CELL ADAPTATION, INJURY
AND DEATH
By Larry Nichols, MD
TYPE OF NECROSIS DETERMINES
TREATMENT
Liquefactive: Drainage
Caseous:
Anti-fungal and –TB
Gangrenous: Amputation
HIGH “LIVER FUNCTION TESTS”
REFLECT INJURY, NOT FUNCTION
Double misnomer: “LFTS” are
neither specific for liver
nor tests of function
ISCHEMIA =
REVERSIBLE
CELL INJURY
Infarction = irreversible cell necrosis
due to ischemia not relieved in time
METAPLASIA
= REPLACEMENT OF A TISSUE
TYPE BY ANOTHER ONE,
FULLY DIFFERENTIATED BUT
NOT NORMAL FOR THE SITE
= a breeding ground for cancer
PATHOLOGIC APOPTOSIS
Important in certain cancers
chemotherapy
radiation
transplant rejection
Fundamental Vocabulary
Etiology = doctorspeak for “cause”
Morphology = pathologistspeak for
“visible manifestation”
Gross = pathologistspeak for
“visible without a microscope”
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
Injury = reversible pathophysiologic
and morphologic response to stress
or noxious stimulus exceeding cell
capacity to adapt, but not enough
to kill it
Cellular Adaptations
Hypertrophy
increase in cell size
(+/- organ size)
Atrophy
decrease
in same
Hyperplasia
increase in cell number
All can be physiologic or pathologic
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
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
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
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
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)
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)
“LFTs” slang jargon for “liver function
tests” usually include bilirubin,
alkaline phosphatase (“alk phos”),
alanine aminotransferase (“ALT”,
“SGPT”) and aspartate aminotransferase (“AST”, “SGOT”)
Elevated alk phos, ALT & AST are
exceedingly imperfect measures of
liver injury, and not at all of function
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)
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
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
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
Caseous necrosis = distinctive form of
coagulative necrosis grossly
resembling cheese
Gangrene = distinctive form of coagulative necrosis with blackening and
shrinkage, typically of distal extremity
Fat necrosis = digested by pancreatic
lipase, chalky white saponification
Type of necrosis determines
treatment:
Liquefactive: drainage (surgery)
Caseous:
anti-TB and anti-fungal
Gangrene:
amputation (surgery)
PATHOLOGIC APOPTOSIS
Important in
Certain cancers (not too many)
Chemotherapy
Radiation (and heat)
Transplant rejection
Hypoxia
Certain viral infections
APOPTOSIS versus NECROSIS
single cells or
small clusters
large groups
of cells
cell membrane
intact
disrupted
inflammatory response
yes
no
STEATOSIS (fatty change)
Abnormal accumulation of lipid
in hepatocytes
Due to obesity, alcohol,
diabetes mellitus, anoxia,
protein malnutrition
HEMOSIDEROSIS
Accumulation of hemoglobinderived, refractile, large, granular
brown iron pigment
Due to recent bleeding, hemolysis
or iron overload
“secondary hemochromatosis”
HEMOCHROMATOSIS
Accumulation of hemosiderin in
liver, heart, pancreas, joints and
endocrine organs
Due to a genetic disease causing
excess dietary iron absorption
“primary hemochromatosis”
LIPOFUSCIN
Wear-and-tear (aging) pigment,
intracellular insoluble small
granular brown material
composed of lipids & phospholipid
polymers complexed with protein
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
INFLAMMATION-1
By Larry Nichols, MD
ACUTE INFLAMMATION:
4 CARDINAL SIGNS & SYMPTOMS
Redness
Swelling
Heat
Pain
NEUTROPHILS:
Polymorphonuclear leukocytes
(“polys”, “PMNs”)
Granulocytes with neutral granules,
variably shaped 3- to 5-lobed nuclei
First responder phagocytes
IMPORTANT MEDIATORS OF
INFLAMMATION
Histamine, NO, PAF, arachidonic acid,
thromboxane, prostacyclin, TNF, IL-1, IL8, 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
STEROIDS BLOCK PRODUCTION
OF ARACHIDONIC ACID, PROSTAGLANDINS AND LEUKOTRIENES
Non-steroidal anti-inflammatory drugs
block only prostaglandin production
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.
INFLAMMATION:
Complex reaction to injurious agents
consisting of
(1) vascular responses
(2) leukocyte migration and activation
(3) systemic effects
ACUTE INFLAMMATION:
Rapid onset (seconds to minutes)
Short duration (minutes to a few days)
Exudation of fluid, plasma proteins
and leukocytes (primarily neutrophils)
ACUTE INFLAMMATION:
4 CARDINAL SIGNS & SYMPTOMS
Redness
Swelling
Heat
Pain
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
PUS:
Purulent exudate
rich in neutrophils, cellular debris
and (commonly) microbes
Thick, opaque, variably colored
(light green, yellow, tan, crème,
off-white)
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
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
ACUTE INFLAMMATION: CAUSES
1)
2)
3)
4)
5)
6)
infection
tissue necrosis
immune reaction
trauma
foreign bodies
physical & chemical agents
ACUTE INFLAMMATION:
VASCULAR RESPONSES
1) vasodilatation
2) increased permeability
LEUKOCYTE MIGRATION
1) margination 2) rolling
3) adhesion
4) diapedesis
5) chemotaxis
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
LEUKOCYTE ACTIVATION
Cytokine (response and secretion)
Phagocytosis (recognition, attachment*,
engulfment, killing#, degradation)
* greatly enhanced by opsonins
# hydrogen peroxide, myeloperoxidase
CONGENITAL LEUKOCYTE DEFECTs
Leukocyte adhesion deficiency-1 and -2
Chronic granulomatous disease
Myeloperoxidase deficiency
Chediak-Higashi syndrome
ACQUIRED LEUKOCYTE DEFECTS
Diabetes mellitus
Hemodialysis
Malnutrition
Leukemia
IMPORTANT MEDIATORS OF
INFLAMMATION
Histamine, NO, PAF, arachidonic acid,
thromboxane, prostacyclin, TNF, IL-1, IL8, 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
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
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
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
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
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)
Cell membrane phospholipids
Phospholipases
Arachidonic acid
Lipoxygenases
Cyclooxygenase
Leukotrienes
and Lipoxins
ProstaglandinG2
ProstaglandinH2
Prostacyclin
Thromboxane
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
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 prostaglandinmediated gastric mucosal protection,
leading to gastric bleeding
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)
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
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.
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
INFLAMMATION-2
By Larry Nichols, MD
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
SEPSIS
SYSTEMIC INFLAMMATORY
RESPONSE SYNDROME
DUE TO INFECTION
(PROVEN OR SUSPECTED)
NOT a positive blood culture
Sepsis
Positive
blood
culture
FORMS OF INFLAMMATION
1. Purulent (suppurative)
2. Abscessing (necrotizing)
3. Fibrinous
4. Serous
5. Granulomatous
[none mutually exclusive]
PURULENT INFLAMMATION
Also called suppurative
Usually acute
Production of abundant pus
Commonly caused by infection
with pyogenic bacteria
ABSCESS
(don’t 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
FIBRINOUS INFLAMMATON
Deposition of fibrin-rich exudate
on serosal surfaces
(peritoneum, pericardium, pleura)
or on meninges or in interstitium
Usually acute
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)
CHRONIC INFLAMMATION
Prolonged duration (weeks to years)
1) Active inflammation,
2) Tissue destruction and
3) Attempted repair
all proceeding simultaneously
CHRONIC INFLAMMATION:
CAUSES
1) Persistent infection (e.g. TB)
2) Prolonged toxin exposure
(e.g. silicosis)
3) Autoimmunity (e.g. lupus)
4) Unknown (e.g. atherosclerosis,
sarcoidosis, Alzheimer disease)
CHRONIC INFLAMMATION:
Cellular Players
1) Macrophages
2) Lymphocytes
3) Plasma cells
4) Eosinophils
5) Mast cells
6) Multinucleated giant cells
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)
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
MACROPHAGES
Chemotaxis by MCP-1, C5a, PDGF,
TGF-alpha, fibrinonectin and
fibrinopeptides (fragments)
Proliferation and immobilization
important in maintaining chronic
inflammation, especially in
atherosclerosis
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
PLASMA CELLS
Derived from activated B cells
Produce large amounts of singlespecificity antibody
Prominent in syphilis and
rheumatoid arthritis
EOSINOPHILS
Granulocytes with granules with
major basic protein (toxic to
parasites but also host cells)
Important in parasitic infestations
and IgE-mediated allergic reactions
MULTINUCLEATED GIANT CELLS
= syncytium of macrophages
1. Foreign body type (with nuclei
arranged haphazardly)
2. Langhans type (with nuclei
arranged peripherally)
associated with immune granulomas
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
TYPES OF GRANULOMA
1. 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)
EXAMPLES OF GRANULOMATOUS
DISEASES
1. Tuberculosis (the prototype)
2. Leprosy
3. Syphilis
4. Cat-scratch disease
5. Sarcoidosis
TB Granulomas resemble tiny
potatoes (tubercles), commonly
cheesy (caseous)
Aggregates 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
Tuberculosis is most common in lungs
spreads to nearby lymph nodes
Note: Caseating necrosis resembles
cheese grossly (not microscopically!)
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
Sarcoidosis
Tight naked granulomas without rim
of lymphocytes, not necrotizing
(non-caseating)
Sarcoidosis is most common in lungs
spreads to nearby lymph nodes
LYMPHATICS: The sewer system
Lined by endothelium with scant
basement membrane
Secondary line of defense with
police stations (lymph nodes)
at intervals
LYMPHATICS: The sewer system
Inflammation of channels =
lymphangitis, of nodes =
lymphadenitis
Enlargement of lymph nodes =
lymphadenopathy
(confusing slang “adenopathy”)
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)
SYSTEMIC INFLAMMATORY
RESPONSE SYNDROME (SIRS)
Heart rate >90/minute
Temperature >38 (100.4) degrees
or <36 (96.8) degrees
Respiratory rate >20/min
or pCO2 <32 mm Hg
White blood cell count >12,000/cu mm
or <4,000/cu mm, or >10% bands
LEUKOCYTOSIS
Neutrophilia:
bacterial infections
Lymphocytosis: viral infections
Eosinophilia:
allergies, parasites
Shift to the left: release of immature
neutrophils from bone marrow,
especially adolescents (bands)
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
OTHER SYSTEMIC EFFECTS
OF INFLAMMATION
Anorexia (loss of appetite),
Somnolence,
Malaise (feeling sick),
Chills, Rigors (shivering),
Decreased sweating,
Increased blood pressure
SEPSIS
SYSTEMIC INFLAMMATORY
RESPONSE SYNDROME
DUE TO INFECTION
(PROVEN OR SUSPECTED)
NOT a positive blood culture
Sepsis
Positive
blood
culture
REPAIR
By Larry Nichols, MD
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…
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)
CONSEQUENCES OF DEFECTIVE
OR EXCESSIVE INFLAMMATION
Defective: Opportunistic infections
Excessive: End-stage organ disease
(destruction and fibrosis)
and Cancer
REPAIR
Regeneration
(growth of fully
functional tissue
to replace injured
tissue)
Healing
Scarring
(replacement
of functional
tissue with
non-functional
fibrous tissue)
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
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
Fibrous adhesions
= an inevitable side-effect of surgery
intestinal obstruction = a common
complication of adhesions, requiring
surgery (lysis of adhesions) with
inevitable side-effect…
STEM CELLS
Prolonged self-renewal capacity
and asymmetric replication
(in every cell division, one retains
self-renewing capacity, other
enters a differentiation pathway)
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)
GERM CELL LAYER DERIVATIVES
Endoderm: epithelial lining of gastrointestinal 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
Mesenchyme = loosely organized
embryonic connective tissue
mostly from mesoderm
Mesonephros = embryonic
precursor of the ovary
Mullerian derivatives: uterus and
fallopian tubes
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)
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
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
CELL SIGNAL MECHANISMS
Autocrine: responding to own
secretions
Paracrine: responding to nearby
cell secretions
Endocrine: responding to distant
cell secretions (hormones)
EXTRACELLULAR MATRIX =
Basement membrane + Interstitium
Type IV collagen
Fibrillar collagen
Laminin
Elastin
Heparan sulfate
Hyaluronic acid
Proteoglycans
Proteoglycans
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)
ANGIOGENESIS
also called NEOVASCULARIZATION
Formation 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
GRANULATION TISSUE
Healing tissue with residual chronic
inflammatory cells (lymphocytes
and macrophages), cellular debris,
fibroblasts, neovascularization
and new collagen
Commonly red and granular grossly
GRANULOMA vs GRANULATION
TISSUE
(The multiple choice downfall of
many a medical student)
CUTANEOUS WOUND HEALING
Three overlapping phases
1. Inflammation
2. Granulation tissue
3. Wound contraction
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
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
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)
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])
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
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
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
NEOPLASIA-1
By Larry Nichols, MD
NEOPLASM
(synonym “tumor”)
autonomous clonal irreversible
benign or malignant cell proliferation
outside of normal control by
contact inhibition, hormones, etc.
MALIGNANCY
(synonym “cancer”)
Neoplasm that invades
and/or metastasizes
METASTASIS
Secondary site of tumor
discontinuous with the primary site
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)
SARCOMA
Malignant neoplasm of
mesenchyme-derived tissue
(Mesenchyme = the part of the
embryo giving rise to connective
tissue including bone, cartilage,
blood vessels, etc.)
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)
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)
POLYP
Macroscopic projection above
mucosal surface
a bump or a nodule on a stalk
(Mucosa = lining of respiratory,
gastrointestinal and genitourinary
tracts)
ADENOMA
Benign epithelial neoplasm
forming glands or
derived from glands
ANAPLASIA
Lack of visible differentiation
of malignant tumor cells
giving them the appearance
of primitive unspecialized cells
DYSPLASIA
Disordered growth: 2 types
1. congenital embryonically abnormal
organization of cells
2. acquired cellular atypia
usually premalignant, +/- reversible
DESMOPLASIA
Formation of abundant fibrous
stroma by some carcinomas
(reactive)
(Stroma = infrastructural part of
tissue, opposite of parenchyma,
the functional part)
BENIGN
versus
MALIGNANT
Cohesive
expansile
local growth
Progressively
infiltrative invasive
local growth
Commonly with
fibrous capsule
Commonly with
destruction of
surrounding tissue
PATTERNS OF METASTATIC SPREAD
1.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
MOST COMMON CAUSES OF
CANCER DEATH*
1.Lung
2. Breast (women), Prostate (men)
3. Colon
* Not the same as incidence
CHANGING INCIDENCE OF CANCER
DEATH IN THE UNITED STATES
1950-2000
Greatly increased: Lung
Greatly decreased: Stomach, Uterus
CAUSES OF CANCER
Smoking
Alcohol
Diet
Ultraviolet light
Asbestos
Human papilloma virus
Obesity
GENETIC PREDISPOSITIONS
TO CANCER
Retinoblastoma
Familial adenomatosis polyposis
Li-Fraumeni syndrome
Multiple endocrine neoplasia
Xeroderma pigmentosum
Ataxia-telangiectasia
BRCA-1 and BRCA-2
MALIGNANT TRANSFORMATION
1. self-sufficiency in growth signals
2. growth inhibitory signal insensitivity
3. evasion of apoptosis
4. defects in DNA repair
5. limitless replicative potential
6. sustained angiogenesis
7. ability to invade and metastasize
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)
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.)
RB gene product (retinoblastoma
susceptibility protein) hypophosphorylated, 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)
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
p53 GUARDIAN OF THE GENOME
Short half-life (20 minutes) ended
by ubiquitin proteolysis
Resistance 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
APC gene product breaks down
beta-catenin so it doesn’t 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
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
At least 1 of 4 key cell cycle regulators
(RB, p16INK4a, CYCLIN D, CDK4)
is bad in vast majority of cancers
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)
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)
Inherited mutation neurofibromatosis
type 1, numerous benign neurofibromas
due to second hit mutations
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
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
NEOPLASIA-2
By Larry Nichols, MD
DEFECTS IN DNA REPAIR
Hereditary non-polyposis cancer
syndrome
Xeroderma pigmentosum
Ataxia telangiectasia
Bloom syndrome
Fanconi anemia
BRCA-1 and BRCA-2
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)
CHROMOSOMAL ALTERATIONS
Aneuploidy (abnormal number)
Translocations (e.g. Burkitt lymphoma
t(8:14) translocating MYC oncogene)
Amplifications (e.g. Her2/neu
amplification of ERB B2, breast cancer)
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
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)
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)
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
METASTATIC ORGAN TROPISM:
MECHANISMS
Differential concentration of
endothelial cell ligands for adhesion
molecules in different organs
Chemokines (e.g. CXCR4 and
CCR7 receptors in breast cancer)
METASTASIS mediated by
adhesion molecules
(integrins, laminin receptors, CD44)
Degradation of laminin-5 by
matrix metalloproteinase-2
generating a fragment
enhancing cell motility
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
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
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
CHEMICAL CARCINOGENS
Anti-cancer drugs
Polycyclic & heterocyclic aromatic
hydrocarbons
Aromatic amines, amides, azo dyes
Asbestos
Estrogen
Alcohol, etc.
RADIATION CARCINOGENESIS
Long latent period (years-decades)
Ultraviolet light causes skin cancer
Radiation therapy causes sarcomas
Nuclear power plant leaks cause
thyroid cancer
MICROBIAL CARCINOGENESIS
HPV causes uterine cervical cancer
EBV causes lymphoma
HBV and HCV cause hepatic cancer
Helicobacter pylori causes gastric
carcinoma and lymphoma
ANTI-TUMOR IMMUNE
SURVEILLANCE: TUMOR ANTIGENS
Mutated oncogene products
Products of other mutated genes
Overly or aberrantly expressed proteins
Oncogenic viral products
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
IMMUNE SURVEILLANCE:
EFFECTOR MECHANISMS
Principal: CD8+ cytotoxic lymphocytes
Other: Natural killer cells
(activated by IL-2)
Macrophages (activated)
Antibodies
IMMUNE SURVEILLANCE:
RESISTANCE MECHANISMS
Selective outgrowth of Ag-neg cells,
Decreased MHC molecules
Lack of co-stimulation,
Antigen masking
Apoptosis of cytotoxic lymphocytes
Immunodeficiency
DIRECT EFFECTS OF TUMORS
Impingement on adjacent structures
Obstruction (e.g. of intestine)
Functional activity (e.g. hormones)
Surface ulceration
+/- bleeding +/- infection
Infarction
+/- rupture
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]
PARANEOPLASTIC SYNDROMES
Can be the earliest manifestation of
occult tumor
Can be sickening, even fatal by
themselves
May mimic metastatic disease
PARANEOPLASTIC SYNDROMES
Hypercalcemia (most common)
Cushing syndrome (ACTH)
Syndrome of inappropriate ADH
Hypoglycemia (insulin)
Carcinoid syndrome (serotonin)
Eaton-Lambert syndrome (myasthenia)
PARANEOPLASTIC SYNDROMES
Acanthosis nigricans
Dermatomyositis
Hypertrophic osteoarthropathy
Migratory thrombophlebitis
(Trousseau syndrome)
Marantic (non-bacterial thrombotic)
endocarditis
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)
DIAGNOSIS OF CANCER:
DISCOVERY
Symptoms, Signs, Radiology
Serum markers (e.g. PSA, CA-125,
CA-19-9, HCG, AFP, CEA,
Immunoglobulins)
DIAGNOSIS OF CANCER:
SPECIFIC DIAGNOSIS
Biopsy (most common, usually best)
Fine needle aspiration cytology
Exfoliative cytology
+/- immunohistochemistry
+/- flow cytometry
+/- molecular testing
HEMOSTASIS-1
By Larry Nichols, MD
EDEMA = Increased fluid
in interstitial tissue spaces
Can be localized or generalized
Hydrothorax = fluid in pleural cavity
Ascites = fluid in abdominal cavity
Anasarca = generalized edema
EDEMA: PATHOPHYSIOLOGIC
CATEGORIES
Increased hydrostatic pressure
Decreased plasma osmotic pressure
Lymphatic obstruction
Sodium retention
Inflammation
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
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 subcutaneous tissue leaving a temporary
impression = pitting edema
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
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 elephant’s legs)
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
EDEMA DUE TO INFLAMMATION
Can be localized (at site of infection)
or generalized (with systemic
inflammatory response syndrome
[SIRS] or sepsis)
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.
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
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
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 centrilobular and tan peripherilobular tissue,
and hemophages in pulmonary alveoli
* may occur without congestion
HEMORRHAGE = extravasation of
blood due to blood vessel rupture
Hematoma = hemorrhage enclosed
within tissue
Petechia = tiny (1-2 mm) hemorrhage
due to platelet deficiency
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
Hemopericardium = hemorrhage into
pericardial space
Hemoperitoneum = hemorrhage into
abdominal cavity
Hemarthrosis = hemorrhage into a
joint (associated with hemophilia)
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
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)
4 STAGES OF HEMOSTASIS
AT SITE OF VASCULAR INJURY
1. vasoconstriction
2. primary hemostasis
3. secondary hemostasis
4. thrombus and antithrombotic events
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)
STAGE 2: PRIMARY HEMOSTASIS
Platelet adhesion to thrombogenic
extracellular matrix, activation,
release of ADP and thromboxane A2,
additional platelet recruitment and
aggregation
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
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
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
Adenosine diphosphatase degrades
ADP (platelet aggregation signal)
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
Endothelial fibrinolytic antithrombotic
factors in normal blood vessels
Tissue-type plasminogen activator
(t-PA) promotes fibrinolytic activity
to clear fibrin deposits on
endothelium surface
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
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 ADPinduced conformational change of
GpIIb-IIIa receptors for fibrinogen
PLATELET BLOCKING BY DISEASE
VonWillebrand disease: vWF deficiency
Bernard-Soulier syndrome: GpIb defect
Glanzmann thrombasthenia: GpIIb-IIIa
deficiency
(all congenital genetic diseases)
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
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
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]
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
COAGULATION CASCADE CONTROL
Fibrinolysis by plasmin generated from
plasminogen by t-PA (and urokinaselike 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
HEMOSTASIS-2
By Larry Nichols, MD
THROMBOSIS
Inappropriate formation of blood clot
in a blood vessel (usually occlusive)
Three predisposing factors:
1. Endothelial injury
2. Abnormal blood flow
3. Hypercoagulability
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.
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
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)
HYPERCOAGULABILITY
Secondary (acquired)
Bed-ridden state
Cancer
Surgery or trauma
Disseminated intravascular coagulation
Heparin-induced thrombocytopenia
Antiphospholipid antibody syndrome
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
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
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”
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]
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”
THROMBI
On heart valves = “vegetations”
(non-bacterial thrombotic endocarditis,
until infected, then infective endocarditis, but some are autoimmune,
e.g. Libman-Sacks endocarditis
in systemic lupus erythematosus)
THE 4 FATES OF A THROMBUS
1.Propagation
2.Embolization
3.Dissolution
4.Organization (& recanalization)
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
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
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
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
SYSTEMIC THROMBOEMBOLI
Most commonly from the heart
Most commonly to the legs
(or brain)
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
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
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
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
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
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
LIKELIHOOD OF INFARCTION
Determined by
1. 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
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
Systemic inflammatory response
syndrome (SIRS): criteria
1. heart rate over 90/minute
2. respiratory rate over 20/min
(or arterial pCO2 <32 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
SEPTIC SHOCK
Commonly caused by endotoxins,
gram-negative bacillary bacterial
cell wall lipopolysaccharides that
bind to circulating protein, then
CD14 receptor, then Toll-like
receptor protein 4, decreasing
TFPI and thrombomodulin,
increasing TNF, then IL-1, then IL-6
3 STAGES OF SHOCK
1. Non-progressive
reflex compensatory mechanisms
maintain perfusion of vital organs
2. Progressive
worsening lactic acidosis, etc.
3. Irreversible
death even if cause of shock
reversed
SHOCK: Histological Manifestations
Red (dead) neurons
Pulmonary diffuse alveolar damage
Myocardial coagulation or contraction
band necrosis
Renal acute tubular necrosis
Centrilobular hepatic necrosis
Hemorrhagic ischemic enteritis
Adrenal cortical lipid depletion
SHOCK: Clinical Manifestations
Decreasing mental status
(confusion, lethargy, delirium, coma)
Decreasing urine output
If hypovolemic or cardiogenic: weak
rapid pulse, cool clammy cyanotic skin
If septic: warm flushed skin