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EDEMA

Abnormal increase in interstitial fluid within tissues


Either increased capillary pressure or diminished colloid osmotic pressure = increased interstitial fluid
If movement of water into tissues (or body cavities) exceeds lymphatic drainage = fluid accumulates
hydrothorax, hydropericardium, hydroperitoneum (Ascites) = fluid collections in the different body cavities depending on the
location
anasarca = sever and generalized edema with widespread subcutaneous tissue swelling
Transudate = edema caused by increased hydrostatic pressure or reduced plasma protein (protein-poor flui)
Ex. Heart failure, renal failure, hepatic failure, and certain forms of malnutrition
Exudate = inflammatory edema (protein-rich) result of increase vascular permeability
Increased Hydrostatic Pressure
- Regional increases in hydrostatic pressure = result from a focal impairment in venous return
o DVT in lower extremity may cause localized edema in the affected leg
- Generalized increases in venous pressure = systemic edema
o CHF compromised RV function = pooling of blood on the venous side of the circulation
Reduced Plasma Oncotic Pressure
- Albumin not synthesized in adequate amounts/ lost from the circulation

Nephrotic syndrome albumin loss, glomerular capillaries become leaky (generalized edema)

Liver disease, protein malnutrition


- Net movement of fluid into the interstitial tissues with subsequent plasma volume contraction
- Reduced intravascular volume = decreased renal perfusion = increased production of renin, angiotensin, and aldosterone = cannot
correct plasma volume deficit (primary defect of low sesrum protein)
Sodium and Water Retention
- Increased salt retention increased hydrostatic pressure (intravascular fluid volume expansion) and diminished vascular colloid
osmotic pressure (dilution)
o Salt retention compromised renal function

CHF activation of the RAAS


o Managing generalized edema salt restriction diuretics and aldosterone antagonists
o Release of ADH primary retention of water (vasoconstriction)

Malignancies and lung and pituitary disorders increase in ADH (hyponatremia and cerebral edema)
Lymphatic Obstruction
- Lymphedema impaired lymphatic drainage (localized)
o Causes: chronic inflammation with fibrosis, invasive malignant tumors, physical disruption, radiation damage, and certain infectious
agents (filariasis)
MORPHOLOGY:
Microscopically:
- clearing and separation of the ECM and subtle cell swelling
- subcutaneous tissues, lungs, brain
Subcutaneous Edema:
- diffuse or more conspicuous in regions with high hydrostatic pressures
- dependent edema: distribution is influenced by gravity

legs when standing

sacrum when recumbent


Pitting edema:
- finger pressure over substantially edematous subcutaneous tissue that displaces the interstitial fluid and leaves a depression
Clinical Consequences:
- Subcutaneous tissue edema signals potential underlying cardiac or renal disease
- Impair wound healing or the clearance of infection
- Pulmonary edema most frequently seen: Left ventricular failure
- Brain edema life threatening; brain substance can herniated through the foramen magnum or the brain stem vascular supply can
be compressed (can injure medullary centers)
HYPEREMIA and CONGESTION
Hyperemia
- Active process
- Arteriolar dilation = increased blood flow (exercise or sites of inflammation)

Affected tissues: red (erythema) reduced outflow of blood


Systemic: cardiac failure
Local: isolated venous obstruction
Congested tissues: dusky reddish-blue (cyanosis) red cell stasis and accumulation of deoxygenated hemoglobin

Congestion
- Increased volumes and pressures
- Commonly leads to edema
- Chronic passive congestion: lack of blood flow = chronic hypoxia resulting in ischemic tissue injury and scarring
- Capillary rupture causing small hemorrhagic foc
-Subsequent catabolism of extravasated red cells can leave residual telltale clusters of hemosiderin-laden macrophages
MORPHOLOGY
- Cut surfaces of congested tissues: discolored due to the presence of high levels of poorly oxygenated blood
Microscopically:
- Acute pulmonary congestion:
o engorged capillaries
o alveolar septal edema
o focal intra-alveolar hemorrhage
- Chronic pulmonary congestion:
o septa are thick and fibrotic
o alveoli with numerous hemosiderin-laden macrophages (heart failure cells)
- Acute hepatic congestion:
o central vein and sinusoids are distended
o centrilobular hepatocyes can be ischemic
o periportal hepatocytes are better oxygenated (proximity to hepatic arterioles), may only develop fatty change
- Chronic hepatic congestion:
o centrilobular regions grossly red-brown and slightly depressed (because of cell death)
o accentuated against the surrounding zones of uncongested tan liver (nutmeg liver)
Microscopically:
Centrilobular hemorrhage
Hemosiderin-laden macrophages
Degeneration of hepatocytes
! Centrilobular area (distal end of blood supply) more prone to undergo necrosis
HEMORRHAGE
-

Extravasation of blood into the extravascular space


Capillary bleed can occur under conditions of chronic congestion
Hemorrhagic diatheses: increased tendency to hemorrhage (insignificant injury)
Rupture of large artery/vein = severe hemorrhage due to:
o Vascular injury
o Trauma
o Atherosclerosis
o Inflammatory or neoplastic erosion of the vessel wall

Clinical Implications:
- Hematoma: any accumulation; may be relatively significant/ massive (death can ensues)
- Petechiae: 1-2mm hemorrhages into skin, mucous membranes or serosal surfaces
o Locally increased intravascular pressure
o Low platelets counts (thrombocytopenia)
o Defective platelet function (uremia)
- Purpura: slightly larger (3mm) hemorrhages
o Same disorders that caused petechiae
o Secondary to trauma, vascular inflammation (vasculitis), increased vascular fragility (amyloidosis)
- Ecchymoses: larger ( 1 to 2 cm) subcutaneous hematoma
o Red cells are degraded and phagocytized by macrophages
o Hemoglobin (red-blue) enzymatically converted into bilirubin
o Bilirubin (blue-green color)
o Hemosiderin (gold-brown)
- Large accumulation of blood in a body cavity (depending on the location)
o Hemothorax
o Hemopericardium
o Hemoperitoneum
o Hemarthrosis (joints)
- Patients with extensive bleeding can develop jaundice from the massive breakdown of RBC and hemoglobin

Hemostasis

Hemostasis and Thrombosis


Involves3 components: vascular wall (particularly the endothelium), platelets, and the coagulation cascade.
Hemostasis
maintain blood in a fluid state in
normal vessels and forms hemostatic
clot rapidly in cases of injury.

Thrombosis
Counterpart of hemostasis. blood clot
(thrombus) formation within intact
vessels.

Process of Normal Hemostasis:


o After tissue injury, brief period of arteriolar vasoconstriction occurs.
mediated by reflex neurogenic mechanism and local secretion of endothelin (a potent endothelium-derived
vasoconstrictor).

o Exposure of highly thrombogenic subendothelial extracellular matrix (ECM)that will facilitate platelet activation and adherence.
shape change (from small rounded discs to flat plates with markedly increased surface area)
release of secretory granules platelet recruitment platelet aggregation PLATELET PLUG [Primary
hemostasis]

o Tissue factor (AKA. factor III and thromboplastin) is also exposed at the site of injury.
actsin conjunction with factor VII - major in vivo initiator of the coagulation cascade; thrombin generation fibrinogen to
FIBRIN meshwork consolidates the platelet plug [Secondary hemostasis]

PRIMARY HEMOSTASIS
Stimuli: exposed endothelial
tissue Product: Platelet plug
formation Clotting cascade

SECONDARY HEMOSTASIS
Stimuli: tissue factor exposed
Product: fibrin formation
Coagulation cascade

permanent plug- polymerized fibrin and platelet plug.


counter-regulatory mechanisms (e.g., tissue plasminogen activator, t-PA) are set into motion to limit the hemostatic plug to the site
of injury.

Normal hemostasis. A, After vascular injury local neurohumoral factors induce a transient vasoconstriction. B, Platelets bind via
glycoprotein Ib (GpIb) receptors to von Willebrand factor (vWF) on exposed extracellular matrix (ECM) and are activated, undergoing a
shape change and granule release. Released adenosine diphosphate (ADP) and thromboxane A 2 (TxA2) induce additional platelet
aggregation through platelet GpIIb-IIIa receptor binding to fibrinogen, and form the primary hemostatic plug. C, Local activation of the
coagulation cascade (involving tissue factor and platelet phospholipids) results in fibrin polymerization, cementing the platelets into
a definitive secondary hemostatic plug. D, Counter-regulatory mechanisms, mediated by tissue plasminogen activator (t-PA, a
fibrinolytic product) and thrombomodulin, confine the hemostatic process to the site of injury.
1) Endothelium
key players in the regulation of homeostasis
exhibit antiplatelet, anticoagulant, and fibrinolytic properties
with procoagulant activities.

Anti- and procoagulant activities of endothelium. NO, nitric oxide; PGI 2, prostacyclin; t-PA, tissue plasminogen activator; vWF, von
Willebrand factor. The thrombin receptor is also called a protease-activated receptor (PAR)

ANTI-THROMBOTIC
PROPERTY
a. Antiplatelet effects

PRO-THROMBOTIC
PROPERTY

a. Platelet effects
interactions with von

Willebrand factor (vWF), from


endothelial cells and an
essential cofactor for platelet
binding to matrix elements.

Intact endothelium does


not cause platelet adhesion
and activation.
Even though platelets
may be activated, with intact
endothelium, prostacyclin
(PGI2) and nitric oxide
produced by the endothelial
cells impede platelet
adhesion. *potent
vasodilators as well*
** adenosine diphosphatase
also cleaves ADP that further
inhibits platelet
aggregation**
b. Anticoagulant effects

heparin-like molecules,
thrombomodulin, and tissue
factor pathway inhibitor

Thrombomodulin
converts thrombin from
pro-coagulant into anticoagulant via protein C
activation (inactivates
factors Va and VIIIa).

also produces protein S,


a co-factor for protein C, and
tissue factor pathway
inhibitor (TFPI), that directly
inhibits tissue factorfactor
VIIa and factor Xa
activities.

b. Procoagulant
effects
In response to cytokines
(e.g., tumor necrosis factor
[TNF] or interleukin-1 [IL-1])
or bacterial endotoxin, tissue
factor is activated.

tissue factor, the


major activator of the
extrinsic clotting cascade

augment the catalytic


function of activated
coagulation factors IXa and
Xa

c. Antifibrinolytic
effects
EC secretes inhibitors
of plasminogen activator
(PAIs), which limit
fibrinolysis and tend to favor
thrombosis

c. Fibrinolytic effects

Endothelial cells
synthesize tissue-type
plasminogen activator (t-PA),
a protease that cleaves
plasminogen to form plasmin
cleaves fibrin that will
degrade thrombi.

Platelet adhesion and aggregation. Von Willebrand factor functions as an adhesion bridge between subendothelial collagen and the
glycoprotein Ib (GpIb) platelet receptor. Aggregation is accomplished by fibrinogen bridging GpIIb-IIIa receptors on different platelets.

Congenital deficiencies in the various receptors or bridging molecules lead to the diseases indicated in the colored boxes. ADP,
adenosine diphosphate.
2) Platelets

Megakaryocytes
disc-shaped, anucleate cell fragments
2 types of cytoplasmic granules:

-Granules
-P-selectin on their membranes contain fibrinogen, fibronectin, factors V and VIII, platelet factor 4 (a heparin-binding
chemokine), platelet-derived growth factor (PDGF), and transforming growth factor- (TGF-).
Dense (or ) granules
-contain ADP and ATP, ionized calcium, histamine, serotonin, and epinephrine

Platelets undergo :
Platelet adhesion to ECM
vWF - acts as a bridge between platelet surface receptors.
vWF-GpIb associations are necessary to overcome the high shear forces of flowing blood.
Secretion (release reaction) of both granule types occurs soon after adhesion
ADP is a potent activator of platelet aggregation
Platelet activation leads to the appearance of negatively charged phospholipids (particularly phosphatidylserine) on their
surfaces which will bind calcium and serve as critical nucleation sites for the assembly of complexes
Platelet aggregation follows adhesion and granule release.
vasoconstrictor thromboxane A2 amplifies platelet aggregation
concurrent activation of the coagulation cascade generates thrombin stabilizes the platelet plug via:
1) binding with protease activated receptor that will further ion platelet contraction - creates an irreversibly fused mass of
platelets (SECONDARY HEMOSTATIC PLUG).
2) converts fibrinogen to fibrin in the vicinity of the platelet
plug, functionally cementing the platelets in place.
therapeutic agents that block platelet aggregation:
a. by interfering with thrombin activity
b. by blocking ADP binding (clopidogrel)
c. by binding to the GpIIb-IIIa receptors (synthetic antagonists or monoclonal antibodies). Antibodies against GpIb are on the
horizon.
Platelet plugs also contain RBC and WBC. Leukocytes adhere to platelets via P-selectin and to endothelium using several
adhesion receptors

Coagulation Cascade
third arm of the hemostatic process
Thrombin is the most important coagulation factor
Elements of the reaction:
A) enzyme (activated coagulation factor)
B) substrate (proenzyme form of coagulation factor)
C) cofactor (reaction accelerator)
coagulation factors be brought close together ensures localized clotting.
Vitamin K is the cofactor used antagonized by Coumadin

Schematic illustration of the conversion of factor X to factor Xa via the extrinsic pathway, which in turn converts factor II (prothrombin)
to factor IIa (thrombin). The initial reaction complex consists of a proteolytic enzyme (factor VIIa), a substrate (factor X), and a reaction
accelerator (tissue factor), all assembled on a platelet phospholipid surface. Calcium ions hold the assembled components together
and are essential for the reaction. Activated factor Xa becomes the protease for the second adjacent complex in the coagulation
cascade, converting prothrombin substrate (II) to thrombin (IIa) using factor Va as the reaction accelerator
Extrinsic Pathway of
coagulation
equired the addition of an
exogenous trigger (originally
provided by tissue extracts)

Intrinsic Pathway of
coagulation
only required exposing factor
XII (Hageman factor) to
thrombogenic surfaces (even

most physiologically relevant


pathway for coagulation
occurring when vascular
damage has occurred
activated by tissue factor
(also known as
thromboplastin or factor
III) prothrombin time (PT)
assesses factors VII, X, II,
V, and fibrinogen

glass would suffice). partial


thromboplastin time (PTT)
assesses factors XII, XI, IX,
VIII, X, V, II, and
fibrinogen)

Role of thrombin in hemostasis and cellular activation. Thrombin plays a critical role in generating cross-linked fibrin (by cleaving
fibrinogen to fibrin, and by activating factor XIII), as well as activating several other coagulation factors (see Fig. 4-8 ). Through
protease-activated receptors (PARs, see text), thrombin also modulates several cellular activities. It directly induces platelet
aggregation and TxA2 production, and activates ECs to express adhesion molecules, and a variety of fibrinolytic (t-PA), vasoactive (NO,
PGI2), and cytokine mediators (e.g., PDGF). Thrombin also directly activates leukocytes. ECM, extracellular matrix; NO, nitric oxide;
PDGF, platelet-derived growth factor; PGI2, prostacyclin; TxA2, thromboxane A2; t-PA, tissue plasminogen activator. See Figure 4-7 for
additional anticoagulant activities mediated by thrombin, including via thrombomodulin.
coagulation cascade must be restricted to the site of vascular injury.
Categories of endogenous anticoagulants:
(1) Antithrombins (e.g., antithrombin III) inhibit the activity of thrombin, factors IXa, Xa, XIa, and XIIa.
(2) Proteins C and S are vitamin Kdependent proteins that act in a complex that proteolytically inactivates factors Va and
VIIIa
(3) TFPI is a protein produced by endothelium (and other cell types) that inactivates tissue factorfactor VIIa complexes
fibrinolytic cascade that moderates the size of the ultimate clot
plasmin, which breaks down fibrin and interferes with its polymerization
(plasminogen, converted either by a factor XIIdependent pathway or by plasminogen activators: Urokinase-like PA (uPA), streptokinase)
fibrin split products (FSPs or fibrin degradation products) can also act as weak anticoagulants
can be used in diagnosing abnormal thrombotic states including disseminated intravascular coagulation (DIC),
deep venous thrombosis, or pulmonary embolism
most important of the PAs is t-PA;

Endothelial cells also fine-tune the coagulation/anticoagulation balance by releasing plasminogen activator inhibitor (PAI)
Thrombosis
Virchow's triad
1. endothelial injury
2. stasis or turbulent blood flow
3. hypercoagulability of the blood
Endothelial injury
**it should be emphasized that endothelium need not be denuded or physically disrupted to contribute to the development of
thrombosis; any perturbation in the dynamic balance of the prothombotic and antithrombotic activities of endothelium can influence
local clotting events.**
Turbulent or stasis of blood flow
o Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction
o Stasis - major contributor in the development of venous thrombi
Hyperviscosity polycythemia vera
Vascular occlusion sickle cell anemia.
o Normal blood flow is laminar - flow centrally in the vessel lumen
o Promote endothelial activation, enhancing procoagulant activity,
leukocyte adhesion, etc., in part through flow-induced
changes in endothelial cell gene expression.
o Disrupt laminar flow and bring platelets into contact with the endothelium
o Prevent washout and dilution of activated clotting factors by fresh flowing blood and the inflow of clotting factor inhibitors.
Hypercoagulability
o (also called thrombophilia)
o primary (genetic) and secondary (acquired) disorders
o point mutations in the factor V gene (Leiden mutation) and prothrombin gene are the most common cause of hereditary
hypercoagulability.
o Leiden mutation results in a glutamine to arginine substitution at position 506 that renders factor V resistant to cleavage by protein
C

o A single nucleotide change (G20210A) in the 3-untranslated region of the prothrombin gene is another fairly common mutation
o Elevated levels of homocysteine (inherited deficiency of cystathione synthetase) contribute to arterial and venous
thrombosis, as well as the development of atherosclerosis
o Deficiencies in: antithrombin III, protein C, or protein S
o due to oral contraceptive use or the hyperestrogenic state of pregnancy is probably caused by increased hepatic synthesis of
coagulation factors and reduced anticoagulant synthesis.
o Disseminated cancers, release of procoagulant tumor products predisposes to thrombosis with advancing age may be due to
reduced endothelial PGI2

Heparin-induced thrombocytopenia (HIT) syndrome


o administration of unfractionated heparin
o induce the appearance of antibodies that recognize complexes of heparin and platelet factor 4 on the surface of platelets
o Binding of these antibodies to platelets results in their activation, aggregation, and consumption
o prothrombotic state
o fondaparinux also causes HIT
Antiphospholipid antibody syndrome
o previously called the lupus anticoagulant syndrome
o pulmonary embolism, pulmonary hypertension (from recurrent subclinical pulmonary emboli), stroke, bowel infarction, or
renovascular hypertension
o Fetal loss is attributable to antibody-mediated inhibition of t-PA activity necessary for trophoblastic invasion of the uterus.
o hypercoagulable state
o aggressive form (catastrophic antiphospholipid syndrome
Primary
exhibit only the manifestations of a
hypercoagulable state and lack
evidence of other autoimmune
disorders.

Secondary
well-defined autoimmune disease
systemic lupus erythematosus

Morphology: and shape of thrombi depend on the site of origin and the cause.
Arterial or
cardiac
thrombi

venous thrombi

mural
thrombi

vegetatio
ns

site of
turbulence or
injury
retrograde
growth
-occlusive
-most
common
sites:
coronary,
cerebral, and
femoral
arteries
Atheroscler
osis is a
major cause
of arterial
thromboses

site of stasis
-extend in the
direction of blood
flow

-cardiac
chambers
and aortic
lumen

(phlebothrombosi
s)/ red or stasis
thrombi

-abnormal
myocardial
contraction
and
endocardia
l injury
-may
cause
brain,
kidneys,
and spleen
embolizati
on for their
rich blood
supply.

-invariably
occlusive
-more enmeshed
red cells (and
relatively few
platelets) -lower
extremities (most
common) upper
extremities,
periprostatic
plexus, or the
ovarian and
periuterine veins

-heart
valves
-may result
to infective
endocarditi
s or
nonbacter
ial
thromboti
c
endocardi
tis

-Special
circulation: dural
sinuses, portal and
hepatic vein.
- Superficial
venous thrombi
typically occur in
the saphenous
veins and rarely
embolize
- Deep venous
thrombosis (DVT) in
the larger leg veins
at or above the
knee (e.g.,
popliteal, femoral,
and iliac veins
commonly embolize
in the lungs

lines of Zahn - represent pale platelet and fibrin deposits alternating with darker red cellrich layers; laminations in the
flowing blood.
distinguish antemortem thrombosis from the bland nonlaminated clots that occur postmortem

The propagating portion of a thrombus is often poorly attached and therefore prone to fragmentation and embolization

** migratory thrombophlebitis or Trousseau syndrome - increased risk of thromboembolism in disseminated cancers**

Mural thrombi. A, Thrombus in the left and right ventricular apices, overlying white fibrous scar. B, Laminated thrombus in a dilated
abdominal aortic aneurysm. Numerous friable mural thrombi are also superimposed on advanced atherosclerotic lesions of the more
proximal aorta (left side of picture).
Fate of the thrombus
a. Propagation.
b. Embolization - Thrombi dislodge and travel to other sites in the vasculature
c. Dissolution- the extensive fibrin deposition and crosslinking in older thrombi renders them more resistant to lysis.

d. Organization and recanalization- Older thrombi become organized by the ingrowth of endothelial cells, smooth muscle
cells, and fibroblasts.

Low-power view of a thrombosed artery stained for elastic tissue. The original lumen is delineated by the internal elastic lamina
(arrows) and is totally filled with organized thrombus, now punctuated by several recanalized endothelium-lined channels (white
spaces).
Clinical consequence:
o they cause obstruction of arteries and veins, and are sources of emboli.
o DISSEMINATED INTRAVASCULAR COAGULATION (DIC)
sudden or insidious onset of widespread fibrin thrombi in the microcirculation
can cause diffuse circulatory insufficiency, particularly in the brain, lungs, heart, and kidneys
results in platelet and coagulation protein consumption
not a primary disease but rather a potential complication of any condition associated with widespread activation of
thrombin.

Embolism
An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant from its point of
origin.
coined by Rudolf Virchow in 1848
Thromboembolism thrombus that has been dislodged
Rare forms of emboli include fat droplets, nitrogen bubbles, atherosclerotic debris (cholesterol emboli), tumor fragments, bone
marrow, or even foreign bodies.
Pulmonary
Systemic
Fat embolism
embolism
thromboembolis
m
can occlude the
emboli in the
after fractures of
main pulmonary
arterial circulation
long bones, soft
artery, straddle
tissue trauma and
the pulmonary
lower extremities
burns
artery bifurcation
(75%) and the
(saddle embolus),
brain (10%), with
Fat and marrow
or pass out into
the intestines,
PEs are very
the smaller,
kidneys, spleen,
common
branching arteries
and upper
incidental findings
extremities
after vigorous
the patient who
cardiopulmonary
has had one PE is
cause infarction
resuscitation
at high risk of
having more
Sudden death,
right heart failure
(cor pulmonale)
60% of the lungs
has been blocked

Embolus from a lower extremity deep venous thrombosis, now impacted in a pulmonary artery branch.

Bone marrow embolus in the pulmonary circulation. The cellular elements on the left side of the embolus are hematopoietic
precursors, while the cleared vacuoles represent marrow fat. The relatively uniform red area on the right of the embolus is an early
organizing thrombus
Air embolism

Amniotic fluid embolism

Gas bubbles within the


circulation can coalesce to
form frothy masses that
obstruct vascular flow

fifth most common cause of


maternal mortality worldwide

decompression sickness
sudden dec. in atmospheric
pressure.

infusion of amniotic fluid or


fetal tissue into the maternal
circulation via a tear in the
placental membranes or
rupture of uterine veins

Scuba and deep sea divers,


underwater construction
workers, and individuals in
unpressurized aircraft in
rapid ascent

sudden severe dyspnea,


cyanosis, and shock, followed
by neurologic impairment
ranging from headache to
seizures and coma.

Caisson disease- more


chronic form of
decompression sickness;
femoral heads, tibia, and
humeri

Morphology: presence of
squamous cells shed from
fetal skin, lanugo hair, fat
from vernix caseosa, and
mucin derived from the fetal
respiratory or gastrointestinal
tract in the maternal
pulmonary microvasculature

When air is breathed at high


pressure (e.g., during a deep
sea dive), increased amounts
of gas (particularly nitrogen)
are dissolved in the blood
and tissues. If the diver then
ascends (depressurizes) too
rapidly, the nitrogen comes
out of solution in the tissues
and the blood.
the bends - gas bubbles

within skeletal muscles and


supporting tissues in and
about joints
chokes - gas bubbles in the
vasculature of the lungs
cause edema, hemorrhage,
and focal atelectasis or
emphysema
Acute decompression
sickness is treated by placing
the individual in a high
pressure chamber, which
serves to force the gas
bubbles back into solution

Amniotic fluid embolism. Two small pulmonary arterioles are packed with laminated swirls of fetal squamous cells. There is marked
edema and congestion, and elsewhere in the lung were small organizing thrombi consistent with disseminated intravascular
coagulation.
Infarction
an area of ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage.
Nearly all infarcts result from thrombotic or embolic arterial occlusions.
dominant histologic characteristic of infarction is ischemic coagulative necrosis

Other causes include:

local vasospasm, hemorrhage into an atheromatous plaque, or extrinsic vessel compression (e.g., by tumor).

torsion of a vessel (e.g., in testicular torsion or bowel volvulus), traumatic rupture, or vascular compromise by edema
(e.g., anterior compartment syndrome) or by entrapment in a hernia sac
Infarcts caused by venous thrombosis are thus more likely in organs with a single efferent vein (e.g., testis and ovary).
Venous thrombosis = most common outcome is congestion
Morphology: classified according to color and the presence or absence of infection
Red infarcts
1. with venous occlusions
(e.g., ovary)
2. in loose 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 flow from an
unobstructed parallel supply
into a necrotic zone
4. in tissues previously
congested by sluggish
venous outflow
5. when flow is re-established

White infarcts
occur with arterial
occlusions in solid organs
with end-arterial circulation
(e.g., heart, spleen, and
kidney),
where tissue density
limits the seepage of
blood from adjoining
capillary beds into the
necrotic area.

to a site of previous arterial


occlusion and necrosis (e.g.,
following angioplasty of an
arterial obstruction)
Infarcts tend to be wedge-shaped, with the occluded vessel at the apex and the periphery of the organ forming the base.
Extravasated red cells in hemorrhagic infarcts are phagocytosed by macrophages, which convert heme iron into hemosiderin
discoloration of the tissue into dark brown residuum.
Septic infarctions occur when infected cardiac valve vegetations embolize or when microbes seed necrotic tissue converted
into an abscess.

Red and white infarcts. A, Hemorrhagic, roughly wedge-shaped pulmonary red infarct. B, Sharply demarcated white infarct in the
spleen.

Remote kidney infarct, now replaced by a large fibrotic scar


Factors That Influence Development of an Infarct

1)

Nature of the vascular supply


RESISTANT TO INFARCTION
o lungs have a dual pulmonary and bronchial artery blood supply
o liver, with its dual hepatic artery and portal vein circulation,
o hand and forearm, with their dual radial and ulnar arterial supply
NOT RESISTANT
o renal and splenic circulations are end-arterial

2)

Rate of occlusion development- Slowly developing occlusions are less likely to cause infarction, because they provide time to
develop alternate perfusion pathways:
o Ex. collateral circulation- coronary artery occlusion; small interarteriolar anastomoses - interconnect the three major
coronary arteries in the heart

3)

Vulnerability to hypoxia:
o neurons - 3 to 4 minutes irreversible damage.
o Myocardial cells - die after only 20 to 30 minutes of ischemia
o fibroblasts within myocardium remain viable even after many hours of ischemia

4)

Oxygen content of blood partial obstruction to a vessel may have a more severe effect on the tissue in an anemic or cyanotic
patient.
Shock

final common pathway for several potentially lethal clinical events


characterized by systemic hypotension due either to reduced cardiac output or to reduced effective circulating blood volume.
consequences are impaired tissue perfusion and cellular hypoxia.

Cardiogenic
shock

low cardiac output


due to myocardial
pump failure

Hypovolemic
shock

due to the loss of


blood or p lasma
volume
vasodilation and
peripheral pooling
of blood as part of
a systemic
immune reaction
to bacterial or
fungal infection
anesthetic
accident or a
spinal cord injury
loss of vascular
tone and
peripheral pooling
of blood
widespread
vasodilation
results in tissue
hypo-perfusion
and hypoxia

Septic shock

Neurogenic
shock

Anaphylactic
shock

the patient
presents with
hypotension; a
weak, rapid pulse;
tachypnea; and
cool, clammy,
cyanotic skin.

skin may initially


be warm and
flushed because of
peripheral
vasodilation

Pathogenesis of septic shock


o ranks first among the causes of death in intensive care units and accounts for over 200,000 lost lives each year in US.
o most frequently triggered by gram-positive bacterial infections, followed by gram-negative bacteria and fungi
o Major contributing factors:
A) Inflammatory mediators
o TNF, IL-1, IFN-, IL-12, and IL-18
o Reactive oxygen species and lipid mediators such as prostaglandins and platelet activating factor (PAF)

o Endothelial activation results to adhesion molecule expression, a procoagulant phenotype, and secondary waves of
cytokine production.
o The complement cascade is also activated by microbial components, both directly and through the proteolytic activity of
plasmin production of anaphylotoxins (C3a, C5a), chemotactic fragments (C5a), and opsonins (C3b) that contribute to the
pro-inflammatory state
o endotoxin can activate coagulation directly through factor XII and indirectly through altered endothelial function
B)

Endothelial cell activation and injury

o three major sequelae: (1) thrombosis; (2) increased vascular permeability; and (3) vasodilation
o Pro-inflammatory cytokines result in increased tissue factor production by endothelial cells
C)

Metabolic abnormalities

o exhibit insulin resistance and hyperglycemia


o cytokines suppress insulin release while simultaneously promoting insulin resistance in the liver and other tissues, likely
by impairing the surface expression of GLUT-4
o Hyperglycemia decreases neutrophil functionthereby suppressing bactericidal activityand causes increased
adhesion molecule expression on endothelial cells
D) Immune suppression
o Proposed mechanisms:

1.
2.
3.
4.
5.
E)

a shift from pro-inflammatory (TH1) to anti-inflammatory (TH2) cytokines


production of anti-inflammatory mediators (e.g., soluble TNF receptor, IL-1 receptor antagonist, and IL-10),
lymphocyte apoptosis
the immunosuppressive effects of apoptotic cells
the induction of cellular anergy

Organ dysfunction

-Systemic hypotension, interstitial edema, and small vessel thrombosis dec. delivery of O2 in the tissues
-High levels of cytokines and secondary mediators may diminish myocardial contractility and cardiac output
-increased vascular permeability and endothelial injury can lead to the adult respiratory distress syndrome

severity and outcome of septic shock are dependent upon


1.
2.
3.
4.

the extent and virulence of the infection;


the immune status of the host;
the presence of other co-morbid conditions;
the pattern and level of mediator production

Standard of care:
1. appropriate antibiotics,
2. intensive insulin therapy for hyperglycemia,
3. fluid resuscitation to maintain systemic pressures,
4. physiologic doses of corticosteroids to correct relative adrenal insufficiency

Stages of shock:
o progressive disorder

initial nonprogressive
phase

reflex compensatory
mechanisms activated.
neurohumoral mechanisms
help to maintain cardiac

output and blood pressure:


baroreceptor reflexes,
catecholamine release,
activation of the reninangiotensin axis, ADH
release, and generalized
sympathetic stimulation.
net effect is tachycardia,
peripheral vasoconstriction,
and renal conservation of
fluid.

progressive stage

characterized by tissue
hypoperfusion and onset of
worsening circulatory and
metabolic imbalances (ex.
acidosis)
widespread tissue hypoxia
intracellular aerobic
respiration is replaced by
anaerobic glycolysis with
excessive production of lactic
acid.

irreversible stage

lowers the tissue pH and


blunts the vasomotor
response; arterioles dilate,
and blood begins to pool
in the microcirculation
severe cellular and tissue
injury lysosomal enzyme
leakage

Morphology:
cellular and tissue changes caused by cardiogenic or hypovolemic shock are essentially those of hypoxic injury
particularly evident in brain, heart, lungs, kidneys, adrenals, and gastrointestinal tract
adrenal gland: cortical cell lipid depletion.
kidneys typically exhibit acute tubular necrosis
lungs: resistant to hypoxic injury; diffuse alveolar damage (SHOCK LUNG) caused by bacterial sepsis or trauma

Clinical consequence:
o Individuals who survive the initial complications may enter a second phase dominated by renal insufficiency and marked by a
progressive fall in urine output as well as severe fluid and electrolyte imbalances.