An increase in organ size by hypertrophy or hyperplasia.
Card 2
By what three general processes does cellular hypertrophy occur?
Answer
Gene activation
Increased Protein synthesis
Increased production of organelles.
Card 3
By what general mechanism does hyperplasia occur?
Answer
Production of new cells from stem cells.
Card 4
Is the pregnant uterus an example of hypertrophy or hyperplasia?
Answer
Both
Card 5
What is a permanent tissue? Can a permanent tissue grow? What are the (3) permanent tissues?
Answer
A permanent tissue is one that cannot make new cells (no lingering stem cells/progenitors).
Permanent tissues can only grow by hypertrophy.
Skeletal muscle, cardiac muscle, and nerve.
Card 6
How does the heart respond to persistent hypertension? What are the two basic types of cardiac hypertrophy and what causes them?
Answer
Being a permanent tissue, it grows via hypertrophy.
Pressure overload → concentric hypertrophy (sarcomeres added in parallel. HCM)
Volume overload → eccentric hypertrophy (sarcomeres added in sequence. DCM)
Card 7
What concern exists with endometrial hyperplasia? What hyperplastic process doesn't carry this same concern?
Answer
As a general rule: pathologic hyperplasias increase risk for cancer.
Endometrial hyperplasia is a pathologic hyperplasia (caused by excess estrogen secretion) that carries a risk for progression to dysplasia and eventually cancer.
BPH is a type of pathologic hyperplasia does not increase the risk for cancer (is an exception to the rule)
Card 8
What are three examples of "decreases in stress" that lead to atrophy?
How is cell number decreased in an atrophic process?
Answer
Apoptosis
Card 11
In what two ways is cell size reduced in atrophy?
Answer
Ubiquitin-proteosome degradation of the cytoskeleton and autophagy of cellular components.
Card 12
What is ubiquitin-proteosome degradation?
Answer
Proteins (in atrophic processes, intermediate filaments of the cytoskeleton) are tagged with ubiquitin and destroyed by proteosomes.
Card 13
How does autophagy occur in atrophy?
Answer
Autophagic vacuoles engulf cellular components that are no longer needed.
These vacuoles then fuse with lysosomes.
Card 14
What does a change in stress on an organ lead to?
Answer
Metaplasia
Card 15
What is metaplasia?
Answer
A change in cell type, most commonly involving surface epithelium (changing to a type more suitable to handle the change in stress)
Card 16
Describe the metaplastic process observed in Barrett esophagus:
Answer
Change from non-keratinizing stratified squamous (handles friction of food bolus) to non-ciliated columnar with goblet cells (better for handling acid).
Card 17
How does metaplasia occur?
Answer
Reprogramming of stem cells
Card 18
Is metaplasia reversible?
Answer
Yes, in theory, with the removal of the stressor.
Card 19
How do you treat Barrett esophagus?
Answer
Remove the stressor, i.e. treat the acid reflux
Card 20
Are we concerned about metaplastic processes?
Answer
Yes - metaplasia can progress to dysplasia and eventually cancer
Card 21
Does all metaplasia lead to cancer? Can you name a metaplastic process that has 0% chance of causing cancer?
Answer
Though most types of metaplasias can theoretically progress to cancer (e.g. Barrett esophagus->adenocarcinoma), many do not.
Apocrine metaplasia of breast has no propensity for malignant transformation
Card 22
What processes is vitamin A essential for?
Answer
It's necessary for differentiation of specialized epithelial surfaces (e.g. conjunctiva), and essential for the maturation of certain immune cells (such as neutrophils).
*Note: also helps reduce mortality in measles
Card 23
Describe the pathological effects of vitamin A deficiency:
Answer
Deficiency of vitamin A results in metaplastic specialized epithelium. For example, the squamous epithelium of the conjunctiva undergoes metaplasia into stratified keratinizing squamous epithelium. This is keratomalacia.
Vitamin A is also important for maturation of immune cells. Remember that retinoic acid (vitmain A derivative) is important for neutrophil maturation (remember, ATRA is used to treat APL).
Card 24
What is myositis ossificans?
Answer
Inflammation of the skeletal muscle induces metaplastic change in the connective tissue of the muscle to produce bone.
*Note: it's clinically important to differentiate this process from osteosarcoma. myositis ossificans is clearly detached from bone on imaging. osteosarcoma would not be.
Card 25
What is dysplasia?
Answer
Disordered cellular growth. Often refers to proliferation of precancerous cells.
Card 26
What pathologic proliferation is a precursor to cervical cancer? How is it categorized?
Answer
Cervical intraepithelial neoplasia (CIN), which is a dysplastic process.
A: CIN1: dysplastic cells in lower 1/3 of epithelium
B: CIN2: dysplastic cells in lower 2/3 of epithelium
C: CIN3: dysplastic squamous cells throughout full thickness of epithelium
Hypoxemia
Reduced carrying capacity of blood (anemia)
Ischemia (infarct or hypovolemic shock)
Card 41
When does decreased O₂ carrying capacity arise? Examples?
Answer
With hemoglobin loss or dysfunction. Examples include anemia and CO poisoning.
Card 42
How does CO poisoning reduce O₂ carrying capacity?
Answer
CO binds Hb more avidly than O₂ does.
Card 43
What are the PaO₂ and SaO₂ in anemia? CO poisoning?
Answer
Anemia: both normal.
CO Poisoning: PaO₂ normal, SaO₂ decreased.
Card 44
Common exposures to CO?
Answer
Smoke from fires and exhast from cars or gas heaters (common suicide attempt).
Card 45
What's the classic physical finding in CO poisoning? Other findings?
Answer
Cherry-red appearance of skin. The early sign of expsure is headache. Significant exposure leads to coma and death.
Card 46
What is methemoglobinemia?
Answer
When Fe²⁺ is oxidized to Fe³⁺, RBCs can't bind O₂.
Card 47
PaO₂ and SaO₂ in methemoglobinemia?
Answer
PaO₂ normal, SaO₂ decreased. Similar to CO poisoning
Anemia: normal PaO₂, normal SaO₂
Card 48
Under what conditions does methemoglobinemia occur?
Answer
With oxidant stress (e.g. sulfa and nitrate drugs) and in newborns (immature Fe-reducing enzymes).
Card 49
What's the classic finding in methemoglobinemia?
Answer
Chocolate-colored blood.
Card 50
Tx for methemoglobinemia?
Answer
Intravenous methylene blue helps reduce Fe³⁺ to Fe²⁺.
Card 51
What cellular functions does low ATP affect? Consequences?
Answer
Na⁺-K⁺ pumps, resulting in Na/H₂O buildup and swelling
Ca²⁺ pumps, resulting in Ca²⁺ buildup in cytosol (can activate hydrolytic lysosomal enzymes)
Aerobic glycolysis, resulting in a switch to anaerobic glycolysis and lactic acid buildup, denaturing proteins and precipitating DNA.
Card 52
Is cellular injury reversible? What's the hallmark of reversible injury?
Answer
It is in the initial phase. The hallmark is cellular swelling.
Card 53
What histologic findings indicate reversible injury?
Answer
Loss of microvilli and membrane blebbing indicate cytosol swelling.
Dissociation of ribosomes and decreased protein synthesis indicate RER swelling
*These changes are reversible
Card 54
What is the hallmark of irreversible cellular injury?
Answer
Membrane damage.
Card 55
What are the consequences of specific membranes in the cell being damaged?
Answer
-Plasma membrane damage results in leakage of cytosolic enzymes into the serum (e.g. cardiac troponin) and additional Ca++ entering the cell.
-Mitochondrial membrane damage results in loss of ETC (innter mito membrane) and cytochrome c leaking into the cytosol (activates apoptosis)
-Lysosome membrane damage results in hydrolytic enzymes leaking into the cytosol, which then become activated by the high intracellular Ca++.
Card 56
What is the morphologic hallmark of cell death? How does it occur?
Answer
Loss of the nucleus
By condensation (pyknosis)
fragmentation (karyorrhexis), and
dissolution (karyolysis)
*Remember:
Swelling = reversible injury
Membrane damage = irreversible injury
Loss of nucleus = death
Card 57
What are the 2 types of cell death?
Answer
Necrosis (murder) and apoptosis (suicide).
Card 58
Describe the main differences between necrosis and apoptosis
Answer
Apoptosis is self-initiated, necrosis is not.
Necrosis involves a large group of cells and is followed by acute inflammation.
Necrosis is always pathologic, never physiologic.
Card 59
Describe coagulative necrosis
Answer
Necrosis where the organ and cell structures are preserved by coagulation of proteins. The nucleus disappears though. The necrotic tissue remains firm.
Card 60
When and where does coagulative necrosis occur?
Answer
Ischemic infarction in any organ but the brain.
Card 61
How do you recognize an organ that has undergone coagulative (vs. other) necrosis?
Answer
It will have maintained its shape. The infarcted area is often wedge-shaped and pale.
Card 62
When does red infarction arise? Examples?
Answer
When blood re-enters a loosely organized tissue (e.g. an organ that has undergone coagulative necrosis). Examples include testicular and pulmonary infarctions.
*Note that red infarcts are actually defined as infarcts in the venous drainage of a tissue or in a tissue with dense collaterals/dual blood supply
Card 63
What is liquefactive necrosis?
Answer
Necrotic tissue that becomes liquefied by enzymatic lysis of cells and proteins.
Card 64
When and where does liquefactive necrosis occur (3)?
Answer
Any time an organ is exposed to proteolytic enzymes.
It occurs in the brain - enzymes of the microglial cells;
in abscesses - enzymes from neutrophils;
and in pancreatitis - liquification of parenchyma (autodigestion)
Card 65
When does acute inflammation arise?
Answer
It is the result of either infection or necrosis
Card 66
What type(s) of necrosis are associated with the pancreas?
Answer
Fat and liquefactive
Card 67
What are the types of necrosis?
Answer
Coagulative, liquefactive, gangrenous, caseous, fat, and fibrinoid.
Card 68
What is gangrenous necrosis?
Answer
Coagulative necrosis that resembles mummified tissue (dry gangrene). If superimposed infection of the dead tissue occurs, liquefactive necrosis ensues (wet gangrene).
Card 69
Where does gangrenous necrosis most often occur (2 places)?
Answer
It is characteristic of ischemia of the lower limb and GI tract.
Card 70
Describe caseous necrotic tissue
Answer
Soft and friable, cottage cheese appearance.
Card 71
When does caseous necrosis occur? What is it?
Answer
It is characteristic of granulomatous inflammation due to tuberculous or fungal infection. It's a combination of coagulative and liquefactive necrosis.
Card 72
What is fat necrosis?
Answer
Necrotic adipose tissue with a chalky-white appearance due to the deposition of Ca.
Card 73
Where and how does fat necrosis occur?
Answer
Trauma to fat (e.g. breast) and pancreatitis-mediated damage of peripancreatic fat. These 2 processes release fatty acids, which then bind Ca in saponification.
Card 74
What is dystrophic calcification?
Answer
Calcium deposition in the context of normal calcium levels
Card 75
What does fat necrosis have to do with dystrophic calcification?
Answer
Saponification is an example of dystrophic calcification (Ca deposits on dead tissue). The necrotic tissue acts as a nidus for calcification.
Card 76
What are the serum Ca and P levels in dystrophic calcification? metastatic calcification?
Answer
Dystrophic (e.g. saponification): Ca and P levels are normal. Deposition occurs where there is a nidus, for example dead tissue.
Metastatic (e.g. hyperPTH → nephrocalcinosis): Ca and P levels are high, leading to deposition in normal tissues
Card 77
What's the differential for Ca²⁺ deposits in the breast?
Answer
Carcinoma in situ or fat necrosis.
Card 78
Why might a patient with fat necrosis think they have breast cancer?
Answer
The release of fatty acids can sometimes lead to a giant cell reaction, in which the patient might present with a mass consisting of fat, giant cells, and calcification.
Card 79
What is fibrinoid necrosis?
Answer
Necrotic damage to the blood vessel wall causes proteins (including fibrin) to leak into the wall.
Card 80
How do you identify fibrinoid necrosis?
Answer
It stains bright pink.
Card 81
For what two general pathologies can fibrinoid necrosis occur?
Answer
Characteristic of malignant hypertension and vasculitis.
Card 82
What is malignant hypertension?
Answer
More commonly referred to as "hypertensive emergency" - defined as a BP of 180/120 or greater with papilledema. Presence of end organ damage would be called a "hypertensive crisis"
Card 83
What kind of necrosis would pre-eclampsia lead to?
Answer
Fibrinoid necrosis of the placental vessels.
Card 84
What is a free radical?
Answer
A chemical species with unpaired electrons in its outer orbit
Card 85
What is apoptosis?
Answer
Energy dependent, genetically programmed cell death involving single cells or groups of cells.
*Apoptosis takes ATP!!!
Card 86
Three examples of physiologically appropriate apoptosis?
Answer
Endometrial shedding during menstruation.
Removal of cells during embryogenesis (e.g. malfunction -> syndactyly)
CD8 T cell-mediated killing of virally infected cells.
Card 87
Describe the morphologic changes in the apoptotic process
Answer
As the dying cell shrinks,
the cytoplasm becomes more eosinophilic (pink).
The nucleus condenses (pyknosis) and fragments (karyorrhexis),
and then apoptotic bodies fall (apoptosis means "falling of leaves" in greek) from the cell and are removed by macrophages.
Card 88
What are the main enzymatic mediators of apoptosis? How do they work?
Answer
Caspases, which activate proteases and endonucleases.
Card 89
In what 3 ways can caspases be activated?
Answer
Via 3 pathways:
1. Intrinsic mitochondrial pathway (cytochrome c)
2. Extrinsic receptor-ligand pathway (FAS ligand)
3. Cytotoxic CD8⁺ T cell-mediated pathway (granzyme)
Card 90
What is Bcl2?
Answer
It stabilizes the mitochondrial membrane by binding to Bax/Bak, in order to inhibit leakage of cytochrome c into the cytosol
Card 91
What kinds of events lead to the inactivation of Bcl2? What's the consequence?
Answer
Cellular injury,
DNA damage,
or loss of hormonal stimulation.
Inactivation of Bcl2 allows cytochrome c to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases.
Card 92
What is the extrinsic receptor-ligand pathway? How does CD95 play a role?
Answer
FAS ligand binds FAS death receptor (CD95) on the target cell, activating caspases.
Alternatively, TNF binds the TNF receptor on the target cell, activating caspases.
Card 93
What is the cytotoxic CD8 T cell-mediated pathway?
Answer
CD8 T cells secrete perforins, which create pores in the membrane of target cells. They then secrete granzymes, which can enter through the pores and activate caspases. This is how CD8 T cells kill virally infected cells.
Card 94
When does apoptosis occur in aberrant T cell maturation?
Answer
Negative selection in the thymus, which assesses whether or not the T cell binds too avidly to self-Ag.
If it does, FAS ligand is expressed, binds FAS death receptor, apoptosis.
Positive selection, on the other hand, tests to make sure that the T cell can properly bind self-Ag on MHC.
+selection: do you bind?
-selection: do you bind too strongly?
Card 95
What are the 2 ways a cytotoxic T cell kills cells expressing foreign Ag?
Answer
FAS-induced apoptosis and perforin pathway.
*Just a note to remember that FAS ligand is a cytokine of the TNF family
Card 96
What process is involved in physiologic free radical generation?
Answer
Oxidative phosphorylation
Card 97
What enzyme transfers electrons to O₂, the final electron acceptor?
Answer
Cytochrome c oxidase (complex IV).
(Inhibited by cyanide and CO)
Card 98
What are the free radicals produced in oxidative phosphorylation? How many accepted electrons does each radical state represent?
Answer
O₂ + 1 electron=superoxide (O₂⁻)
2=hydrogen peroxide (H₂O₂)
3=hydroxyl radical (*OH)
4=water (H₂O) (not a free radical, just here for completion's sake)
Card 99
When does pathologic generation of free radicals arise (5 scenarios)?
Answer
Ionizing radiation,
inflammation,
metals accumulation,
drugs and chemicals,
reperfusion after ischemic injury
Card 100
How does ionizing radiation generate free radicals?
Answer
Water is hydrolyzed to hydroxyl free radical (•OH)
Card 101
What is the most damaging free radical?
Answer
Hydroxyl (*OH)
Card 102
How does inflammation generate free radicals?
Answer
NADPH oxidase generates superoxide during oxygen dependent killing by neutrophils.
Card 103
Which metals create free radicals? Through which reaction?
Answer
Copper and iron. Fenton reaction.
Card 104
How do drugs and chemicals create free radicals?
Answer
The P450 system can generate free radicals in the process of metabolism (e.g. of acetaminophen).
Card 105
How do our bodies eliminate free radicals (3 modalities)?
Answer
Antioxidants (glutathione, vitamins A, C, E)
Enzymes (glutathione peroxidase, catalase, SOD)
Metal carrier proteins (transferrin and ceruloplasmin)
Card 106
What antioxidants do our bodies use?
Answer
Glutathione, vitamins A, C, E, etc.
Card 107
What enzymes do our bodies use to eliminate free radicals? Mechanism of each?
What are 2 examples of metal carrier proteins that reduce free radical damage?
Answer
Transferrin and ceruloplasmin
Card 109
What is the mechanism of tissue damage in hemochromatosis and Wilson dz?
Answer
Free radical damage
Card 110
What 2 key features will indicate an apoptotic cell?
Answer
Small nucleus, pink cytoplasm.
Card 111
What is CCl₄ and what is its significance? What cellular and gross changes will be seen?
Answer
It's an organic solvent used in dry cleaning. It's converted to CCl₃ (a free radical) by the P450 system. Results in cell injury with swelling of RER; as ribosomes detach, protein synthesis is impaired. This decreases apolipoprotein production, leading to fatty changes in the liver as fat can't be mobilized.
Card 112
How does reperfusion injury work? How will you detect it?
Answer
As blood returns to ischemic tissue, O₂-derived free radicals further damage the tissue (burst of oxidative respiration)
For example, in an MI, cardiac enzymes will rise (e.g. troponin). When you reperfuse (cath), they will continue to rise rather than fall.
Card 113
What is amyloidosis?
Answer
Misfolded proteins get deposited in the extracellular space, damaging tissues.
Card 114
What are the shared features among all amyloid?
Answer
β pleated sheet structure
Congo red staining/apple green birefringence under polarized light:
Card 115
Where does amyloid deposition occur (types)?
Answer
Can be systemic (Primary AL or Secondary AA)
or localized.
Card 116
What is primary amyloidosis? What conditions is it associated with?
Answer
Systemic deposition of AL amyloid, which is derived from Ig light chain. It's associated with plasma cell dyscrasias (e.g. multiple myeloma).
Card 117
What is secondary amyloidosis?
Answer
Systemic deposition of AA amyloid, which is derived from serum amyloid-associated protein (SAA).
SAA is an acute phase reactant, meaning that in chronic inflammatory states, development of secondary amyloidosis is possible
Card 118
What is SAA (serum amyloid associated) protein? In what three conditions is it increased?
Answer
An acute phase reactant that is increased in
chronic inflammatory states,
malignancy, and
Familial Mediterranean Fever (FMF).
Card 119
What is Familial Mediterranean Fever?
Answer
Dysfunction of neutrophils (AR); occurs in persons of Med origin.
Presents with episodes of fever and acute serosal inflammation (pericardium, MI, appendicitis)
High SAA (acute phase reactant) attacks deposits as AA amyloid.
Card 120
Classic clinical findings of systemic amyloidosis (5)?
Answer
Nephrotic Syndrome: kidney is most commonly involved
Restrictive Cardiomyopathy
Tongue Enlargement
Malabsorption
Hepatosplenomegaly
Card 121
What is senile cardiac amyloidosis?
Answer
Non-mutated serum transthyretin deposits in the heart.
ASYMPTOMATIC.
Commonly seen in the elderly. (25% of eldrly >80 y/o)
*Contrast to familial amyloid cardiomyopathy
Card 122
What is familial amyloid cardiomyopathy?
Answer
Mutated serum transthyretin deposits in the heart (ATTR).
Leads to restrictive cardiomyopathy.
5% of african americans carry mutated gene.
*Contrast to senile cardiac amyloidosis
Card 123
Compare and contrast Familial Amyloid Cardiomyopathy and Senile Cardiac Amyloidosis:
Answer
Familial amyloid cardiomyopathy:
Mutated serum transthyretin deposits in the heart.
Leads to restrictive cardiomyopathy.
5% of african americans carry mutated gene.
Senile Cardiac Amyloidosis:
Non-mutated serum transthyretin deposits in the heart.
ASYMPTOMATIC.
Commonly seen in the elderly.
Card 124
What kind of amyloidosis are noninsulin-dependent diabetics (T2DM) at risk for developing?
Answer
Amylin deposits in islets of pancreas
*Amylin is derived from insulin
Card 125
What is the type of amyloid that is deposited in dialysis associated amyloidosis?
Answer
β2-microglobulin deposits in joints. This protein is normally filtered by kidneys, is not filtered by dialysis.
β2-microgoblulin is a structural component of MHC1.
Card 126
How is amyloid associated with medullary carcinoma of the thyroid?
Answer
Classic histology is tumor cells with an amyloid background.
Calcitonin deposits also seen within the tumor
*Note, MCT is a cancer of the parafollicular (C) cells of the thyroid.
Card 127
What's the main difference between acute and chronic inflammation?
Edema and neutrophils in response to infection (to eliminate the pathogen) or tissue necrosis (to clear necrotic debris).
Card 129
Acute inflammation: rapidity of response? Specificity?
Answer
Rapid response at the expense of specificity - for example, neutrophils, though quick to arrive on the scene, are fairly destructive to everything around them.
Card 130
What cells possess toll-like receptors (TLRs) and what do they do?
Answer
TLRs are present on many cells of the innate immune system; canonically macrophages and dendritic cells. However, most immune cells carry TLRs.
They are activated by pathogen-associated molecular patterns (PAMPs)
Card 131
What TLR co-receptor is canonically present on macrophages? What does it recognize?
Answer
CD14. Recognizes LPS on the outer membrane of gram(-) bacteria.
*Note that CD14 is a co-receptor for TLR4
1: T
4: R
Card 132
TLR activation leads to what downstream molecular effects?
Answer
Upregulation of NFkB,
...which is a nuclear transcription factor that activates immune response genes responsible for producing a number of immune mediators (most importantly, TNF)
Card 133
Do lymphocytes ever express TLRs?
Answer
Yes. TLRs 1,3,4,6,9 - you get the idea - all found on B lymphocytes
Card 134
Cyclooxygenase produces what immune mediators, and from what substrate? What do they do?
Answer
Prostaglandins I₂, D₂, and E₂. Arachidonic acid is substrate.
All three mediate vasodilation and increased vascular permeability.
E₂ also mediates pain.
Card 135
What immune factors does 5-lipoxygenase produce, and from what substrate? What do they do?
Answer
Leukotrienes B4, C4, D4, E4. From arachidonic acid.
B4 attracts and activates neutrophils.
C4, D4, and E4 mediate vasoconstriction, bronchospasm, and increased vascular permeability (all consequences of smooth muscle contraction)
Card 136
What are the 2 main mediators of pain?
Answer
PGE2 and bradykinin.
Card 137
What are the 2 functions of PGE2?
Answer
Mediates fever (synthesized in hypothalamus to increase temperature setpoint) and pain (sensitizes nerve endings)
Card 138
What 4 mediators that attract neutrophils?
Answer
LTB₄, IL-8, C5a, and bacterial products.
Card 139
Where are mast cells located?
Answer
They are widely distributed throughout connective tissue.
Card 140
What 3 processes can activate mast cells?
Answer
Tissue trauma
C3a and C5a
or cross-linking of cell-surface IgE by antigen
Card 141
Compare and contrast the immediate and delayed responses of mast cells to activation:
Answer
Immediate response: release of pre-formed histamine granules, which cause vasodilation and increased vascular permeability at the post-capillary venule
Delayed response: arachidonic metabolite production, particularly leukotrienes, to maintain the acute inflammatory response.
Card 142
What is the complement system?
Answer
Proinflammatory serum proteins that "complement" inflammation
Card 143
Describe the final pathway of complement activation:
Answer
Pathways converge on:
production of C3 convertase (mediates C3 → C3a & C3b)
C3 convertase then produces C5 convertase (mediates C5 → C5a & C5b)
C5b then complexes with C6-C9 to form the membrane attack complex (MAC).
Card 144
Describe the classical pathway of complement activation:
Answer
C1 binds IgG or IgM that is bound to antigen.
"GM makes classic cars."
Card 145
Describe the alternative pathway of complement activation:
Answer
Microbial products directly activate complement (C3 to C3a and C3b)
Card 146
Describe the mannose-binding lecithen (MBL) pathway of complement activation:
Answer
MBL binds to mannose on microbes and activates complement
Card 147
What are the anaphylatoxins and what do they do?
Answer
C3a and C5a trigger mast cell degranulation.
Card 148
Two functions of C5a?
Answer
Anaphylatoxin - causes mast cell degranulation (vasodilation, increased vascular permeability)
Acts as a chemoattractant for neutrophils.
Card 149
One function of C3b?
Answer
Opsonin for phagocytosis
Card 150
Function of MAC?
Answer
Creates a hole in the cell membrane; lysis
Card 151
What is Hageman factor? How is it activated? What 3 functions does it carry out once activated?
Answer
Factor XII. It is an inactive proinflammatory protein produced in the liver.
It is activated upon exposure to tissue factor. In turn it then:
1) Activates the coagulation and fibrinolytic systems
2) Activates complement
3) Activates kinin system
Card 152
Describe the kinin system:
Answer
Kinin cleaves high molecular weight kininogen (HMWK) to bradykinin...
...which mediates vasodilation,
increased vascular permeability (similar to histamine),
as well as pain.
Card 153
What are the 5 cardinal signs of inflammation?
Answer
Rubor, calor, dolor, tumor, fever
Card 154
What causes rubor and calor? Three key mediators?
Answer
Vasodilation (due to relaxation of arteriolar smooth muscle).
Key mediators are histamine, prostaglandins, and bradykinin.
Card 155
What causes tumor? Two key mediators?
Answer
Leakage of fluid from post-capillary venules into the interstitial space (exudate).
Key mediators are histamine (endothelial cell contraction) and tissue damage (endothelial cell disruption).
Card 156
2 key mediators of dolor (pain)?
Answer
PGE2 and bradykinin, which sensitize sensory nerve endings.
Card 157
Describe the pathway by which pyrogens induce fever:
Answer
Pyrogens (e.g. LPS) cause macrophages to release IL-1 and TNF, which increase COX activity in perivascular cells of the hypothalamus. This increases PGE₂ production, raising the temperature set point.
Card 158
What are the (7) steps of neutrophil arrival and function?
Answer
1. Margination
2. Rolling
3. Adhesion
4. Transmigration and chemotaxis
5. Phagocytosis
6. Destruction of phagocytosed material
7. Resolution
Card 159
How does margination mechanistically occur?
Answer
1) Vasodilation slows the blood flow in postcapillary venules
2) Decreased velocity causes cells to marginate from center of flow to periphery
Card 160
What are the 3 steps that induce leukocyte rolling?
Answer
1) P-selectin release (mediated by histamine
2) E-selectin release (induced by TNF and IL-1)
3) Selectins bind sialyl Lewis X on leukocytes
...and then rolling occurs
Card 161
How does adhesion occur (leukocyte) (be specific with which cytyokines upregulate which receptors)?
Answer
1) Cellular adhesion molecules (ICAM and VCAM) are upregulated on endothelium by TNF and IL-1.
2) Integrins are upregulated on leukocytes by C5a and LTB₄.
3) Interaction between -CAMs and integrins results in firm adhesion.
Card 162
What two substances are released from Weibel-Palade bodies?
Answer
von Willebrand factor, P-selectin
Card 163
What is leukocyte adhesion deficiency? What specific molecules are involved?
Answer
An autosomal recessive defect in β₂-integrin subunit (aka CD 18), shared by LFA-1 and Mac-1 integrins
Card 164
What are the clinical features of leukocyte adhesion deficiency (3)?
Answer
Delayed umbilical separation (neutrophils are partially responsible for detachment)
recurrent bacterial infections that lack pus
increased circulating neutrophils (marginated pool unable to adhere)
Card 165
During transmigration/chemotaxis, what chemical attractants do neutrophils follow?
Answer
bacterial products, IL-8, LTB₄, and C5a (should look familiar)
Card 166
What is phagocytosis, and what are its targets?
Answer
Cellular consumption of pathogens or necrotic tissue
Card 167
What factors enhance phagocytosis?
Answer
Opsonins: IgG and C3b
Card 168
How does phagocytosis occur?
Answer
Pseudopods extend from leukocytes to form phagosomes, which are internalized and merge with lysosomes to produce phagolysosomes
Card 169
What are the 3 phases of acute inflammation?
Answer
Fluid phase (brings serum and its factors in),
Neutrophil phase (peaks around 24 hr), and
Macrophage phase (peaks around 2-3 days).
Card 170
What is Chediak-Higashi syndrome? What are the 6 clinical symptoms?
Answer
A autosomal recessive protein trafficking defect characterized by impaired phagolysosome formation.
1) Recurrent pyogenic infections
2) Neutropenia (no microtubules for cell div ⇒ intrameduallary death of Nφ)
3) Giant granules in leukocytes (fusion of granules)
4) Defective primary hemostasis (defective dense granules in platelets)
5) Albinism
6) Peripheral neuropathy (long axons require transport)
Card 171
Where does the marginated pool of neutrophils primarily exist within the body?
Answer
The lung vasculature
Card 172
What are the 2 mechanisms of phagolytic killing? Which is most effective?
Answer
O₂-dependent (most effective, involves oxidants and bleach)
O₂-independent (involves lysozyme and major basic protein)
Card 173
What broader pathway is the oxidative burst part of? Describe the entire pathway, paying special attention to the enzymes involved:
Answer
Oxidative burst is the first step in producing HOCl (bleach) in the phagolysosomes.
1. O2 is converted to superoxide by NADPH oxidase.
2. Superoxide is converted to H₂O₂ by superoxide dismutase (SOD)
3. H₂O₂ is converted to HOCl by myeloperoxidase (MPO)
Card 174
What is chronic granulomatous disease (CGD) (also state inheritence pattern)?
Answer
An AR or XLR inherited defect in NADPH oxidase, impairing production of superoxide from oxygen, which in turn impairs O₂-dependent killing.
Card 175
What infections are patients with CGD inclined to acquire?
Answer
Infection with catalase(+) organisms, specifically:
Pseudomonas
S. aureus
Nocardia
Aspergillus
Candida
Serratia (nosocomial)
Burkholderia cepacia (“foot rot”)
E. coli
Listeria
Staphylococci
H. pylori
Card 176
What is the screening test for CGD?
Answer
*Current clinical standard is the dihydrorhodamine flow cytometry test
Nitroblue tetrazolium test. Test is negative in CGD.
Card 177
What are the molecular and infectious consequences of MPO deficiency?
Answer
Inability to convert H₂O₂ to HOCl, which increases the risk for Candida infections.
However, most patients are asymptomatic
Card 178
Can you detect MPO deficiency with nitroblue tetrazolium test?
Answer
No, nitroblue tetrazolium test can only screen for presence/absence of NADPH oxidase
Card 179
What enzymes are contained within macrophage and eosinophil secondary granules, respectively?
Answer
Lysozyme in macrophages, major basic protein in eosinophils.
Card 180
Describe resolution of a pyogenic infection:
Answer
Neutrophils undergo apoptosis and disappear within 24 hours after resolution of the inflammatory stimulus
Card 181
Why do catalase(+) organisms and not catalase(-) cause infection in chronic granulomatous disease?
Answer
Even in the absence of NADPH oxidase (which normally functions to produce H₂O₂), H₂O₂ produced by phagocytosized bacterial organisms can be converted to HOCl by MPO.
However, catalase(+) organisms degrade the H₂O₂ they produce, leaving the leukocyte completely unable to make HOCl
Card 182
Where do monocytes become macrophages?
Answer
In peripheral tissue
Card 183
How do macrophages enter the tissue in inflammation?
Answer
Same way as all leukocytes (margination, rolling, adhesion, transmigration, chemotaxis, phagocytosis).
Card 184
How do macrophages kill pathogens?
Answer
Injestion (phagocytosis) and enzymatic degradation (e.g. lysozyme) in secondary granules (O₂-independent killing).
Card 185
What anti-inflammatory cytokines produced by macrophages initiate infection resolution?
Answer
IL-10, TGF-β
Card 186
Macrophages can direct the progression of inflammation in 4 ways - what are they?
Answer
1) Continued acute inflammation
2) Abscess
3) Chronic inflammation
4) Resolution and healing
Card 187
What is continued acute inflammation? What cytokine is it mediated by?
Answer
Inflammation with persistent pus formation. IL-8 from macrophages recruits additional neutrophils.
Card 188
What is an abscess?
Answer
Acute inflammation surrounded by fibrosis, which is mediated by macrophages via fibrogenic growth factors and cytokines.
Card 189
Generally speaking, how is chronic inflammation mediated by macrophages?
Answer
Macrophages continue to present antigen to activate CD4+ helper T cells, which secrete cytokines that promote chronic inflammation.
Card 190
What are 4 general stimuli for chronic inflammation?
Answer
Persistent infection (most common cause, e.g. viruses, mycobacteria, parasites, fungi);
autoimmune disease;
foreign material;
and some cancers.
Card 191
What the most common cause of chronic inflammation?
Answer
Persistent infection
Card 192
What makes up the TCR complex? What does it do?
Answer
TCR and CD3. Recognizes antigen presented on MHC molecules.
Card 193
What MHC molecules do CD4 cells use? CD8?
Answer
CD4 - MHC II
CD8 - MHC I
Card 194
What 2 signals are required for T cell activation?
Answer
Binding of antigen/MHC complex to TCR,
Co-stimulation - B7/CD28 interaction for CD4+, IL-2 for CD8+
Card 195
What is the 2nd signal for CD4 helper T cell activation?
Answer
B7 (on APC) binds CD28 (on CD4+ T cell)
Card 196
What cytokines do Th1 cells secrete? What functions do they perform?
Answer
IFN-γ has 3 key functions:
1) activates macrophages
2) promotes class-switching from IgM to IgG
3) skews helper response towards Th1
IL-2 - co-stimulation for CD8+ T cell activation
Card 197
What cytokines do Th2 cells secrete? What are their functions?
Answer
IL-4 (facilitates B cell class switching to IgG and IgE)
IL-5 (eosinophil chemotaxis and activation, maturation of B cells to plasma cells, and class switching to IgA)
IL-10 (Th2 skewing)
IL-13 (functions like IL-4)
Card 198
What cells express MHC I? What does MHC I do?
Answer
Expressed on all nucleated cells in the body and platelets (RBCs are the only exception).
MHC I presents intracellular antigen to CD8 T cells
*Interesting to note, the body has developed mechanisms for dealing with pathogens that disrupt MHC I killing - namely, NK cells
Card 199
How are B cells activated (2 pathways)?
Answer
1) Antigen binds to surface IgM or IgD; results in maturation to IgM or IgD secreting plasma cells.
-or-
1) B cell presents antigen to CD4+ helper T cells via MHC class II
2) CD40 (on B cells) binds to CD40L (on CD4 T cell)
3) CD4 T cell secretes IL-4 and IL-5 to induce class switching, hypermutation, maturation
Card 200
What is the 2nd signal for B cell activation?
Answer
CD40 (on B cell) interaction CD40L (on helper T cell)
Card 201
What is the 2nd signal for CD8 T cell activation?
Answer
IL-2 from CD4 Th1
Card 202
How do cytotoxic CD8+ T cells kill (2 pathways)?
Answer
1) secretion of perforin or granzyme
2) by the expression of FasL, which binds Fas on target cells
Card 203
What's the defining key feature of granulomas?
Answer
Epithelioid histiocytes
Card 204
Describe the structure of a granuloma:
Answer
A collection of epithelioid histiocytes (macrophages with abundant pink cytoplasm), surrounded by giant cells and a rim of lymphocytes
Card 205
What are 2 broad categories of chronic inflammation?
Answer
Granulomatous and non-granulomatous
Card 206
What are the 2 categories of granulomatous inflammation?
Answer
Caseating and non-caseating
Card 207
What distinguishes caseating granulomas from non-caseating granulomas? What organisms cause caseating granulomas?
Answer
Central necrosis (interior cells lack nuclei). Characteristic of tuberculosis and fungal infections
Card 208
Describe non-caseating granulomatous inflammation. Common causes?
Answer
Lacks central necrosis.
Reaction to foreign material
sarcoidosis
beryllium exposure
Crohn disease
Bartonella henselae
sarcoidosis:
beryllium:
Crohn:
Bartonella
Card 209
What disease is associated with stellate-shaped granulomas?
Answer
Cat scratch disease (Bartonella)
Card 210
What is the hallmark lesion in Crohn disease? Ulcerative colitis?
What stains can you use to determine the etiology of a caseating granuloma?
Answer
AFB (Ziehl Neelsen) stain to detect TB.
GMS (silver) stain to detect fungus.
Card 212
What are the steps involved in granuloma formation?
Answer
1) Macrophages process and present antigen to CD4 T cells on MHC II
2) Macrophages then secrete IL-12, which induces CD4 cells to differentiate into the Th1 subtype.
3) Th1 cells secrete IFN-γ, which converts macrophages to epithelioid histiocytes and giant cells.
Card 213
What are the primary immunodeficiencies (8)?
Answer
DiGeorge syndrome
Severe Combined Immunodeficiecy (SCID)
Common Variable Immunodeficiency (CVID)
X-linked agammaglobulinemia (XLA)
IgA deficiency
Hyper-IgM syndrome
Wiskott-Aldrich syndrome
Complement deficiencies
Card 214
SLE represents what type of hypersensitivity?
Answer
Type mixed typeII/III (immune-complex mediated)
*If they ask you for one or the other on step, the answer is Type III.
Card 215
What is Mixed Connective Tissue Disease (MCTD)? What is a classic "presenting complaint"?
Answer
An autoimmune disease of proximal muscles with mixed features of SLE, systemic sclerosis, and polymyositis.
"Patient complains of difficulty combing hair or walking up stairs."
Card 216
What is the difference between regeneration and repair?
Answer
Regeneration is replacement of damaged tissue with native tissue.
Repair refers to replacement with a fibrous scar.
Card 217
What is the most common immunodeficiency?
Answer
IgA deficiency. Remember that most patients are asymptomatic.
Card 218
Where does T cell negative selection occur?
Answer
In the medulla of the thymus.
*Positive selection occurs in the cortex
Card 219
What cells can present self-antigen to the T cell during Negative Selection (2)?
Answer
The Medullary Epithelial Cell or a Dendritic Cell.
Card 220
What is AIRE?
Answer
AutoImmune REgulator - a transcription factor expressed by medullary epithelial cells of the thymus that expresses self-antigen.
Card 221
Where are the stem cells in the small and large bowel located?
Answer
Mucosal Crypts
Card 222
Where are the stem cells of the skin located?
Answer
In the basal layer
Card 223
What is the stem cell of the lung?
Answer
Type II Pneumocytes
Card 224
What are the three types of tissues (based on regenerative capacity)?
Answer
Labile Tissues: continuously cycle to regenerate tissue (Small & Large Bowel, Skin, BM)
Stable Tissues: quiescent, but can reenter cell cycle (regeneration of liver by hyperplasia if resected, cells of proximal collecting tubule after acute tubular necrosis).
Permanent Tissue: lack significant regerative potential (myocardia, skeletal muscle, neurons)
Card 225
What does granulation tissue consist of (3 important components)?
Answer
Fibroblasts (deposits Type III collagen: will be replaced by Type I collagen when scar begins to form)
Capillaries (provide nutrients)
Myofibroblasts (contract wound)
Card 226
What is collagenase? What cofactor does it require?
Answer
Collegenase removes Type III collagen and requires zinc as a cofactor.
Card 227
What are the two types of cutaneous healing?
Answer
Primary intention: wound edges brought together (suture); no scar
Secondary intention: edges are not approximated; granulation tissue fills the defect
Card 228
What cell is responsible for mediating wound contraction?
Answer
Myofibroblasts
Card 229
What are four possible causes of delayed wound healing? How does each cause a delay?
Answer
1) Infection
2) Vitamin C deficiency (required for hydroxylation of Pro/Lys)
3) Copper deficiency (lysyl oxidase required for cross-linking of collagen)
4) Zinc deficiency (required for collegenase to convert T3 to T1 collagen)
Card 230
What are keloids? What material are they made of?
Answer
Excess production of scar tissue out of proportion to the wound, characterized by excess Type III collagen.
More common in african americans (genetically predisposed)
Affectes earlobes, face, and UEs.
Card 231
What causes DiGeorge Syndrome?
Answer
22q11 microdeletion which causes third and fourth pharyngeal pouches to never form. Thymus and parathyroid glands are absent as a result.
Card 232
What are the 3 most common cardiac abnormalities seen in DiGeorge syndrome?
What are three causes of severe combined immunodeficiency (SCID)?
Answer
1) Cytokine receptor defects (IL-2R defect most common) - no signal to T or B cells to mature and proliferate
2) Adenosine deaminase (ADA) deficiency - causes toxic buildup of metabolites in lymphocytes
(*remember 2-CDA tox in Hairy Cell Leukemia)
3) MHC Class II deficiency - inability to activate CD4+ helper T cells
Card 235
What kinds of infections are people with SCID susceptible to?
Answer
All of them
Card 236
What class of therapeutics is contraindicated in patients with SCID? Name examples.
Answer
Live vaccines
"Live! One night only! See small yellow rotating chickens get vaccinated with Sabin's and MMR! Incredible!
Smallpox,
yellow fever,
rotavirus,
varicella,
sabin polio,
MMR,
intranasal flu
What therapeutic must be avoided in patients with XLA?
Answer
Live vaccines
"Live! One night only! See small yellow rotating chickens get vaccinated with Sabin's and MMR! Incredible!
Smallpox,
yellow fever,
rotavirus,
varicella,
sabin polio,
MMR,
intranasal flu
Card 242
What causes common variable immunodeficiency (CVID)?
Answer
Low immunoglobulin due to a variety of B cell or helper T cell defects
Card 243
CVID increases risk for the development of what two noninfectious conditions?
Answer
1) Autoimmune disease
2) Lymphoma
Card 244
IgA deficiency presents with an increased risk for developing what kinds of infection? What autoimmune disease is it associated with?
Answer
1) Mucosal infection - particularly viral.
2) Associated with Celiac
Card 245
Hyper IgM syndrome is caused by what?
Answer
A mutation in either CD40 on B cells or CD40L on helper T cells.
B cells are unable to get co-stimulation, and subsequently unable to class-switch
vs. Waldenström Macroglobulinemia (B-cell lymphoma)
Card 246
What kinds of infection are typical of hyper IgM syndrome?
Wiskott-Aldrich syndrome is characterized by a triad of what 3 clinical findings
Answer
1) thrombocytopenia (defective platelets)
2) eczema (defective lymphocytes)
3) recurrent infections (defective lymphocytes)
Pathophysiology:
X-linked recessive,
mutant WASP (normally links membrane receptors to cytoskeleton),
petechiae due to ↓Plt
Tx: HSC transplant
Card 248
C5-C9 deficiency renders a patient susceptible to what kinds of infection?
Answer
Neisseria spp - meningitis and gonorrheae
Card 249
C1 inhibitor (or "esterase") deficiency results in what clinical condition?
Answer
Hereditary angioedema, which is characterized by edema of the skin and mucosal surfaces
Card 250
What antibody is associated with mixed connective tissue disease?
Answer
Anti-U1 ribonucleoprotein
Card 251
Under what circumstance(s) does a scar form?
Answer
1) When wound disrupts regenerative stem cells (e.g. cut through stratum basale)
2) In tissues without regerative capacity (brain, heart)
Card 252
What role does collagenase play in scar formation?
Answer
Replaces type III collagen with denser, sturdier type I collagen.
Card 253
List the 5 important mediators of tissue regeneration and the roles they play:
Answer
1) TGF-α: epithelial and fibroblast growth factor
2) TGF-β: fibroblast growth factor, inhibits inflammation
3) PDGF: growth factor for endothelium, smooth muscle, and fibroblasts
4) FGF: important for angiogenesis and skeletal muscle development (ironically not fibroblasts)
5) VEGF: important for angiogenesis
Card 254
What is the US prevalence of autoimmune disease?
Answer
1-2%
Card 255
Self reactive T lymphocytes can develop tolerance in two ways. Describe:
Answer
1) Central tolerance (in the thymus) - self reactive T cells either apoptose or develop into Tregs
2) Peripheral tolerance (in bone marrow) - anergy or apoptosis
Card 256
Mutation of AIRE leads to what condition?
Answer
Autoimmune polyendocrine syndrome
Card 257
Where do B cells undergo central tolerance? What can their fates be?
Answer
In the bone marrow - apoptosis or receptor editing of light chain
Card 258
Autoimmune lymphoproliferative syndrome (ALPS) is caused by what?
Answer
Mutations in the fas apoptosis pathway. Peripheral tolerance mechanisms fail to induce apoptosis in inappropriately self-reactive T cells.
"Ski fas down the ALPS!"
Card 259
What immunosuppressive cytokines do Tregs secrete?
Answer
IL-10, TGF-β
Card 260
CD25 (AKA the IL-2 receptor) polymorphisms are associated with what autoimmune conditions?
Answer
MS and DM1
T1DM Memory Associations:
Type 1 DM
CD 25,
HLA-DR3,
HLA-DR4
MS Memory Association:
MS & DM both have associated charity athletic events (MS-150 cycling & JDRF walk)
Card 261
FOXP3 mutations are associated with what disorder?
Why do we think that autoimmunity is more common in women?
Answer
Estogen may inhibit apoptosis of self-reactive B cells
Card 263
Overlapping features of autoimmune disease are generally explainable by what immunologic concept?
Answer
Epitope spreading:
immune resp vs. self-Ag dmgs tissue, releasing other Ag, activating lymphocytes w/ new epitopes
Card 264
Describe the pathophysiologic progression of SLE:
Answer
1) Poorly cleared apoptotic debris activates self-reactive lymphocytes
2a) Immune complexes are generated at low levels and taken up by dendritic cells
2b) DNA antigens activate TLRs and amplify immune response (via TNF, etc.)
3) Immune complexes are generated at higher levels and deposit in multiple tissues
Card 265
Deficiencies in which three complement proteins are associated with SLE?
Answer
C1q, C2, C4
Card 266
What are some common clinical features of SLE?
Answer
1) Constitutional or "B" symptoms (such as fever, lymphadenopathy, etc)
2) Malar and discoid rashes
3) Arthritis
4) Renal damage
5) Libman-Sacks endocarditis (small fibrous/neutrophilic vegetations on the heart valve - usually mitral - both sides of valve are affected)
Card 267
Most common form of kidney injury in SLE?
Answer
Diffuse proliferative glomerulonephritis
Card 268
What are 5 antibodies associated with SLE?
Answer
1) Anti-nuclear antibody (ANA) (not specific)
2) Anti-dsDNA (very specific)
3) Anti-Sm (core unit of snRNP, v specific)
4) Anti-snRNP antibody
5) Anti-phospholipid antibody
Card 269
What are the 3 important antiphospholipid antibodies seen in SLE? Do any yield important clinical findings?
Answer
1) Anticardiolipin - causes false(+) on VDRL and RPR tests
2) anti-β₂-glycoprotein I
3) lupus anticoagulant - falsely elevated PTT
Card 270
What are four common locations of thrombosis seen in antiphospholipid antibody syndrome? What are the significant clinical sequelae of each?
What autoimmune disorder is Sjögren syndrome associated with?
Answer
Rheumatoid arthritis
Called "sicca syndrome" when primary
Card 277
What biomarker is usually present in both primary and secondary Sjögren syndrome?
Answer
Rheumatoid factor - often present even with rheumatoid arthritis is absent
This is why CCP is a better test for diagnosing rheumatoid arthritis.
Card 278
What three antibodies is Sjögren syndrome associated with, and what key clinical manifestation is associated with one of them?
Answer
1) ANA
2) anti-SSA/Ro (an anti-ribonucleoprotein Ab) - pregnant women who express this can deliver babies with neonatal lupus and congenital heart block
3) anti-SSB/La
Both anti-SSA and SSB are associated with extraglandular manifestations (neuropathy)
Card 279
Lymphocytic sialadenitis on lip biopsy is a diagnostic criterion for what disease?
Answer
Sjögren
Card 280
What cancer are Sjögren patients at increased risk for developing? Where does it develop?
Answer
Marginal zone lymphoma - in the parotid gland.
Card 281
What is systemic sclerosis (scleroderma) and who does is most commonly present in?
Answer
An autoimmune disorder characterized by sclerosis of the skin and visceral organs.
Women aged 30-55
Card 282
Describe the pathogenesis of scleroderma:
Answer
1) Autoimmune damage to mesenchyme is a potential initiator
2) Endothelial dysfunction leads to inflammation, vasoconstriction, and release of TGF-β and PDGF
3) Fibroblast activation results in perivascular fibrosis that spreads to involve organs
Card 283
What are the two types of scleroderma?
Answer
Limited type - in which skin involvement is limited to the hands and face with late visceral involvement
Diffuse type - skin involvement is diffuse with early visceral involvement
Card 284
What is the protypical limited type scleroderma and what are the important clinical features?
Answer
CREST syndrome
Calcinosis/anti-Centromere Abs
Raynaud phenomenon
Esophageal dysmotility
Sclerodactyly
Telangiectasias of the skin
shown: sclerodactyly (thick, tight skin) and calcinosis
Card 285
What are 4 organs most commonly involved in diffuse-type scleroderma?
Answer
1) Vessels (raynaud phenomenon)
2) GI tract (esophageal dysmotility and reflux)
3) Lungs (interstitial fibrosis and pulmonary arterial hypertension)
4) Kidneys (renal crisis)
Card 286
What antibody is most classically associated with diffuse-type scleroderma?
Answer
Anti-Scl-70, an anti-DNA topoisomerase antibody
Card 287
What is the key distinguishing characteristic of neoplasia?
Answer
Monoclonality: Neoplastic cells (benign or malignant) are derived from a single progenitor.
Card 288
How is the clonality of B cells determined?
Answer
Ig light chain phenotype (kappa or lamba)
Normal kappa:lambda ratio is 3:1
In a polyclonal proliferation, the ratio would remain the same.
In a monoclonal proliferation, the ratio would change (↑ or ↓)
Card 289
3 major causes of death in adults:
Answer
1. Coronary artery disease
2. Cancer
3. Cerebrovascular Disease
Card 290
3 major causes of death in children:
Answer
1. Accidents
2. Cancer
3. Congenital defects
Card 291
Cancer begins as a single mutated cell. How many divisions occurs before the earliest symptoms arise?
Answer
Approximately 30 divisions occur before the earliest symptoms arise.
Card 292
What cancer is associated with Aflatoxin?
Answer
Hepatocellular Carcinoma
*Derived from Aspergillus, which can contaminate stored grains.
Card 293
What cancers are associated with alkylating agents?
Answer
Leukemia/lymphoma
*long term side effect of chemotherapy.
Card 294
What cancers are associated with alcohol consumption (2)?
Answer
Squamous cell carcinoma of oropharynx and upper esophagus
Hepatocellular carcinoma
Card 295
What cancers are associated with arsenic exposure (3)?
Answer
Squamous cell carcinoma of the skin
Lung cancer (arsenic is present in cigarette smoke)
Angiosarcoma of the liver
Card 296
What cancers are associated with asbestos exposure?
Answer
Lung cancer (bronchogenic carcinoma)
Mesothelioma
*Exposure to asbestos is more likely to lead to lung cancer rather than mesothelioma.
Card 297
What cancers are associated with smoking (5)?
Answer
Carcinoma of the oropharynx,
Esophagus,
Lung,
Kidney, and
Bladder
*Polycyclic hydrocarbons are particularly carcinogenic.
Card 298
What cancer is associated with nitrosamines?
Answer
Gastric adenocarcinoma (intestinal type)
*Found in smoked foods; responsible for high rate of stomach carcinoma in Japan.
Memory Tips:
NITROsamine - can eat something cooked w/ nitro fuel
naphTHYLamine - "filling" is a bladder problem (filling the stomach? no problem!)
Card 299
What cancer is associated with naphthylamine?
Answer
Urothelial carcinoma of the bladder
*Naphthylamine is derived from cigarette smoke
Memory Tips:
NITROsamine - can eat something cooked w/ nitro fuel
naphTHYLamine - "filling" is a bladder problem (filling the stomach? no problem!)
Card 300
What cancer is associated with vinyl chloride?
Answer
Angiosarcoma of the liver
*Occupational exposure used to make PVC pipes.
Card 301
What cancer is associated with nickel, chromium, beryllium, or silica?
Answer
Lung carcinoma
Card 302
What cancers are associated with EBV (4)?
Answer
Nasopharyngeal Carcinoma (Chinese males & africans)
Burkitt Lymphoma
CNS Lymphoma in AIDS
Hodgkin Lymphoma
Card 303
What cancers are associated with HHV-8? Which patients get this and what would be the treatment for each?
Answer
Kaposi Sarcoma (carcinoma of endothelial cells in the skin)
1. Older Eastern European Males; excision
2. AIDS patients; HAART
3. Transplant Patients; reduce immunosuppression
Card 304
What cancer is associated with HBV and HCV?
Answer
Hepatocellular carcinoma
Card 305
What cancer is associated with HTLV-1?
Answer
Adult T Cell Leukemia/Lymphoma
Card 306
What cancers are associated with HPV 16, 18, 31, 33?
Answer
Squamous cell carcinoma of the vulva, vagina, anus, and cervix;
Adenocarcinoma of the cervix
Card 307
What cancers are associated with ionizing radiation (nuclear reactor accidents and radiotherapy)?
Answer
Papillary carcinoma of the thyroid
AML
CML
*Generates hydroxyl free radicals.
Memory Tip:
Associate "nuclear blasts" with "blast crises"
Card 308
What cancers are associated with non-ionizing radiation (UVB sunlight)?
Answer
Basal Cell Carcinoma
Squamous Cell Carcinoma
Melanoma
*Results in formation of pyrmidine dimers in DNA, which are normally excised by restriction endonuclease. Ergo, patients with Xeroderma Pigmentosum develop these cancers
Card 309
Which proto-oncogene is dysfunctional in astrocytoma? How does it become aberrantly expressed?
Answer
PDGF-β, hence fibrous growths. Autocrine loop/overexpression.
*Tie-in: remember that scleroderma also involves a postive feedback loop involving PDGF
Card 310
What cancer is associated with ERBB2 overexpression? What mechanism leads to this overexpression?
Answer
ERBB2 (HER2/neu) - Breast Cancers; amplification
Card 311
What (3) cancer syndromes/cancers are associated with RET mutations? What kind of mutation is typical?
Answer
MEN2A
MEN2B
MEdullary carcinoma of thyroid (*note: often seen in MEN2A and 2B)
Often a point mutation
*Important to remember: medullary carcinoma of the thyroid is a malignancy of the C cells (calcitonin producing). Classic histology is malignant cells amongst a background of amyloid protein.
Card 312
What cancer is associated with a KIT mutation? What type of mutation is it?
Answer
Gastrointestinal Stromal Tumor (GIST)
Point mutation
Card 313
Ras mutations are associated with what cancers? What kind of mutation?
Answer
Carcinomas, melanoma, lymphoma
Point mutation
E.g. present in
90% of pancreatic adenocarcinomas and cholangiocarcinomas,
50% of colon, endometrial, and thyroid cancers,
30% of lung adenocarcinomas and myeloid leukemias
Remember that vemurafenib (B-Raf inhibitor) treats metastatic melanoma
Card 314
What are the 3 MYC family regulators? What cancers is each associated with?
Answer
C-myc: Burkitt Lymphoma
L-myc: Lung carcinoma (smaLL ceLL)
N-myc: Neuroblastoma
Memory Tip:
Cancer cells are "CLoNes" of one another
Card 315
Cyclin D1 rearrangment is associated with what cancer? CDK4 amplification?
p53 regulates progression from which cell cycle checkpoint? What will it do in the event of reparable DNA damage?
Answer
Regulates G₁ → S progression
In response to fixable damage, p53 slows the cell cycle and upregulates DNA repair enzymes.
Card 317
What cellular progression checkpoint does Retinoblastoma protein (Rb) regulate? How does it do this?
Answer
Like p53, regulates progression from G1 to S phase.
1) Rb is normally bound to E2F (transcription factor).
2) When Rb is phosphorylated by Cyclin D/CDK4, it releases E2F
Rb mutation results in constitutively active E2F
Loss of Rb, E2F is constitively active --> TUMOR
Card 318
How will sporadic vs. germline mutation of Rb present?
Answer
Sporadic: unilateral retinoblastoma
Germline (familal): bilateral retinoblastoma and osteosarcoma
Card 319
What is the function of Bcl2?
Answer
Broadly: to prevent apoptosis in healthy cells and induce it in damagd cells.
Specifically: blocks release of cytochrome c through Bak/Bax
Card 320
How does a constitutively active Bcl2 induce follicular lymphoma pathogenesis?
Answer
1) Mitochondrial membrane further stabilized by Bcl2 overexpression
2) B cells that would undergo apoptosis during somatic hypermutation in the lymph node germinal center accumulate
Card 321
What two growth factors are commonly produced by tumor cells? Why?
Answer
FGF
VEGF
*Required for angiogenesis
Card 322
Tumor cells often evade immune surveillance by?
Answer
Downregulating MHC I
*Reminder that immunodeficiency increases risk for cancer
Card 323
The process of tumor invasion and spread is well-modeled by considering the epithelial tumor. What are the 5 steps of epithelial tumor invasion and spread?
Answer
1. Downregulation of E-cadherin leads to disassociation of cells
2. Cells attach to laminin (anchors cells to basal lamina)
3. Cell destroy basement membrane via type IV collagenase
4. Cells attach to fibronectin in the ECM and spread locally
5. Cells enter into blood vessels or lymphatics and metastasize
Card 324
Lymphatic spread is most characteristic of carcinomas. However, some carcinomas spread hematogenously - which ones?
Neuroendocrine cells (e.g. small cell lung carcinoma, carcinoid tumors)
Card 333
What cancers/tumors are S-100 positive? (3)
Answer
Melanoma
Schwannoma
Langerhans cell histiocytosis
Card 334
How was cell clonality historically determined?
Answer
Characterization of G6PD isoforms, or androgen receptor isoforms.
Card 335
What ratio of G6PD isoforms would you expect to see in hyperplasia?
Answer
1:1. Hyperplasia involves multiple progenitors, so normal G6PD isoform ratio is preserved.
Remember that G6PD has many isoforms, but only 2 are inherited (1 from each parent).
Card 336
Why did early modes of clonality determination necessitate use of female model organisms?
Answer
G6PD and androgen receptors (both historically used to determine clonality) are found on the X chromosome.
Random lyonization (activation/deactivation of X chromosomes) results in one (but not both) isoforms to be expressed in any particular cell.
E.g. G6PDA & G6PDB is randomly distributed in female tissue, one can compare respective ratios in cancer vs. control samples
Card 337
What kappa/lambda Ig light chain ratios are necessary to diagnose a monoclonal B cell proliferation?
Answer
Normal kappa:lambda is 3:1.
Ratio increases > 6:1 indicate monoclonality.
Switch to a 1:3 ratio also indicates monoclonality. This is termed an inversion.
Card 338
What is the primary difference between a benign and malignant tumor?
Answer
A malignant tumor has the potential to metastasize
Card 339
Give the appropriate benign and malignant name for tumors arising from each of the following tissues:
Epithelium (2):
Mesenchyme:
Lymphocyte:
Melanocyte:
What are the 3 most common cancers by incidence in adults?
Answer
1) Breast/prostate
2) Lung
3) Colorectal
Card 341
What are the 3 most common causes of cancer mortality in adults?
Answer
1) Lung
2) Breast/Prostate
3) Colorectal
Card 342
Each full cancer division (doubling time) in a cancer yields an increase in what?
Answer
Mutations
Card 343
What are 3 important general classes of carcinogen?
Answer
1) Chemicals
2) Oncogenic viruses
3) Radiation
Card 344
DNA mutations eventually disrupt key regulatory systems allowing for tumor promotion (growth) and progression (spread). What are 3 general disruptable systems?
Answer
1) Proto-oncogenes
2) Tumor suppressors
3) Regulators of apoptosis
Card 345
Proto-oncogenes are essential for what non-pathological functions?
Answer
Cell growth and differentiation
Card 346
What are the 5 categories of proto-oncogenes and what is an example of each?
Growth factor receptors have what general function?
Answer
Mediate signals from growth factors
Card 349
Signal transducers play what general function?
Answer
Relay signals from receptors to the nucleus
Card 350
How is the Ras pathway normally activated?
Answer
1) Ras is associated with growth factor receptor on cytoplasmic surface of cell membrane; bound to GDP
2) Receptor activation causes GDP to be replaced by GTP ("activation")
3) Activated Ras send signals to the nucleus via the Raf/MEK/ERK pathway
Card 351
How is Ras normally deactivated?
Answer
Ras inactivates itself by cleaving GTP to GDP with help from a GTPase activating protein
Card 352
What is the most common functional mutation of the Ras protein?
Answer
Mutated Ras inhibits the activity of the GTPase activating protein, causing Ras to stay active longer
Card 353
How do cyclinD/CDK4 complexes promote progression through the cell cycle (give an example pathway)?
Answer
cyclinD/CDK4 complex phosphorylates the Rb protein, causing it to release E2F (global transcription factor), pushing the cell from G1 to S
Card 354
In the event that DNA damage is too great heading into S phase, how does p53 induce apoptosis?
Answer
1) p53 upregulates Bax
2) Bax expression overwhelms Bcl2
3) Cytochrome c leaks from membrane, triggering caspases
Card 355
Must both copies of p53 be lost for tumorigenisis to occur?
Answer
Yes; it only takes one functional copy to suppress cancer
Card 356
What percentage of cancers possess loss of p53?
Answer
> 50%
Card 357
Germline mutations in p53 result in what genetic disorder?
What function do active telomerases play in tumor development?
Answer
Active telomerases confer immortality to the tumor cell line
Card 359
How do sarcomas typically metastasize?
Answer
Hematogenously
Lymphatics are lined by epithelium, so it makes sense for epithelial cancers (i.e. carcinomas) to metastasize via lymph. Mesenchymal tissues are deeper and more vascularized, hence the hematogenous spread of sarcomas.
Card 360
Describe the 4 clinically apparent characteristics of benign tumors:
Answer
1) Slow-growing
2) Well circumscribed
3) Distinct
4) Mobile
Card 361
What are 4 clinically apparant characteristics of a malignant tumor?
Answer
1) Rapidly growing
2) Poorly circumscribed
3) Infiltrative
4) Adherent to surrounding tissues and structures
Card 362
What must be done before a tumor can be classified as benign or malignant with certainty?
Answer
Biopsy/excision, histologic examination
Card 363
What are the 5 histologic characteristics of benign tumors?
Answer
1) Organized growth
2) Uniform nuclei
3) Low nuclear/cytoplasmic ratio
4) Minimal mitotic activity
5) Lack of invasion
Card 364
What are the 5 histologic characteristics of a malignant tumor?
Answer
1) Disorganized growth
2) Nuclear polymorphism and hyperchromasia
3) High nuclear to cytoplasmic ratio
4) High mitotic activity
5) Invasion
Card 365
What cell type is PSA positive?
Answer
Prostatic epithelium
Card 366
In what cell type is estrogen receptor (ER) positive?
Answer
Breast epithelium
E.g. raloxifene antagonizes ER in the breast and uterus to minimize pro-cancer effects while blocking bone resorption.
Card 367
What tool is used to commonly characterize tumors that are difficult to classify on histology?
Answer
Immunohistochemistry
Card 368
What must be done to confirm a diagnosis in the case of an elevated serum tumor marker?
Answer
Biopsy
Card 369
What is more important in terms of cancer prognosis: grading or staging?
Answer
Staging
Card 370
Grading of a tumor is based on what property?
Answer
Differentiation - high grade is poorly differentiated
Card 371
Describe the TNM tumor staging system:
Answer
T: tumor, size and depth of invasion
N: nodes, spread
M: metastasis - single most important prognostic factor
Card 372
What is the goal of primary hemostasis? What process mediates primary hemostasis?
Answer
To generate a weak platelet plug; mediated by interaction between platelets and vessel wall
Card 373
What is the goal of secondary hemostasis? What process mediates secondary hemostasis?
Answer
To stabilize the platelet plug (converting fibrinogen to fibrin); mediated by the coagulation cascade
Card 374
How is damage to a vessel wall repaired?
Answer
Via hemostasis which involves the formation of a thrombus at the site of injury
Card 375
Where is von Willibrand factor stored (2 locations)?
Answer
1) Endothelial Cells (found in Weibel-Palade bodies, which also contain P-selectin)
2) Platelets (found in alpha-granules, which also contain PDGF and fibrinogen)
Card 376
What are the 4 steps of primary hemostasis (pay attention to chemical mediators of each)?
Answer
1) Transient vasoconstriction of affected vessel - neural stimulation and endothelin
2) Platelet adhesion - vWF and Gp1b
3) Platelet degranulation - release of ADP and TXA2 (upregulates GpIIb/IIIa)
4) Platelet aggregation - crosslinking fibrin
Card 377
What happens after platelets adhere to the surface of injured vessels? What mediators are involved?
Answer
The platelets are activated (they change shape and degranulate releasing multiple mediators)
These mediators include:
ADP - released from platelet dense granules; promotes exposure of GPIIb/IIIa receptor.
TXA2 - Synthesized by platelet cyclooxygenase and released; promotes platelet aggregation
Card 378
What is the function of ADP after it is released from an activated platelet?
Answer
It promotes exposure of GPIIb/IIIa receptor on platelets
Card 379
What is the function of TXA2 (thromboxin A2) after it is released from an activated platelet?
Answer
Promotes platelet aggregation
Card 380
What is GPIIb/IIIa's function?
Answer
Acts as the receptor for fibrin polymers to cross-link platelets
Card 381
Is the primary platelet plug a durable or weak structure?
Answer
Weak. Secondary hemostasis will stabilize it.
Card 382
Disorders of primary hemostasis are due to dysfunction of what? How are these disorders broadly classified?
Answer
Abnormalities in platelets; disorders of primary hemostasis are divided into quantitative or qualitative disorders
Card 383
What are classical mucosal symptoms of primary hemostasis (platelet) disorders (5)?
Answer
1) Epistaxis (most common symptom)
2) Hemoptysis
3) GI bleeding
4) Hematuria
5) Menorrhagia
Card 384
What are the classic skin bleeding symptoms of primary hemostatic (platelet) disorders (4)? Which of these symptoms is not expected to be seen in patients with qualitative disorders?
Answer
1) petechiae (1-2 mm)
2) purpura (> 3 mm)
3) ecchymoses (> 1 cm)
4) easy bruising
Petechiae are exclusively a sign of thrombocytopenia - one would not expect to see them in qualitative platelet disorders.
Card 385
What is a normal platelet count? How low must it be for symptoms to manifest?
Answer
150,000-400,000/microliter;
< 50,000/microliter leads to symptoms
Card 386
What can a blood smear tell you about a disorder of primary hemostasis?
Answer
Used to assess number and size of platelets, which helps to distinguish between qualitative and quantitiative disorders.
Card 387
Why do a bone marrow biopsy when dealing with suspected disorder of primary hemostasis?
Answer
To assess megakaryocytes
Card 388
What is Immune Thrombocytopenic Purpura? How prevalent is it?
Answer
Autoimmune production of IgG against platelet antigens (e.g. GPIIb/IIIa) - *important to note that antibodies are produced by splenic plasma cells;
It is the most common cause of thrombocytopenia in children and adults
Card 389
What are the two types of ITP? What initiates each? What is the natural history of each?
Answer
Acute: arises in children after viral infection or immunization; self-limiting
Chronic: arises in adults (usually women of childbearing age). May be primary or secondary (SLE).
*Important to note: in preganant women, short-lived thrombocytopenia can occur in offspring, since maternal antiplatelet IgG can cross the placenta
Card 390
Where are antibody-bound platelets destroyed?
Answer
In the spleen by splenic macrophages
Card 391
What are the lab findings of ITP (3)?
Platelet count:
PT/PTT:
Bone marrow biopsy:
Answer
1) Decreased platelet count
2) Normal PT/PTT - coagulation factors are not affected
3) Increased megakaryocytes on bone marrow biopsy
Card 392
How is ITP (immune thrombocytopenic purpura) treated (3)?
Answer
1) Initial treatment is corticosteroids (especially effective in children)
2) IVIG is used to raise platelet count in symptomatic bleeding (acts as a false target; effects are short-lived)
3) Splenectomy eliminates the primary source of antibody and the site of platelet destruction (performed in refractory cases)
Card 393
What can be seen on this peripheral blood smear? What underlying conditions might cause this pathology?
Answer
Schistocytes (sheared red blood cells).
It is caused by microangiopathic hemolytic anemia.
Causes include:
Thrombotic Thrombocytopenic Purpura (TTP),
Hemolytic Uremic Syndrome (HUS),
Disseminated Intravascular Coagulation (DIC),
Hemolysis Elevated Liver Enzymes and Low Platelets (HELLP) (a form of ecclampsia),
Prosthetic heart valves and aortic stenosis
Card 394
What is Thrombotic Thrombocytopenic Purpura? Who is at risk? What is the pathogenesis?
Answer
An acquired microangiopathic hemolytic anemia (usually an acquired antibody).
Typical patient is an adult female.
It is caused by decreased ADAMTS13, an enzyme that normally cleaves vWF multimers into smaller monomers for eventual degradation. Large multimers lead to abnormal platelet adhesion resulting in microthrombi.
Card 395
What is Hemolytic Uremic Syndrome usually a consequence of?
Answer
Endothelial damage by drugs or infection.
Classically seen in children with E. coli O157:H7 dysentery which results from exposure to undercooked beef. E.coli verotoxin damages endothelial cells resulting in platelet microthrombi.
Card 396
What are clinical findings of HUS and TTP (5)?
Answer
1) Fever
2) Microangiopathic hemolytic anemia
3) Skin and mucosal bleeding (due to thrombocytopenia)
4) Renal insufficiency (more common in HUS - thrombi involve vessels of the kidney)
5) Neurologic abnormalities (more common in TTP - thrombi involve vessels of the CNS)
Mnemonic:
"FAT RN" - fever, anemia, thrombocytopenia, renal, neuro
Card 397
What are the laboratory/histological findings for TTP and HUS (4)?
Answer
1) Thrombocytopenia with ↑ bleeding time (interaction of Plt w/ vessel wall)
2) Normal PT/PTT (coag cacade not activated - even in TTP, clots are just aggrates of platelets on vWF polymers - no clotting factors involved)
3) Anemia with schistocytes
4) Increased megakaryocytes on bone marrow biopsy
Card 398
How are HUS and TTP treated?
Answer
1) Plasmapheresis
2) Corticosteroids
*Particularly in TTP. HUS treatment can be supportive if not severe.
Card 399
What are the qualitative platelet disorders?
Answer
Bernard-Soulier syndrome and Glanzmann thrombasthenia
Card 400
What causes Bernard-Soulier syndrome? What is the classic finding on blood smear? What results do you expect from a ristocetin cofactor assay?
Answer
Genetic GP1b deficiency; platelet adhesion is impaired (vs. impaired aggregation in Glanzmann thrombocytopenia)
Blood smear shows mild thrombocytopenia with enlarged platelets
No agglutination on ristocetin cofactor assay
Card 401
What causes Glanzmann thrombasthenia? What result do you expect from a ristocetin cofactor assay?
Answer
Genetic GPIIb/IIIa deficiency; platelet aggregation is impaired (vs. impaired adhesion in Bernard-Soulier)
There will be agglutination with ristocetin cofactor assay
Card 402
How does uremia affect coagulation? What lab values do you expect?
Answer
Disrupts platelet function; both adhesion and aggregation are impaired
Normal PT/PTT,
normal platelet count,
↑ bleeding time
Card 403
What does the coagulation cascade ultimately generate?
Answer
Thrombin, which converts fibrinogen in the platelet plug to fibrin.
Card 404
Where are the factors of the coagulation cascade produced?
Answer
In the liver, in an inactive form
Card 405
What does activation of the coagulation cascade factors require (3 options)?
Answer
1) Exposure to an activating substance (tissue thromboplastin for VII, subendothelial collagen for XII)
2) Phospholipid surface of platelet
3) Calcium (from dense granules)
Card 406
What usually causes disorders of secondary hemostasis?
Answer
Usually due to factor abnormalities (quantity or quality)
Card 407
What are the 2 clinical features of disorders of secondary hemostasis?
Answer
1) Deep tissue bleeding into muscles and joints (hemarthrosis)
2) Rebleeding after surgical procedures (e.g. circumcision and wisdom tooth extraction)
Card 408
What does the PT test stand for and what does it measure?
Answer
Prothrombin time. It measures extrinsic (Factor VII) and common (Factors II, V, X and fibrinogen) pathways of coagulation cascade.
Card 409
What does PTT stand for and what does it measure?
Answer
Partial thromboplastin time (PTT) - measures intrinsic (factors XII, XI, IX, VIII) and common (factors II, V, X and fibrinogen) pathways of the coagulation cascade
Card 410
What is Hemophilia A? Mode of inheritence?
Answer
A genetic factor VIII deficiency.
It is X-linked recessive (predominantly affects males), but can arise from a new mutation without any family history
Card 411
What are the laboratory findings of Hemophilia A (4)?
Answer
1) Increased PTT
2) Normal PT
3) Decreased factor VIII
4) Normal platelet count and bleeding time
Card 412
What is the treatment for Hemophilia A?
Answer
Recombinant factor VIII
*Desmopressin is also used to increase circulating vWF, which will help to maintain higher levels of factor VIII, as it will not be degraded as quickly (remember the vWF holds onto factor VIII)
Card 413
What is Hemophilia B (AKA "Christmas disease")?
Answer
Genetic factor IX deficiency. Also X-linked. It resembles hemophilia A, except factor IX levels are decreased instead of factor VIII.
Card 414
What is coagulation factor inhibitor?
Answer
Acquired antibody against coagulation factor resulting in impaired factor function. Anti-factor VIII is most common.
Card 415
How does one distinguish between Coagulation Factor VIII Inhibitor and Hemophilia A?
Answer
In patient with Coagulation Factor VIII Inhibitor, PTT does not correct upon mixing normal plasma with patient's plasma (mixing study) due to inhibitor.
PTT does correct in hemophilia A.
Card 416
What is Von Willebrand Disease? What is its inheritance pattern? What is the most common subtype?
Answer
Genetic vWF deficiency. Most common inherited coagulation disorder. There are multiple subtypes (quantitative or qualitative deficiency).
Most common type is autosomal dominant with decreased vWF levels.
Card 417
What are the laboratory findings of the most common type of Von Willebrand Disease (4)?
Answer
1) ↑ bleeding time (decreased platelet count)
2) ↑ PTT (vWF is needed to stabilize factor VIII) but not increased enough to cause problems with secondary hemostasis
3) Normal PT
4) Abnormal ristocetin test (ristocetin causes agglutination by forcing vWF to bind to Gp1b)
Card 418
What is the treatment for von Willebrand disease?
Answer
Desmopressin (ADH analog). It induces vWF release from Weibel-Palade bodies.
Card 419
How does Vitamin K deficiency cause secondary coagulation problems?
Answer
Vitamin K is activated by epoxide reductase in the liver.
Activated vitamin K gamma carboxylates factors II, VII, IX, X and proteins C and S.
Gamma carboxylation is necessary for factor function.
Card 420
3 causes/cases of vitamin K deficiency?
Answer
1) Newborns (due to lack of GI colonization by bacteria that normally synthesize vitamin K)
2) Long-term antibiotic therapy (Vitamin K producing bacteria die off)
3) Malabsorption - leads to deficiency of fat-soluble vitamins, including vitamin K
Card 421
What is hemorrhagic disease of the newborn?
Answer
Results from a deficiency of vitamin K in newborns - presents with bleeding around the umbilical cord stump, visceral bleeds and CNS bleeds.
Card 422
Why can liver failure cause a secondary hemostasis issue? How do we monitor liver failure-related secondary hemostasis issues?
Answer
Decreased production of coagulation factors and decreased activation of vitamin K by epoxide reductase.
Typically monitored with PT (factor VII has fastest turnover, so PT is a more accurate measure than PTT)
Card 423
Why does large-volume transfusion result in secondary hemostasis disorder?
Answer
The large volume dilutes coagulation factors, resulting in a relative deficiency
Card 424
What is Heparin-induced Thrombocytopenia?
Answer
- Platelet destruction that arises secondary to heparin therapy
- Heparin can form a complex with PF-4 (platelet factor 4) on the surface of the platelet, creating a hapten. This complex can be recognized by some IgG autoantibodies, leading to splenic destruction of platelets.
- Fragments of destroyed platelets may activate remaining platelets, leading to thrombosis
Card 425
What is DIC?
Answer
Pathologic activation of the coagulation cascade
Card 426
What are the two main problems associated with DIC?
Answer
1) Widespread microthrombi resulting in ischemia and infarction
2) Consumption of platelets and factors results in bleeding (especially from IV sites and mucosal surface)
Card 427
What are 5 common causes of DIC?
Answer
1) Obstetric complications - amniotic fluid can can activate coagulation
2) Sepsis - endotoxins and TNF/IL-1 release induce endothelial production of tissue factor
3) Adenocarcinoma - mucin activates coagulation
4) Acute promyelocytic leukemia - primary granules activate coagulation (DIC is a hugely indicative sign of APL)
5) Rattlesnake bite - venom activates coagulation
How is disseminated intravascular coagulation treated?
Answer
Addressing the underlying cause and transfusing blood products and cryoprecipitate (contains coagulation factors) as necessary
Card 431
What is fibrinolysis?
Answer
The very end stage of coagulation (the removal of the thrombus). This is mediated by plasmin. Plasminogen is converted to plasmin by tPA (tissue plasminogen activator).
Due to plasmin overactivity resulting in excessive cleavage of fibrinogen
Card 434
How can a radical prostatectomy cause a disorder of fibrinolysis?
Answer
Release of urokinase activates plasmin
Card 435
How does cirrhosis of the liver result in a disorder of fibrinolysis?
Answer
It causes a reduced production of α2-antiplasmin
Card 436
What are the laboratory findings of disorders of fibrinolysis (3)?
Answer
1) Increased PT/PTT (plasmin destroys coagulation factors)
2) Increased bleeding time with normal platelet count (plasmin blocks platelet aggregation)
3) Increased fibrinogen split products without D-dimers (Serum fibrinogen is lysed; however, D-dimers are not formed because fibrin thrombi are absent)
*Disorders of fibrinolysis look very clinically similar to DIC, but there are no clots (no schistocytes); plasmin (over)acts before clots fully form
Card 437
How are disorders of fibrinolysis treated?
Answer
Aminocaproic acid which blocks activation of plasminogen
Card 438
What two features distinguish a premortem thrombus from a postmortem clot?
Answer
1) Lines of Zahn (alternating layers of platelets/fibrin and RBCS)
2) Attachment to vessel wall
Card 439
What are the three major risk factors for thrombosis?
Answer
1) Stasis (Disruption in blood flow)
2) Hypercoagulable state
3) Endothelial cell damage
Also known as the Virchow Triad
Card 440
What is this a picture of?
Answer
A thrombosis (lines of Zahn are visible)
Card 441
Why does disruption in normal blood flow cause thrombosis?
Answer
Normal blood flow is laminar; this keeps platelets and factors dispersed and inactivated
Card 442
5 ways in which endothelial cells prevent thrombosis?
Answer
Typically endothelial cells prevent thrombosis by:
1) Block exposure to subendothelial collagen and underlying tissue factor
2) Produce Prostacyclin (PGI₂) and NO - vasodilation and inhibition of platelet aggregation
3) Secrete heparin-like molecules - augment antithrombin III (ATIII) which inactivates thrombin and coagulation factors
4) Secrete tissue plasminogen activator (tPA) - converts plasminogen to plasmin which (1) cleaves fibrin and serum fibrinogen (2) destroys coagulation factors, and (3) blocks platelet aggregation
5) Secrete thrombomodulin - redirects thrombin to activate protein C, which inactivates factors V and VIII
Card 443
How do cobalamin (vitamin B12) and folate (vitamin B9) deficiencies increase the risk for thrombosis?
Answer
Lack of B12 or folate results in mildly elevated homocysteine levels due to ↓ conversion of homocysteine to methionine. Increased homocysteine is damaging to the endothelium.
Card 444
How does a protein C or S deficiency result in a hypercoagulable state? What complication is associated with protein C or S deficiency?
Answer
Protein C and S normally inactivate factors V and VIII. Deficiency increased risk of coagulation cascade activation.
Protein C or S deficiency (particularly Protein C deficiency) greatly increases the risk of developing warfarin skin necrosis.
Card 445
How does AT III deficiency result in a hypercoagulable state? How does AT III deficiency affect heparin dosing?
Answer
Heparin-like molecules normally activate ATIII, which inactivates thrombin (factor II) and other coagulation factors.
In ATIII deficiency, PTT does not rise with standard heparin dosing, because AT III is the target of heparin.
High doses of heparin must be given to activate limited ATIII, coumadin is then given to maintain anticoagulated state.
Card 446
Why are oral contraceptives associated with a hypercoagulable state?
Answer
Estrogen induces increased production of coagulation factors while decreasing AT III
Card 447
What is an embolism?
Answer
An intravascular mass that travels and occludes downstream vessels
What is the classic presentation of an amniotic fluid embolus (3)?
Answer
Shortness of breath (emboli to the lungs),
Neurologic symptoms (emboli to the brain),
and Disseminated Intravascular Coagulation (amniotic fluid is loaded with tissue thromboplastin which can activate the coagulation cascade)
*If a patient survives the DIC, they might then develop ARDS
Card 451
What is a pulmonary embolism (PE) typically caused by?
Answer
Usually due to a thromboembolus; common source is DVT of the lower extremity usually involving the femoral, iliac or popliteal veins
Card 452
How do pulmonary embolisms typically present?
Answer
Usually they are clinically silent due to dual blood supply to lungs and small size of embolus
In 10%, a pulmonary infarction can result. It presents with:
1) shortness of breath
2) hemoptysis
3) pleuritic chest pain
4) pleural effusion
Card 453
When will a pulmonary embolism cause pulmonary infarction?
Answer
If a large or medium sized artery is obstructed in patients with pre-existing cardiopulmonary compromise.
Card 454
When will a pulmonary embolus cause sudden death? Why does death occur?
Answer
When a large saddle embolus blocks left and right pulmonary arteries or with significant occlusion of a large pulmonary artery; death is due to electromechanical dissociation
Card 455
What diagnostic findings would you expect for a patient with a PE (3)?
Answer
1) V/Q lung scan shows mismatch (defect is in perfusion)
2) Spiral CT shows vascular filling defect in lung
3) D-dimer elevated
Card 456
What is factor V Leiden and how does it produce a hypercoagulable state?
Answer
Mutated Factor V that lacks the cleavage site for inactivation by proteins C and S.
Most common cause of inherited hypercoagulable state.
Card 457
What is prothrombin 20210A and how does it impact coagulation?
Answer
An inherited point mutation in the prothrombin gene that results in increased gene expression. Increased prothrombin leads to increased thrombin which promotes coagulation.
Card 458
A fat embolus is associated with what inciting event? How does it clinically present?
Answer
Typically follows a bone fracture.
Characterized by dyspnea and petechiae overlying the chest.
Marrow elements may be seen in embolus.
Card 459
2 causes of gas emboli?
Answer
1) Decompression sickness (Caisson disease, "the Bends")
2) Laparascopic surgery
Card 460
3 clinical symptoms of decompression sickness?
Answer
1) Joint and muscle pain
2) Dyspnea
3) If chronic, multifocal ischemic necrosis of the bone