Path Chapter 4: Hemodynamic Disorders, Thromboembolic Disease and Shock (p. 126-133)
Embolus – detached mass that is carried by the blood to a site distant from where it originated
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An embolus can be solid, liquid, or gas
Almost all emboli are a part of a dislodged thrombus, so it’s often called thromboembolism
Emboli will lodge in vessels eventually that are too small to allow them to pass through, causing
a partial or complete vascular occlusion
o This causes a localized ischemic necrosis called an infarction, of the downstream tissue
Pulmonary embolism:
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In more than 95% of cases, pulmonary embolisms originate from leg deep vein thrombosis
(DVTs)
o DVTs though happen way more often without causing a pulmonary embolism
Fragments of thrombi from DVTs are carried through the bigger vessels fo the right heart,
before getting stuck in the pulmonary arteries
Depending on the size of the embolus, it can occlude the main pulmonary artery, straddle the
pulmonary artery bifurcation (saddle embolus), or pass out into the smaller branching arteries
Often there are multiple emboli
Usually, someone who has had one pulmonary embolism is at high risk for having more
Most pulmonary emboli are clinically silent because they are small
o Over time, they get organized and incorporated into the vascular wall
o Sometimes organization of the thromboembolus leaves behind a fibrous web
When emboli obstruct 60% of more of the pulmonary circulation, it can cause sudden death,
right heart failure (cor pulmonale), or cardiovascular collapse
When an emboli obstructs a medium-sized artery and causes vascular rupture, it can cause
pulmonary hemorrhage
o This usually isn’t bad enough to cause pulmonary infarction, because the lung has two
blood supplies, so the intact bronchial circulation continues to perfuse the affected area
o If bronchial artery flow is compromised, like in left heart failure, you get infarction
When emboli obstruct a small arteriole of the pulmonary branches, it causes hemorrhage or
infarction
Multiple emboli over time can cause pulmonary hypertension and right heart failure
Rarely, an emboli can pass through an interatrial or interventricular defect, and enter the systemic
circulation, called a paradoxical embolism
Emboli in the arterial system are called systemic thromboembolism
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Most systemic emboli come from a mural thrombi in the heart, most of which come from left
ventricle wall infarcts
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The rest come from left atrial dilation and fibrillation, aortic aneurysms, thrombi from
atherosclerotic plaques, valve vegetation, or rarely a paradoxical embolism
Major sites for artery emboli are the lower extremities (3/4 of them) and brain, leading to
infarction
Fat and marrow emboli:
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Microscopic fat globules, with or without hematopoietic marrow elements, can be found in
circulation after fractures of long bones, which have fatty marrow, or rarely in soft tissue
trauma or burns
Fat and marrow pulmonary embolisms are very common findings after vigorous
cardiopulmonary resuscitation, and are probably of no clinical consequence
o Fat embolism happens in 90% of people with severe skeletal injuries, but less than 10%
have any issues from it
Fat embolism is the term for the minority of patients who are symptomatic
Fat embolism is characterized by pulmonary insufficiency, neuro symptoms, anemia, and
thrombocytopenia, and can be fatal
Usually, a couple days after injury, there is a sudden onset of tachypnea, dyspnea, and
tachycardia
Irritability and restlessness can progress to delirium or coma
Thrombocytopenia can happen from platelet adhesion to fat globules and therefore
aggregation or getting stuck in the spleen
o The thrombocytopenia will show a rash up to half the time
Anemia can happen from RBC aggregates with the fat and/or hemolysis
The fat emboli can occlude vessels, and release free fatty acids that cause local toxic injury to
endothelium, leading to platelet activation and WBC recruitment
Air embolism:
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Gas bubbles in circulation can form frothy masses that obstruct vascular flow
Gas bubbles can be put into circulation by surgery, or in chest wall injury
Decompression sickness – happens when people experience sudden decreases in atmospheric
pressure
o Happens in people who deep sea dive or work in the sky
o When air is breathed in at high pressure, increased amounts of gas are dissolved in the
blood and tissues
o If the person then rapidly depressurizes (like a deep sea diver coming to surface) too
quickly, the gases, mainly nitrogen, come out of solution in the tissues and blood
The rapid making of gas bubbles in skeletal muscles and tissues around joints is what causes
“the bends”
In the lungs, gas bubbles in the vasculature can cause edema, hemorrhage, and focal atelectasis
or emphysema, causing a respiratory distresses called “the chokes”
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Caisson disease – chronic decompression sickness where persistence of gas emboli int eh
skeletal system leads to many areas of ischemic necrosis, most often in the femoral heads, tibia,
and humerus
o Seen in people who work in caissons for bridge making
You treat decompression sickness by putting them in a high pressure chamber, which forces gas
bubbles back into solution, and then you slowly decompress them so that the gas is gradually
resorbed and exhaled without bubbles reforming
Amniotic fluid embolism – rare, but happens in labor and immediately postpartum
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Has a high death rate, and causes 10% of maternal deaths in the US
Most of the survivors have permanent neuro problems
Onset is characterized by sudden severe dyspnea, cyanosis, and shock, followed by neuro
impairment with headache, seizures, and coma
If they survive the initial crisis, pulmonary edema develops, along with disseminated
intravascular coagulation (DIC) in half of them, from release of thrombotic stuff from the
amniotic fluid
The cause is amniotic fluid or fetal tissue get into mom circulation through a tear in the
placental membranes or rupture of uterine veins
Classic findings include squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa,
and mucin from the fetal respiratory or GI tract, in the mom pulmonary vessels
Can also show pulmonary edema, diffuse alveolar damage, and presence of fibrin thrombi in
many vascular beds due to DIC
Infarct – area of ischemic necrosis caused by occlusion of either the arterial supply or venous drainage
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Almost half of US deaths are from cardiovascular disease, and most of these are an MI or
cerebral infarction
Ischemic necrosis of the extremities is called gangrene
Nearly all infarcts happen from thrombotic or embolic artery occlusion
Other causes of infarcts include local vasospasm, hemorrhage into an atheromatous plaque, or
compression on a vessel (like a tumor)
Venous thrombosis can cause infarction, but more often it will just cause congestion, leading to
other channels allowing the built up fluid to flow through them
o So an infarct of a vein usually happens when there’s just one draining vein, like in the
testis or ovaries
Infarcts are classified according to color – red (hemorrhagic) or white (anemic)
o Red infarcts – page 128 left bottom pic
 Happens in:
 Venous occlusions
 Loose tissues like the lung where blood can collect in the infarcted zone
 In tissues with dual circulations that allow blood flow from an
unobstructed supply into the necrotic area
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In tissues previously congested by sluggish vein outflow, and when flow
is re-established to a site of previous artery occlusion and necrosis
o White infarcts – happen in artery occlusions in solid organs with end-arterial circulation
(like the heart, spleen, and kidney), and where the tissue is too dense to let blood drain
from nearby capillaries pool into it – page 128 bottom right pic
Infarcts are usually wedge-shaped, with the occluded vessel at the apex, and the periphery of
the organ forming the base
o When the base is a serosal surface, there can be an overlying fibrinous exudate
Acute infarcts have poorly defined borders, which getter better defined with time due to
congestion from inflammation
Infarcts in artery occlusions in organs without a dual blood supply usually get progressively paler
and more defined with time – page 128 bottom right pic
In the lung, hemorrhagic infarcts are the norm – page 128 bottom left pic
Extravastated RBCs in hemorrhagic infarcts are phagocytosed by macrophage, which convert
heme iron into hemosiderin
o Small amounts don’t change the color of the tissue, but lots of hemorrhage causes a
firm brown residue
The main characteristic of infarction is ischemic coagulative necrosis
If the occlusion happens shortly before the death of the person, you may not see any histo
changes, because it takes 4-12 hours for the tissue to show necrosis
Acute inflammation is seen along the margins of the infarcts in hours, followed eventually by
repair that is mostly through forming a scar
o The brain is the exception to this, and CNS infarcts show liquefactive necrosis
Septic infarcts are converted into an abscess, causing much more of an inflammatory response
The main things that determine the outcome of an infarct are blood vessel network involved,
the rate the occlusion happens, vulnerability to hypoxia, and how much oxygen is in the blood
o The availability of another blood supply is the most important thing in determining if
vessel occlusion will cause damage or not
 The lungs have both pulmonary and bronchial circulations, the liver has both
hepatic arteries and portal veins, the hand has both radial and ulnar arteries
 The kidney and spleen don’t have alternative circulations and are end-arterial,
so occlusion usually causes tissue death
o Slow developing occlusions are less likely to cause infarction, because it allows time to
develop alternate perfusion pathways
 Ex: the 3 major coronary arteries have little connecting vessels between them
 So if one of the big arteries gets occluded slowly by a atheromatous
plaque, the little arteries can shunt blood through the other vessels
o Neurons and myocardial cells need lots of oxygen, so they’re very vulnerable to hypoxia,
and get very hurt quickly during hypoxia
 Unlike them, fibroblasts in the heart can go hours without oxygen
o People who already have anemia or cyanosis with low oxygen are more prone to an
event from a partial obstruction than a normal person
Shock is the end result of lots of bad stuff, like severe hemorrhage, extensive trauma or burns, large
MI’s, massive pulmonary embolisms, and sepsis
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Shock is characterized by systemic hypotension from decreased cardiac output or decreased
circulating blood volume
This leads to impaired tissue perfusion, and cell hypoxia
At first the cell injury is reversible, but eventually it becomes irreversible and fatal
3 main categories of causes of shock – table page 130
o Cardiogenic shock – happens from low cardiac output from poor heart pumping
 Ex: MI
o Hypovolemic shock – low cardiac output from loss of blood or plasma volume
 Ex: hemorrhage
o Septic shock – happens from vasodilation and peripheral pooling of blood as part of a
systemic immune rxn to bacteria or fungi
Less often, shock can happen from anesthesia or a spinal cord injury (neurogenic shock) from
loss of vascular tone and peripheral pooling of blood
Anaphylactic shock – systemic vasodilation caused by an IgE-mediated type 1 allergic
hypersensitivity rxn
Septic shock is the most common cause of death in intensive care units (ICU’s)
o Most often caused by gram positive bacteria
o The systemic vasodilation and pooling of blood in the periphery leads to tissue
hypoperfusion, even though cardiac output is fine or even high to try and compensate
o This is accompanied by widespread endothelial cell activation and injury, leading to a
hypercoagulable state that can lead to DIC
o Septic shock also causes changes in metabolism that directly suppress cell function
o Septic shock is produced by the effect of inflammatory cells on the endothelium
o Inflammatory mediators in shock:
 Inflammatory cells use TLR’s to bind microbe stuff, and trigger the responses
that start sepsis
 Inflammatory cells then release TNF, IL-1, IFN-γ, Il-12, and Il-18, reactive oxygen
species, and platelet activating factor (PAF)
 These all activate endothelial cells, resulting in adhesion molecule expression,
the cell becomes procoagulant, and inflammation is increased
 Complement also gets activated by microbe stuff, by plasmin cleaving it into
anaphylotoxins (C3a and C5a), chemotactic stuff (C5a), and opsonins (C3b)
 Microbe endotoxin (LPS) can also activate coagulation directly at factor 12, and
indirectly through changing endothelial function
 This causes a systemic procoagulant state to ↑ thrombosis and inflammation
o Endothelial cell activation and injury:
 When endothelial cells get activated, it causes thrombosis, increased vascular
permeability, and vasodilation
 These issues can cause DIC in up to half of septic people
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Pro-inflammatory cytokines cause more tissue factor making by
endothelial cells, & inhibits fibrinolysis by making more PAI-1, &
inhibiting making of anticoagulant stuff like tissue factor pathway
inhibitor and protein C
 There’s now decreased blood flow in small blood vessels, causing stasis
that decreases washout of all this procoagulant stuff
 This all promotes thrombi making in small vessels, throughout the body,
adding to the hypoperfusion of the tissues
 In fullblown DIC, the use of the clotting factors and platelets to make all
these little plugs causes a deficiency in this stuff, allowing easy bleeding
 The increase in vascular permeability leads to exudation of fluid into the
interstitum, causing edema & an ↑ in interstitial pressure that further impedes
blood flow into tissues, especially after trying to help them by giving them fluids
 The endothelium also makes more NO
 All of this plus the inflammatory mediators cause systemic relaxation of
vascular smooth muscle, leading to hypotension & decreased tissue perfusion
Metabolic changes:
 Septic patients become insulin resistant and get hyperglycemia
 Cytokines like TNF and Il-1, stress hormones like glucagon, GH, and
glucocorticoids, and catecholamines, all promote gluconeogenesis
 Hyperglycemia decreased neutrophil function, and causes increased adhesion
molecule expression on endothelial cells
 Sepsis has an initial acute surge in glucocorticoid making, followed by adrenal
insufficiency with decreased glucocorticoids
 Can happen from less ability of the adrenals to make stuff, or from
adrenal necrosis from DIC, called Waterhouse-Friderichsen syndrome
Immune suppression – the inflammatory state activates counter-regulatory
immunosuppression
 There’s a shift from pro-inflammatory cytokines from TH1’s, to antiinflammatory cytokines from TH2’s
Systemic hypotension, interstitial edema, and small vessel thrombosis all decrease the
delivery of oxygen and nutrients to the tissues, which also can’t even use the nutrients
right because of changes to their cell metabolism
 High levels of cytokines can decrease heart contractility and cardiac output
 Increased vascular permeability and endothelial injury can cause adult
respiratory distress syndrome
 This all leads to failure of the organs, especially the kidneys, liver, lungs, and
heart, leading to death
Since so much is going on in septic shock, it’s very hard to intervene and stop it
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The standard of care is antibiotics, intense insulin therapy for hyperglycemia,
fluid resusication to keep systemic pressure up, and corticosteroieds at
physiologic doses to correct adrenal insufficiency
Bacterial proteins called superantigens can cause a septic shock called toxic shock syndrome,
by activating T cells that then release tons of cytokines
3 phases of hypovolemic and cardiogenic shock:
o Nonprogressive phase – reflex compensatory action kicks in and perfusion of vital
organs is maintained
 Neurohumoral mechanisms kick in to maintain cardiac output & blood pressure
 Includes baroreceptor reflexes, release of catecholamines, renin, and
ADH, and symp stimulation
 This leads to tachycardia, peripheral vasoconstriction, and renal
conservation of fluid
 Skin vasoconstriction causes the characteristic coolness and pallor of
the skin
o Septic shock can cause vasodilation and warm flushed skin
o Progressive stage – there’s tissue hypoperfusion and circulatory and metabolic issues
start showing up
 All the stuff in the nonprogressive phase weren’t corrected, so now there’s
widespread hypoxia
 The lack of oxygen causes a switch from aerobic respiration to anaerobic
glycolysis, causing excess lactic acid, leading to metabolic lactic acidosis that
lowers the tissue pH and blocks the vasomotor response
 This causes the arterioles to dilate, and blood starts to pool in the vessels, which
worsens cardiac output
 When this gets widespread, tissues don’t get enough nutrients and start to fail
o Irreversible stage – when the cell and tissue injury is too severe, and there’s no way to
prevent death
 You see lysosomal enzyme leakage, which makes things worse
 Heart contraction gets weaker from more NO making
 Ischemic bowel can let intestine flora into the blood, adding septic shock to this
 The kidneys then shutdown from acute tubular necrosis
The cell changes seen in cardiogenic and hypovolemic shock are hypoxic injury
o The brain, heart, lungs, kidneys, adrenals, and GI are most affected
o Adrenals – show low adrenal cortex cell lipids (cholesterol for making steroids)
 So they aren’t exhausted, but instead so many lipids are being turned into
steroids that you don’t see any
o Kidneys – show acute tubular necrosis
o Lungs – they can resist hypovolemic shock from dual circulation, but when bacteria or
trauma happen, they show diffuse alveolar damage
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In septic shock, DIC causes lots of microthrombi in these organs and causes petechial
hemorrhages on the skin and organs
o All of these tissues except the myocardium and neurons can recover if you fix it in time
Clinical manifestations of shock:
o Hypovolemic and cardiogenic – hypotension, weak rapid pulse, tachypnea, cool
clammy cyanotic skin
o Septic shock – skin is initially warm and flushed from peripheral vasodilation
o Initial events are followed by renal failure, showing progressive fall in urine output
and severe fluid and electrolyte imbalances