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CELL ADAPTATION, INJURY

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Title: CELL ADAPTATION, INJURY


1
CELL ADAPTATION, INJURY AND DEATH By Larry
Nichols, MD
2
TYPE OF NECROSIS DETERMINES TREATMENT Liquefacti
ve Drainage Caseous Anti-fungal and
TB Gangrenous Amputation
3
HIGH LIVER FUNCTION TESTS REFLECT INJURY, NOT
FUNCTION Double misnomer LFTS are neither
specific for liver nor tests of function
4
ISCHEMIA REVERSIBLE
CELL INJURY Infarction irreversible cell
necrosis due to ischemia not relieved in time
5
METAPLASIA REPLACEMENT OF A TISSUE TYPE BY
ANOTHER ONE, FULLY DIFFERENTIATED BUT NOT
NORMAL FOR THE SITE a breeding ground for
cancer
6
PATHOLOGIC APOPTOSIS Important in certain
cancers chemotherapy
radiation
transplant rejection
7
Fundamental Vocabulary Etiology doctorspeak
for cause Morphology pathologistspeak for
visible manifestation Gross pathologistspeak
for visible without a microscope
8
Spectrum of Cellular Responses to Stress and
Noxious Stimuli ADAPTATION - INJURY -
DEATH Adaptation physiologic and morphologic
changes, modulating cell function, bringing it
to a new altered steady state of homeostasis
9
Injury reversible pathophysiologic and
morphologic response to stress or noxious
stimulus exceeding cell capacity to adapt, but
not enough to kill it
10
Cellular Adaptations Hypertrophy -
Atrophy increase in cell size
decrease (/- organ size) in
same Hyperplasia increase in cell number All
can be physiologic or pathologic
11
Metaplasia replacement of a tissue type by
another one, fully differentiated but not normal
for the site, pathologic Examples replacement
of bronchial respiratory epithelium by squamous
epithelium due to smoking
replacement of esophageal squamous mucosa by
intestinal type epithelium due to reflux
12
Metaplasia commonly caused by processes leading
to cancer Examples gastroesophageal reflux
leading to intestinal metaplasia Barrett
esophagus leading to adenocarcinoma of
esophagus smoking leading to
bronchial squamous metaplasia leading to
squamous carcinoma
13
Causes of Cell Injury Hypoxia (deficiency of
oxygen) Ischemia (deficiency of blood) Physical
agents (trauma, burns, etc.) Chemical agents
(alcohol, drugs, etc.) Infectious agents
(bacteria, etc.) Immunologic reactions Genetic
derangements Nutritional imbalances
14
Mechanisms of Cell Injury Depletion of
ATP Impaired cell surface sodium pump (sodium
influx, potassium efflux) Cellular
swelling Anaerobic glycolysis Impaired calcium
pump (calcium influx) Reduction in protein
synthesis
15
Mechanisms of Cell Injury Unfolded protein
response Mitochondrial permeability transition
(loss of cytochrome c) Activation of ATPases,
phospholipases, proteases, endonucleases by
calcium Accumulation of free radicals (lipid
peroxidation of membranes, oxidation of
proteins, DNA breaks)
16
Mechanisms of Cell Injury Defects in membrane
permeability (mitochondrial dysfunction,
cytoskeletal abnormalities, leakage from
lysosomes, detergent effect of degraded
membrane phospholipids, loss of membrane
phospholipids)
17
LFTs slang jargon for liver function tests
usually include bilirubin, alkaline phosphatase
(alk phos), alanine aminotransferase (ALT,
SGPT) and aspartate amino- transferase
(AST, SGOT) Elevated alk phos, ALT AST
are exceedingly imperfect measures of liver
injury, and not at all of function
18
True Liver Function Tests 1. Albumin (sometimes
low level due to low liver
production) 2. Prothrombin time INR (commonly
prolonged due to hepatic coagulopathy) 3. Glucose
(sometimes low level due to deficient
hepatic gluconeogenesis) 4. Ammonia NH3 (high
level correlates with hepatic
encephalopathy) 5. Bilirubin (sometimes)
19
Coagulative necrosis morphological
manifestation of irreversible cell injury (cell
death) due to ischemia except in

brain Liquefactive necrosis necrosis with
conversion of solid tissue to liquid due to
severe acute infection, toxicity or (brain only)
ischemia
20
Key point ischemia is reversible (for 3 minutes
in brain, for 20 minutes in heart, for 2
hours in liver) Ischemia not relieved in time
causes irreversible cell necrosis INFARCTION
21
Coagulative necrosis features Preservation of
ghost cell outline Cytoplasm increased pink
eosinophilia Nucleus pyknosis (increased blue
basophilia and shrinkage)
karyorrhexis (fragmentation)
karyolysis (fading away) Acute inflammatory
response
22
Caseous necrosis distinctive form of
coagulative necrosis grossly resembling
cheese Gangrene distinctive form of coagu-
lative necrosis with blackening and shrinkage,
typically of distal extremity Fat necrosis
digested by pancreatic lipase, chalky white
saponification
23
Type of necrosis determines treatment Liquefact
ive drainage (surgery) Caseous anti-TB
and anti-fungal Gangrene amputation (surgery)
24
PATHOLOGIC APOPTOSIS Important in Certain
cancers (not too many) Chemotherapy Radiation
(and heat) Transplant rejection Hypoxia Certain
viral infections
25
APOPTOSIS versus NECROSIS single cells or
large groups small clusters
of cells cell membrane intact
disrupted inflammatory response
yes no
26
STEATOSIS (fatty change) Abnormal accumulation
of lipid in hepatocytes Due to obesity,
alcohol, diabetes mellitus, anoxia, protein
malnutrition
27
HEMOSIDEROSIS Accumulation of hemoglobin-
derived, refractile, large, granular brown iron
pigment Due to recent bleeding, hemolysis or
iron overload secondary hemochromatosis
28
HEMOCHROMATOSIS Accumulation of hemosiderin in
liver, heart, pancreas, joints and endocrine
organs Due to a genetic disease causing excess
dietary iron absorption primary hemochromatosis
29
LIPOFUSCIN Wear-and-tear (aging) pigment,
intracellular insoluble small granular brown
material composed of lipids phospholipid
polymers complexed with protein
30
CALCIFICATION Dystrophic abnormal localized
deposition of calcium salts in injured, dying or
dead tissues Metastatic abnormal deposition in
otherwise normal tissues due to hypercalcemia,
usually due to deranged calcium homeostasis
31
INFLAMMATION-1 By Larry Nichols, MD
32
ACUTE INFLAMMATION 4 CARDINAL SIGNS
SYMPTOMS Redness Swelling Heat Pain
33
NEUTROPHILS Polymorphonuclear leukocytes
(polys, PMNs) Granulocytes with neutral
granules, variably shaped 3- to 5-lobed
nuclei First responder phagocytes
34
IMPORTANT MEDIATORS OF
INFLAMMATION Histamine, NO, PAF,
arachidonic acid, thromboxane, prostacyclin, TNF,
IL-1, IL-8, interferon-g, VEGF, selectins,
ICAM-1, VCAM-1, integrins, CD31, CD44, complement
C3a and C5a, bradykinin, thrombin, XIIa,
leukotriene B4, Toll-like receptors, G-protein
receptors, serotonin, chemokines, substance P,
prostaglandinD2, E2 F2alpha
35
STEROIDS BLOCK PRODUCTION OF ARACHIDONIC ACID,
PROSTA- GLANDINS AND LEUKOTRIENES Non-steroidal
anti-inflammatory drugs block only
prostaglandin production
36
MANY IMPORTANT MEDIATORS OF INFLAMMATION ARE
ALSO IMPORTANT MEDIATORS OF BLOOD
CLOTTING Mess with these important mediators of
inflammation and you are messing with blood
clotting.
37
INFLAMMATION Complex reaction to injurious
agents consisting of (1) vascular responses
(2) leukocyte migration and activation (3)
systemic effects
38
ACUTE INFLAMMATION Rapid onset (seconds to
minutes) Short duration (minutes to a few
days) Exudation of fluid, plasma proteins and
leukocytes (primarily neutrophils)
39
ACUTE INFLAMMATION 4 CARDINAL SIGNS
SYMPTOMS Redness Swelling Heat Pain
40
EXUDATE Inflammatory extracellular fluid
with high protein content, cells
and cellular debris TRANSUDATE Thin
serous fluid with low protein content
and few (if any) cells
41
PUS Purulent exudate rich in
neutrophils, cellular debris and
(commonly) microbes Thick, opaque, variably
colored (light green, yellow, tan, crème,
off-white)
42
NEUTROPHILS Polymorphonuclear leukocytes
(polys, PMNs, segs) Granulocytes with
neutral granules (neither blue or red on
smear), and variably shaped nuclei, segmented
into 3 to 5 lobes First responder phagocytes
43
NEUTROPHILS Very short-lived (1-2 days)
Normally 40-70 of the leukocytes in the blood
Bands immature (adolescent) neutrophils, with
nuclei with 2 lobes normally 0-5 of
blood leukocytes
44
ACUTE INFLAMMATION CAUSES 1) infection 2)
tissue necrosis 3) immune reaction 4)
trauma 5) foreign bodies 6) physical
chemical agents
45
ACUTE INFLAMMATION VASCULAR RESPONSES 1)
vasodilatation 2) increased permeability
LEUKOCYTE MIGRATION 1) margination 2)
rolling 3) adhesion 4) diapedesis 5)
chemotaxis
46
ACUTE INFLAMMATION RECEPTORS P-selectin Rolling
E-selectin Rolling, adhesion
L-selectin Adhesion VCAM-1 Adhesion
VLA-4 integrin Adhesion ICAM-1 Adhesion,
diapedesis PECAM Diapedesis polys
monos lymphs
47
LEUKOCYTE ACTIVATION Cytokine (response and
secretion) Phagocytosis (recognition,
attachment, engulfment, killing,
degradation) greatly enhanced by opsonins
hydrogen peroxide, myeloperoxidase
48
CONGENITAL LEUKOCYTE DEFECTs Leukocyte adhesion
deficiency-1 and -2 Chronic granulomatous
disease Myeloperoxidase deficiency Chediak-Higas
hi syndrome
49
ACQUIRED LEUKOCYTE DEFECTS Diabetes
mellitus Hemodialysis Malnutrition Leukemia
50
IMPORTANT MEDIATORS OF
INFLAMMATION Histamine, NO, PAF,
arachidonic acid, thromboxane, prostacyclin, TNF,
IL-1, IL-8, interferon-g, VEGF, selectins,
ICAM-1, VCAM-1, integrins, CD31, CD44, complement
C3a and C5a, bradykinin, thrombin, XIIa,
leukotriene B4, Toll-like receptors, G-protein
receptors, serotonin, chemokines, substance P,
prostaglandinD2, E2 F2alpha
51
HISTAMINE Most in mast cells granules some
in basophils and platelets Released by trauma,
cold, heat, immune reactions, anaphylatoxins,
IL-1, IL-8 Binds to H1 endothelial
receptors Causes vasodilation of arterioles and
increased permeability of venules Can be blocked
by anti-histamine drugs
52
MAST CELLS Bone-marrow-derived cells around
blood vessels, nerves and skin Granules loaded
with histamine, neutrophil chemotactic factor,
eosinophil chemotactic factor, platelet
activating factor, proteases
53
MAST CELLS Tissue counterpart to blood
basophils Activated by cross-linking of IgE Fc
receptors, complement C5a and C3a
(anaphylatoxins), some drugs (codeine,
morphine), adenosine, mellitin (in bee venom),
heat, cold and sunlight
54
NITRIC OXIDE Produced by endothelial
cells Short-lived (seconds), acting only on
cells close by (paracrine) Causes
vasodilatation, reduces platelet aggregation and
adhesion Deficient production a feature of
atherosclerosis, diabetes, hypertension
55
COMPLEMENT Group of 20 related plasma
proteins and their cleavage products, which
mediate increased vascular permeability and
chemotaxis, and opsonize stuff for
phagocytosis liquid part of unclotted blood
vs serum (liquid part of clotted blood)
56
Cell membrane phospholipids Phospholipases
Arachidonic acid Lipoxygenases
Cyclooxygenase Leukotrienes
ProstaglandinG2 and Lipoxins
ProstaglandinH2
Prostacyclin Thromboxane
57
Steroids block production of arachidonic acid,
prostaglandins, leukotrienes and lipoxins,
masking signs and symptoms of inflammation,
causing opportunistic infection and a whole
host of other side effects Non-steroidal
anti-inflammatory drugs block only prostaglandin
production
58
Prostaglandins mediate much of the pain, fever
and other signs and symptoms of
inflammation Non-steroidal anti-inflammatory
drugs (NSAIDs) are analgesics (pain killers)
and antipyretics (fever breakers), but also
interfere with prostaglandin- mediated gastric
mucosal protection, leading to gastric bleeding
59
Non-steroidal anti-inflammatory drugs (NSAIDs)
block cyclooxygenase Cyclooxygenase in
endothelium makes prostacyclin (vasodilator,
platelet aggregation inhibitor) Cyclooxygenase
in platelets makes thromboxane
(vasoconstrictor, platelet aggregation promoter)
60
Most NSAIDs block cyclooxygenase reversibly,
except aspirin, which irreversibly acetylates
it Endothelium makes more enzyme, prostacyclin,
vasodilation and platelet aggregation
inhibition Platelets cannot make new enzyme, so
vasodilation and platelet aggregation inhibition
for the life of those platelets
61
MANY IMPORTANT MEDIATORS OF INFLAMMATION ARE
ALSO IMPORTANT MEDIATORS OF BLOOD
CLOTTING Mess with these important mediators of
inflammation and you are messing with blood
clotting.
62
Cyclooxygenase-1 is constitutively expressed and
cyclooxygenase-2 inducible, suggesting that
rofecoxib (Vioxx) a COX-2 inhibitor might have
all the anti-inflammatory effects of other
NSIADs with less gastric bleeding, but it caused
more heart attacks, possibly due to inhibiting
endothelial prostacyclin production more than
platelet thromboxane
63
INFLAMMATION-2 By Larry Nichols, MD
64
GRANULOMA AN AGGREGATE OF ACTIVATED
MACROPHAGES a distinctive form of chronic
inflammation associated with autoimmune and
infectious diseases such as sarcoidosis,
Wegener granulomatosis and tuberculosis
65
SEPSIS SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
DUE TO INFECTION (PROVEN OR SUSPECTED) NOT a
positive blood culture
66

Sepsis
Positive blood culture

67
FORMS OF INFLAMMATION 1. Purulent
(suppurative) 2. Abscessing (necrotizing) 3.
Fibrinous 4. Serous 5. Granulomatous none
mutually exclusive
68
PURULENT INFLAMMATION Also called
suppurative Usually acute Production of
abundant pus Commonly caused by infection with
pyogenic bacteria
69
ABSCESS (dont forget the s before the
c) Localized area of liquefactive necrosis
packed with neutrophils, cell debris and
(commonly) microbes From necrotizing
inflammation, usually
acute Treatment (surgical) drainage
70
FIBRINOUS INFLAMMATON Deposition of fibrin-rich
exudate on serosal surfaces (peritoneum,
pericardium, pleura) or on meninges or in
interstitium Usually acute
71
SEROUS INFLAMMATON Usually
acute Outpouring of thin serous fluid from blood
(transudate) or mesothelium serosal lining of
peritoneum, pericardium, pleura (effusion) or
skin blister (effusion into space created
between epidermis and dermis by burn or virus)
72
CHRONIC INFLAMMATION Prolonged duration (weeks
to years) 1) Active inflammation, 2) Tissue
destruction and 3) Attempted repair all
proceeding simultaneously
73
  • CHRONIC INFLAMMATION
  • CAUSES
  • Persistent infection (e.g. TB)
  • Prolonged toxin exposure
  • (e.g. silicosis)
  • 3) Autoimmunity (e.g. lupus)
  • 4) Unknown (e.g. atherosclerosis,
  • sarcoidosis, Alzheimer disease)

74
  • CHRONIC INFLAMMATION
  • Cellular Players
  • Macrophages
  • Lymphocytes
  • Plasma cells
  • Eosinophils
  • Mast cells
  • Multinucleated giant cells

75
CHRONIC INFLAMMATION Dominant cellular player
Macrophage Phagocyte derived from blood
monocytes, who live only 1-2 days, but months to
years if get recruited to become tissue
macrophages (histiocytes)
76
MACROPHAGES Activated by cytokines (IFN-gamma),
bacterial endotoxins, etc. Secrete neutrophil
chemotactic factor and growth factors (TGF-beta,
PDGF, FGF), leak proteases and reactive oxygen
species
77
MACROPHAGES Chemotaxis by MCP-1, C5a, PDGF,
TGF-alpha, fibrinonectin and fibrinopeptides
(fragments) Proliferation and immobilization
important in maintaining chronic inflammation,
especially in atherosclerosis
78
LYMPHOCYTES Bidirectional interactions with
macrophages, who present antigens to T cells
with costimulators and produce cytokines (IL-12)
that stimulate T cells Activated T cells
secrete IGN-gamma
79
PLASMA CELLS Derived from activated B
cells Produce large amounts of single-
specificity antibody Prominent in syphilis and
rheumatoid arthritis
80
EOSINOPHILS Granulocytes with granules with
major basic protein (toxic to parasites but also
host cells) Important in parasitic infestations
and IgE-mediated allergic reactions
81
  • MULTINUCLEATED GIANT CELLS
  • syncytium of macrophages
  • Foreign body type (with nuclei
  • arranged haphazardly)
  • 2. Langhans type (with nuclei
  • arranged peripherally)
  • associated with immune granulomas

82
GRANULOMA AN AGGREGATE OF ACTIVATED
MACROPHAGES a distinctive form of chronic
inflammation associated with autoimmune and
infectious diseases such as sarcoidosis,
Wegener granulomatosis and tuberculosis
83
  • TYPES OF GRANULOMA
  • Foreign body persistent material
  • too large or undigestible for
  • clearance (e.g. suture, talc)
  • 2. Immune persistent antigen
  • induces cell-mediated immune
  • reaction (e.g. TB, cat-scratch dis)

84
EXAMPLES OF GRANULOMATOUS DISEASES 1.
Tuberculosis (the prototype) 2. Leprosy 3.
Syphilis 4. Cat-scratch disease 5. Sarcoidosis
85
TB Granulomas resemble tiny potatoes
(tubercles), commonly cheesy (caseous) Aggregate
s of activated macrophages resembling epithelial
cells, central amorphous granular debris with
loss of cellular outlines, rim of lymphocytes
fibroblasts, occasional Langhans giant cells and
rare acid-fast bacilli
86
Tuberculosis is most common in lungs spreads to
nearby lymph nodes Note Caseating necrosis
resembles cheese grossly (not microscopically!)
87
Cat-scratch disease granulomas Rounded or
stellate, with central necrotic granular debris
and neutrophils Cat-scratch disease starts in
skin spreads to nearby lymph nodes
88
Sarcoidosis Tight naked granulomas without rim
of lymphocytes, not necrotizing
(non-caseating) Sarcoidosis is most common in
lungs spreads to nearby lymph nodes
89
LYMPHATICS The sewer system Lined by
endothelium with scant basement
membrane Secondary line of defense with police
stations (lymph nodes) at intervals
90
LYMPHATICS The sewer system Inflammation of
channels lymphangitis, of nodes
lymphadenitis Enlargement of lymph nodes
lymphadenopathy (confusing slang adenopathy)
91
SYSTEMIC EFFECTS OF INFLAMMATION (acute phase
response) 1. Fever (or hypothermia) 2.
Leukocytosis (more white blood cells in
circulation in the blood) 3. Tachycardia (rapid
heart rate) 4. Hyperventilation (tachypnea
rapid respiratory rate)
92
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
(SIRS) Heart rate gt90/minute Temperature gt38
(100.4) degrees or lt36 (96.8) degrees Respiratory
rate gt20/min or pCO2 lt32 mm Hg White blood cell
count gt12,000/cu mm or lt4,000/cu mm, or gt10
bands
93
LEUKOCYTOSIS Neutrophilia bacterial
infections Lymphocytosis viral
infections Eosinophilia allergies,
parasites Shift to the left release of
immature neutrophils from bone marrow,
especially adolescents (bands)
94
Acute phase reactants produced in abundance with
inflammation Complement, amyloid A, C-reactive
protein, fibrinogen and other clotting factors,
alpha-1-antitrypsin and other antiproteases,
ferritin, etc. Fibrinogen causes sticky
erythrocytes and increased sedimentation rate
95
OTHER SYSTEMIC EFFECTS OF INFLAMMATION
Anorexia (loss of appetite), Somnolence,
Malaise (feeling sick), Chills, Rigors
(shivering), Decreased sweating, Increased
blood pressure
96
SEPSIS SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
DUE TO INFECTION (PROVEN OR SUSPECTED) NOT a
positive blood culture
97

Sepsis
Positive blood culture

98
REPAIR By Larry Nichols, MD
99
ADHESION an abnormal connection between any 2
things in the body an inevitable side-effect of
surgery intestinal obstruction a common
complication of adhesions, requiring surgery
100
ULCER Excavation (local defect) in the surface
of an organ or tissue produced by sloughing
(shedding) of inflamed necrotic tissue (deeper
than erosion superficial sloughing of mucosa
or epidermis)
101
CONSEQUENCES OF DEFECTIVE OR EXCESSIVE
INFLAMMATION Defective Opportunistic
infections Excessive End-stage organ disease
(destruction and fibrosis) and
Cancer
102
REPAIR Regeneration
Healing (growth of fully
functional tissue Scarring to
replace injured (replacement tissue)
of functional
tissue with
non-functional
fibrous tissue)
103
REGENERATION Much less common than healing with
scarring Requires intact connective tissue
scaffold or only superficial injury (epidermal
or epithelial layer only) exception bone
marrow
104
ADHESION an abnormal connection between any 2
things in the body Fibrinous early Fibrous
late, requiring scalpel or scissors to
separate Commonly between loops of bowel, bowel
and peritoneum, fallopian tube and ovary, lung
and pleura
105
Fibrous adhesions an inevitable side-effect of
surgery intestinal obstruction a common
complication of adhesions, requiring surgery
(lysis of adhesions) with inevitable
side-effect
106
STEM CELLS Prolonged self-renewal capacity and
asymmetric replication (in every cell division,
one retains self-renewing capacity, other
enters a differentiation pathway)
107
Embryonic stem cells can give rise to any tissue
(pluripotent) Adult stem cells can only give
rise to one or a limited number of tissues
(multipotent)
108
GERM CELL LAYER DERIVATIVES Endoderm epithelial
lining of gastro- intestinal and respiratory
tracts, liver, pancreas, thyroid, parathyroid
Mesoderm bone, muscle, blood vessels,
urogenital organs, spleen, adrenal
cortex Ectoderm nervous system, skin, breasts,
pituitary, adrenal medulla
109
Mesenchyme loosely organized embryonic
connective tissue mostly from mesoderm Mesonephr
os embryonic precursor of the
ovary Mullerian derivatives uterus and
fallopian tubes
110
GROWTH FACTORS Epidermal growth factor
(EGF) Fibroblast growth factor
(FGF) Platelet-derived growth factor
(PDGF) Transforming
growth factor (TGF-alpha and
TGF-beta) Vascular endothelial growth factor
(VEGF)
111
ROLES IN REPAIR EGF fibroblast migration,
proliferation FGF fibroblast migration,
proliferation monocyte chemotaxis,
angiogenesis PDGF fibroblast migration,
proliferation monocyte chemotaxis, collagen
making TGF-beta fibroblast migration, monocyte
chemotaxis, collagen making
112
Monocyte chemotaxis PDGF,
FGF, TGF-beta Fibroblast migration PDGF, EGF,
FGF, TGF-beta, TNF Fibroblast proliferation
PDGF, EGF, FGF, TNF Angiogenesis
VEGF, FGF, angioproteins Collagen
synthesis PDGF,
TGF-beta
113
CELL SIGNAL MECHANISMS Autocrine responding to
own secretions Paracrine responding to nearby
cell secretions Endocrine responding to
distant cell secretions (hormones)
114
EXTRACELLULAR MATRIX Basement membrane
Interstitium Type IV collagen Fibrillar
collagen Laminin
Elastin Heparan sulfate Hyaluronic
acid Proteoglycans Proteoglycans
115
ORGANIZATION The replacement of injured,
necrotic and inflamed tissue by healing and scar
tissue Key cellular player fibroblast
(collagen engineer) spindle-shaped with
basophilic cytoplasm
(lots of RNA)
116
ANGIOGENESIS also called NEOVASCULARIZATION Forma
tion of new blood vessels in healing tissue (and
in tumors) Mediated by VEGF (induced by TGF,
PDGF and hypoxia), which also increases vascular
permeability and endothelial migration
proliferation
117
GRANULATION TISSUE Healing tissue with residual
chronic inflammatory cells (lymphocytes and
macrophages), cellular debris, fibroblasts,
neovascularization and new collagen Commonly
red and granular grossly
118
GRANULOMA vs GRANULATION
TISSUE (The multiple choice downfall of
many a medical student)
119
  • CUTANEOUS WOUND HEALING
  • Three overlapping phases
  • Inflammation
  • Granulation tissue
  • Wound contraction

120
CUTANEOUS WOUND HEALING Healing by first
intention clean uninfected incision with edges
approximated by surgical sutures Healing by
second intention larger wound with (commonly
irregular) edges not approximated by surgical
sutures
121
Healing by first intention narrow space fills
with blood clot (scab dehydrated surface
clot) day 1 neutrophils infiltrate day 2
epithelial cells move into it day 3 macrophages
infiltrate day 5 granulation tissue days
7-14 increasing collagen
122
Healing by second intention Larger blood clot,
More intense inflammation, More granulation
tissue, Wound contraction (done by
myofibroblasts, altered fibroblasts with smooth
muscle cell features) Scar formation (
epidermal thinning)
123
Skin wound strength day 7 10 of normal skin
month 4 75 of normal skin (for
life) Dehiscence rupture of a surgical
wound most common with abdominal
surgery associated with high intra-abdominal
pressure (vomiting, coughing, ileus shutdown of
intestinal motility)
124
KELOID hypertrophic scar more common in
African-Americans surgery to get rid of it makes
more DESMOID TUMOR also called aggressive
fibromatosis rare, borderline condition in the
grey zone between benign and malignant neoplasms
125
CONTRACTURE Abnormal excess wound contraction
resulting in deformity and impaired
movement Particularly common on palms, soles
and anterior thorax Associated with
stromelysin-1 (matrix metalloproteinase-3)
defects
126
FIBROSIS Abnormal interstitial collagen
deposition, commonly replacing normal functional
(parenchymal) tissue, usually due to chronic
inflammation, recurring injury (e.g. alcoholic
hepatitis, pancreatitis), persistent toxin
(e.g. silica, asbestos) or radiation
127
NEOPLASIA-1 By Larry Nichols, MD
128
NEOPLASM (synonym tumor) autonomous clonal
irreversible benign or malignant cell
proliferation outside of normal control by
contact inhibition, hormones, etc.
129
MALIGNANCY (synonym cancer) Neoplasm that
invades and/or
metastasizes METASTASIS Secondary site of
tumor discontinuous with the primary site
130
CARCINOMA Malignant neoplasm of epithelial cell
origin (Epithelium the purely cellular
avascular layer covering and lining all the
external and internal surfaces of the body, and
associated glands)
131
SARCOMA Malignant neoplasm of
mesenchyme-derived tissue (Mesenchyme the part
of the embryo giving rise to connective tissue
including bone, cartilage, blood vessels, etc.)
132
TERATOMA synonym MIXED GERM CELL TUMOR Benign
or malignant neoplasm with components of more
than one germ cell layer, usually all three
(ectoderm, mesoderm, endoderm)
133
HAMARTOMA Mass of mature but disorganized tissue
indigenous to its site (developmental
anomaly) CHORISTOMA Ectopic rest mass of
normal tissue present outside its normal site
(developmental anomaly)
134
POLYP Macroscopic projection above mucosal
surface a bump or a nodule on a stalk (Mucosa
lining of respiratory, gastrointestinal and
genitourinary tracts)
135
ADENOMA Benign epithelial neoplasm forming
glands or derived from glands
136
ANAPLASIA Lack of visible differentiation of
malignant tumor cells giving them the
appearance of primitive unspecialized cells
137
  • DYSPLASIA
  • Disordered growth 2 types
  • congenital embryonically abnormal
  • organization of cells
  • 2. acquired cellular atypia
  • usually premalignant, /- reversible

138
DESMOPLASIA Formation of abundant fibrous
stroma by some carcinomas (reactive) (Stroma
infrastructural part of tissue, opposite of
parenchyma, the functional part)
139
BENIGN versus MALIGNANT Cohesive
Progressively expansile
infiltrative invasive local growth
local growth Commonly with Commonly with
fibrous capsule destruction of
surrounding tissue
140
  • PATTERNS OF METASTATIC SPREAD
  • Lymphatic (to regional lymph nodes)
  • typical of carcinomas
  • 2. Hematogenous (to lung or liver)
  • typical of sarcomas
  • 3. Seeding (of body cavities or surfaces)
  • typical of ovarian carcinoma

141
  • MOST COMMON CAUSES OF
  • CANCER DEATH
  • Lung
  • 2. Breast (women), Prostate (men)
  • 3. Colon
  • Not the same as incidence

142
CHANGING INCIDENCE OF CANCER DEATH IN THE
UNITED STATES 1950-2000 Greatly increased
Lung Greatly decreased Stomach, Uterus
143
CAUSES OF CANCER Smoking Alcohol
Diet Ultraviolet light Asbestos Human papilloma
virus Obesity
144
GENETIC PREDISPOSITIONS TO CANCER Retinoblastoma
Familial adenomatosis polyposis Li-Fraumeni
syndrome Multiple endocrine neoplasia Xeroderma
pigmentosum Ataxia-telangiectasia BRCA-1 and
BRCA-2
145
  • MALIGNANT TRANSFORMATION
  • self-sufficiency in growth signals
  • growth inhibitory signal insensitivity
  • evasion of apoptosis
  • 4. defects in DNA repair
  • 5. limitless replicative potential
  • 6. sustained angiogenesis
  • 7. ability to invade and metastasize

146
ONCOGENES Genes that drive autonomous cell
growth in cancer cells like an accelerator pedal
stuck to the floor SIS gene (some brain, bone
cancers) ERB-B2 (Her2/neu, some breast) K-RAS
(some colon, lung, pancreas) C-MYC (Burkitt
lymphoma)
147
TUMOR SUPPRESSOR GENES Genes that apply brakes
to cell proliferation RB gene
(retinoblastoma) p53 gene (many tumor
types) APC/beta-catenin pathway (colon) INK4a/ARF
locus (pancreas, etc.)
148
RB gene product (retinoblastoma susceptibility
protein) hypophosphory- lated, prevents cell
proliferation by binding up transcription factor
E2F Phosphorylated by cyclin D1-CDK4, it lets
E2F go start cell proliferation Infants born
with one defective copy (first hit) get
retinoblastomas at an early age when their
second copy goes bad (second hit)
149
p53 GUARDIAN OF THE GENOME Molecular policeman,
prevents propagation of genetically damaged
cells, binds to DNA, arrests cell cycle for DNA
repair, initiates apoptosis if repair
impossible Most common target of genetic
alteration in human tumors
150
p53 GUARDIAN OF THE GENOME Short half-life (20
minutes) ended by ubiquitin proteolysis Resistanc
e to p53 mediated by increased MDM2 or by E6
protein of HPV, which degrade p53 Response to
chemoradiotherapy mediated by p53 p53 family
p63 and p73
151
APC gene product breaks down beta-catenin so it
doesnt bind to transcription factor that turns
on c-MYC, CYCLIN D1 other genes that drive
cell proliferation APC mutations are in 100 of
colon cancers with familial adenomatous
polyposis, 70-80 of the rest and 20 of
hepatocellular carcinomas
152
p16INK4a competes with cyclin D1 for binding to
CDK, decreasing the amount of cyclin D1-CDK,
which would phosphorylate RB, releasing E2F to
start cell proliferation p16INK4 mutations are
in 50 of pancreatic cancers and squamous cell
carcinomas of esophagus
153
At least 1 of 4 key cell cycle regulators (RB,
p16INK4a, CYCLIN D, CDK4) is bad in vast
majority of cancers
154
MORE TUMOR SUPPRESSOR GENES NF-1 and NF-2
(neurofibromatosis) VHL (Von Hippel Lindau,
kidney etc.) PTEN (endometrium, brain) TGF-beta
pathway (pancreas, etc.) WT-1 (Wilms tumor)
Cadherins (esophagus, colon, etc.) KLF6
(prostate) Patched (PTCH, basal cell carcinoma)
155
NF-1 gene product (neurofibromin) activates
GTPase, creating GDP that binds to cell membrane
RAS protein making it inactive (not transducing
growth factor signals for proliferation) Inherite
d mutation neurofibromatosis type 1, numerous
benign neurofibromas due to second hit mutations
156
Von Hippel Lindau (VHL) gene product causes
ubiquitination and degradation of hypoxia
inducible transcription factor-1 that would
yield increased PDGF and VEGF and tumor
angiogenesis Germ line mutation kidney
cancer, pheochromocytoma (adrenal medulla
tumor), retinal angioma other tumors with
second hit mutations
157
Phosphate and tensin homologue (PTEN) gene
product increases transcription of p27 Cip/Kip
cell cycle inhibitor, causes cell cycle arrest,
apoptosis and inhibition of cell motility PTEN
deletions are in many cancers, but particularly
malignancies of endometrium, prostate and brain
158
NEOPLASIA-2 By Larry Nichols, MD
159
DEFECTS IN DNA REPAIR Hereditary non-polyposis
cancer syndrome Xeroderma pigmentosum Ataxia
telangiectasia Bloom syndrome Fanconi
anemia BRCA-1 and BRCA-2
160
SUSTAINED ANGIOGENESIS Required to grow larger
than 2 mm Tortuous irregular leaky tumor-induced
blood vessels mediated by VEGF Angiogenic switch,
bFGF, loss of p53, decreased thrombomodulin-1,
increased HIF-1 Overcoming anti-angiogenic
factors (angiostatin, endostatin, tumstatin)
161
CHROMOSOMAL ALTERATIONS Aneuploidy (abnormal
number) Translocations (e.g. Burkitt lymphoma
t(814) translocating MYC oncogene) Amplification
s (e.g. Her2/neu amplification of ERB B2,
breast cancer)
162
CANCER INVASION 4 STEPS 1. Detachment of
tumor cells from each other 2. Attachment
of tumor cells to basement membrane 3.
Degradation of basement membrane
extracellular matrix 4. Migration
163
CANCER INVASION Detachment of tumor cells
from each other (down-regulation of E-cadherin
or mutated catenin) Attachment of tumor cells
to basement membrane (by laminin or fibronectin
receptors)
164
CANCER INVASION Degradation of basement
membrane extracellular matrix (type IV
collagen by matrix metalloproteinases) Migration
through basement membrane and extracellular
matrix (mediated by e.g. autocrine motility
factor)
165
METASTASES Millions of cancer cells released
for each one that metastasizes Characteristic
patterns (e.g. colon to liver, prostate and
breast to bone) due to drainage pathways and
organ tropism
166
METASTATIC ORGAN TROPISM MECHANISMS Differenti
al concentration of endothelial cell ligands for
adhesion molecules in different
organs Chemokines (e.g. CXCR4 and CCR7
receptors in breast cancer)
167
METASTASIS mediated by adhesion molecules
(integrins, laminin receptors, CD44) Degradation
of laminin-5 by matrix metalloproteinase-2
generating a fragment enhancing cell motility
168
GATEKEEPERS AND CARETAKERS Gatekeeper genes
directly control tumor growth like an
accelerator pinned to the floor (oncogenes) or
faulty brakes (tumor suppressor genes) Caretaker
genes affect genetic stability by e.g. causing
defective DNA repair
169
CHEMICAL CARCINOGENESIS Initiators cause
mutations, which become irreversible in the
progeny of the mutated cell, if not reversed in
it Promoters cause reversible proliferation of
initiated cells
170
CHEMICAL CARCINOGENESIS Direct chemical
carcinogens are few, generally reactive
electrophiles Indirect chemical carcinogens
require metabolic activation of procarcinogens
commonly by cytochrome P450-dependent
mono-oxygenases
171
CHEMICAL CARCINOGENS Anti-cancer
drugs Polycyclic heterocyclic aromatic
hydrocarbons Aromatic amines, amides, azo
dyes Asbestos Estrogen Alcohol, etc.
172
RADIATION CARCINOGENESIS Long latent period
(years-decades) Ultraviolet light causes skin
cancer Radiation therapy causes
sarcomas Nuclear power plant leaks cause
thyroid cancer
173
MICROBIAL CARCINOGENESIS HPV causes uterine
cervical cancer EBV causes lymphoma HBV and HCV
cause hepatic cancer Helicobacter pylori causes
gastric carcinoma and lymphoma
174
ANTI-TUMOR IMMUNE SURVEILLANCE TUMOR
ANTIGENS Mutated oncogene products Products of
other mutated genes Overly or aberrantly
expressed proteins Oncogenic viral products
175
ANTI-TUMOR IMMUNE SURVEILLANCE TUMOR
ANTIGENS Oncofetal antigens (e.g. CEA,
AFP) Altered cell surface glycolipids or
glycoproteins (e.g. CA-125, CA-19-9) Cell type
specific differentiation antigens
176
IMMUNE SURVEILLANCE EFFECTOR MECHANISMS Principa
l CD8 cytotoxic lymphocytes Other Natural
killer cells (activated by IL-2)
Macrophages (activated)
Antibodies
177
IMMUNE SURVEILLANCE RESISTANCE
MECHANISMS Selective outgrowth of Ag-neg
cells, Decreased MHC molecules Lack of
co-stimulation, Antigen masking Apoptosis of
cytotoxic lymphocytes Immunodeficiency
178
DIRECT EFFECTS OF TUMORS Impingement on adjacent
structures Obstruction (e.g. of
intestine) Functional activity (e.g.
hormones) Surface ulceration /- bleeding /-
infection Infarction /- rupture
179
PARANEOPLASTIC SYNDROMES Symptoms not
attributable to direct effects of tumor (or
hormones native to the primary tumor
organ) Occur in about 10 of cancer
patients Not counting cachexia (wasting) in a
class by itself
180
PARANEOPLASTIC SYNDROMES Can be the earliest
manifestation of occult tumor Can be sickening,
even fatal by themselves May mimic metastatic
disease
181
PARANEOPLASTIC SYNDROMES Hypercalcemia (most
common) Cushing syndrome (ACTH) Syndrome of
inappropriate ADH Hypoglycemia (insulin) Carcinoid
syndrome (serotonin) Eaton-Lambert syndrome
(myasthenia)
182
PARANEOPLASTIC SYNDROMES Acanthosis
nigricans Dermatomyositis Hypertrophic
osteoarthropathy Migratory thrombophlebitis
(Trousseau syndrome) Marantic (non-bacterial
thrombotic) endocarditis
183
TUMOR STAGE Anatomic extent of tumor, including
primary tumor size, extent of lymph node and
distant metastases TUMOR GRADE Qualitative
assessment of the differentiation of a tumor
(extent to which it resembles normal tissue at
primary site)
184
DIAGNOSIS OF CANCER DISCOVERY Symptoms,
Signs, Radiology Serum markers (e.g. PSA,
CA-125, CA-19-9, HCG, AFP, CEA, Immunoglobulins)
185
DIAGNOSIS OF CANCER SPECIFIC DIAGNOSIS Biopsy
(most common, usually best) Fine needle
aspiration cytology Exfoliative cytology /-
immunohistochemistry /- flow cytometry /-
molecular testing
186
HEMOSTASIS-1 By Larry Nichols, MD
187
EDEMA Increased fluid in interstitial tissue
spaces Can be localized or generalized Hydrothor
ax fluid in pleural cavity Ascites fluid in
abdominal cavity Anasarca generalized edema
188
EDEMA PATHOPHYSIOLOGIC
CATEGORIES Increased hydrostatic
pressure Decreased plasma osmotic
pressure Lymphatic obstruction Sodium
retention Inflammation
189
EDEMA Increased hydrostatic pressure For
example, in leg, due to deep venous
thrombosis in lungs, due to left heart
failure in lower body, due to right heart failure
190
Edema due to increased hydrostatic pressure is
commonly worse in the legs when standing and
sacrum when recumbent dependent edema but
this is not specific for increased hydrostatic
pressure as the etiology Finger pressure on
edematous sub- cutaneous tissue leaving a
temporary impression pitting edema
191
EDEMA Decreased plasma osmotic pressure For
example due to nephrotic syndrome protein
loss Edema from hepatic cirrhosis is due to
increased hydrostatic pressure in the portal
venous system, but also decreased plasma osmotic
pressure due to protein loss into ascites and
deficient hepatic protein synthesis
192
LYMPHEDEMA Edema due to lymphatic
obstruction Usually localized and caused by
tumor, inflammation, surgery or radiation For
example due to scarring from parasitic
filariasis (causing elephantiasis with legs
resembling elephants legs)
193
EDEMA DUE TO SODIUM RETENTION Always
generalized, with increased hydrostatic pressure
(and, to a lesser extent, dilutional decrease in
plasma osmotic pressure) Usually caused by
renal failure or heart failure
194
EDEMA DUE TO INFLAMMATION Can be localized (at
site of infection) or generalized (with systemic
inflammatory response syndrome SIRS or
sepsis)
195
Generalized edema due to, for instance, renal
failure may appear initially in tissues with a
loose connective tissue matrix such as, for
instance, around the eyes, causing periorbital
edema.
196
PULMONARY EDEMA Most common cause left heart
failure Others acute respiratory distress
syndrome (ARDS), hypersensitivity reaction,
pneumonia, renal failure Typically frothy fluid
(pink if blood in it) Symptom dyspnea Sign
pulmonary rales
197
CEREBRAL EDEMA Can be localized (abscess or
tumor) or generalized (encephalitis,
etc.) Generalized swollen gyri and narrowed
sulci Can be fatal due to herniation of
cerebellar tonsils into foramen magnum
compressing brainstem respiratory center
198
HYPEREMIA (erythema) active increase in arterial
blood flow CONGESTION (cyanosis) passive
decrease in venous outflow When due to heart
failure, get nutmeg liver alternating red
centri- lobular and tan peripherilobular
tissue, and hemophages in pulmonary alveoli
may occur without congestion
199
HEMORRHAGE extravasation of blood due to blood
vessel rupture Hematoma hemorrhage enclosed
within tissue Petechia tiny (1-2 mm)
hemorrhage due to platelet deficiency
200
Purpura medium (3-10 mm) bleed due to
vasculitis, vessel fragility, etc. Ecchymosis
larger (over 1 cm) subcutaneous hemorrhage, goes
from red-blue to blue-green to gold-brown as
the hemoglobin breaks down Hemothorax
hemorrhage into a pleural cavity
201
Hemopericardium hemorrhage into pericardial
space Hemoperitoneum hemorrhage into
abdominal cavity Hemarthrosis hemorrhage into
a joint (associated with hemophilia)
202
HEMOSTASIS the maintenance of blood in a
free-flowing liquid state in normal blood
vessels and formation of a blood clot
(hemostatic plug) at a site of vascular
injury Regulated by three components vascular
wall (endothelium), platelets, coagulation
cascade
203
Platelets cellular component of blood,
anucleate pieces of megakaryocyte cytoplasm
important in initiation and propagation of
clotting Platelets contain ADP, fibrinogen,
clotting factors V and VIII, calcium and
epinephrine (all important in hemostasis)
204
  • 4 STAGES OF HEMOSTASIS
  • AT SITE OF VASCULAR INJURY
  • vasoconstriction
  • primary hemostasis
  • secondary hemostasis
  • thrombus and antithrombotic events

205
STAGE 1 VASOCONSTRICTION Brief arteriolar
vasoconstriction mediated by reflex neurogenic
mechanisms, augmented by local secretion of
vasoconstrictors (e.g. endothelin, a potent
endothelium-derived vasoconstrictor)
206
STAGE 2 PRIMARY HEMOSTASIS Platelet adhesion to
thrombogenic extracellular matrix, activation,
release of ADP and thromboxane A2, additional
platelet recruitment and aggregation
207
STAGE 3 SECONDARY
HEMOSTASIS Activation of the coagulation
cascade by tissue factor (membrane-bound
procoagulant made by endothelium) and platelet
factors Culminating in conversion of fibrinogen
to fibrin by activated thrombin
208
STAGE 4 THROMBUS AND
ANTITHROMBOTIC EVENTS Formation of solid
permanent plug of aggregated platelets and
polymerized fibrin Counterregulatory mechanisms
to limit the hemostatic plug to the site of
injury
209
Endothelial antiplatelet antithrombotic factors
in normal blood vessels Prostacyclin
(prostaglandin I-2) and nitric oxide inhibit
platelet adhesion to endothelium and
aggregation, and are potent vasodilators Adenosi
ne diphosphatase degrades ADP (platelet
aggregation signal)
210
Endothelial anticoagulant antithrombotic factors
in normal blood vessels Membrane-bound
heparin-like molecules interact with
antithrombin-III to inactivate thrombin and
factor Xa Thrombomodulin converts thrombin to
anticoagulant which activates protein C Tissue
factor pathway inhibitor inhibits factor Xa and
factor VIIa-tissue factor
211
Endothelial fibrinolytic antithrombotic factors
in normal blood vessels Tissue-type plasminogen
activator (t-PA) promotes fibrinolytic activity
to clear fibrin deposits on endothelium surface
212
Endothelial prothrombotic factors at a site of
vascular injury vonWillebrand factor
(vWF) essential cofactor for platelet adhesion
to collagen Tissue factor (induced by IL-1, TNF
endotoxin) activates extrinsic pathway of
coagulation cascade Plasminogen activator
inhibitors
213
Platelet prothrombotic factors at a site of
vascular injury Adhesion to collagen via GpIb
receptor for vWF Release of ADP and thromboxane
A2 Aggregation mediated by ADP- induced
conformational change of GpIIb-IIIa receptors
for fibrinogen
214
PLATELET BLOCKING BY DISEASE VonWillebrand
disease vWF deficiency Bernard-Soulier
syndrome GpIb defect Glanzmann thrombasthenia
GpIIb-IIIa deficiency (all congenital genetic
diseases)
215
PLATELET BLOCKING BY MEDICINE Aspirin
irreversible block of TxA2 synthesis by
cyclooxygenase inactivation Eptifibatide
(Integrilin) inhibition of platelet
GpIIb-IIIa receptors Clopidogrel (Plavix)
irreversible block of platelet ADP receptors
216
SIMPLIFIED COAGULATION CASCADE Intrinsic
pathway Factor XII activates XI, which
activates IX, which activates VIII Extrinsic
pathway Tissue factor activates VII, which
activates IX Common pathway IX activates X,
which activates II, which activates I
217
SIMPLIFIED COAGULATION CASCADE Factor II
prothrombin, activated (factor
IIa) thrombin Factor I fibrinogen, factor Ia
fibrin Cascade requires phospholipid surface,
calcium and cofactors, complex only available on
activated platelet or endothelial surface
yields limit control
218
COAGULATION CASCADE CONTROL Antithrombins, e.g.
ATIII, activated by heparin-like molecules on
endothelium, inhibit thrombin, IXa, Xa, XIa and
XIIa Proteins C and S, protein C activated by
thrombomodulin, inactivates Va VIIIa Tissue
factor pathway inhibitor secreted by
endothelium, inactivates Xa and tissue
factor-VIIa
219
COAGULATION CASCADE CONTROL Fibrinolysis by
plasmin generated from plasminogen by t-PA (and
urokinase- like PA and factor XII-dependent
path) Plasmin breaks down fibrin interferes
with polymerization, generating fibrin split
products, and is itself inactivated by
alpha-2-antiplasmin
220
HEMOSTASIS-2 By Larry Nichols, MD
221
  • THROMBOSIS
  • Inappropriate formation of blood clot
  • in a blood vessel (usually occlusive)
  • Three predisposing factors
  • Endothelial injury
  • Abnormal blood flow
  • Hypercoagulability

222
ENDOTHELIAL INJURY The most important factor
predisposing to thrombosis The hemodynamic
stress of hypertension or the toxicity of
hypercholesterolemia or products absorbed from
smoking can increase endothelial procoagulant
factors or decrease their anticoagulant factors
enough to cause thrombosis.
223
ABNORMAL BLOOD FLOW Either turbulence or stasis
predisposes to thrombosis Turbulent blood flow
over ulcerated atherosclerotic plaques promotes
arterial thrombosis So does stasis in arterial
aneurysms
224
HYPERCOAGULABILITY Primary (genetic) Factor V
Leiden mutation (activated protein C
resistance, 2-15 of whites) Prothrombin gene
mutation (1-2) Methyltetrahydrofolate reductase
gene mutation (mild hyperhomocystenemia)
ATIII, protein C or protein S deficiency (all
rare)
225
HYPERCOAGULABILITY Secondary (acquired)
Bed-ridden state Cancer Surgery or trauma
Disseminated intravascular coagulation
Heparin-induced thrombocytopenia
Antiphospholipid antibody syndrome
226
Disseminated intravascular coagulation Widespread
fibrin thrombi in arterioles, capillaries and
venules Complication of severe infection,
advanced malignancy, massive trauma, various
obstetric crises, etc. Worst in brain, heart,
lungs kidneys Leads to consumptive coagulopathy
227
Heparin-induced thrombocytopenia Autoimmune
formation of antibodies against complexes of
heparin and platelet factor 4 Causes platelet
activation and thrombosis Much less common with
low-molecular weight heparin than unfractionated
228
Antiphospholipid antibody syndrome Formation of
antibodies to plasma protein epitopes unveiled
by binding to phospholipid Causes syndrome of
arterial venous thromboses (rarely) but
artefactual prolongation of clotting in test
tube Commonly associated with lupus Hence
misnomer lupus anticoagulant
229
THROMBOSIS Treatment Thrombolytic therapy
(t-PA) Thrombectomy (surgery) Anticoagulation
Acute heparin (IV or subcutaneous) Chronic
oral warfarin (Coumadin) inhibits synthesis
of active form of vitamin K-dependent clotting
factors II, VII, IX and X
230
THROMBI Arterial thrombi tend to be rich in
platelets (white thrombi) Venous thrombi tend
to be rich in erythrocytes (red thrombi) On
the wall of the heart mural thrombi
231
THROMBI On heart valves vegetations
(non-bacterial thrombotic endocarditis, until
infected, then infective endo- carditis, but
some are autoimmune, e.g. Libman-Sacks
endocarditis in systemic lupus erythematosus)
232
  • THE 4 FATES OF A THROMBUS
  • Propagation
  • Embolization
  • Dissolution
  • Organization ( recanalization)

233
ORGANIZATION Can occur in pneumonias, exudates,
injuries, etc., not just thrombi Ingrowth by
FIBROBLASTS, who convert it to fibrous tissue,
with ingrowth of new capillaries, who can
coalesce to recanalize a thrombosed blood vessel
234
EMBOLUS Detached intravascular solid, liquid or
gaseous mass carried by the blood to a site
distant from its point of origin Types thrombus
(overwhelmingly most common), atheromatous
debris, fat, air, amniotic fluid, fragments of
tumor
235
PULMONARY THROMBOEMBOLI very common 95 from
deep vein thrombosis in legs, most clinically
silent, Medium size can cause hemorrhagic
infarction (if bronchial arterial part of dual
lung blood supply impaired), Large ones can cause
acute cor pulmonale (right heart failure) and
sudden death
236
PULMONARY THROMBOEMBOLI Saddle emboli are in
pulmonary trunk Paradoxical emboli pass through
patent foramen ovale or atrial septal defect to
go to organs besides lungs Numerous small emboli
can cause pulmonary hypertension
237
SYSTEMIC THROMBOEMBOLI Most commonly from the
heart Most commonly to the legs (or brain)
238
FAT EMBOLISM Most commonly from long bone
fractures Most clinically silent, but can cause
syndrome of sudden onset dyspnea, tachypnea,
tachycardia, irritability, restlessness, anemia
and thrombocytopenia 1-3 days following trauma
239
AIR EMBOLISM Can be caused by getting air into
intravenous infusion, sudden change in
atmospheric pressure, chest wall injury or back
surgery in prone position Generally, more than
100 ml needed to have a clinical effect, but it
can be fatal
240
AMNIOTIC FLUID EMBOLISM Caused by tear in
placental membrane Get fetal squamous cells,
lanugo hair, vernix caseosa fat and mucin in
pulmonary microcirculation Syndrome of sudden
severe dyspnea, cyanosis and shock during
delivery Causes diffuse alveolar damage DIC
241
INFARCT area of ischemic necrosis usually due
to thrombotic or embolic occlusion of an
artery Vasospasm, atheroma expansion by
intraplaque hemorrhage, tumor compressing
artery, twisting of blood vessels (torsion or
volvulus), trauma or incarcerated hernia much
less common causes
242
INFARCTS white anemic infarcts typical of
solid organs with end-arterial circulation
(heart, spleen, kidney) red hemorrhagic
infarcts typical with venous occlusion (e.g.
ovarian torsion) dual or anastomosing blood
supply (e.g. lung, intestine) or reperfusion
243
COAGULATIVE NECROSIS Most common histologic
form of infarct Usually apparent after 12-18
hours Usually with an acute inflammatory
response, peaking at 1-2 days, followed by
macrophages, fibroblasts Ischemic necrosis in
brain liquefactive Necrotizing infection can
abscess
244
  • LIKELIHOOD OF INFARCTION
  • Determined by
  • vulnerability to hypoxia (neurons
  • dead after 3 min, heart after 20 min)
  • 2. rate of development of occlusion
  • (slow allows collaterals to develop)
  • 3. nature of blood supply
  • (e.g. dual is protective, e.g. liver)
  • 4. oxygen content of blood

245
SHOCK cardiovascular collapse, systemic
hypoperfusion caused by decreased cardiac
output, decreased circulating blood volume or
sepsis Sepsis infection (proven or highly
suspected) 2 or more of the criteria for
systemic inflammatory response syndrome
246
  • Systemic inflammatory response
  • syndrome (SIRS) criteria
  • heart rate over 90/minute
  • respiratory rate over 20/min
  • (or arterial pCO2 lt32 mmHg)
  • 3. temperature over 38 degrees (100.4)
  • (or under 36 96.8)
  • 4. white blood cell count over 12,000
  • or under 4,000 or with over 10 bands

247
SEPTIC SHOCK Commonly caused by endotoxins,
gram-negative bacillary bacterial cell wall
lipopolysaccharides that bind to circulating
protein, then CD14 receptor, t
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