MOD 3 lectures: Nutritional/hyperproliferative anemias, Hemolytic anemias, & Transfusion medicine Flashcards
What is hemoglobin?
The oxygen carrying molecule on a RBC
What is MCV? (mean corpuscular volume)
Measures size of RBC
What is MCHC
measures hb conc per RBC
What is RDW
measures how variable/uniform the cell size is
What is anisocytosis
degree of variation between RBCs
reticulocyte count
measures bone marrow response to anemia
TBIC
total iron binding capacity, measures TRANSFERRIN molecs in blood
Ferritin
storage form of iron
Hepcidin
regulates iron absorption
normal hb and hcrt?
Hb 12-16 g/dL
Hcrt 35-50%
Normal MCV, microcytic, macrocytic
microcytic <80
Normal: 80-100
Macro >100
what blood disorders are assoc with microcytic anemia <80
iron def, thalassemia, anemia of chronic disease
What should normal RBCs on slides look like
mature lympho nucleus same size as RBC
area of central pallor 1/3 diameter, lil platelets
What IS anemia?
Decreased number of RBCs in blood, OR decreased oxygen-carrying capacity of blood due to reduced RBC mass etc
can cause fatigue etc
3 main causes of anemia
Blood loss
Increased DESTRUCTION of RBC
impaired PRODUCTION of RBCs
What are 3 main nutritional anemias
Iron, B12, and folate def
Iron def
impaired heme synthesis, microcytic anemia
B12 and folate def
imparied DNA synthesis (nucl need B12 and folate to make DNA), causing macrocytic anemia (present similarly but B12 involves neuro sx)
Where is iron absorbed?
proximal duodenum!
What forms is iron abs and stored>
absorbed in ferrous Fe2+ form (two-inTO), stored in Fe3+ ferric form (while bound to ferritin), recticuloendothelial sys
What is hepcidin
rel by the liver and regulates iron absorption.
incr iron presence in liver stimulates hepcidin synth so it can absorb more (?) by sequestering iron in storage sites
what level is hepcidin at in adequate iron levels?
High hepcidin
What stain can visualize iron?
PRUSSIA BLUE (more blue= more iron stored)
What does serum ferritin represent?
Iron stored in macros and liver
high serum ferritin means increased iron storage
What does TBIC measure
measures transferrin molecules in blood! (eg number of iron transport proteins in blood)
What does high TBIC correlate with?
Low iron in blood (lots of unoccupied transferrin circulating)
(% saturation is percent of transferrin molecs bound by iron, normal is 1/3)
How does iron def lead to micro anemia?
Decreased iron means decreased heme which means decreased hemoglobin which means micorcytic anemia
What will iron def look like in terms of lvls and cells?
Low hb, RBC, hcrt, MHCH, microcytosis with MCV<80, Hypochromic/pale, incr RDW (central pallor>1/3 RBC)
DECREASED serum iron so INCREASED TIBC
-elliptocytes (pencil cells) and Target cells
Which anemia/deficiency may pencil cells and target cells indicate?
Iron deficiency anemia!
Anemia of Chronic disease
1 in US hospitalized pts
(iron is common in world?)
Assoc with chronic infxn/inflam/malig, IL-6 inflam mediator incr -> incr hepcidin -> decr EPO
(hepcidin tries to prevent bacteria from accessing iron which they use for survival, by sequestering it in storage)
Anemia of chronic disease iron issues?
Impaired iron utilization (low serum iron, low TIBC reflects incr storage of iron in tissue macros, so less storage in blood)
Iron deficiency anemia: TIBC, serum iron, marrow stores (increased or decreased)?
Iron def anemia: INCREASED TIBC transferrin (bc not enough iron to bind up the transferrin, and liver senses low iron and produces more transferrin to pick up iron), decreased serum ferritin bc not enough iron to get stored in cells. Decreased marrow stores.
Anemia of chronic disease: TIBC, serum iron, marrow stores (increased or decreased)?
-Anemia of chronic disease: DECREASED TIBC bc iron stored in places other than blood, and INCREASED serium ferritin bc iron being stored in cells and not in blood. INCREASED marrow stores bc hepcidin drives iron into storage
Macrocytosis can be caused by…
Reticulocytosis (prolif of immature RBCs, which are bigger), caused by EPO prod
and Megaloblastic anemia (vit b12 and folate def, alcoholism, liver dis, MDS, hypothy, drugs etc)
What does periph blood smear show in macrocytosis
pancyto
large oval RBCs hyperchormic
NUCLEATED RBCs!
LARGE HYPERSEGMENTED NEUTROS!
Bone marrow in macro anemia?
hypercellular (bc ineffective hematopoeisis), marrow responds to low cell counts by incr cell prod but eventually leads to pancytopenia bc ineffective dna synth as they mature
(normal cellularity is 100-age)
more (next)
What is megaloblastic change in macro anemia?
nuclear/cytoplasmic asynchrony of all cells, mature cytoplasm but chromatin looks like cut salami (nucl remains immautre), hyperseg neutros, or bands, large hyperlobated megakaryocytes
What are B12 and folate needed for? Why does this cause macro anemia?
coenzymes for thymidine synth in dna syth
If cant make dna, can grow but not divide causing amcro (nucleus remains immature)
pancyto
What chemicals buildup due to B12 def?
HOMOCYSTINE cannot be conv to methionine
and METHYLMALONIC ACID incr bc cant be conv to succinyl coa for krebs
Where is vitamin B12 absorbed?
Terminal ileum!
What does b12 due in absorption?
pepsin frees it from food, then b12 copmlexes with IF from parietal cells in stomach and is abs in terminal iluem
what can cause b12 def?
vegetarians impaired absorption (eg GI issues), crohns, tapeworm, ileal resecetion, bacterial overgrowth etc
What can IF def cause?
pernicious anemia (can be from autoimm gastritis so parietal cells with IF destroyed), IF ab test, schilling test
Replenish folate by eating?
green leafy veggies!
Where is FOLATE absorbed?
Proximal jejunum!
What can cause folate def?
decr intake, alcoholism, infatns imparied abs due to GI/intestines etc pregnancy cancer drugs like methotrexate so impaired utilization
How does folate def present?
like b12 def but no neuro sx
Where is Iron, Folate, and B12 absorbed?
Iron- proximal DUODENIM
Folate- proximal JEJUNUM
B12- terminal ILEUM
Aplastic anemia
Chronic primary bone marrow failure
What causes aplastic anemia
a lot idiopathic, drug/chem, viral eg hep, irradiation, fanconi
Patho of aplastic anemia?
Assoc?
autoimm rxn against bone marrow progenitors, dmg to hematopoeitic stem cells
Assoc with PNH (paroxysmal nocturnal hemoglobinuria_
Biopsy of aplastic anemia
Fatty marrow
Tx for aplastic anemia
Immunosuppr drugs bc autoimm
if not, then bone marrow transplant
Pure red cell aplasia
primary bone marrow disorder where only erythroid progenitors are suppressed
assoc with a bunch of disorders
Space in between RBCs on histo may suggest…
anemia
What occurs in hemolytic anemia?
RBCs destroyed and removed before normal lifespan over
3 main indicators of hemolytic anemia? (levels)
INCREASED total/indirect(unconj) BILIRUBIN INCREASED LDH (spills out when cells lyse) DECREASED haptoglobin (prot made by liver, bc bound up by the free hb circulating)
Other indicators of hemolytic anemia
elevated EPO causing hypercellularity
Periph blood recticulocytosis
EMH extramedullary hematopoeisis (hematopo outside marrow)
Hemolysis 2 types
INTRAVASCULAR or EXTRAVASCULAR(spleen)
Histo of intra vs extravascular hemolysis?
intra; schistiocytes (fragments
Extra-microspherocytes (v small fully sphere RBCs)
Defect in what causes sickle cell anemia?
Thalassemia?
Defect in one of the Hb chains (qualitiative hb-pathy)
vs
Low production of an Hb chain (structurally normal, just low lvl, so imbalance of a and b chains)
Sickel Cell Disease
HEREDITARY, and intrinsic (rel to RBC itself)
eg sickle cell (histo: sickles and targets), val replaces glu acid on B-globin chain, changes RBC to sickle shape, which clogs microvasculature, esp in SPLEEN
Tests for SS
Sickle sol test, metabisulfite slide test, then electrophoreisis to verify (alkaline)
Hemoglobin C
mutation, histo
similar to SS but Lysine replaces gluatmic acid instead of valine replacing it
-see rhomboid crystals but also target cells (nonspec, all hemoglobinopathies have this)
Thalassemia
defect, dx, more markers
decr prod of normal Hb chains, uunparied chains
-can dx with just CBC (have elev RBC but still anemic), low MCV Mentzner index<13 (MCV/RBC ratio)
Mentzner index
Thalassemia vs iron def
MCV/RBC ratio
For Thalassemia is < 13, for Iron def is > 13 (bc RBC in denom is so small)
B-thalassemia
B globin chain(s) absent or reduced due to pt mutat’n, microcytosis, unpaired a chains ppt causing inclusions, further lower Hb levls due to cell lysis
B thalassemia minor (mild), intermedia, and major (need transfusions)
a-Thalassemia
reduction in any/all of 4 a-globin chains from deletion
causes excess of y-globin in fetus and b-globin in adults
-accum, but milder than B-thalass
-1 gene deletion is silent carrier, asympo, slight jmicryctosis, 4 is more and hydrops etc, death without transfusion
A diff between who B vs a thalassemia effects?
a-thalassemia can also affect fetuses
RBC membrane defects involve mutations of which 4 genes?
Band 3,
Lipophorin
Ankyrin
Spectrin
Hereditary Spherocytosis
defect
histo
tests
defects in membrane prots, causes cell to become spherical and more sus to destruction in spleen (histo missing central pallor, normal size, hereditary)
test with osmotic fragility (place RBCs in hypotonic soln, spherocytes rupture)
Hereditary Elliptocytosis
similar but more elliptical RBC, normochromic
Enzyme defects affecting RBCs include…
G6PDH def and PK def!
spherocytes on histo means
defect in membrane prot!
G6PDH deficiency and mech
X-linked, males, INTERMITTENT acute hemolytic anemia from oxygen stress eg fava beans drugs infxns
(G6PDH maintains NADPH which maintins rbc GSH to conv ROS to O2), so if G6PDH low incr oxidative damage to RBCs
HISTO of G6PDH deficiency
HEINZ BODIES (denatured ppt'd hemoglobin, can see lil dot in cell) BITE CELLS (rbc with proteins removed by spleen macros) dx w ascorbate cyanide test and fluro spot test, but can give false negatives
Pyruvate kinase deficiency anemia (all these are hemolytic)
deficiency in enzy in glycolysis pathway, so ATP depleted
A diff bn PK and G6PDH def
PK is def in ATP so continuous, not intermittent
PNH (paroxysmal nocturnal hemoglobinuria)
caused by acquired intrinsic clonal stem cell disorder (marrow), complement sys destroys rbc’s
PNH mutation
PIG-A, which causes disruption of synth of
GFP (anchoring memb prot)
Lack of GPI means cells are destroyed (bc complement detsr of RBC can occur), causing anemia
What anemias show up in PNH
APLASTIC ANEMIA, and strange thrombosis events, pancyto, mds, etc
Dx of PNH?
Flow cyotometry, look for GPI anchor prots on surface of RBC
(decr CD55 and CD59 on neutros and rbc, whcih are COMPLEMENT REGULATORY PROTS)
-also decr FLAER
What does absence of CD55 and CD59 on cells mean?
These are compelment regulatory prots, so their absence means PNH bc RBCs will be destroyed by complement
Extrinsic anemias can be from
immune, trauma, infexn, toxin induced
Warm antibody anemia
caused by IgG (georgia warm) binding to RBCs at body temp, causing spleen macros to destroy them
Warm ab anemia assocs?
malignancies like CLL/SLL, infxns, lupus, drugs like pencillins
Warm ab anemia histo?
Testing?
SPHEROCYTES and MICROSPHEROCYTES
Dx with direct coombs
Cold agglutination disease
caused by IgM (minnesota cold) binding to RBCs below body temp. IgM fixes complement, so macros destroy these cells
Cold agglutination assocs?
Histo?
B-cell neoplasms, infxns
CLUMPING! (clumps of RBCs)
Microangiopathic hemolytic anemia
Pathological acitvation of coagulation cascade!
causes fibrin clots in microvessels
Microangiopathic hemolytic anemia histo/dx?
As RBCs pass thru fibrin clots, they fragment forming schistiocytes
TPP/HUS, DIC assocs etc etc
Malaria induced anemia histo
can see parasitic inclusions in periph blood smear, eg ringed trophoblasts
What does increased LDH, total/indirect bilirubin, and decreased haptoblogin indicate?
HEMOLYTIC ANEMIA!
Why can type O blood only accept blood from other type O?
bc has antibodies to all others
Diff between type and screen, vs type and match pre-transfusion tests?
Type and Screen- quicker, test blood sample for disease, abo, rh, unexpected ab’s, then stored in blood bank
Type and Match- same, but donors and recipients blood mixed to see if compatible, stored away (takes longer)
What type of blood transfusions do we usu give?
components rather than whole blood
What are RBCs transfused for?
HgB of 7 and Hct of 21% (v low)
replacing iron, wound healing, anemia, but can give too much volume
What is apheresis
take whole blood out, then remove component, then return rest of blood
When do u give platelets? shelf life?
Apherese them out of blood, give for decr production, platelet dysfxn (not for autoimm)
v short shelf life and need gentle agitation to prevent clotting
Fresh frozen plasma use
gives coag factors to pts with multifactor clotting defs (eg PT>18, PTT>50), or v low coag factors
- can reverse warfarin overdose (make blood thicc again), liver disease
- dont use for vol expansion nutrition etc
Cryoprecipitated antihemophilic factor
Plasma prots that ppt when fresh frozen plasma is thawed (ppts out), has factor VIII fibrinogen , XIII etc
-use in hypo-fibrinogen-emia, von willebrand, hemophilia etc etc
Do we transfuse WBCs?
NO! can cause bad rxns
What can transfused WBCs cause?
- autoimm
- TA-GVHD (transfusion assoc graft vs host dis where DONOR lymphos attadck recipients body), vv high mortality
- TRALI-recip wbc gets activated by DONOR’S AB’s against HLA, causes cytokines and pulm edema
- can also have viruses or bacteria etc
- so usu irradiate blood product to destroy RBCs (no need if infant, non-immunocompr pt with solid tumor, or aplastic anemia pt)
