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Heme and Lymph > Week 2 (Anemia) > Flashcards

Week 2 (Anemia) Flashcards

1
Q

Heme

A 
Heme = ferroprotoporphyrin IX
contains ferrous (Fe2+) iron
Hemin = ferric Fe3+ iron (useless,, metHb)
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2
Q

Heme synthesis

A

1st and last 3 steps in mitochondria, rest in cytoplasm
1 succinyl coa + glycine -ALAS-> ALA (rate limiting)
–is PLP dependent,, schiff base
ALAS1=liver (subject to feedback inhibition and increases by drugs),, ALAS2=erythroid (always on)
2 ALA -ALAD-> PBG (req Zn, inhibited by lead)
3 PBGD makes a chain of PBGs, UROS ensures stereochem
4 UROD changes side groups
5 CPO changes side groups
6 PPO oxidizes
7 ferrochelatase adds Fe2+,, inhibited by lead

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3
Q

Porphyrias

A

Defect in Heme synthesis
autosomal dominant, rare
early defects= ALA accumulation = neurologic dysfunction
later defects = cyclic tetrapyrroles accumulate = sunlight-induced cutaneous lesions
can be acute or chronic

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4
Q

Hemoglobin

A

R=relaxed=high affinity
T=taut=low affinity
CO locks in R state (as does high O2 conc)
High CO2, H+, temp, DPG = curve shift right = O2 released from Hb
Normal adults: 96% HbA (a2b2), 1% HbF (a2g2), 3% HbA2 (a2d2)
Can use electrophoresis or HPLC to detect abnormalities (most silent)

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5
Q

Sickle Cell Anemia

A

homozygous recessive mutation in B-globin gene
Val for Glu at aa6 = HbS
deoxyHbS forms long chains
chronic hemolytic anemia, shorter RBC lifespan of 20days,, microvascular occlusion
chain formation depends on: degree of deoxygenation, cellular Hb conc, relative HbF conc, time through microvasculature
Promote sickling: hypoxia, acidosis, dehydration, cold temps, infxns
Clinical: severe anemia, acute pain crises (vaso-occlusion in marrow), auto-splenectomy, acute chest syndrome (bad), stroke, aplastic crisis (parvo B19), splenic sequestration crisis (infants, treat w transfusion), megaloblastic anemia (folate shortage), etc
Labs: anemia, increased bilirubin, sickled cells, increased retics, normal MCV
ALSO: causes endothelial activation, recruites neutrophils, clogs vasculature, increased transit, bad loop
Tx: hydroxyurea

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6
Q

Thalassemia Syndromes

A

decrease synthesis of HbA (a2b2)
microcytic/hypochromic anemias
severity related to degree of chain imbalance (excess normal chains accumulate and cause cell death)
B-thal major: homozygous, severe, transfusion dependent,, also need aggressive iron chelation therapy
B-thal minor: heterozygous, mild microcytic anemia, elevated HbA2
a-thal: severity ranges widely based on number of alpha genes (out of 4) deleted

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7
Q

Microcytic anemias

A

Normochromic: iron def (early), thalassemia trait, anemia of chronic disease, some Hb-opathies
Hypochromic: iron def, thalassemia, sideroblastic anemia, anemia of chronic disease

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8
Q

Normochromic/Normocytic anemias

A

anemia of chronic disease, renal failure, marrow infiltration, aplastic anemia, blood loss, hemolysis

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9
Q

Macrocytic anemias

A

Megaloblastic (impaired DNA synthesis): B12, folate deficiency, myelodysplastic syndromes
Non-megaloblastic: reticulocytosis, liver sidease, hypothyroidism, drugs

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10
Q

CBC measurements

A

Hb conc = important assessment of O2 carrying capacity
Hct = not useful
RBC = not useful
MCV = very useful for micro/macrocytic
MCH = not useful
MCHC = mean Hb conc per cell, determines hypo/hyperchromic
RDW = variability in RBC volume

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11
Q

Spherocytes

A

round small, hyperchromic RBCs, also fragile
hereditary spherocytosis
autoimmune hemolytic anemia

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12
Q

Target cells

A

liver disease, splenectomy, hemoglobinopathies

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13
Q

Elliptocytes

A

hereditary elliptocytisis
megaloblastic anemia
iron def
myelofibrosis

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14
Q

Teardrop cells

A

megaloblastic anemia
myelofibrosis
extramedullary hematopoiesis

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15
Q

Fragments (schistocytes)

A

TTP, DIC, malignant HTN

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16
Q

Bite cells

A

oxidant hemolysis (G6PD deficiency)

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17
Q

Howell-Jolly Bodies

A

nuclear fragments in RBCs

splenectomy, megaloblastic anemia

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18
Q

Pappenheimer bodies

A

iron granules in RBCs

splenectomy, iron overload

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19
Q

Basophilic stippling

A

lots of blue dots in RBCs

Thalassemias, MDS, lead poisioning

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20
Q

Rouleaux

A

RBCs arranges in a line, stack of coins

increased serum protein

21
Q

Hypersegmented neutrophil

A

megaloblastic anemia

22
Q

Ineffective Erythropoiesis

A

increased RDW
decreased retics
inappropriate increased iron absorption

23
Q

Hemolytic anemias

A

RBC destruction, loss of RBC mass, release cellular content, increased hematopoiesis, increased retics
most common: extravascular (spleen)
normocytic, reticulocytosis, increased LDH, AST, K, bilirubinemia (unconj, jaundice), Hb-emia, decreased haptoglobin
organomegaly, skeletal changes (chipmunk facies), asplenia, cholectectasis (gall stones)
hemoglobinuria and hemosiderinuria mostly in intravascular process
Rare complications: kidney tubular obstruction, folate def, thrombosis

24
Q

Mostly extravascular hemolytic anemias

A 
RBC membrane disorders
RBC enzyme disorders
sickle cell
Thalassemia
autoimmune
25
Q

Mostly Intravascular hemolytic anemias

A

PNH
mechanical
malaria

26
Q

Damage from Fe and Heme

A

Fe2+ causes ROS (Fenton rxn), lipid peroxidation
Heme can intercalate into lipid bilayers
Causes endothelial activation
free Hb scavenges NO - vasoconstriction and HTN

27
Q

Clearance of Hb

A

90% extravascular: macrophages of spleen and liver
10% intravascular: CD163 macrophages scavenge hemoglobin-haptoglobin complex
If haptoglobin overwhelmed: converts to metHb, liberates heme, binds to hemopexin - then CD91(LRP1)

28
Q

Haptoglobin

A

acute-phase glycoprotein
produced by liver, circulates
increase with inflammation
decrease with hemolysis
binds to Hb so CD163 can sequester it (receptor mediated endocytosis, recycled)
Hp2-2 is over-expressed in autoimmune and inflammatory disease – defective HDL function

29
Q

Heme catabolism

A

globin protein is degraded in lysosome
heme in cytosol catabolized by HO-1 in assoc with ER -> CO(bound by Hb) + Fe (bound by ferritin)
biliverdin (green) -> bilirubin (orange) catalyzed by biliverdin reductase
bilirubin is released in travels with albumin, then taken care of by the liver

30
Q

G6PD deficiency

A

Bite cells
monocytes phagocytose denatured protein to cause bites
enzyme def causes buildup of oxidants -> Heinz bodies
usually triggered by drug or infxn, fava beans
X-linked
G6PD A-: 11% of AA, enzyme function decreases with cell age, so selectively hemolyses old RBCs

31
Q

Hereditary spherocytosis

A 
spherocytes, hemolytic anemia
autosomal dominant
usually ankyrin, also spectrin or band 3 mutations
widely variable, splenomegaly
Tx: splenectomy
32
Q

Autoimmune hemolytic anemias

A

Makes spherocytes
warm (IgG)or cold (IgM)
can be idiopathic or decondary to lymphoprolif disorders, autoimmune, neoplasms, drugs, etc
Cold: can be from infectious mono (anti-i) or mycoplasma (anti-I),, also can get clumps of RBCs on smear
Warm is acute/rapid, wide range of severity,, cold is acute or chronic, follows cold exposure, wide range
Diagnosed by direct Coombs antiglobulin test (DAT)

33
Q

Microangiopathic hemolytic anemias

A

mehanical trauma to RBCs
fragments on smear
thrombotic thrombocytopenic purpura (TTP, clots in microvasculature)
malignant HTN (hyaline vessels)
antiphospholipid antibody syndrome
dissemninated intravascular coagulation (DIC)
disseminated cancer

34
Q

Paroxysmal Nocturnal Hemoglobinuria (PNH)

A

rare, mutation in PIGA gene (X-linked)
decreased GPI-linked proteins (membrane bound proteins)
makes cells susceptable to complement lysis
chronic low level hemolysis, acute episodic hemolytic events, hemoglobinuria
diagnosed: flow cytometry for GPI-linked proteins (CD55,59)

35
Q

Anemia of Chronic Disease

A

mild to moderate anemia, common, assoc with inflammation
resembles anemia of low iron (but ferritin is high),, high levels of plasma hepcidin downregulate ferroportin
chronic microbial, osteomyelitis, endocarditis, lung abscess, chronic immune such as RA, neuplasms, carcinomas, lymphomas
Effectively reduced transport of iron to precursors
normocytic, normochromic at first, becomes hypochromic, microcytic bc of lack of iron
ferritin is often elevated, transferrin can be low

36
Q

Inherited bone marrow failure (aplastic anemia)

A

telomerase mutations= dyskeratosis congenita - short telomeres, dystrophic fingernails
DNA repair mutations= Faconi anemia - normal phys exam in some, DO NOT give chemo. Always order DEB test first

37
Q

Acquired aplastic anemia

A

immune mediated, T-cells attack blood stem cells, triggered by inciting event like infxn or drugs

38
Q

Camitta criteria

A

differentiates severe aplastic anemia
Peripheral blood (2/3): platelets<20000
AND Marrow: less than 65% (hypocellular)

39
Q

Aplastic anemia treatment

A

1 sibling HLA-matched bone marrow transplant
2 (acq only) intensive immune suppression, ATG + CSA + prednisone
3 unrelated bone marrow transplant
4 thrombopoietin agonist (stim marrow stem cells)

40
Q

Megaloblastic anemia

A

Deficient B12 or Folate
hypersegmented neutrophils, teardrop cells, oval macrocytes, anisopoikilocytosis (variable)
hypercellular marrow, giant bands, nuclear to cytoplasmic dyssynchrony
low retics, elevated methylmalonic acid
Folate is needed for DNA and thymidylate synthesis
B12 is needed for DNA synthesis too
ineffective hematopoiesis
B12 def causes: Diphyllobothrium latum tapeworm, impaired absorbtion, inc req, dec intake (vegetarians)
B12: neurological probs, dorsal/lateral tract demyelination
Folate def causes: dec intake, increase req, bad absorption, more rare
Folate: neural tube defects (spina biffida-anencephaly
Tx: supplements

41
Q

Pernicious anemia

A

type of megaloblastic anemia
immune destruction of epithelial cells (parietal) in stomach -> lack of intrinsic factor -> lack of B12 absorption (ilium)

42
Q

Impaired prolif/differentiation of stem cell anemias (hypoproliferative)

A

[low retic count, can have hypo or hyperceullar bone marrow]
aplastic anemia
red cell aplasia (Parvovirus)
PNH

43
Q

Impaired prolif/maturation of erythroid precursors anemias

A 
megaloblastic anemia
renal failure
chronic disease
endocrine disorders
myelodysplastic syndromes
44
Q

Defective hemoglobin synthesis anemias

A

iron deficiency (heme)
sideroblastic (heme)
Thalassemias (globin)

45
Q

Marrow replacement/infiltration anemias

A

hematopoietic tumors
metastatic tumors
granulomatous inflammation

46
Q

DDX of pancytopenia

A

stem cell (aplastic anemia, PNH)
hematopoiesis (myelodysplastic, megaloblastic anemia)
marrow infiltration (leukemia, metastatic, myelofibrosis)
splenic sequestration (splenomegaly, myeloproliferative neoplasms, portal HTN)
Drugs (immunosupp, chemo/rad, etc)

47
Q

Iron deficiency

A 
common, microcytic, hypochromic anemia
stored with ferritin or hemosiderin
causes: dietary lack, imapired absorption, inc req, chronic blood loss
ferritin is best lab measure
platelets often elevated (unknown why)
RDW increases, low retics, normal RBC count
menstrual cycle or colon cancer
Tx: supplement Fe
48
Q

Absorption of Iron

A

Fe3+ -cytochrome B (vit C) -> Fe2+
Fe2+ -DMT1 -> ferritin in cell
ferritin - ferroportin1 - out of cell - converted back to Fe3+ by hephaestin - transported to liver, stored with ferritin
Hepcidin from liver inhibits Ferroportin1
CD71= uptakes Fe into erythrocytes

Heme and Lymph (3 decks)

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