Week 2 (Anemia) Flashcards
Heme
Heme = ferroprotoporphyrin IX contains ferrous (Fe2+) iron Hemin = ferric Fe3+ iron (useless,, metHb)
Heme synthesis
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
Porphyrias
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
Hemoglobin
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)
Sickle Cell Anemia
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
Thalassemia Syndromes
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
Microcytic anemias
Normochromic: iron def (early), thalassemia trait, anemia of chronic disease, some Hb-opathies
Hypochromic: iron def, thalassemia, sideroblastic anemia, anemia of chronic disease
Normochromic/Normocytic anemias
anemia of chronic disease, renal failure, marrow infiltration, aplastic anemia, blood loss, hemolysis
Macrocytic anemias
Megaloblastic (impaired DNA synthesis): B12, folate deficiency, myelodysplastic syndromes
Non-megaloblastic: reticulocytosis, liver sidease, hypothyroidism, drugs
CBC measurements
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
Spherocytes
round small, hyperchromic RBCs, also fragile
hereditary spherocytosis
autoimmune hemolytic anemia
Target cells
liver disease, splenectomy, hemoglobinopathies
Elliptocytes
hereditary elliptocytisis
megaloblastic anemia
iron def
myelofibrosis
Teardrop cells
megaloblastic anemia
myelofibrosis
extramedullary hematopoiesis
Fragments (schistocytes)
TTP, DIC, malignant HTN
Bite cells
oxidant hemolysis (G6PD deficiency)
Howell-Jolly Bodies
nuclear fragments in RBCs
splenectomy, megaloblastic anemia
Pappenheimer bodies
iron granules in RBCs
splenectomy, iron overload
Basophilic stippling
lots of blue dots in RBCs
Thalassemias, MDS, lead poisioning
Rouleaux
RBCs arranges in a line, stack of coins
increased serum protein
Hypersegmented neutrophil
megaloblastic anemia
Ineffective Erythropoiesis
increased RDW
decreased retics
inappropriate increased iron absorption
Hemolytic anemias
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
Mostly extravascular hemolytic anemias
RBC membrane disorders RBC enzyme disorders sickle cell Thalassemia autoimmune
Mostly Intravascular hemolytic anemias
PNH
mechanical
malaria
Damage from Fe and Heme
Fe2+ causes ROS (Fenton rxn), lipid peroxidation
Heme can intercalate into lipid bilayers
Causes endothelial activation
free Hb scavenges NO - vasoconstriction and HTN
Clearance of Hb
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)
Haptoglobin
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
Heme catabolism
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
G6PD deficiency
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
Hereditary spherocytosis
spherocytes, hemolytic anemia autosomal dominant usually ankyrin, also spectrin or band 3 mutations widely variable, splenomegaly Tx: splenectomy
Autoimmune hemolytic anemias
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)
Microangiopathic hemolytic anemias
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
Paroxysmal Nocturnal Hemoglobinuria (PNH)
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)
Anemia of Chronic Disease
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
Inherited bone marrow failure (aplastic anemia)
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
Acquired aplastic anemia
immune mediated, T-cells attack blood stem cells, triggered by inciting event like infxn or drugs
Camitta criteria
differentiates severe aplastic anemia
Peripheral blood (2/3): platelets<20000
AND Marrow: less than 65% (hypocellular)
Aplastic anemia treatment
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)
Megaloblastic anemia
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
Pernicious anemia
type of megaloblastic anemia
immune destruction of epithelial cells (parietal) in stomach -> lack of intrinsic factor -> lack of B12 absorption (ilium)
Impaired prolif/differentiation of stem cell anemias (hypoproliferative)
[low retic count, can have hypo or hyperceullar bone marrow]
aplastic anemia
red cell aplasia (Parvovirus)
PNH
Impaired prolif/maturation of erythroid precursors anemias
megaloblastic anemia renal failure chronic disease endocrine disorders myelodysplastic syndromes
Defective hemoglobin synthesis anemias
iron deficiency (heme)
sideroblastic (heme)
Thalassemias (globin)
Marrow replacement/infiltration anemias
hematopoietic tumors
metastatic tumors
granulomatous inflammation
DDX of pancytopenia
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)
Iron deficiency
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
Absorption of Iron
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
