Hemodynamic Disorders

Dr. Ellen Joy F. Duran

Anatomic & Clinical Pathologist
Outline:
Overview
Edema
Hyperemia & congestion
Hemorrhage
Hemostasis & thrombosis
Embolism
Infarction
Shock
Overview
The health of cells & organs critically depends on an
unbroken circulation to deliver oxygen & nutrients & to
remove wastes.
The well-being of tissues also requires normal fluid
balance; abnormalities in vascular permeability or
hemostasis can result in injury even in the setting of an
intact blood supply.
Normal fluid homeostasis encompasses maintenance of
vessel wall integrity as well as intravascular pressure &
osmolarity within certain physiologic ranges.
Changes in vascular volume, pressure, or protein content,
or alterations in endothelial function, all affect the net
movement of water across the vascular wall. Such water
extravasation into the interstitial spaces is called edema &
has different manifestations depending on its location.
 Normal fluid homeostasis also means
maintaining blood as a liquid until such time as
injury necessitates clot formation.

Clotting at inappropriate sites (thrombosis) or

migration of clots (embolism) obstructs blood
flow to tissues & leads to cell death (infarction).

Conversely, inability to clot after vascular injury

results in hemorrhage; local bleeding can
compromise regional tissue perfusion, while
more extensive hemorrhage can result in
hypotension (shock) and death.
 Some of the failures of fluid homeostasis reflect a
primary pathology in a discrete vascular bed (e.g.,
hemorrhage due to local trauma) or in systemic
coagulation (thrombosis due to hypercoagulability
disorders); others may represent a secondary
manifestation of some other disease process.

Overall, disturbances in normal blood flow are major

sources of human morbidity and mortality.

Thrombosis, embolism, & infarction underlie 3 of the

most important causes of pathology in Western
society myocardial infarction, pulmonary embolism,
& cerebrovascular accident (stroke).
Edema
60% of lean body weight is water
2/3 is intracellular
remainder - extracellular space, mostly as interstitial
fluid
5% of total body water is in blood plasma

Edema signifies increased fluid in the interstitial tissue

spaces.
Depending on the site:
hydrothorax, hydropericardium, & hydroperitoneum
(ascites)
Anasarca is a severe & generalized edema with
profound subcutaneous tissue swelling.
Figure 4-1 Factors affecting fluid balance across capillary walls. Capillary hydrostatic and osmotic
forces are normally balanced so that there is no net loss or gain of fluid across the capillary bed.
However, increased hydrostatic pressure or diminished plasma osmotic pressure leads to a net
accumulation of extravascular fluid (edema). As the interstitial fluid pressure increases, tissue
lymphatics remove much of the excess volume, eventually returning it to the circulation via the
thoracic duct. If the ability of the lymphatics to drain tissue is exceeded, persistent tissue edema
results.
Physiologic Causes of Edema
Increased hydrostatic pressure
Reduced plasma oncotic pressure
(hypoproteinemia)
Lymphatic obstruction
Sodium retention
Inflammation
Table 4-1 -- Pathophysiologic
Categories of Edema
Increased Hydrostatic Pressure
Impaired venous return
Congestive heart failure
Constrictive pericarditis
Ascites (liver cirrhosis)
Venous obstruction or compression
Thrombosis
External pressure (e.g., mass)
Lower extremity inactivity with prolonged dependency
Arteriolar dilation
Heat
Neurohumoral dysregulation
Reduced Plasma Osmotic Pressure
(Hypoproteinemia)
Protein-losing glomerulopathies (nephrotic syndrome)
Liver cirrhosis (ascites)
Malnutrition
Protein-losing gastroenteropathy
Lymphatic Obstruction
Inflammatory
Neoplastic
Postsurgical
Postirradiation
Sodium Retention
Excessive salt intake with renal insufficiency
Increased tubular reabsorption of sodium
Renal hypoperfusion
Increased renin-angiotensin-aldosterone
secretion
Inflammation
Acute inflammation
Chronic inflammation
Angiogenesis
Figure 4-2 Sequence of events leading to systemic edema due to primary heart failure, primary
renal failure, or reduced plasma osmotic pressure (as in malnutrition, diminished hepatic protein
synthesis, or loss of protein owing to the nephrotic syndrome). ADH, antidiuretic hormone; GFR,
glomerular filtration rate.
Morphology
Edema is most easily recognized grossly
Microscopic - edema fluid generally manifests only as
subtle cell swelling, with clearing & separation of the
extracellular matrix elements.
Any organ or tissue in the body may be involved, most
commonly encountered in subcutaneous tissues, lungs,
& brain.
Anasarca - severe, generalized edema
 Subcutaneous edema may have different distributions
depending on the cause.
Diffuse
Dependent - more conspicuous at the sites of highest
hydrostatic pressures. The edema distribution is typically
influenced by gravity

Edema of the dependent parts of the body (e.g., the legs

when standing, the sacrum when recumbent) is a prominent
feature of congestive heart failure, particularly of the
right ventricle.
 Edema as a result of renal dysfunction or nephrotic
syndrome -more severe & affects all parts of the body
equally.
Initially manifest itself as periorbital edema - a
characteristic finding in severe renal disease.
Pitting edema - finger pressure over substantially
edematous subcutaneous tissue displaces the interstitial
fluid and leaves a finger-shaped depression
 Pulmonary edema is a common clinical problem most
typically seen in the setting of left ventricular failure but
also occurring in renal failure, acute respiratory distress
syndrome, pulmonary infections, & hypersensitivity
reactions.
Lungs 2-3x their normal weight, & sectioning reveals
frothy, blood-tinged fluid representing a mixture of air,
edema fluid, & extravasated red blood cells
 Edema of the brain may be localized (e.g., owing to
abscess or neoplasm) or may be generalized, as in
encephalitis, hypertensive crises, or obstruction to the
brain's venous outflow.
Trauma may result in local or generalized edema
depending on the nature & extent of the injury. With
generalized edema, the brain is grossly swollen, with
narrowed sulci & distended gyri, showing signs of
flattening against the unyielding skull
Clinical Correlation
Effects of edema may range from merely annoying to fatal.
Subcutaneous tissue edema in cardiac or renal failure is
important primarily because it signals 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 ventilatory function. Not only does fluid collect in the
alveolar septa around capillaries & impede oxygen diffusion,
but edema fluid in the alveolar spaces also creates a
favorable environment for bacterial infection.
Brain edema is serious and can be rapidly fatal; if severe,
brain substance can herniate (extrude) through, for
example, the foramen magnum, or the brain stem vascular
supply can be compressed. Either condition can injure the
medullary centers & cause death
Hyperemia and Congestion
Both indicate a local increased volume of blood in a
particular tissue.
Hyperemia - an active process resulting from augmented
tissue inflow because of arteriolar dilation
as in skeletal muscle during exercise or at sites of
inflammation
affected tissue - redder because of the engorgement of
vessels with oxygenated blood
Congestion - a passive process resulting from impaired
outflow from a tissue
may occur systemically, as in cardiac failure
may be local - resulting from an isolated venous obstruction
blue-red color (cyanosis) - particularly as worsening
congestion leads to accumulation of deoxygenated hemoglobin
in the affected tissues
Figure 4-3 Hyperemia
versus congestion. In
both cases there is an
increased volume and
pressure of blood in a
given tissue with
associated capillary
dilation and a potential
for fluid extravasation.
In hyperemia, increased
inflow leads to
engorgement with
oxygenated blood,
resulting in erythema. In
congestion, diminished
outflow leads to a
capillary bed swollen
with deoxygenated
venous blood and
resulting in cyanosis.
 Congestion & edema commonly occur together,
primarily since capillary bed congestion can result in
edema due to increased fluid transudation.
In long-standing congestion, called chronic passive
congestion, the stasis of poorly oxygenated blood also
causes chronic hypoxia, which can result in
parenchymal cell degeneration or death, sometimes
with microscopic scarring. Capillary rupture at these
sites of chronic congestion may also cause small foci
of hemorrhage; breakdown& phagocytosis of the red
cell debris can eventually result in small clusters of
hemosiderin-laden macrophages.
Morphology
Gross: hyperemic or congested tissues have hemorrhagic & wet
cut surfaces

Microscopic:
acute pulmonary congestion - alveolar capillaries
engorged with blood; there may be associated alveolar
septal edema &/or focal intraalveolar hemorrhage
chronic pulmonary congestion - the septa are thickened
& fibrotic, & the alveolar spaces may contain numerous
hemosiderin-laden macrophages (heart failure cells)
acute hepatic congestion - the central vein & sinusoids
are distended with blood, central hepatocyte degeneration;
the periportal hepatocytes, better oxygenated because of
their proximity to hepatic arterioles, experience less severe
hypoxia & may only develop fatty change
 chronic passive congestion of the liver
Gross: central regions of the hepatic lobules are red-brown &
slightly depressed (owing to a loss of cells) & are
accentuated against the surrounding zones of uncongested
tan liver (nutmeg liver)

Microscopic: evidence of centrilobular necrosis with loss of

hepatocytes dropout and hemorrhage, including
hemosiderin-laden macrophages
Severe, long-standing hepatic congestion (most commonly
associated with heart failure) - grossly evident hepatic fibrosis
(cardiac cirrhosis)
centrilobular necrosis - because the central portion of the
hepatic lobule is the last to receive blood; can also occur
whenever there is reduced hepatic blood flow (including shock
from any cause)
Figure 4-4 Liver with chronic passive congestion and hemorrhagic necrosis. A, Central areas are red
and slightly depressed compared with the surrounding tan viable parenchyma, forming the so-called
"nutmeg liver" pattern. B, Centrilobular necrosis with degenerating hepatocytes, hemorrhage, and
sparse acute inflammation.
Hemorrhage
Generally indicates extravasation of blood due to vessel
rupture.
Capillary bleeding can occur under conditions of chronic
congestion, & an increased tendency to hemorrhage
from usually insignificant injury is seen in a wide variety
of clinical disorders collectively called hemorrhagic
diatheses.
Rupture of a large artery or vein is almost always due to
vascular injury, including trauma, atherosclerosis, or
inflammatory or neoplastic erosion of the vessel wall.
May be manifested in a variety of patterns, depending on
the size, extent, & location of bleeding.
Morphology
Hemorrhage may be external or enclosed
Hematoma - accumulation of blood within tissue
may be relatively insignificant (a bruise)
may be sufficiently large as to be fatal (e.g., a massive
retroperitoneal hematoma resulting from rupture of a dissecting
aortic aneurysm
Petechiae - Minute 1- to 2-mm hemorrhages into skin, mucous
membranes, or serosal surfaces; typically associated with
locally increased intravascular pressure, low platelet counts
(thrombocytopenia), defective platelet function (as in uremia),
or clotting factor deficits.
Purpura - Slightly larger (3 mm) hemorrhages; may be
associated with many of the same disorders that cause
petechiae and may also occur secondary to trauma, vascular
inflammation (vasculitis), or increased vascular fragility (e.g.,
in amyloidosis)
 Ecchymoses - Larger (>1 to 2 cm) subcutaneous hematomas
(i.e., bruises); characteristically seen after trauma but may be
exacerbated by any of the aforementioned conditions.
The erythrocytes in these local hemorrhages are degraded and
phagocytosed by macrophages; the hemoglobin (red-blue
color) is then enzymatically converted into bilirubin (blue-green
color) & eventually into hemosiderin (gold-brown color),
accounting for the characteristic color changes in a hematoma.
Large accumulations of blood in one or another of the body
cavities:
Hemothorax
Hemopericardium
Hemoperitoneum
Hemarthrosis (in joints)

Patients with extensive hemorrhage occasionally develop

jaundice from the massive breakdown of red cells and systemic
release of bilirubin
Figure 4-5 A, Punctate petechial hemorrhages of the colonic mucosa, seen here as a consequence
of thrombocytopenia. B, Fatal intracerebral bleed. Even relatively inconsequential volumes of
hemorrhage in a critical location, or into a closed space (such as the cranium), can have fatal
outcomes.
Clinical significance of hemorrhage
Depends on the volume and rate of bleeding
Rapid loss of up to 20% of the blood volume or slow losses of
even larger amounts may have little impact in healthy adults
Greater losses - may result in hemorrhagic (hypovolemic)
shock
Site of hemorrhage is also important
bleeding that would be trivial in the subcutaneous tissues may
cause death if located in the brain because the skull is
unyielding & bleeding there can result in increased intracranial
pressure & herniation
.
Loss of iron and subsequent iron-deficiency anemia become
a consideration in chronic or recurrent external blood loss
(e.g., peptic ulcer or menstrual bleeding). In contrast, when
red cells are retained, as in hemorrhage into body cavities
or tissues, the iron can be reused for hemoglobin synthesis
Hemostasis & Thrombosis
Normal hemostasis - result of a set of well-regulated
processes that accomplish 2 important functions:
(1) They maintain blood in a fluid, clot-free state in
normal vessels
(2) They are poised to induce a rapid and localized
hemostatic plug at a site of vascular injury.

Thrombosis - the pathologic opposite to hemostasis; it

can be considered an inappropriate activation of
normal hemostatic processes, such as the formation
of a blood clot (thrombus) in uninjured vasculature or
thrombotic occlusion of a vessel after relatively minor
injury.
 Both hemostasis and thrombosis are
regulated by 3 general components
Vascular wall (endothelium)
Platelets
Coagulation cascade
 Normal Hemostasis

After initial injury, there is a

brief period of arteriolar
vasoconstriction, largely
attributable to reflex
neurogenic mechanisms &
augmented by the local
secretion of factors such as
endothelin (a potent
endothelium-derived
vasoconstrictor). The effect is
transient, however, &
bleeding would resume if not
for activation of the platelet
and coagulation systems
Endothelial injury exposes
highly thrombogenic
subendothelial extracellular
matrix (ECM), which allows
platelets to adhere & become
activated, that is, undergo a
shape change & release
secretory granules. Within
minutes, the secreted
products have recruited
additional platelets
(aggregation) to form a
hemostatic plug; this is the
process of primary
hemostasis
Tissue factor, a membrane-
bound procoagulant factor
synthesized by endothelium, is
also exposed at the site of injury.
It acts in conjunction with the
secreted platelet factors to
activate the coagulation cascade,
culminating in the activation of
thrombin. In turn, thrombin
converts circulating soluble
fibrinogen to insoluble fibrin,
resulting in local fibrin
deposition. Thrombin also
induces further platelet
recruitment & granule release.
This sequence, secondary
hemostasis, takes longer than
the initial platelet plug
Polymerized fibrin &
platelet aggregates form a
solid, permanent plug to
prevent any further
hemorrhage. At this stage,
counterregulatory
mechanisms (e.g., tissue
plasminogen activator {t-
PA}) are set into motion to
limit the hemostatic plug to
the site of injury
1. Endothelium
Endothelial cells modulate severaland frequently
opposingaspects of normal hemostasis.
On the one hand, the normal flow of liquid blood is
maintained by endothelial antiplatelet, anticoagulant,
& fibrinolytic properties.
On the other hand, after injury or activation,
endothelium exhibits several procoagulant activities
Endothelium may be activated by infectious agents,
hemodynamic factors, plasma mediators, & most
significantly, cytokines.
The balance between endothelial antithrombotic and
prothrombotic activities critically determines whether
thrombus formation, propagation, or dissolution
occurs.
Antithrombotic Properties
Antiplatelet effects. An intact endothelium prevents
platelets & plasma coagulation factors from meeting
the highly thrombogenic subendothelial ECM.
Nonactivated platelets do not adhere to the
endothelium, a property intrinsic to endothelial plasma
membrane. Even if platelets are activated after focal
endothelial injury, they are inhibited from adhering to
the surrounding uninjured endothelium by endothelial
prostacyclin (PGI2) & nitric oxide. Both mediators are
potent vasodilators & inhibitors of platelet
aggregation; their synthesis by endothelial cells is
stimulated by a number of factors (e.g., thrombin and
various cytokines) produced during coagulation.
Endothelial cells also express adenosine
diphosphatase, which degrades ADP & thereby
contributes to the inhibition of platelet aggregation.
 Anticoagulant effects. Mediated by membrane-
associated heparin-like molecules & by
thrombomodulin, a specific thrombin receptor. The
heparin-like molecules act indirectly; they are
cofactors that interact with antithrombin III to
inactivate thrombin, factor Xa, & several other
coagulation factors. Thrombomodulin also acts
indirectly; it binds to thrombin, converting it from a
procoagulant to an anticoagulant capable of activating
protein C. Activated protein C, in turn, inhibits clotting
by proteolytic cleavage of factors Va and VIIIa; it
requires protein S, synthesized by endothelial cells, as
a cofactor. Endothelium is also a major synthetic
source for tissue factor pathway inhibitor, a cell-
surface protein that complexes and inhibits activated
tissue factor-factor VIIa and factor Xa molecules.
 Fibrinolytic effects. Endothelial cells
synthesize tissue-type plasminogen
activator (t-PA), promoting
fibrinolytic activity to clear fibrin
deposits from endothelial surfaces.
Prothrombotic Properties
While endothelium normally limits blood
clotting, it can also become prothrombotic, with
activities that affect platelets, coagulation
proteins, and the fibrinolytic system.

Platelet effects. Endothelial injury leads to

adhesion of platelets to the underlying
extracellular matrix; this is facilitated by
endothelial production of von Willebrand factor
(vWF), an essential cofactor for platelet binding
to collagen & other surfaces. It should be noted
that vWF is a product of normal endothelium; it
is not specifically synthesized after endothelial
injury.
 Procoagulant effects. Endothelial cells are
also induced by bacterial endotoxin or by
cytokines (e.g., tumor necrosis factor [TNF] or
interleukin-1 [IL-1]) to synthesize tissue factor,
which activates the extrinsic clotting cascade.
By binding activated factors IXa and Xa,
endothelial cells further augment the catalytic
activities of these coagulation factors
Antifibrinolytic effects. Endothelial cells
also secrete inhibitors of plasminogen activator
(PAIs), which depress fibrinolysis
Figure 4-7 Schematic illustration of some of the pro- and anticoagulant activities of
endothelial cells.
2. Platelets
Play a central role in normal hemostasis.
When circulating, they are membrane-bound smooth discs
expressing a number of glycoprotein receptors of the
integrin family on their surfaces.
Contain 2 specific types of granules.
Alpha granules express the adhesion molecule P-selectin on
their membranes & contain fibrinogen, fibronectin, factors V &
VIII, platelet factor 4 (a heparin-binding chemokine), platelet-
derived growth factor, & transforming growth factor-.
Dense bodies, or granules, which contain adenine
nucleotides (ADP and adenosine triphosphate [ATP]), ionized
calcium, histamine, serotonin, & epinephrine.
After vascular injury, platelets encounter ECM constituents
that are normally sequestered beneath an intact
endothelium; these include collagen (most important),
proteoglycans, fibronectin, & other adhesive glycoproteins.
 On contact with ECM, platelets undergo
3 general reactions:
(1) adhesion & shape change
(2) secretion (release reaction)
(3) aggregation
 The series of platelet events can be summarized as
follows:

Platelets adhere to ECM at sites of endothelial injury

& become activated.
On activation, they secrete granule products (e.g.,
ADP) & synthesize TxA2.
Platelets also expose phospholipid complexes that
are important in the intrinsic coagulation pathway.
Injured or activated endothelial cells expose tissue
factor, which triggers the extrinsic coagulation
cascade.
Released ADP stimulates the formation of a primary
hemostatic plug, which is eventually converted (via
ADP, thrombin, & TxA2) into a larger, definitive,
secondary plug.
Fibrin deposition stabilizes & anchors the aggregated
platelets.
Figure 4-8 Platelet adhesion and aggregation. von Willebrand factor functions as an adhesion bridge
between subendothelial collagen and the GpIb platelet receptor complex (the functional complex is
composed of GpIb in association with factors V and IX). Aggregation involves linking platelets via
fibrinogen bridges bound to the platelet GpIIb-IIIa receptors.
3. Coagulation Cascade

Constitutes the 3rd component of the

hemostatic process & is a major contributor
to thrombosis
Essentially a series of enzymatic
conversions, turning inactive proenzymes
into activated enzymes & culminating in the
formation of thrombin. Thrombin then
converts the soluble plasma protein
fibrinogen precursor into the insoluble
fibrous protein fibrin.
Each reaction in the pathway results from the assembly of a complex
composed of an enzyme (activated coagulation factor), a substrate
(proenzyme form of coagulation factor), and a cofactor (reaction
accelerator). These components are typically assembled on a
phospholipid complex and held together by calcium ions. Thus, clotting
tends to remain localized to sites where such assembly can occur (e.g.,
on the surface of activated platelets or endothelium)
Figure 4-11 The central roles of thrombin in hemostasis and cellular activation. In addition to a critical
function in generating cross-linked fibrin (via cleavage of fibrinogen to fibrin and activation of factor XIII),
thrombin also directly induces platelet aggregation and secretion (e.g., of TxA2). Thrombin also activates
endothelium to generate leukocyte adhesion molecules and a variety of fibrinolytic (t-PA), vasoactive (NO,
PGI2), or cytokine (PDGF) mediators. Likewise, mononuclear inflammatory cells may be activated by the
direct actions of thrombin. ECM, extracellular matrix; NO, nitric oxide; PDGF, platelet-derived growth factor;
PGI2, prostacyclin; TxA2, thromboxane A2; t-PA, tissue type plasminogen activator.
 Besides restricting factor activation to sites of exposed
phospholipids, clotting is also regulated by3 types of natural
anticoagulants:
Antithrombins (e.g., antithrombin III) inhibit the activity of
thrombin & other serine proteasesfactors IXa, Xa, XIa,
and XIIa. Antithrombin III is activated by binding to
heparin-like molecules on endothelial cells; hence the
clinical usefulness of administering heparin to minimize
thrombosis.
Proteins C and S, two vitamin K-dependent proteins, are
characterized by their ability to inactivate factors Va &
VIIIa.
Tissue factor pathway inhibitor (TFPI), a protein secreted
by endothelium (and other cell types), complexes to factor
Xa & to tissue factor-VIIa & inactivates them to rapidly limit
coagulation
 Besides inducing coagulation, activation of the clotting cascade
also sets into motion a fibrinolytic cascade that limits the size
of the final clot.

This is primarily accomplished by the generation of

plasmin.
Plasmin is derived from enzymatic breakdown of its
inactive circulating precursor plasminogen, either by a
factor XII-dependent pathway or by 2 distinct types of
plasminogen activators (PAs):
Urokinase-like PA (u-PA) - present in plasma &
various tissues & capable of activating plasminogen in
the fluid phase. Plasmin, in turn, converts the inactive
pro-urokinase precursor to the active u-PA molecule,
thus creating an amplification loop.
Tissue-type PA (t-PA) - physiologically the most
important; synthesized principally by endothelial cells &
is most active when attached to fibrin. The affinity for
fibrin makes t-PA a much more useful therapeutic
reagent, because it targets the fibrinolytic enzymatic
activity to sites of recent clotting.
 Plasminogen can also be activated by the bacterial
product streptokinase, which may have some
significance in certain bacterial infections.
Plasmin breaks down fibrin & interferes with its
polymerization. The resulting fibrin split products (FSPs
or so-called fibrin degradation products) can also act as
weak anticoagulants.
Elevated levels of FSPs (the fibrin split product
characteristically measured by clinical laboratories is the
fibrin D-dimer) - helpful in diagnosing abnormal
thrombotic states, such as DIC, deep venous
thrombosis, or pulmonary thromboembolism.
Any free plasmin rapidly complexes to 2-plasmin
inhibitor & is inactivated.
Figure 4-12 The fibrinolytic system, illustrating the plasminogen activators
and inhibitors.
 Thrombosis
Pathogenesis
3 primary influences predispose to thrombus formation, the so-
called Virchow triad: (1) endothelial injury; (2) stasis or
turbulence of blood flow; and (3) blood hypercoagulability

Figure 4-13 Virchow triad in thrombosis. Endothelial integrity is the single most important factor. Note
that injury to endothelial cells can affect local blood flow and/or coagulability; abnormal blood flow (stasis
or turbulence) can, in turn, cause endothelial injury. The elements of the triad may act independently or
may combine to cause thrombus formation.
1. Endothelial Injury
The dominant influence; By itself can lead to
thrombosis
Thrombus formation within the cardiac chambers
(e.g., following endocardial injury due to myocardial
infarction), over ulcerated plaques in atherosclerotic
arteries, or at sites of traumatic or inflammatory
vascular injury (vasculitis) is largely due to
endothelial injury.
Physical loss of endothelium will lead to exposure of
subendothelial ECM, adhesion of platelets, release of
tissue factor, & local depletion of PGI2 & PAs.
Any perturbation in the dynamic balance of the pro-
and antithrombotic effects of endothelium can
influence local clotting events
 Dysfunctional endothelium may elaborate greater
amounts of procoagulant factors (e.g., platelet
adhesion molecules, tissue factor, PAI) or may
synthesize less anticoagulant effectors (e.g.,
thrombomodulin, PGI2, t-PA).
Significant endothelial dysfunction (in the absence of
endothelial cell loss) may occur due to the
hemodynamic stresses of hypertension, turbulent flow
over scarred valves, or bacterial endotoxins.
Even relatively subtle influences, such as
homocystinuria, hypercholesterolemia, radiation, or
products absorbed from cigarette smoke may initiate
endothelial injury.
2. Alterations in Normal Blood Flow

Turbulence contributes to arterial & cardiac

thrombosis by causing endothelial injury or
dysfunction as well as by forming
countercurrents & local pockets of stasis
Stasis is a major factor in the development
of venous thrombi
Normal blood flow is laminar such that the
platelets flow centrally in the vessel lumen,
separated from the endothelium by a
slower-moving clear zone of plasma.
 Stasis and turbulence therefore --
(1) disrupt laminar flow & bring platelets into
contact with the endothelium
(2) prevent dilution of activated clotting factors
by fresh flowing blood
(3) retard the inflow of clotting factor inhibitors
& permit the build-up of thrombi
(4) promote endothelial cell activation,
predisposing to local thrombosis, leukocyte
adhesion, & a variety of other endothelial
cell effects
Turbulence & stasis clearly contribute to
thrombosis in a number of clinical settings:
Ulcerated atherosclerotic plaques not only expose
subendothelial ECM, but are also sources of turbulence.
Aneurysms - Abnormal aortic & arterial dilations, cause
local stasis & are favored sites of thrombosis.
Myocardial infarctions not only have associated endothelial
injury, but also have regions of noncontractile myocardium,
adding an element of stasis in the formation of mural
thrombi.
Mitral valve stenosis (e.g., after rheumatic heart disease)
results in left atrial dilation. In conjunction with atrial
fibrillation, a dilated atrium is a site of profound stasis & a
prime location for thrombus development.
Hyperviscosity syndromes (such as polycythemia) cause
small vessel stasis; the deformed red cells in sickle cell
anemia cause vascular occlusions, with the resulting stasis
predisposing to thrombosis.
3. Hypercoagulability

Contributes less frequently to thrombotic

states but is nevertheless an important
component in the equation.
Any alteration of the coagulation pathways
that predisposes to thrombosis.
The causes of hypercoagulability may be
primary (genetic) & secondary (acquired)
disorders
Table 4-2 -- Hypercoagulable States

Primary (Genetic)
Common
Mutation in factor V gene (factor V Leiden)
Mutation in prothrombin gene
Mutation in methyltetrahydrofolate gene
Rare
Antithrombin III deficiency
Protein C deficiency
Protein S deficiency
Very rare
Fibrinolysis defects
Secondary (Acquired)
High risk for thrombosis
Prolonged bed rest or immobilization
Myocardial infarction
Atrial fibrillation
Tissue damage (surgery, fracture, burns)
Cancer
Prosthetic cardiac valves
Disseminated intravascular coagulation
Heparin-induced thrombocytopenia
Antiphospholipid antibody syndrome (lupus
anticoagulant syndrome)
 Lower risk for thrombosis
Cardiomyopathy
Nephrotic syndrome
Hyperestrogenic states (pregnancy)
Oral contraceptive use
Sickle cell anemia
Smoking
Heparin-induced thrombocytopenia syndrome
5% of the population
Occurs when administration of unfractionated heparin
(for purposes of therapeutic anticoagulation) induces
formation of antibodies that bind to molecular
complexes of heparin & platelet factor 4 membrane
protein
This antibody can also bind to similar complexes
present on platelet & endothelial surfaces; the result
is platelet activation, endothelial injury, & a
prothrombotic state.
To reduce this problem, specially manufactured low-
molecular-weight heparin preparationswhich retain
anticoagulant activity but do not interact with
plateletsare used.
Antiphospholipid antibody syndrome
(APAS)
Has protean clinical presentations, including multiple
thromboses
Associated with high titers of circulating antibodies
directed against anionic phospholipids (e.g.,
cardiolipin) or, against plasma protein epitopes that
are unveiled by binding to such phospholipids (e.g.,
prothrombin).
Patients with anticardiolipin antibodies also have a
false-positive serologic test for syphilis because the
antigen in the standard tests is embedded in
cardiolipin. In vitro these antibodies interfere with the
assembly of phospholipid complexes & thus inhibit
coagulation. However, in vivo, the antibodies induce a
hypercoagulable state.
 Patients with antiphospholipid antibody syndrome fall
into 2 categories:

Many have a well-defined autoimmune disease, such

as systemic lupus erythematosus & have secondary
antiphospholipid syndrome (lupus anticoagulant
syndrome).
Primary antiphospholipid syndrome - no evidence of
other autoimmune disorder & exhibit only the
manifestations of a hypercoagulable state.
Occasionally the syndrome can occur in association
with certain drugs or infections.
How antiphospholipid antibodies lead to
hypercoagulability is not clear, but possible
explanations include - direct platelet activation,
inhibition of PGI2 production by endothelial cells, or
interference with protein C synthesis or activity
Have also been identified in 5% - 15% of apparently
normal individuals
Clinical manifestations:

recurrent venous or arterial thrombi

repeated miscarriages
cardiac valvular vegetations
thrombocytopenia

Venous thromboses occur most commonly in deep leg veins,

but renal, hepatic, & retinal veins are also susceptible.
Arterial thromboses typically occur in the cerebral
circulation, but coronary, mesenteric, & renal arterial
occlusions have also been described.
Depending on the vascular bed involved, the clinical
presentations can vary from pulmonary embolism (due to a
lower extremity venous thrombus), to pulmonary
hypertension (from recurrent subclinical pulmonary emboli),
to stroke, bowel infarction, or renovascular hypertension.
 Fetal loss - attributable to antibody-mediated
inhibition of t-PA (tissue-type plasminogen
activator) activity necessary for trophoblastic
invasion of the uterus
Also a cause of renal microangiopathy,
resulting in renal failure owing to multiple
capillary & arterial thromboses.
Current treatment: anticoagulation therapy
(aspirin, heparin, & warfarin) &
immunosuppression in refractory cases
Morphology
Thrombi may develop anywhere in the cardiovascular
system: within the cardiac chambers; on valve cusps;
or in arteries, veins, or capillaries.
Variable size & shape, depending on the site of origin
& the circumstances leading to their development.
Arterial or cardiac thrombi usually begin at a site of
endothelial injury (e.g., atherosclerotic plaque) or
turbulence (vessel bifurcation); venous thrombi
characteristically occur in sites of stasis.
Arterial thrombi tend to grow in a retrograde direction
from the point of attachment, whereas venous
thrombi extend in the direction of blood flow (i.e.,
toward the heart).
The propagating tail may not be well attached and,
particularly in veins, is prone to fragmentation,
creating an embolus.
 When formed in the heart or aorta, thrombi may have
grossly (& microscopically) apparent laminations,
called lines of Zahn ---produced by alternating pale
layers of platelets admixed with some fibrin & darker
layers containing more red cells. Lines of Zahn are
significant only in that they imply thrombosis at a site
of blood flow.
When arterial thrombi arise in heart chambers or in
the aortic lumen, they usually adhere to the wall of
the underlying structure & are termed mural
thrombi.
Abnormal myocardial contraction (arrhythmias,
dilated cardiomyopathy, or myocardial infarction) -
leads to cardiac mural thrombi
Ulcerated atherosclerotic plaque & aneurysmal dilation
- precursors of aortic thrombus formation
 Arterial thrombi are usually occlusive
Most common sites: (in descending order)
coronary, cerebral, & femoral arteries
The thrombus is usually superimposed on
an atherosclerotic plaque, although other
forms of vascular injury (vasculitis, trauma)
may be involved.
Thrombi - typically firmly adherent to the
injured arterial wall; gray-white & friable,
composed of a tangled mesh of platelets,
fibrin, erythrocytes, & degenerating
leukocytes
 Venous thrombosis, or phlebothrombosis -
almost invariably occlusive; the thrombus often
creates a long cast of the vein lumen.
Because these thrombi form in a relatively static
environment, they tend to contain more enmeshed
erythrocytes & are therefore known as red, or stasis,
thrombi.
Most commonly affects the veins of the lower
extremities (90% of cases).
Less commonly, venous thrombi may develop in the
upper extremities, periprostatic plexus, or the ovarian
& periuterine veins; under special circumstances, they
may be found in the dural sinuses, the portal vein, or
the hepatic vein.
 At autopsy, postmortem clots may be
confused for venous thrombi. Postmortem
clots - gelatinous with a dark red
dependent portion where red cells have
settled by gravity & a yellow chicken fat
supernatant resembling melted & clotted
chicken fat; they are usually not attached
to the underlying wall.
Red thrombi - firmer, almost always have a
point of attachment, & on transection
reveal vague strands of pale gray fibrin
 Under special circumstances, thrombi may form on
heart valves.
Bacterial or fungal blood-borne infections may
establish a foothold, leading to valve damage and the
development of large thrombotic masses, or
vegetations (infective endocarditis)
Sterile vegetations can also develop on noninfected
valves in patients with hypercoagulable states, so-
called nonbacterial thrombotic endocarditis.
Less commonly, noninfective, verrucous (Libman-
Sacks) endocarditis attributable to elevated levels
of circulating immune complexes may occur in
patients with systemic lupus erythematosus.
Fate of the Thrombus

If a patient survives the immediate effects of a thrombotic

vascular obstruction, thrombi undergo some combination of
the following four events in the ensuing days to weeks:
Propagation. The thrombus may accumulate more
platelets & fibrin (propagate), eventually leading to vessel
obstruction.
Embolization. Thrombi may dislodge & travel to other
sites in the vasculature.
Dissolution. Thrombi may be removed by fibrinolytic
activity.
Organization & recanalization. Thrombi may induce
inflammation & fibrosis (organization) & may eventually
become recanalized; that is, may reestablish vascular flow,
or may be incorporated into a thickened vascular wall.
Figure 4-15 Potential outcomes of venous thrombosis.
 Older thrombi tend to become organized - refers to the
ingrowth of endothelial cells, smooth muscle cells, & fibroblasts
into the fibrin-rich thrombus.
In time, capillary channels are formed, which may anastomose
to create conduits from one end of the thrombus to the other,
re-establishing, to a limited extent, the continuity of the
original lumen. Although the channels may not successfully
restore significant flow to many obstructed vessels, such
recanalization can potentially convert the thrombus into a
vascularized mass of connective tissue
Clinical Correlations
Thrombi are significant because they cause
obstruction of arteries & veins, & they are possible
sources of emboli.
The significance of each depends on where the
thrombus occurs.
Thus, while venous thrombi may cause congestion &
edema in vascular beds distal to an obstruction, a far
graver consequence is that they may embolize to the
lungs, causing death.
Conversely, although arterial thrombi can embolize,
their role in vascular obstruction at critical sites (e.g.,
coronary arteries resulting in myocardial infarction) is
much more important.
Venous Thrombosis (Phlebothrombosis)
The great preponderance of venous thrombi occur
in either the superficial or the deep veins of the
leg.
Superficial venous thrombi usually occur in the
saphenous system, particularly when there are
varicosities. Such thrombi may cause local
congestion, & swelling, pain, & tenderness along
the course of the involved vein but rarely
embolize.
Local edema & impaired venous drainage
predispose the involved overlying skin to infections
from slight trauma & to the development of
varicose ulcers.
 Deep thrombi in the larger leg veins at or
above the knee (e.g., popliteal, femoral, &
iliac veins) are more serious because they may
embolize. Although they may cause local pain
and distal edema, the venous obstruction may
be rapidly offset by collateral bypass channels.

Deep vein thromboses - entirely asymptomatic

in approximately 50% of affected patients &
are recognized only in retrospect after they
have embolized.
may occur with stasis & in a variety of
hypercoagulable states
 Tumor-associated procoagulant release is largely
responsible for the increased risk of
thromboembolic phenomena seen in disseminated
cancers, so-called migratory thrombophlebitis
or Trousseau syndrome.

Regardless of the specific clinical setting, advanced

age, bed rest, & immobilization increase the risk of
deep venous thrombosis, particularly in those who
have inherited susceptibility states; reduced
physical activity diminishes the milking action of
muscles in the lower leg & so slows venous return.
Arterial and Cardiac Thrombosis
Atherosclerosis - major initiator of thromboses,
related to the associated abnormal vascular flow &
loss of endothelial integrity.
Cardiac mural thrombi can arise in the setting of
myocardial infarction related to dyskinetic contraction
of the myocardium as well as damage to the adjacent
endocardium.
Rheumatic heart disease may result in atrial mural
thrombi due to mitral valve stenosis, followed by left
atrial dilation; concurrent atrial fibrillation augments
atrial blood stasis.
Cardiac & arterial (in particular, aortic) mural thrombi
can also embolize peripherally. Virtually any tissue
may be affected, but the brain, kidneys, and spleen
are prime targets because of their large flow volume.
DISSEMINATED INTRAVASCULAR COAGULATION
(DIC)
A variety of disorders ranging from obstetric complications
to advanced malignancy may be complicated by DIC, the
sudden or insidious onset of widespread fibrin thrombi in
the microcirculation.
Although these thrombi are not usually visible on gross
inspection, they are readily apparent microscopically & can
cause diffuse circulatory insufficiency, particularly in the
brain, lungs, heart, &kidneys.
With the development of the multiple thrombi, there is a
rapid concurrent consumption of platelets & coagulation
proteins (hence the synonym consumption coagulopathy);
at the same time, fibrinolytic mechanisms are activated, &
as a result an initially thrombotic disorder can evolve into a
serious bleeding disorder.

DIC is not a primary disease but rather a potential

complication of any condition associated with widespread
activation of thrombin.
Embolism
Embolus - a detached intravascular solid, liquid, or
gaseous mass that is carried by the blood to a site
distant from its point of origin.
Almost all emboli represent some part of a dislodged
thrombus, hence the commonly used term
thromboembolism.
Rare forms of emboli: droplets of fat, bubbles of air or
nitrogen, atherosclerotic debris (cholesterol emboli),
tumor fragments, bits of bone marrow, or even foreign
bodies such as bullets.
Unless otherwise specified, an embolism should be
considered to be thrombotic in origin
The potential consequence of such thromboembolic
events is the ischemic necrosis of distal tissue, known as
infarction.
PULMONARY THROMBOEMBOLISM
Incidence: 20 25/100,000 hospitalized patients
Causes about 200,000 deaths per year in the US
In more than 95% of instances, venous emboli originate
from deep leg vein thrombi above the level of the knee
Depending on the size of the embolus, it may occlude
the main pulmonary artery, impact across the bifurcation
(saddle embolus), or pass out into the smaller,
branching arterioles
In general, the patient who has had one
pulmonary embolus is at high risk of
having more.
Rarely, an embolus may pass through an
interatrial or interventricular defect to gain
access to the systemic circulation
(paradoxical embolism)
Pulmonary emboli

60% to 80% - clinically silent because they are

small
Sudden death, right heart failure (cor pulmonale)-
or cardiovascular collapse occurs when 60% or
more of the pulmonary circulation is obstructed
with emboli.
Embolic obstruction of medium-sized arteries may
result in pulmonary hemorrhage but usually does
not cause pulmonary infarction because of the dual
blood flow into the area from the bronchial
circulation.
Multiple emboli over time may cause pulmonary
hypertension with right heart failure.
SYSTEMIC THROMBOEMBOLISM
Refers to emboli traveling within the arterial
circulation
80% arise from intracardiac mural thrombi, 2/3s
of which are associated with left ventricular wall
infarcts & another quarter with dilated &
fibrillating left atria (e.g., secondary to mitral
valve disease)
The remainder originate from aortic aneurysms,
thrombi on ulcerated atherosclerotic plaques, or
fragmentation of a valvular vegetation, with a
small fraction due to paradoxical emboli
10% to 15% - unknown origin
In contrast to venous emboli, arterial emboli can
travel to a wide variety of sites
 The major sites for arteriolar embolization
are the lower extremities (75%) & the brain
(10%), with the intestines, kidneys, spleen,
& upper extremities involved to a lesser
extent.
consequences - depend on the extent of
collateral vascular supply in the affected
tissue, the tissue's vulnerability to
ischemia, & the caliber of the vessel
occluded
Figure 4-14 Mural thrombi. A, Thrombus in the left and right ventricular
apices, overlying a white fibrous scar. B, Laminated thrombus in a dilated
abdominal aortic aneurysm.
FAT EMBOLISM
Microscopic fat globules may be found in the circulation
after fractures of long bones (which have fatty marrow)
or, rarely, in the setting of soft tissue trauma & burns.
Although traumatic fat embolism occurs in some 90% of
individuals with severe skeletal injuries, less than 10% of
such patients have any clinical findings.
Fat embolism syndrome is characterized by pulmonary
insufficiency, neurologic symptoms, anemia, &
thrombocytopenia.
Symptoms begin 1 to 3 days after injury, with sudden
onset of tachypnea, dyspnea, & tachycardia.
Neurologic symptoms include irritability & restlessness,
with progression to delirium or coma.
 Patients may present with thrombocytopenia,
presumably caused by platelets adhering to the
myriad fat globules & being removed from the
circulation; anemia may result as a
consequence of erythrocyte aggregation &
hemolysis.
A diffuse petechial rash in nondependent areas
(related to rapid onset of thrombocytopenia) is
seen in 20% to 50% of cases & is useful in
establishing a diagnosis.
In its full-blown form, the syndrome is fatal in
up to 10% of cases.
AIR EMBOLISM
Gas bubbles within the circulation can obstruct
vascular flow (and cause distal ischemic
injury). Air may enter the circulation during
obstetric procedures or as a consequence of
chest wall injury.

Generally, in excess of 100 cc is required to

have a clinical effect; the bubbles act like
physical obstructions & may coalesce to form
frothy masses sufficiently large to occlude
major vessels.
 Decompression sickness - form of gas embolism,
occurs when individuals are exposed to sudden
changes in atmospheric pressure.
Scuba & deep sea divers, underwater construction
workers, & individuals in unpressurized aircraft in
rapid ascent are all at risk.
When air is breathed at high pressure (e.g., during
a deep sea dive), increased amounts of gas
(particularly nitrogen) become dissolved in the
blood & tissues. If the diver then ascends
(depressurizes) too rapidly, the nitrogen expands in
the tissues & bubbles out of solution in the blood to
form gas emboli.
 The rapid formation of gas bubbles within skeletal
muscles & supporting tissues in & about joints is
responsible for the painful condition called the
bends (1880s-afflicted individuals characteristically
arched their backs in a manner reminiscent of a
then popular women's fashion called the Grecian
Bend).

Gas emboli may also induce focal ischemia in a

number of tissues, -- brain & heart.

In the lungs, edema, hemorrhages, & focal

atelectasis or emphysema may appear, leading to
respiratory distress, the so-called chokes.
 Treatment of gas embolism requires placing the
individual in a compression chamber where the
barometric pressure may be raised, thus forcing the gas
bubbles back into solution. Subsequent slow
decompression theoretically permits gradual resorption &
exhalation of the gases so that obstructive bubbles do
not re-form.
A more chronic form of decompression sickness is called
Caisson disease (named for the pressurized vessels
used in the construction of the base of the Brooklyn
Bridge in New York; workers digging in these vessels
suffered both acute & chronic forms of decompression
sickness); persistence of gas emboli in the skeletal
system leads to multiple foci of ischemic necrosis; the
more common sites are the heads of the femur, tibia, &
humerus.
AMNIOTIC FLUID EMBOLISM
A grave but fortunately uncommon complication of
labor & the immediate postpartum period (1 in 50,000
deliveries).
Mortality rate - 20% to 40%
Important cause of maternal mortality.
Sudden onset of severe dyspnea, cyanosis, &
hypotensive shock, followed by seizures & coma.
If the patient survives the initial crisis, pulmonary
edema typically develops, along with (in half the
patients) DIC, owing to release of thrombogenic
substances from amniotic fluid.
The underlying cause - infusion of amniotic fluid or
fetal tissue into the maternal circulation via a tear in
the placental membranes or rupture of uterine veins.
 Classic findings - presence in the
pulmonary microcirculation of squamous
cells shed from fetal skin, lanugo hair, fat
from vernix caseosa, and mucin derived
from the fetal respiratory or
gastrointestinal tract.
Marked pulmonary edema & changes of
diffuse alveolar damage as well as systemic
fibrin thrombi indicative of DIC.
Infarction

An infarct is an area of ischemic necrosis caused by

occlusion of either the arterial supply or the venous
drainage in a particular tissue.
In the US, more than half of all deaths are caused by
cardiovascular disease, & most of these are
attributable to myocardial or cerebral infarction.
Pulmonary infarction is a common complication in a
number of clinical settings, bowel infarction is
frequently fatal, and ischemic necrosis of the
extremities (gangrene) is a serious problem in the
diabetic population.
Causes
Nearly 99% of all infarcts result from
thrombotic or embolic events, & almost all
result from arterial occlusion.
Occasionally, local vasospasm, expansion of
an atheroma owing to hemorrhage within a
plaque, or extrinsic compression of a vessel
(e.g., by tumor).
Uncommon causes - twisting of the vessels
(e.g., in testicular torsion or bowel
volvulus), compression of the blood supply
by edema or by entrapment in a hernia sac,
or traumatic rupture of the blood supply.
 Although venous thrombosis may cause
infarction, it more often merely induces
venous obstruction & congestion.
Usually, bypass channels rapidly open after
the thrombosis, providing some outflow
from the area, which, in turn, improves the
arterial inflow.
Infarcts caused by venous thrombosis are
more likely in organs with a single venous
outflow channel, such as the testis & ovary.
Morphology

Infarcts are classified on the basis of their

color (reflecting the amount of hemorrhage)
& the presence or absence of microbial
infection.

Infarcts may be either red (hemorrhagic)

or white (anemic) & may be either septic
or bland.
Red (hemorrhagic) infarcts occur
(1) with venous occlusions (such as in ovarian torsion)

(2) in loose tissues (such as lung), which allow blood to

collect in the infarcted zone
(3) in tissues with dual circulations (e.g., lung & small
intestine), permitting flow of blood from the
unobstructed vessel into the necrotic zone
(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 & necrosis (e.g., following
fragmentation of an occlusive embolus or angioplasty
of a thrombotic lesion)
 White (anemic) infarcts occur with
arterial occlusions in solid organs
with end-arterial circulation
(heart, spleen, & 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
 Dominant histologic characteristic of
infarction - ischemic coagulative
necrosis
If the vascular occlusion has occurred
shortly (minutes to hours) before the death
of the patient, no demonstrable histologic
changes may be evident; if the patient
survives even 12 to 18 hours, the only
change present may be hemorrhage.
Clinical Correlations: Factors That Influence
Development of an Infarct.

The consequences of a vascular occlusion can

range from no or minimal effect, all the way up
to death of a tissue or even the individual.

The major determinants include:

(1) nature of the vascular supply
(2) rate of development of the occlusion
(3) vulnerability of a given tissue to hypoxia
(4) blood oxygen content
Shock (cardiovascular collapse)
Final common pathway of potentially lethal clinical
events, including severe hemorrhage, extensive trauma
or burns, large myocardial infarction, massive pulmonary
embolism, & microbial sepsis.
Regardless of the underlying pathology, shock gives rise
to systemic hypoperfusion caused by reduction either in
cardiac output or in the effective circulating blood
volume.
The end results are hypotension, followed by impaired
tissue perfusion & cellular hypoxia.
Hypoxic & metabolic effects of hypoperfusion initially
cause only reversible cellular injury but persistence of
shock eventually causes irreversible tissue injury & can
culminate in the death of the patient.
 Shock may be grouped into 3 general categories:

Cardiogenic shock results from myocardial pump failure.

--caused by intrinsic myocardial damage (infarction), ventricular
arrhythmias, extrinsic compression (cardiac tamponade), or
outflow obstruction (e.g., pulmonary embolism).

Hypovolemic shock results from loss of blood or plasma

volume. -- caused by hemorrhage, fluid loss from severe burns,
or trauma.

Septic shock is caused by systemic microbial infection.

Most commonly occurs in the setting of gram-negative
infections (endotoxic shock), but it can also occur with gram-
positive & fungal infections.
 Less commonly, shock may occur in the setting of
anesthetic accident or spinal cord injury (neurogenic
shock), owing to loss of vascular tone & peripheral
pooling of blood.

Anaphylactic shock - initiated by a generalized IgE-

mediated hypersensitivity response, is associated with
systemic vasodilation & increased vascular
permeability. --widespread vasodilation causes a
sudden increase in the vascular bed capacitance,
which is not adequately filled by the normal
circulating blood volume. Thus, hypotension, tissue
hypoperfusion, & cellular anoxia result.
PATHOGENESIS OF SEPTIC SHOCK
25% - 50% mortality rate
ranks first among the causes of mortality in ICUs
accounts for over 200,000 deaths annually in the US
results from spread & expansion of an initially localized
infection (e.g., abscess, peritonitis, pneumonia) into the
bloodstream
70% - caused by endotoxin-producing gram-negative bacilli,
hence the term endotoxic shock
Endotoxins - bacterial wall lipopolysaccharides (LPSs) that
are released when the cell walls are degraded (e.g., in an
inflammatory response).
LPS consists of a toxic fatty acid (lipid A) core & a complex
polysaccharide coat (including O antigens) unique to each
bacterial species.
Analogous molecules in the walls of gram-positive bacteria
& fungi can also elicit septic shock
Figure 4-21 Cytokine cascade in sepsis. After release of lipopolysaccharide (LPS) from
invading gram-negative microorganisms, there are successive waves of tumor necrosis
factor (TNF), interleukin-1 (IL-1), and IL-6 secretion.
Figure 4-22 Effects of
lipopolysaccharide (LPS) & secondarily
induced effector molecules. LPS initiates
the cytokine cascade; in addition, LPS
and the various factors can directly
stimulate downstream cytokine
production, as indicated. Secondary
effectors that become important include
nitric oxide (NO) and platelet-activating
factor (PAF). At low levels, only local
inflammatory effects are seen. With
moderate levels, more systemic events
occur in addition to the local vascular
effects. At high concentrations, the
syndrome of septic shock is seen.
 The hypoperfusion resulting from the combined effects of
widespread vasodilation, myocardial pump failure, and
DIC induces multiorgan system failure affecting the liver,
kidneys, & central nervous system

An interesting group of bacterial proteins called

superantigens also cause syndromes similar to septic
shock. These include toxic shock syndrome toxin-1,
produced by staphylococci & responsible for the toxic
shock syndrome.

Superantigens are polyclonal T-lymphocyte activators that

induce systemic inflammatory cytokine cascades similar to
those occurring downstream in septic shock. Their actions
can result in a variety of clinical manifestations ranging
from a diffuse rash to vasodilation, hypotension, & death.
Stages of Shock
An initial nonprogressive phase during which reflex
compensatory mechanisms are activated & perfusion
of vital organs is maintained
A progressive stage characterized by tissue
hypoperfusion & onset of worsening circulatory &
metabolic imbalances, including acidosis
An irreversible stage that sets in after the body has
incurred cellular & tissue injury so severe that even if
the hemodynamic defects are corrected, survival is
not possible.
Morphology
The cellular and tissue changes induced by shock are
essentially those of hypoxic injury
failure of multiple organ systems, the cellular
changes may appear in any tissue.
brain - ischemic encephalopathy
heart - may undergo focal or widespread coagulation
necrosis or may exhibit subendocardial hemorrhage
and/or contraction band necrosis
kidneys typically exhibit extensive tubular ischemic
injury (acute tubular necrosis)
lungs are seldom affected in pure hypovolemic shock
because they are resistant to hypoxic injury. When shock
is caused by bacterial sepsis or trauma, however,
changes of diffuse alveolar damage may appear, the so-
called shock lung.
 adrenal changes in shock are those seen in all
forms of stress; essentially, there is cortical cell
lipid depletion

gastrointestinal tract may suffer patchy

mucosal hemorrhages and necroses, referred
to as hemorrhagic enteropathy

liver - may develop fatty change &, with

severe perfusion deficits, central hemorrhagic
necrosis
Clinical Course
The clinical manifestations depend on the precipitating
insult.
In hypovolemic & cardiogenic shock - patient presents
with hypotension; a weak, rapid pulse; tachypnea; &
cool, clammy, cyanotic skin.
In septic shock - the skin may initially be warm and
flushed because of peripheral vasodilation.
The original threat to life stems from the underlying
catastrophe that precipitated the shock state (e.g.,
myocardial infarct, severe hemorrhage, or
uncontrolled bacterial infection).
Eventually, electrolyte disturbances & metabolic
acidosis also exacerbate the situation.
 If the patient survives the initial complications, he or
she enters a second phase dominated by renal
insufficiency & marked by a progressive fall in urine
output as well as severe fluid & electrolyte imbalances
The prognosis varies with the origin of shock & its
duration.
80% - 90% of young, otherwise healthy patients with
hypovolemic shock survive with appropriate
management
Cardiogenic shock associated with extensive
myocardial infarction & gram-negative shock -
mortality rates of up to 75%, even with the best care
currently available