This document summarizes key concepts related to hemodynamic disorders, thrombosis, and shock. It discusses edema, including the mechanisms and clinical significance of edema. It also covers hyperemia and congestion, hemorrhage, and thrombosis. For edema, it describes how fluid moves between vascular and interstitial spaces and the causes of increased interstitial fluid. It discusses the pathologic features and clinical significance of pulmonary, subcutaneous, and brain edema. For thrombosis, hemorrhage, hyperemia and congestion, it outlines the mechanisms, morphological changes, and clinical implications.

1. HEMODYNAMIC DISORDERS, THROMBOSIS, & SHOCK
EDEMA
Sixty percent of lean body weight is water, 2/3 intracellular & 1/3 is in extracellular. The
latter is mostly interstitial fluid; only 5% of total body water is in blood plasma.
Edema refers to” increased fluid in the interstitial tissue spaces.”
Hydrothorax, hydropericardium, or hydroperitoneum (ascites) refer to fluid collection
in the respective body cavity.
Anasarca is a severe and generalized edema with profound subcutaneous tissue swelling.
Mechanisms of edema:
The movement of fluid between vascular and interstitial spaces is controlled mainly by
the opposing effects of vascular hydrostatic pressure and plasma colloid osmotic
pressure. Normally, the exit of fluid into the interstitium from the arteriolar end of the
microcirculation is nearly balanced by inflow at the venular end; the lymphatics drain a
small residual amount of excess interstitial fluid. Either increased capillary pressure or
diminished colloid osmotic pressure can result in increased interstitial fluid. As
extravascular fluid accumulates in either case, the increased tissue hydrostatic and plasma
osmotic pressures eventually achieve a new equilibrium, and water re-enters the venules.
Excess interstitial edema fluid is removed by lymphatic drainage, ultimately returning to
the bloodstream via the thoracic duct; clearly, lymphatic obstruction (e.g., due to
scarring or tumor) can also impair fluid drainage and cause edema. Sodium and water
retention due to renal disease can also cause edema. The mechanism of inflammatory
edema mostly involves increased vascular permeability;
The edema fluid may be either a transudate or exudate.
A transudate occurs with volume or pressure overload, or under conditions of reduced
plasma protein; it is typically protein-poor with a specific gravity less than 1.012.
An exudate occurs due to increased vascular permeability in inflammation. It is protein-
rich with a specific gravity greater than 1.020.
The principal causes of non-inflammatory edema are:
1. Increased Hydrostatic Pressure
This is either localized or generalized (systemic)
Localized increases in intravascular pressure can result from impaired venous return; for
example, deep venous thrombosis of leg veins can cause edema restricted to the distal
portion of the affected leg, liver cirrhosis ascites, acute LVF pulmonary edema.
Generalized increases in venous pressure, with resultant systemic edema, occur most
commonly in congestive heart failure, with involvement of the right ventricular cardiac
function.
Although increased venous hydrostatic pressure is contributory, the pathogenesis of
cardiac edema is more complex. In congestive heart failure, reduced cardiac output leads
to reduced renal perfusion. Renal hypoperfusion in turn triggers the renin-angiotensin-
aldosterone axis, inducing sodium and water retention by the kidneys (secondary
aldosteronism). This mechanism normally functions to increase intravascular volume and
1

2. thereby improve cardiac output to restore normal renal perfusion. However, if the failing
heart cannot increase cardiac output, the extra fluid load causes increased venous
pressure and, eventually, edema. Unless cardiac output is restored or renal water retention
reduced (e.g., by salt restriction, diuretics, or aldosterone antagonists), a cycle of renal
fluid retention and worsening edema ensues.
2. Reduced Plasma Osmotic Pressure
Albumin is the most important serum protein responsible for maintaining intravascular
colloid osmotic pressure. Reduced osmotic pressure occurs when there is reduced
synthesis or loss of this plasma protein from the circulation. Albumin loss is exemplified
by the nephrotic syndrome (glomerular capillary walls become leaky) that is associated
with generalized edema. Reduced albumin synthesis occurs in the setting of diffuse liver
diseases (e.g., cirrhosis) or protein malnutrition. In all the above reduced plasma
osmotic pressure leads to a net movement of fluid into the interstitial tissues.
3. Lymphatic Obstruction
Impaired lymphatic drainage and consequent lymphedema is usually localized; it can
result from inflammatory or neoplastic obstruction. The parasitic infection filariasis can
cause extensive inguinal lymphatic and lymph node fibrosis. The resultant edema of the
external genitalia and lower limbs can be so massive that it has been likened to the limbs
of an elephant (elephantiasis). Cancer of the breast can be treated by resection and/or
irradiation of the associated axillary lymph nodes; the resultant scarring and loss of
lymphatic drainage can cause severe upper extremity edema. In breast carcinoma
infiltration and obstruction of superficial lymphatics can also cause edema of the
overlying skin, the so-called peau d'orange (orange peel) appearance. Such a finely pitted
surface results from an accentuation of depressions in the skin at the site of hair follicles.
4. Sodium and Water Retention
Salt retention can also be a primary cause of edema. Increased salt-with the obligate
accompanying water-causes both increased hydrostatic pressure (due to expansion of the
intravascular volume) and reduced vascular osmotic pressure. Salt retention can occur
with any impairment of renal function, as in poststreptococcal glomerulonephritis and
acute renal failure.
Pathologic features of edema
Edema is most easily recognized grossly. Microscopically, edema fluid is reflected
primarily as a 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, lungs, and brain.
Subcutaneous edema
• This can be diffuse or more prominent in regions with high hydrostatic pressures; the
ultimate distribution depends on the underlying etiology.
• Even diffuse edema is usually more prominent in certain body areas as a result of the
effects of gravity- dependent edema (e.g., involving the legs when standing, or
involving the sacrum when recumbent). Dependent edema is a prominent feature of
cardiac failure, particularly of the right ventricle.
• Edema due to renal dysfunction or nephrotic syndrome is generally more severe than
cardiac edema and affects all parts of the body equally. Nevertheless, severe edema
2

3. early in the disease course can still manifest disproportionately in tissues with a loose
connective tissue matrix (e.g., the eyelids, causing periorbital edema).
Finger pressure over significantly edematous subcutaneous tissue displaces the interstitial
fluid and leaves a finger-shaped depression, so-called pitting edema.
Pulmonary edema
• This is a common clinical problem that is encountered with
a. left ventricular failure (most frequent association)
b. renal failure
c. acute respiratory distress syndrome (ARDS)
d. pulmonary infections
e. hypersensitivity reactions
Gross features
• The lungs typically heavy
• Sectioning reveals frothy, sometimes blood-tinged fluid representing a mixture of air,
edema fluid, and extravasated red cells.
Microscopic features
• The alveolar spaces are filled with pale pink edema fluid
• There is congestion of the capillaries within the alveolar walls due to the increase in
venous pressure.
Brain Edema
• This may be localized to sites of focal injury (e.g., infarct, abscesses or neoplasms) 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.
Gross features
With generalized edema, the brain is grossly swollen with narrowed sulci and distended
flattened gyri due to compression against the unyielding skull.
Clinical significance of edema
Subcutaneous tissue edema in cardiac or renal failure is important primarily because it
indicates underlying disease; however, when significant it can also impair wound healing
or the clearance of infection. Pulmonary edema can cause death by interfering with
normal ventilation. In chronic venous congestion of the lung, edema fluid in the alveolar
spaces also creates a favorable environment for bacterial infection. Brain edema is
serious and can be rapidly fatal due to increased intracranial pressure. Marked Edema of
the larynx may cause suffocation
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 blood flow
due to arteriolar dilation (e.g., at sites of inflammation or in skeletal muscle during
exercise). The affected tissue is redder than normal because of engorgement with
oxygenated blood. Congestion is a passive process resulting from impaired venous
return out of a tissue. It may occur systemically, as in heart failure (right ventricular
failure or congestive HF), or it may be local, resulting from an isolated venous
3

4. obstruction. The tissue has a blue-red color (cyanosis), especially as worsening
congestion leads to accumulation of deoxygenated hemoglobin in the affected tissues.
Congestion of capillary beds is closely related to the development of edema, so that
congestion and edema commonly occur together. In long-standing congestion, called
chronic passive congestion, the stasis of poorly oxygenated blood causes chronic
hypoxia, which in turn can result in degeneration or death of parenchymal cells and
subsequent tissue fibrosis. Capillary rupture at such sites of chronic congestion can also
cause small foci of hemorrhage; phagocytosis and catabolism of the erythrocyte debris
can result in accumulations of hemosiderin-laden macrophages.
Localized venous congestion:
A. Pulmonary venous congestion: Occurs in Left sided heart (ventricular) failure and in
mitral valve stenosis
B. venous outflow obstruction: Occurs in
1. Venous thrombosis of major vein e.g. thrombosis of lower limb veins congestion
+ swelling of lower limb
2. Cirrhosis of the liver  portal hypertension  congestive splenomegaly, ascites,
esophageal varices and hemorrhoids
3. Mechanical compression of veins e.g. strangulated hernia, volvulus small intestine,
torsion of ovary/testis
Morphological changes in chronic venous congestion of the liver:
Gross appearance: The liver is enlarged and firm in consistency. Its cut surface shows a
mottled appearance of dark areas (of centrilobular zones congestion), and pale peripheral
(peri-portal) areas, similating the appearance of the cut surface of a nutmeg, hence the
term “nutmeg liver”.
Microscopically, the central vein and the central ends of the sinusoids appear distended
and packed with red cells. The hepatic cells in the center of the lobule undergo
degeneration and sometimes necrosis as a result of the anoxia and the pressure
effects of congested (dilated) sinusoids. The hepatic cells at the periphery of
the lobule (around portal tracts) are either normal or show mild form of injury
such as fatty changes.
Morphological changes in Chronic venous congestion of the Lungs
Grossly: The lungs are heavy, dark red in color and firm in consistency.
Microscopically
The alveolar capillaries and venules are dilated, and packed with red cells. Some of the
alveolar capillaries rupture leading to intra-alveolar hemorrhage. Macrophages move into
the alveolar spaces to engulf the red cells and store the iron in hemoglobin as
hemosiderin granules. These macrophages are called heart failure cells because of their
4

5. common association in heart failure. Some of the excess iron is deposited in interstitial
tissue stimulating fibrosis and causing brown induration of the lung. In consequence of
the venous congestion a transudate collects in the alveolar spaces (edema fluid), which
microscopically appears as pale eosinophilic homogeneous material.
HEMORRHAGE
Hemorrhage is “extravasation of blood from vessels into the extravascular space”.
• Capillary bleeding can occur under conditions of chronic congestion or capillaritis.
• Hemorrhagic diatheses refer to an increased tendency to hemorrhage (usually with
insignificant injury). This occurs in a wide variety of clinical disorders.
• Rupture of a large artery or vein results in severe hemorrhage, and is almost always
due to
1. Vascular injury, including trauma,
2. Ruptured aneurismal dilatation (e.g. atherosclerotic aortic aneurysm)
3. inflammatory or neoplastic erosion of the vessel wall
• Hemorrhage can be external to or confined within a tissue.
Hematoma refers to any localized accumulation of blood. Hematomas can be relatively
insignificant (e.g., a bruise) or can be due to massive bleeding as to cause death (e.g., a
massive retroperitoneal hematoma resulting from rupture of a dissecting aortic aneurysm.
Petechiae are minute (1- to 2-mm) hemorrhages into skin, mucous membranes, or serosal
surfaces and are typically associated with
1. Low platelet counts (thrombocytopenia)
2. Defective platelet function.
3. Locally increased intravascular pressure
4. Clotting factor deficiencies.
Purpura is raised slightly larger than petechiae (3- to 5-mm) hemorrhages and can be
associated with many of the same disorders that cause petechiae; in addition, purpura can
occur with trauma, vascular inflammation (vasculitis), or increased vascular fragility.
Ecchymoses are larger (1- to 2-cm) subcutaneous hematomas (bruises). The erythrocytes
in these local hemorrhages are phagocytosed and degraded by macrophages; the
hemoglobin (red-blue color) is enzymatically converted into bilirubin (blue-green color)
and eventually into hemosiderin (golden-brown), accounting for the characteristic color
changes in a hematoma.
Large accumulations of blood in one or another of the body cavities are called
Hemothorax, hemopericardium, hemoperitoneum, or hemarthrosis refer to large
accumulation of blood in the pleural, pericardial, peritoneal or synovial cavities
respectively.
Clinical significance of hemorrhage
This depends on: 1- The volume of blood loss, 2-Its rate, and 3-Its location
Rapid loss (internal or external) of as much as 20% of the blood volume or slow losses of
even larger amounts may have little impact in healthy adults; greater losses, however, can
cause hemorrhagic (hypovolemic) shock. The site of hemorrhage is also important;
bleeding that would be trivial in the subcutaneous tissues may cause death if located in
5

6. the brain. Finally, chronic or recurrent external blood loss (e.g., a peptic ulcer or
menstrual bleeding) causes a net loss of iron, frequently culminating in an iron deficiency
anemia.
THROMBOSIS
Normally the blood is kept in a fluid state with rapid formation of a plug at the site of
injury. This is normal hemostasis. The pathologic opposite to hemostasis is thrombosis;
it can be considered an inappropriate activation of normal hemostatic processes.
Thrombosis is defined as the formation of a solid or semi-solid mass from the
constituents of the blood within the vascular system during life. The mass itself is
called a thrombus.
Both hemostasis and thrombosis involve three components:
1. Vascular wall
2. Platelets
3. Coagulation cascade
Pathogenesis of thrombosis
There are three predisposing factors for thrombus formation (Virchow's triad):
1. Endothelial injury
2. Stasis or turbulence of blood flow
3. Blood hypercoagulability (Changes in the composition of blood)
Endothelial injury
A. Mechanical injury such as , pressure, ruptue or tortion of the vessel
B. Degeneration of vascular endothelium at sites of
1. Atherosclerosis e.g. of the coronaries, cerebral arteries and aorta.
2. Aneurysm e.g. aortic aneurysm
3. endothelium overlying a myocardial infarction.
C. Inflammatory processes as in Phlebitis , Arteritis, and inflammation of heart valves.
However, it is important to note that endothelium need not be denuded or physically
disrupted to contribute to the development of thrombosis; any disturbance in the balance
of the prothrombotic and antithrombotic activities of endothelium can influence local
clotting events. Thus, dysfunctional endothelium may elaborate greater amounts of
procoagulant factors (e.g., platelet adhesion molecules, tissue factor, plasminogen
activator inhibitors) or may synthesize reduced amounts of anticoagulant effectors.
Significant endothelial dysfunction in the absence of endothelial cell loss may occur in:
1. Hypertension 4. Hypercholesterolemia
2. Turbulent flow over scarred valves 5. Radiation
3. Bacterial endotoxins 6. Products absorbed from cigarette smoke
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 contributor to the development of venous thrombi.
Stasis and turbulence therefore:
1. Disrupt laminar flow and bring platelets into contact with the endothelium
6

7. 2. Prevent dilution of activated clotting factors by fresh-flowing blood
3. Retard the inflow of clotting factor inhibitors and permit the buildup of thrombi
4. Promote endothelial cell activation, resulting in local thrombosis, leukocyte adhesion,
etc.
Turbulence and stasis contribute to thrombosis in several other clinical settings:
• Ulcerated atherosclerotic plaques not only expose subendothelial ECM but also cause
turbulence
• Aneurysms (abnormal dilations) of the aorta & other arteries create local stasis and
consequently a fertile site for thrombosis.
• Myocardial infarction. Mural thrombi may form over infarcted non-contractile
myocardium, or within ventricular aneurysm complicating old MI, due to stasis and
local turbulance
• 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 development of thrombi.
• Hyperviscosity syndromes (such as polycythemia) increase resistance to flow and
cause small vessel stasis
• The deformed red cells in sickle cell anemia cause vascular occlusions, with the
resultant stasis also predisposing to thrombosis.
Hypercoagulability
Hypercoagulability is defined as any alteration of the coagulation pathways that
predisposes to thrombosis, and it can be divided into primary (genetic) and secondary
(acquired) disorders.
Causes of the primary (inherited) hypercoagulable states include most commonly
mutations in the factor V gene and the prothrombin gene.
The pathogenesis of acquired thrombotic diatheses is frequently multifactorial & include
• Cardiac failure, major surgery or trauma: In addition to hypercoagulability (increased
platelets and they become stickier, increased clotting factors), stasis or vascular
injury may be more important.
• Oral contraceptive use & pregnancy: probably related to the hyperestrogenic state that
is associated with increased hepatic synthesis of coagulation factors and reduced
synthesis of antithrombin III.
• Disseminated cancers, release of procoagulant tumor products predisposes to
thrombosis.
• Advancing age: is associated with hypercoagulability & this has been attributed to
increasing platelet aggregation and reduced endothelial PGI2 release.
• Smoking & obesity promote hypercoagulability by unknown mechanisms.
• The antiphospholipid antibody syndrome comprise recurrent thrombosis, repeated
abortions, cardiac valve vegetations and thrombocytopenia. It is associated with
autoantibodies directed against plasma proteins (e.g. prothrombin) which would bind
to anionic phospholipids (cardiolipin). These antibodies induce a hypercoagulable
state, by platelet activation or by interfering with endothelial cell production of PGI2.
There are two types of anti-phospholipid antibody syndrome.
1. Primary (idiopathic)
7

8. 2. Secondary to a well-defined autoimmune disease, such as systemic lupus
erythematosus.
Pathological features of thrombosis
• Thrombi can develop anywhere in the cardiovascular system (e.g., in cardiac
chambers, on valves, or in arteries, veins, or capillaries).
• The size and shape of a thrombus depend on the site of origin and the cause. Arterial or
cardiac thrombi typically begin at sites of endothelial injury or turbulence; venous
thrombi characteristically occur at sites of stasis.
• Thrombi are focally attached to the underlying vascular surface; arterial thrombi tend
to grow (propagate) in a retrograde direction from the point of attachment, while
venous thrombi extend in the direction of blood flow (thus both tend to propagate
toward the heart).
• The propagating portion of a thrombus tends to be poorly attached and therefore prone
to fragmentation, generating an embolus especially in venous thrombi.
• Thrombi can have grossly (and microscopically) apparent laminations called lines of
Zahn; these represent pale platelet and fibrin layers alternating with darker
erythrocyte-rich layers. Their presence can distinguish ante-mortem thrombosis from
the non-laminated postmortem clots that occur after death. Such lines are less
prominent in venous thrombi compared to arterial ones.
• Venous thrombi are formed in the sluggish venous flow & thus tend to contain more
enmeshed erythrocytes and are therefore called red, or stasis, thrombi. They usually
resemble statically coagulated blood. Never the less, careful evaluation of venous
thrombi generally reveals ill-defined laminations.
• Postmortem clots can sometimes be mistaken at autopsy for venous thrombi. However,
postmortem "thrombi" are gelatinous, with a dark red dependent portion where red
cells have settled by gravity, and a yellow "chicken fat" supernatant, and they are
usually not attached to the underlying wall. In contrast, red thrombi are firmer and are
focally attached, and sectioning reveals strands of gray fibrin.
• Thrombi occurring in heart chambers or in the aortic lumen are designated mural
thrombi. Abnormal myocardial contraction (resulting from arrhythmias or myocardial
infarction) or endomyocardial injury (caused by myocarditis, catheter trauma)
promotes cardiac mural thrombi, while ulcerated atherosclerotic plaques and
aneurismal dilation promote aortic thrombosis.
• Arterial thrombi are frequently occlusive. Arterial thrombi are usually superimposed
on an atherosclerotic plaque, however, other vascular injury (vasculitis, trauma) can be
involved.
• Venous thrombosis (phlebothrombosis) is almost invariably occlusive, and the
thrombus can create a long cast of the lumen; venous thrombosis is largely the result of
stasis. The veins of the lower extremities are most commonly affected (90% of venous
thromboses); however, venous thrombi can occur in the upper extremities, periprostatic
plexus, or ovarian and periuterine veins; under special circumstances they may be
found in the dural sinuses, portal vein, or hepatic vein.
8

9. • Thrombi on heart valves are called vegetations (as in rheumatic valvulitis). Bacterial or
fungal blood-borne infections can cause valve damage, subsequently leading to large
thrombotic masses (infective endocarditis).
Fate of the Thrombus
In the ensuing days or weeks after the formation of thrombi, they undergo some
combination of the following four events:
1. Propagation: thrombi may accumulate additional platelets and fibrin, eventually
causing vessel obstruction.
2. Embolization: thrombi may dislodge or fragment and are transported elsewhere in the
vasculature.
3. Dissolution is the result of fibrinolytic activation, which leads to rapid shrinkage and
even total lysis of recent thrombi. Old thrombi are resistant to proteolysis. This is
clinically significant because therapeutic administration of fibrinolytic agents (in the
setting of acute coronary thrombosis) is generally effective only within a few hours of
thrombus formation.
4. Organization and recanalization: Older thrombi become organized by the ingrowth of
endothelial cells, smooth muscle cells, and fibroblasts into the fibrin-rich clot. Capillary
channels are eventually formed that can create conduits along the length of the thrombus
and thereby re-establish the continuity of the original lumen. Although the channels may
not successfully restore significant flow to many obstructed vessels, recanalization can
potentially convert a thrombus into a vascularized mass of connective tissue that is
eventually incorporated into the vessel wall and remains as a subendothelial swelling.
Eventually, with contraction of the mesenchymal cells 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 because of the release of lysosomal
enzymes from trapped leukocytes and platelets.
Clinical significance of venous & arterial thrombosis
Thrombi are significant because they
1. Cause obstruction of arteries and veins
2. Are potential sources of emboli.
Which effect is most important depends on the site of thrombosis.
Venous thrombi can cause congestion and edema in vascular beds distal to an
obstruction, but they are most troublesome for their capacity to embolize to the lungs and
cause death.
While arterial thrombi can embolize and even cause downstream tissue infarction, their
role in vascular obstruction at critical sites (e.g., coronary and cerebral vessels) is much
more significant clinically.
Venous Thrombosis (Phlebothrombosis)
Most venous thrombi occur in the superficial or deep veins of the leg.
Superficial venous thrombi usually occur in the saphenous system, particularly when
there are varicosities. Such superficial thrombi can cause local congestion, swelling, pain,
and tenderness along the course of the involved vein, but they rarely embolize.
Nevertheless, the local edema and impaired venous drainage do predispose the overlying
skin to infections from minor trauma and to the development of varicose ulcers.
9

10. Deep venous thrombi in the larger leg veins at or above the knee joint (e.g., popliteal,
femoral, and iliac veins) are more serious because they may embolize. Although they
may cause local pain and edema, the venous obstruction may be rapidly offset by
collateral bypass channels. Consequently, deep venous thromboses are entirely
asymptomatic in approximately 50% of patients and are recognized in retrospect only
after they have embolized to the lung.
Deep venous thrombosis can complicate :
1. Advanced age, bed rest, and immobilization all increase the risk of deep venous
thrombosis because reduced physical activity diminishes the milking action of muscles in
the lower leg and so slows venous return.
2. Cardiac failure causes stasis in the venous circulation.
3. Trauma, surgery, and burns usually result in reduced physical activity, injury to
vessels and release of procoagulant substances from tissues.
4. Peripartum and postpartum states; in addition to the potential for amniotic fluid
infusion into the circulation during parturition, late pregnancy and the postpartum period
are associated with hypercoagulability.
5. Hypercoagulable states .
6. Disseminated cancers: tumor-associated procoagulant release increases the risk of
thromboembolic phenomena (including migratory thrombophlebitis).
Arterial Thrombosis
Atherosclerosis is a major initiator of thromboses, because it is associated with loss of
endothelial integrity and abnormal vascular flow.
Myocardial infarction may be complicated by cardiac mural thrombi as a result of
dyskinetic myocardial contraction as well as damage to the adjacent endocardium.
Rheumatic heart disease can cause atrial mural thrombi due to mitral valve stenosis,
followed by left atrial dilation and concurrent atrial fibrillation.
Arterial aneurysms (e.g. aortic) are frequently filled by thrombi.
In addition to the obstructive consequences, cardiac and aortic mural thrombi can also
embolize peripherally. Virtually any tissue can be affected, but brain, kidneys, and spleen
are prime targets because of their large volume of blood flow.
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.
Forms of emboli
1. Thromboemboli: representing a dislodged thrombus or part of it. This type virtually
constitutes 99% of all emboli. Thus, unless otherwise specified, an embolism should be
considered to be thrombotic in origin.
Rare forms of emboli include
2. Fat emboli consisting of fat droplets
3. Air emboli consisting of bubbles of air or nitrogen
4. Atherosclerotic emboli (cholesterol emboli) consisting of athermatous debris
5. Tumor emboli made up of fragments of a tumor
6. Bone marrow emboli: consisting of bits of bone marrow
7. Foreign body emboli as bullets or shrapnel .
10

11. Inevitably, emboli lodge in vessels too small to permit further passage, resulting in partial
or complete vascular occlusion. The consequences of thromboembolism include ischemic
necrosis (infarction) of downstream tissue.
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.
PULMONARY THROMBO-EMBOLISM
This has an incidence of 25/100,000 hospitalized patients. It is considered the most
common preventable cause of death in hospitalized patients. In more than 95% of cases,
venous emboli originate from deep leg vein thrombi above the level of the knee such as
the popliteal, femoral, or iliac veins. These emboli are carried through progressively
larger channels and pass through the right side of the heart before entering the pulmonary
arterial circulation.
Depending on its size, the embolus may settle within
1. The main pulmonary trunk
2. Across the bifurcation (saddle embolus)
3. The main pulmonary arteries
4. The medium sized pulmonary arteries
5. Pass out into the smaller branching arteries or arterioles
Frequently, there are multiple emboli, perhaps sequentially, or as a shower of smaller
emboli from a single large thrombus; The patient who has had one pulmonary embolus is
at high risk of having more.
6. Rarely, an embolus can pass through an interatrial or interventricular defect, thereby
entering the systemic circulation (paradoxical or crossing embolism).
CLINICAL OUTCOME OF PULMONARY THROMBO-EMBOLISM
Depends on
1. Severity of occlusion
a. Size of pulmonary artery occluded
b. Number of occluding emboli
2. Cardio-respiratory status of the patient
• Most pulmonary emboli (60% to 80%) are clinically silent because they are small.
They eventually become organized and become incorporated into the vascular wall.
• Sudden death due to cardiovascular collapse or right ventricular failure (cor
pulmonale) (incidence 5%), occurs when 60% or more of the pulmonary circulation is
obstructed with emboli. This is also described as massive pulmonary embolism.
• Embolic obstruction of medium-sized arteries can cause pulmonary hemorrhage (10%)
but usually not pulmonary infarction because the lung has a dual blood supply and the
intact bronchial arterial circulation continues to supply blood to the area. However, a
similar embolus in the setting of left-sided cardiac failure (and resultant sluggish
bronchial artery blood flow) may result in a large infarct (10% incidence).
• Many emboli occurring over a period of time may cause pulmonary hypertension with
right ventricular failure. This is an uncommon event.
SYSTEMIC THROMBO-EMBOLISM
This refers to emboli in the arterial circulation. Sources include
11

12. 1. Intracardiac mural thrombi (80%) that complicate
a. infarction of the left ventricular wall (70%)
b. dilated left atria (e.g., secondary to mitral valve disease) (25%).
2. Aortic aneurysms
3. Ulcerated atherosclerotic plaques
4. Valvular vegetations.
5. A very small fraction of systemic emboli appear to arise in veins but end up in the
arterial circulation, through interventricular or interatrial septal defects ( paradoxical
emboli).
6- 10-15% are of unknown origin.
The major sites for arteriolar embolization are
1. The lower extremities (75%)
2. The brain (10%)
3. The intestines (mesenteric vessels), kidneys, and spleen.
4. The upper limbs are the least common sites
Clinical significance
The consequences of embolization in a tissue depend on
1. Vulnerability of the tissue to ischemia
2. Caliber of the occluded vessel
3. The efficiency of the collateral blood supply
Generally speaking, arterial embolization causes infarction of the affected tissues.
Emboli from cases of infective (bacterial) endocarditis à septic infarcts (abscesses)
Fat & bone marrow embolism
Although fat and marrow embolism occurs in some 90% of individuals with severe
skeletal injuries including major fractures, only about 10% of such patients show any
clinical findings. The Fat embolism syndrome is characterized by pulmonary
insufficiency, neurologic symptoms, anemia, thrombocytopenia, & globules of fat in the
urine; it is fatal in about 10% of cases. The pathogenesis of this syndrome involves both
mechanical obstruction & biochemical injury. It may further be complicated by DIC.
Air Embolism
Gas bubbles or Air may enter the circulation during obstetric procedures (air insufflation
of tubes) or as a consequence of chest wall injury. Generally, more than 100 ml of air are
required to produce a clinical effect; bubbles can coalesce to form frothy masses
sufficiently large to occlude major vessels. A particular form of gas embolism, called
decompression sickness, occurs when Deep-sea divers and underwater construction
workers are brought to the surface quickly.
Amniotic Fluid Embolism
Amniotic fluid embolism is a grave but uncommon complication of labor (1 in 50,000
deliveries). It has a mortality rate of up to 40%. The underlying cause is entry of amniotic
fluid into the maternal circulation via a tear in the placental membranes with the fluid
gaining access into ruptured uterine veins. Classically, there is marked pulmonary edema
and diffuse alveolar damage, with the pulmonary microcirculation containing squamous
12

13. cells and hair shed from fetal skin, and mucin derived from the fetal respiratory or
gastrointestinal tracts. DIC may also occur.
INFARCTION
This is defined as “localized area of ischemic cell necrosis in a living organ or tissue,
resulting most often from sudden reduction or cessation of its arterial blood supply or
occasionally its venous drainage”
Causes of vascular obstruction
1. Nearly 99% of all infarcts result from thrombotic or embolic events, and almost all
result from arterial occlusion.
Uncommon causes include
2. Expansion of atheromatous plaques by intraplaque hemorrhage
3. Spasm of coronary arteries
4. Pressure on a vessel from outside
- Tumor
- Fibrous adhesions
- Narrow mouthed hernia sac
5. Twisting (torsion) of the pedicle of mobile organ e.g. loop of small intestine
(volvulus), ovary and testis.
External pressure and torsion (causes 4 and 5) usually interfere with venous drainage,
since veins are more readily compressed than arteries.
Gross features
• Infarcts are classified on the basis of their color (reflecting the amount of hemorrhage)
into red (hemorrhagic) or white (pale, anemic). They are also classified according to
the presence or absence of microbial infection into septic or bland.
• Red infarcts occur
1. with venous occlusions (such as in ovarian torsion)
2. in loose tissues (such as lung) that allow blood to collect in the infarcted zone
3. in tissues with dual circulations such as lung and small intestine, permitting flow of
blood from an unobstructed parallel supply into a necrotic area (such perfusion not being
sufficient to rescue the ischemic tissues)
4. in tissues that were previously congested because of sluggish venous outflow
5. when flow is re-established to a site of previous arterial occlusion and necrosis (e.g.,
fragmentation of an occlusive embolus or angioplasty of a thrombotic lesion).
• White infarcts occur with arterial occlusions or in solid organs (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.
• All 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 can be
an overlying fibrinous inflammation and exudate.
• 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
congestion attributable to inflammation at the edge of the lesion (line of demarcation).
• In solid organs, the relatively few extravasated red cells are lysed, with the released
hemoglobin remaining in the form of hemosiderin. Thus, such infarcts become
13

14. progressively paler and sharply defined with time. While in spongy organs, the
hemorrhage is too extensive so it doen’t pale, but in few days, it becomes firmer and
browner, reflecting the accumulation of hemosiderin pigment.
• Infarcts within the brain could be pale or hemorrhagic.
Microscopic features
The dominant histologic characteristic of infarction is ischemic coagulative necrosis.
The brain is an exception in that ischemic tissue injury in the central nervous system
results in liquefactive necrosis.
• An inflammatory response begins to develop along the margins of infarcts within a few
hours and is usually well defined within 1 to 2 days.
• Eventually the inflammatory response is followed by a reparative response beginning
in the preserved margins.
• In stable or labile tissues, parenchymal regeneration can occur at the periphery, where
underlying stromal architecture is spared. However, most infarcts are ultimately
replaced by scar. This, depending on the size of the infarct, may take several months.
• Septic infarctions occur when bacterial vegetations from a heart valve embolize, when
microbes seed an area of necrotic tissue, or when infarction occurs in an already
infected area. In these cases the infarct is converted into an abscess.
Factors That Influence Development of an Infarct
1- Nature of the Vascular Supply
The most important factor that determines whether occlusion of a vessel will cause
damage is the presence or absence of an alternative blood supply. For example, lungs
have a dual pulmonary and bronchial artery blood supply; thus, obstruction of small
pulmonary artery or arterioles does not cause infarction in an otherwise healthy
individual with an intact bronchial circulation. Similarly, the liver, with its dual hepatic
artery and portal vein circulation, and the hand and forearm, with their dual radial and
ulnar arterial supply, are all relatively resistant to infarction. In contrast, renal and splenic
tissues are supplied by end arteries, and obstruction of such vessels generally causes
infarction.
2- Rate of Development of Occlusion
Slowly developing occlusions are less likely to cause infarction because they provide
time for the development of collateral vessels. For example, small interarteriolar
anastomoses ( normally with minimal functional flow) interconnect the three major
coronary arteries in the heart. If one of the coronaries is slowly occluded (e.g., by
atherosclerotic plaque), flow within this collateral circulation may increase sufficiently to
prevent infarction, even though the major coronary artery is eventually occluded.
3- Vulnerability of tissue to Hypoxia
The susceptibility of a tissue to hypoxia influences the likelihood of infarction. Neurons
undergo irreversible damage when deprived of their blood supply for only 3 to 4 minutes.
Myocardial cells, though more resistant to hypoxic damage than neurons, are also quite
sensitive and die after only 20 to 30 minutes of ischemia. In contrast, skeletal muscles &
fibroblasts within a limb may remain viable after many hours of ischemia.
4- Oxygen Content of Blood
The partial pressure of oxygen in blood also determines the outcome of vascular
occlusion. Partial flow obstruction of a small vessel in an anemic or cyanotic patient
might lead to tissue infarction, whereas it would be without effect under conditions of
14

15. normal oxygen tension. In this way congestive heart failure, with impaired flow flow and
ventilation, could cause infarction in the setting of an otherwise inconsequential
blockage.
Clinical significance of infarction
• Tissue infarction is a common and extremely important cause of clinical illness.
More than half of all deaths are caused by cardiovascular disease, and most of these are
due to myocardial or cerebral infarction.
• Pulmonary infarction is a common complication in several clinical settings
• Ischemic necrosis of the extremities (gangrene) is a serious problem in the
diabetics.
SHOCK
Shock in essence is a state of systemic hypoperfusion that is caused either by reduced
cardiac output or by reduced effective circulating blood volume. The end results are
hypotension, impaired tissue perfusion, and cellular hypoxia. It is the final common
pathway for a number of potentially lethal clinical events. 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.
Categories of shock
A. Cardiogenic
B. Hypovolemic
C. Septic
D. Neurogenic – less common
E. Anaphylactic- less common
Pathogenesis & clinical examples
Cardiogenic shock is due to myocardial pump failure resulting from intrinsic myocardial
damage, extrinsic pressure, or obstruction to outflow. Examples include
• Myocardial infarction
• Ventricular rupture
• Arrhythmia
• Cardiac tamponade
• Pulmonary embolism
Hypovolemic shock is due to inadequate blood or plasma volume. Examples include
• Hemorrhage (external or internal)
• Fluid loss (e.g., severe continuous vomiting &/or diarrhea, extensive burns)
Septic shock is due to peripheral vasodilation and pooling of blood; endothelial
activation/injury; leukocyte-induced damage; disseminated intravascular coagulation;
activation of cytokine cascades. Examples include:
• Overwhelming microbial infections
- Endotoxic shock
- Gram-positive septicemia
- Fungal sepsis
15

16. Neurogenic shock is due to loss of vascular tone and peripheral pooling of blood.
Examples include
• Anesthetic accidents
• Spinal cord injury
Anaphylactic shock is caused by an Ig E mediated (type I) hypersensitivity reaction. In
these situations, acute severe widespread vasodilation with subsequent pooling of the
blood results in tissue hypoperfusion and cellular anoxia. Examples include drugs
anaphylaxis.
Pathogenesis of Septic Shock
Septic shock ranks first among the causes of death in intensive care units (25% to 50%
mortality rate), and is particularly seen in immunocompromised patients (secondary to
chemotherapy, immunosuppression, or HIV infection).
Most cases of septic shock (70%) are caused by endotoxin-producing gram-negative
bacilli-hence the term endotoxic shock. Endotoxins are bacterial wall lipopolysaccharides
(LPS). Analogous molecules in the walls of gram-positive bacteria and fungi can also
elicit septic shock. These microbial products will attach to receptors on monocytes,
macrophages and neutrophils resulting in their activation and production of potent
cytokines such as IL-1 and TNF. These cytokines in high levels result in:
1. Systemic vasodilation (hypotension)
2. Diminished myocardial contractility
3. Widespread endothelial injury and activation, causing systemic leukocyte adhesion and
diffuse alveolar capillary damage in the lung (ARDS)
4. Activate the coagulation system causing disseminated intravascular coagulation (DIC)
The hypoperfusion resulting from the combined effects of widespread vasodilation,
myocardial pump failure, and DIC causes multiorgan system failure that affects 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.
Stages of Shock
Shock is a progressive disorder that if uncorrected passes into deeper levels of
homodynamic/metabolic deterioration that eventuates in 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 stages. These stages have been documented most
clearly in hypovolemic shock but are common to other forms as well:
1- Nonprogressive (compensated) stage during which reflex compensatory mechanisms
are activated and perfusion of vital organs is maintained. Various neurohumoral
mechanisms help maintain cardiac output and blood pressure near normal levels. The aim
is maintain enough blood supply to vital organs. A number of compensatory mechanisms
are set into motion, these include
1. Arteriolar constriction leading to increase in peripheral vascular resistance & hence
blood pressure.
2. Increase in heart rate leading to increase in cardiac output.
3. Renal conservation of fluids to increase intravascular volume; this occurs through
a. Increase secretion of antidiuretic hormone (ADH).
16

17. b. Activation of renin/angiotensin/aldosterone axis.
Cutaneous vasoconstriction is responsible for the characteristic coolness and pallor of
skin in shock (although septic shock may initially cause cutaneous vasodilation and thus
present with warm, flushed skin). Coronary and cerebral vessels are less sensitive to the
sympathetic response and thus maintain relatively normal caliber, blood flow, and
oxygen delivery.
2- Progressive (decompensated) stage characterized by tissue hypoperfusion and onset of
worsening circulatory and metabolic imbalances if the cause is not dealt with or the
clinical condition of the patient worsens e.g. hypovolemia in the elderly complicated by
MI. During this stage there is widespread tissue hypoxia causing intracellular shift into
anaerobic glycolysis, with excessive production of lactic acid. The resultant metabolic
lactic acidosis causes arteriolar dilation, and blood begins to pool in the microcirculation.
Peripheral pooling reduces the cardiac output and exposes endothelial cells to anoxic
injury with subsequent DIC. With widespread tissue hypoxia, vital organs are affected
and begin to fail.
3- Irreversible stage; Unless there is intervention, the process eventually enters an
irreversible stage when the resulting hemodynamic & biochemical abnormalities have
caused cellular and tissue injury so severe that even if these are corrected, survival is not
possible. Widespread cell injury is reflected in lysosomal enzyme leakage, further
aggravating the shock state. Myocardial contractile function worsens, in part because of
nitric acid synthesis. If ischemic bowel allows intestinal flora to enter the circulation,
endotoxic shock may also be superimposed. At this point, the patient has complete renal
shutdown due to ischemic acute tubular necrosis, and, despite intensive correcting
measures, the patient may die.
Pathologic features
• The cellular and tissue changes induced by shock are essentially those of hypoxic
injury, due to some combination of hypoperfusion and microvascular thrombosis.
• Ischemic and metabolic injuries that threaten life are those of the brain, heart, lungs
and kidney. However, changes are also frequent in the GIT, liver and adrenals.
• The brain: show changes collectively known as hypoxic encephalopathy.
• The heart: Foci of hemorrhage and necrosis are seen in the sub-epicardial and sub-
endocardial regions of the myocardium.
• The lungs: the changes are referred to as shock lung or adult respiratory distress
syndrome (ARDS). These changes are in essence those of pulmonary edema and fibrin
deposition on the alveolar walls.
• The kidneys: the tubules are affected principally and the changes are referred to as
acute tubular necrosis.
17