1

DR. MOHAMMED SAMI SAEEDASSISTANT PROFESSOR/CONSULTANT HISTOPATHOLOGIST

HEMODYNAMIC DISORDERS

HEMODYNAMIC DISORDERS The health of cells critically depends on an unbroken circulation to deliver oxygen and nutrients and to remove wastes. The well-being tissues also requires normal fluid balance (homeostasis), which encompasses maintenance of vessel wall integrity as well as intravascular pressure and osmolarity within certain physiologic ranges.

oedema

Approximately 60% of lean body weight is water, of which 2/3 is intracellular, 1/3 extracellular (mainly interstitial) only 5% of total body water is plasma oedema means increased fluid in the interstitial tissue spaces.

Serous effusions

means excess fluid in the serous or coelomic cavities e.g.Peritoneal cavity→ ascitesPleural cavity → hydrothoraxPericardium→ hydropericardiumanasarca means severe & generalized oedeme with profound subcutaneous tissue swellings.

The main ingredient of the fluid is always water. Exudate----- is a protein-rich edema with a specific gravity of over 1.020. Transudate------ is a protein-poor edema with a specific gravity of 1.012.

Pathogenesis

There are 2 opposing factors which govern the movement of the fluid between vascular & interstitial spaces: hydrostatic pressure i.e. capillary blood pr.(BP) encouraging the passage of fluid through the capillary wall to the extra vascular compartment =35mmHg . oncotic pressure (op) the plasma protein encourages the retention of fluid in the capillaries to maintain osmotic equilibrium, this pr. Is equivalent to 25mmHg.

At the arterial end the hydrostatic Pr is greater than the OP→ fluid is forced out the capillaries , of the microcirculation. The reverse occurs at the venous end &the fluid is attracted into the vessels.A small amount of fluid enters the lymphatics.

Pathophysiology, oedema results from;

1. Increased hydrostatic pressure, 2. Reduced plasma osmotic pressure, 3. Lymphatic obstruction. 4. Sodium and water retention. 5. local effects of inflammatory mediators on vascular permeability


Oedema may be1-- localized to a part of the body or  2---generalized.
local oedema:1-acute inflammation: oedema due to local effects of inflammatory mediators---increase vascular permeability.→ accumulation of protein rich fluid (exudates) in the interstitial spaces.2-Hypersensitivity (allergic) oedema due to increase ↑vascular permeability.3-Venous obstruction → venous congestion increase →↑capill. perm. → transudation of fluid e.g. in the legs during pregnancy due to pressure on the veins by the gravid uterus Also after sitting for long periods without moving the legs. Impaired venous out flow e.g. secondary to deep venous thrombosis(DVT) in the lower extremities → oedema restricted to the affected leg

4-lymphatic: due to obstruction of lymphatic drainage e.g. by tumor cells ,trauma ,by radiation or by inflamm. injury e.g. Filariasis →fibrosis of lymphatic vessels & L.N. of the inguinal region → oedema of lower limbs (elephantiasis). In carcinoma of breast →infiltration & obstruction of superficial lymphatics → oedema of overlying skin → "peau d 'orange" also after surgery or irradiation of breast cancer →sever oedema of the arm.

Generalized edema

Either due to:1----increased hydrostatic pressure, most commonly in congestive heart failure affecting the right ventriclular cardiac function.CHF is associated with reduced renal perfusion →stimulate rennin –angiotensene-aldosteron axis → induce Na+ and water retention by the kidney (secondary hyperaldosteronism).

2----reduced plasma oncotic pressure

hypoalbuminaemia ,this result from excessive loss f or reduced synthesis of albumin.an important cause of albumin loss is nephrotic syndrome characterized by a leaky glomerular basement memb.→ excessive loss of protein (albuminurea)→ generalized oedema. Pitting oedema can be manifested in oedematous tissues (because the finger pressure will displace the interstitial fluid leaving a finger shaped depression).


reduced albumin synthesis: e.g. in diffuse liver diseases as in cirrhosis , or as consequence of protein malnutrition, protein –loosing enteropathy .reduced plasma oncotic pr.→ movement of fluid into the interstitial→↓plasma vol.→↓ renal perfusion → 2'ry aldosteronism.Morphology:Oedema is most easily recognized grossly .Microscopically →oedema fluid generally manifested as clearing &separation of the extracellular matrix elements.

Pulmonary oedema

is common clinical problem & frequently follow Left side heart failure & The lungs are typically 2-3 times their normal wt.. On sectioning frothy & sometimes blood-tinged fluid representing a mixture of air and oedema fluid and extravasated RBCs. .


Morphology, edema is most commonly encountered in subcutaneous tissues, the lungs, and the brain. Edema of the dependent parts of the body is a prominent feature of congestive heart failure.Generalized and more severe edema, is usually due to renal failure. In both conditions, the edema is pitting. The distribution of oedematous fluid by gravity & is called (dependant oedema) . when the patient is ambulant the legs are first affected (ankle oedema),when the patient is recumbent →sacral oedema.:

Hyperemia and congestion Both terms indicate a local increased volume of blood in a particular tissue Hyperemia It is increase flow of the blood to the area. It is an active process, the affected tissue is red, resulting from sympathetic stimulation which causes arteriolar dilatation &local redness produced owing to the engorgement of oxygenated Bd e.g. pathological as in acute inflammation physiological as in exercise



Congestion It is a stasis of the deoxygenated blood in the area is a passive process, which could be localized or generalized, and the affected tissue is red-blue (cyanosis). congestion is a passive dilatation of veins as a result of partial obstruction to the venous return, this will cause bluish coloration due to accumulation of deoxygenated blood .

Venous congestion  can be either general or local.

General venous congestion:Where the whole venous return is impaired by chronic obstructions e.g.Pulmonary congestion: in cases of left sided heart failure as in mitral stenosis →raised pressure in the pulmonary veins →alveolar capillaries become tortous & distended with red cells →break down of RBCs & phagocytosis of intra-alveolar red cell debris leading to accumulation of (hemosidrin–laden macrophages) (heart failure cells) with transudate in the alveolar spaces esp the posterior & basal lobes of the lungs).

Congestion and edema commonly occur together. In long-standing congestion, there is chronic hypoxia. Morphology, grossly, the cut surface is hemorrhagic and wet. Microscopically, there is engorgement of capillaries by blood, pulmonary edema and heart-failure cells.

Congestion of the liver

usually follows right sided heart failure →liver moderately enlarged & tender.Micro: red cells accumulate in the sinusoids around the central veins surrounded by the peripheral hepatocytes which are better oxygenated because of their proximity to hepatic arterioles so they are less hypoxic &may only develop fatty changes giving it an appearance called "nut meg liver".


Congestion of the spleen: produce enlargement of the spleen "splenomegaly " with focal hemorrhage & eventually fibrous scars.

Local venous congestion: follows mechanical interference with the venous drainage from an organ --- e.g. limbs in DVT caused by venous thrombosis . --- compression of a vein by tumor or bandage. Local venous congestion will result in localized oedema & ischemic necrosis.

Hemorrhage : It indicates extravasations of blood due to vascular rupture. Causes are; 1. Chronic congestion. 2. Hemorrhagic diatheses. 3. Vascular injury (trauma, atherosclerosis, inflammation, Neoplastic erosion). Patterns include; 1. External bleeding. 2. Internal bleeding (hematoma, hemothorax, hemoperitoneum, hemopericardium, hemarthrosis). 3. Petechiae (1- to 2-mm). 4. Purpura (>3mm). 5. Ecchymoses (>1 to 2cm).

The clinical significance of hemorrhage depends on;

1. Volume and rate of bleeding. 2. The site involved. 3. Duration (acute versus chronic or recurrent).


Hemostasis and thrombosis
Normal hemostasis means 1. Maintaining blood in a fluid, clot-free state in normal vessels. 2. Rapid localized plug at a site of vascular injury. Thrombosis, is the pathologic opposite to hemostasis, and it means an inappropriate activation of normal hemostatic process.

Both hemostasis and thrombosis are regulated by;

1. Vascular wall. 2. Platelets. 3. Coagulation cascade.

Normal hemostasisthe general sequence of events  AFTER INITIAL INJURY include

1. Brief period of arteriolar vasoconstriction. 2. Primary hemostasis (transient platelet plug). 3. Secondary hemostasis (activation of coagulation cascade). 4. Permanent plug.

Endothelial cells modulate several aspects of normal hemostasis, by having;

1. Anti-platelet, anticoagulant, and fibrinolytic properties. Antiplatelet effects. An intact endothelium prevents platelets and plasma coagulation factors from meeting the highly thrombogenic subendothelial ECM. Nonactivated platelets do not adhere to the endothelium, Anticoagulant effects. These effects are mediated by membrane-associated heparin-like molecules and by thrombomodulin, a specific thrombin receptor

2. Pro-coagulant activities

Procoagulant effects of Endothelial cells are also induced by Bacterial endotoxin or by cytokines (eg.---- tumor necrosis factor [TNF] or interleukin-l [IL-l]) , which activates the extrinsic clotting cascade. Platelets play a central role in hemostasis, (adhesion, secretion, aggregation).

Coagulation cascade, is essentially a series of enzymatic conversions, turning inactive pro-enzymes into active enzymes and culminating in thrombin formation. Thrombin converts soluble fibrinogen into insoluble fibrin. Beside inducing coagulation, activation of the clotting cascade also sets into motion a fibrinolytic cascade that limits the size of the final clot.

Thrombosis, Virchow triad

three primary influences predispose to thrombus formation (Virchow triad); 1. Endothelial injury, leading to; Exposure of sub-endothelial extracellular matrix. Adhesion of platelets



2. Stasis or turbulence of blood flow, by causing; a. Endothelial injury . b. Disruption of laminar flow. c. Preventing dilution of activated clotting factors by fresh blood. d. Retarding the inflow of clotting factor inhibitors. 3. Blood hypercoagulability


Morphology, thrombi may develop anywhere in the CVS Grossly and microscopically have apparent laminations (lines of Zahn), produced by alternating pale layers of platelets admixed with some fibrin and darker layers containing more red cells. Arterial thrombi are usually occlusive, are firmly attached to the wall, and are gray-white and friable. Venous thrombi are almost invariably occlusive, are less firmly attached to the wall, and are red. Postmortem clots are gelatinous, dark red, usually not attached to the wall, and lack lines of Zahn. Mural thrombi, are those attached to the wall of a spacious cavity e.g., cardiac ventricles Vegetations, are thrombi formed on heart valves.


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.

Fate of the thrombus, include

1. Propagation. 2. Embolization. 3. Dissolution. 4. Organization and re-canalization. thrombi are significant because; 1. They cause obstruction of vessels. 2. They are possible sources of emboli.

Disseminated intravascular coagulation (DIC), it is a sudden or insidious onset of widespread fibrin thrombi formation in the micro-circulation, associated with rapid consumption of platelets and coagulation proteins (consumption coagulopathy) that results in activation of fibrinolytic mechanisms. So, a thrombotic disorder evolves into a serious bleeding disorder. DIC is not a primary disease but rather a potential complication of many conditions have in common, the widespread activation of thrombin, (obstetric complications, infections, neoplasm, massive tissue injury).

Embolism

is a detached intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant from its point of origin. There are many types of emboli; 1. Thrombo-emboli. 2. Fat. 3. Gas (air, nitrogen). 4. Atheromatous emboli. 5. Tumor fragments. 6. Bone marrow. 7. Foreign body (bullet). The potential effect of embolism is ischemic necrosis (infarction)

Pulmonary thrombo-embolism, in more than 95% of instances, venous emboli ,,,deep leg vein thrombi, are the source. Depending on the size of the embolus; 1. Impact across the bifurcation (saddle embolus). 2. It may occlude the main pulmonary artery. 3. Or pass out into the smaller branching arterioles. 4. Rarely, an embolus may pass through an inter-atrial or inter-ventricular defect to gain access to the systemic circulation (paradoxical embolism).

Here is a "saddle embolus" that bridges across the pulmonary artery from the heart, as it divides into right and left main pulmonary arteries.


This pulmonary thromboembolus is occluding the main pulmonary artery. (gross)

Clinical consequences

include; 1. Most pulmonary emboli are silent. 2. Sudden death (acute corpulmonale). 3. Obstruction of medium-sized arteries may result in pulmonary hemorrhage. 4. Obstruction of small end-arterioles result in infarction. 5. Multiple emboli over time may cause chronic corpulmonale.

Here is a large wedge hemorrhagic area of infarction produced by a medium-sized thromboembolus to the lung. Diagnosis: pulmonary infarction (hemorrhagic infarction)


Systemic thrombo-embolism, they may originate from; 1. Intra-cardiac mural thrombi, (about 80% of emboli). 2. Aortic aneurysm. 3. Thrombi on ulcerated atherosclerotic plaques. 4. Fragmentation of a valvular vegetation. 5. Paradoxical emboli. 6. Up to 15% of emboli are of unknown origin.

The main sites involved are;

1. Lower extremities (75%). 2. Brain (10%). 3. Intestines. 4. Kidneys. 5. Spleen. 6. Upper extremities.

Fat embolism, it may result from; 1. Fractures of long bones (most common). 2. Soft tissue trauma and burns (rare).

Gas embolism, air may enter the circulation during; 1. Obstetric procedures. 2. Chest wall injury. In excess of 100 cc is required to have a clinical effect. The bubbles produce physical obstruction to vessels, and may lead to infarction.

Decompression sickness

is a type of gas embolism occurring in individuals who are exposed to sudden changes in atmospheric pressure (deep sea divers). When air is breathed at high pressure, increased amounts of gas (particularly nitrogen), become dissolved in the blood and tissue. If the diver ascends (depressurizes) too rapidly, the nitrogen expands in the tissues and bubbles out of solution in the blood to form gas emboli. Clinically, the diver suffers from; 1. Muscle and joint pain. 2. Respiratory distress. 3. Infarctions in various tissues.



Amniotic fluid embolism, is a grave but uncommon complication of labor. 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. 1. Sudden severe dyspnea. 2. Cyanosis. 3. Hypotensive shock. 4. Seizure and coma. 5. If the patient survives, pulmonary edema and DIC develop.

Infarction : It is an ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage. Causes, include; 1. Thrombosis or embolism (99%). 2. Local vasospasm. 3. Expansion of atheroma. 4. Extrinsic compression of a vessel (tumor, twisting, edema, hernia). 5. Traumatic rupture.

Morphology

infarcts are classified on the basis of their color and the presence or absence of infection, into; 1. Red (hemorrhagic). 2. White (anemic) And 1. Septic. 2. Sterile.

Red infarcts occur in the following situations; 1. Venous occlusion (testis, ovary). 2. Loose tissue. 3. Tissues with dual circulation. 4. Previously congested tissues. 5. Re-established blood flow


White infarcts occur in arterial occlusion in solid organs with end-arterial circulation. Most infarcts tend to be wedge-shaped, with the occluded vessel at the apex and the periphery of the organ forming the base. At the outset, all infarcts are poorly defined and slightly hemorrhagic. Over the course of few days, they become more firm and brown. Most infarcts are replaced by scar tissue. In septic infarcts, abscess is produced. .

Clinical correlation

The consequences of a vascular occlusion can range from no or minimal effect, to death of a tissue or even the individual. The factors that influence the outcome include; 1. Nature of the vascular supply. 2. Rate of development of occlusion. 3. Vulnerability to hypoxia. 4. Oxygen content of blood


Shock : Also called cardio-vascular collapse, is defined as systemic hypo-perfusion caused by reduction either in cardiac output or in the effective circulating blood volume. The end results are; 1. Hypotension. 2. Impaired tissue perfusion. 3. Cellular hypoxia. Initially, cellular injury is reversible, followed in sustained shock by cell death.

Shock is categorized into;

1. Cardiogenic. 2. Hypovolemic. 3. Septic. 4. Neurogenic. 5. Anaphylactic.

Cardiogenic Shock

Myocardial pump failure: which may be caused by: myocardial infarction, ventricular rupture, arrhythmias, cardiac temponade, pulmonary embolism, open heart surgery………Principle mechanism is failure of myocardial pump → sudden fall in C.O.

Hypovolemic Shock

result from:loss of blood or plasma volume e.g. hemorrhage ,fluid loss as in vomiting & diarrhea, burns or trauma. Principle mechanism: inadequate blood or plasma volume→ low Cardiac Output

Septic Shock

is caused by systemic microbial infections (endotoxic shock) & it can occur after gram + bacteria septicemia or even fungal sepsis. The toxins produced by these bacteria causes arteriolar vasodilatation & pooling of blood.

Neurogenic shock in severe pain following fracture bone. Anaphylactic shock :initiated by type 1 hypersensitivity reaction → systemic vasodilatation & ↑vascular permeability .

Stages of shock

unless the insult is massive and rapidly lethal, shock tends to evolve through 3 phases;1. Initial non-progressive phase, during which reflex compensatory mechanisms are activated & perfusion of vital organs is maintained which include: neurohumoral mechanisms help to maintain the cardiac output & blood pressure. These mechanisms include:*baroreceptors reflexes *release of catecholamines*activation of rennin–angiotensin axis *release of antidiuretic hormone ADH*& generalized sympathetic stimulation

The net effect is tachycardia, renal conservation of fluid .Coetaneous vasoconstricon is responsible for coolness & pallor of skin in shock .coronary & cerebral vessels are less sensitive to the sympathetic response & thus maintain relatively normal caliber, blood flow → oxygen delivery to the vital organs .Septic shock ------vasodilatation of skin →skin feel warm & flushed

2--progressive stage

characterized by tissue hypoperfusion & worsening of circulatory & metabolic imbalance.if tissue hypoxia is persistent → intracellular aerobic respiration is replaced by anaerobic glycolysis → exessive production of lactic acid →lactic acidosis →↓tissue pH→ blunts the vasomotor response → pooling of blood in the microcirculation →worsen the C.O. ,anoxic injury to the endothelia with subsequent DICWith this wide tissue hypoxia, vital organs begin to fail; clinically the patient may become confused & urinary output declines.

3-irreversible stage

cellular & tissue injury is so severe that even if the hemodynamic defects are corrected, survival is not possible. The patient has complete renal shutdown due to acute tubular necrosis.



Morphology, the changes are those of hypoxic injury. Most particularly involved organs are; Brain, Heart, Lungs, Kidneys, Adrenals, and Gastro-intestinal tract. Clinical features, they depend on the precipitating insult. In hypovolemic and cardiogenic shock, the patient presents with hypotension; weak, rapid pulse; and cool, clammy, cyanotic skin. In septic shock, the skin initially is warm and flushed. The prognosis varies with the origin of shock and its duration. The best is in a young patient with hypovolemic shock, and the worst is in an old patient with cardiogenic shock and that with septic shock.