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RBC, WBC disorders

thalassemia

microcytic anemia (Cooley = homozygous)
etio: congen vHb a/B chain synth rate
-a = insuff a chain -> B4 tetramers
-B = insuff B chain -> a4 tetramers

normal Hb synthesis: chains

y = most active in infancy -> HbF
B = most active in adult -> HbA
d = made by infants + adults -> HbA2

B-thalassemia

vB chain -> a4 tetramers accum:
-heterozygote: mild anemia, HbA2>3.5%
-homozyote: Cooley anemia, intramedullary hemolysis, crew cut sign, splenomeg, 2o hemochromatosis, HbF>30%

B-thalassemia Hb electrophoresis: heterozyogote (HbA2>3.5%)

B-thalassemia crew cut

B-thalassemia blood smears

a-thalassemia: genetics

1 gene mut -> silent carrier: no anemia
2 gene mut -> a-thal trait: mild anemia
3 gene mut -> Hb H dx (B4): mod anemia
4 gene mut -> Hb Barts dx (y4): severe anemia

microcytic anemia: common etio

Fe2+ deficiency
anemia of chronic dx: impaired Fe2+ release
thalassemia: B type > a type

macrocytic anemia: common etio

Vit B12 (cobalamin) >> FA (Vit B9) def
--| thymidine synth delay/--| erythroblast div

Vit B12 (cobalamin) def

etio: vIntake, vAbs -pernicious anemia, ^use
takes 3-6y for onset of Sx
Px: --| thymidine synth
-> delay/no erythroblast div, v myelin synth
Sx: macrocytic anemia, neuro Sx

Vit B12 deficiency: serum

v VitB12 (50% will be normal)
^methylmalonic acid
^homocysteine
macro-ovalocytes, hyperseg PMN

Vit B12 deficiency: imaging

Vit B12 deficiency: histo

macro-ovalocyte
hypersegmented PMN: 6+
megaloblastic erythroblasts in BM

pernicious anemia

autoi2 Ab *gastric parietal cells
-> lower IF -> no IF-Vit B12 complex
-> no Vit B12 abs
-> macrocytic anemia

etio: tapeworm i2

FA (Vit B9) deficiency

etio: v intake, abs @jej, phenytoin, ^use
takes 1-6mo to see Sx
Sx: VitB12 def-like, NO NEURO Sx, NT defect
serum: vFA serum + RBC, ^homocysteine

hemolysis: lab pathway

hemolysis: 2 basic signatures

1: BM compensation: reticulocytosis
2: ^LDH1, 2 + Hb (and ^bili) in serum

what is intravascular hemolysis?

occurs in circulation
how: free Hb binds +Haptoglobin -> clear *liver
dx: vHaptoglobin, Hb in serum + urine

what is extravascular hemolysis?

occurs in spleen
how: Hb phagocytosed *resident MF
-> unconj bili +Alb ->liver: conj bili ->biliary exc
dx: normal Haptoglobin, no Hb in serum or urine

how to distinguish between intravascular and extravascular hemolysis by labs?

intravascular: vHaptoglobin, free Hb *serum, UA
extravascular: ok Haptoglobin, no free Hb

hemolysis: intrinsic causes

mut Hb: SCD, thalassemia
mut RBC memb: hered spherocytosis, HPN
mut enz: G6PDH deficiency

SCD: sickle cell disease

etio: 6Glu->Val on Hb B chain -> HbS 85-90%
crisis: HbS precip (when de-O2)
Sx: splenic trapping, microvascular occlusion, abd/extremity pain, hemolysis
trait: hetero HbA + HbS

hereditary spherocytosis

mut RBC memb: ankyrin >spectrin, band 3
AD 75%
Sx: spherocytes, splenomegaly, cholelithiasis, extravasc hemolysis, macrocytic anemia, ^osmotic fragility to low ionic strength
Tx: splenectomy

hereditary spherocytosis: proteins

transmemb prot: band 3
x-linking prot: ankyrin (of spectrin + band 3)
intracellular prot: spectrin

hereditary spherocytosis: smear

spherocytes

PNH: paroxysmal nocturnal hemoglobinuria

etio: acq mut GPI-link glycoprot: PI glycan A
-> no CD55/DAF, CD59/ C3 convertase inhib
-> depo MAC + C3b
-> HSC derivatives opsonized + phagocytosed
= complement-mediated hemolytic anemia

PNH: labs + Sx

RBC: no CD55, CD59 - none on flow cytometry
normocytic anemia
vFe2+, hemosiderinuria
hematuria 25% intermittent
VTE 50% fatal: cerebral, portal
may tx -> AML

normocytic anemia: etio

aplastic anemia
pure RBC anemia
paroxysmal nocturnal hemoglobinuria

G6PDH deficiency: enzymes

part of PPP

G6PDH deficiency: epidemiology

X-linked recessive
Kurdish Jews, West Africans
^ risk oxidative stress-> precip Hb: Heinz body
rf: oxidizers (dapsone, chloroquine), fava beans
-> intravascular hemolysis

G6PDH deficiency: histo

what is a Heinz body?

precipitated Hb
-due to oxidative damage of Hb in G6PDH def

warm autoi2 hemolytic anemia

extravasc hemolysis
IgG *RBC Ag (ie Rh) -> spleen MF FcR
labs: + direct Coombs a-IgG, a-C3b 70%
smear: spherocytes
tx: prednisone 2/3, splenectomy 1/3

warm autoi2 hemolytic anemia: smear

spherocytes (like hereditary spherocytosis)

what causes RBC spherocytes?

1 warm autoi2 hemolytic anemia: IgG *RBC Ag
2 heredit spherocytosis: ankyrin mut...

cold autoi2 hemolytic anemia

intravasc + extravasc hemolysis
etio:idio, nHL, mycoplasma, EBV
IgM *RBC Ag -> spleen MF C3bR, RBC agg
bind @0-4C
labs: direct Coombs +Cb3-RBC, agg titer

what are schistocytes and what causes them?

fragmented RBC
etio: hemolytic trama = macro/microangioPx
-DIC, TTP

trauma: macroangioPx - hemolytic anemia

#1 cause traumatic hemolytic anemia
Px: RBC fragmentation in capillaries
smear: schistocytes
etio: DIC: fibrin strands, TTP: vWF strands, malig HTN, vasculitis, meta Ca

trauma: microangioPx - hemolytic anemia

causes: traumatic hemolytic anemia
etio: defective heart valves
smear: schistocytes

blood loss anemia

acute: fluid shift slow -> no immediate ΔHb, hypovolemic shock, slow RBC mass recov

chronic: anemia if v[Fe2+] -> Fe2+ def anemia

erythrocytosis/polycythemia

^RBC mass: M: Hct >54%, F: Hct >47%
hyperviscosity synd: vBF when Hct >60%
relative etio (common): vH2O, tobacco smoke
absolute etio: ^RBC mass, PV, v/^Epo

hyperviscosity syndrome

vBF when Hct>60%
Sx: visual, neuro
dx: PCV, Waldenstrom macroGbemia

neutropenia

ANC <1.8K/uL
suppressed HSC/ committed precursors
Rx: alkylating agent, antimetab, aminopyrine, sulfonamides, chlorpromazine, chloramphenicol, phenylbutazone, thiouracil
neoplasia: large granular lymphocytic leukemia
congenital
ineffective hematopoiesis/MDS
^destruction/use: i2, splenic seq, ^margination

agranulocytopenia

ANC <500/uL
#1 etio: Rx
-dose dept: alkylating agents, antimetabolites
-idiosyncratic: chloramphenicol, aminopyrine, sulfonamides, chlorpromazine, phenylbutazone, thiouracil

neutrophilia

ANC >7K/uL
^granulopoiesis: i2, neoplasia, drugs (G-CSF)
^release from BM: i2, hypoxia
v margination: exercise, catecholamines
^ extravasation: GC, i2

neutrophilia: smear

congenital neutrophil disorders

LAD1, LAD2, CGD (x-linked, AR), MPO def, Chediak-Higashi syndrom

LAD1

defect: B-chain of Cd11/18 integrins
-> no ^aff binding of PMN @site i2

LAD2

defect: fucosyl transferase -> mut selectin ligand
-> no rolling adhesion @site i2: selectin + ligand

CGD

v Oxidative burst: NADPH oxidase
-memb (X-linked)
-cyto (AR)

MPO deficiency

defective MPO-H2O2 system: v microbicide

Chediak-Higashi syndrome

mut LYST: lysosomal mt polymerization
-> no phagocytosis by WBC

acquired neutrophil disorders

DM, malignancy, sepsis, dialysis: adh/chemotax
leukemia, anemia, sepsis, DM, malnut: phag

eosinophlia

allergy
parasite
peripheral T-cell lymphoma

basophilia

CML
allergy

monocytosis

chronic i2, ie IBD
collagen vasc dx: SLE

lymphocytosis

>4K/uL adults
>7K/uL ped
>9K/uL infants

etio: viral, acute/chronic bacterial, proliferative

atypical lymphocytes

viral i2, CD8+ T cells, skirting cytoplasm
seen in i2 mononucleosis +EBV

lymphocyte: blast v atypical

lymphocytopenia

ANC<1.5K/uL adults
<3K/uL ped

v pdt: congen/acq, HL
^ destruction: chemo/rad, steroids, ACTH, AIDS
^loss: lymph dx, prot losing enteroPx, Whipple dx, ^central venous P

LN hyperplasia: patterns

1 follicular
2 paracortical/interfollicular
3 sinus histiocytosis
4 mixed pattern

follicular hyperplasia

2o follicles:^# + size
etio: i2, RA, Rx, AIDS
ddx: follicular lymphoma

follicular hyperplasia: biopsy

compare follicular hyperplasia v follicular lymphoma

follicular hyperplasia: no Bcl2
follicular lymphoma: ^Bcl2 due to t(8;14)

paracortical/interfollicular hyperplasia

Px: paracortex expands by heterogenous pop
etio: viral i2, SLE, Rx ADR

paracortical/interfollicular hyperplasia: biopsy

sinus histiocytosis

^MF in sinuses
LN: neck, axillay
etio: i2, cancer drainage

mixed cell hyperplasia

toxoplasmosis: follicular hyperplasia +
granuloma + sinusoidal dilation

neoplasia: all myeloid + lymphoid

neoplasia: division of myleoid v lymphoid

myeloproliferative neoplasms

CML: chronic myeloid leukemia
PCV: polycythemia vera
PMF: 1o myelofibrosis
ET: essential thrombocytosis
mastocytosis

myeloproliferative neoplasia: histo

myeloproliferative: compare

CML

Bcr-Abl: t(9;22)(q34;q11) 90% Philadelphia prot
-> Ras, Jak/STAT, Akt constit ON
20% all leukemia; mid-elderly
tx: Imatinib/Gleevec

CML: histo

what 2 myeloproliferative diseases are definitively diagnosed by cytogenetics?

CML: Bcr-Abl
PCV: JAK2

BCR-Abl rearrangement: Philadelphia protein = P210 fusion prot

BCR-Abl = tyrosine kinase
inhibited by Imatinib/Gleevec
WBC >20K/uL

CML presentation

hepatosplenomegaly - LUQ pain
insiduous
thrombosis/bleeding

CML pathology

leukocytosis >> 20K/uL: all stages maturation
BM <10% blasts, hypercellular, mild fibrosis
spleen: extramedullary hematopoiesis
basophilia

CML natural history

chronic: 2-8y
accelerated: blasts 10-19%; karyotype evo
blast crisis: <1YS, >20% blasts
-70% AML, 30% ALL - this is unique to CML!!

PCV: polycythemia vera

^RBC mass
etio: Jak2: chrom9p 1849 G->T 97% ->
-> loss autoinhib ->STAT5 -> ^Epo, IL-3 sens
epid: mid-elderly, rare
tx: Ruxolitinib --| Jak2

PCV Sx

^RBC mass: hyperviscosity syndrome
splenomealy
thrombosis/bleeding

PCV: labs

^RBC, Hb, HCT: normocytic unless Fe2+ def
thrombocytosis/eosinophilia/basophilia
Epo: low/normal (high sens)
BM: hypercellular: ^RBC, vFe2+, ^megakaryo
spleen: extramedullary hematopoiesis

PCV natural history

prolif phase: 10y avg; RBC prolif
spent phase: stable RBC mass, Fe2+ depletion
post-PCV myelofibrosis: 15-20%; anemia
AML 2%

PM: 1o myelofibrosis

HSC neoplasia + reactive fibrosis
leukoerythroblastosis +extramed hematopoiesis
tear drop anisopoikilocytes
JAK2 mut: 50%, MTL mut 1-5%
-Ruxolitinib *JAK2
5-20% -> AML

ET: essential thrombocytosis

^platelets + abnorm fcn: plt >1M/uL
circulating megakaryocyte fragments
mid-elderly
JAK2 mut 50%, MPL mut 5-10%
indolent

mastocytosis

^mast cells + abnorm fcn
etio: c-Kit RTK mut (CD117), tryptase +
urticaria pigmentosa 50% ped, systemic 10%

mastocytosis histo

AML

>20% blasts in BM
20% leuk, 85% adult leuk; ^incid post-mid age

AML etiology

100% untreated CML->AML
benzene
ionizing rad/chemo
alkylating agents
trisomy 21
chromosomal instability
hema dx: MDS, MPN, PNH, aplastic anemia

AML classification

WHO: +genetic aberrations, MDS-like, tx-related, not otherwise specified

FAB: 0-7
-3: promyelocytic t(15;17)
-4: inv(16)/t(16;16)

AML: labs

blasts - blood + BM
-Sudan black B+, myeloperoxidase +
-CD13, 33, 34, 117, Tdt(-)
-Auer rods - confirm myeloid lineage

BM: hypercellular

AML: histo

AML genetic aberrations

t(15;17) - M3, PML-RARα
FLT3 - bad prognosis -> high risk
NPM1; CEBPA - good prog -> low risk

AML: systemic Px

leukostasis
granulocytic Sa

AML: acute promyelocytic leukemia

AML-M3
t(15;17) PML-RARa --| RAR-a gene
promyelocytes: granulocytes + Auer rods
Sx: DIC
Tx: ATRA + good prog

AML: acute promyelocytic leukemia

promyelocyte: butterfly nuc
lots Auer rods

AML natural history

rapidly fatal
+chemo: 60% remission, 15-30% 5YS
good prog: t(15;17), t(8;21), inv(16)
poor prog: >60yo, MDS, 5q-, 7q-, LC>100K/uL

MDS: myelodysplasic syndromes

clonal SC dx -> ineffective hematopoiesis
Px: pancytopenia, hypercell BM, macro anemia
etio: benzene, rad, alk chemo Rx, TopoII inhib, chrom 5 deletion
course: smoldering -BMT dept; 10-40% ->AML

MDS: histo

mickey mouse cells
bi-lobe PMN
ringed sideroblast: Fe2+ locked in

MDS: Sx

cytopenia, macrocytic anemia, abnorm granulo
BM: hypercellular, ^blasts, cytogen weird

Langerhans cell histiocytosis

uncommon
mixed eos, plasma, PMN
cells: coffee-bean nuc, Birbeck granules

Langerhans cell histiocytosis: histo

coffee-bean nuclei

Langerhans cell histiocytosos: types

Letterer-Siwe dx: <2yo - most severe; 50% 5YS
Hand-Schuller-Christian dx: 2-5yo
eosinophilic granuloma: 5-30yo
pulmonary histiocytosis: smokers

Letterer-Siwe dx

most severe Langerhans cell histiocytosis

leukemia v lymphoma

leukemia: 1o BM + blood, myeloid/lymphoid origin, 2o LN + solid

lymphoma: 1o LN + solid, lymphoid origin, 2o BM + blood

CLL/SLL (leuk/lymph)
ALL/LL

LBL: lymphoblastic lymphoma

solid
<25% blasts in BM
rare

ALL: acute lymphoblastic leukemia/
LBL: lymphoblastic lymphoma

ALL: blood + BM, >25% blasts in BM, common
LBL: LN, <25% blasts in BM, rare

ALL: B v T - determines Tx

ped: 85% B cell; adult: B>T
favorable: 85% cure +chemo

ALL: histo

no: Auer rods, granules (v myeloblasts)
express Tdt

ALL: epidemiology

#1 malig ped (75% of cases), also >50yo
-ped 85% B-ALL, adult: B>T
etio: rad, i2 state, trisomy 21

ALL:Sx

very acute onset + progress (weeks)
anemia + thrombocytopenia - severe
fever
bone pain: LC blasts highjack BM + divide!
hepatosplenomegaly
lymphadenoPx

ALL Px

blood: leukocytosis + blasts (50/50%), anemia,
thrombocytopenia
BM: hypercellular, ^mitosis, blast sheets

ALL: B v T markers

both: Sudan black -, myeloperoxidase -, Tdt+

ALL genetics

favorable: hyperdiploidy, t(12;21), B-ALL, 4-10yo
WBC <10K/uL, no organ involved

unfav: t(4;11), t(9;22), T-ALL, <2y, >10y

+chemo -> 95% remission ped; lower for adults
75-86% cure if favorable

CLL/SLL: chronic lymphocytic leuk/small lymphocytic lymphoma

mature B-LC
65yo avg: no ped
#1 leukemia in US

CLL/SLL Sx

most: aSx
ser: lymphocytosis, anemia, thrombocytopenia
BM: small LC infiltrate, diffuse, nodular
i2: autoi2 hemolysis, hypo-yGb, paraprotein
LN: diffuse small, round, dense LC

CLL/SLL histo

CLL/SLL dx

CD5*, 19, 20, sIg (monoclonal K or λ)
(-) CD10

*CD5 normally only expressed by T cells

CLL/SLL flow cytometry

CLL/SLL grade

low: mutated/ M-CLL/SS
mut Ig +IgVh somatic hypermut; >50%
>7YS - don't treat + BMT if aSx

high: unmutated/U-CLL/SLL
mut Ig + unmut IgVh; <50%
3YS

CLL/SLL poor prognosis

U-CLL/SLL: 3YS avg
-prolymphocytic tx: 15-30% splenomegaly <2YS
-Richter tx: 5-10% large cell lymphoma <1YS

Richter tranformation

CLL/SLL 5-10%
large cell lymphoma
^lymphadenoPX
<1YS

hairy cell leukemia

mature B LC + villous cytoplasmic projection
mid-elderly, M>F
Sx: indolent course
blood: hairy cells, absolute monocytopenia
BM: reticulin fibrosis
spleen: red pulp involved

hairy cell leukemia: histo

hairy cell leukemia: markers

CD19, 20, 11c, 25, 103, sIg
TARP: tartare restistant acid Ptase +
(-) CD5, 10

Which pathology is associated with TARP?

hairy cell leukemia

What pathology is associated with B-cell markers and CD5?

CLL/SLL
mantle cell lymphoma

follicular lymphoma

common lymphoma in US
indolent 7-9YS
hepatosplenomegaly + lymphadenoPx
LN: nodular infiltrate; no mantle zones, no MF
large cells: poor prognosis

follicular lymphoma: histo

make sure to rule out follicular hyperplasia
LN: small, cleaved LC

follicular lymphoma: markers

CD10, 19, 20, sIg
(-) CD5
gen: t(14;18) -> Bcl2 overexp --| apoptosis

Bcl2 is a marker of which condition?

follicular lymphoma; hyperplasia will be (-)

DLBCL: diffuse large B cell lymphoma

#1 lymphoma in US
extranodular Sx
cleaved cells

DLBCL: histo

germinal center blasts + extranodal blasts
non-cleaved large B LC

DLBCL: markers

large, non-cleaved LC
CD19, 20, sIg, may have CD10
(-) CD5
assoc + EBV, KSHV/HHV8

which pathology is associated with viral pathogens?

DLBCL - assoc + EBV, HHV8/KSHV (HIV pt)
Burkitt: EBV, t(8;14) c-myc
HL: EBV
Adult T-cell leuk/lymph: HTLV-1

what is the ratio of B/T lymphoid neoplasms?

B 80%, T20%

plasma cell neoplasms

MM
smoldering myeloma
MGUS
all: paraproteins (M component), mid-elderly

other: solitary extra/osseous plasmacytoma,
Waldenstrom's macroglobulinemia, light chain
depo dx, heavy chain dx, 1o amyloidosis

what are Bence-Jones proteins?

paraproteins in urine

what is a paraprotein?

immunoglobulin (Ig) or fragment
M component (monoclonal)
secreted by plasma cell
found in serum - electrophoresis, urine, depo

MGUS

BM <10% plasma cells
1%/y tx -> MM

Waldenstrom macroglobulinemia

hyperviscosity syndrome
^IgM paraprotein: underlying LL or B-CLL/SLL

MM: diagnosis

BM >10% plasma cells
serum, UA: paraprotein Ig-k/λ, BJ prots
imaging: bone lesions
smear: Rouleaux formation

MM: Sx features (CRAB)

C: ^Ca2+
R: renal dx
A: anemia
B: bone lysis: ^RANK-L -> osteoclast act

avg 4-6YS

Burkitt lymphoma/leukemia

endemic: equit Afria; ped; 95% EBV, extranodal
sporadic: US, ped/adult, extranodal - abdomen
HIV-assoc: EBV 25%

90% cure in ped

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