KEY POINTS

Edema
Edema is the result of the movement of fluid from the vasculature into
the interstitial spaces; the fluid may be protein-poor (transudate) or
protein-rich (exudate).
Edema may be caused by:
Increased hydrostatic pressure (e.g., heart failure)
Decreased colloid osmotic pressure caused by reduced
plasma albumin, either due to decreased synthesis (e.g., liver
disease, protein malnutrition) or to increased loss (e.g.,
nephrotic syndrome)
Increased vascular permeability (e.g., inflammation), which is
usually localized but may occur throughout the body in severe
systemic inflammatory states such as sepsis
Lymphatic obstruction (e.g., infection or neoplasia)
Sodium and water retention (e.g., renal failure)

Thrombosis
Thrombus development usually is related to one or more
components of the Virchow triad:
Endothelial injury (e.g., by toxins, hypertension, inflam-
mation, or metabolic products) associated with endo- thelial
activation and changes in endothelial gene expression that
favor coagulation
Abnormal blood flowstasis or turbulence (e.g., due to
aneurysms, atherosclerotic plaque)
Hypercoagulability, either primary (e.g., factor V Leiden,
increased prothrombin synthesis, antithrombin III defi- ciency)
or secondary (e.g., bed rest, tissue damage, malignancy, or
development of antiphospholipid anti- bodies [antiphospholipid
antibody syndrome]) or anti- bodies against platelet factor
IV/heparin complexes [heparin-induced thrombocytopenia])
Thrombi may propagate, resolve, become organized, or
embolize.
Thrombosis causes tissue injury by local vascular occlu- sion or
by distal embolization.

Embolism
An embolus is a solid, liquid, or gaseous mass carried by the
blood to a site distant from its origin; most are dis- lodged
thrombi.
Pulmonary emboli derive primarily from lower extremity deep
vein thrombi; their effects depend mainly on the size of the
embolus and the location in which it lodges. Consequences
may include right-sided heart failure, pul- monary hemorrhage,
pulmonary infarction, or sudden death.
Systemic emboli derive primarily from cardiac mural or
valvular thrombi, aortic aneurysms, or atherosclerotic plaques;
whether an embolus causes tissue infarction depends on the
site of embolization and the presence or absence of collateral
circulation.

Infarction
Infarcts are areas of ischemic necrosis most commonly caused
by arterial occlusion (typically due to thrombosis or
 embolization); venous outflow obstruction is a less fre- quent
cause.
Infarcts caused by venous occlusion or occurring in spongy
tissues with dual blood supply and where blood can collect
typically are hemorrhagic (red); those caused by arterial
occlusion in compact tissues typically are pale (white).
Whether or not vascular occlusion causes tissue infarction is
influenced by collateral blood supplies, the rate at which an
obstruction develops, intrinsic tissue susceptibility to ischemic
injury, and blood oxygenation.

Shock
Shock is defined as a state of systemic tissue hypoperfu- sion
due to reduced cardiac output and/or reduced effec- tive
circulating blood volume.
The major types of shock are cardiogenic (e.g., myocardial
infarction), hypovolemic (e.g., blood loss), and shock asso-
ciated with systemic inflammatory responses (e.g., in the
setting of severe infections); acute spinal or brain injuries and
severe hypersensitivity reactions can also cause neu- rogenic
and anaphylactic shock, respectively
Shock of any form can lead to hypoxic tissue injury if not
corrected.
Septic shock is caused by the host response to bacterial, viral
or fungal infections; it is a systemic inflammatory condition
characterized by endothelial cell activation, tissue edema,
disseminated intravascular coagulation, and metabolic
derangements that often lead to organ failure and death.

MORPHOLOGY

Edema is easily recognized grossly; microscopically, it is appre- ciated

as clearing and separation of the extracellular matrix and subtle cell
swelling. Any organ or tissue can be involved, but edema is most
commonly seen in subcutaneous tissues, the lungs, and the brain.
Subcutaneous edema can be diffuse or more conspicuous in regions
with high hydrostatic pressures. Its distribution is often influenced by
gravity (e.g., it appears in the legs when standing and the sacrum
when recumbent), a feature termed dependent edema. Finger
pressure over mark- edly edematous subcutaneous tissue displaces
the interstitial fluid and leaves a depression, a sign called pitting
edema.
Edema resulting from renal dysfunction often appears ini- tially in
parts of the body containing loose connective tissue, such as the
eyelids; periorbital edema is thus a characteristic finding in severe
renal disease. With pulmonary edema, the lungs are often two to
three times their normal weight, and sectioning yields frothy, blood-
tinged fluida mixture of air, edema, and extravasated red cells.
Brain edema can be local- ized or generalized depending on the
nature and extent of the pathologic process or injury. The swollen brain
exhibits nar- rowed sulci and distended gyri, which are compressed by
the unyielding skull (Chapter 28).
Effusions involving the pleural cavity (hydrothorax), the peri- cardial
cavity (hydropericardium), or the peritoneal cavity
(hydroperitoneum or ascites) are common in a wide range of clinical
settings. Transudative effusions are typically protein- poor, translucent
and straw colored; an exception are perito- neal effusions caused by
lymphatic blockage (chylous effusion), which may be milky due to the
presence of lipids absorbed from the gut. In contrast, exudative
effusions are protein-rich and often cloudy due to the presence of white
cells.

Congested tissues take on a dusky reddish-blue color (cyanosis) due to

red cell stasis and the presence of deoxygenated hemo- globin.
Microscopically, acute pulmonary congestion exhibits engorged
alveolar capillaries, alveolar septal edema, and focal intraalveolar
hemorrhage. In chronic pulmonary congestion, which is often
caused by congestive heart failure, the septa are thickened and
fibrotic, and the alveoli often contain numerous hemosiderin-laden
macrophages called heart failure cells. In acute hepatic
congestion, the central vein and sinusoids are distended. Because the
centrilobular area is at the distal end of the hepatic blood supply,
centrilobular hepatocytes may undergo ischemic necrosis while the
periportal hepatocytesbetter oxy- genated because of proximity to
hepatic arteriolesmay only develop fatty change. In chronic passive
hepatic congestion, the centrilobular regions are grossly red-brown
and slightly depressed (because of cell death) and are accentuated
against the surrounding zones of uncongested tan liver (nutmeg
liver) (Fig. 4-3A). Microscopically, there is centrilobular hemorrhage,
hemosiderin-laden macrophages, and variable degrees of hepa- tocyte
dropout and necrosis (Fig. 4-3B).

Thrombi can develop anywhere in the cardiovascular system and vary

in size and shape depending on the involved site and the underlying
cause. Arterial or cardiac thrombi usually begin at sites of turbulence
or endothelial injury, whereas venous thrombi characteristically occur
at sites of stasis. Thrombi are focally attached to the underlying
vascular surface, particularly at the point of initiation. From here,
arterial thrombi tend to grow retrograde, while venous thrombi extend
in the direction of blood flow; thus both propagate toward the heart.
The propa- gating portion of a thrombus is often poorly attached and
there- fore prone to fragmentation and embolization.
Thrombi often have grossly and microscopically apparent laminations
called lines of Zahn, which are pale platelet and fibrin deposits
alternating with darker red cellrich layers. Such laminations signify
that a thrombus has formed in flowing blood; their presence can
therefore distinguish antemortem clots from the bland nonlaminated
clots that occur postmortem (see later).
Thrombi occurring in heart chambers or in the aortic lumen are
designated mural thrombi. Abnormal myocardial contrac- tion
(arrhythmias, dilated cardiomyopathy, or myocardial infarc- tion) or
endomyocardial injury (myocarditis or catheter trauma) promotes
cardiac mural thrombi (Fig. 4-13A), while ulcerated atherosclerotic
plaque and aneurysmal dilation are the precur- sors of aortic thrombi
(Fig. 4-13B).
Arterial thrombi are frequently occlusive; the most common sites in
decreasing order of frequency are the coro- nary, cerebral, and femoral
arteries. They typically consist of a friable meshwork of platelets, fibrin,
red cells, and degenerating leukocytes. Although these are usually
superimposed on a rup- tured atherosclerotic plaque, other vascular
injuries (vasculitis, trauma) may be the underlying cause.
Venous thrombosis (phlebothrombosis) is almost invari- ably
occlusive, with the thrombus forming a long luminal cast. Because
these thrombi form in the sluggish venous circulation, they tend to
contain more enmeshed red cells (and relatively few platelets) and are
therefore known as red, or stasis, thrombi. Venous thrombi are firm,
are focally attached to the vessel wall, and contain lines of Zahn,
features that help distin- guish them from postmortem clots (see later).
The veins of the lower extremities are most commonly involved (90%
of cases); however, upper extremities, periprostatic plexus, or the
ovarian and periuterine veins can also develop venous thrombi. Under
special circumstances, they can also occur in the dural sinuses, portal
vein, or hepatic vein.
Postmortem clots can sometimes be mistaken for ante- mortem
venous thrombi. However, clots that form after death are gelatinous
and have a dark red dependent portion where red cells have settled by
gravity and a yellow chicken fat upper portion, and are usually not
attached to the underly- ing vessel wall.
Thrombi on heart valves are called vegetations. Bloodborne bacteria
or fungi can adhere to previously damaged valves (e.g., due to
rheumatic heart disease) or can directly cause valve damage; in either
case, endothelial injury and disturbed blood flow can induce the
formation of large thrombotic masses (infective endocarditis;
Chapter 12). Sterile vegetations can also develop on noninfected
valves in persons with hypercoagulable states, so-called nonbacterial
thrombotic endocarditis (Chapter 12). Less commonly, sterile
verrucous endocarditis (Libman-Sacks endocarditis) can occur in
the setting of systemic lupus erythematosus (Chapter 6).

Infarcts are classified according to color and the presence or absence

of infection; they are either red (hemorrhagic) or white (anemic) and
may be septic or bland.
Red infarcts (Fig. 4-18A) occur (1) with venous occlusions
(e.g., testicular torsion, Chapter 19), (2) in loose, spongy tissues (e.g.,
lung) where blood can collect in the infarcted zone, (3) in tissues with
dual circulations (e.g., lung and small intestine) that allow blood to flow
from an unobstructed parallel supply into a necrotic zone, (4) in tissues
previously congested by sluggish venous outflow, and (5) when flow is
reestablished to a site of previous arterial occlusion and necrosis (e.g.,
following angioplasty of an arterial obstruction).
White infarcts (Fig. 4-18B) occur with arterial occlusions in solid
organs with end-arterial circulation (e.g., heart, spleen, and kidney),
and where tissue density limits the seepage of blood from adjoining
capillary beds into the necrotic area.
Infarcts tend to be wedge-shaped, with the occluded vessel at the apex
and the periphery of the organ forming the base (Fig. 4-18); when the
base is a serosal surface there may be an overlying fibrinous exudate
resulting from an acute inflammatory response to mediators release
from injured and necrotic cells. Fresh infarcts are poorly defined and
slightly hemorrhagic, but over a few days the margins tend to become
better defined by a narrow rim of congestion attributable to
inflammation. With further passage of time, infarcts resulting from
arterial occlu- sions in organs without a dual blood supply typically
become progressively paler and more sharply defined (Fig. 4-18B). In
comparison, in the lung hemorrhagic infarcts are the rule (Fig. 4-18A).
Extravasated red cells in hemorrhagic infarcts are phagocytosed by
macrophages, which convert heme iron into hemosiderin; small
amounts do not grossly impart any appre- ciable color to the tissue,
but extensive hemorrhage can leave a firm, brown hemosiderin-rich
residuum.
The dominant histologic characteristic of infarction is isch- emic
coagulative necrosis (Chapter 2). Importantly, if the vascular
occlusion has occurred shortly (minutes to hours) before the death of
the person, histologic changes may be absent; it takes 4 to 12 hours
for the dead tissue to show microscopic evidence of frank necrosis.
Acute inflammation is present along the margins of infarcts within a
few hours and is usually well defined within 1 to 2 days. Eventually a
reparative response begins in the preserved margins (Chapter 3). In
stable or labile tissues, parenchymal regeneration can occur at the
periphery where underlying stromal architecture is preserved.
However, most infarcts are ultimately replaced by scar (Fig. 4-19). The
brain is an exception to these generalizations, in that central nervous
system infarction results in liquefactive necro- sis (Chapter 2).
Septic infarctions occur when infected cardiac valve veg- etations
embolize or when microbes seed necrotic tissue. In these cases the
infarct is converted into an abscess, with a correspondingly greater
inflammatory response (Chapter 3). The eventual sequence of
organization, however, follows the pattern already described.

The cellular and tissue changes induced by cardiogenic or hypovolemic

shock are essentially those of hypoxic injury (Chapter 2); changes can
manifest in any tissue although they are particularly evident in brain,
heart, lungs, kidneys, adrenals, and gastrointestinal tract. The adrenal
changes in shock are those seen in all forms of stress; essentially there
is cortical cell lipid depletion. This does not reflect adrenal exhaustion
but rather conversion of the relatively inactive vacuolated cells to
metabolically active cells that utilize stored lipids for the synthe- sis of
steroids. The kidneys typically exhibit acute tubular necrosis (Chapter
20). The lungs are seldom affected in pure hypovolemic shock,
because they are somewhat resistant to hypoxic injury. However, when
shock is caused by sepsis or trauma, diffuse alveolar damage
(Chapter 15) may develop, the so-called shock lung. In septic shock,
the development of disseminated intravascular coagulation leads to
widespread deposition of fibrin-rich microthrombi, particularly in the
brain, heart, lungs, kidney, adrenal glands, and gastrointestinal tract.
The consumption of platelets and coagulation factors also often leads
to the appearance of petechial hemorrhages on serosal surface and the
skin.
With the exception of neuronal and myocyte ischemic loss, virtually all
of these tissues may revert to normal if the individual survives.
Unfortunately, most patients with irreversible changes due to severe
shock die before the tissues can recover