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Cellular changes

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1. Growth Adaptations
Hyperplasia and Hypertrophy
o Hypertrophy (increase in cell size)
Involves gene activation, protein synthesis, & production of organelles
o Hyperplasia (increase in cell number)
Involves production of new cells from stem cells

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Pathologic hyperplasia can progress to dysplasia and cancer
Ex: endometrial hyperplasia endometrium grows and sheds each month, but if its
overexposed to estrogenhyperplasiacarcinoma
Classic Exception: benign prostatic hyperplasia (BPH) no inc risk for cancer
o Both generally occur together
Ex: uterus during pregnancy
Pi o Exception: permanent tissues do not have stem cells and can ONLY undergo hypertrophy
Cardiac myocytes, skeletal muscle, and nerve are all permanent hypertrophy only
Atrophy decrease in cell size & number
o 1. Decrease in cell number, via apoptosis (see later)
o 2. Decrease in cell size via
1. Ubiquitin-proteosome degradation of cytoskeleton pathway
Cytoskeleton intermediate filaments must be broken down proteasome
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recognizes Ubiq-tagged cytoskeleton
2. Autophagy of cellular components
Cell consumes its own components in vacuoles, which fuse with lysosomes
Metaplasia change in cell type
o General: most commonly involving surface epithelium (new cells can handle stress better)
o Example
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Barrett Esophagus esoph-gastro jxn is squamous-columnar

Too much refluxstress squamous to columnar nonciliated mucinous
o Mechanism
Via reprogramming of stem cells
Reversible with removal of driving stressor (ie, treating the GERD)
o Metaplasia can progress to dysplasia & cancer (Barretts)
Exception: Apocrine metaplasia
Seen with fibrocystic changes of the breast NO inc risk for cancer
o Vitamin A deficiency has three main consequences/associations (plus those in FA)
1. Night-blindness
2. Associated with APML (AML M3 subtype) as a treatment (all-trans retinoic acid)
VitA is necessary for maturation of the immune system
3. Metaplasia
The conjunctiva of the eye is a very delicate squamous epithelium that requires vitA
to remain in that state with a deficiencymetaplasia
Thickening of the conjunctival surface is called Keratomalacia
o Mesenchymal tissues can also undergo metaplasia
Note: mesenchyme (conn tissue) includes bone, fat, cartilage, etc
Ex: myositis ossificans: inflammation of the skeletal muscle causes metaplasia of bone
Inflammation of muscle due to trauma, and as it heals, muscle forms bone
Dysplasia
o Disordered cellular growth - refers to proliferation of precancerous cells (ie, CIN)
o Arises from longstanding pathologic hyperplasia (endometrial h.plasia) or metaplasia
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o Dysplasia is reversible, but if it persists, can progress to carcinoma (irreversible)
Aplasia failure of cell production during embryogenesis (unilateral renal agenesis)

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Hypoplasia decrease in cell prod during embryogenesis
o Results in a small organ (ex: streak ovary in Turner syndrome)

Cellular Injury
General
o Injury occurs when stress exceeds cells ability to adapt (rather than growth, you get injured)

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o Depends on 3 major factors
Stress (inflammation will prob cause a growth adaptation), severity (rapid = infarction vs
gradual = atrophy ischemia), and type of cell affected (neurons vs skel musc)
Common causes of injury
o Inflammation, nutritional def or excess, hypoxia, trauma, genetic mutations
Hypoxia (low O2 delivery to tissue)
o General: Low o2 = low respiration = low ATP = injury
Pi Low ATP disrupts key cell functions
Na-K pump: Na cant get out, so water stays in toocell swells
Ca pump: Goal of cell is to maintain super LOW Ca conc inside cytosol
Aerobic glycolysis
o Etiology
Ischemia:
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1. Dec blood flow thru artery a thrombus for ex
2. Dec blood flow thru vein (no fresh blood to organ) Budd Chiari, for ex
o Budd due to polycythemia vera or Lupus anticoagulant (anti-phospholoipid
Abhypercoagulable)
3. Shock: hypoperfusion
o Cardiogenic, hypovolemic, neurogenic, septic shock
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Hypoxemia: low partial pressure of O2 in the blood (Pa02<60mm, Sa02<90%)

O2 goes from air (Fi02)PA02Pa02Sa02 (on Hb)
o KEY: Pa02 is low in hypoxemia, so anything before it being low too
Ex: high altitude Fi02 is decreased, causing hypoxemia
Ex: inc PAco2 = dec PA02 (hypoventilation, COPD, fibrosis)
Decreased O2-carrying capacity of blood
o Arises with Hb loss or dysfunction
Anemia: decreased RBC mass, but Pa02 and Sa02 are NORMAL (just dec O2 content)
CO Poisoning: normal Pa02, dec O2 content, dec Sa02 (CO w/ higher affinity for Hb)
o Exposures include smoke from fires & car exhaust/gas heaters
o Earliest sign of exposure is headache
o Cherry red appearance of skin
Methemoglobinemia
o Fe in heme is oxidized to Fe3+, which can NOT bind o2 - Fe2 binds o2
o Pa02 is normal, Sa02 is decreased (like CO poisoning)
o Seen with oxidant stress (sulfa, nitrite) or in newborns
o PRESENTATION: Cyanosis with chocolate-colored blood
Treat with methylene blue (reducing agent)
o Initial phase of injury is reversible
Hallmark is cellular swelling
Leads to loss of microvilli (due to swelling of cell), membrane blebbing (swelling causes
bumps), & swelling of RER (decreased protein synthesis)
o Eventually, damage becomes irreversible
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Hallmark is membrane damage
Three main membranes that get damaged

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1. Plasma membrane: ie, if troponin leaks into blood = irreversible damage (MI)
o Leads to enzymes leaking into blood, & Ca rushing into cell
2. Inner mitochondrial membrane
o Irreversible, bc giving O2 wont even help
o Cytochrome c in mito leaks into cytoplasminduces apoptosis
3. Lysosome

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o Contains lytic enzymes so if they get out cell damage
o Ca, which rushes in activates these enzymes bad problem!
o End result of irreversible injury is cell death see next lecture

Cell Death
General irreversible injury
o Hallmark is loss of nucleus, via pyknosis (shrinks), karyorrhexis (break up nuc), & karyolysis
Pi o Two mechanisms: necrosis and apoptosis
Necrosis
o General
Death of a large group of cells, followed by acute inflammation
Due to underlying pathologic process NEVER physiologic
o Coagulative Necrosis
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Seen with ischemic infarct of any organ, except the brain
Necrotic tissue that remains firm, Nucleus disappears
Cell shape & organ structure are preserved by coagulation of cellular proteins
Usually area of infarct is wedge-shaped (tip points to occlusion) and pale
Red infarct is when blood re-enters loosely organized tissue
o Liquefactive Necrosis
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Enzymatic lysis of cells & proteins results in liquefaction of necrotic tissue

Seen in 3 circumstances
Brain infarction (microglial digestion), abscess (PMNs destroy tissue), pancreatitis
(autoactivation of enzymes & digestion of pancreatic parenchyma itself vs fatty
necrosis which is of surrounding fat)
o Gangrenous necrosis
Coag necrosis that resembles mummified tissue (dry gangrene)
Characteristic of ischemia of lower limb & GI tract
If infection occurs on top of dead tissue, then liquefactive necrosis ensues (wet gangrene)
o Caseous Necrosis
Soft, friable necrotic tissue w/ cottage-cheese appearance
Combo of coag and liquefactive necrosis (watery but with some substance)
Characteristic of granulomatous inflammation due to TB or fungal infection
o Fatty Necrosis
Necrotic adipose tissue w/ chalky-white appearance due to deposition of Ca
SAPONIFICATION
Seen in trauma to fat (breast), & pancreatitis (peripancreatic fat, NOT parenchyma)
Can present as a mass a giant cell reaction; you see a mass, giant cells, and calcium
o Saponification
Fatty acids released by trauma or lipase join w/ calcium
Its an ex of dystrophic calcification dead tissue is a perfect place for Ca to deposit
Dead fat (saponification) and psammoma bodies are places Ca deposits
o Serum Ca and phosphate are NORMAL
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Vs metastatic calcification (not cancer) elevated serum Ca/po4, Cainto tissue

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o Fibrinoid Necrosis
Necrotic damage to blood vessel wallproteins leakbright pink staining
Characteristic of malignant hypertension or vasculitis
Woman in third trimester with proteinuria think preeclampsiafibrinoid necrosis
of the placenta
Apoptosis

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o General
Energy-dependent, genetically programmed cell death of single/small grps of cells
Endometrial shedding, embryogenesis, CD8 T-cell mediated killing virally infected cells
o Morphology
1. Dying cell shrinks (becomes eosinophilic and pink) as everything condenses
2. Nucleus condenses & fragments
Pi 3. Apoptotic bodies fall from cell and are removed by mphages NO inflammation follows
o Pathogenesis
Caspases mediated apoptosis via activation of:
Proteases to break down cytoskeleton, & Endonucleases to break down DNA
Caspases are activated by 3 pathways
1. Intrinsic mitochondrial pathway
o Bcl2 normally stabilizes cytochrome c - cellular injury (remember mito
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membrane damage is irreversible), DNA damage, or dec hormonal
stimulation inactivates Bcl2
o Cytochrome c leaks into cytoplasm & activates caspases - KEY
2. Extrinsic receptor-ligand pathway
o FAS ligand-FAS death R (CD95) on target cell for T-cell negative selection
o TNF binds TNF receptor on target cell
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o Ex: negative selection of T cells in thymus

3. Cytotoxic CD8 T-cell pathway
o CD8 recognize Ag on MHC I, & kill by secreting perforins (to create pore) and
granzymes to activate caspases

Free Radical Injury

General
o FR is a chemical species with an unpaired electron in outer orbit
o FR are generated both pathologically AND physiologically
o FR peroxidize lipids, and oxidize DNA (mutationscancer!) and proteins
Oxidative Phosphorylation review
o Cytochrome c transfers e- to O2; partial reduction creates O2radical, H2O2, and OHradical
o O2O2- (superoxide) H2O2 OHH2O
Thus, needs 4 electrons to become water if it only gets a few electronsradicals
Pathological generation
o Ionizing radiation: The radiation hits water within tissuesOHrad formation
Note: of all the free radicals, the OHrad is the MOST DAMAGING
o Inflammation: PMNs have two mechanisms of killing
O2 dependent: oxidative burst O2O2- via NADPH oxidaseH2O2 via superoxide
dismutaseHOCl via myeloperoxidase (MPO) (see next chapter)
Key is the first step, which generates a FR
O2 independent: see next chapter
o Metals (copper, iron): Cu and Fe are usually well-bound
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Fenton reaction allows Fe to create a OH free radical
These build up and cause FR (Hemochromotosis & Wilsons)

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KEY: underlying cause of damage in these diseases is the generation of FR
o Drugs & chemicals (acetaminophen) - CCl4 (carbon tetrachloride) see below
Elimination of FR
o Antioxidants: vitA, E, C
o Metal carrier proteins: Cu and Fe generate FR, so transferrin & ferritin bind them
o Enzymes: 3 major ones - Remember: 0202- H202OH-H2O

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SOD: deals with O2-
Catalase: deals with hydrogen peroxide, H2O2
Glutathione peroxidase: deals with OH- by using glutathione
Carbon tetrachloride, CCl4 classic in the dry-cleaning industry
o Gets converted to CCl3 in the blood via p450 system in liver
o CCl3 builds up in liver and causes damage reversible cellular swellingdec RER protein synthesis
Pi dec cholesterol synthesis & lack of apolipoproteins
Thus, fat can get into the liver, but cant get packaged to get outfatty liver change
Reperfusion injury
o Irreversible injurymembrane damageenzymes leak out into the blood
o Returning blood to organO2 and inflammatory cells return and generate FR more damage
Continued elevation of cardiac enzymes w/ reperfusion (ie, in cath lab)
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Amyloidosis
Amyloid: misfolded protein that deposits in extracellular space, & can damage tissues
Multiple proteins can deposit as amyloid
o B-pleated sheet config, w/ congo red staining & apple-green birefringence under polarized light
o Tends to deposit around blood vessels
Systemic Amyloidosis
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o Primary Type
Systemic deposition of AL amyloid derived from Ig light chain
Associated with plasma cell dyscrasias overproduction of light chain
Plasma cell normally produces light & heavy chain in equal proportions
o Secondary Type
Systemic deposition of AA amyloid derived from SAA (
SAA is an acute phase reactant that is increased during chronic inflammation, malignancy, &
Familial Mediterranean fever (PMN dysfxnhigh SAA, esp at serosal surfaces like heart)
o Clinical findings
Nephrotic Syndrome; kidney is MC organ involved
Restrictive cardiomyopathy or arrhythmia
Tongue enlargement, malabsorption, & hepatosplenomegaly
o Diagnosis
Requires tissue biopsy (usually at abnormal fat pad or rectum - easy targets)
o Damaged organs must be transplanted, amyloid can NOT be removed
Localized Amyloidosis
o Senile Cardiac Amyloidosis
Non-mutated serum transthyretin (2nd MC protein) deposits in heart usually asx
Associated with age (25% of people >80yo)
o Familial amyloid cardiomyopathy
Mutated serum transthyretin deposits in heartrestrictive CM
5% of blacks carry mutated gene
o Type 2DM (NIDDM)
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Amylin (derived from insulin) deposits in islets of pancreas
o Alzheimer disease

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Abeta (AB) amyloid deposits in brain forming amyloid plaques
Derived from B-amyloid precursor protein on chromosome 21 (down syndrome!)
o Dialysis-assd amyloidosis
B2-microglobulin (normally stabilizes MHC I), & isnt filtered well in dialysis patient builds
up & deposits in joints
o Medullary carcinoma of Thyroid
Calcitonin deposits within tumor

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C-cells within the neuroendocrine cells of thyroid secrete calcitonin; a tumor of C
cells causes an overprod of calcitoninamyloid production
Thyroid mass with fine needle aspiration shows tumor cells in amyloid background)
Note: We Bx thyroid masses via FNA

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2. Inflammation and Wound Healing

Fluid phase is first, followed by PMN stage at 24 hrs, and then mphage stage at ~2-3 days
Acute inflammation (AI)
General
o Characterized by presence of edema & neutrophils in tissue
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o Arises in response to two stimuli: 1. Infection or 2. Tissue necrosis
o AI is an IMMEDIATE response w/ limited specificityInnate immunity
Note: innate immunity includes: epithelium protects, mucus secretions, complement
system, mast cells, mphages, PMNs
Vs adaptive immunity, which takes longer & more spp includes lymphocytes
AI mediated by several factors:
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Toll-like receptors (TLRs): present on cells of innate immune sys (mphages, dendritic cells)
o Recognize PAMPs (pathogen assd molecular patterns) & lets body know
o Ex: CD14 is a TLR on mphage surface that recognizes LPS on outer membrane of G- bacteria
o TLR activationupregulation of NF-kB, which turns on the molecular response
o TLRs are also present on cells of adaptive immunity (mediating chronic inflammation)
Arachidonic Acid
o Released from phospholipid membrane by phospholipase A2
o Acted on by cyclooxygenase or 5-lipooxygenase
COX pathway produces prostaglandins
PGD2, PGI2, PGE2 mediate vasodilation (at arterioles) & inc vascular permeability
(at post-capillary venules) - PGE2 also mediates fever (fEEEver) & pain
5-lipooxygenase pathway produces leukotrienes
LTB4 attracts & activates PMNs
o 4 mediators activating PMNs: LTB4, C5a, IL-8, & bac products
LTC4, LTD4, LTE4 mediate v.constriction, bronchospasm, & inc vascular permeability
(contract pericytes) basically contract sm muscle
Mast Cells
o Activated by 3 things
o 1. Tissue trauma
o 2. Complement proteins C3a & C5a
o 3. Cross-linking of cell-surface IgE by Ag
o Immediate response: release of preformed histamine granules
v.dilation (dilation of arteriole sm musc), & inc vasc permeability (post-cap venule)
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o Delayed Response
Prod of AA metabolites, esp leukotrienes to maintain the acute inflammatory response

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Complement
o Pro-inflammatory serum proteins; complement inflammation; Circulate as inactive precursors
o Activation of Complement: 3 pathways
o 1. Classical pathway: C1 binds to IgG or IgM that is bound to Ag
o 2. Alternative pathway: Microbial products directly activate complement
o 3. Mannose-binding lectin pathway: MBL binds mannose on microorganisms & activate complement

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o Result of all pathways:
C3 convertaseC3a & C3b; C3b helps produce C5 convertaseC5a & C5b; C5b complexes
with C6 to C9 to form MAC
o Key products
C3a & C5a: trigger mast cell degranulation
C5a: chemotactic for neutrophils (C5a, IL-8, LTB4, & bac products)
Pi NOTE: C5a & LTB4 upregulate Integrin production (PMN adhesion)
C3b: opsonin for phagocytosis
MAC: lyses microbes by creating holes in membrane
Hageman factor
o Inactive pro-inflammatory protein produced in liver
o Activated upon exposure to subendothelial or tissue collagen, which activates:
Coagulation & fibrinolytic systems (role in DIC & G- sepsis); complement
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Kinin system: cleaves HMWkininogen to bradykinin, which mediates vasodilation, increased
vascular permeability, & pain (as well as PGE2)
Cardinal Signs of Acute Inflammation
o Redness (rubror) and warmth (calor)
Due to vasodilation (inc bl flow); occurs via relaxation of arteriolar sm musc
Key mediators: histamine (MAIN ONE), PGs (D2, I2,E2), & bradykinin
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o Swelling (tumor)
Due to leakage of fluid from postcapillary venules into interstitial space
Key mediators: 1. Histamine; 2. Tissue damage
o Pain (Dolor)
Bradykinin & PGE2 (fEEEver & pain), sensitize sensory nerve endings
o Fever
Pyrogens cause mphages to release IL-1 & TNF, which go thru blood to perivascular cells of
hypothalamus (temp regulation site) to increase COX activity
Inc COX activityincreased PGE2, which raises temp set point
Neutrophil Arrival & Function
o Step 1: Margination
Vasodilation slows blood flow in postcap venulesturbulent flow
Cells marginate from center of flow to periphery
o Step 2: Rolling
Marginated cells at periphery slow down via Selectins
Selectins are upregulated on endothelial cells
P-selectin is released from Weibel-Palade bodies; mediated by histamine
WP bodies also secrete vWF
E- selectin is induced by TNF & IL-1
While P and E selectin are on endothelial cells, L-selectin is on PMNs
Selectins bind sialyl Lewis X on leukocytes: interaction = rolling along vessel wall
o Step 3: Adhesion
Stop the leukocyte dead in its tract so it can cross firm adhesion
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Cellular adhesion molecules (I-CAM) are upregulated by TNF & IL-1
Integrins (LFA-1) upregulated on leukocytes by C5a & LTB4 (activate PMNs!)

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o Step 4: Transmigration & chemotaxis
Leukocytes transmigrate endothelium of postcap venules & move via chemical attractants
PMNs are attracted by LTB4, C5a, IL-8, and bacterial products
o Step 5: Phagocytosis
Consumption of pathogens or necrotic tissue, & Enhanced by opsonins (IgG and C3b)
Pseudopods from leukocytes extend to form phagosomes
Its internalized & merged w/ lysosomes to form phagolysosomes

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Impairment of phagolysosome Chediak-Higashi Syndrome
o Step 6: Destruction of phagocytosed material
Phagolysosome is where the consumed material is destroyed
Occurs via 2 ways: o2 dependent (better mechanism) and independent (see below)
o Step 7: Resolution
Pi PMNs disappear within 24 hours via apoptosis (this is what pus is)
Leukocyte Adhesion Deficiency: AutoR defect of integrins (CD18 subunit) no PMN adhesion
o Delayed separation of umbilical cord (when UC necroses, no PMNs to separate)
o Increased circulating PMNs (lost margination pool) & recurrent bacterial infections that lack pus
Chediak-Higashi Syndrome (AR)
o Protein trafficking (microtubule) defect, cant get phagosome to lysosome to form phagolysosome
o Features:
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Inc risk for pyogenic infections
Neutropenia (BM problem), defective primary hemostasis (bad platelet granules)
Giant granules in leukocytes: the granules keep building up bc cant be moved
Albinism: 1 melanocyte forms melanin (pigments) for ~25 keratinocytes; if cant move the
melanin albinism
Peripheral neuropathy: need to traffic proteins down axons if absentneuropathy
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O2 dependent killing:
o HOCl generated by oxidative burst in phagolysosome
o O2O2- via NADPH oxidaseH2O2 via superoxide dismutaseHOCl via myeloperoxidase
Diseases of O2-dependent Killing:
Chronic Granulomatous Disease
o Due to NADPH oxidase defect (X-linked or autoR)
o Infection & granuloma formation with catalase-positive organisms
Most bacteria naturally form H2O2, so even if were NADPH oxidase deficient, we can
bypass the step and form bleach (HOCl) to kill them except those that degrade this H2O2
with catalase
S. Aureus, Pseudomonas cepacia, S. marcescens, Nocardia, Aspergillus
o Nitroblue tetrazolium test to screen
Turns blue if NADPH oxidase can convert O2 to O2- (thus, neg test or colorless = bad)
MPO deficiency: defective conversion of H2O2 to HOCl
o Increased risk for Candida infections, but most pt are asymptomatic
o NORMAL NBT test (turns blue)
O2-Independent Killing:
o Less effective; occurs via enzymes in leukocyte 2ndary granules (lysozyme & major basic protein)
Macrophage predominates after PMNs
o Derived from monocytes in blood, which enter via SAME STEPS AS PMNS
o Ingest via phagocytosis and destroy via O2-independent mechanism, esp lysozyme
o Mphages manage next step of acute inflammatory process by doing diff things:
Resolution/healing via IL-10 & TGF-B: anti-inflammatory & call in healing
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Or if more needs to be done, continued acute inflammation via IL-8 (call in more PMN)
As long as mphages secrete IL-8, we keep having AI via more PMNs

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Or can form abscess (forming wall of fibrosis to confine inflammation)
Or cause chronic inflammation (ie a virus, which isnt handled well by AI) via MHC II

Chronic Inflammation
General
o Lymphos & plasma cells in tissue delayed response, but more spp (adaptive immunity)

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Stimuli
o Persistent inflammation (MC)
o Infection w viruses, mycobacteria, parasites, & fungi, AI disease, Foreign material, Some cancers
Immunology
o T lymphos produced in BM as progenitor T cells and develop in thymus
In thymus, TCR undergoes rearrangement
Progenitor cells become CD4 helper (MHCII) or CD8 cytotoxic T cells (MHC i)
Pi o Activation of T cells requires:
1. Binding of Ag/MHC complex
2. Additional 2nd signal (see below)
o CD4 T cell activation
Extracellular Ag is phagocytosed & presented via MHC II (APCs)
B7 on APC binds CD28 on CD4 T cell, providing 2nd activation signal
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28 divided by 7 = 4
These activated cd4 T cells secrete 2 subsets of cytokines to help inflammation:
1. Th1: helps the CD8 T cells
IL-2 (T cell growth factor & CD8 t cell activator)
IFN-y (mphage activator)
2. Th2: helps B cells
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IL-4: class switching to IgG and IgE

IL5: eosinophil chemotaxis & activation, maturation of B cells to plasma cells, & class
switching to IgA
IL-10: inhibits Th1
o Mphages can secrete IL-10 to shut off the inflammatory response
o CD8 T cell activation
Intracellular Ag processed & presented via MHC I tells CD8 if foreign protein or not
2nd signal is from IL-2 of CD4 Th1 cell
Ag killing via CD8 (see apoptosis lecture) caspases activeated via 2 ways
1. Secretion of perforins & granzyme to induce apoptosis of target cell
o Key enzyme activated by granzyme: caspases
2. Expression of FasL, binds Fas on target cellapoptosis
Three ways of activating Caspases - Review
o 1. Intrinsic mitochondrial pathway: driven by cytc leaking out
o 2. Extrinsic receptor pathway: Fas-FasL and TNF binding cells
o 3. CD8 T cell dumping granzyme, activating caspases
o B- Cell Activation: 2 ways
Immature B cells are produced in bone marrow & undergo Ig rearrangement to become
nave B cells that express surface IgM and IgD
1. Ag binding by surface IgM or IgD
The B cell becomes a plasma cell secreting IgM (or IgD)
2. B-cell Ag presentation to CD4 T cell via MHC II (B cell acts as an APC)
2nd signal: CD40 receptor on B cells binds CD40L on helper T cell to activate it
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Activation of helper T cell then secretes Il-4 & IL-5 to mediate B-cell isotype
switching, hypermutation, & maturation to plasma cells

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Granulomatous inflammation: subtype of chronic inflammation
o General
Defining characteristic of granuloma: epitheliod histiocyte (mphage w/ pink cytoplasm)
May or may not be surrounded by giant cell & rim of lymphocyte
o Types:
o Noncaseating Granulomas Lack Central Necrosis

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Ex: reaction to foreign material, sarcoidosis, beryllium, Crohns, Cat-Scratch Dz
Be sure to be able to differentiate sarcoidosis & beryllium look similar!
Ulcerative Colitis does NOT have granulomatous inflammation
o Hallmark of UC: Crypt Abscesses
Cat-Scratch Dz: stellate-shaped noncaseating granulomas, usually in neck
o Caseating Granuloma
Characteristic of TB (stain with AFB) or Fungal infection (stain with GMS/silver)
Pi o Steps involved in granuloma formation (both types)
1. Mphages present Ag via MHC II to CD4 T cells key interaction of mphage and CD4
2. Mphages then secrete IL-12, inducing CD4 helper T cells into Th1 subtype
3. Th1 then secrete IFN-y, converting mphages into epitheliod histiocytes & giant cells

Primary Immunodeficiency
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DiGeorge Syndrome
o General
Developmental failure of the 3rd & 4th pharyngeal pouches
Due to 22q11 microdeletion
o Presentation
T-cell deficiency (lack of thymus): problems fighting viruses & fungal infections
Te

Hypocalcemia (lack of parathyroids)

Abnormalities of heart, great vessels, & face
SCID
o General
Defective cell-mediated (T cell) & humoral (B cell) immunity
o Etiologies
1. Cytokine receptor defects: cytokines secreted by CD4 T cell helps B cells mature & CD8 T
cells, so if missingSCID
2. Adenosine deaminase deficiency: it usually deaminates adenosine and deoxyadenosine
If def so these two build up, they are toxic to lymphocytes
3. MHC II deficiency: its usually recognized by CD4 T cells, which is important for CD8 and B
cells causes problems in many things
o Clinical
Fungal, viral, bacterial, & protozoal infections also, opportunistic infx & live vaccines
o Tx: Sterile isolation (bubble boy); stem-cell transplant (stem cell can generate normal cells)
X-linked agammaglobulinemia:
o General: Due to disordered B-cell maturationnave B cells cant mature to plasma cells, so they
cant drop immunoglobulins into the blood
o Complete lack of Ig in the blood
o Due to mutated Bruton tyrosine kinase (BTK)
A signaling molecule necessary for B cell to become a plasma cell
o Presentation
After 6 months of life pt has transient immunity from mother
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Bacterial (no opsonization), enterovirus (no IgA), & Giardia infections KEY w/ no Ig
Live vaccines (polio) must be avoided

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Common Variable Immune Deficiency (CVID)
o Low Ig (vs XLA) due to B-cell or helper T cell defects
o Inc risk for bacerital, entrovirus, & Giardia infx, usually late in childhood (again, bc low Ig)
o Inc risk for AI diseases and lymphoma
IgA Deficiency
o Low serum & mucosal IgA MC Ig deficiency

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o Increased risk for mucosal infections, especially viral
o IgA def common in Celiac Dz
Hyper-IgM syndrome
o Characterized by elevated IgM
o Due to mutated CD40L or CD40 receptor
Remember 2 ways B cells get activated
1. Nave B cells express IgM and bind an AgIgM secreting plasma cell
Pi nd
2. B cells can internalize the Ag and present it on MHC IICD4 1st stimulus
o The 2nd stimulus is CD40, expressed by B cell to bind Receptor on T cell
o T cell then secretes Il-4 & IL-5 to allow class-switching
2 signal cant be delivered to helper T cells during B cell activation
Cytokines necessary for Ig class switching are then not produced
Low IgA, IgG, & IgEpyogenic infections, especially at mucosal sites
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Wiskott-Aldrich Syndrome
o Triad: Thyrombocytopenia bleeding, petechiae; Eczema skin rash; Recurrent infections (defective
humoral & cellular immunity)
o Due to mutation in WASP gene: X-linked
Complement Deficiencies
o C5-C9 deficiency: increased risk for Neisseria infection
Te

o C1 inhibitor deficiency: hereditary angioedema - characterized by edema of skin (esp periorbital) &
mucosal surfaces
No inhibitor, so overactive complementvasodilation, vascular perm, etc

Autoimmune Disorders
General: Characterized by immune-mediated damage of tissues 1% prevalence in US
Pathophys: Involves loss of self-tolerance
o Self-reactive lymphos normally undergo apoptosis or become anergic
Etiology: Enviro triggers in genetically susceptible individuals
o Increased incidence in twins & association with certain HLA subtypes
SLE
o General
Ab versus host damage multiple tissues (Systemic AI disease)
Type 2 (cytotoxic, Ab binds and destroyes) and type 3 (Ag-Ab complex) HSR
o Clinical
Fever & weight loss, Pleuritis & pericarditis, Arthritis, CNS psychosis
Malar butterfly rash, esp upon exposure to sunlight
Renal damage diffuse proliferative GN is MC injury & common COD
Heart - Endocarditis, myocarditis, or pericarditis; Libman-Sacks endocarditis
LSE: vegetations on both sides of the valve
Anemia, TCP, or leukopenia due to Ab against all three of these
o Diagnosis
Characterized by ANA & anti-dsDNA Ab
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ANA is sensitive, anti-dsDNA is specific
Antihistone Ab is characteristic of drug-induced lupus PIMPS-HQ

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Procainamide, INH, minocycline, phenytoin, sulfonamides, hydralazine, quinidine
S
o Anti-phospholipid Syndrome
Ab against proteins bound to phospholipids
2 MC Ab:
Anticardiolipin: false-pos syphilis test

ra
Lupus anticoagulant: falsely elevated PTT lab studies
These patients are actually hypercoagulable they form arterial & venous thrombi
o DVT, hepatic vein thrombosis (Budd-Chiari), placental thrombosis (recurrent
pregnancy loss), & stroke
o Requires lifelong anticoagulation
Sjogren Syndrome
o General
Pi AI destruction of lacrimal & salivary glands
Lymphocyte-mediated damage (type 4 HSR) with fibrosis
o Clinical
Dry eyes, dry mouth, & recurrent dental carries in an older women (saliva cleans teeth)
Cant chew a cracker, & dirt in my eyes
Increased risk for B-cell lymphoma
st
Presents as unilateral enlargement of parotid late in disease course
o The parotids are usually bilaterally fibrosed and big, so if one suddenly gets
biggerlymphoma
o Diagnosis
Characterized by ANA & anti-ribonucleoprotein Ab
Anti-SSA, & anti-SSB: the target is RIBONUCLEAR PROTEINS
Te

Assd with other AI diseases, especially RA

Scleroderma
o General
AI tissue damage w/ activation of fibroblasts & deposition of collagen (fibrosis)
Can be diffuse or localized type
o Diffuse Type: exhibits diffuse skin & early visceral involvement
Almost any organ can be involved
Esophagus commonly affected low LES pres poor motility of liquids & solids
Characterized by ANA and anti-DNA topoisomeraise I (Scl-70) Ab
o Localized Type: local skin and late visceral involvement
CREST
C: calcinosis/ anti-Centromere Ab
R: Raynaud phenomenon
E: esoph dysmotility
S: sclerodactyly
T: telangiectasias of skin
Mixed Connective Tissue Disease
o AI-mediated tissue damage w/ mixed features of SLE, systemic sclerosis (SS), polymyositis
o Characterized by serum Ab against U1 ribonucleoprotein

Wound Healing
General
o Healing is initiated when inflammation begins
 s
Occurs via combo of regeneration (replace w/ same tissue) & repair (scar placement)
Regeneration

te
o Replaces damaged tissue w/ native tissue
o Dependent on regenerative capacity of tissue
o Tissues are divided into 3 types based on regenerative capacity
o 1. Labile Tissue
Tissues that continuously cycle to regenerate tissue
Bowels: stem cells in mucosal crypts

ra
Skin: stem cells in the basal layer (most inner layer of epidermis)
Bone marrow: hematopoietic stem cells (MARKER: CD34+)
o 2. Stable tissues
Quiescent, but can reenter cell cycle
Liver: regeneration by compensatory hyperplasia after partial resection
Renal Tubular Cells: after ATN
Pi o 3. Permanent tissue
Lack significant regenerative potential you get REPAIR
Myocardium, Skeletal muscle, neurons
Repair
o Replaces damaged tissue with fibrous scar
Occurs when regenerative stem cells are lost, or if tissue lacks regenerative capacity
o Granulation tissue is INITIAL phase of repair, and have 3 components
1. Fibroblasts deposit type III collagen
st
2. Capillaries provide nutrients
3. Myofibroblasts contract wound
o Eventually results in scar formation
Type III collagen is replaced with type I collagen (stronger)
o Type 1: in Bone, B-one high tensile strength
Te

o Type 2: cartilage, car two lage

o Type 3: bl vessels, granulation tissue, embryonic tissue - very pliable
o Type 4: Basement Membrane
Collagenase removes type III collagen, & requires zinc as a cofactor
Mechanisms of regeneration & repair
o Mediated by paracrine signaling via growth factors (by mphages, for ex)
o Interaction of factors w/ receptors results in gene expression & cellular growth
o Ex:
TGF-a: epithelial & fibroblasts growth factor
TGF-B: important fibroblast growth factor, & inhibits inflammation
Remember mphages secrete TGF-B & IL-10 to inhibit inflammation
PDGF: endothelium, sm muscle, fibroblast growth factor
Platelets are activated to seal a damaged vessel by secreting PDGF
FGF: angiogenesis; skeletal development (misnomer fibroblast growth factor)
VEGF: angiogenesis
Cutaeneous healing occurs via primary or secondary intention
o Primary: wound edges brought together with minimal scar formation
o Secondary: edges are NOT approximated granulation tissue fills in the defect
Myofibroblasts of granulation causes contraction of the wound
Delayed Wound Healing
o Infection is MCC
o VitC (hydroxylation), copper (lysyl oxidase), or zinc deficiency
Need hydroxylation of proline or lysine residues to make strong procollagen
 s
o Other causes include foreign body, ischemia, diabetes, & malnutrition
Dehiscence: Rupture of wound: MC to be seen after abdominal surgery

te
Hypertrophic Scar
o Excess production of scar tissue that is localized to wound
o Predominantly made of type 1 collagen
Keloid
o Excess production of scar tissue that is WAY out of proportion of the wound
o Characterized by excess type III collagen

ra
o More common in blacks, and classic at earlobes, face, & upper extremities

3. Neoplasia
Neoplasia
Basic Principles
o New tissue growth unregulated, irreversible, & monoclonal (vs hyperplasia and repair)
Pi o Monoclonal: cells are derived from single mother cell
Clonality can be determined by G6PD isoforms (or androgen receptor isoforms)
In hyperplasia, G6PD isoform ratio will be maintained (polyclonal)
Clonality of B cells is determined by Ig light chain phenotype LC is either kappa or lambda (3:1)
o Ie, infection: hyperplasia (polyclonal proliferation) ratio is maintained at 3:1
o Ie, lymphoma one cell making all the malignant cells ratio is changed! (20:1, for ex)
st
Both benign & malignant tumors are monoclonal, but B remain local and do NOT met; malignant tumors
(cancer) invade locally, and CAN metastasize
Tumor nomenclature
o Epithelium can be adenoma/adenocarcinoma or papilloma/papillary carcinoma)
Adeno = glandular
o Mesenchyme (conn tissue) lipoma/liposarcoma; angio, osteo, chondro, etc
Te

o Lymphocyte no benign form! Malignant forms: lymphoma/leukemia

o Melanocyte Nevus (mole) is benign/melanoma is malignant
Epidemiology
o Cancer is 2nd leading COD in both adults & children
Adults COD: 1. Cardiovascular; 2. Cancer; 3. Cerebrovascular dz
Children: 1. Accidents; 2. Cancer; 3. Congenital defects
o MC cancer in adults
By incidence: breast/prostate>lung>colorectal
By mortality: lung>breast/prostate>colorectal
o Goal of screening is to catch dysplasia (reversible mutations) before it becomes carcinoma
(irreversible mutations), and/or detect carcinoma before clinical Sx arise
Pap smear helps detect cervical dysplasia
Mammography picks up breast cancer before Sx, and ductal carcinoma in situ
PSA & DRE
Remember prostate cancer tends to grow from posterior peripheral aspect
o Rarely causes Sx bc urethra is in center (BPH)
Hemoccult test & colonoscopy (remove the adenomas before they become carc)
Approximately 30 divisions of the single mutated cell occur before earliest Sx arise
o Each division (doubling time) = more mutations; late detection = poor prognosis

Carcinogenesis
General
o Carcinogens are things that damage DNA (oncogenic viruses, chemicals)
 s
See slide in book for carcinogens
We use alkylating agents as chemo to treat cancer can cause 2ndary lymphoma/leukemia

te
Oncogenic Viruses
o EBV: nasopharyngeal carcinoma (Chinese & African male presents as neck mass), Burkitt
lymphoma, & CNS lymphoma in AIDS
o HHV-8: Kaposi sarcoma tumor of endothelial cells; seen in eastern European males,
immunosuppressed
o HBV/HCV: HCC

ra
o HTLV-1: adult T-cell leukemia/lymphoma
o High-risk HPV: squamous cell carcinoma of vulva, vagina, anus, cervix; also adeno of cervix
Radiation
o Ionizing: nuclear reactor accidents/radiotherapy splits h2o to generate OH- free radicals
Assd with AML, CML, & papillary carcinoma of thyroid
o Nonionizing (UVB sunlight) formation of pyrimidine dimers in DNA, which are normally excised by
endonucleases (absent in xeroderma pigmentosum)
Pi
Carcinogenesis 2
Assd with basal cell carcinoma, squamous cell carc, & melanoma of skin

3 key regulatory systems: proto-oncogenes, tumor suppressor genes, & regulators of apoptosis
Proto-oncogenes: genes essential for cell growth & differentiation
o Mutations = oncogenes, and broken into 4 categories (when any get mutated):
st
o Normally these are proto-oncogenes: 1. Growth factors 2. Growth factor receptors 3. Signal
transducers 4. Cell cycle regulators when mutated, they become oncogenes
o GF binds to receptor, signal transduced to nucleus and deals with regulators NORMAL
See slide in book for growth factors
o The main thing with RAS is the mutation in the GTPase-activating protein that doesnt let RAS
convert GTP (active) to GDP (inactive), resulting in too much signal being sent
Te

o ABL: the 9-22 translocation defines CML, but can also be seen in some ALL
9-22 is the Philadelphia chromosome, and when assd w/ ALL, poor prognosis
o Nuclear regulators are a group of transcription factors that go to the nucleus and upregulate genes
necessary for growth
m-MYC: Burkitts Lymphoma - the Ig heavy chain sits on chr14 (on state), and the myc
gene is on chr8 if theres a translocation, so myc is sitting in the chr14 location, it will be
turned on as welloverproduction of myc
starry sky appearance of the burkitt lymphoma (mphages eating dying cell)
o Cell-cycle regulators assist movement thru cell cycle
G1-s phase is the most highly-regulated phase
Mantle-cell lymphoma is due to the 11-14 translocation (cyclin D1 is on chr11)
Cyclin D allows cell to go G1 to S, and when translocated to chr14 (which is where
the IgH was) gets turned on and over expressed
Note that in the lymph node, you have a follicle (where B cells are), and the mantle
surrounds the follicle (marginal zone can sometimes be present and surround the
mantle) note mantle is region immediately adjacent to follicle

Carcinogenesis 3: Clinical characteristics of neoplasia

General
o Low nuclear : cytoplasm ratio = benign, with no metastatic potential
o Benign tumors NEVER metastasize, malignant tumors do have metastatic potential The ABSOLUTE
distinction bw benign and malignant
Benign tumors are also slow-growing, well-circumscribed, distinct, and MOBILE
 s
Malignants are rapid-growing, infiltrative, poorly circumscribed, and fixed to surr tissues
o Carcinoma: epithelial in origin; sarcoma = mesenchymal in origin

te
The only way to make a definitive diagnosis is EXCISION or BIOPSY done by pathologist

Immunohistochemistry
o See slide in book
Muscle Immunohistochemistry (IHC): can be desmin, caldesmon, or actin
Myeloperoxidase IHC: myeloid cells

ra
Serum tumor markers: proteins released by the tumor
o Even with a high serum tumor marker, diagnosis can ONLY BE MADE WITH BIOPSY
Grading of cancer is microscopic assessment of differentiation
o How much like the parent tissue does it look well differentiated = resembles parent tissue
Also look at mitotic activity, etc
Staging is more important than grading for prognosis (grade is for differentiation)
o Stage: determines size and spread determined AFTER resection of tumor use TNM
Pi o T (tumor size or depth)
o N (spread to regional lymph nodes)
o M (metastasis staging) the single MOST important prognostic factor

Tumor Progression
Characteristics required for tumor to spread (locally & metastasis)
st
o Downregulation of E-cadherin (so epithelial cells arent attached together anymore)
o Cells attach to and destroy BM (laminin + type Iv collagen) (collagen via collagenases)
o Attach to fibronectin (local spread), and then spread to blood vessels or lymphatics (met)
Carcinoma
o Spread via LYMPHATICS (regional nodes) breast cancers initial site is axillary lymph nodes
Sarcoma: Hematogenously spreads
Te

o Exceptions of carcinomas that spread via blood

RCC (renal vein), HCC (hepatic vein), follicular carcinoma of thyroid, choriocarcinoma
Ovarian carcinoma spreads via seeding of body cavities
o omental cracking

4. Hemostasis and related disorders

Primary Hemostasis & Related Bleeding Disorders
Primary Hemostasis
o Goal is to form platelet plug, which is weak so we need 2ndary hemostasis to stabilize plug
o 1. Transient vasoconstriction of damaged vessels mediated by neural stimulation & endothelin
o 2. Platelet Adhesion: vWF comes in and lines the endothelium at level of subendothelial collagen
and acts as a linker to bind platelet via Gp1b
vWF comes from: endothelial cell (WeibelPalade body) & alpha granules of platelet itself
WP has p-selectin and vWF
o 3. Plt Degranulation: Shape change w/in platelets allows dumping of mediators (ADP, TXA2)
ADP induces platelets to express Gp2b/3aR, essential for plt aggregation
TXA2 (der of COX) is signal to allow for further plt aggregation
Note: TXA2 is a v.constrictor, bronchoconstrictor, and platelet aggregator
o 4. Aggregation: plt join together on top of the adhesed platelets via Gp2b/3a, using fibrinogen as
linking molecule
 s
Results in formation of WEAK platelet plug
Disorders of primary hemostasis

te
o General
Usually due to abnormalities in platelets
Divided into quantitative (not enough plt) or qualitative disorders
o Sx: MUCOSAL & SKIN BLEEDING
Epistaxis, hemoptysis, GI bleed, hematuria, menorrhagia
Intracranial bleeding occurs w/ severe TCP

ra
Sx of skin bleeding: petechiae, purpura (>3mm), ecchymoses (>1cm), easy bruising
Petechiae are a sign of TCP, and NOT usually seen w/ qualitative disorders
Not seen with qualitative problems
Disorders of Quantity
ITP: autoimmune production of IgG against platelet antigens (eg Gp2b/3a)
o General
MCC of TCP in adults and children
Pi AutoAb are produced by plasma cells in spleen and then once they bind the ab-bound plt,

o Acute form
they are consumed by m.phages in the spleen again! TCP

Arises in children weeks after viral infection/immunization

Self-limited, usually resolving w/in weeks of presentation
o Chronic form
st
Usually in adults women of child-bearing age, and 2ndary to SLE
May cause TCP in offspring anti-platelet IgG can cross placenta
o Labs: low PC, often <50K
Normal PT/PTT
Increased megakaryocytes on bone marrow biopsy (platelets destroyed outside BM)
o Tx
Te

Corticosteroids: children respond well, but adults often relapse

IVIg can raise PC in symptomatic bleeding, bc the mphages in spleen will eat these instead of
the platelet-bound immunoglobulin
Effect is short-lived
Splenectomy: eliminates both the source of the Ab AND site of destruction
Microangiopathic Hemolytic Anemia: pathologic formation of platelet microthrombi in small vessels
o Pathophys: the microthrombi occludes vessel, and causes RBC to shear as it passes thru, creating
schistocyteshemolysis of RBC (hemolytic anemia)
o Etiology: TTP or HUS
TTP: thrombotic thrombocytopenic purpura
Again, thrombotic = thrombi, TCP = platelets being used up
Due to decreased ADAMSTS13, a metalloprotease that when missing leaves vWF
undegradedmore platelet aggregationmicrothrombi
HUS
Due to endothelial damage by drugs or infectionmicrothrombi & TCP
o Due to e. coli O157:H7 in undercooked beef
o Clinical findings (TTP & HUS)
Skin & mucosal bleeding, microangiopathic hemolytic anemia, fever, renal insufficiency, CNS
abnormalities
In TTP, main problem is CNS; in HUS, main prob is renal
o Labs
TCP, increased BT
Normal PT/PTT you get adhesion but not activation of coag cascade
 s
Anemia with schistocytes
Increased megakaryocytes on bone marrow bx

te
o Tx
Plasmaphoresis (ie, to remove autoAb against ADAMST13) and corticosteroids (decreased
Ab production), esp in TTP
Disorders of Quality
Bernard-Soulier Syndrome
o A genetic GP1b deficiency: impairment of platelet ADHESION

ra
Blood smear shows mild TCP (early destruction of platelets) & enlarged platelets (released
more prematurely)
Glanzmann Thrombasthenia
o Genetic GIIb/IIIa deficiency: impaired platelet AGGREGATION
Aspirin Use ASA irreversibly inactivates COX (by acetylation)
o You get a lack of TXA2, which also impairs platelet aggregation
o TXA2 calls in other platelets for aggregation, so if not derived from COX poor aggregation

Pi
Uremia: disrupts platelet function
o Both adhesion and aggregation impairment

Secondary Hemostasis and Bleeding Disorders

General
o End product of coag cascade is thrombin, which comes in and converts fibrinogen (the linker of
st
platelets) to fibrin, which cross-links to be much more stableplatelet-fibrin thrombus
o Coag factors made by liver in inactive state until activated by: activating substances, phospholipid
surface (from platelet surface), and calcium (from dense core granules of plt)
Coagulation Cascade (@5 min on video has good explanation)
o Goal: produce factor X
o Common pathway is 10, 5, 2, 1
Te

Disorders of Secondary Hemostasis

o Clinical characteristics
Deep tissue bleeding into muscles & joints, & rebleeding after surgeries
o Labs
PT: measures extrinsic & common pathway; PTT measures intrinsic & common
PTT: fac 12 activatd by subendothelial collagen (SEC also has 3 letters like PTT)
Pt: activated by tissue thromboplastin (TT activates fac7)
Hemophilia A
o Genetic FVIII deficiency, x-linked R (thus, predominant in males), but can also get de novo
mutations, with no FHx
o Presents with deep tissue, joint, & post-surgial bleeding
Severity depends on degree of deficiency
o Labs
Elevated PTT, normal PT (bc dec fac8), normal PC and BT
o Treatment: give back factor 8
Hemophilia B: Factor IX deficiency
o Clinically resembles hemophilia A, except 9 instead of 8 is decreased
Coagulation Factor Inhibitor
o An acquired Ab against coagulation factor; anti FVIII is most common
o Same findings as hemophilia A, except when you do mixing study (mix normal plasma with
patients, PTT will NOT improve bc of inhibitor (vs hemoA will)
Von Willebrand Disease
o Genetic auto dominant vWF deficiency (MC inherited coagulation disorder)
 s
o Subtypes: can be quantitative or qualitative
o Clinical Presentation

te
Mild mucosal & skin bleeding (bc low vWF impairs plt adhesion)
Increased BT (poor adhesion), increased PTT (need vWF to stabilize fac 8), normal PT,
abnormal ristocetin test
Even though they have increased PTT, no secondary bleeding problems
Ristocedin causes aggregation, but bc no vWF, the plt wont aggregate
o Treatment

ra
Desmopressin: increases vWF release from Weibel-Palade bodies of endo cells
Vitamin K deficiency
o General
VitK is needed for gamma-carboxylation of factors 2, 7, 9, 10, C, S
VitK activated by epoxide reductase (Coumadin blocks it) in the liver
o Etiology
Pi Newborns: gut not yet colonized by bacteria; long-term abx; malabsorption
Liver Failure: no production of coag factors & decreased epoxide reductase
Effects will be seen via PT
Large-Volume Transfusion
o Dilutes coag factors and results in a relative deficiency

Other disorders of hemostasis

st
Heparin-Induced Thrombocytopenia, HIT
o Hep forms complex with platelet factor 4IgGconsumption by spleenTCP
o fragments may activate remaining plateletsthrombosis
Do NOT give Coumadin, due to risk of skin necrosis in these patients!
DIC
o Pathophys
Te

Pathologic activation of the coag cascadewidespread microthrombiischemia/infarction

Consuming platelets/factorsbleeding, esp from IV sites & all mucosal surfaces
o Etiology
2ndary to other dz
Obstetrics: amniotic fluid has tissue thromboplastin, activating coag cascade
Sepsis, rattlesnake (venom gets into circulation)
APL auer rods and granules get into circulation and activate cascade
Adenocarc mucin activates coag cascade
o Labs
Consuming platelets and coag factors, so PC decreases & PT/PTT increases, decreased
fibrinogen
Microangiopathic hemolytic anemia microthrombi cause schistocytes
Elevated fibrin split products (D-dimer) due to lysing cross-linked fibrin
Elevated D-dimer is BEST test for DIC
o Treatment: transfuse blood & cryoprecipitate (address underlying issue)
Disorders of Fibrinolysis - plasmin overactivityexcessive fibrinogen cleavage
o Normal
Its the very end stage of coagulation removing the thrombus via plasminogen being
activated to plasmin (via tPA)
Plasmin does 3 things
Cleaves fibrin AND serum fibrinogen (to stop future thrombi from forming)
Destroys coagulation factors, shutting down ability to form clots
Blocks platelet aggregation
 s
Alpha-2 antiplasmin is what normally shuts plasmin off
o Radical Prostatectomy release of urokinase activates plasmin

te
o Cirrhosis of Liver reduced production of a2-antiplasmin
o Presentation
Same as DIC know how to differentiate it!
Elevated PT/PTT bc plasmin degrades coag factors
Inc bleeding time (due to platelet aggregation inhibition) with NORMAL platelet count
Vs DIC, which will have decreased platelets!

ra
Increased fibrinogen split products, BUT NO INCREASE IN D-dimers (bc no thrombus
formation to be broken down and no fibrin is cleaved)
o Treatment: aminocaproic acid to block activation of plasminogen

Thrombosis
Definition: pathologic formation of an intravascular blood clot
Pio Thrombus has: 1. Lines of Zahn, and 2. Attachment to bl vessel wall
These differentiate it from a postmortem clot
o 3 major risk factors: disruption of blood flow, endothelial damage, & hypercoagulable state
Disruption of Normal Blood Flow
o General
Stasis or turbulence of blood flow increases risk for thrombus
o Examples
st
Immobilization
Cardiac Wall Dysfunction: A.fib is a big risk factor bc now blood is static; MI is another
Aneurysm: blood becomes turbulent as it flows into the balloon dilation (aneurysm)
Endothelial Damage
o Disrupts protective function of endothelial cells, which are:
Forming a barrier dont want to expose the subendothelial collage
Te

Secreting PGI2, which block aggregation, and NO

Secretes Heparin-Like Molecules: activate antithrombin III
Secretes tPA: converts plasminogen to plasmin, which has 3 functions:
1. Cleaves fibrin and fibrinogen
2. Destroys coagulation factors
3. Blocks platelet aggregation
Secretes Thrombomodulin: takes thrombin and modulates it to activate protein C to
inactivate factor 5 and factor 8 (instead of regularly converting fibrinogen to fibrin)
o Causes
Atherosclerosis
Vasculitis
High levels of homocysteine
VitB12 or folate deficiency: can no longer convert homocysteine to methionine
o Folate comes into body as THF and gets methylated (m-THF) to participate
in DNA synth, needs to lose its methyl, so gives it to B12 (m-B12); m-B12
then gives its methyl group to homocysteine to form methionine
Cystathionine beta synthase deficiency
o Cant convert homocysteine to cystathioninehomocystinuria
Vessel thrombosis, mental retardation, lens dislocation, long fingers
Hypercoagulable State
o Excessive progoagulant or defective anticoagulant proteins
o Classically present with recurrent DVT or DVT at a young vein, and can involve hepatic & cerebral v.
o Examples
 s
o Protein C or S deficiency
Normally inactivate factor 5 and 8

te
No negative feedback on coag cascadehypercoagulative state
Increased risk for warfarin skin necrosis
Remember warfarin blocks 2, 7, 9, 10, C, S, but C & S have shorter t1/2
If they are deficient in C and S, they are at even inc risk for coagulation, and it can
happen in the skin causing necrosis
o Factor V leiden

ra
Mutated form of factor 5 that cant be cleaved by factor C and S
MC inherited cause of hypercoagulable state
o Prothrombin 20210A
Inherited point mutation in prothrombin (converts fibrinogen to fibrin) now too much!
Results in increased gene expression, promoting thrombus formation
o ATIII deficiency
Pi Decreases protective effect of heparin-like molecules produced by endotheliumthrombus
Remember the heparin-like molecules bind ATIII so it can inactivate thrombin and
coagulation factors if youre deficient in ATIII, HLM cant activate it
PTT does NOT rise with standard heparin dosing
Heparin works by activating ATIII, so if youre deficient then it wont work
Tx: high doses of heparin to activate limited ATIII; Warfarin to maintain anticoag
o OCPs are assd with hypercoagulable state
st
Estrogen induces increased production of coagulation factorsinc risk for thrombus

Embolism
General
o An atherosclerotic embolus is characterized by cholesterol crystals in the clefts
Fat embolus
Te

o Can occur while bone is still broken or soon after its repaired
o Dyspnea & petechiae on skin overlying the chest
Gas embolus
o Commonly seen in decompression sickness
Divingincreased pressure forces nitrogen into the blood; when rapidly ascend, the
nitrogen can get out and in the wrong places
Presents with joint & muscle pain & respiratory Sx (the bends and the chokes)
Chronic form (caisson disease) characterized by multifocal ischemic necrosis of bone
o During laparoscopic surgery
Air is pumped into abdomen, so some can get into blood stream
Amniotic Embolus
o Usually during labor or delivery
o Sx
SOB, neuro Sx, & DIC (bc amniotic fluid is FULL of tissue thromboplastincoag cascade)
Characterized by squamous cells & keratin debris from fetal skin in embolus
Pulmonary Embolism
o Most are clinically asymptomatic (bc most are small & lung has dual blood supply)
o Infarction occurs when a large or medium-sized artery is obstructed & a pt with pre-existing
cardiopulmonary dysfxn
o Saddle embolus can cause sudden death bc it blocks entire pulm system
o Sx
Hemoptysis, pleuritic chest pain, pleural effusion
V/Q scan shows mismatch, while perfusion is normal
 s
Spiral CT shows a vascular filling defect in the lung
D-dimers will be elevated because lysing the PE & DVT

te
o Infarcts are hemorrhagic & wedge-shaped, and the tip of wedge points to area of occlusion
Blood re-enters via dual blood supply & there is a loose consistency to hold the blood
o Chronic emboli that reorganize over timepulmHTN

ra
5. RBC Disorders
Anemia
Definition: reduction in circulating RBC mass (hard to measure, so we use Hb, Hct, RBC count)
o Not always a good replacement of RBC mass; ie, pregnant women have lower Hb/Hct but normal
Pi RBC mass; gunshot wound blood loss, but Hb/Hct is normal
o Hb<13.5 in males and Hb<12.5 in females = anemia
o Anemia can be micro (MCV<80), normo (MCV 80-100), or macrocytic, MCV >100)
Presents with weakness, fatigue, & dyspnea
o Pale conjunctiva and skin
o Headache and lightheadedness
o Angina, especially with preexisting CAD
Note: RBC is about the size of the nucleus of a lymphocyte
st
Microcytic Anemia (MCV<80)
General
o miA are always due to a decreased production of Hb
o Erythroblast becomes the RBC by dividing numerous times, & getting smaller
Te

o Microcytic anemias occur bc theres an extra division

o Hemoglobin = Heme + globin; Heme = iron + protoporphyrin
o Causes of anemia due to missing of any from above point
Iron is missing (IDA)
Iron is locked away in mphages = anemia of chronic disease (ACD)
ACD may first present as normocytic anemia & progress to micro
Decreased protoporphyrin = sideroblastic anemia (SBA)
Decreased production of globin chain = Thalassemia
Inhibited heme formation = lead poisoning
Iron Def Anemia, IDA - MC nutritional deficiency of the world
o Normal Absorption
Heme (meat-derived) & non-heme (veggie-derived) forms; abs in duodenum
Enterocytes transport iron into blood via ferroportin, IF signal tells it to
Because theres no way for body to get rid of Fe, need to make sure we want it if
ferroportin doesnt transport it, it will slough off w/ enterocyte
Transferrin transports Fe & delivers it to liver & BM mphages for storage
Strored intracellular Fe is bound to ferritin (to prevent FR formation via Fentin rxn)
o Etiology: dietary lack, blood loss, malnutrition, malabsorption, gastrectomy
Infants: breast feeding contains almost no Fe
Children: poor diet
Adults: PUD (males), menorrhagia or pregnancy (females)
Elderly: colon polyps/carcinoma, or hookworm (developing world)
Malabsorption: celiac
 s
Gastrectomy: acidity maintains the Fe2+ state (more readily absorbed than Fe3+), so
decreased acid means dec bioavailability of Fe2+

te
o Normal Lab Measurements
General
For every 3 transferrin (TF) molecules, one will have bound Fe
Fe is bound to Ferritin when inside the mphage
Serum Fe: amount of Fe in blood bound to TF
TIBC: amount of TF in the blood (bound OR unbound to Fe)

ra
% saturation: amount of Fe on TF
Serum ferritin: how much Fe is in the storage sites
Inversely related to TIBC when it goes down, TIBC GOES UP
o Stages of Iron Deficiency
1. Storage iron is depleted: Fe was stored as Ferritin!
Thus, the serum Ferritin will go down, and thus, TIBC goes up (opposites), bc liver is
sending out TF to try and bind more Fe
Pi And TIBC represents the amount of transferrin
2. Serum iron is depleted: now, serum Fe will go down (being used up), & % sat dec
Less Fe to bind to TF, so the %saturation will go down
3. Normocytic anemia: normal size, but less made (want good RBC, even if less #)
4. Microcytic, hypochromic anemia: now less # and smaller, w/ less color (less Hb)
o Clinical
st
Anemia, Koilonychia (spoon-shaped nailes), Pica (chewing on abnormal things)
o Labs of IDA
Microcytic, hypochromic anemia, w/ inc RDW
Decreased ferritin, increased TIBC, decreased serum Fe, decreased %sat see above
Inc free erythrocyte protoporphyrin, FEP: Theres more proto around than Fe
o Blood Smear: RBC size should equal size of the nucleus of a lymphocyte
Te

o *Side note about Plummer-Vinson Syndrome

IDA with esophageal web & atrophic glossitisanemia, dysphagia, & beefy-red tongue
Anemia of Chronic Disease, ACD
o General: MC anemia in hospitalized patients
Results in acute phase reactants
o Pathophysiology
Hepcidin (an acute phase reactant): sequesters iron storage in sites
Limits iron transfer from mphage to erythroid precursors
Suppresses EPO production
Chronic inflammation triggers body to release Hepcidin to hide the iron from what it
thinks is a microbe, bc bacteria use iron to survive
Decreased available iron leads to a microcytic anemia
o Labs
Increased ferritin (thus, decreased TIBC) due to an inability to use stored iron, so it piles up
(stored as ferritin)
We know the opposite happens with TIBC (decreases) because less TF molecules
floating around to bind Fe
Decreased serum iron: the bone marrow will use up whatever it can; if the Fe is locked away
in the mphages then it will take it from serum
Decreased %saturation: same reason as above
Increased free erythrocyte protoporphyrin: excess free proto around
o Stages of Anemia: same as IDA
o Treatment: Tx underlying cause to reduce inflammation; EPO can help (ESP in cancer)
 s
Sideroblastic Anemia, SBA
o General

te
Due to defective protoporphyrin synthesis
o Synthesis of Protoporphyrin
See P 358 of FA2013
SuccinylcoAd-ALA via ALA synthase, ALAS (RLS), and requires B6
D-ALAporphobilinogen via ALAD (dehydrogenase)
After other rxns, protoporphyrin + Feheme via ferrochelatase in MITO

ra
Iron is transferred to erythroid precursor, which delivers it to mitochondria this is KEY,
because if proto is deficient, IRON REMAINS TRAPPED IN MITO
o Etiology
Congenital: MC due to defect in ALAS
Acquired: alcohol (bc etoh is a poison to mitochondria), lead poisoning (can denature ALAD
and ferrochelatase), vitB6 def (isoniazid treatment)
Pi o Labs think iron-overloaded state
Increased ferritin (stored Fe & the leaked Fe gets taken up), thus, decreased TIBC
Increased serum Fe, Increased %saturation
Note: similar lab findings in hemochromatosis
Thalassemias
o Decreased production of globin chains of Hbmicrocytic anemia
o Inherited mutation: carriers are protected against p. falciparum
st
o Normal Globin: a2b2 (HbA), a2d2 (HbA2), and a2y2 (HbF)
A-Thalassemia
o General: usually due to gene deletion
Normally, there are FOUR alpha alleles (vs betas two) on chr 16
o Clinical
1 gene deleted: asymptomatic
Te

2 genes deleted: mild anemia w/ slightly increased RBC count

Can be cis if on same chr: WORSE bc assd with increased risk of severe thalassemia
in offspring (passing both del copies to kis) seen in Asians
Or can be trans if on diff chr more common in Africa
3 genes deleted: severe anemia
Risk of forming tetramers of beta chains, B4 (HbH) because so little alpha
o HbH is seen on electrophoresis
4 genes deleted: lethal in utero (hydrops fetalis) HbBarts (y tetramers, y4)
B-Thalassemia
o General: 2 beta genes on chr11 due to gene MUTATIONS (splice site), NOT gene deletions (a-thal)
Mutations result in absent (B0) or diminished (B+) production of B globin chain
Can be BB+, B+B+. B+B0, B0B0, - lots of combos
o B/B+: mildest form of disease (B-thal minor)
Usually asymptomatic with increased RBC count
Microcytic, hypochromic RBCs and target cells on blood smear
Target cell: bleb of membrane in the center where Hb fills up, causing a small dark
circle in the center of the pale area
o Occurs when theres decreased cytoplasm or increased membrane
Electrophoresis
Isolated increase in HbA2 >3.5%
Electrophoresis would be normal in alpha-thal
o B0/B0: most severe form of dz (B-thal major)
Presents w/ severe anemia few mo after birth (HbF) at birth is temporarily protective
 s
No beta chains around, so alpha tetramers form, which damage RBCineffective
erythropoiesis even if a-tetramer gets out of BM, spleen destroys ithemolysis

te
Extravascular hemolysis
Patients have such a severe anemia that they get Massive Erythroid Hyperplasia
Expansion of hematopoiesis into marrow of skull/facial bones
o Crew-cut appearance on XR + chipmunk face
Extramedullary hematopoiesis with HSM
o Liver/spleen making RBC

ra
Risk of aplastic crisis with parvovirus B19
o These patients are dependent on EVERY SINGLE RBC; so if B19 infects and
shuts down erythroid precursorsCRISIS
Treatment: chronic transfusion
Risk for 2ndary hemochromatosis (iron overload)
Blood Smear: microcytic, hypochromic target cells & nucleated RBC (bc RBC made in
abnormal places)
Pi Electrophoresis: little or no HbA (bc no beta), & inc HbF and HbA2

Macrocytic Anemia (MCV>100)

General
o Mainly due to folate or B12 deficiency (megaloblastic anemia) impaired DNA precursors
o When folate comes into the body, (as THF), its quickly methylated, and needs to lose this methyl to
st
go on as a DNA precursor
B12 takes the methyl off so THF can go on for DNA, and passes the methyl to homocysteine,
which becomes methionine
o All rapidly dividing cells will be affected and become bigMEGALOBLASTIC changes/anemia
Ie, intestines
o Hypersegmented neutrophils: greater than 5 lobes
Te

Other causes of macrocytic anemia

o Alcoholism, liver dz, drugs (5-FU)
o We would NOT call these megaloblastic anemias
Folate
o General: from green veggies & fruits (diet), and absorbed in jejunum
o Deficiency develops within MONTHS, bc stores are minimal
o Etiology of deficiency
Poor diet (etoh & elderly), increased demand (pregnancy), folate antagonists (MTX)
o Clinical
Macrocytic RBCs and hypersegmented neutrophils
Glossitis (tongue cells not dividing), Decreased serum folate
Increased serum homocysteine (bc B12 cant add methyl to homocys to make Met)
Normal methylmalonic acid: B12 converts it to succinylcoA, NOT folate!
B12
o General: from animal-derived proteins, & R-binder binds B12 in saliva until small bowel, where
proteases degrade R-binder, and B12 binds to IF until ileum, where its absorbed
o Deficiency: takes YEARS due to large hepatic stores of B12
o Etiology
Pernicious anemia: AI destruction of parietal cells* (in body of stomach, make IF)
Pancreatic insufficiency: panc makes proteases to degrade R-binder
Crohns disease or Diphyllobothrium latum (tapeworm)
Dietary deficiency is RARE, except maybe in vegans
o Clinical: like folate, except you also get subacute degeneration of spinal cord
 s
If methylmalonic acid cant be converted to succinylcoA (no B12), it builds up in myelin of sp
cord, causing degeneration

te
o *Side note: Parietal Cells Ps Parietal cells, Proton Pumps, Pink in body of stomach (chief cells are
blue), and Pernicious anemia

Normocytic Anemia
Main question to ask is: is the anemia due to peripheral destruction or underproduction
o Reticulocyte count helps distinguish bw these two

ra
Corrected >3% = good BM response, must be peripheral destruction
Corrected <3% indicates poor BM response, prob due to underproduction
Reticulocyte count
o Young RBC that are released from BM larger cells with bluish cytoplasm (residual RNA)
o Normal RC is 1-2% bc 1-2% of cells removed each day from circulation; RBC live for 120 days
o Properly functioning BM responds to anemia by increased RC to >3%
Pio RC measured as % of RBC, so it will be falsely elevated in someone w/ anemia
Need to Correct for the RC by multiplying it by the Hct/45
After correcting, if RC isnt high, then the BM is the problem
Peripheral RBC destruction (hemolysis)
o Divided into extra and intravascular both result in good BM response
o Extravascular: RBC destroyed by reticuloendothelial system (mphages of spleen, liver, Lymph Nodes)
outside of the bl vessel
st
Mphages consume RBCs and break down the Hb
GlobinAA; hemeFe + protoporphyrin; protounconjugated BRliver via
albuminconjugationbile
Clinical findings
Anemia with splenomegaly
Jaundice due to more unconj BR than liver can conjugate now (RBC destruction)
Te

Increased risk for BR gallstones because more BR getting conjugated

Marrow hyperplasia with corrected RC>3%
o b/c the BM is fine, so it will undergo hyperplasia to compensate
o Intravascular: RBC destroyed INSIDE the bl vessel, so Hb gets into the blood
Hb gets spilled into blood, and it quickly gets bound by Haptoglobin to take it to spleen to be
reprocessed
Clinical findings
Hemoglobinemia leaking RBC into blood
Hemoglobinuria Hb spilling into urine (Hb IS WATER SOLUBLE)
Hemosiderinuria: when the Hb is taken up by the renal tubular cells, it will pile up
and be stored as hemosiderin; then when it sloughs off days later, hemosiderin ends
up in urine
o Thus, initially, Hb in urine; few days later, hemosiderin in urine
Decreased serum haptoglobin (more being bound to Hb) initial change seen

Normocytic Anemias with predominant Extravasular Hemolysis

Hereditary Spherocytosis
o Inherited defect of RBC cytoskeleton-membrane tethering proteins (spectrin, ankyrin, band 3.1)
o Membrane blebs are formed & lost over time (spleen removes themanemia)
Loss of membrane = lost biconcavity and lost central pallorspherocyte
HIGH RDW some cells lost more membrane blebs than others
o Clinical
Spherocytes w/ lost central pallor and increased RDW
 s
Increased MCHC (mean corpuscular Hb concentration) cell shrinks = more conc Hb
This and AI anemia are the only ones with INCREASED MCHC

te
Splenomegaly bc its where the spherocytosis is occurring mphageshypertrophy
As spleen eats up RBC-UCB overwhelms liverJaundice + gallstones
Increased risk for aplastic crisis with parvovirus B19 infection of erythroid precursors
o Diagnosis: osmotic fragility test
Usually, the RBC has some wiggle room and is resistant to hypotonic soln
If the biconcavity is lost (spherocyte), the RBC has more fragility

ra
o Treatment: splenectomy
Anemia resolves, but spherocytes PERSIST (bc membrane still removed by RES such as in
liver and lymph nodes)
The spherocytes isnt the problem, its that spleen is destroying them
Howell-Jolly Bodies emerge on blood smear
An RBC with nuclear fragment usually the frag or cell is removed by spleen, but pt
Pi has no spleen! indicates splenic dysfunction
Hemoglobin C
o AR mutation in B chain of Hb glutamic acid replaced by lysine (lyCCCene)
o Less common than sickle cell disease
o Characteristic Hb C crystals on blood smear
st

Sickle Cell Anemia (SCA or HbS)
General
o AR mutation (vs B-thal) in B chain of Hb
o Normal glutamic acid (hydrophilic) replaced with valine (hphobic)
Te

o Carried by 10% people of African descent due to protection against falciparum

Sickle Cell Disease
o Arises when 2 abnormal B genes are presentleads to >90% HbS in RBCs
o Pathophys
HbS polymerizes (reversible) when doxygenated (hypoxemia, dehydration, acidosis)
Polymers aggregate into needle-like structuressickle cells
Note: HbF protects against sickling
High HbF at birth is protective for 1st ~6mo (SCA dont present til 6mo)
Hydroxyurea increases levels of HbF
Cells continuously sickle and de-sickle while passing thru microcirculation
Results in complications related to RBC membrane damage
Membrane damageextravascular hemolysis
Anemia, jaundice with UCB hyperBR (UCB overwhelms liver), & increased risk for
gallstones (backed-up bile into gallbladder)
ALSO get some intravascular hemolysis due to RBC lysing right in the vessels
Causes decreased haptoglobin & target cells on blood smear (dehydration causes
cytoplasm to decreasecentral bleb)
o Complications
Main one is anemia, jaundice, etc we saw above
Consequences of intra/extra vascular hemolysis
Massive erythroid hyperplasia
o Expansion of hematopoiesis into skull & facial bones
Crew-cut appearance on XR + chipmunk face
 s
As we saw in B-thal major
o Extramedullary hematopoiesis w/ hepatomegaly

te
Predominantly in the liver (these pt dont have spleens)
o Risk of aplastic crisis w/ parvovirus B19 @ erythroid precursors
Irreversible sickling: 2nd major complication
o Leads to vaso-occlusioninfarcted tissues
o Dactylitis: swollen hands & feet due to vaso-occlusive infarcts of bones
Common presenting sign in infants (not earlier than 6mo!)

ra
o Autosplenectomyshrunken, fibrotic spleen causes problems
Inc risk for infections w/ encapsulated organisms MCC death in
KIDS (H.flu, S. pneumo, etc)
Risk of Salmonella paratyphi osteomyelitis
Howell-Jolly bodies on blood smear cant remove nuclear frags
o Acute Chest Syndrome: Vaso-occlusion in pulmonary microcirc.
Pi Presents w/ chest pain, dyspnea, lung infiltrates often precipitated
by pneumonia
MCC death in ADULTS
o Pain Crisis vaso-occlusion in other places
o Renal Papillary Necrosis: vaso-occlusion in kidney
Results in gross hematuria & proteinuria
Sickle Cell Trait: one mutated & one normal B chain - <50% HbS in RBC (55% HbA)
Important bc, you NEED >50% HbS to sickle (one exception below)
st
o Generally asymptomatic with NO anemia exception in the renal medulla
Extreme hypoxia & hypertonicity cause sicklingmicroinfarctions
Starts as microscopic hematuria, and then dec ability to concentrate urine
Labs of BOTH SCA AND SCT
o Sickle cells & target cells seen in sickle cell DISEASE, but NOT sickle cell trait
Te

o Metabisulfite screen: causes any cell with HbS to sickle positive in both SCA and SCT
o Hb electrophoresis confirms presence & amount of Hbs
Disease: 90% HbS, 8% HbF, 2%HbA2 (NO HbA)
Trait: hh% HbA, 43% Hbs, 2% HbA2

Normocytic Anemias with predominant intravascular hemolysis

Paroxysmal Nocturnal Hemoglobinuria (PNH)
o Acquired (NOT inherited) defect in myeloid stem cells absent GPI
RBC have DAF and MIRL, anchored by GPI, to inactivate complement
Any cell derived from myeloid lineage (RBC, platelet, WBC (esp granulocyte) missing GPI
o Why the name?
More shallow breathing when asleepinc co2acidosiscomplement activation
o Clinical: Intravascular hemolysis
Hemoglobinemia & hemoglobinuria
Tubular cells take up some Hbhemosiderinhemosiderinuria DAYS later
Main cause of death is thrombosis of hepatic, portal, or cerebral veins
Complement destroys RBC, granulocytes, and platelets
Destroyed platelets release cytoplasmic contents into circthrombosis
o Diagnosis
Sucrose test to screen: sucrose activates complement
Confirmation: acidified serum test or flow cytometry to detect lack of CD55 (DAF)
Acidified serum also activates complement
o Complications
 s
IDA: patients lose Hb AND IRON in urine
AML (in 10% of cases): dz is mutation in myeloid stem cells, so potential for another

te
mutation to formAML
G6PD deficiency
o General
X-linked R disorder with reduced half-life of G6PD susceptible to oxidative stress
African variant: mildly reduced half-life
Only the older cells will get destroyed

ra
Mediterranean variant: markedly reduced G6PD half-life
Even the younger cells will get destroyed
Both variants due to protective role against falciparum
o Oxidative stress precipitates Hb as Heinz bodies
Oxidative stress due to: infections, drugs (primaquine, sulfa, dapsone, fava bean)
Heinz bodes: removed by splenic mphagesbite cellsintravascular hemolysis
There might be some extravascular (if mphage consumes entire cell)
Pi o Pathophys
RBC protects against oxidative stress (h202, for ex) by using GSH to reduce the insult, and
oxidizing itself in the process to GS-SG
Need NADPH to go back to GSH, and its the G6PD that provides this NADPH
o Clinical
Hemoglobinuria & back pain (Hb is nephrotoxic)
st
Occurs hours after exposure of oxidative stress
o Diagnosis
Heinz preparation: used to screen for disease
Shows aggregated/precipitated Hb
Enzyme study confirms deficiency, which you test AFTER dz resolves because during disease,
al the cells missing the enzyme will be killed off so test will be false neg!
Te

Immune Hemolytic Anemia

o General
Ab-mediated (IgG or IgM) destruction of RBC
o IgG-mediated dz usually involved extravascular hemolysis
IgG binds RBC in the warm central body warm agglutinin
Membrane of Ab-coated RBC consumed by splenic mphagespherocytes
Similar to hereditary spherocytosis (losing excess membrane)
Assd with SLE, CLL, and drugs
Drug can bind to RBC membrane (penicillin) and Ab binds the complex
Drug can induce production of auto-Ab itself (methyldopa) then bind Ag
Treatment
Cessation of drug, steroids, IVIG (mphages eat this instead), splenectomy
o IgM-mediated dz usually involves intravascular hemolysis
Binds RBC and fixes complement in the cold temp of extremities (cold agglutinin)
Assd with Mycoplasma pneumoniae and infectious mononucleosis
o Diagnosis: Coombs test
Direct: Do I have RBC already bound by IgG?
Confirms presence of Ab-coated RBCs
Anti-IgG is added to pt RBC and agglutination occurs if RBC are already coated w/
IgG
Most important test for IHA
Indirect: Does the pt have Ab in their serum?
Anti-IgG & test RBCs are mixed w/ patients serum
 s
Agglutination occurs if serum Ab are present
Microangiopathic hemolytic anemia

te
o General
Intravascular hemolysis due to vascular pathology
RBCs are destroyed as they pass thru circulation
o Pathophysiology
Microthrombi cause RBC to form schistocytes
o Etiology

ra
Seen in TTP: platelet thrombi + lack of ADAMS13
HUS: platelet thrombi due to toxin (O157:H7)
DIC: platelet+fibrin thrombischistocytes
HELLP (hemolysis, elevated liver enzymes, low platelets): pregnant women getting micro
hem anemia
Prosthetic heart valves
Pi Aortic stenosis
Malaria: infection of RBCs and liver with plasmodium (Anopheles mosquito)
RBCs rupture as part of plasmodium life cyle
Falciparum: daily fever
Vivax: fever every other day
Spleen can also consume RBC
Anemia due to underproduction
st
General
o Decreased production of RBCs by BM
o Characterized by LOW CORRECTED reticulocyte count (poor response)
Etiology
o Anything that causes a micro or macrocytic anemia will usually have a low RC
o Renal failure decreased EPO production
Te

o Damage to BM precursor cells

Parvovirus B19 infects progenitor red cells
Temporarily halts erythropoiesis
Leads to significant anemia in setting of preexisting marrow stress (people highly
dependent on their reserve)
Tx: supportive, week to 10 days
Aplastic Anemia: damage to hematopoietic stem cell
Results in pancytopenia w/ low RC
Etiology: drugs, chemicals, viral infections, autimmune
Biopsy shows empty marrow (filled with FAT)
Tx: stop drugs, give transfusions, marrow-stimulating factors (EPO, GM-CSF, G-CSF),
immunosuppression, BM transplant (last resort)
Myelophthisic Process: pathologic process that replaces BM
Hematopoiesis is thus impairedpancytopenia

6. WBC Disorders

Leukopenia and Leukocytosis

Basic principles
 s
o Granulocytes are derived from myeloblastsPMNs, basophils, eosinophils
o Normal WBC is 5-10k; leukocytosis & lymphocytosis usually due to increase in ONE cell type

te
o Myeloid and lymphoid stem cells are also called myeloid and lymphoid BLASTS
Leukopenia
o Neutropenia (low PMNs)
Drug toxicity (chemo)
Tx: GM-CSF or G-CSF (granulocyte monocyte colony-stimulating factor)
Severe infections

ra
Most of the PMNs will be out of the blood and into the tissue
o Lymphopenia (low lymphos)
Immunodeficiency
Di-George for ex: fail to form 3rd and 4th pharyngeal pouch = no thymus
High cortisol state: induce apoptosis in lymphocytes
Autoimmune destruction
Ie, pt with lupus (often produce Ab against cells in the blood)

Pi Whole body radiation
The most sensitive cells to radiation are LYMPHOCYTES die quickly
Leukocytosis elevated WBC
o Neutrophilic leukocytosis
Bacterial infection via inflammation
Tissue necrosis via inflammation
st
In both above circumstances, BM will be pushed to produce as much granulocytes
as possible immature cells are releasedleft-shift
Immature cells are characterized by decreased Fc receptors (important for PMNs
recognizing immunoglobulins) they dont function as well
o Decreased CD16 is the marker for this decreased Fc receptor
High cortisol state many PMNs are attached to the endothelium (marginal pool); when
Te

stimulated by cortisol, the PMNs will fall into bloodelevated

o Monocytosis (elevated WBC)
Chronic inflammatory states
Malignancy
o Eosinophilia
Allergic reactions
Parasitic infection
Hodgkin lymphoma both assd with tumor and circulating in blood
Mechanism is via increased IL-5 production
o Basophilia
CML - classic
o Lymphocytic leukocytosis
Viral infections
Bordetella pertussis the exception (most bacteria cause elevated PMNs)
Releases factor called: Lymphocytosis Promoting Factor blocks lymphos from leaving blood
into lymph node stuck in the blood (cant enter lymph node)leukocytosis
Infectious Mononucleosis
o General
EBV infectionlymphocytic leukocytosis with CD8+ T cells
CMV is a less common cause
Virus is transmitted via saliva and classically affects teenagers
o Pathophys
EBV primarily infects oropharynx (sore throat), liver (hepatitis), B cells
 s
CD8+
Generalized LAD (at paracortex)

te
o LN broken down into Cortex, Paracortex, and Medulla
Cortex: where B cells live
Paracortex: where T cells live EBV causes hyperplasia here
Splenomegaly
o Red pulp contains blood
o White pulp contains lymphoid tissue T cell area will be expanded

ra
periarterial lymphatic sheath (PALS) is the spp part
High WBC with atypical lymphos (these cells are CD8+ T cells)
o Nucleus is enlarged, excess cytoplasm
o Diagnosis
Monospot test for screening: detects IgM heterophile antibodies
Turns pos within 1 week after infection
Neg test suggests CMV as the cause
Pi o
EBV viral capsid antigen test use for definitive diagnosis
Complications
Increased risk for splenic rupture: tell pt to avoid contact sports for a year
Rash if exposed to PCN (or ampicillin)
Dormancy of virus in B cells: inc risk for recurrence and lymphoma
st
Acute Leukemia
General
o Disruption in the cells ability to mature
Myeloblast/lymphoblast cant mature so it piles up
o Acute Leukemia is a neoplastic proliferation of blasts
o Defined as accumulation of >20% blasts in BM (1-2% is normal)
Te

Blasts will crowd-out normal hematopoiesis

Results in acute presentation w/ anemia, thrombocytopenia, neutropenia because the
cells arent being formed will have Sx assd with whatever cell is missing
o Blasts: large, immature cells with punched-out nucleolus on smear - enter bloodhigh WBC
o AML: accumulation of the myeloid blast
KEY: myeloperoxidase, MPO+ positivity
MPO can crystallize into Auer Rods tells us were dealing with AML
o ALL: accumulation of the Lymphoid Blast (LB)
KEY: TdT+ positivity in the nucleus its a DNA polymerase found ONLY in the LB
ALL
o General
Neoplastic accumulation of lymphoblasts
Positive nuclear staining for TdT (DNA polymerase) absent in BM and mature lymphos
o Diagnosis
Most commonly in children, and assd with Down Syndrome (after age 5)
o Classification (based on surface markers)
B-ALL: most common type of ALL
Express CD10, CD19, & CD20
Excellent response to chemo (CTX) but need prophylaxis to scrotum & CSF because
of blood testes barrier and BBB
Prognosis: based on cytogenetic abnormalities
o T(12;21) has good prognosis, & more common in kids
o T(9:22) has poor prognosis & more common in adults
 s
This one is CLASSIC FOR CML but can also be seen with ALL
Aka Ph+ALL

te
T-ALL: (T for T-ALL, Thymus, and Teenager)
Express markers ranging from CD2-CD8; do NOT express CD10
Presents as mediastinal (thymic) mass in teenager
We call it an Acute Lymphoblastic Lymphoma because its a thymic mass instead of
cells floating around in the blood
AML: Acute myeloblastic leukemia

ra
o General
Neoplastic accumulation of myeloblasts
Crystal aggregates of MPO may be seen as Auer Rods like the others, we still see the
punched-out nucleolus
More common in older adults (50-60yo)
o Classification based on: Cytogenetic abnormalities (main), lineage of myeloblasts, & surface markers
APL: t(15:17)
Pi Retinoic Acid Receptor, RAR receptor disrupted; promyelocytes accumulate and
have numerous Auer rodsrisk for DIC (activation of coag C)
All-trans retinoic acid (vitA deriviative), ATRA, binds to the disrupted RAR and
causes blasts to mature and become neutrophils
o Myeloblast can produce erythroblast ,monoblasts, megakaryoblast , and each can accumulate to be
its own respective AML
st
AML subtypes
o Acute Monocytic Leukemia: proliferation of monoblasts that LACK MPO
Blasts characteristically infiltrate gums (pt has gum involvement)
o Acute megakaryoblastic leukemia
Proliferation of megakaryoblasts that also lack MPO
Assd with Down Syndrome, but this time BEFORE AGE 5
Te

o AML arising from pre-existing dysplasia

Prior exposure to alkylating agents or radiotherapy 2ndary cancer due to chemo
These pt develop Meyelodysplastic Syndrome
Cytopenias with hypercellular BM (the cells cant get out)
Abnormal maturation with increased blasts (but <20%)
Most patients die from infection or bleeding
May progress to acute leukemia (>20% blasts)

Chronic Leukemia
General
o Proliferation of MATURE lymphos (CD 4 or CD8 T cells) w/ elevated WBC count
o Insidious onset & usually in older adults can live a long time with this disease
CLL
o General
Neoplastic proliferation of nave B cells
Cells co-express CD5 and CD20
CD5 is normally present on T cells; here, its on a B cell
Increased lymphos & smudge cells on blood smear
Smudge cell: fragile, immature B lympho - Looks like a splattered cell
Lymphocytes can go to lymph nodesgeneralized LAD: Small Lymphocytic Lymphoma
o Complications
Hypogammaglobulinemia: the neoplastic cells dont do much
Important bc MCC death in these pt is INFECTION
 s
Autoimmune hemolytic anemia: not only do the cells not make immunoglobulin, if they do,
they do a bad job and make Ab against RBCs

te
Transformation to diffuse large B-cell lymphoma
If the CLL goes to the lymph node & is a SLL, it can get more mutations and become
a large B-cell lymphoma
o Pt presents with enlarged LN or spleen
Hairy Cell Leukemia, HCL
o General

ra
Neoplastic proliferation of mature B cells (plasma cells)
Characterized by hairy cytoplasmic processes
Cells are positive for TRAP (Tartrate Resistant Acid Phosphatase)
o Clinical Features
Splenomegaly (red pulp, NOT WHITE, which is where wed usually expect)
NO LYMPHADENOPATHY (bc the cells cant get out of the BM and into the LN)
Pi Dry tap with BM aspiration (bc BM is fibrosed)
o Treatment
Excellent response to 2-CDA (cladribine) an adenosine deaminase inhibitor so adenosine
accumulates to toxic levels in the B cells
ATLL
o General: neoplastic proliferation of mature CD4 T cells
Assd with HTLV-1 (Japan and Caribbean)
st
o Clinical
Rash (T-cell leukemias like to go to skin and form a rash)
Generalized LAD with hepatosplenomegaly
Lytic bone lesions with hypercalcemia
Would make you think about multiple myeloma, but use RASH to differentiate the
two
Te

Mycosis Fungoides
o General
Neoplastic proliferation of mature CD4 T cells
Remember, T cell leukemias like to go to skin, so will get rash, plaques, nodules
Pautrier Microabscesses: Aggregates of neoplastic T-cells in epidermis
o Calls can also spread to the blood
Called Sezary Syndrome
Characteristic lymphos with cerebriform nuclei on blood smear
o Looks like a brain

Myeloproliferative Disorders
GENERAL diagnostic features (the latter three due to JAK2 mutation)
CML: constitutional Sx (fatigue, WL, sweating), splenomegaly, and leukocytosis w/ marked left shift (eg,
myelocytes, metamyelocytes, band forms) due to BCR-ABL fusion protein t(9;22)
o If you see elevated WBC and pt aged 30-60, think CML or leukomoid reaction!
o Vs CLL, where you have increased mature lymphoid cells, not myeloid cells
Essential thrombocytosis: hemorrhagic & thrombotic sx (easy bruising, microangiopathic occlusion),
thrombocytosis, & megakaryocytic hyperplasia
PCV: pruritis, erythromelalgia, splenomegaly, thrombotic complications, erythrocytosis, & thrombi
Myelofibrosis: fatigue, HSM(satiety, ab pain), anemia, & BM fibrosis megakaryocyte hyperplasia
General
o Remember an accum of myeloid lineage = AML; accum of lymphoid lineage = ALL
o Accum of mature T cells = CLL
 s
o Accum of mature myeloid cells = myeloproliferative disorders, MPD
ALL increase (RBC, granulocytes, platelets) however, we name it based on the

te
PREDOMINANT CELL
Ie, in polycythemia vera, we will also have increased granulocytes & plt
o Its a dz of late adulthood and results in high WBC (granulocytes are part of WBC count) with
hypercellular BM
General Complications
o Increased risk for hyperuricemia & gout

ra
o Progression to marrow fibrosis (sphent phase)
o Transformation to acute leukemia with more mutations halts it in the myeloid phase
Chronic Myeloid Leukemia, CML
o General
Predominance of granulocytes, esp BASOPHILS (basophilia)
Driven by t(9:22) BCR-ABL fusion with increase tyrosine kinase activity
Pi o Clinical
Splenomegaly is common (chronic phase)
An enlarging spleen suggests accelerated phase of dztransformation into AML /ALL
o Transformation
Can become AML (2/3) or ALL (1/3)
Mutation is in a pluripotent stem cell (ie hematopoietic stem cell)AML or ALL
o Treatment: Imatinib which blocks tyrosine kinase activity
st
o Differentiating CML from leukemoid reaction (an infection)
CML granulocytes are leukocyte alkaline phosphatase (LAP) negative
LAP pos cells are trying to fight infections
CML is assd with basophilia
CML granulocytes exhibit t(9:22)
Polycythemia Vera
Te

o General
Neoplastic prolif of mature myeloid cells, but especially RBCs
Granulocytes & platelets are also increased
Assd with JAK2 kinase mutation
o Clinical Sx of hyper-viscosity
Blurry vision & headache
Increased risk of venous thrombosis
Budd-Chiary: thrombosis in hepatic veinliver infarction
Flushed face due to congestion
Itching after bathing (mast cells are increased too, and histamine can be released)
o Treatment
Phlebotomy
2nd line: hydroxyurea
If you dont treat, pt can die within one year
o Differentiating PV from reactive polycythemia
In PV, SaO2 is normal (no hypoxemia) and EPO is decreased (due to neg feedback)
In reactive polycythemia due to lung dz, SaO2 is low (hypoxemia) and EPO is increased
In reactive poly due to ectopic EPO (renal call carc), EPO is high and SaO2 is normal
Essential Thrombocythemia
o General
Neoplastic prolif of mature myeloid cells, ESP platelets
RBC and granulocytes are also increased
Asss w JAK2 kinase mutation
 s
o Clinical
Increased risk of bleeding (gums & nose) and/or thrombosis (plt over-activation or

te
underfunctioning)
Erythromelalgia: burning sensation of hands/feet due to occlusion of small arterioles by
platelets
Rarely progresses to marrow fibrosis or acute leukemia
Vs other diseases can commonly progress to both
No risk for hyperuricemia or gout
Vs other MDS, there IS an inc risk for gout bc of all the cell turnover

ra
This is because platelets never really had nuclei to be broken down
o IDA can also cause there to be extra platelets keep it in mind
Myelofibrosis
o General
Neoplastic proliferation of mature myeloid cells, ESP megakaryocytes
Assd with JAK2 kinase mutation
Pi Megakaryocytes produce excess PDGFmarrow fibrosis
o Clinical
Splenomegaly: BM gets fibrosed, so spleen does hematopoiesis (extramedullary)
Leukoerythroblastic smear
Spleen has no reticulin to prevent immature cells from getting out
Increased risk for infection, thrombosis, and bleeding
st
BM cant produce RBC, WBC, or platelets and spleen cant make nearly as much as
BM
o Tear Drop cells
Some of the hematopoiesis stays in the BM (totally fibrosed) as the RBC are generated,
theyll be stretched as they try to leave into the blood-tear-drop shape
Te

Lymphadenopathy (LAD)
Painful LAD seen w/ acute infection; painless LAD w/ chronic inflammation, met, or lymphoma
In inflammation, enlargement is due to hyperplasia of LN regions
o Follicles (cortex) rheumatoid arthritis and early HIV
Remember HIV infects CD4 cells follicular cells are also CD4+
o Paracortex where the T cells live viral infection, EBV for ex
Remember the cortex is where the B cells live
o Sinus histiocytes (in medulla) LN draining a region of cancer

Lymphoma
General
o Neoplastic proliferation of lymphoid cells, that forms a mass
o May arise in LN (where lymphos usually live) or in extranodal tissue
o Divided into NHL (60%) and HL (40%)
o NHL further classified by: cell type & size, pattern of cell growth, expression of surface markers,
cytogenetic translocations
Small lymphocytes seem to be more differentiated and look more like normal
Normal lymph node, w/ respect to B cells
Found at cortex, at the follicle follicle is surrounded by mantle
Margin can sometimes be formed around the mantle
Thus, zones of cortex are: follicle, mantle, & margin
We can get lymphomas at each of these zones!
Small B-cell lymphomas that mimic normal tissue (+ small lymphocytic lymphoma see above)
 s
Follicular lymphoma
o General

te
Neoplastic small B cells (CD20+) that make follicle-like nodules
Driven by t(14;18): BCL2 on chr18 translocates to Ig heavy chain locus on chr 14
Results in overexpressed Bcl2 and inhibition of apoptosis by preventing cytochrome
c form being leaked into cytoplasm
o Clinical: Presents in late adulthood with painless, generalized LAD
Patients are relatively asymptomatic and live long with it

ra
o Treatment: low-dose CTX or rituximab (anti CD20 Ab)for symptomatic patients
o Complication
Can progress to diffuse large B-cell lymphoma (presents as enlarging lymph node)
o Distinguished from follicular hyperplasia (from infection) by:
Disruption of normal LN architecture in follicular lymphoma infiltrates deep
Lack of tingible body mphages in Germinal Center (GC) mphages normally come in and eat
Pi the dying cells that underwent apoptosis
Expression of Bcl2 in follicles normal follicles have no Bcl2 because we want the failed
hypermutation B cells to die (in lymphoma they build up and dont die off)
Monoclonality
Remember a reactive prolif of lymphos, it would be polyclonal (3:1)
If it was a neoplastic prolif of lymphos, it would be monoclonal (25:1)
o Note: remember clonality is measured by looking at ratio of kappa to
st
lambda light chain (3:1 in polyclonal)
Mantle cell Lymphoma
o General
Neoplastic small B cells (CD20+) that expand the mantle zone
Expands the region IMMEDIATELY adjacent to the follicle
Driven by t(11;14): Cyclin D1 on chr11 translocates to Ig heavy chain on crh14
Te

Overexpression of cyclinD1 promotes G1/S transition in cell cycle by phosphorylating the

regulators
o Clinical: also painless LAD in late adulthood
Marginal Zone lymphoma
o General
Neoplastic small B cells (CD20+) that expand the marginal zone
This is the region outside of the mantle
Assd with chronic inflammatory states
Hashimotos thyroiditis, Sjogren, H. pylori (MALToma in mucosa sites)
Marginal zone is formed by post-germinal center B-cells
o Most lymph nodes dont have marginal zones
Intermediate Size B cell lymphomas
Burkitt lymphoma
o General
Neoplastic intermediate sized B cells (cd20+)
Assd with EBV
o Clinical
Classically presents as extranodal mass in child or young adult
African formjaw mass
Sporadic formabdominal mass
o Pathophys
Driven by translocation of c-myc (chr8)
T(8;14) most common: c-myc to Ig heavy chain locus on chr14
 s
Overexpression of c-myc oncogene promotes growth
High mitotic rate & starry-sky appearance

te
FAST GROWTH doubles in 24 hours!
Starry sky: lymphos make up the sky, and there are mphages eating up the dying
cells (the stars)
Large B cell lymphomas
Diffuse large B cell lymphoma, DLBCL
o General

ra
Neoplastic large b cells (cd20+) that grow diffusely in sheets
Most common form of NHL
Clinically aggressive
o Path
Arise sporadically or from ransformation of follicular lymphoma
Presents late dulthood as enlarging LN or extranodal mass
Pi
Hodgkin Lymphoma
General
o Instead of a whole mass of malignant cells, you have rare neoplastic cells (reed-sternberg cells) that
secrete cytokines that draw in other inflammatory cells which then results in a mass
o Reed-sternberg cell
Large B cell w multilobed nuclei & prominent nucleoli - CD15+ AND CD30+
st
Note theres no CD20 positivity!
Can have an owl-eye look too
Clinical
o RS cells secrete cytokines
Occasionally results in B symptoms (fevers, night sweats, chills)
Attract reactive lymphos, plasma cells, mphages, eos all form the mass
Te

Thus, the mass is actually the reactive lymphos

May lead to fibrosis
Subtypes
o Nodular sclerosis (70% of cases)
Presentation: enlarging cervical neck or mediastinal LN in young female
Biopsy shows lymph node divided by broad bands of fibrosis
RS cells are present in open spaces - lake-like cells (lacunar cells)
o Lymphocyte-rich: tons of lymphos best prognosis
o Mixed cellularity: mixed, esp with eos (IL-5)
o Lymphocyte-depleted: minimal lymphos worst prognosis (seen in elderly & HIV+ patients)
Thus, more lymphocytes is better

Plasma Cell Disorders/Dyscrasia

Multiple Myeloma
o General
Malignant proliferation of plasma cells in BM
MC primary malignancy of bone (metastatic carc is overall most common in bone)
High serum IL-6 is sometimes present, (an important growth factor for plasma cells)
o Clinical
Bone pain with hypercalcemia
Neoplastic plasma cells activate RANK receptor on oclasts (oclast activating factor)
Lytic punched-out lesions seen on XR, esp in vertebrae & skull
Increased risk of fracture
 s
Elevated serum protein
Neoplastic plasma cells produce immunoglobulin

te
M spike is present on serum protein electrophoresis (SPEP), most commonly due to
IgG or IgAM spike means Monoclonal
o Due to gamma band (normally wide, but shouldnt be taller than albumin
band)
o When plasma cells increase immunoglobulinssharp M spike
Increased risk for infection due to monoclonal increase in Ig

ra
Bc the monoclonal plasma cells all produce the exact same Ab no diversity
Infection is the MCC of death in these patients
Rouleaux formation on blood smear
Having too much protein will also interfere with the charge on the RBC (decreased
charge bw the RBC)
RBCs pile up instead of spreading out on blood smear
Primary AL amyloidosis

Pi Plasma cells overproduce light chain, which circulates in serum & deposits in tissues
Free light chain excreted in urine as Bence-Jones proteins
Deposition in kidney tubules leads to risk for renal failure (myeloma kidney)
Monoclonal Gammopathy of Undetermined Significance (MGUS)
o Increased serum protein with M spike on SPEP
o Other features of multiple myeloma are ABSENT (no lytic lesions, hyperCa, or AL)
st
o Seen in 5% of 70yo individuals, & 1% go on to develop multiple myeloma each year
Waldesterom Macroglobulinemia
o B-cell lymphoma with monoclonal IgM production
o We call it macro because IgM is a pentamer HUGE
o Clinical
Generalized LAD, but ABSENT lytic bone lesions
Te

Increased serum protein with M spike (of IgM)hyperviscosity

Hyperviscosity
Visual & neuro probs (retinal hemorrhage or stroke)
Bleeding platelets arent working right
o Treatment: Acute complications Tx with plasmaoharesis to remove IgM from serum

Langerhans Cell Histiocytosis

General
o Langerhans cells are specialized dendritic cells (APC) found in skin derived from BM
o Neoplastic proliferation of Langerhans cells
o Characteristic Birbeck (tennis racket) granules on EM
o Cells are CD1a+ and S100+ by immunohistochemistry
3 Subtypes
o If the disease is named after someone, proliferation is malignant
o Usually involve the skin
o If has 2 peoples names in it, usually seen in kids <2yo; if 3 peoples names, >3yo
Letterer-Siwe Disease
o Malignant proliferation of Langerhans cells
o Classic presentation is skin rash & cystic skeletal defects in infant (<2yo)
o Multiple organs may be involvedrapidly fatal
Eosinophilic Granuloma
o Benign prolif [no persons name in it] of Langerhans cells in bone
o Classic presentation is pathologic fracture in adolescent; skin is NOT involved
 s
o Bx shows Langerhans cells with mixed inflammatory cells, including eosinophils
o Make sure to have this & osteosarcoma on differential in pathologic fracture of adolescent

te
Hand-Schuller-Christian dz
o Malignant prolif of Langerhans cells
o Presents with: scalp rash, lytic skull defects, diabetes insipidus, & exophthalmos in a child >3yo

ra
7. Vascular & 8. Cardiovascular
Vasculitis read alongside FA
General
o Inflammation of bl vessel wall
o Made up of
Pi Intima: endothelial cells sitting on a basement membrane
Media: smooth muscle
Adventitia: connective tissue
o Etiologies are not known, but usually not infectious
o Clinical
Can get Sx of organ ischemia because endothelial damage exposes collagencoag cascade;
can also get ischemia due to inflammationfibrosis (narrow lumen)
Large-vessel (aorta and major branches)
st
Temporal Giant Cell Arteritis
o Common at branches of carotid artery
Temporal arteryheadache - CLASSIC
Ophthalmic arteryvisual disturbances
Jaw claudication
Te

Flu-like Sx w/ joint & muscle pain assd with polymyalgia rheumatica

Elevated ESR >100
o Biopsy
Inflamed vessel wall with giant cells (granulomatous vasculitis) & intimal fibrosis
Segmental lesions: only one area of a vessel is involved thus, take a very long piece for bx
and examine the entire vessel
Negative Bx does NOT exclude disease bc may have missed it
o Treatment: corticosteroids give before Bx - ASAP to prevent irreversible blindness
Takayasus arteritis
o General
Basically the same dz as TCA, a few exceptions:
Patients <50yo (young Asian female)
o Affects aortic arch at branch points
Visual and neurologic symptoms
Weak/absent pulses in upper extremity (pulseless dz)
Medium-vessels (muscular arteries)
Polyarteritis Nodosa
o General: Necrotizing vasculitis involving most organs lungs are spared
o Clinical young adult
Hypertension (renal artery)
Abdominal pain with melena (mesenteric artery)
Neuro disturbances, skin lesions
Assd with serum HbsAg
 s
o Lesions are in different stages (some early lesions w
Early lesions with fibrinoid necrosis (also seen with malignant HTN)

te
String of pearls appearance bc aneurysm-fibrosis-aneurysm
Kawasaki disease
o General: classically affects Asian kids <4yo
o Clinical: nonspecific symptoms
Fever, conjunctivitis, erythematous rash of palms/soles, enlarged cervical LN
o Tx: Aspirin and IVIG - a self-limited dz so try and treat it so they can live!

ra
Buerger Disease
o General
Necrotizing vasculitis involving digits Raynauds is often present too
Presents with ulceration, gangrene, & autoamputation of fingers/toes
Highly assd with smoking
Small-Vessel (arterioles, caps, venules)
Wegener Granulomatosis weCeners: C distribution, C-ANCA, Cyclophosphamide
Pi o General: Necrotizing granulomatous vasculitis w/ nasopharynx, lungs, & kidneys
o Clinical
Sinusitis or nasopharyngeal ulceration
Hemoptysis w/ bilateral nodular lung infiltrates
Hematuria due to RPGN
Serum c-ANCA correlate w/ disease activity
st
Churg-Strauss: see fa
Microscopic Polyangiitis: see fa
HSP: see fa

Hypertension
Systemic HTN: : <140/90 25% of the US population
Te

o Can have isolated increases in sys OR dias pressure and its still HTN
Primary HTN
o Risk factors
Age, race (Asians), obesity, stress, lack of physical activity. High NaCl diet
Salt increases TPR and total blood volume affects SBP and DBP
Unknown etiology in 90%
Secondary HTN (5% of cases)
o Etiology (due to identifiable causes)
Renal artery stenosis
Increased plasma renin &
Decreased blood flow to JGAincreased plasma renin
Unilateral atrophy of affected kidney due to dec blood flow
RAS caused by:
o Atherosclerosis (elderly males)
o Fibromuscular dysplasia (young females): irregular thickening of medium-
sized arteries (renal artery)
Benign HTN
o Mild or moderate elevation in blood pressure
o Clinically silent vessels & organs are damaged OVER TIME
Malignant HTN
o Severe elevation in BP >200/120
o May arise from preexisting benign HTN, or de novo (no hx of HTN)
o Presentation
 s
Acute end-organ damage (acute renal failure), headache, & papilledema
Fibrinoid necrosis of blood vessel wall

te
Arteriolosclerosis
Atherosclerosis thickening of intima of vessel wall often in medium/large vessels
o Abdominal>Coronary>Popliteal>Carotid
o Risk factors: modifiable (HTN, hyperchol, smoking, DM) and non (age, gender, genetics)
o Pathogenesis

ra
Endothelial damage lipid enters intima & gets oxidized, taken up by mphages
Now called fatty streak then get healing & depositionthickening and formation
of fibromuscular cap
FMcap causes prolif of ECM and smooth muscle occludes blood flow!
o Complications
1. Stenosis of vessel causing symptoms
PVD (popliteal); angina (coronary), ischemic bowel dz (mesenteric arteries)
Pi No symptoms until >70% stenosis
2. Plaque rupture with thrombosis
Rupture usually occurs at the neck of plaquethrombusinfarction
MI (coronary artery); stroke (middle cerebral artery)
3. Plaque rupture w/ embolization
Emboli characterized by cholesterol clefts in emboli
st
4. Weakening of vessel wall
Results in aneurysm (abdominal aorta)
Arteriolosclerosis due to deposition of protein (hyaline) or hyperplasia of sm musc (hyperplastic)
o Hyaline Arteriolosclerosis
Protein leaking into vessel wallthickening (pink hyaline)
Consequence of two things
Te

Benign HTN: high BP forces protein into the wall

Diabetes: non-enzymatic glycosylation
Results in reduced vessel caliber w/ end-organ ischemia
Classically produces glomerular scarring & progresses to renal failure
o Hyperplastic arteriolosclerosis
Thickening due to hyperplasia of smooth muscleonion-skin appearance
Consequence of malignant HTN
Results in reduced vessel caliber w/ end-organ ischemia
May lead to fibrinoid necrosis of vessel wall
Classically causes ARF w/ flea-bitten appearance (pinpoint hemorrhage)
Monckeberg Medial Sclerosis calcification of media
o Calcification of the media: non-obstructive (thus, not clinically significant)
Seen incidentally on mammography or X-ray
Does NOT alter the luminal caliber -

Aortic Dissection & Aneurysm

AD
o General: Intimal tear w/ dissection of blood through the media of the aortic wall
Occurs in proximal 10cm of aorta, w/ pre-existing weakness of media
o AD requires two things: Stress and Pre-existing weakness of the media
Weakness caused by:
 s
Hypertension (MC): it results in hyaline arteriolosclerosis, and can decrease caliber
of lumen to vasa vasorum, causing atrophy of the smooth muscle and weakening of

te
the media
Inherited defects of connective tissue
o Marfans (fibrillin-1), Ehlers Danlos
o Clinical
Presents with tearing chest pain radiating to the back
Can result in pericardial tamponade the MCC of death

ra
Can also get rupture w/ hemorrhage
Aneurysms
o General: balloon-like dilation of vessel - Classic in the thorax and abdomen
MUST have weakness in aortic wall
Classically seen in tertiary syphilis (an end-arteritis) tree-bark appearance of aorta
o Complications of thoracic aneurysm
Dilation of aortic valve root w/ insufficiency, resulting in aortic REGURG
Pi Compression of mediastinal structures as the aneurysm pushes on other things
Thrombosis/embolism: disrupted blood flow will activate coag cascade
o Abdominal Aortic Aneurysm, AAA
Usually below renal arteries, but above aortic bifurcation
Primarily due to atherosclerosis male smokers>60yo with HTN
Presents with pulsatile abdominal mass that grows with time (can rupture!)
st
Major complication: RUPTURE, esp when >5cm
Triad: hypotension, pulsatile ab mass, & flank pain

Vascular Tumors
Hemangioma
o Benign tumor comprised of blood vessels, presents at birth but regresses during childhood
Te

o Most often involves skin (face) & liver

o Can differentiate it from a purpura because it BLANCHES (purpura doesnt)
Angiosarcoma
o Malignant proliferation of endothelial cells highly aggressive
o Common sites include skin, breast, & liver
o Liver angiosarcoma assd with exposure to PVC, arsenic, & Thorostrast
Kaposi Sarcoma
o Low-grade malignant proliferation of endothelial cells assd with HHV-8
o Purple patches, plaques, or nodules on skin, and CAN involve visceral organs
o Would NOT blanche because blood is in bw the endothelial cells, NOT in a vessel
o Classic in:
Older Eastern European males need surgical removal
AIDS (tx with anti-retrovirals), & transplant recipient (Tx w/ dec immunosuppression)

Ischemic Heart Disease

General: Usually due to atherosclerosis of coronary arteries feed heart from EPI to MYO to ENDO
Stable angina
o Chest pain with exertion or stress (NOT AT REST) need >70% stenosis
o Reversible injury to myocytes (hallmark is cellular swelling)
o Presentation: Chest pain <20min, radiated to left arm/jaw; diaphoresis, SOB
EKG shows ST depressionsubendocardial ischemia relieved by rest/nitroglycerin
Unstable Angina
o Chest pain at rest - rupture of atherosclerotic plaque w/ thrombosis & incomplete occlusion
 s
o Represents reversible myocyte injury
EKG shows ST depression due to subendocardial depression gets better with NG

te
Assd with high risk for progression to MI because can get complete occlusion
Prinzmetal Angina
o Due to coronary artery vasospasm leads to episodic chest pain unrelated to exertion
o Again, REVERSIBLE injury to myocytes
EKG shows ST elevation due to transmural ischemia better w/ NG or CCB
Myocardial Infarction

ra
o General
Necrosis of cardiac myocytes rupture of athero plaque w/ thrombosis & complete
occlusion of coronary artery
Other causes include vasospasm, emboli, & vasculitis
Initiall: subendocardial necrosis involving <50% of myocardial thickness (ST-depression)
o Clinical
Pi Severe, crushing chest pain >20min radiating to left arm/jaw, diaphoresis, dyspnea, and Sx
NOT relieved by NG
o Diagnosis
Labs:
Troponin I: most sensitive & specific marker
o Rises 2-4 hrs after MI, peaks at 24 hours, normal by 7-10 days
CK-MB
st
o Rises 4-6hrs, peaks at 24hrs, but normal by 72hrs
o Used to check for re-infarction (a complication of MI)
o Treatment
ASA/Heparin, supplemental o2, nitrates, B-blocker, ACE inhibitor
Fibrinolysis or angioplasty causes 2 complications
Contraction band necrosis: returning blood brings Cacontraction (pink bands)
Te

Reperfusion injury: returned O2 = generation of free radicalsmore injury

o Complications

o
o Simply remember: 1 day, 1 week, 1 month
First day: coag necrosis
Bw 1 day and 1 week, you get inflammation (starts with PMNs, then mphages)
1 week to 1 month you get granulation tissue; After 1 month you get a scar
See FA for more
Sudden Cardiac Death: unexpected death due to cardiac dz, w/out sx or <1hr after onset of symptoms
usually due to fatal ventricular arrhythmia
o 90% pt have preexisting severe artherosclerorsis
o Can also occur with MVP, cardiomyopathy, & cocaine abuse
 s
Chronic Ischemic Heart Dz
o Poor myocardial function due to chronic damage (w/ OR w/out infarction) progresses to CHF

te
CHF
Etiology of left-sided failure
o Ischemia, HTN, dilated CM (poor filling), restricted cardiomyopathy (poor contraction), MI
Consequences of L-sided heart failure
o Leads to pulmonary congestion (backs up)edema, dyspnea, PND, orthopnea, crackles

ra
Heart failure cells aka hemosiderin-laden: mphages consuming blood & iron in alveoli
o Decreased forward perfusion activates renin-angiotensin system (give ACEi)
Right sided failure: MCC due to L-sided failure
Also caused by L to R shunts & chronic lung disease (cor pulmonale)
RV pumps against higher resistance (hypoxiaconstriction in the lungs)
o Clinical: JVD, painful HSM (may lead to cardiac cirrhosis), dependent pitting edema
Pi
Congenital Defects see FA
VSD: MC congenital heart defect assd with fetal alcohol syndrome
o Can reverse shunt (blue blood) when pressure is higher in RV than LV (bc high pulm pres)
o Hypoxemia causes release of EPO, and cyanosis causes clubbing
ASD
o MC type is ostium secundum
st
Ostium primum is assd with down syndrome
o Because you have a R-L shunt, an emboli can pass R circulation and end up on systemic
circulationlodge in the brain or distal extremities = paradoxical embolus
Tetralogy of Fallot
o Squatting increases PVR to help reduce cyanotic spells
o Boot-shaped heart
Te

Coarctation of the Aorta

o Infantile type
Assd with a PDA and the coarctation is BEFORE the PDA some of the blood from RV goes
thru PDA instead of pulmonary circ because of the low pressure formed after the
PDAlower extremity cyanosis
o Adult form
NOT assd with a PDA
Collateral circulationengorged arteries and notching of the ribs

Valvular Disorders See FA

Rheumatic Fever
o Must have involvement of the mitral valve to say you have rheumatic valve dz
If you have isolated aortic involvement, think about something else
Aortic Stenosis
o Complications can include concentric LVH, angina/syncope, microangiopathic hemolytic anemia
Aortic Regurg
o Due to aortic root dilation (ie syphilitic aneurysm or infective endocarditis)

Endocarditis
General
o Inflammation of endocardium lining cardiac valves usually due to bacterial infection
Bugs
o S. viridans: MC overall cause subacute endocarditis
 s
Low-virulence organism can ONLY infect previously damaged valves
Results in small vegetations that do NOT destroy valve

te
Pathogenesis
Damaged endocardial surface develops thrombotic vegetations (plt & fibrin)
Transient bacteremia leads to trapping of bacteria in vegetations
o S. aureus: MCC in IVDA acute endocarditis
High virulence org infects normal tricuspid valves
Results in large vegetations that destroy valve

ra
o S. epidermidis: endocarditis in prosthetic valves
o S. bovis: endocarditis in pt with underlying colorectal carcinoma
o HACEK organisms cause endocarditis in culture-negative organisms
Hemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella
Clinical
o Fever, murmur, janeway lesions, osler nodes, anemia of chronic dz
Labs
Pi o Positive blood culture, anemia of chr dz (high ferritin, low TIBC, high hepcidin) dx with TEE
Nonbacterial thrombotic endocarditis
o Sterile vegetations that arise w/ hypercoagulable state or underlying adenocarcinoma
o Vegetations arise on mitral valve along lines of closure & result in regurgitation
Libman-Sacks endocarditis
o Sterile vegetations assd with SLE
st
o Vegetations present on surface & undersurface (both sides) of mitral valveregurg
Cardiomyopathy (CM) see FA
Dilated CM MC form
o Dilation of ALL 4 chambers
Cardiac Tumors see FA
Te

9. Respiratory
Nasopharynx
Rhinitis: inflammation of nasal mucosa MCC is adenovirus (FA says rhinovirus??)
o Presents with sneezing, congestion, & runny nose (common cold)
Allergic Rhinitis: rhinitis due to type 1 HSR (eg, pollen) inflammatory infiltrate w EOSINOPHILS
o Assd with asthma & eczema
Nasal Polyp: protrusion of edematous, inflamed nasal mucosa
o Usually 2ndary to repeated bouts of rhinitis
o CHECK FOR CF & ASA-intolerant asthma (asthma + ASA-induced bronchospasm + polyps triad)
Angiofibroma: benign tumor of nasal mucosa composed of large blood vessels & fibrous tissue
o Only in young males, & presents with profuse epistaxis
Nasopharyngeal Carcinoma: malignant tumor of nasopharyngeal epithelium
o Assd with EBV, & classic in black kids and Chinese adults
o Biopsy shows pleomorphic keratin-pos epithelial cells in background of lymphocytes
Larynx
Acute epiglottitis: inflammation due to H. influenza, MC in nonimmunized kids
Laryngotracheobronchitis (croup): inflammation of UA, MC due to parainfluenza virus
o Presents w/ hoarse barking cough & inspiratory stridor
Vocal Cord nodule: usually bilateral nodules due to over use & composed of myxoid tissue
Laryngeal papilloma: benign papillary tumor of vocal cord (single in adults, multiple in kids)
 s
o Due to HPV 6 & 11 presents with hoarseness
Can lead to carcinoma

te
Laryngeal carcinoma: squamous cell carcinoma (smoking & etoh are risk factors)
o
Pneumonia
Lobar Pneumonia
o Congestionred hepatizationgray hepatizationresolution
o Mostly due to strep pneumo, but also Klebsiella (in diabetics/alcoholics, and can lead to abscess

ra
formation)
Bronchopneumonia
o S. aureus MCC of 2ndary pneumo complicated by abscess or empyema
o H flu superimposed on COPD
o Pseudomonas in CF pt
o Moraxella superimposed on COPDexacerbation
Pio Legionella on COPD, or immunocomp from a water source (intracellular org on silver stain)
Interstitial pneumonia
o Of the CONNECTIVE TISSUE OF THE AIR SACS (the walls) no consolidation
o Milder sx (not a high fever and minimal sputum)
Looks like an URI
o Mycoplasma: military recruits & young adults + dorm students
Can lead to hemolytic anemia (IgM against I Ag on RBCscold agglutinin) + erythema
st
multiforme
o Chlamydia pneumonia:
o RSV: MCC pneumo in infants
o CMV: immunosupp
o Influenza: can lead to superimposed s aureus or h flu!
o Coxiella: Q fever seen in farmers, vetsXCoxiella spores
Te

Other rickettsias dont cause pneumonia and have arthropod vectors and causes rash(Q
doesnt)
Aspiration pneumonia
o At risk pt epileptic, alcoholic
o Due to bacteroides, fusobacterium, & peptococcus
o RIGHT LOWER LOBE ABSCESS is classic bc thats where we aspirate to
Tuberculosis
o Primary TB
Focal caseating necrosis in lower lobe and hilar lymphadenopathy
Foci undergo fibrosis & calcificationGHON complex (usually subpleural)
Usually asymptomatic, but with a pos PPD
o 2ndary TB
Commonly due to AIDS and aging
Occurs at apex of lungcaseous necrosis
Can lead to miliary pulmonary TB (tiny regions of TB across entire lung), or TB
bronchopneumonia
Fever, night sweats, cough + hemoptysis; caseating granulomas
Do AFB to rule out fungus
Systemic spread to any tissue, but HY are
Meninges (meningitis at the BASE OF THE BRAIN), cervical lymph nodes, kidney is
MC (sterile pyuria), lumbar vertebrae (Pott disease)
COPD
General: key is that there is obstruction to getting air out of the lung TLC is increased (air trapping)
 s
o Note: FVC is the maximum inspiration to max expiration
Chronic Bronchitis

te
o Cough > 3mo for at least 2 years highly assd with smoking
o Involves large airways like the bronchus
Note: respiratory epi is pseudostratified columnar ciliated
o Glands are found in the submucosa (under the lamina propria which have blood vessels)
Contains serous and mucinous glands
Normal ratio of glands to entire thickness of wall is <40%; in CB, >50% (Reid index)

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Mucus can plug the airways and create infections
o Cyanosis
Increased PaCo2, dec PaO2:
Cor pulmonale: vasoconstriction at the site of lack of oxygenation
Slowly, all the parts start clamping downincreased pres RV pumps against
Cor pulmonale directly means failure of the right heart
Emphysema: destruction of alveolar air sacs + lost elastic recoilair trapping
Pi o Obstruction is physiologic 2 reasons
1. Air sacs lose their elastic recoil so air cant get out well
2. When you breath out (high acceleration) drags wall in tendency to collapse
The cartilage keeps wall open higher up, but no cartilage down below
o Pathophys
Due to imbalance of proteases & antiproteases
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Proteases are triggered during inflammation - A1AT is an antiprotease
Overproduction of Proteases (P) or underproduction of A
MC with high P SMOKINGCENTRIACINAR and in UPPER lobes
Low A A1AT deficiency PiZZ (vs PiMM is normal) PANACINAR, LOWER lobes
may also see liver cirrhosis bc gets stuck in ENDOPLASMIC RETICULUM
o Curative with liver tplant extra A1AT just fixes lung problem
Te

o The A1AT globules in liver are PAS positive

Remember, collapsing tendency of lung is balanced by chest = FRC higher in emphysema
and lower in pulmonary fibrosis (higher elastic recoil)
o Clinical
Dyspnea, cough (NO SPUTUM), PURSED LIPS (back pressure), inc AP diam, skinny
Hypoxemia (destroyed walls = poor PaO2<60) + cor pulmonale like before
Asthma
o REVERSIBLE bronchoconstriction type 1HSR due to allergen
o Assd with allergic rhinitis, eczema, & family Hx or atopy
o Pathogenesis
Allergens induce Th2 of CD4IL-4, 5, & 10
IL-4: allows IgE production; IL-5 calls in eosinophils; IL-10: inhibits Th1
Reexposure to allergen: IgE activation of mast cell (early-phase) dumps Histamine
granulesvasodilation (@arterioles) & vascular permeability (@post cap venules)
Leukotriene productionCONSTRICTION + inc permeability
Inflammation (MBP) perpetuates bronchoconstriction (late-stage)
o Clinical
Dyspnea, wheezing, productive cough; Curschmann spirals + Charcot-Leyden crystals
(crystalline aggregates of eosinophil major basic protein)
Can lead to status asthmaticus & death
o Can also get asthma from Aspirin (plus nasal polyps and bronchospasm)
Bronchiectasis (necrotizing inflammation of large airway walls) loss of tone
o CF, Kartagener (dynein arm), tumor, infection, allergic bronchopulmonary aspergillosis
 s
ABA is a hypersensitivity rxn seen in asthmatics and CF pt
o Cough, dyspnea, foul-smelling sputum

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o Can lead to hypoxemia, cor pulmonale, & secondary amyloidosis (AA amyloid look up)

Restrictive Diseases
General: increased FEVFVC ratio, dec TLC MC with interstitial dz of the lung
Idiopathic Pulmonary Fibrosis: fibrosis of lung interstitium
o Due to cyclical lung injury TGF-Binduces fibrosis (begins at subplural but can go on to involve

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entire lunghoneycomb lung) Tx is tplant
o Make sure to rule out bleomycin & amiodarone & radiation b4 making Dx
Pneumoconioses
o Mediated by macrophages, need chronic exposure of small particles
See slide in book for various types
o Note: silica in mphae impairs the function of the phagolysosome
Pi SILICA IS THE ONLY ONE TO INC RISK FOR TB THUS, FOUND IN UPPER LOBE
Beryliosis sounds like sarcoidosis noncaseating granulomas systemically!
Pay attn to NASA etc
Mesothelioma: fibrosis of the lung/pleura & cancer of lung/pleura
Look for asbesthos bodies (golden-brown)
Sarcoidosis
o Also systemic noncaseating granulomas (esp in lung/hilar lymp) classic in black women
st
Remember noncaseating means cells in center are ALIVE
Look for asteroid body!
Can mimic Sjogren at the salivary & lacrimal glands watch out
o Clinical
Dyspnea/cough; elevated ACE, hypeerCa Tx with steroids, but resolves on its OWN
hyperCa because noncaseating granuloma can activate 1a hydroxlase & activate vitD
Te

Hypersensitivity Pneumonitis
o Granulomatous rxn WITH EOSINOPHILS pigeon-breeders lung
o Fever, cough, dyspnea remove exposure!
o Chronic exposure = interstitial fibrosis

Pulmonary Hypertension
Definition: MAP>25mmHg (normal is <10)
o Atherosclerosis of pulmonary trunk, sm musc hypertrophy, intimal fibrosis
o Plexiform lesions with severe, long-standing dz as consequence of the BMPR2 mutation
Clinical
o Present with exertional dyspnea or right-sided H failure - RVH & cor pulmonale
Etiology
o Primary: unknown, assd with young adult females and BMPR2 mutationproliferation of vascular
smooth muscle + thickening of wallshypertension
o 2ndary: due to hypoxemia (COPD, congenital heart dz) lungs constrict with poor O2
May also arise with recurrent pulmonary embolism
RDS
Acute RDS: Diffuse damage to alveolar-capillary interface (diffuse alveolar damage) protein-rich fluid leaks
(edema) & reorganizes to form a hyaline membrane
o Complications
Thickened diffusion barrier poor gas exchangehypoxemia & cyanosis
Hyaline membranes increases surface tension of air sacdiffuse collapse of lung
o Clinical features: hypoxemia & cyanosis w/ respiratory distresswhite out on CXR
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o Etiology: anything (sepsis, shock, aspiration, pancreatitis, DIC, hypersensitivity rxn)
Key is activation of PMN to induce protease-mediated & FR damage of type 1 & 2

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pneumocytes
o Treatment: Tx underlying cause, ventilate with PEEP (bc lung collapse), but can get fibrosis
Knocked out type 2 pneumocytes prevents regenerationfibrosis
Neonatal Respiratory Distress Syndrome
o Respiratory distress due to inadequate surfactant levels (type 2 pneumocyte)
o Clinical: inc respiratory effort after birthtachypnea + access muscles

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Can lead to hypoxemia and cyanosis: CXR shows diffuse granularity of lung
o Etiology
Prematurity (L:S ratio >2 = normal), C-section (low stress envirolow steroid levels),
maternal diabetes (insulin inhibits type 2 pneumocytes)
o Complications
Hypoxemia increases risk for persistence of PDA & necrotizing enterocolitis
Pi Supplemental O2 = inc risk for free radical injury (retina & blindness, & bronchopulmonary
dysplasia)
Lung Cancer
See FA

Pleura
General: Visceral pleura directly attached to lung; parietal pleura attached to chest wall; both lined with
st
mesothelial cells; pleural space in between them
Pneumothorax: accumulation of air in the pleural space
o Spontaneous: rupture of emphysematous (apical) bleb in young adult
Trachea shifts to SIDE of collapse
o Tension: due to penetrating chest wall injury
Trachea shifts to OPPOSITE side a medical emergency!
Te

Air gets in upon inspiration, but doesnt get out with expiration one way valve
compressing lung down and pushing trachea to opposite side
Mesothelioma
o Malignant neoplasm of mesothelial cells assd with asbestos exposure
o Clinical: recurrent pleural effusions, dyspnea, & chest pain
o Tumor encases the lung
o Psammoma bodies