Heme/Onc Notes:
BM (mesoderm) has stem cell that differentiates into: common myeloid and common lymphoid.
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CMP: RBC, mast, megakaryocytes, myeloblast (baso/eos/neutron/monocyte, mono gives mac).
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CLP: NK cell, small lympho (T lympho, B lympho: gives plasma cells).
RBC: 120 days life, no mito, only uses glucose (obtain ATp via glycolysis), degraded by splenic mac.
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Reticulocytes: immature RBC, has mesh of rRNA, blue on giemsa, 2% in peripheral blood.
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Aniso (not equal), poikilo (abnormal), erythrocytosis (aka polycythemia; inc viscosity).
Leukocytes: neutron/eosin/baso/mono/lymphocytes.
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Neutrophils: acute inflame, pus. Morpho types: nonsegmented (band; immature, seen in infection/cancer), segmented (mature, 3-5 lobes),
hypersegmented (>5 lobes, vit B12/folate def).
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Left shift: immature cells pumped out (due to high demand or not enough space). Leuko (band), RBC (reticulo), or both (leucoerythroblastic
rxn).
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Basophils: bilobed, 1% of wbc, called mast in tissues (baso in blood), mediate allergy, express IgE rec, IgE crosslinking (rel of:
hista/heparin/PG/leukotriene/vasoactive amine). Cromolyn sodium prevents degran (asthma prophylaxis).
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Eosin: bilobed, 1-6% of wbc, contains MBP and hista, inc in parasitic/allergy/neoplasm. Dec by cortisol (sequesters eosin in LN, impairs
migration: neutrophilia).
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Monocytes becomes mac as they enter tissue. Dendritic cells are phagocytic APCs. Lympho are small round cell with scanty cyto, 25-35% of
wbc. B cell mature in BM where they receive rec (CD19/20/21), can migrate to tissue/LN, acts as APC/memory cell/produce Ig. NK cell doesn’t
require signal to kill, targets cancer/virus.
Histiocyte disorder: malformed/uncontrolled prolif of histio (aka mac); mac in brain (microglia), in skin (langerhan), in liver (Kupffer). Group of
disorders now called langerhan cell histiocytosis:
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Character: birbeck (tennis racket) granule, CD1a and S100 positive (IHC), aggressive (tx: intensive chemo).
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S/S: cutaneous eruption (skin/scalp), cystic skeletal defect, BM failure, lymphadenopathy, hepatospleno.
Plasma cell disorder: B cell becomes malig (prolif of plasma cell and monoclonal sec of Ig); M spike (inc of Ig), heavy chain is not produced enough
thus inc in light chain forms bence jones protein (urine/blood).
Multiple myeloma: malig prolif of plasma cell in BM, MC prim bone malig, elevated IL6 (helps B cell prolif), inc Ig (esp IgG), 50-60 yo, many organs
affected (BM destruction, IL1 or osteoclast activating fac activation, ab depo on organs).
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S/S: hypercalcemia (bone breakdown; confusion), RF and rouleax formation (+/- proteinuria, due to: metastatic calcif of RT/CD, bence jones
protein is toxic too, prim amyloidosis as light chain depo can switch to amyloid), anemia (blood is thickened by protein despite anemia,
recurrent infection as Ig lacks specificity), bone lesion (Ig depo and rel IL1 creating puched out lesions/rib #).
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Lab: BM Bx (>10% clonal plasma cells), smear (rouleaux), M spike (MC is IgG), BJ protein (urine), inc ESR/Cr/calcium, anemia, do skeletal survey
(lesions). Tx: chemo, BM tranx
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Monoclonal spike: serum protein electrophoresis (inc IgG or IgA). So look for spike in gamma region.
Waldenstrom macroglobulinemia (lyphoplasmacytic lymphoma): similar to MM but is a lymphoma. Plasma cell prolif (thus inc Ig and M spike, but
IgM not IgG). MYD88 mut. S/S: lympadeno, no/less CRAB, hyperviscosity sym (stroke, retinal hem, gum/nose bleed, raynauds). Tx: chemo and IgM
plasmapheresis.
Monoclonal gammaopathy of undetermined significance: dx of exclus (after MM and WM is ruled out), asym with IgM spike, BM (<10% plasma
cell), no BJ/CRAB, benign but may become WM/MM (follow up).
Myeloproliferative disorder: neoplasm where too much myeloid cells are made, inc risk of AML, 50-60 yo, due to de novo mut/envir, you see:
hypercell BM with inc myeloid cells. Types: PV, essential thrombocythemia, myeloid metaplasia with myelofibrosis, CML. All (except CML) have
V617F JAK 2 kinase mut (chromo 9; valine to phenylalanine at 617 position; JAK controls blood cell production from stem cell, this mut makes stem
cell more sensitive to growth fac that needs JAK2 for signal transduction). All (exc CML) can be tx with hydroxyurea.
PV: inc RBC (and wbc/plt, hence poly), inch b/hct, prim (EPO indep, normal SaO2, low EPO), sec (due to inc EPO, normal in high altit where SaO2
becomes low or patho like in EPO secreting tumor), relative (MC, loss of plasma volume leads to hemoconcentration eg dehyd).
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Lab: relative (normal SaO2, inc RBC, normal RBC mass, dec plasma vol), physiologically approp sec (dec Sao2, which inc EPO, inc RBC
count/mass, normal plasma vol). If you see inc EPO and normal O2: cancer.
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S/S: pruritis post-shower (abn hista release), hyperviscosity (flushed face, thrombosis, MCC of bud chiari syn, erythromyalgia of extremities,
visual/mental changes, gouty arthritis (inc cell turnover of immature rbc), spent phase (fibrosis of BM: anemia).
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Tx: phlebotomy (goal hct <45; chronic tx: iron def and reactive thrombocytosis), pharm (hydroxyurea: - ribonucleotide reductase needed to
make DNA), aspirin (dec viscosity), IFN a (disrupts cell prolif and induces immune resp against abn cell; may induce gout due to cell
destruction).
Essential thrombocythemia: neoplastic megakaryocyte prolif, inc plt (but dysfxn plt). S/S: bleeding, thrombosis, splenomegaly, erythromelalgia,
rarely becomes acute leuk/BM fibrosis. No gout since plt has no nucleus. Dx: plt >450k for >2mo. Tx: aspirin, hydroxyurea, INF a, plateletpheresis
(for 911).
Myeloid metaplasia with myelofibrosis: myeloid stem cell neoplasia esp megakaryocytes (rel cytokines and fibroblast GF: BM fibrosis), dysfxn
RBC/plt/WBC and pancytopenia (bleed /infec/thrombosis /anemia); hematopoiesis in spleen (splenomegaly), liver (hepatomeg/portal HTN), serosal
surface (pleural/pericardial effusion). BM is initially hyper then hypocellular (dry tap). Smear: teardrop RBC with nucleus. Large plt.
Leukopenia: caused by radiation/chemo/lupus. Types: lymphopenia (due to immunodef like HIV, digeorge, high cortisol) and neutropenia (has tx:
GM-CSF or G-CSF; both are synthetic cytokine that helps proliferation).
Leukocytosis: neutrophilic (due to inc cortisol, necrosis, infection, can cause left shifting: immature neu has dec CD 16 rec), monocytosis (chronic
inflame: AI, malig), basophilia (CML), eosinophilia (allergy, para, Hodgkin lymp: inc IL5), lyphocytosis (viral, bordatella pertussis).
Infectious mononucleosis: CMV/EBV; lympadeno (paracortex hyperplasia), fever, exudative pharyngitis, t cell hyperplasia (EBV; leukocytosis),
aplenomegaly (periarterial lymph sheath hyperplasia).
WBC neoplasia: leukemia (BM, blood) and lymphoma (LN, tissues).
Leukemia: anemia, pancytopenia, raised WBC on smear (blasts). Acute (prolif of immature stem cell aka blast in BM and blood; aggressive; bimodal;
pancytopenia eventually) and chronic (mature tumor cell in BM and blood); adults, fewer blast).
Acute leukemia: >20% blast in BM (ALL if >20% lymphoblast, AML if >20% myeloid SC). Blast: large, big nucleus, little cyto, to diff between
lympho/myeloid: lympho (stains tdt a DNA polymerase) and myeloid (stains + for MPO enzyme).
Lymphoblast will make T and B lymphoblasts, they differ by B ALL (CD 10, 19, 20; markers of B cell; types: T(12;21) children/good prog and T(9;22)
phil chromo/adult/poor prog) and T ALL (CD2-8; teen with thymic mass). Tx of ALL: chemo, child has good prog, prophylactic chemo (to BBB and
BTB).
AML: types:
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Acute promyelocytic leuk: aka M3 AML; t15:17 transloc of retinoic rec to chromo 17 > blocks WBC maturation > blasts accum; tx: ATRA (vit A
deriv that binds bad rec > maturation); cx: DIC.
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Acute monocytic leuk: blast infiltrate gum, maybe MPO -.
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Acute megakaryoblastic leuk: ass with downs (<50 yo; >5: ALL); may be MPO -.
Myelodysplastic syn: myeloid SC dysplasia, may > to AML; 3<blasts<20; die due to infect/bleed; pseudo Pelger Huet anomaly (bilobed nuclei, similar
to the one seen post chemo: Pelger Huet anomaly).
Chronic leukemia: slower, incidental find, <10% blast. Types: CML, CLL, hairy cell, adult T cell leukemia/lymphoma, mycosis fungoides.
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CLL: MC leuk, old, inc WBC/generalized lymphadeno, smear: smudge cell, express CD19 and 20, as well as CD5 on B cell (normally found on T
cell). Cx: Richter transformation (becomes aggressive diffuse large B cell lymphoma), hypogammaglobulinemia (infection MCC of demise),
AIHA (warm/cold).
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CML: mature myeloid disorder, BCR-ABL (t9;22) transloc aka phd chromo, the fusion protein is a TK signaling protein that is always turned on
and also – DNA repair; detected by FISH/karyotyping. Cx: blast crisis (BM >20% blast), becomes like acute. Tx: imatinib (gleevac; TKI, c-kit is a
TK seen in GIT stromal cancer, imatinib works for that too), hydroxyurea, IFN a.
o Leukemoid rxn: inc in immature WBC in blood due to infection, must distinguish from CML. Leuk rxn (mainly neutron, inc leuykocyte
alkaline phosphatase aka LAP an enzyme in neutrophil) while CML (mainly eosin/basophil; malig cell lost ability to make LAP so low;
phd chromo +).
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Hairy cell leuk: only one that lacks lymphadenopathy; mature B cell neo; dry tap, pancyto, splenomeg. BM: TRAP + cell (tartrate resis aid
phosphatase), fibrosis, cells with hair-like projection. Tx: purine analog (cladribine: 2-CDA and pentostatin).
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Adult T cell leuk/lymphoma: japan/Caribbean; mature T cell neo; ass w HTLV 1; tdt -, CD4+; rash, gen lymphadeno, hepatosplenomeg,
hypercal, lytic bone lesion. Tx: chemo, prog is good.
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Mycosis fungoides (cutaneous T cell lymphoma): prolif of mature CD4+ T cell, accum in skin (nodule/plaque); smear: Sezary cell (cerebriform
or brain like nuc); skin histo: pautrier microabscess.
Lymphomas:
Hodgkin vs NHL:
Hodgkins: malig cell (reed Sternberg: aka owl eyes, large B cells that has CD15 and 30, they induce inflame/fibrosis; used to differentiate types of
HL); bimodal; painless lympadeno, splenomegaly, B symptoms (generalized sym due to cytokine rel: fever/wt loss/night sweats), contiguous spread
(rare: extranodal), EBV ass; tx: radiation (staging imp), better prog.
NHL: MC, malig cell (lymphoid cells: B > T cells); late adult, painless lymphadeno, no splenomegaly, diffuse extranodal spread; leukemic phase, ass
w HIV/AI dis/chronic immunosuppression.
HL subtypes: nod sclerosing, mixed cellularity, lympho depleted, lympho predom.
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Nodular sclerosing: only one F>M; MC; collagen fibrosis around the few RSC and lacunar (RSC of NS type); mediastinal LN involvement, prx
early, no EBV ass.
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Mixed cellularity: 2nd MC; numerous RSC and inflam cell (inc eosin/plasma cell/histiocytes); mononuclear RSC, male in their 50s; EBV ass.
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Lymphocyte depleted: rare, numerous RSC but few inflam cell; male >50 yo; worst; HIV ass.
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Lympho predominant: rare; hard to see RSC (lymphohistiocytic RSC: popcorn); young male with cervical or supraclav LN.
NHL subtypes: B cell (SLL/CLL, follicular, DLBL, mantle cell, Burkitt, MALT), T cell (adult T cell, mycosis fungoides), NK (extranodal NK, blastic NK cell).
RF: hx of radiation, EBV, HTLV1, hep C, h pylori (MALT).
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Follicular lymphoma: MC; resembles GC of LN follicle; abn LN architecture (GC past cortex, nodules that contains centrocytes [small lympho
with cleaved nuc] and centroblasts [large with uncleaved]). Due to t(14;18) transloc > fuse gene that controls heavy chain prod on chr 14 to
BCL2 locus (antiapoptotic gene on chr 18) > inc BCL2. Middle age, M=F, painless/generalized lympadeno. How to differentiate from reactive
follicular hyperplasia? Reactive (polyclonal, no BCL2 in follicle, LN archi preserved, tangible mac eat bad B cell) while FL (mono, no tangible
mac).
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Diffuse large B cell lymp: common, aggressive, has diffuse sheets of large cell instead of follicles. 20% had t(14;18) mut thus FL can > DLBL.
May have abn BCL2/BCL6/MYC gene.
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Mantle cell lymp: rare, cells resemble mantle zone B lymho; mantle zone is around GC. Diffuse; cells have cleaved nuc (but no centroblasts), B
cells are immature/mut/has CD5 (thus confused with CLL but has no CD23). Ass w t(11;14): fuses IgH (chr11) to cyclin D/BCL1 (chr14) > cyclin D
(+progression of G1 to S phase).
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Burkitt lymphoma: mature B cell neo; has lymphoid sheet instead of follicles, high mitotic/apoptotic index, starry sky appearance (stars:
reactive mac and night: malig cell); t(8;14): c-myc oncogene (chr8) fuse with heavy chain Ig gene (vhr 14) > c-myc overexpression > encodes for
Ras-MAPK path > protein for cell cycle progression; has 3 types (only prx differs):
o Endemic: Africa, head/neck LN, jaw bone involved, MC child neo there; EBV ass (chronic malaria – ability to fight EBV).
o Sporadic: USA, ileocecal (distal small bowel) LN involved, EBV ass.
o Immnuodef: HIV/immunosuppressant.
Tx of lymphoma: CHOP-R: Cytoxan (cyclophosphamide), hydroxydaunorubicin (doxorubicin), oncovin (vincristine), prednisone, Rituxan (rituximab:
mab against CD20). Blocks B cell prolif. SE: immune suppression, progressive multifocal leukoencephalopathy (JC virus causing demyelination, MRI:
multiple diffuse lesion).
Rare NHL: extranodal ones: MALT lymphoma (mucosa ass lymphoid tissue found in GIT, ass w h pylori, abx against pylori causes regression) and
primary CNS lymphoma (sz/confusion, ass w AIDS, ring enhancing lesion on MRI).
Anemias: hb (<13.5 in M, <12 F, <11 in preg); S/S: pallor, syncope, HF, fatigue. RBC distribution width (RDW; variation in RBC size, so anisocytosis:
inc RDW). RBC count vs mass (count is total RBC in sample while mass is total RBC in body). Causes: membrane defect (PNH, spherocytosis), blood
loss, extrinsic hemolyisis (infection), heme def (iron def, porphyria), enzyme defect (G6PD, PK def), EPO defect (EPO def, aplastic anemia), DNA
synthesis defect (folate/B12 def), Hb defect (sickle, thal, hem C dis).
Approaching anemia: check Hb, categorize by MCV (normo, micro, macro).
Microcytic anemia: inherited (XL sideroblastic anemia and thalessemias) or acquired (iron def, ACD, lead poisoning, sideroblastic anemia:
protoporphyrin def).
Fetal erythropoesis: yolk sac (3-8wk), liver (6wk-birth), spleen (10-28wk), BM (18wk-adult). Embryo globulin (zeta and epsilon), fetal Hb
(a2gamma2), adult (a2beta2). HbF has higher O2 affinity (weak 2,3 BPG binding to take O2 from maternal hbs: HbA1 and HbA2: 2a and 2D globin).
Blood type: ABO grouping (codominance) and Rh system.
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ABO: O has no Ag on surface and makes anti-A/B Ab. A genotype (AA or AO) produces A Ag and anti-B Ab). AB has A and B Ag, no Ab.
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Rh: based on pres/absence of 5 Ag on RBC surface (D, c/C, e/E). Rh+ means they have D Ag. If RH- mom has Rh+ fetus and there is a bleed, the
blood can mix and develop anti-Rh+ Ig. Rh Ig (rhogam) can be given at 28wk and in 72hr post-delivery, to prevent maternal Ab production via
binding all Rh Ag and prevent its exposure to mom. Else if they get pregnant again with Rh+ baby, the Ab will cross placenta and destroy
baby’s RBC (Rh hemolytic disease of newborn).
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So if a primie has a baby with hemolytic dis of newborn: ABO incompatibility not Rh. O mom with A/B/AB child, self limited jaundice, tx:
phototherapy.
Structure of Hb: heme + 4 globin protein. Each protein has a heme group made of porphyrin ring holding a iron in the center, iron is what binds O2.
Myoglobin: polypeptide chain + heme; skeletal/cardiac mus, can only bind to one O2 molecule (sigmoidal not hyperbolic binding curve); lower p50
(50% saturated at lower level aka greater O2 affinity).
Heme synthesis: heme is also in catalase and cytochrome. Made in liver (by cytochrome p450) and BM. First and last 3 rxn in mito, rest in cytosol
(thus mature RBC cant make heme). Any problem in syn: inc Fe (iron cant bind heme).
1. Glycine + succinyl coA = (aminolevulinic acid synthase: RLE) = aminolevulinic acid. Enzyme defect (XL): sideroblastic anemia. Enzyme: - by B6
def, isoniazid, heme (-ve feedback), glucose (dec transcription).
2. ALA = (ALA dehydratase: - by lead: anemia and inc ALA in lead tox) = porphobilinogen = (porphobilinogen deaminase: def: acute intermittent
porphyria: AD, PBG and d-ALA accum causes myelin degen, liver toxicity, buildup in urine. S/S: abdo pain, purple urine upon standing, peri
neuropathy, mental alter. Dx: inc urine PBG/coproporphyrinogen, enzyme/gene test. Tx: high gluc in acute attack, heme arginate to resolve)
3. HMB = uroporphyrinogen III = (uroporphyrinogen decarboxylase: def: porphyria cutanea tarda: exacerbated by liver toxic things (alcohol/hep).
Tx: phlebotomy (to remove Fe/antimalarial), hydroxy/chloroquine (aggreg heme to make blood toxic to bugs, here to induce neg feedback))
4. Coproporphyrinogen III = protoporphyrin (+ Fe + ferrochelatase (- by lead) = heme.
Note: when drugs are meta by cyto P450 > inc in cyto P450 prod > heme is used > +ALA synthase activity > worsens symptom of all dis above.
Lead poisoning recap: affects ALA dehyrdratase and ferrochelatase. Inc serum protoporphyrin/Fe/ALA/ ferritin/urine lead, dec TIBC. S/S: GIT pain,
neuro sym, deposit in gum/metaphysis, basophilic stippling (lead – RNA degrad, RBC retains rRNA). Tx: chelators (succimer, penicillamine,
dimercaprol).
Iron poisoning: kids with tablet overdose. S/S: gastric bleed, N/V. Tx: chelation, dialysis, deferoxamine.
IDA: MC nutritional def, meat (Fe2+ reduced form, directly absorbed), plant (Fe3+ oxidized, must be red first), gastric acid releases Fe+ from food
(achlorhydria: absent stom acid: dec Fe), vit C (reduces Fe3+, def: dec Fe).
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Iron is abs in duodenum via metal transporter and enters blood via ferroportin. Carrier protein transferrin binds iron to deliver and store
(binds to ferritin in liver/BM). Regulated by: hepcidin: blocks ferroportin and mac (eats RBC and rel Fe). Terms: ferritin (storage), TIBC
(transferritin; inv to ferritin), % saturation (% of bound tranferritin).
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Labs: low Fe/ferritin/iron saturation, inc TIBC/FEP (free erythrocyte protoporphyrin)/RDW. Tx: tx cause, Fe sulfate, vit C.
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Order: low storage > low serum > normocytic anemia > chronic (microcytic hypochromic anemia).
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Causes: physio (preg, lactation, breastmilk only) or patho (bleeding, meckels in kid, colon ca, GIT, hookworms). S/S: glossitis, pica, plummer
vinson syn (IDA, esophageal web, glossitis), koilonychia.
Sideroblastic anemia: defective heme syn > Fe cant be incorp > iron accum in periphery (sideroblasts: stains with Prussian). Inc ferritin/iron sat/Fe,
dec TIBC. Causes: XLR defect in ALA synthase gene, alcoholism, vit B6 pyridoxine def (heme syn cofactor), lead poison, Cu def. Tx: vit B6,
transfusion.
Inherited microcytic anemia: thalassemia and ACD.
ACD: MC in hospitalized pt; during infection, body takes Fe away from bac via cytokine (IL6: + liver to rel hepcidin, bac LPS also + it) > blocks
ferroportin and Fe rel from mac > if prolonged (chronic ill) pseudo iron def (BM doesn’t get Fe despite it being available). Labs: inc ferritin/FEP, dec
TIBC. Tx: cause.
Thalessemias: AR, defective globin (a and B) production. When one grp is dec, the other inc. Body compensate for dysfxn RBC by pushing out
immature RBC (n/inc RBC).
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A thal: 4 genes encode (2 on each chromo 16) to make a globin. One gene deletion (asym), 2 (a thal trait: 2 forms: cis deletion of both a gene
on same chromo seen in south asian, more severe, spontaneous abortion; trans del of 1 a gene on each chromo 16 copy seen in African), 3
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(severe anemia, when HbF disappears B chain aggreg to form HbH tetramer to compensate; fetal time is ok), 4 (hydrops, gamma chain
tetramers: Hb Barts).
B thal: 2 genes, one on each copy of chr 11 makes B globin. Mediterranean/African; protective against malaria; point mut in splice site and
promoter seq > dec B globin > imbalance cause cessation of HbA1 and aggreg of a-globin chain inside RBC and inc in HbF. Findings: BM
expansion, extramedullary hematopoiesis (crew cut skull xray, chipmunk face, hepatosplenomegaly), absent HbA1, inc HbA2 and HbF, inc
unconjug bili (jaundice), risk of aplastic crisis with parvovirus inf (further dec RBC prod).
o B thal trait: 1 gene defective; mild microcytic anemia, inc RBC count, target cells: a globin aggreg. Tx: none req, monitor Fe (intestinal
absorp inc).
o B thal major: mut in both globin chain; a chain tetramize (unsoluble unlike B tetramer and destroys RBC). RBC prod by extramed
hemato > dysmorphic thus destroyed > severe hemolytic anemia + inc Fe absorp (intest) = iron overload. Tx: lifelong transfusion,
iron chelator, splenectomy (slow hemolysis), BM trans.
Normocytic anemias: non-hemolytic (no reticulocytes; eg: early ACD/IDA, CKD, aplastic anemia) and hemolytic (reticulocyte: compensatory).
Aplastic anemia: fatty infil/dry tap (BM), pancytopenia. Labs: dec everything, inc EPO. DDx: pure red blood aplasia: loss of RBC, ass w. thymomas.
Causes: drugs (chloramphenicol, alkal chemo, anti malaria, sulfon, benzene, DDT insecticide), infection (parvo, EBV, HIV, hep), radiation, Fanconi
anemia (inherited DNA repair defect with inc leukemia risk. S/S: short, café au lait, thumb/radial defect). Tx: immunosuppressant, BM stimulant
(GM-CSF).
CKD anemia: dec EPO > anemia, burr cell on smear (aka echinocytes: membrane projection seen in metabolic/pH changes), plt aggreg defect
(thrombocytopenia, prolonged BT; reversible with dialysis).
Myeolphthistic process: any patho that replaces BM > pancytopenia.
Hemolytic anemias: inc bili/LDH; intravascular hemolysis (dec haptoglobin, hemoglobinemia, hemoglobinuria, hemosiderinuria follows) and
extravascular (spleen/LN mac recycles RBC). Haptoglobin is what recycles RBC intravascularly but is limited > excess Hb and iron (hemosiderin) >
urine.
Extrinsic hemolytic anemia: infect (babesia, malaria), microangiopathic (DIC, TTP/HUS, SLE, malig HTN), macroangiopathic (calcifiec/mech valve).
You see shistocytes in the later 2.
AI hemolytic anemia: Ab against RBC, type 2 hypersen. Types: IgG (attacks/aggreg RBC at body temp, aka warm agluttinin; ass w.: SLE, CLL, PCN,
ametyldopa), IgM (works best at cold temp, aka cold aglut, more acute course, S/S: painful digits in cold; ass w: EBV, M. pneu).
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Dx: coombs test. Direct (aka DAT, we add anti IgG to pt’s RBC, if + pt’s RBC should be attached to IgG to which the anti IgG will bind to >
agglutination/+ result; for pt with cold type: we use anti C3) or indirect (add pt’s serum which has Ab and add/let it attack donor blood > then
add anti IgG/C3).
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Tx: glucocorticoid, immunosuppressant, IVIG, folate (to – def due to inc RBC turnover), rituximab (destroys B cell > - Ab prod), keep warm.
Intrinsic hemolytic anemia:

Here. Spherocytosis: AD, mut in gene for mem protein (spectrin, ankyrin, band 3.1), RBC lack central pallor and gets lysed/removed easily >
splenomegaly. Dx: osmolarity fragility test (hypotonic sol > lyse). Tx: Fe, folate, splenectomy, transfusion.
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Here. Elliptocytosis: AD spectrin/band 4.1 defect. Milder, same S/S. Smear: elliptocytes. Tx: splenectomy.
Howell Jolly bodies: nuclei aggregates (Heinz is Hb aggreg). Indicates: splenectomy/spleen dysfxn.
Paroxysmal nocturnal hemoglobinuria: acquired intrinsic RBC surface protein (GPI) defect, mut in stem cell. Surface protein: prevents body from
attacking RBC, are GPI linkages which helps to bind CD55 (decay accelerating factor, - C3 convertase) and CD59 (protectin/MIRL, binds C9/MAC).

Why paroxysmal? Attacks during night (resp acidotic state). S/S: red urine. Dx: sucrose lysis test, flow cyto (absent CD55/59 on RBC). Cx:
thrombotic event (due to complement activation), aplastic anemia/AML (plt and granulocyte eventually becomes affected). Tx: eculizumab (C5
inhib, SE: Neisseria).
G6PD def: XLR, G6PD is 1st step in hmp shunt which makes nucleotide, step itself makes NADPH which restored glutathione that reduces ROS to
H2O protecting RBCs. No G6PD > oxidative stress (infec, sulf drug, anti malarial, fava beans) > hemolysis (Heinz body and bite cells: formed when
mac tries to clear Heinz). MC in Africa/Mediterranean. Protects against malaria.
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S/S: hemoglobinuria, back pain (Hb is nephrotoxic), asym, hx of neonatal jaundice/cholelithiasis, episodic anemia symp (+/- splenomegaly). Dx:
Heinz body preparation, enzymatic study post acute phase (when RBCs are not already dead).
Pyruvate kinase def: AR, chronic lack of ATP in RBC due to impaired glycolysis (sole source of ATP). S/S: baby with: jaundice, anemia, high 2,3 BPG,
low PK activity.
HbC dis: AR, lysine replaces glutamic acid at 6 position on B chain. African/meditt, hetero are asym, homo have mild anemia. HbA1 cant form, HbC
forms (crystallizes). If HbA and HbC + > HbC trait.
HbS (sickle cell dis): AR, glutamic acid to valine at 6 position. HbS polymerizes (esp at low O2) > sickling. Hetero (asym, little sickling, painless
hematuria as medulla has low O2) and hetero (vasoocclusion). Exacerbated by: low O2/pH or high PCO2/2,3BPG in RBC.

Dx: sodium metabisulfite (screening) > electrophoresis (to distinguish between trait) > if homo (inc HbS and no HbA).

S/S: HbF masks dis early on, vasooclusive crises: dactylitis, AVN of femur, priapism, autosplenectomy with inc risk of encap infection esp
salmonella osteomyelitis, acute chest syn (MCC of mortality), renal pap nec (hematuria and proteinuria), extramed hematopoiesis
(hepatomegaly, in skull/face bones: chipmunk face and crewcut xray).

Tx: O2, hydration, exchange transfusion, prophy abx after birth screening, vaccination, hydroxyurea (inc HbF), gardos channel blocker (dec K
efflux > dec RBD dehydration by – Ca activated K channel), allogenic SC transplant.
HbSC dis: combination of the 2. Moderate severity.
Note: if you see electrophoresis, its either thalassemia or HbS/C dis. Microcytic > thal, no anemia > SC trait, normocytic anemia > SC dis. Thal B
major and SC dis has no HbA.
Macrocytic anemias: due to DNA syn disruption (B12/folate def, folate -ing drugs, orotic aciduria; cant mitosis w/o DNA > arrested in G phase >
cant mature > macrocytic megaloblastic anemia with hyperseg neutrophils) or alcoholism, liver dis/hypothyroidism (inc chol/phospholipid
deposition), diamond blackfan.

Folate/B12 def: inc homocysteine, tx: folate/B12. B12 def: inc methylmalonic acid.

Diamond blackfan anemia: rapid onset anemia, 1st year, defect in progenitor cell > dec Hb > inc HbF (compensate). S/S: MSK abn,
triphalangeal thumbs.

Orotic aciduria: AR, megaloblastic anemia unresponsive to fol/B12 in child: FTT, dev delay. Defective pyrimidine synthesis (defective UMP
synthase) > cant convert orotic acid to UMP > orotic acid accum. Dx: urine orotic acid (no hyperammonemia as in ornithine transcarbamylase
def). Tx: UMP.
Hemostasis: clots form by primary hemo (plt makes plug draped with fibrinogen) and sec hemo (clotting factors convert fibrinogen to fibrin and
stabilizes plug).

Plt: has surface glycoprotein (for activation, adhesion and aggreg), dense granules (contains serotonin, ADP, Ca), A granules (vWF, fibrinogen,
fibronectin) and membrane (makes thromboxane A2). Life is 7-10 d, 1/3 are stored in spleen, count 150-400K/mm3, controlled by
thrombopoetin (kidney/liver).

Intact endothelium makes VD (NO, PGI2, ADPase: to break down ADP) > - plt +/aggregation. Endothelial injury > releases endothelin (potent
VC) and exposes vWF/collagen to the outside > + clot signal.

vWF (in plasma bound to factor 8, in endothelium’s weibel palade bodies which plays a role in hemo and inflammation since it has P selectin
and in plt) > binds collagen > plt binds exposed vWF by glycoprotein Ib > plt undergoes conformational change > release granules > aggreg.

Dense granules: releases serotonin (VC), ADP (helps plt adhere to endo by putting out GpIIb/IIIa which binds fibrinogen), Ca (for 2nd hemo).

A granules: release more vWF and fibrinogen.

Membrane: makes thromboxane A2 (thromboxane synthase) and puts out GpIIb/IIIa (like dense) which binds fibrinogen > plug.
Anti-plt:

Aspirin: NSAID, irreversibly – COX1/2 (prevents conversion of arachidonic acid to PG/TXA2) > analgesia, anti inflam, dec plt aggreg. SE: gastric
ulcer/bleed, renal tox, reyes syn, central effects of metabolic toxicity (tinnitus, hyperventilation).

Clopidogrel: thienopyridine derivative, irreversibly – ADP rec > cant express GpIIb/IIIa. Other ADP rec -or: prasugel, ticlopidine (reversible, ass
w neutropenia and thrombocytopenia). Uses: post MI/cardiac surgery. SE: bleed.

Phosphodiesterase inhibitors (cilostazol, dipyridamole): inc cAMP in plt > - aggreg and causes VD. Use: intermittent claudication, stroke/TIA
prevention, angina. SE: N/H, hypotension, flushing, abd pain.

ABCiximab and Eptifibatide and tirofiban: - plt aggreg by binding GpIIB/IIIa on plt. Use: anticoag in ACS and to prevent restenosis. SE: GI bleed,
thrombocytopenia.
Plt disorder: test for plt fxn: BT (plt fxn) and risocetin assay (vWF fxn; causes plt aggreg if vWF is normal). Thrombocytopenia (aplastic anemia, RF)
or thrombocytosis (polycythemia, essential thrombocytosis). Prolonged BT: aspirin (normal count), RF/uremia (toxin destroys plt, tx: desmopressin
(+ vWF rel from weibel) and dialysis can reverse it) and thrombocytopenia.

Bernard soulier syn: plt lack GpIb rec > no adhesion, large short lived plt, prolonged BT, thrombocytopenia, inc megakaryocytes, abn risocetin
(not corrected by adding normal plasma).

Glanzmann dis: AR, plt lacks GpIb/IIIa rec > no aggreg, prolonged BT, normal risocetin, similar to ABCiximab.
Immune causes of thrombocytopenia:

Drug induced thrombocytopenia: heparin, quinidine, sulfonamide. Heparin (post 5-14 d) bind plt factor 4 > forms hapten (molecule that illicits
immune response) > body makes IgG against heparin-plt fac 4 complex that also + plt > plt are consumed (thrombi forms) >
thrombocytopenia, PBT, thrombi. Tx: stop hep, give anticoag (not warfarin: inc risk of skin necrosis).

Thrombotic thrombocytopenic purpura: consumptive thrombocytopenia > widespread microthrombi > plt used up. ADAMTS-13 enzyme
regulated vWF, def or AI mediated inhibition of it > accum of vWF and prothrombic environment at capillary > microangiopathic hemolytic
anemia (inc LHD and shisto). S/S: H, fever, purpura, RF, transient neuro deficit. Tx: plasmapheresis, steroids, immunosuppressants.


Immune thrombocytopenic purpura: child, post virus, body makes IgG against GpIIb/IIIa > spleen removes these plt > thrombocytopenia, inc
megakaryocytes. Chronic seen in adult women, child may have thrombocytopenia in newborn if preg. Tx: self lim, steroid, severe:
splenectomy.
Hemolytic uremic syn: child post E.coli O517:H7, shigella, or campylobacter. Toxin > bloacks ADAMTS13 and dmg endothelium > microthrombi
form > uses up plt . S/S: like TTP but bloody diarrhea, shisto, purpura, RF (oligouria). Tx: supportive.
Secondary hemostasis: with help of coagulation fac which can be + intrinsically or extrinsically, which converges into the common pathway to
convert fibrinogen to fibrin.

Common pathway: + of fac X > fac X and V turn prothrombin (II) to thrombin (IIa) > thrombin: turns fibrinogen (I) into fibrin (Ia), + fac V, VIII,
XIII (stabilizes fibrin).

Extrinsic pathway: dmg > tissue fac and fac III is rel > fac VII and tissue fac complex forms with Ca’s help > complex with Ca in turn acts on fac X
to form > activated Xa > converges into common pathway.

Intrinsic pathway: exposed collaged > fac XII autoactivates facilitated by also kininogen and prekallikrien > fac XIIa + coag and anti coag
cascade > coag cascade: XII > IX > IXa, fac VIII, Ca and plt phospholipis forms complex > + X (common pathway).
Clot degradation (fibrinolytics): urokinase/tPA + plasminogen > plasmin > degrades plasmin and coag fac (V, VIII) and cleaves fibrin > forming D
dimer (fibrin fragments). Regulated: activators: fac XII and kinin system (kallikrein).
Other system that regulate clot formation: Protein C (inhib cofactors and fac V & VIII > dec thrombin, activated by thrombomodulin which is
thrombin attached to endo mem), protein S (cofactor of pro C) and antithrombin III (- serine proteases: fac IIa, VIIa, IXa, Xa, XIa, XIIa and kallikrein;
main anticoag effect: due to – of fac IIa and Xa).
Coagulation fac: made/removed by liver; fac 2/7/9/10/pro C/S need vit K to be + by y-glutamyl carboxylase; liver renew vit K by epoxide reductase.
Plt granule rel Ca that is needed by these factors.
Clotting fac disorder: bleeding. Plt dis: no initial plug > early/superficial bleed (petechia, epistaxis, intracranial bleed). Coag fac dis: can form plug >
late and deep bleed (muscle/joint bleed, rebleed post-op).

How to test? BT for plt, risocetin for vWF, coagulation has paths: partial thromboplastin time PTT (intrinsic path: fac VIII, IX, I, XI, XII),
prothrombin time PT (extrinsic: fac VII) and INR (standardized PT test: 1=n, >1= prolonged).

Dec coag fac: liver dis or vit K def. Liver dis: dec all coag facs > elevated PT/PTT, dec thrombopoetin, inc spleen plt sequestering > inc BT; also
destroys epoxide reductase > no vit K. Vit K def: dec fac II, VII, IX, X, C, S > inc in PT/PTT; due to: malab, bowel dis, pancreatic insuff, prolonged
abx, breastmilk only (newborn also lack bac).

Why does large volume transfusion lead to 2ndary coag problems? Bec it dilutes coag fac. Tx: coag fac.
Heparin: natural polysac; IV/subQ; binds/+ AT III to inc its protease activity against fac II and X; fast acting, short t1/2, used as post op prophy or
acute setting (PE), doesn’t cross placenta, monitor by PTT (fac X). SE: bleed, thrombocytopenia, osteoporosis; reversed by: protamine sulfate. C/I:
bleed, aortic dis.

LMWH: enoxaparin, dalteparin, fondaparin. Binds fac X more strongly and fac II less strongly than hep. Don’t need monitoring (out pt use), not
reversible.
Direct Xa inhibitor: apixaban, rivaroxaban.
Direct thrombin inhibitors: argatroban, jdabigatran, bivalirudin, lepirudin. Fun fact: hirudin is a leach anticoagulant. Used: hep allergic pt. SE: bleed,
no reversal (try prothrombin or antifibrinolytic like tranexamic acid).
Warfarin: oral, long t1/2, - prod of vit k dependent fac and epoxide reductase. Crosses placenta, teratogenic, monitored by PT (fac VII), reversed by
FPP (contains factors) and vit K. Pt are given hep first then warfarin for chronic use. Metabolism is affected in VKKORC1 (vit K epoxide reductase
complex) gene polymorphism. SE: warfarin skin necrosis (pro C/S have shorter t1/2 than the rest so when all vit K fac (2,7,9,10,C,S) is blocked >
2,7,9,10 have little to regulate clot > early hypercoag > thrombi > necrosis. Avoid by heparin bridging. Reversal: stop warfarin, give protein C.
Thrombolytics: alteplase (tPA), reteplase (rPA), streptokinase, tenecteplase (TNK-tPA). Converts plasminogen to plasmin; elevated PT/PTT. SE:
bleed. Reversal: aminocaproic acid (- fibrinolysis).
Coagulation fac def: hemophilia: defect in intrinsic path. A & B are XLR, C is AR. Cx: acute hemarthrosis and chronic joint dmg (bleeding > chronic
inflame as blood protease dmg cartilage and hemosiderin accum). Types:

Hemophilia A: dec fac VIII; lab: inc PTT only, dx confirmed by: clotting fac assay for fac VIII. Tx: desmopressin acetate (inc vWF rel from weibel
palade > complex stabilizes VIII), fac VIII infusion (severe).

Hemophilia B (dec fac IX) and hemophilia C (dec fac XI): inc PTT, dx: slotting fac assy for def fac, tx: fac replacement (severe).
Coagulation fac inhibitor dis: pt develops auto-ab against coag fac (esp fac VIII); similar to hemo A, diff by mixing pt plasma with normal plasma > in
hem A PTT will dec, in caog fac inhib dis ab will destroy new fac VIII (no dec in PTT/clot).
vWF dis: AD coag disorder, def vWF > dec fac VIII > combined plt and coag fac disorder (problem in prim and sec hemostasis). Inc BT/PTT, abn
risocetin (normalized with normal plasma as it has vWF or desmopressin). S/S: mainly prim hemo symptoms: mucosal/superficial bleed.
DIC: large no of intravascular thrombi > depletes plt and coag fac. Has 2 stages:

First, prothrombic stage (systemic inflam eg sepsis > large rel of TF > large amount of thrombin > initiates clotting cascade > plt, fibrin, and
coag fac (esp V and VIII) depletion and end organ dmg (clots). BV narrows > shistocytes > hemolytic anemia.

Prohemorrhagic stage: body responds to clot > inc fibrinolysis > plasmin degrades microthrombi (cleaves fibrin > d dimer) > hemorrhage/shock
(pt bleeds everywhere: mucosa, petechia, epistaxis, IH, IV line).

Causes: sepsis (N men, E coli; endotoxin dmg vessels), trauma (rel of procoagulants), obstetric cx (retained fetus, AFE, abruption all > inflame
and pro coagulation, amniotic fluid rel thromboplastin which is similar to TF), pancreatitis (enzyme dmg vessel), malig (AML > rel TF, adenocar
> rel mucin which + coagulation), transfusion, nephrotic syn (due to coag fac loss), rattlesnake (venom is pro coagulant).

Lab: inc BT/PT/PTT/d dimer, low fibrinogen, dec factor (esp V and VIII), shistocyte/inc LDH.

Tx: stabilize, tx underlying, FPP, plt, cryoprecipitate; basically replenish factors.
Blood transfusion therapy: packed rbc (blood loss, severe anemia), plt (to stop bleed due to thrombocytopenia/plt defect), coag fac (FFP: DIC,
warfarin reversal, has most fac; cryoprecipitate: tons of fac VIII and fibrinogen). Risk: infec, trans rxn, iron overload, hypocal (blood pack has citrate
that chelates Ca), hyperkalemia.
Hyperactive plasmin: Urokinase/tPA/streptokinase > converts plasminogen to plasmin > plasmin degrades: fibrin/clot > then fibrinogen > then coag
fac > ultimately: prevents clot formation. Plasmin is inactivated by a-2-antiplasmin. Seen in: radical prostatectomy (rel urokinase), liver dis (dec a-2antiplasmin).

Labs: inc BT (due to dec in fibrinogen > dec plt aggreg)/PT/PTT, normal plt count (unlike DIC). Low d dimer (initially inc). Tx: aminocaproic acid
(- plasminogen activation).
Hereditary thrombosis syn: dis that causes hypercoagubility (fac V leiden, protein C/S def, ATIII def, prothrombin gene mutation). S/S: young pt
with multiple preg loss/DVT/PE.
Factor V leiden: MC, mut in fac V (missense near cleavage > G base to A base > arginine to glutamine at 506 or 534 position) > resistant to
degradation by active pro C > inc fac Va and thrombin. S/S: white, <45 yo, hx of thrombotic events.
Protein C/S def: activated C > - fac Va and VIIIa > - clot form, so w/o C > thrombosis. C def: heterozygous (homo dies), serious, ass w warfarin skin
nec, tx with anticoagulant (heparin then low dose warfarin and titrate up). Dx: check pro C/S level.
Antithrombin III def: ATIII – coag fac (esp fac IIa and Xa). Heparin inc inhibitory affect of ATIII > pt’s PTT will not inc much after heparin in ATIII def.
Thus higher heparin doses will be required. Can be caused by nephrotic syn (antithrombin lost). Severe prothrombotic dis that requires lifelong
anticoag.
Prothrombin gene mut: prothrombin gene mut (point mut in 3’ untranslated region 20210A) > inc expression.
Note: why are OCP ass w hypercoag state? Estrogen inc production of coag fac, so in pt with hx of thromboemboli, avoid the pill.
Oncology pharmacology:
Antimetabolites: drug that interfere with DNA syn. Includes: MTX, hydroxyurea, pyrimidine analogs (cytarabine, 5-fu), purine analogs (6
mercaptopurine, azathioprine, cladribine: tx of hairy cell leuk, 6-thioguanine).

6 mercaptopurine/azathioprine: 6MP is an adenine analog that – enzyme of purine syn during S phase; must be converted to HGPRT
(hypoxanthine-guanine-phosphoribosyltransferase). Azathioprine is a 6MP prodrug that needs to be metabolized to turn into 6MP. SE: BM
supp, GIT mucositis, liver dmg. Metabolized by XO, may lead to inc toxicity in pt taking allopurinol.

6 thioguanine: guanine anolog, similar to 6MP (effect and SE), metabolized by thiopurine methyltransferase, safe to give with allopurinol.

Cytarabine: deoxycytidine analog, uses: acute leuk, induction tx of lymphomas, SE: BM supp, pancytopenia.



MTX: anti folate, = dihydrofolate reductase > - folate regeneration needed for DNA syn. Uses: anticancer, immunosuppressant, abortant. SE:
BM supp, liver tox, pulmonary fibrosis, mucositis (oral ulcer); SE dec with leucovorin (folic acid derivative).
5 fluorouracil: pyrimid analog that acts on S phase. Once activated, - thymidylate synthase > - thymidine production. SE: leucovorin may inc its
effect!
Hydroxyurea: S phase drug that – DNA syn by – ribonucleotide reductase > - conversion of ribonucleotides to deoxyribonucleotides. Also acts
by inc HbF level.
Topoisomerase inhibitors: - unwinding of DNA during replication, includes:

Irinotecan/topotecan: - topoisomerase I > - DNA unwinding and replic.

Etoposide/teniposide: podophyllotoxin chemo; - topo II > inc DNA degrad. Topo I unwinds DNA while II relieves tension and prevents degrad.
Anticancer abx: affects bacterial and human DNA. Includes:

Bleomycin: G2 drug, mixture of glycoprotein that makes free rads once binding to DNA destroying it > cell death. SE: minimal BM supp, skin
changes (alopecia, ulcer, hyperpig), pulmonary fibrosis (mortal, monitor PFT).

Dactinomycin (actinomycin D): abx that – RNA polymerase. Fungal toxin a-amantinin works similarly. SE: BM supp, GIT mucositis.

Doxorubicin/daunorubicin: integrates itself into DNA and makes free rad, can also affect topo II. SE: red urine, cardiotox (DCM due to free rad,
Fe chelators: defriprone/dexrazoxane prevent it).
Microtubule inhibitors: microtubule pulls chromo in M phase, this drug acts by – prod or breakdown (cant progress to next phase). Vinca alkaloids
vincristine/vinblastine bind b tubulin > - microtub prod, arresting cell in M phase. Paclitaxel - its breakdown > cant progress to anaphase. SE:
peripheral neuropathy, constipation (vinca).
Alkylating agents: bind (O6 or N7 position of guanine) and crosslink DNA, non cell cycle specific. Includes:

Busulfan: SE pulm fibrosis

Cyclophosphamide/ifosfamide: prodrug activ by liver, N7, SE: hemorrhagic cystitis (prevented by MESNA and N acetylcysteine, both binds
acrolein the main toxin).

Nitrosureas (-mustine, streptozocin): lipophilic, can cross BBB (used for brain tumor), SE: CNS tox (sz, ataxia, N/V).

Platinum agent (cisplatin/carboplatin): SE neuropathy, ototox, nephrotox. Prevent with amifostine (dec free rad) and fluid (diuresis).
Misc agent: growth fac inhibitor:

Bevacizumab: - VEGF, SE: bleeding, clot, impaired healing.

Erlotinib: - EGFR (epidermal GF rec; eg Her2/neu, mab that – Her2/neu is trastuzumab: SE cardiotox) tyrosine kinase, used in lung cancer, not a
mab (cetuximab: mab that – EGFR).