic, and the alveolar spaces may contain numerous hemosiderin-laden macrophages (heart failure cells). In acute hepatic congestion, the central vein and sinusoids are distended with blood, and there may even be central hepatocyte degeneration; the periportal hepatocytes, better oxygenated because of their proximity to hepatic arterioles, experience less severe hypoxia and may only develop fatty change. In chronic passive congestion of the liver, the central regions of the hepatic lobules are grossly red-brown and slightly depressed (owing to a loss of cells) and are accentuated against the surrounding zones of uncongested tan liver (nutmeg liver)

). Microscopically, there is evidence of centrilobular necrosis with loss of hepatocytes dropout and hemorrhage, including hemosiderin-laden macrophages In severe, long-standing hepatic congestion (most commonly associated with heart failure), there may even be grossly evident hepatic fibrosis (cardiac cirrhosis). Because the central portion of the hepatic lobule is the last to receive blood, centrilobular necrosis can also occur whenever there is reduced hepatic blood flow (including shock from any cause); there need not be previous hepatic congestion

Hemorrhage

Hemorrhage generally indicates extravasation of blood due to vessel rupture. As described previously, capillary bleeding can occur under conditions of chronic congestion, and an increased tendency to hemorrhage from usually insignificant injury is seen in a wide variety of clinical disorders collectively called hemorrhagic diatheses However, rupture of a large artery or vein is almost always due to vascular injury, including trauma, atherosclerosis, or inflammatory or neoplastic erosion of the vessel wall. Hemorrhage may be manifested in a variety of patterns, depending on the size, extent, and location of bleeding.

ü Hemorrhage may be external or may be enclosed within a tissue; accumulation of blood within tissue is referred to as a hematoma. Hematomas may be relatively insignificant (a bruise) or may be sufficiently large as to be fatal (e.g., a massive retroperitoneal hematoma resulting from rupture of a dissecting aortic aneurysm;

ü Minute 1- to 2-mm hemorrhages into skin, mucous membranes, or serosal surfaces are denoted as petechiae (and are typically associated with locally increased intravascular pressure, low platelet counts (thrombocytopenia), defective platelet function (as in uremia), or clotting factor deficits.

ü Slightly larger (≥3 mm) hemorrhages are called purpura. These may be associated with many of the same disorders that cause petechiae and may also occur secondary to trauma, vascular inflammation (vasculitis), or increased vascular fragility (e.g., in amyloidosis).

ü Larger (>1 to 2 cm) subcutaneous hematomas (i.e., bruises) are called ecchymoses and are characteristically seen after trauma but may be exacerbated by any of the aforementioned conditions. The erythrocytes in these local hemorrhages are degraded and phagocytosed by macrophages; the hemoglobin (red-blue color) is then enzymatically converted into bilirubin (blue-green color) and eventually into hemosiderin (gold-brown color), accounting for the characteristic

ü color changes in a hematoma.

ü Large accumulations of blood in one or another of the body cavities are called hemothorax, hemopericardium, hemoperitoneum, or hemarthrosis (in joints). Patients with extensive hemorrhage occasionally develop jaundice from the massive breakdown of red cells and systemic release of bilirubin.

The clinical significance of hemorrhage depends on the volume and rate of bleeding. Rapid loss of up to 20% of the blood volume or slow losses of even larger amounts may have little impact in healthy adults; greater losses, however, may result in hemorrhagic (hypovolemic) shock (discussed later). The site of hemorrhage is also important; bleeding that would be trivial in the subcutaneous tissues may cause death if located in the brain because the skull is unyielding and bleeding there can result in increased intracranial pressure and herniation Finally, loss of iron and subsequent iron-deficiency anemia become a consideration in chronic or recurrent external blood loss (e.g., peptic ulcer or menstrual bleeding). In contrast, when red cells are retained, as in hemorrhage into body cavities or tissues, the iron can be reused for hemoglobin synthesis.

THROMBOSIS

Pathogenesis. Three primary influences predispose to thrombus formation, the so-called Virchow triad: (1) endothelial injury; (2) stasis or turbulence of blood flow; and (3) blood hypercoagulability

Endothelial Injury. This is the dominant influence; endothelial injury by itself can lead to thrombosis. It is particularly important for thrombus formation occurring in the heart or in the arterial circulation, where the normally high flow rates might otherwise hamper clotting by preventing platelet adhesion or diluting coagulation factors. Thus, thrombus formation within the cardiac chambers (e.g., following endocardial injury due to myocardial infarction), over ulcerated plaques in atherosclerotic arteries, or at sites of traumatic or inflammatory vascular injury (vasculitis) is largely due to endothelial injury. Clearly, physical loss of endothelium will lead to exposure of subendothelial ECM, adhesion of platelets, release of tissue factor, and local depletion of PGI₂ and PAs. However, it is important to note that endothelium need not be denuded or physically disrupted to contribute to the development of thrombosis; any perturbation in the dynamic balance of the pro- and antithrombotic effects of endothelium can influence local clotting Thus, dysfunctional endothelium may elaborate greater amounts of procoagulant factors (e.g., platelet adhesion molecules, tissue factor, PAI) or may synthesize less anticoagulant effectors (e.g., thrombomodulin, PGI₂, t-PA). Significant endothelial dysfunction (in the absence of endothelial cell loss) may occur due to the hemodynamic stresses of hypertension, turbulent flow over scarred valves, or bacterial endotoxins. Even relatively subtle influences, such as homocystinuria, hypercholesterolemia, radiation, or products absorbed from cigarette smoke may initiate endothelial injury.

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 factor in the development of venous thrombi.Normal blood flow is laminar such that the platelets flow centrally in the vessel lumen, separated from the endothelium by a slower-moving clear zone of plasma. Stasis and turbulence therefore (1) disrupt laminar flow and bring platelets into contact with the endothelium; (2) prevent dilution of activated clotting factors by fresh flowing blood; (3) retard the inflow of clotting factor inhibitors and permit the build-up of thrombi; and (4) promote endothelial cell activation, predisposing to local thrombosis, leukocyte adhesion, and a variety of other endothelial cell effects

Turbulence and stasis clearly contribute to thrombosis in a number of clinical settings. Ulcerated atherosclerotic plaques not only expose subendothelial ECM, but are also sources of turbulence. Abnormal aortic and arterial dilations called aneurysms cause local stasis and are favored sites of thrombosis Myocardial infarctions not only have associated endothelial injury, but also have regions of noncontractile myocardium, adding an element of stasis in the formation of mural thrombi. Mitral valve stenosis (e.g., after rheumatic heart disease) results in left atrial dilation. In conjunction with atrial fibrillation, a dilated atrium is a site of profound stasis and a prime location for thrombus development. Hyperviscosity syndromes (such as polycythemia; cause small vessel stasis; the deformed red cells in sickle cell anemia cause vascular occlusions, with the resulting stasis predisposing to thrombosis.

Hypercoagulability. Hypercoagulability contributes less frequently to thrombotic states but is nevertheless an important component in the equation. It is loosely defined as any alteration of the coagulation pathways that predisposes to thrombosis. The causes of hypercoagulability may be primary (genetic) and secondary (acquired) disorders

Morphology. Thrombi may develop anywhere in the cardiovascular system: within the cardiac chambers; on valve cusps; or in arteries, veins, or capillaries. They are of variable size and shape, depending on the site of origin and the circumstances leading to their development. Arterial or cardiac thrombi usually begin at a site of endothelial injury (e.g., atherosclerotic plaque) or turbulence (vessel bifurcation); venous thrombi characteristically occur in sites of stasis. An area of attachment to the underlying vessel or heart wall, frequently firmest at the point of origin, is characteristic of all thromboses. Arterial thrombi tend to grow in a retrograde direction from the point of attachment, whereas venous thrombi extend in the direction of blood flow (i.e., toward the heart). The propagating tail may not be well attached and, particularly in veins, is prone to fragmentation, creating an embolus

When formed in the heart or aorta, thrombi may have grossly (and microscopically) apparent laminations, called lines of Zahn; these are produced by alternating pale layers of platelets admixed with some fibrin and darker layers containing more red cells. Lines of Zahn are significant only in that they imply thrombosis at a site of blood flow; in veins or in smaller arteries, the laminations are typically not as apparent, and, in fact, thrombi formed in the sluggish flow of venous blood usually resemble statically coagulated blood (similar to blood clotted in a test tube). Nevertheless, careful evaluation generally reveals irregular, somewhat ill-defined laminations

These are "lines of Zahn" which are the alternating pale pink bands of platelets with fibrin and red bands of RBC's forming a true thrombus.

When arterial thrombi arise in heart chambers or in the aortic lumen, they usually adhere to the wall of the underlying structure and are termed mural thrombi. Abnormal myocardial contraction (arrhythmias, dilated cardiomyopathy, or myocardial infarction) leads to cardiac mural thrombi , while ulcerated atherosclerotic plaque and aneurysmal dilation are the precursors of aortic thrombus formation

Arterial thrombi are usually occlusive; the most common sites, in descending order, are coronary, cerebral, and femoral arteries. The thrombus is usually superimposed on an atherosclerotic plaque, although other forms of vascular injury (vasculitis, trauma) may be involved. The thrombi are typically firmly adherent to the injured arterial wall and are gray-white and friable, composed of a tangled mesh of platelets, fibrin, erythrocytes, and degenerating leukocytes.

Here is the anterior surface of the heart with the left anterior descending coronary artery opened longitudinally. This is coronary thrombosis, one of the complications of atherosclerosis. The occlusive dark red thrombus is seen within the lumen of the coronary artery. This produces an acute coronary syndrome.

Here is a closer view of the gross appearnace of a coronary thrombosis. The thrombus occludes the lumen and produces ischemia and/or infarction of the myocardium. Atherosclerosis is an ongoing process that takes years to decades for clinically apparent problems to appear.

A coronary thrombosis is seen microscopically occluding the remaining small lumen of this coronary artery. Such an acute coronary thrombosis is often the antecedent to acute myocardial infarction.

Venous thrombosis, or phlebothrombosis, is almost invariably occlusive; the thrombus often creates a long cast of the vein lumen. Because these thrombi form in a relatively static environment, they tend to contain more enmeshed erythrocytes and are therefore known as red, or stasis, thrombi. Phlebothrombosis most commonly affects the veins of the lower extremities (90% of cases). Less commonly, venous thrombi may develop in the upper extremities, periprostatic plexus, or the ovarian and periuterine veins; under special circumstances, they may be found in the dural sinuses, the portal vein, or the hepatic vein. At autopsy, postmortem clots may be confused for venous thrombi. Postmortem clots are gelatinous with a dark red dependent portion where red cells have settled by gravity and a yellow chicken fat supernatant resembling melted and clotted chicken fat; they are usually not attached to the underlying wall. In contrast, red thrombi are firmer, almost always have a point of attachment, and on transection reveal vague strands of pale gray fibrin

Under special circumstances, thrombi may form on heart valves. Bacterial or fungal blood-borne infections may establish a foothold, leading to valve damage and the development of large thrombotic masses, or vegetations (infective endocarditis; Sterile vegetations can also develop on noninfected valves in patients with hypercoagulable states, so-called nonbacterial thrombotic endocarditis Less commonly, noninfective, verrucous (Libman-Sacks) endocarditis attributable to elevated levels of circulating immune complexes may occur in patients with systemic lupus erythematosus.

Fate of the Thrombus. If a patient survives the immediate effects of a thrombotic vascular obstruction, thrombi undergo some combination of the following four events in the ensuing days to weeks

• Propagation. The thrombus may accumulate more platelets and fibrin (propagate), eventually leading to vessel obstruction.
• Embolization. Thrombi may dislodge and travel to other sites in the vasculature.
• Dissolution. Thrombi may be removed by fibrinolytic activity.

(organization) and may eventually become recanalized; that is, may reestablish vascular flow, or may be incorporated into a thickened vascular wall.

Propagation and embolization are discussed further below. As for dissolution, activation of the fibrinolytic pathways can lead to rapid shrinkage and even total lysis of recent thrombi. With older thrombi, extensive fibrin polymerization renders the thrombus substantially more resistant to proteolysis, and lysis is ineffectual. This is important because therapeutic infusions of fibrinolytic agents such as t-PA (e.g., for pulmonary thromboemboli or coronary thrombosis) are likely to be effective for only a short time after thrombi form

Older thrombi tend to become organized. This refers to the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts into the fibrin-rich thrombus. In time, capillary channels are formed, which 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. Although the channels may not successfully restore significant flow to many obstructed vessels, such recanalization can potentially convert the thrombus into a vascularized mass of connective tissue). With time and contraction of the mesenchymal cells (and particularly for smaller thrombi), the connective tissue may be incorporated as a subendothelial swelling of the vessel wall; eventually, only a fibrous lump may remain to mark the original thrombus site. Occasionally, instead of organizing, the center of a thrombus undergoes enzymatic digestion, presumably as a result of the release of lysosomal enzymes from trapped leukocytes and platelets. This is particularly likely in large thrombi within aneurysmal dilations or the cardiac chambers. If bacterial seeding occurs, such a degraded thrombus is an ideal culture medium, resulting, for example, in a so-called mycotic aneurysm

Venous Thrombosis (Phlebothrombosis). The great preponderance of venous thrombi occur in either the superficial or the deep veins of the leg. Superficial venous thrombi usually occur in the saphenous system, particularly when there are varicosities. Such thrombi may cause local congestion, and swelling, pain, and tenderness along the course of the involved vein but rarely embolize. Nevertheless, the local edema and impaired venous drainage do predispose the involved overlying skin to infections from slight trauma and to the development of varicose ulcers. Deep thrombi in the larger leg veins at or above the knee (e.g., popliteal, femoral, and iliac veins) are more serious because they may embolize. Although they may cause local pain and distal edema, the venous obstruction may be rapidly offset by collateral bypass channels. Consequently, deep vein thromboses are entirely asymptomatic in approximately 50% of affected patients and are recognized only in retrospect after they have embolized

Deep venous thrombosis may occur with stasis and in a variety of hypercoagulable states as described earlier Cardiac failure is an obvious reason for stasis in the venous circulation. Trauma, surgery, and burns usually result in reduced physical activity, injury to vessels, release of procoagulant substances from tissues, and/or reduced t-PA activity. Many factors act in concert to predispose to thrombosis in the puerperal and postpartum states. Besides the potential for amniotic fluid infusion into the circulation at the time of delivery, late pregnancy and the postpartum period are also associated with hypercoagulability. Tumor-associated procoagulant release is largely responsible for the increased risk of thromboembolic phenomena seen in disseminated cancers, so-called migratory thrombophlebitis or Trousseau syndrome. Regardless of the specific clinical setting, advanced age, bed rest, and immobilization increase the risk of deep venous thrombosis, particularly in those who have inherited susceptibility reduced physical activity diminishes the milking action of muscles in the lower leg and so slows venous return

Arterial and Cardiac Thrombosis. Atherosclerosis is a major initiator of thromboses, related to the associated abnormal vascular flow and loss of endothelial integrity Cardiac mural thrombi can arise in the setting of myocardial infarction related to dyskinetic contraction of the myocardium as well as damage to the adjacent endocardium Rheumatic heart disease may result in atrial mural thrombi due to mitral valve stenosis, followed by left atrial dilation; concurrent atrial fibrillation augments atrial blood stasis. In addition to the local obstructive consequences, cardiac and arterial (in particular, aortic) mural thrombi can also embolize peripherally. Virtually any tissue may be affected, but the brain, kidneys, and spleen are prime targets because of their large flow volume.

While we clearly understand a number of conditions that predispose to thrombosis, the phenomenon remains somewhat unpredictable. It continues to occur at a distressingly high frequency in healthy, ambulatory individuals without apparent provocation or underlying patholog

DISSEMINATED INTRAVASCULAR COAGULATION (DIC)

DIC is an acute, subacute, or chronic thrombohemorrhagic disorder occurring as a secondary complication in a variety of diseases. It is characterized by activation of the coagulation sequence that leads to the formation of microthrombi throughout the microcirculation of the body, often in a quixotically uneven distribution. Sometimes the coagulopathy is localized to a specific organ or tissue. As a consequence of the thrombotic diathesis, there is consumption of platelets, fibrin, and coagulation factors and, secondarily, activation of fibrinolytic mechanisms. Thus, DIC can present with signs and symptoms relating to tissue hypoxia and infarction caused by the myriad microthrombi or as a hemorrhagic disorder related to depletion of the elements required for hemostasis (hence, the term "consumption coagulopathy" is sometimes used to describe DIC). Activation of the fibrinolytic mechanism aggravates the hemorrhagic diathesis

Etiology and Pathogenesis. At the outset, it must be emphasized that DIC is not a primary disease. It is a coagulopathy that occurs in the course of a variety of clinical conditions. In discussing the general mechanisms underlying DIC, it is useful to briefly review the normal process of blood coagulation and clot removal. Clotting can be initiated by either of two pathways: (1) the extrinsic pathway, which is triggered by the release of tissue factor ("tissue thromboplastin"), and (2) the intrinsic pathway, which involves the activation of factor XII by surface contact with collagen or other negatively charged substances. Both pathways, through a series of intermediate steps, result in the generation of thrombin, which in turn converts fibrinogen to fibrin. Once activated at the site of injury, thrombin further augments local fibrin deposition through feedback activation of the intrinsic pathway and inhibition of fibrinolysis. Remarkably, as excess thrombin is swept away in the blood from sites of tissue injury it is converted to an anticoagulant. Upon binding a surface protein called thrombomodulin on intact endothelial cells, thrombin becomes capable of

activating protein C, an inhibitor of the pro-coagulant factors V and VIII. Other important clot-inhibiting factors include the activation of fibrinolysis by plasmin and the clearance of activated clotting factors by the mononuclear phagocyte system and the liver. These and additional checks and balances normally ensure that just enough clotting occurs at the right place and time.From this brief review, it should be clear that DIC could result from pathologic activation of the extrinsic and/or intrinsic pathways of coagulation or impairment of clot-inhibiting influences. Since the latter rarely constitute primary mechanisms of DIC, we focus our attention on the abnormal initiation of clotting

Acute intravascular hemolysis, snakebite, giant hemangioma, shock, heat stroke, vasculitis, aortic aneurysm, liver disease

Two major mechanisms trigger DIC: (1) release of tissue factor or thromboplastic substances into the circulation and (2) widespread injury to the endothelial cells. Tissue thromboplastic substances can be derived from a variety of sources, such as the placenta in obstetric complications and the granules of leukemic cells in acute promyelocytic leukemia. Mucus released from certain adenocarcinomas can also act as a thromboplastic substance by directly activating factor X, independent of factor VII. In gram-negative sepsis (an important cause of DIC), bacterial endotoxins cause activated monocytes to release interleukin-1 and TNF, both of which increase the expression of tissue factor on endothelial cell membranes and simultaneously decrease the expression of thrombomodulin.⁷² The net result is a shift in balance toward procoagulation

Endothelial injury, the other major trigger, can initiate DIC by causing release of tissue factor, promoting platelet aggregation, and activating the intrinsic coagulation pathway. TNF is an extremely important mediator of endothelial cell inflammation and injury in septic shock. In addition to the effects previously mentioned, TNF up-regulates the expression of adhesion molecules on endothelial cells and thus favors adhesion of leukocytes, which in turn damage endothelial cells by releasing oxygen-derived free radicals and preformed proteases. Even subtle endothelial injury can unleash procoagulant activity by enhancing membrane expression of tissue factor. Widespread endothelial injury may be produced by deposition of antigen-antibody complexes (e.g., systemic lupus erythematosus), temperature extremes (e.g., heat stroke, burns), or microorganisms (e.g., meningococci, rickettsiae).

. The initiating factors in these conditions are often multiple and interrelated. For example, particularly in infections caused by gram-negative bacteria, released endotoxins can activate both the intrinsic and extrinsic pathways by producing endothelial cell injury and release of thromboplastins from inflammatory cells; furthermore, endotoxins inhibit the anticoagulant activity of protein C by suppressing thrombomodulin expression on endothelium. Endothelial cell damage can also be produced directly by meningococci, rickettsiae, and viruses. Antigen-antibody complexes formed during the infection can activate the classical complement pathway, and complement fragments can secondarily activate both platelets and granulocytes. Endotoxins as well as other bacterial products are also capable of directly activating factor XII. In massive trauma, extensive surgery, and severe burns, the major mechanism of DIC is believed to be the release of tissue thromboplastins. In obstetric conditions, thromboplastins derived from the placenta, dead retained fetus, or amniotic fluid may enter the circulation. However, hypoxia, acidosis, and shock, which often coexist with the surgical and obstetric conditions, also cause widespread endothelial injury. Supervening infection can complicate the problems further. Among cancers, acute promyelocytic leukemia and carcinomas of the lung, pancreas, colon, and stomach are most frequently associated with DIC. These tumors release of a variety of thromboplastic substances, including tissue factors, proteolytic enzymes, mucin, and other undefined tumor products

The consequences of DIC are twofold. First, there is widespread deposition of fibrin within the microcirculation. This can lead to ischemia of the more severely affected or more vulnerable organs and to a hemolytic anemia resulting from fragmentation of red cells as they squeeze through the narrowed microvasculature (microangiopathic hemolytic anemia). Second, a hemorrhagic diathesis can dominate the clinical picture. This results from consumption of platelets and clotting factors as well as activation of plasminogen. Plasmin can not only cleave fibrin, but also digest factors V and VIII, thereby reducing their concentration further. In addition, fibrinolysis leads to the formation of fibrin degradation products, which inhibit platelet aggregation and fibrin polymerization and have antithrombin activity. All these influences lead to the hemostatic failure seen in DIC

Morphology. In general, thrombi are found in the following sites in decreasing order of frequency: brain, heart, lungs, kidneys, adrenals, spleen, and liver. However, no tissue is spared, and thrombi are occasionally found in only one or several organs without affecting others. In giant hemangiomas, for example, thrombi are localized to the neoplasm, where they are believed to form due to local stasis and recurrent trauma to fragile blood vessels. The affected kidneys can reveal small thrombi in the glomeruli that may evoke only reactive swelling of endothelial cells or, in severe cases, microinfarcts or even bilateral renal cortical necrosis. Numerous fibrin thrombi may be found in alveolar capillaries, sometimes associated with pulmonary edema and fibrin exudation, creating "hyaline membranes" reminiscent of acute respiratory distress syndrome . In the central nervous system, fibrin thrombi can cause microinfarcts, occasionally complicated by simultaneous hemorrhage. Such changes are the basis for the bizarre neurologic signs and symptoms sometimes observed in DIC. The manifestations of DIC in the endocrine glands are of considerable interest. In meningococcemia, fibrin thrombi within the microcirculation of the adrenal cortex are the likely basis for the massive adrenal hemorrhages seen in Waterhouse-Friderichsen syndrome Similarly, Sheehan postpartum pituitary necrosis is a form of DIC complicating labor and delivery. In toxemia of pregnancy the placenta exhibits widespread microthrombi, providing a plausible explanation for the premature atrophy of the cytotrophoblast and syncytiotrophoblast encountered in this condition

The bleeding manifestations of DIC are not dissimilar to those encountered in the hereditary and acquired disorders affecting the hemostatic mechanisms discussed earlier

Embolism

An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant from its point of origin. Almost all emboli represent some part of a dislodged thrombus, hence the commonly used term thromboembolism. Rare forms of emboli include droplets of fat, bubbles of air or nitrogen, atherosclerotic debris (cholesterol emboli), tumor fragments, bits of bone marrow, or even foreign bodies such as bullets. However, unless otherwise specified, an embolism should be considered to be thrombotic in origin. Inevitably, emboli lodge in vessels too small to permit further passage, resulting in partial or complete vascular occlusion. The potential consequence of such thromboembolic events is the ischemic necrosis of distal tissue, known as infarction. Depending on the site of origin, emboli may lodge anywhere in the vascular tree; the clinical outcomes are best understood from the standpoint of whether emboli lodge in the pulmonary or systemic circulations.

The capillary loops of this glomerulus contain fat globules in a patient with fat embolism syndrome

PULMONARY THROMBOEMBOLISM

Pulmonary embolism has an incidence of 20 to 25 per 100,000 hospitalized patients. Although the rate of fatal pulmonary emboli (as assessed at autopsy) has declined from 6% to 2% over the last quarter century, pulmonary embolism still causes about 200,000 deaths per year in the United States. In more than 95% of instances, venous emboli originate from deep leg vein thrombi above the level of the knee as described previously. They are carried through progressively larger channels and usually pass through the right side of the heart into the pulmonary vasculature. Depending on the size of the embolus, it may occlude the main pulmonary artery, impact across the bifurcation (saddle embolus), or pass out into the smaller, branching arterioles Frequently, there are multiple emboli, perhaps sequentially or as a shower of smaller emboli from a single large mass; in general, the patient who has had one pulmonary embolus is at high risk of having more. Rarely, an embolus may pass through an interatrial or interventricular defect to gain access to the systemic circulation (paradoxical embolism).

• Most pulmonary emboli (60% to 80%) are clinically silent because they are small. With time, they undergo organization and are incorporated into the vascular wall in some cases, organization of the thromboembolus leaves behind a delicate, bridging fibrous web.
• Sudden death, right heart failure (cor pulmonale), or cardiovascular collapse occurs when 60% or more of the pulmonary circulation is obstructed with emboli.
• Embolic obstruction of medium-sized arteries may result in pulmonary hemorrhage but usually does not cause pulmonary infarction because of the dual blood flow into the area from the bronchial circulation. A similar embolus in the setting of left-sided cardiac failure (i.e., with sluggish bronchial artery flow), however, may result in a large infarct.
• Embolic obstruction of small end-arteriolar pulmonary branches usually does result in associated infarction.

Multiple emboli over time may cause pulmonary hypertension with right heart failure

The main pulmonary trunk and pulmonary arteries to the right and to the left lung are seen here opened to reveal a large "saddle" pulmonary thromboembolus. Patients with such an embolus will have a high mortality rate.

Here is another large pulmonary thromboembolus seen in cross section of this lung. The typical source for such thromboemboli is from large veins in the legs and pelvis.

Pulmonary emboli can be classified by size as small, medium, and large. Small ones may be clinically inapparent. Medium-sized ones may not kill the patient, but may lead to pulmonary infarction. Large ones can be life-threatening. Recurrent pulmonary embolization can reduce pulmonary vascular flow and cause pulmonary hypertension.

This is the microscopic appearance of a pulmonary embolus (PE) in a major pulmonary artery branch. The layering of the RBC's and the lighter pink fibrin enmeshing leukocytes and platelets occurred in the vein in which the thrombus originally formed.

This pulmonary embolus is adherent to the pulmonary arterial wall. If the patient survives, the thromboembolus will organize and, for the most part, be removed.

SYSTEMIC THROMBOEMBOLISM

Systemic thromboembolism refers to emboli traveling within the arterial circulation. Most (80%) arise from intracardiac mural thrombi, two thirds of which are associated with left ventricular wall infarcts and another quarter with dilated and fibrillating left atria (e.g., secondary to mitral valve disease;. The remainder originate from aortic aneurysms, thrombi on ulcerated atherosclerotic plaques, or fragmentation of a valvular vegetation with a small fraction due to paradoxical emboli; 10% to 15% of systemic emboli are of unknown origin. In contrast to venous emboli, which tend to lodge primarily in one vascular bed (the lung), arterial emboli can travel to a wide variety of sites; the point of arrest depends on the source of the thromboembolus and the volume of blood flow through the downstream tissues. The major sites for arteriolar embolization are the lower extremities (75%) and the brain (10%), with the intestines, kidneys, spleen, and upper extremities involved to a lesser extent. The consequences of systemic emboli depend on the extent of collateral vascular supply in the affected tissue, the tissue's vulnerability to ischemia, and the caliber of the vessel occluded; in general, arterial emboli cause infarction of tissues downstream of the obstructed vessel

FAT EMBOLISM

Microscopic fat globules may be found in the circulation after fractures of long bones (which have fatty marrow) or, rarely, in the setting of soft tissue trauma and burns. Presumably the fat is released by marrow or adipose tissue injury and enters the circulation by rupture of the marrow vascular sinusoids or of venules. Although traumatic fat embolism occurs in some 90% of individuals with severe skeletal injuries less than 10% of such patients have any clinical findings. Fat embolism syndrome is characterized by pulmonary insufficiency, neurologic symptoms, anemia, and thrombocytopenia. Symptoms typically begin 1 to 3 days after injury, with sudden onset of tachypnea, dyspnea, and tachycardia. Neurologic symptoms include irritability and restlessness, with progression to delirium or coma. Patients may present with thrombocytopenia, presumably caused by platelets adhering to the myriad fat globules and being removed from the circulation; anemia may result as a consequence of erythrocyte aggregation and hemolysis. A diffuse petechial rash in nondependent areas (related to rapid onset of thrombocytopenia) is seen in 20% to 50% of cases and is useful in establishing a diagnosis. In its full-blown form, the syndrome is fatal in up to 10% of cases

The rounded clear holes seen in the small pulmonary arterial branch in this section of lung are characteristic for fat embolism. Fat embolism syndrome is most often a consequence of trauma with long bone fractures. It can also be seen with extensive soft tissue trauma, burn injuries, severe fatty liver, and very rarely with orthopedic procedures.

An Oil Red O stain demostrates the fat globules within the pulmonary arterioles. The globules stain reddish-orange. The cumulative effect of many of these gobules throughout the lungs is similar to a large pulmonary embolus, but the onset of dyspnea is usually 2 to 3 days following the initiating event, such as blunt trauma with bone fractures.

The pathogenesis of fat emboli syndrome probably involves both mechanical obstruction and biochemical injury. Microemboli of neutral fat cause occlusion of the pulmonary and cerebral microvasculature, aggravated by local platelet and erythrocyte aggregation; this is further exacerbated by release of free fatty acids from the fat globules, causing local toxic injury to endothelium. Platelet activation and recruitment of granulocytes (with free radical, protease, and eicosanoid release; complete the vascular assault. Because lipids are dissolved out of tissue preparations by the solvents routinely used in paraffin embedding, the microscopic demonstration of fat microglobules (i.e., in the absence of accompanying marrow) typically requires specialized techniques, including frozen sections and fat stains

From several days to a week following the event initiating fat embolism syndrome, there may be loss of consciousness from lesions evidenced by the "brain purpura" as shown here. Numerous petechial hemorrhages are produced by fat emboli to the brain, particularly in the white matter. Subsequent to this there can be brain edema with herniation.

With cerebral fat embolism syndrome, there is loss of consciousness. Note the multitude of petechial hemorrhages here, most in white matter. Cerebral edema and herniation may follow. Overall, few persons with a history of trauma will develop fat embolism, but it is difficult to predict which patients will.

AIR EMBOLISM

Gas bubbles within the circulation can obstruct vascular flow (and cause distal ischemic injury) almost as readily as thrombotic masses can. Air may enter the circulation during obstetric procedures or as a consequence of chest wall injury. Generally, in excess of 100 cc is required to have a clinical effect; the bubbles act like physical obstructions and may coalesce to form frothy masses sufficiently large to occlude major vessels

A particular form of gas embolism, called decompression sickness, occurs when individuals are exposed to sudden changes in atmospheric pressure. Scuba and deep sea divers, underwater construction workers, and individuals in unpressurized aircraft in rapid ascent are all at risk. When air is breathed at high pressure (e.g., during a deep sea dive), increased amounts of gas (particularly nitrogen) become dissolved in the blood and tissues. If the diver then ascends (depressurizes) too rapidly, the nitrogen expands in the tissues and bubbles out of solution in the blood to form gas emboli

The rapid formation of gas bubbles within skeletal muscles and supporting tissues in and about joints is responsible for the painful condition called the bends (so named in the 1880s because afflicted individuals characteristically arched their backs in a manner reminiscent of a then popular women's fashion called the Grecian Bend). Gas emboli may also induce focal ischemia in a number of tissues, including brain and heart. In the lungs, edema, hemorrhages, and focal atelectasis or emphysema may appear, leading to respiratory distress, the so-called chokes. Treatment of gas embolism requires placing the individual in a compression chamber where the barometric pressure may be raised, thus forcing the gas bubbles back into solution. Subsequent slow decompression theoretically permits gradual resorption and exhalation of the gases so that obstructive bubbles do not re-form

A more chronic form of decompression sickness is called caisson disease (named for the pressurized vessels used in the construction of the base of the Brooklyn Bridge in New York; workers digging in these vessels suffered both acute and chronic forms of decompression sickness). In caisson disease, persistence of gas emboli in the skeletal system leads to multiple foci of ischemic necrosis; the more common sites are the heads of the femurs, tibia, and humeri

AMNIOTIC FLUID EMBOLISM

Amniotic fluid embolism is a grave but fortunately uncommon complication of labor and the immediate postpartum period (1 in 50,000 deliveries). It has a mortality rate of 20% to 40%, and as other obstetric complications (e.g., eclampsia, pulmonary embolism) have been better managed, amniotic fluid embolism has become an important cause of maternal mortality. The onset is characterized by sudden severe dyspnea, cyanosis, and hypotensive shock, followed by seizures and coma. If the patient survives the initial crisis, pulmonary edema typically develops, along with (in half the patients) DIC, owing to release of thrombogenic substances from amniotic fluid.

The underlying cause is the infusion of amniotic fluid or fetal tissue into the maternal circulation via a tear in the placental membranes or rupture of uterine veins. The classic findings are therefore the presence in the pulmonary microcirculation of squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa, and mucin derived from the fetal respiratory or gastrointestinal tract. There is also marked pulmonary edema and changes of diffuse alveolar damage as well as systemic fibrin thrombi indicative of DIC.

Infarction

An infarct is an area of ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage in a particular tissue. Infarction involving different organs is a common and extremely important cause of clinical illness. In the United States, more than half of all deaths are caused by cardiovascular disease, and most of these are attributable to myocardial or cerebral infarction. Pulmonary infarction is a common complication in a number of clinical settings, bowel infarction is frequently fatal, and ischemic necrosis of the extremities (gangrene) is a serious problem in the diabetic population

Nearly 99% of all infarcts result from thrombotic or embolic events, and almost all result from arterial occlusion. Occasionally, infarction may also be caused by other mechanisms, such as local vasospasm, expansion of an atheroma owing to hemorrhage within a plaque, or extrinsic compression of a vessel (e.g., by tumor). Other uncommon causes include twisting of the vessels (e.g., in testicular torsion or bowel volvulus), compression of the blood supply by edema or by entrapment in a hernia sac, or traumatic rupture of the blood supply. Although venous thrombosis may cause infarction, it more often merely induces venous obstruction and congestion. Usually, bypass channels rapidly open after the thrombosis, providing some outflow from the area, which, in turn, improves the arterial inflow. Infarcts caused by venous thrombosis are more likely in organs with a single venous outflow channel, such as the testis and ovary

Morphology. Infarcts are classified on the basis of their color (reflecting the amount of

hemorrhage) and the presence or absence of microbial infection. Therefore, infarcts may be either red (hemorrhagic) or white (anemic) and may be either septic or bland.

• Red (hemorrhagic) infarcts occur with venous occlusions (such as in ovarian torsion); in loose tissues (such as lung), which allow blood to collect in the infarcted zone; in tissues with dual circulations (e.g., lung and small intestine), permitting flow of blood from the unobstructed vessel into the necrotic zone (obviously such perfusion is not sufficient to rescue the ischemic tissues); in tissues that were previously congested because of sluggish venous outflow; and when flow is re-established to a site of previous arterial occlusion and necrosis (e.g., following fragmentation of an occlusive embolus or angioplasty of a thrombotic lesion)

White (anemic) infarcts occur with arterial occlusions in solid organs with end-arterial circulation (such as heart, spleen, and kidney), where the solidity of the tissue limits the amount of hemorrhage that can seep into the area of ischemic necrosis from adjoining capillary beds

Most infarcts tend to be wedge-shaped, with the occluded vessel at the apex and the periphery of the organ forming the base when the base is a serosal surface, there is often an overlying fibrinous exudate. The lateral margins may be irregular, reflecting the pattern of vascular supply from adjacent vessels. At the outset, all infarcts are poorly defined and slightly hemorrhagic. The margins of both types of infarcts tend to become better defined with time by a narrow rim of hyperemia attributable to inflammation at the edge of the lesion

In solid organs, the extravasated red cells from the limited hemorrhage are lysed. The released hemoglobin remains in the tissue in the form of hemosiderin within macrophages; this can microscopically identify sites of previous infarction but does not grossly impart any significant color to the tissue. White infarcts resulting from arterial occlusions typically become progressively more pale and sharply defined with time By comparison, in spongy organs the hemorrhage is too extensive to permit thelesion ever to become pale Over the course of a few days, it does, however, become more firm and brown, as the extensive bleeding progressively degrades into hemosiderin pigmentThe dominant histologic characteristic of infarction is ischemic coagulative necrosis It is important to recall that if the vascular occlusion has occurred shortly (minutes to hours) before the death of the patient, no demonstrable histologic changes may be evident; if the patient survives even 12 to 18 hours, the only change present may be hemorrhage

An inflammatory response begins to develop along the margins of infarcts within a few hours and is usually well defined within 1 or 2 days. Inflammation at these sites is incited by the necrotic material; given sufficient time, there is gradual degradation of the dead tissue with phagocytosis of the cellular debris by neutrophils and macrophages. Eventually the inflammatory response is followed by a reparative response beginning in the preserved margins In stable or labile tissues, some parenchymal

Infarction of the brain can result from thrombosis, though most cases occur following embolization, involving cerebral arteries, often the circle of Willis. Cerebral infarction typically results in liquefactive necrosis, as shown here with beginning cystic resolution of the infarct.

An inflammatory response begins to develop along the margins of infarcts within a few hours and is usually well defined within 1 or 2 days. Inflammation at these sites is incited by the necrotic material; given sufficient time, there is gradual degradation of the dead tissue with phagocytosis of the cellular debris by neutrophils and macrophages. Eventually the inflammatory response is followed by a reparative response beginning in the preserved margins In stable or labile tissues, some parenchymal regeneration may occur at the periphery where the underlying stromal architecture has been spared. However, most infarcts are ultimately replaced by scar tissue .The brain is an exception to these generalizations; as with all other causes of cell death, ischemic injury in the central nervous system results in liquefactive necrosis.

Infarction of many internal organs leads to a "pale" infarct from loss of hte blood supply, resulting in coagulative necrosis. Shown here is a myocardial infarction from occlusion of a major coronary artery, here the left anterior descending artery.

Infarction of many internal organs leads to a "pale" infarct with a wedge-shaped gross appearance (conical in 3 dimensions) from occlusion of a branching blood supply. Here are splenic infarcts in a patient with infective endocarditis. Portions of the vegetations have embolized to the spleen. These infarcts are typical of ischemic infarcts: they are based on the capsule, pale, and wedge-shaped. The remaining splenic parenchyma appears dark red.

Here are petechial hemorrhages seen on the epicardium of the heart. Petechiae (pinpoint hemorrhages) represent bleeding from small vessels and are classically found when a coagulopathy is due to a low platelet count. They can also appear following sudden hypoxia

Septic infarctions may develop when embolization occurs by fragmentation of a bacterial vegetation from a heart valve or when microbes seed an area of necrotic tissue. In these cases, the infarct is converted into an abscess, with a correspondingly greater inflammatory response. The eventual sequence of organization, however, follows the pattern already described

Shock

Shock, or cardiovascular collapse, is the final common pathway for a number of potentially lethal clinical events, including severe hemorrhage, extensive trauma or burns, large myocardial infarction, massive pulmonary embolism, and microbial sepsis. 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. Although the hypoxic and metabolic effects of

hypoperfusion initially cause only reversible cellular injury, persistence of shock eventually causes

irreversible tissue injury and can culminate in the death of the patient

Shock may be grouped into three general categories The mechanisms underlying cardiogenic and hypovolemic shock are fairly straightforward, essentially involving low cardiac output. Septic shock, by comparison, is substantially more complicated and is discussed in further detail below.

• Cardiogenic shock results from myocardial pump failure. This may be caused by intrinsic myocardial damage (infarction), ventricular arrhythmias, extrinsic compression (cardiac tamponade; or outflow obstruction (e.g., pulmonary embolism).
• Hypovolemic shock results from loss of blood or plasma volume. This may be caused by hemorrhage, fluid loss from severe burns, or trauma.

Septic shock is caused by systemic microbial infection. Most commonly, this occurs in the setting of gram-negative infections (endotoxic shock), but it can also occur with gram-positive and fungal infections.

Less commonly, shock may occur in the setting of anesthetic accident or spinal cord injury (neurogenic shock), owing to loss of vascular tone and peripheral pooling of blood. Anaphylactic shock, initiated by a generalized IgE-mediated hypersensitivity response, is associated with systemic vasodilation and increased vascular permeability. In these instances, widespread vasodilation causes a sudden increase in the vascular bed capacitance, which is not adequately filled by the normal circulating blood volume. Thus, hypotension, tissue hypoperfusion, and cellular anoxia result.

PATHOGENESIS OF SEPTIC SHOCK

Three Major Types of Shock

Type of Shock	Clinical Examples	Principal Mechanisms
Cardiogenic
	Myocardial infarction	Failure of myocardial pump owing to intrinsic myocardial damage, extrinsic pressure, or obstruction to outflow
	Ventricular rupture
	Arrhythmia
	Cardiac tamponade
	Pulmonary embolism
Hypovolemic
	Hemorrhage	Inadequate blood or plasma volume
	Fluid loss, e.g., vomiting, diarrhea, burns, or trauma
Septic
	Overwhelming microbial infections	Peripheral vasodilation and pooling of blood; endothelial activation/injury; leukocyte-induced damage; disseminated intravascular coagulation; activation of cytokine cascades
	Endotoxic shock
	Gram-positive septicemia
	Fungal sepsis
	Superantigens

Septic shock, with a 25% to 50% mortality rate, ranks first among the causes of mortality in intensive care units and is estimated to account for over 200,000 deaths annually in the United States. Moreover, the reported incidence of sepsis syndromes has increased dramatically in the past two decades, owing to improved life support for high-risk patients, increasing use of invasive procedures, and growing numbers of immunocompromised hosts (secondary to chemotherapy, immunosuppression, or human immunodeficiency virus infection). Septic shock results from spread and expansion of an initially localized infection (e.g., abscess, peritonitis, pneumonia) into the bloodstream

Most cases of septic shock (approximately 70%) are caused by endotoxin-producing gram-negative bacilli, hence the term endotoxic shock. Endotoxins are bacterial wall lipopolysaccharides (LPSs) that are released when the cell walls are degraded (e.g., in an inflammatory response). LPS consists of a toxic fatty acid (lipid A) core and a complex polysaccharide coat (including O antigens) unique to each bacterial species. Analogous molecules in the walls of gram-positive bacteria and fungi can also elicit septic shock

All of the cellular and resultant hemodynamic effects of septic shock may be reproduced by injection of LPS alone. Free LPS attaches to a circulating LPS-binding protein, and the complex then binds to a cell-surface receptor (called CD14), followed by binding of the LPS to a signal-transducing protein called mammalian Toll-like receptor protein 4 (TLR-4). (Toll is a Drosophila protein involved in fly development; a variety of molecules with homology to Toll [i.e., "Toll-like"] participate in innate immune responses to different microbial components Signals from TLR-4 can then directly activate vascular wall cells and leukocytes or initiate a cascade of cytokine mediators, which propagates the pathologic state. Engagement of TLR-4 on endothelial cells can lead directly to down-regulation of natural anticoagulation mechanisms, including diminished synthesis of tissue factor pathway inhibitor (TFPI) and thrombomodulin. Engagement of the receptor on monocytes and macrophages (even at doses of LPS as minute as 10 picograms/ml) causes profound mononuclear cell activation with the subsequent production of potent effector cytokines such as IL-1 and TNF Presumably, this series of responses helps to isolate organisms and to trigger elements of the innate immune system to efficiently eradicate invading microbes. Unfortunately, depending on the dosage and numbers of macrophages that are activated, the secondary effects of LPS release can also cause severe pathologic changes, including fatal shock.

• At low doses, LPS predominantly serves to activate monocytes and macrophages, with effects intended to enhance their ability to eliminate invading bacteria. LPS can also directly activate complement, which likewise contributes to local bacterial eradication. The mononuclear phagocytes respond to LPS by producing cytokines, mainly TNF, IL-1, IL-6, and chemokines. TNF and IL-1 both act on endothelial cells to stimulate the expression of adhesion molecules and the production of other cytokines and chemokines. Thus, the initial release of LPS results in a circumscribed cytokine cascade doubtless intended to enhance the local acute inflammatory response and improve clearance of the infection.
• With moderately severe infections, and therefore with higher levels of LPS (and a consequent augmentation of the cytokine cascade), cytokine-induced secondary effectors (e.g., nitric oxide; become significant. In addition, systemic effects of the cytokines such as TNF and IL-1 may begin to be seen; these include fever and increased synthesis of acute phase reactants LPS at higher doses also results in diminished endothelial cell production of thrombomodulin and TFPI, tipping the coagulation cascade toward thrombosis.
• Finally, at still higher levels of LPS, the syndrome of septic shock supervenes the same cytokines and secondary mediators, now at high levels, result in:
• Systemic vasodilation (hypotension)
• Diminished myocardial contractility
• Widespread endothelial injury and activation, causing systemic leukocyte adhesion and pulmonary alveolar capillary damage (acute respiratory distress syndrome;

Activation of the coagulation system, culminating in DIC

The hypoperfusion resulting from the combined effects of widespread vasodilation, myocardial pump failure, and DIC induces multiorgan system failure affecting the liver, kidneys, and central nervous system, among others. Unless the underlying infection (and LPS overload) is rapidly brought under control, the patient usually dies. Of note, mice lacking LPS-binding protein, CD14, or the mammalian TLR-4 are protected against the effects of LPS. Clinical efforts to take advantage of these insights and induce pharmacologic blockade of the same pathways (e.g., soluble CD14 or antibodies to LPS-binding protein) have yet to bear fruit. Antibodies or antagonists to IL-1 or TNF (or their receptors), or pharmacologic inhibitors of various other secondary mediators (e.g., nitric oxide or prostaglandins) have some efficacy in animal models of septic shock, but they have not shown significant clinical benefit in human disease. Indeed such failure of "anti-inflammatory" therapy in human shock has caused some investigators to challenge the model presented hereInstead, it has been argued that in later stages, sepsis is associated with a state of immunosuppression (rather than uncontrolled inflammation). These observations may dictate different forms of therapy, but this remains to be tested.

An interesting group of bacterial proteins called superantigens also cause syndromes similar to septic shock. These include toxic shock syndrome toxin-1, produced by staphylococci and responsible for the toxic shock syndrome. Superantigens are polyclonal T-lymphocyte activators that induce systemic inflammatory cytokine cascades similar to those occurring downstream in septic shock. Their actions can result in a variety of clinical manifestations ranging from a diffuse

rash to vasodilation, hypotension, and death

Stages of Shock. Shock is a progressive disorder that, if uncorrected, leads to death. Unless the insult is massive and rapidly lethal (e.g., a massive hemorrhage from a ruptured aortic aneurysm), shock tends to evolve through three general (albeit somewhat artificial) phases. A brief discussion here can help to integrate the sequential pathophysiologic and clinical events in the progression of shock. These have been documented most clearly in hypovolemic shock but are common to other forms as well:

• An initial nonprogressive phase during which reflex compensatory mechanisms are activated and perfusion of vital organs is maintained
• A progressive stage characterized by tissue hypoperfusion and onset of worsening circulatory and metabolic imbalances, including acidosis

An irreversible stage that sets in after the body has incurred cellular and tissue injury so severe that even if the hemodynamic defects are corrected, survival is not possible

In the early nonprogressive phase of shock, a variety of neurohumoral mechanisms help maintain cardiac output and blood pressure. These include baroreceptor reflexes, release of catecholamines, activation of the renin-angiotensin axis, antidiuretic hormone release, and generalized sympathetic stimulation. The net effect is tachycardia, peripheral vasoconstriction, and renal conservation of fluid. Cutaneous vasoconstriction, for example, is responsible for the characteristic coolness and pallor of skin in well-developed shock (although septic shock may initially cause cutaneous vasodilation and thus present with warm, flushed skin). Coronary and cerebral vessels are less sensitive to this compensatory sympathetic response and thus maintain relatively normal caliber, blood flow, and oxygen delivery to their respective vital organs

If the underlying causes are not corrected, shock passes imperceptibly to the progressive phase, during which there is widespread tissue hypoxia. In the setting of persistent oxygen deficit, intracellular aerobic respiration is replaced by anaerobic glycolysis with excessive production of lactic acid. The resultant metabolic lactic acidosis lowers the tissue pH and blunts the vasomotor response; arterioles dilate, and blood begins to pool in the microcirculation. Peripheral pooling not only worsens the cardiac output, but also puts endothelial cells at risk for developing anoxic injury with subsequent DIC. With widespread tissue hypoxia, vital organs are affected and begin to fail; clinically the patient may become confused, and the urine output declines

Unless there is intervention, the process eventually enters an irreversible stage. Widespread cell injury is reflected in lysosomal enzyme leakage, further aggravating the shock state. Myocardial contractile function worsens in part because of nitric oxide synthesis. If ischemic bowel allows intestinal flora to enter the circulation, endotoxic shock may be superimposed. At this point, the patient has complete renal shutdown owing to acute tubular necrosis and despite heroic measures, the downward clinical spiral almost inevitably culminates in death

Morphology. The cellular and tissue changes induced by shock are essentially those of hypoxic injury since shock is characterized by failure of multiple organ systems, the cellular changes may appear in any tissue. Nevertheless, they are particularly evident in brain, heart, lungs, kidneys, adrenals, and gastrointestinal tract subendocardial hemorrhage and/or contraction band necrosis Although the cardiac changes are not diagnostic of shock (they may also be seen in the setting of cardiac reperfusion after irreversible injury, or after administration of catecholamines), they are usually much more extensive in the setting of shock. The kidneys typically exhibit extensive tubular ischemic injury (acute tubular necrosis; therefore oliguria, anuria, and electrolyte disturbances constitute major clinical problems. The lungs are seldom affected in pure hypovolemic shock because they are resistant to hypoxic injury. When shock is caused by bacterial sepsis or trauma, however, changes of diffuse alveolar damage (may appear, the so-called shock lung. The adrenal changes in shock are those seen in all forms of stress; essentially, there is cortical cell lipid depletion. This does not reflect adrenal exhaustion but rather conversion of the relatively inactive vacuolated cells to metabolically active cells that utilize stored lipids for the synthesis of steroids. The gastrointestinal tract may suffer patchy mucosal hemorrhages and necroses, referred to as hemorrhagic enteropathy. The liver may develop fatty change and, with severe perfusion deficits, central hemorrhagic necrosis

The brain may develop so-called ischemic encephalopathy, discussed in The heart may undergo focal or widespread coagulation necrosis or may exhibitWith the exception of neuronal and myocyte loss, virtually all of these tissue changes may revert to normal if the patient survives. Unfortunately, most patients with irreversible changes owing to severe shock succumb before the tissues can recover

The prognosis varies with the origin of shock and its duration. Thus, 80% to 90% of young, otherwise healthy patients with hypovolemic shock survive with appropriate management, whereas cardiogenic shock associated with extensive myocardial infarction and gram-negative shock carry mortality rates of up to 75%, even with the best care currently available.

Small fibrin thrombi from widespread activation of the coagulation system with disseminated intravascular coagulopathy (DIC) can be seen in capillary loops in this glomerulus, highlighted by a fibrin stain. Laboratory findings with DIC include decreased platelets, diminished fibrinogen, prolonged prothrombin time, elevated partial thromboplastin time, and elevated D-dimer. Consumption of coagulation factors with generation of fibrin split products, along with platelet consumption, leads to these findings.