digest on pathomorhology

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Isolated vein spasm may cause leukostasis, accumulation of erythrocytes within venules (small veins) and capillaries. It is observed in hypoxia. In shock, leukostasis may be generalized, but as a rule it is localized in the venules.

Microcirculation disturbances. There are four links in microcirculation:

1.The link of inflow and distribution of the blood (arterioles and precapillaries).

2.Intermediate (exchange) link (capillaries).

3.Depot link (postcapillaries and venules).

4.Drainage link (lymphatic capillaries and postcapillaries). The function of microcirculation is exchange between the blood and tissue. Pathology of microcirculatory system is formed of vascular, intravascular and extravascular changes.

Vascular changes are those in the thickness and shape of the vessels, angiopathies with disturbance of vascular permeability as a result of hypoxia.

Intravascular changes manifest as different disturbances of blood rheology (sludge, prestasis, stasis). They are observed in shock of different origin.

Extravascular changes are perivascular edema, hemorrhage, lymphostasis on the lymph vessels.

Thrombosis

Thrombosis is a pathologic process, which denotes the formation of a clotted mass of blood within the noninterruptured vascular system.

Influences predisposing to thrombosis:

1.Injury to endothelium;

2.Alterations in the normal blood flow;

3.Alterations in the blood coagulation system (hypercoagulability).

Mechanisms of formation

Agglutination of platelets. Platelets adhere to the endothelium and to each other forming a projecting mass;

Agglutination of erythrocytes. If the rate of the blood flow is slow, as in veins, red cells are entangled so that the lumen is occluded;

Coagulation of fibrinogen. In front and behind the platelet mass the blood stagnates. Further formation of fibrin takes place resulting in a large solid coagulum. The thrombus extends in either direction to the nearest junction;

Precipitation of plasma proteins. With a slow blood flow in the joining vessel more fibrin is formed by the platelets at the tip of the thrombus, thus occluding the joint vessel. Blood stagnates in the joining vessel and thrombosis forwards to the next joining vessel. There may be a succession of thrombotic episodes – a propagating thrombus.

Types of thrombi

According to the degree of the lumen obstruction, thrombi may be:

Occlusive thrombi most commonly develop in small arteries and veins.

Wall-attached or parietal thrombi develop in large arteries and heart cavities.

Axial.

Globe-shaped (in the heart).

According to the morphology

Thrombi may be of various shapes, size and composition depending upon the site of origin and it is attached to the vascular wall; it is dense, with corrugated surface. It is composed of branching bars of stuck thrombocytes and bands of fibrin with erythrocytes and leukocytes located between them.

Morphological types of thrombi

White thrombus – consists mainly of platelets, fibrin and leukocytes; forms slowly in rapid circulation of the blood (usually in the arteries);

Red thrombus – consists of platelets, fibrin and excessive amount of erythrocytes; forms rapidly at slow blood circulation (usually in veins). Venous thrombi are dark-red colored dry masses with dim surface.

Mixed or laminated thrombus – has laminated structure, contains white and red elements of thrombus (usually forms in veins, aneurysms of aorta and heart). Mixed

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thrombus consists of core or head (white thrombus), body (white and red) and tail (has construction of red thrombus). Core is connected with endothelium. Mixed thrombus is of gray-red color with rough dim surface, fixed to the intima of the vessel. Body and tail are located freely in the vessel‟s lumen.

Hyaline thrombus consists of precipitating plasma proteins, destructed erythrocytes, leukocytes and thrombocytes. They do not contain fibrin. They resemble hyaline and are located in the microcirculatory bed.

Agonal thrombus – consists of the yellowish fibrin and localizes in the apex of the right ventricle of the heart and may extend into pulmonary artery. It is formed in the last minutes of the life when the death occurs slowly. Red clot forms in case of the rapid death.

The distinguishing features between thrombi formed in rapidly-flowing arterial circulation and slow-moving venous blood are given in Table 3.

TABLE 3. Distinguishing Features of Arterial and Venous Thrombi.

Red thrombi (ante-mortem) have to be distinguished from postmortem clots (Table 4).

TABLE 4. Antemortem Thrombi versus Postmortem Clots

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Clinical effects of thrombosis

These depend upon the site, rapidity of formation, and nature of thrombi.

1.Cardiac thrombi. Large thrombi in the heart may cause sudden death by mechanical obstruction of blood flow or through thromboembolism to vital organs.

2.Arterial thrombi. These cause ischemic necrosis of the deprived part (infarct), which may lead to gangrene. Sudden death may occur following thrombosis of coronary artery.

3.Venous thrombi (Phlebothrombosis). These may cause various effects:

Thromboembolism.

Oedema of area drained.

Poor wound healing.

Skin ulcer.

Painful thrombosed veins.

Painful white leg.

Thrombophlebitis migrans in cancer.

4.Capillary thrombi. Microthrombi in microcirculation may give rise to disseminated intravascular coagulation (DIC).

Outcomes of the thrombosis

A.Favourable outcomes:

Aseptic autolysis (dissolution) by fibrinolytic system, proteinolytic enzymes of macrophages and leukocytes.

Organization by the replacement of connective tissue.

Recanalization is the re-establishment of the vascular lumen through occluding thrombus.

Incorporation or vascularization means restoration of the circulation in the vessel because of the formation of the new vessels through the thrombotic mass.

Petrification or dystrophy calcification – accumulation of the calcium salts in the thrombotic masses.

B.Unfavourable outcomes:

Thromboembolism.

Septic autolysis.

Propagation with following obstruction of some critical vessel.

Embolism

Embolism is the passage through the venous or arterial circulations of any material capable of lodging in a blood vessel and they‟re by obstructing the lumen. The transported intravascular mass detached from its site of origin is called an embolus.

Types of embolism

According to localization:

Small blood circulation.

Large blood circulation.

System of vena portae.

According to the direction of the movement of embolus:

Orthograde (by blood flow)

Retrograde (against blood flow). Metastasis of the carcinoma prostate in the spine takes place.

Paradoxical (emboli arising in the venous circulation may by pass the lungs by travelling through an incompletely closed foramen ovale, subsequently blocking flow in systemic arteries).

According to the material of the embolus:

1.Solid:

Thromboembolism.

Atheroembolism.

Tissue (cellular) embolism due to necrosis of tumor, damaged tissue.

Bacterial embolism.

Embolism by parasites.

Embolism by foreign bodies.

2.Liquid:

Fat embolism.

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Amniotic fluid embolism.

3.Gaseous:

Decompression sickness (caisson disease).

Air embolism.

Thromboembolism

A detached thrombus or part of thrombus constitutes the most common type of embolism. These may arise in the arterial or venous circulation:

The effects of arterial emboli depend upon their size, site of lodgement, and adequacy of collateral circulation:

Infarction.

Gangrene.

Arteritis and mycotic aneurysm.

Myocardial infarction.

Sudden death.

The most significant effect of venous embolism is obstruction of pulmonary arterial circulation leading to pulmonary embolism.

Pulmonary thromboembolism

Pulmonary embolism is the most common and fatal form of venous thromboembolism in which there is occlusion of pulmonary arterial tree by thromboemboli. Pulmonary emboli are more common in hospitalised or bedridden patients. The majority of emboli arise from the deep veins of the low extremities; most of the fatal ones arise from the ileofemoral veins. Condition that favor the development of pulmonary thromboembolism are:

Stasis (heart failure, chronic venous insufficiency).

Injury (trauma, surgery, parturition).

Hormonal imbalance (oral contraceptive use).

Advanced age.

Immobilization (orthopedic, paralysis, bed rest).

Sickle cell disease.

Pathogenesis

Detachment of thrombi from any of the above-mentioned sites produces a thromboembolus that flows through venous drainage into the large veins draining into right side of the heart.

If the thrombus is large, it is impacted at the bifurcation of the main pulmonary artery (saddle embolus), or may be found in the right ventricle or its outflow tract.

More commonly, there are multiple emboli, or a large embolus may be fragmented into many smaller emboli.

Paradoxical embolism may occur by passage of an embolus from right heart into the left heart through atrial or ventricular septal defect.

Consequences of thromboembolism

1. Consequences of pulmonary embolism. These include:

Pulmonary Syndrome (Infarction). The pulmonary syndrome clinically resembles pneumonia. Pleural effusion is common and often bloody. Pathologically, pyramidal segments of hemorrhagic infarction are seen at the periphery of the lung. Obstruction of terminal branches (endarteries) leads to central pulmonary hemorrhage.

Circulatory Syndrome (Without Infarction). Embolism produces pulmonary hypertension by mechanical blockage of the arterial bed. Reflex vasoconstriction and bronchial constriction due to release of vasoactive substances may contribute to a reduction in the size of the functional pulmonary vascular bed. Whether a patient develops the pulmonary or the circulatory syndrome depends on the thromboembolic load and the availability of circulatory reserve of the bronchial arteries. Pulmonary hypertension may lead to chronic cor pulmonale and pulmonary arteriosclerosis. Numerous small emboli may obstruct most of the pulmonary circulation resulting in acute right heart failure (Acute cor pulmonale).

Massive Pulmonary Embolism. Massive pulmonary emboli typically cause sudden obstruction of blood flow through one or both of the major pulmonary arteries. The patient often goes into shock immediately - resumably because of certain: neurologic reflexes - and may die within minutes. This catastrophe is characteristically precipitated when a patient who has been recuperating from surgery gets out of bed for the first time.

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2. Consequences of emboli in peripheral arteries. The heart is the most common source of systemic emboli, which usually arise from mural thrombi (in atrial fibrilation, mitral valve disease, myocardial infarction, left ventricular aneurysm, heart failure of any etiology, cardiomyopathy) or diseased valves (bacterial endocarditis, marantic endocarditis).

Clinical and morphological features: arterial emboli to the brain cause strokes; in the mesenteric circulation they cause infarction of the bowel; embolism of an artery of the legs leads to sudden pain, absence of pulse, and a cold limb; renal artery embolism may infarct the entire kidney but more commonly results in small peripheral infarcts; coronary artery embolism results in myocardial infarctions.

Thus, the effects and sites of arterial emboli are in striking contrast to venous emboli, which are often lodged in the lungs.

Atheroembolism. Atheromatous plaques, especially from aorta, may get eroded to form atherosclerotic emboli. The pathologic changes and their effects are:

Ischemia, atrophy and necrosis,

Infarcts in the affected organs,

Gangrene in the lower limbs,

Hypertension.

Fat Embolism. Obstruction of arterioles and capillaries by fat globules constitutes fat embolism. If the obstruction in the circulation is by fragments of adipose tissue, it is called fat-tissue embolism. Important causes are: trauma, inflammation of bones and soft tissues, fatty liver, pancreatitis, extrinsic fat or oils introduced into the body.

Consequence of fat embolism:

Pulmonary fat embolism. Frozen section is essential for confirmation of globules by fat stains such as Sudan dyes (Sudan black, Sudan III and IV), oil red O and osmic acid.

Systemic fat embolism. Some of the fat globules may pass through the pulmonary circulation such as via patent foramen ovale, arteriovenous shunts in the lungs and vertebral venous plexuses, and get lodged in the capillaries of organs like the brain, kidney, skin.

Gas Embolism. Two main forms of gas embolism are air embolism and decompression sickness.

Air Embolism occurs when air is introduced into venous or arterial circulation.

Causes of venous embolism include: operations on head and neck, and trauma, obstetrical operations, intravenous infusion of blood and fluid, angiography. The effects of venous air embolism depend upon the following factors: amount of air usually 100-150 ml of air entry is considered fatal, rapidity, position of the patient during or soon after entry of air. The air bubbles may ascend into the superior vena cava if the position of head is higher than the trunk (e.g. in upright position) and reach the brain. General condition of the patient e.g. in severely ill patients, as little as 40 ml of air may have serious results.

Causes of arterial embolism include: cardiothoracic surgery and trauma, paradoxical air embolism, arteriography. The effects of arterial air embolism are certain characteristic features: marble skin due to blockage of cutaneous vessels, air bubbles in the retinal vessels seen ophthalmoscopically, pallor of the tongue due to occlusion of a branch of lingual artery, coronary or cerebral arterial air embolism may cause sudden death by much smaller amounts of air than in the venous air embolism.

Decompression Sickness. This is a specialized form of gas embolism known by various names such as caisson's disease, divers' palsy or aeroembolism. Decompression sickness is produced when the individual decompresses suddenly, either from high atmospheric pressure to normal level, or from normal pressure to low atmospheric pressure.

Clinical effects of decompression sickness are of 2 types:

1.Acute form occurs due to acute obstruction of small blood vessels in the vicinity of joints and skeletal muscles. The condition is clinically characterized by the following:

“The bends”, as the patient doubles up in bed due to acute pain in joints, ligaments and tendons.

The “chokes” resulting in acute respiratory distress.

Cerebral effects may manifest as vertigo, coma, and sometimes death.

2.Chronic form is due to foci of ischemic necrosis throughout body, especially the skeletal system:

Vascular necrosis of bones.

Neurological symptoms.

Lung involvement.

Skin manifestations.

Other organs like parenchymal cells of the liver and pancreas may show lipidvacuoles.

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Three main pathological processes are observed in shock:

DIC (disseminated intravascular coagulation) syndrome.

Hemorrhagic diathesis.

Liquid cadaver blood.

Microscopically, it is characterized by generalized spasms of the vessels, microthrombosis, signs of increased vascular permeability in microcirculatory system, hemorrhages, degenerations, necroses connected with hypoxia and damaging effect of endotoxins.

Morphologic features of complications in Shock

Shock kidney: degeneration and necrosis in proximal canals with development of necrotic nephrosis (or symmetrical cortical necroses are possible), which results in acute renal insufficiency.

Shock liver: glycogen amount in the hepatocytes decreases, hydropic degeneration and centrolobular necroses resulting in acute hepatic insufficiency develop. Combination of renal and hepatic insufficiency is called hepatorenal syndrome.

Shock lung: atelectasis foci, serous-hemorrhagic edema, stases and thromboses in the microcirculatory bed resulting in acute respiratory insufficiency.

Shock heart: degeneration and necrosis in cardiomyocytes, reduction in glycogen amount, fat degeneration, and necrotic foci.

Shock gastrointestinal: the hypoperfusion of alimentary tract may result in mucosal and mural infarction called hemorrhagic gastroenteropathy.

Shock brain: Hypoxic changes in the brain. Ischemic neurons appear shrunken and have eosinophilic cytoplasm. The pericellular spaces are dilated because of edema. Rarification of brain tissue presents.

Similar changes occur in nervous, endocrine systems, and immune organs.

Shock morphology depends not only on the cause of the shock but also on its stage. At the early stage, disturbances of hemodynamic and DIC syndrome are noted. At the last stages degenerative and necrotic process occurs.

Intensive transfusion therapy of shock masks clinicomorphological picture. But the constant features are liquid cadaver blood irrespective of the composition of transfused fluids. Blood clots in the cardiac cavities and vessels are characteristic for terminal states of nonshock origin. So blood composition is a criterion for differential diagnosis.

Clinical Features

The classical features of decompensated shock are characterized by depression of 4 vital processes:

Very low blood pressure.

Subnormal temperature.

Feeble and irregular pulse.

Shallow and sighing respiration.

Renal dysfunction in shock is clinically characterized by a phase of oliguria due to ATN and a later phase of diuresis due to regeneration of tubular epithelium. With progression of the condition the patient may develop stupor, coma and death.

Disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC) is pathological syndrome, which is characterized by formation of disseminated blood clots in the microcirculatory bed (often in combination with simultaneous reduction of blood coagulability) causing hemorrhages. It often develops in complicated pregnancy, profuse uterine bleedings, large injuries, anemia, thrombocytopenia, leukemia, in 36 - 50% of cases of asphyxia in premature children.

Stages of DIC

At the first stage it is characterized by generalized increase of blood coagulation in the microvessels. Large number of fibrin clots is formed. They close the vessel (fibrinoembolism).

At the second stage the amount of thrombocytes, fibrinogen, prothrombin in the blood decreases sharply because they have already been used at the first stage with the resultant consumption coagulopathy. Thus, hemorrhagic syndrome develops.

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At the third stage fibrinolysis activation takes place in response to generalized increase of coagulation occurring at the first stage, which makes hemorrhagic syndrome more

severe.

In severe cases the three stages develop simultaneously. Disturbance in blood clotting is accompanied by stasis, opening of arteriovenous shunts, capillary paralysis, decrease in arterial pressure. Degenerative and necrotic changes develop in parenchymatous organs.

Morphological changes in DIC syndrome

Large amount of fibrin thrombi and emboli in the small vessels of the liver, red pulp of spleen, adrenals, brain, lungs, kidneys, placenta, thymus.

Mucoid swelling, fibrinoid swelling and fibrinoid necrosis with endothelium desquamation in the walls of small arteries.

In thrombosis of microcirculatory bed, vital processes of blood-tissue metabolism stop. Under these conditions organ pathology is not distinct, general changes (like toxicosis or shock) develop.

In thrombosis of larger arteries, organ pathology prevails, i.e. acute renal or hepatic insufficiency, shock lung, brain edema, and myocardial infarction.

DIC results in hemorrhages in different organs; those in the capsule are most frequent.

Edema

Edema may be defined as abnormal and excessive accumulation of fluid in the interstitial tissue spaces and serous cavities.

Edema fluid lies free in the interstitial space between the cells and can be displaced from one place to another. Edema fluid may be:

Transudate, which is more often the case such as in edema of cardiac and renal disease.

Exudate such as in inflammatory edema.

The differences between transudate and exudate are tabulated in Table 5.

TABLE 5 Differences between Transudate and Exudate

Types of edema

1.According to the presence or absence of inflammation

Inflammatory.

Noniflammatory is a result of (1) increase in intravascular hydrostatic pressure, (2) fall of colloid osmotic pressure of the plasma, (3) impairment in the flow of lymph, and (4) renal retention of salt and water.

2.According to propagation

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Generalized (anasarca).

Localized (hydrothorax or pleural effusion, hydropericardium, hydroperitoneum or ascitis).

Localization of edema

Subcutaneous edema of the lower parts of the body is a manifastation of cardiac failure.

Renal edema as a result of renal dysfunction or nephrotic syndrome tends to be generalized, affecting all parts of the body.

Pulmonary edema is usually confined to the lower lobes.

Edema of the brain (cerebral edema) may be localized to the region of the focal lesions of generalized involving the entire brain, as in encephalitis, hypertensive crises, and the obstruction to the venous outflow of the brain.

Increase in interstitial fluid amount. If transudate accumulates in subcutaneous fat it is called anasarca, in the heart cavity - hydropericardium, in the pleural cavity - hydrothorax, in the abdominal cavity- ascites, in the testis - hydrocele.

Edema develops in the patients with cardiovascular, kidneys, liver, allergic diseases, infections, pathologic conditions of pregnancy (hestosis), in vein thrombosis, lymph congestion, disturbances of nervous trophism, etc.

In these diseases, the following changes are observed: 1) those in hydrostatic blood pressure, 2) those in colloid osmotic pressure of blood plasma, 3) vascular wall permeability increases, 4) retention of water and electrolytes.

These factors accompany each other in the majority of cases, but as a rule one of them prevails, e.g. mechanical or congestive edema develops as a result of increase in hydrostatic pressure in microvessels and in fluid filtration.

Oncotic edema results from reduction in colloid-osmotic pressure in the blood plasma. Membranogenic edema is associated with the increase in capillary permeability, which results in plasma protein exit and its accumulation in the tissues. Electrolyte edema results from retention of water and electrolytes. Lymphogenic edema is caused by lymph congestion.

The outcome of edema is favorable, the fluid resolves, but prolonged edema can result in degeneration, atrophy, sclerosis.

Reduction in interstitial fluid amount (exicosis) may occur in rapid loss of great amount of fluid (cholera, prolonged diarrhea).

INFLAMMATION

Inflammation is fundamentally a protective response whose ultimate goal is to rid the organism of both the initial cause of cell injury and the consequences of such injury, the necrotic cells and tissues. Inflammation of an organ is usually named by adding the suffix-it is to its Latin name.

The agents causing inflammation may be following:

Physical agents (heat, cold, radiation, mechanical injury).

Chemical agents (organic and inorganic poisons).

Infective agents (bacteria, viruses, parasites).

Immunological agents (cell-mediated and antigen-antibody reactions).

Classic clinical signs of inflammation:

Heat (calor).

Redness (rubor).

Edema (tumor).

Pain (dolor).

Loss of Function (functio laesa).

Types of Inflammation

1.Morphological types:

Alterative.

Exssudative.

Proliferative (productive).

2.According to the Type of Tissue Reaction:

Normergic.

Hypoergic.

Hyperergic.

3.According to Etiology:

Specific.

Non-specific.

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4.According to the Duration:

Acute.

Subacute.

Chronic.

5.Types of Exssudative Inflammation:

Pseudomembranous.

Serous.

Fibrinous (croupous and diphtheric).

Suppurative (abscess, phlegmon, empyema).

Putrificative.

Hemorrhagic;

Catarrhal (serous, mucous, and suppurative).

Mixed.

6.Types of Proliferative Inflammation:

Interstitial.

With formation of polyps and condylomas.

Around parasites.

Granulomatous.

7.Specific Inflammation:

A.Accompanied Diseases:

Tuberculosis.

Syphilis.

Leprosy.

Scleroma.

Glanders.

B.Features:

Definite pathogenic organism.

Changing of tissue reactions.

Chronic wavy course.

Prevailed proliferative inflammation with formation of granulomas.

Necrosis of exsudate (primary and secondary).

Acute inflammation

Acute inflammation is the immediate and early response to an injurious agent.

The major components of acute inflammation:

Alterations in vascular caliber that lead to an increase in blood flow.

Structural changes in the microvasculature that permits plasma proteins and leukocytes to leave the circulation.

Emigration of the leukocytes from the microcirculation and their accumulation in the focus of injury.

Vascular changes in acute inflammation:

Vasoconstriction mediated by both neurogenic and chemical mediator system.

Vasodilation caused by the release of specific mediators is responsible for the redness and warmth at sites of tissue injury.

Stasis with leukocytic orientation along the vascular endothelium (leukocytic margination).

Increased vascular permeability, leading to the escape of a protein-reach fluid into the interstitium with following edema.

Extravasation of leukocytes from the vascular lumen into the interstitial tissue as a result of the following steps: (1) in the lumen: margination, rolling, and adhesion; (2) transmigration across the endothelium (diapedesis), and (3) migration in the interstitial tissues toward a

chemotactic stimulus.

Phagocytosis is the process of engulfment and internalization of foreign agents or injuried cell material and cells that possess this function are reffered to as phagocytic cells.

Phagocytosis and the release of enzymes by neutophils and macrophages constitute two of the major benefits derived from the accumulation of the leukocytes at the inflammatory focus. Phagocytosis involves three distinct but inter-related steps: (1) recognition and attachment of the particle to be ingested by the macrophage; (2) its engulfment, with subsequent formation of a phagocytic vacuole; (3) killing or degradation of the ingested material.

Systemic effects of acute inflammation.