Heme/Onc Flashcards
(158 cards)
1
Q
TTP (thrombotic thrombocytopenic purpura) pathophys
A
- due to impaired function of ADAMTS13 (vWf-cleaving protease)
- vWf multimers are PRO-thrombotic and cause:
- diffuse microvascular thrombosis
- microangiopathic anemia
- thrombocytopenia
- vWf multimers are PRO-thrombotic and cause:
- acquired (auto-Ab) or hereditary
2
Q
relationship between HbF and HbA
A
- HbF (alpha 2-gamma 2):
- high oxygen affinity
- made in final 7 mo
- –switches to–
- HbA (alpha 2-beta 2):
- during first 6 months of lide, switch to this
3
Q
What drives angiogenesis?
A
- vascular endothelial GF (VEGF)
- stimulation angiogenesis in: nml, chronically inflammed, healing, or neoplastic tissue
- Fibroblast GF (FGF)
- FGF-2 involved in endothelial cell proliferation, migration and differentiation
- –and–
- embryonic development, hematopoiesis, wound repair
4
Q
Lead Poisoning
A. peripheral blood smear
B. high risk groups
A
A. periph smear:
- coarse erythrocyte basophilic stipling
- microcytic hypochromic anemia
B. high risk groups:
- young kids ingesting paint chips (old, rundown buildings)
- industrial workers inhaling particulate lead
5
Q
Aplastic Anemia
A
- low Hgb
- thrombocytopenia
- no hematopoietic cells in bone marrow
- compensatory: increase in circulating EPO
6
Q
Iron Overload (Hemosiderosis)
A
- common, serious complication of chronic hemolytic anemia AND frequent blood transfusions
- *hemosiderin accumulation
- chelation therapy reduces parenchymal iron deposition
7
Q
What is a patient with chronic hemolytic anemia predisposed to?
A
- folic acid deficiency
- macrocytic changes due to an increase in erythrocyte turnover
8
Q
What is the relationship between Vitamin K and clotting?
A
- Vit K is needed for carboxylation and functionality of conjugation factors 2,7,9,10
- newborns without prophylactic supplementation are at risk for bleeding complications
- patients with CF are at risk for Vit K deficiency due to poor absorption of fat-soluble vitamins
9
Q
Burkitt Lymphoma
A
- aggressive rapid growth
- strry sky microscopic appearance
- Path: translocation of c-myc oncogene on long arm of chromosome 8 with IgHC region on chromosome 14
- produces a nuclear phosphoprotein (c-myc) that functions as a transcription activator
- “african mccormick with a sharp jaw line wears a burkha under the starry night sky”
10
Q
Follicular lymphoma
A
- tumor cells express pan B-cell antigens: CD19, 20, 21, 10 (…a)
- t(14:18); bCl2-IgH
- overexpression of bcl2 protein products inhibits apopotosis of tumor cells and facilitates neoplastic growth
11
Q
Spleen’s Job (2)
A
- BLOOD FILTER-can remove circulating pathogens
- major site of OPSONIZING Ab synthesisi
- asplenic pts prone to infections cause by ncapsulating organisms:
- S. pneumo
- H. flu
- N. mening
- spleen=most commonly injured organ with blunt abdo trauma
12
Q
T-cell ALL
A
- CP: mediastinal mass that…
- can compress great vessels=SVC syndrome
- can compress eophagus=dysphagia
- can compress trachea=dyspnea and stridor
13
Q
Folate deficiency
A
- inhibits the formation of dTMP
- causes limited DNA synthesis
- promotes megaloblastosis and erythroid precursor cell apoptosis
- thymidine supplementation can moderately INC dTMP levels, so it can reduce erythroid precursor cell apoptosis
14
Q
A. Aplastic anemia
B. In a sickle cell pt what is the most common VIRAL cause of an APLASTIC CRISIS?
A
A. AA causes pancytopenia; BM is replaced by fat cells and marrow stroma
**absence of splenomegaly on PE
BM biopsy useful in making diagnosis; marked hypocellularity
B. an infection of erythroid progenitor cells with parvovirus B19 (non envelpped, single-stranded, DNA virus) is the most common viral causes/infection
others: autoimmune, drugs (CARBAMAZEPINE, CHLORAMPHENICOL), exposure to radiation or toxins
15
Q
Vitamin K
A
- needed for CARBOXYLATION and functionality of coagulation factors 2,7,9,10
- newborns without prophylactic supplementation are at risk for bleeding complications
- pts with cystic ibrosis are at risk for Vit K deficiency due to poor absorption of fat-soluble vitamins
16
Q
A pt with chronic hemolytic anemia is predisposed to: (2)
A
- folic acid deficiency
- macrocytic changes due to increase in erythrocyte turnover
17
Q
HgbC due to missense mutation
A
- glutamate is subsituted by lysine (if it were valine, would get HbS) in beta-chain
- causes a decrease in negative charge of Hgb
- speed of Hgb during gel electrophoresis:
- HgbA>HgbS>HgbC
18
Q
Hereditary breast cancer
A
- most commonly associated with mutations in BRCA1 and 2 (tumor suppressor genes involved in DNA repair, mutations increase risk of developping breast and ovarian cancer)
- CP: peau d’orange=pitting edema in subcutaneous breast tissue and skin thickening around exaggerated hair follicles
19
Q
Intravascular hemolytic anemia
A
- INCREASED: LDH and bilirubin
- DECREASED: serum haptoglobin
20
Q
Hemolytic disease of the Newborn (erythroblastosis fetalis)
A
- cause: maternal sensitization to Rh antigens during a prior pregnancy with and Rh(D+) fetus
21
Q
Pure red cell aplasia
A
- rare form of marrow failure
- sever hypoplasia of marrow erythroid elements in the setting of normal granulopoiesis and thrombopoiesis
- associated with:
- thymoma
- lymphocytic leukemias
- parvovirus B19 infection
22
Q
Undifferentiated/Anaplastic Tumors
A
- do NOT resemble tissue of origin
- composition:
- pleomorphic cells with large hyperchromatic nuclei that grow in disorganized fashion
- may have numerous abnormla mitoses and giant tumor cells
23
Q
Tumor Lysis Syndrome
A
- can develop during chemo from cancers with rapid cell turnover (poorly differentiated lymphomas and leukemias)
- substantial tumor burden
- high sensitivity to chemo
- CP:
- hyperphosphatemia
- hypocalcemia
- hyperkalemia
- hyperuricemia
24
Q
RCC and blood d/o
A
- RCC can cause anemia of chronic dz and iron deficiency anemia d/t chronic hematuria
- some renal cell tumors can produce erythropoietin and cause polycythemia
- rare in younger pts
25
common paraneoplastic syndromes
* CP, frequently assoc neoplasms, etiology
* Cushing syndrome
* small cell lung cancer, pancreatic CA
* ectopic production of adenocorticotropic hormone/corticotropin-releasing hormone
* SIADH (syndrom of inapprop antidiuretic hormone secretion)
* small cell lung ca
* ectopic vasopressin production
* subacute cerebellar degeneration
* small cell lung ca
* breat, ovarian, and uterina ca
* anti-Yo anti-P/Q and anti-Hu Ab
* Lambert-Eaton myasthenic syndrome
* small cell lung ca
* voltage gate calcium channel ab
* Myasthenia gravis
* thymoma
* acetylcholine receptor Ab
* Hypercalcemia
* squamous cell lung ca
* ectopic production of parathyroid hormone-related protein
* dermatomyositis/polymyositis
* variable
* autoimmune
* erythrocytosis
* renal cell ca
* ectopic erythropoietin production
26
Paraneoplastic cerebellar degeneration
* CP:
* progressively worsening dizziness
* limb and truncal ataxia
* dysarthria
* visual disturbances
* etio: immune resp against tumor cells that cross reacts with Purkinje neuron Ag leadint to cute onset rapid degen of the cerebellum
27
Restless leg syndrome
* CP:
* uncomfortabe urge to move legs with:
* unpleasant sensations in the legs
* onset with inactivity or at night
* relief with movemet (stretching, walking)
* Etio:
* idiopathic
* iron deficiency
* uremia
* diabetes (especially with neuropathy)
* MS, PD
* drugs (antidepressants, metoclopramide)
* Tx:
* avoidance of aggravating factors (alcohol, sleep deprivation)
* supportive measures:
* leg massage, exercise, heating pads
* dopamine agonists (Pramipexole)
28
Xeroderma pigmentosum
* AR due to decreased ability to repair DNA following damage by UV light
* skin is nml at birth
* CP:
* erythema
* scaling
* subsequent hyperpigmentation and lentigo formation on light-exposed areas (especially face)
* later:
* skin of affected area shows atrophy, telengiectasias, intermingling areas of hypo and hyper-pigmenations
* skin malignancies (SCC, BCC, malignant melanoma) develop as early as 5-6 yo
* Etio: genes that code for various DNA repair enzymes are abnml
* leads to defects in excision of abnml nucleotides or defects in replacement of nucleotides following excision
29
dz associated with impaired DNA repair
* xeroderma pigmentosum
* Fanconi anemia (AR, hypersensitivity to DNA cross-linking agents)
* Bloom syndrome (AR, hypersensitivity to UV damage and chemotherapeutic agents)
30
Great saphenous vein
* located superficially inthe leg, longest vein in the body
* accessed by surgeons in the medial leg (most commonly) or less commonly, near its pt of termination in the femoral triangle of the upper thigh
* femoral triangle:
* inguinal ligament superior
* sartorius muscle lateral
* adductor longus muscle medially
31
Femoral Triangle
consists of (lateral to medial; NAVL):
* femoral nerve
* femoral artery
* emoral vein
* deep inguinal nods/lymphatic vessels
32
Hereditary angioedema
* inherited AD condition
* low C1 esterase inhibitor activity leads to increases in bradykinin activity
* causes episodes of painless, non-pitting, well-circumscribed edema
* face, neck, lips, tongue most commonly affected
* can also be acquired-associated with ACEi tx
* DONT use ACEi with these pts!!
33
Failures of Embryologic processes
* proliferation=unilat aplasia of the fibula
* apoptosis=a.i. dz due to persistence of autorxv B/T cells
* obliteration=branchial cleft cyst
* migration=Hirschsprung dz-failure of migration of neural crest cells that form the colonic ganglion cells
* fusion=hypospadias (failure of urethral folds to fuse)
34
TGA (transposition of the great arteries)
* diagnostic: aorta lying anterior to and to the right of the pulm artery
* TGA results from failure of fetal aorticopulmonary septum to spiral normally during septation of the truncus arteriosus
* life-threatening cyanosis at birth
35
Anaphylactic shock
* charac: vasodilatation, increased vascular permeabilit, bronchoconstriction
* epinephrine counteracts these physiological mechanism, so is drug of choice for tx
36
Actinic keratosis (AK)
* develops on chronically sun-exposed areas of the skin in predisposed indivs
* lesions consist of erythematous papules with a central scale and a rough "sandpaper-like" texture
* considered pre malignant lesions and have the potential to progress to squamous cell carcinoma
37
Bacterial meningitis
* classic triad: fever, stiff neck, altered mentation
* eval: prompt blood cultures, empiric AB, lumbar puncture and CSF analysis to confirm the diagnosis, id the offending organism, and determine AB susceptibility
38
Kozak consensus sequence
* occurs on eukaryotic mRNA
* defined by the following sequence:
* (gcc)gccRccAUGG
* R=adenine or guanine
* sequence helps initiate translation at the methionine start codon (AUG)
39
Seborrheic keratosis (SK)
* benign epidermal tumor, presents as tan or brown, round lesion with well-demarcated border and "stuck-on" appearance
* epi: middle-aged/elderly
* rapid onset of numerous SK=undiagnosed internal malignancy (Leser-Trelat sign)
40
Acanthosis nigricans
* CP: hyperpigmented, velvety plaques found on axilla or neck (flexural areas)
* assoc with insulin-resistant states: DM, obesity, acromegaly and visceral malignancy, or an endocrinopathy
41
Lichen planus
* 5 P's: polygonal, planar, pruritic, purplish plaques on wrists, hands, trunk, legs
* fine white lines: Wickham striae may be rpesent on plaque surface
42
patent foramen ovale (PFO)
* usually remains functionally closed b/c LA pressure\>RA pressure
* most pts: asymptomatic
* BUT! conditions that raise RA pressure above LA pressure (Valsalva) can produce a transient R-to-L shunt across the PFO...may result in paradoxical embolization (stroke in the setting of venous thromboembolism)
43
Rb protein
* regulator of the G1--\>S phase transition
* present in one of two forms:
* active-hypO-phosphorylated
* inactive-HYPER-phosphorylated
* cells are allowed to transition unchecked via proliferation signals which activate CDK4 (=hyperphos)
* resting cells in the G0 phase contain active (hypophosphorylated) Rb protein
44
[cutaneous] Angiosarcoma (Stewart-Treves syndrome)
* RF: chronic lymphedema (axillary LN dissection is a RF for CL involving ipsi arm)
* histo: infiltration of the dermis with slit-like abnml vascular spaces
* prognosis: poor b/c tumor is usually widespread by time of diag
45
viral meningitis
* elevated protein
* nml glucose
* lymphocytic predominance
46
bacterial meningitis
* low glucose
* high protein
* neutrophilic predominance of CSF
47
Leprosy (Hansen dz)
* deforming infection of skin and nerves
* caused by Mycobacterium leprae
* transmission: inhygienic conditions, respiratory route, prolonged skin-to-skin contact
* also armadillo contact
* range of clinical manifestations depends on strength of cell-mediated immune response
* TT (tuberculoid leprosy)=least severe form often self-limited; limited intact CMI (Th1)
* CP: mild skin plaques, hypopigmentation, hair follicle loss, focally decreased sensation
* LL (lepromatous leprosy)=most severe form, occurs in pts with a weak CMI (Th2)
* CP: skin thickening, plaque-like hypopigmentation (often with hair loss), leonine facies, paresis, regional anesthesia, testicular destruction, blindness
48
Melanoma
* most common metastatic tumors to the brain: lung ca, renal ca, melanoma
* malignancy of melanocytes
* embryologically derived from neural crest cells
* ABCDE
* Asymmetry
* border irregularities-uneven edges, pigment fading
* Color variegation-brown, tan, red, blk
* diameter \> or =6mm
* evolving: lesion changing in size, shape, color, or new lesion
49
Mitochondrial encephalomyopathy
* neuromuscular lesions, ragged skeletal mu fibers, lactic acidosis
* mitochondrial d/o follow maternal inheritance pattern
* mit responsible for ATP production via oxidative phosphorylation, so defect=lactic acidosis, affect tissue with highest metab rates (neural tissue, muscular tissue)
* heteroplasmy=having different mitochondrial genomes within a single cell
* variable clinical expression in affected family members
50
Giant cell arteritis (GCA)
* pt with HA, visual and muscular s/s. enlarged temporal artery, elevated erythrocyte sedimentation rate
* Prog: cell-mediated immunity
* production of cytokines, in particular IL-6 closely correlates to severity of s/s
51
what is an important difference between unfractionated heparin and LMWH?
* they can both bind to anti-thrombin to INC its activity against Factor 10a
* only unfractionated can bind both anti-thrombin and thrombin to allow anti-thrombin to inactivate thrombin
*
52
paroxysmal nocturnal hemoglobinuria (PNH)
* d/t gene defect (acquired mut in PIGA gene)
* causes absence of GPI anchor (needed to attach CD55/DAF and CD59/MAC inhibitory protein)
* CD55 and CD59 help inactivate complement and prevent MAC from forming on nml cells
* leads to **uncontrolled *complement-*mediated** hemolysis
* classic triad:
* hemolytic anemia (hemoglobinuria)
* pancytopenia
* thrombosis (at atypical sites)
53
high-affinity hemoglobinopathies
* high-O2-affinity hemoglobins have a DEC P50 that is represented by a leftward shift of the oxygen dissociation curve
* reduced ability to release oxygen within the peripheral tissues (selfish bastard dont want to let the O2 go!), leading to:
* renal hypoxia
* INC erythropoietin synthesis
* compensatory erythrocytosis
54
caseating granulomas of TB
* almost always contain large epitheliod macrophages
* pale pink ranular cytoplasm
* surface CD14 at periphery
* surround a central region of necrotic debris
55
Pol mutation
* responsible for acquired resistance to HIV reverse transcriptase inhibitors and HIV protease inhibitors
* ENV gene mutations enable escape from host neutralizing Ab
* (high mutability of HIV1 allows for evasion of host humoral and cellular immune responses and the development of resistance to anti-retroviral drugs)
56
superficial inguinal nodes
* all skin from the umbilicus down including the anus (below the dentate.pectinate line) drains to the superficial inguinal LN...except for:
* testes
* glans penis (drains into deep inguinal LN)
* (cutaneous) posterior calf (drains into depp inguinal LN)
57
lymph from the testes
* fro the testes to the abdominal para-aortic (retroperitoneal) LN (paralleling blood supply from the testicular arteries which arise directly from the abdominal aorta
58
ISONIAZID and sideroblastic anemia
* ISONIAZID inhibits pyridoxine phosphokinase (converts B6 to active form) =pyridoxine (Vit B6) deficiency
* Pyridoxine (B6) active form is the cofactor for amino-levulinate synthase [catalyzes the rate-limiting step of heme synthesis]
* this is why B6 is prescribed with ISONIAZID!
- inhibition of this step can result in sideroblastic anemia--microcytic hypochromic anemia
59
How is sideroblastic anemia diagnosed
* BM examination with Prussian blue stain
60
Warfarin-induced skin necrosis
* in pts with protein C or S (natural ANTI-coagulants) deficiency who are started on WARFARIN
* after the initiation of WARFARIN a rapid drop in factor 7 and protein C levels
* if there is already protein C deficiency, transien procoag/ANTIcoag imbalance is exaggerated=relative hypercoag state with thrombotic occlusion of the microvasculature and skin necrosis
61
acute intermittent porphyria
* AD condition
* PP: porphobilinogen deaminase deficiency
* S/S: most pts remain asymptomatic
* minority:
* acute attacks with:
* abdominal pain + vomiting
* peripheral neuropathy
* neuro-psych symptoms
* reddish-brown urine
* tx: IV glucose or heme preparations (hemin)
* down regulate ALA synthase (rate-limiting enzyme in hepatic pathway of heme synthesis) activity
62
hereditary spherocytosis: epidemiology and CP
* epi:
* AD inheritance (approx 75%)
* N. euro descent
* CP:
* hemolytic anemia
* jaundice
* splenomegaly
63
hereditary spherocytosis: lab findings
* INC mean corpuscular Hgb concentration
* spherocytes on peripheral smear
* NEG Coombs test
* INC **osmotic fragility** on acidified glycerol lysis test
* d/t DEC SA:volume ratio
64
hereditary spherocytosis: tx and complications
* tx: splenectomy
* complications:
* pigmented gallstones
* aplastic crises f/m parvovirus B19 infection
65
hereditary spherocytosis: pathophys
* red cell cytoskeleton abnormalities
* mc: plasma-membrane scaffolding proteins: spectrin and ankyrin
* without the scaffolding, spherocytes are **less deformable** than nml RBCs and are prone to **sequestration** and subsequent **accelerated destruction in the spleen**
66
ALA synthase
* UPregulated by **CYP450 inducers**:
* most anti-epileptics
* griseofulvin
* rifampin
* DOWNregulated by **heme and glucose**
67
hereditary spherocytosis: complications
* pigmented gallstones
* aplastic crises from parvovirus B19 infection
68
Factor V Leiden
* 1-9% Caucasians worldwide are heterozygote carriers
* modified to resist activated Protein C
* resulting HYPER-coaguable state predisposes to DVT=source of MOST PE
* also: cerbebral vein thrombosis and recurrent preagnancy loss
* mc c/o inherited thrombophiia
69
What are the two main uses for DDAVP/vasopressin therapy
* mild hemophilia A and type 1 von Wilebrand dz
* INC circulating factor 7 (vWF non covalently attached, increases its stability) and endothelial secretion of vWF to stop bleeding
* central diabetes insipidus and nocturnal enuresis
* binds to V2R in renal tubular cells
* leads to:
* INC aquaporin chanels
* INC water reabsorption
* DEC urine output
70
Metalloproteinases and Invasion
* zinc-containing enzymes that degrade the ECM and basement membrane
* composed mostly of: laminin and collagens 4 and 7
* tissue remodeling and embryogenesis
* also: tumor invasion through the BM and connective tissue
71
Metalloproteinases and BM penetration
* tumor cells DETACH from surrounding cells (process determined by DECreased expression of adehesion molecules-E-cadherins)
* tumor cells ADHERE to the BM, facilitated by INC expression of laminin and otehr adhesion molecules
* tumor cells INVADE the BM via enhanced secretion of proteolytic enzymes (metalloproteinases, cathepsin D protease)
72
cytochrome c
* mitochondrial enzyme
* activates caspases
* indirecty brings about cell death through **intrinsic** pathway apoptosis
73
What are the two phases of apoptosis
* initiation phase (two diff pathways)
* protein-hydrolyzing caspases activated
* execution phase
* caspases bring about cell death by cleaving cellular proteins and activating DNAses
74
What are the two diff pathways of the initiation phase of apoptosis
* intrinsic (mitochondrial)
* extrinsic (death receptor)
75
Intrinsic (mitochondrial) pathway of stage 1-initiation of apoptosis
* mit more permeable and pro-apoptotic substances are released into the cytoplasm in resp to stress or the cessation of survival signals
* ANTI-apoptotic proteins (Bcl-2 and Bcl-x) that are in mit membranes and cytoplasm are replaced with PRO-apoptotic proteins (Bak, Bax, Bim)
* PRO-apop allow INC permeability of mit=release of caspase-activating substances: cytochrome c
76
extrinsic pathway of stage 1-initiation of apoptosis
* engagement of death receptors on the cell surface: TNFR1 and Fas (CD95)
* after cross linkage of Fas with its ligand mulecules of Fas come together and form binding site for a death-domain containing adaptor protein called FADD
* FADD binds an inctive form of a caspase...cascade
77
TTP clinical features
* new onset neuro symptoms
* hemolytic anemia with schistocytes
* INC LDH
* DEC haptoglobin
* thrombocytopenia
* INC bleeding time
* nml PT/PTT
* acute kidney injury
78
HbS
* d/t pt mut (valine at 6th position of beta chain for glutamic acid)
* abnl beta chain-polymerize when deoxy or dehydrated
* aggregates in the deoxygenated state!!
* plymers form fibrou strands that reduce RBC membrane flexibility and promote sickling
* under what conditions does sickling occur?
* conditions assoc w/ anoxia: low pH and HIGH 2,3-BPG
* inflexible erythrocytes predispose to microvascular occlusion and micro-infarcts
79
What is the classic triad of Wiskott-Aldrich syndrome?
* triad:
* eczema
* thrombocytopenia
* combined B-lymphocyte and T-lymphocyte deficiency
* dz onset is early in life
* CP: repeated infections, espec by encapsulated organisms
80
Calcium Chelation
* pts who receive the equivalent of more than one body blood volume (5-6L) of whole blood transfusions --or-- packed RBC over a pd of 24 hrs may develop: *elevated plasma levels of CITRATE*
* **CITRATE is a substance added to stored blood
* CITRATE chelates calcium and magnesium and may reduce their plasma levels=**paresthesias**
81
What is one of the mc causes of folate deficiency anemia
* ALCOHOLISM d/t:
* poor dietary intake
* impaired folate absorption, utilization, and enterohepatic recycling
* anemia within a few WEEKS
82
pathophys of folate deificiency
* reduced form of folic acid: tetrahydrofolic acid is necess for synthesis of AA, thymidine, and purine
* impaired nucleotide syn=defective DNA production in blood cell precursors=abnml cell division and **megaloblastic** hyperplasia of the BM
* peripheral blood smear: pancytopenia, hypersegmented neutrophils containing nuclei with \>5 lobes
* RBC abnormalities: ovalocytosis and **macrocytosis**: MCV\>100 nanom^3
83
paraneoplastic cachexia
* cachexia:
* anorexia
* malaise
* anemia
* weight loss
* generalized wasting d/t underlying systemic dz
* mediated by TNF-alpha ("cachectin")
* along with IL-6 and IL-1beta
* how?
* suppresses appetite and INC BMR
84
myeloma and amyloidosis
* AL myloid forms d/t accumulation of monoclonal Ig LC
* apple green on Congo red
* contrib to renal failure in MM
* (also deposited in heart, tongue, nervous system)
85
malig EBV associations
* Hodgkins and NHL (Burkitt)
* nasopharyngeal carcinoma
86
Hydroxyurea MOA
* Hydroxyurea INC fetal Hg (Hb F) synthesis
* reserved for pts with frequent pain crises
*
87
MTX and Folinic acid (LEUCOVORIN)
* leucovorin can reverse the toxicity of MTX in non-cancerous cells in the GI mucosa and BM if administered at the approp time
* Leuco=reduced form of folic acid that does NOT require the action of DHFR
* when used in combo with 5-FU, Leucovorin potentiates the cytotoxic action of 5-FU (by binding thymidylate synthetase)
* frequently used in CRC therapy regimens
88
Beta thalassemia
* DEC beta globin chain synthesis=hypochromic, microcytic anemia (MCV\<80)
* reduced beta glbin synthesis:
* membrane damage
* death of red cell precursors in BM (ineffective erythropoiesis)
* lysis of circulating erythrocytes (extravascular hemolysis)
89
Plummer-Vinson syndrome
* characterized by:
* dysphagia (esophageal web formation)
* iron deficiency anemia
* koilonychia (spoon-shaped nails)
* shiny red tongue
* most symptoms resolve with iron supplementation
90
what are cells commonly seen in beta-thalassemia
* small red cells with INC area of ctl pallor
* alsooo:
* anisopoikilocytosis (variation in size and shape)
* target cells
* teardrop cells
* nucleated red cell precursors
* basophilic stippling
91
Hemophilia lab findings
* PTT prolongation
* nml bleeding time and nml PT
* 8A and 9B (malibu and bitch neighbor)
92
Hemophilia A and B clinical features
* delayed/prolonged bleeding after mild trauma or procedure:
* hemathrosis. hemophilic arthropathy
* intramuscular hematomas
* GI or GU tract bleeding
93
von Willenbrand disease
* mc inherited bleeding d/o
* AD pattern of inheritance and variable penetrance
* absence of vWfactor=
* impaired platelet function (prolonged bleeding time)
* coagulation pathway abnormalities (d/t DEC factor 8 activity)--prolonged PTT)
94
How do you spot Plasmodium infection on a peripheral blood smear
* Giemsa staining
* RBC have multiple small rings (trophozoites) and banana-shaped gametocytes
95
Aspirin and NSAIDS reversible or nah
* Aspirin is a NSAID that IRREVERSIBLY inhibits COX1 and 2 via ACETYLATION
* other NSAIDS (diclofenac, ibuprofen, indomethacin) REVERSIBLY inhibit
96
telomerase
* RNA-dependent DNA polymerase that synthesizes telomeric DNA sequences that can replace lost chromosomal ends of the telomers
* cancer cells typically contain INC telomerase activity to allow for continued proliferation
97
Raltegravir
* integrase inhibitor
* disrupts the ability of dbl-stranded HIV DNA to integrate into the host cells chromosomes=prevent host cellular machinery from transcribing viral mRNA
98
what is the area postrema/chemorceptor trigger zone (CTZ)
* in the fourth ventricle
* area postrema has a CTZ
* it can respond to many NT, drugs, toxins
* sends info to nucleus tractus solitarius (NTS) in the medula
99
what are inputs for the NTS
* area postrema
* GI tract (via vagus)
* vestibular system
* CNS (meninges, hypothalamus)
100
where do neurons from the NTS project
other medullary nuclei and coordinate the vomiting process
101
what are the 5 main receptors that regulate the vomiting reflex
1. M1 muscarinic
2. D2 dopaminergic
3. H1 histaminic
4. 5-HT3 serotonergic
5. neurokinin 1 (NK1) receptors
102
in pts with sickle cell anemia and other chronic hemolytic d/o what is the mc c/o an anaplastic crisis?
infection of erythroid progenitor cells with parvovirus B19 (a non-enveloped ssDNA virus)
103
motion sickness, hyper-emsis gravidarum (Promethazine)
* antimuscarnics (anticholinergics): scopolamine
* antihistamines:
* Diphenhydramine
* Meclizine
* Promethazine
104
dx for chemotherapy-induced emesis
* DA-R ANT-agonists:
* Pr**_ochlorper_**azine
* Met**_oclopra_**mide
* **Sereton**in (5-HT3)-R ANT-agonists
* Ondan**setron**
* Grani**setron**
* Neurokinin 1-R ANT-agonist
* *Aprepitant*
* Fos*aprepitant*
105
What is the mc c/o primary (hereditary) hemochromatosis?
* HFE protein mutations
* inactivation of the HFE protein results in DEC hepcidin synthesis by heptocytes anddd INC DMT1 expression by enterocytes (**\*\*hepatocytes detect falsely low iron levels**)
* ^^^leads to--\>iron overload
* pts at INC risk for:
* liver cirrhosis
* hepatocellular carcinoma
106
nml HFE function
* interacts with transferrin receptor to INC endocytosis of the iron-transferrin complex
* once inside cell, transferin degraded, released iron added to labile iron pool
* controls expression of proteins involved in iron absorption and storage
107
when do pts develop the classic triad of HFE protein mutations
* when body iron levels exceed 20g:
* micronodular cirrhosis
* diabetes mellitus
* skin pigmentation (bronze diabetes)
* at INC risk for: hepatocellular carcinoma, CHF, testicular atrophy/hypogonadism
108
what is the tx for cyanide poisoning?
* NITRITIES
* oxidizing agents
* induce methemoglobinemia
* **methemoglobin contains ferric (Fe3+)** instead of ferroUS (Fe2+)
* CN binds to ferric more avidly than to mitochondrial **cytochrome c oxidase** enzyme, thus diminishing cyanide's toxic effect
109
s/s cyanide poisoning
* reddish skin discoloration
* tachypnea
* HA
* tachycardia
* NV
* confusion
* weakness
* can progress to seizures and CV collapse
* d/t inability of tissue to extract arterial oxgen:
* severe LA + narrowing of venous-arterial PO2 gradient
110
What is methemoglobin
* hemoglobin with ferric iron (Fe3+)
* incapable of carrying oxygen, BUT has high affinity for cyanide
* binds and sequesters CN in th blood=inhibit it from banging a/r with cytochrome oxidase=limits its toxic effects
111
what are three antidotes for cyanide poisoning
1. \*\*inhaled amyl nitrite
2. hydroxycobalamin (Vit B12 precursor)
3. sodium thiosulfate
112
What are anaplastic cells?
* neoplastic cells that demonstrate a complete lack of differentiation
113
What are the (FIVE) main features of anaplastic tumors?
1. loss of cellpolarity with complete disruption of nml tissue architecture
1. cells coalesce into sheets/islands in a disorganized/infiltrative way
2. significant variation in:
1. shape/size of cells (cellular pleomorphism)
2. nuclei (**nuclear pleomorphism**)
3. disproportionately large nuclei (high N:C ratio) that are often deep-staining (HYPER-chromatic) with abundant, coarsely-clumped chromatin and large nucleoli
4. numerous, often abnml **mitotic figures**
5. **giant, multinucleated tumor cells**
114
define metaplasia and give an example
* metaplasia=process of switching from one differentiated cell type to another
* often occurs in response to irritants (tobacco smoke, gastric acid)
* ex: bronchial epithelial cells undergoing phenotypuc switch from columnar epithelium to squamous epithelium
115
AML peripheral blood smear
* very large nucleated cells with scant cytoplasm...BLAST CELLS
* in the cells: linear, purple-red inclusions=AUER RODS
116
AML CP
* complications of PAN-cytopenia
* fatigue from anemia
* bruising/bleeding from thrombocytopenia
* infections from possible functional neutropenia despite leukocytosis
* median white blood ct: 15k mm^3 (nml: 4k-10k)
117
WBC differential from highest to lowest:
* neutrophils like M.E. better
* neutrophils: 55-60
* lymphocytes: 25-35
* monocytes: 5
* eosinophils: 2
* basophils: \<1
118
What are five important neutrophil chemotactic agents?
1. C5a
2. IL-8
3. LTB4
4. kallikrein
5. platelet-activating factor
119
HEME is a PORPHYRIN
* synthesized in the liver for use in the cytochrome p450 enzyme system AND in the BM for Hgb
* deficiency in any of the enzyme respondible for porphyrin synthesis can result in porphyria
* CP result from accumulation of porphyrin precursors in blood, tissues, urine
* AIP attakcs are d/t accumulation of ALA and PBG
120
what causes an accumulation of ALA
* ALA synthase induction, typically precipitated by:
* certain medications:
* Phenobarbital
* Griseofulvin
* Phenytoin
* alcohol use
* smoking
* progesterone (eg puberty)
* low-calorie diet
121
(FOUR) necessary components of PCR
1. **primers** that are complementary to regions fo DNA flanking the segment of interest
2. thermostable DNA polymerase
3. deoxynucleotide triphosphates
4. source DNA template strand
122
three steps of DNApolymerase in PCR
1. denature
2. anneal
3. elongation
123
which signal-transduction pathway is activated when growth factor binds to its receptors?
* PI3k/Akt/mTOR
* 1. GF binds receptor tyrosine kinase
* auto-phosphorylation of specific tyrosine residues within the receptor
* phosphotyrosine residues activate PI3k which phosphoryltes PIP2 (located in plasma membrane) to PIP3
* activation of Akt (protein kinase B)
* Akt activates mTOR
* mTOR translocates to the nucleus and induces genes involved in:
* cell survival
* ANTI-apoptosis
* angiogenesis
* mTOR activation is inhibited by PTEN (tumor suppressor protein that removes the phosphate group from PIP3)
124
inositol phospholipid pathway
* uses Gq proteins that stimulate hydrolysis of membrane-bound phospholipids via phospholipase C
* pathway INC cytoplasmic Ca2+ levels through IP3-mediated Ca2+ efflux from the ER
125
what is the clinical presentation of hemolytic anemia
* anemia
* elevated LDH (lactate dehydrogenase)
* indirect HYPER-bilirubinemia
126
What is the difference between hereditary scperocytosis and autoimmune hemolytic anemia?
* similar findings:
* indirect HYPER-bilirubinemia
* elevated LDH
* spherocytes on peripheral blood smea
* difference with AIHA:
* NOT heritable
* positive direct antiglobulin (Coombs) test
* propensity to develop a.i dz (eg SLE)
127
What are triggers of G6PD deficiency
* drugs:
* sulfonaide
* antimalarials
* fava beans
* infectious:
* viral hepatitis
* pneumonia
* typhoid
128
pentose phosphate pathway (HMP shunt)
* generates:
* NADPH-for use in reductive rxns
* ribose-5-phosphate, precursor for synthesis of nucleotides
* two types ofr rxns: oxidative (IRREVERSIBLE) and nonoxidtive (reversible!!)
* NON-oxi:
* rib5P excess=glycolytic intermediates used for ATP generation
* rib5P low: pathway REVERSES, uses transketolase and transaldolase to convert glycolytic intermediates to rib5P!!
129
What is a major difference between direct factor 10a inhibitors and direct thrombin (2a) inhibitors
* 10a INC:
* NO EFFECT on thrombin time
* PT
* activated PTT
* 2a (thrombin) INC:
* thrombin time
130
isotype switching
* occurs in germinal centers of LN
* requires interaction of the CD40-R on B-cells with the CD40 ligand (CD154) expressed by activated T-cells
* IgG=main serum Ig of the secondary resp
131
negative selection
* deletio of T-cell clones that strongly bind to self-MHC antigens
* occurs in the fetal thymus and contributes to teh development of tolerance to one's own antigens
132
When are mature B-cells exposed to antigens?
* when they leave the BM and migrate to lymphoid organs and peripheral tissues
* once activated, there are two pathways:
* short lived plasma cells that release Ag-specific IgM through a T-cell independent process
* most of them: migrate to lymphoid follicles in LN cortex, form GC (site of B-cell proliferation d/r immune response)
133
what are thalassemias
* disorders presenting with reduced -or- absent globin chain production
* almost all thalassemia cases result in hypO-crhomia and microcytosis (low MCV)
134
chronic alcoholics and megaloblastic macrocytic anemias
* nutritional deficiency of vit B12 or folate
* impaired synthesis of purine and pyrimidine bases
* aka diminished thymidine synthesis
135
where does heme synthesis occur
* partly in the mitochondria (first and final three steps) and cytoplasm
* heme in synthesized principally in:
* erythrocyte precursor cells (in BM)
* hepatocytes (use heme in microsomal cytochrome P450 system)
136
bony metastasis
* two characterizations:
* osteolytic (lucent)-d/t osteoCLAST stimulation=aggressive ca
* osetoblastic (sclerotic)-d/t osteoBLAST=more indolent course
* bony pain in older man with osetoBLASTic lesions on imaging=highly suspicious for prostate ca
* renal cell ca bone mets are commonly **osteoLYTIC**
* myreloma cells *suppress osteoblasts* would cause **osteoLYTIC** lesions
137
(FIVE) osteoLYTIC bone mets
(THREE) osteoBLASTIC
(TWO) mixed
1. multiple myeloma
2. non-small cell lung ca
3. NHL
4. RCC
5. melanoma
1. prostate ca
2. small cell lung ca
3. hodgkin
1. GI
2. breast
138
proto-oncogenes (1-hit GAIN of function)
* **RAS** (GTP-binding protein)
* cholangiocarcinoma
* pancreatic adenocarcinoma
* ***MYC* (TF)**
* burkitt lymphoma
* **ERBB1 (EGFR)**
* lung adenocarcinoma
* **ERBB2 (*HER2)***
* breast cancer
* **ABL**
* CML
* **BRAF**
* hairy cell leukemia
* melanoma
139
tumor suppressor genes (2-hit LOSS of function)
* **BRCA1/2** (DNA repair genes)
* breast and ovarian ca
* **APC/beta-catenin** (Wnt signaling pathway)
* colon, gastric, and pancreatic ca
* familial adenomatous polyposis (FAP)
* **TP53** (genomic stability)
* *\*\*most cancers\*\**
* Li-Farumeni syndrome
* **RB** (G1/S transition inhibitor)
* retinoblastoma
* osetosarcoma
* **WT1** (urogenital differentiation)
* Wilms tumor
* **VHL** (ubiquitin ligase component)
* RCC
* VHL syndrome
140
tumor suppressor genes are involved in (FOUR) processes
1. DNA repair
2. cellular differentiation
3. checkpoint control of the cell cycle
4. transcription factor regulation
141
HEPCIDIN-acute phase reactant
* synthesized by LIVER
* acts as **central regulator of iron homeostasis**
* synthesis INC by:
* high iron levels
* inflamm conditions
* levels lowered by:
* hypoxia
* INC erythropoiesis
* influences body iron storage thru interaction with FERROPORTIN (TM protein, transfers intracellular iron to circulation)
* \*\*upon binding hepcidin, ferro is internalized and degraded=
* DEC intestinal iron absorption
* inhibits release of iron by macrophages
142
8:14
Burkitt lymphoma (c-myc activation)
burke ATE 14 c nugs
143
9:22 Philly
CML (BCR-ABL)
brooke and abel got 9 camels when they turned 22
144
11:14
mantle cell lymphoma (cyclin D1 activation)
the clock on the mantle is lucky plus 3
145
14:18
follicular lymphoma (BCL-2 activation)
dbl 7 and 9
146
15:17
M3 type of AML
wizard AML started at 15, was an M3 by 17
147
GBM macro and micro
* mc primary brain neoplasm in adults
* macro:
* areas of necrosis and hemorrhage
* poorly demarcated from surrounding tissue
* micro:
* **pseudopalisading necrosis** (foci of necrosis surrounded by tumor cells)
* new **vessel** formation
* small round cells, bizarre giant cells, large number of mitoses
148
THREE common causes of acquired thrombocytopenia
* INC platelet consumption
* sequestration
* and/or destruction
149
ITP (immune thrombocytopenic purpura)
* a.i. destruction of platelets by anti-platelet Ab
* likely igG auto-Ab vs. platelet membrane glycoproteins GP2b/3a
* peripheral blood smear: isolated thrombocytopenia
* tx: systemic immunosuppression (corticosteroids)
* sometimes assoc w/ HIV or Hep C
150
OSA and secondary polycythemia
* OSA is characterized by recurrent episodes of asphyxia during slep
* peritubular cells in the renal cortex sense hypoxia and respond by releasing erythropoietin into the bloodstream
* deficient erythropoietin production is the reason many pts with CKD develop anemia
* erythropoietin stimulates erythrocyte production by binding to erythropoietin receptors on erythrocyte precursors in the BM=secondary polycythemia
151
cyclophosphamide and ifosfamide SE
* **hemorrhagic cystitis**
* caused by urinary excretion of toxic metabolite acrolein
* prevented by:
* aggressive hydration
* bladder irrigation
* admin of **MESNA**-sulfhydryl compound that binds **acrolein** in the urine
152
Iron deficiency secondary to menstrual blood loss-LABS
* DEC BM iron stores (ferritin and heosiderin LOW)
* DEC serum ferritin
* INC serum total iron binding capacity (TIBC)--reflecting INC serum transferrin
* DEC serum iron concentration
* DEC blood Hgb
* microcytic, hypO-chromic RBC
153
ferritin and transferrin
* ferritin:
* cellular iron storage protein
* marker of iron stores
* serum ferritin is DEC in iron deficiency, ELEVATED in iron overload
* acute phase reactant, may be elevated in pts with infections or inflamm dz
* transferrin
* transports iron through the plasma
* iron deficiency=make more transferrin
154
Whats so special about Type O moms
Ab are predom IgG--can cross placental and cause hemolysis in the fetus
155
All the directions of all the blots
* Northern: specific (m)RNA
* Southern: specific DNA in an unknown sample
* microarray-similer to south and north, involves hybridization of a large number of probes at once (genomic DNA or cDNA)
* Southwest: DNA-binding proteins
* Western: proteins
156
what is the correlation between half-lives and a transient hypercoaguable state
* occurs d/r first few days of warfarin therapy
* in addition to inhibiting Vit K-dependent clotting factors, warfarin also DEC carboxylation of Protein C and S
* C and S normally ANTI-coag through deactivation of factors 5 and 8
* **Prot C has a short half-life**=anti coag activity quickly reduced when warfarin therapy starts
* now have pro-coag form DEC protein C and pro-coag from persistent clotting factor 2,9,10
* tx: overlapping co-admin of heparin (**heparin bridge**)
157
DIC vs. TTP-HUS
* DIC:
* pts bleed
* coagulation cascade activated
* PT and PTT prolonged
* low fibrinogen and INC FDP
* TTP-HUS
* usually do NOT bleed
* only platelets are activated
* nml PT and PTT
* nml fibrinogen
158
What does the number of reticulocytes in the peipheral blood indicate
* indication of how effectively the BM is producing RBCs and thus responding to anemia
* low or nml retic ct *in setting of anemia*=underproduction anemia
