HEMONC 1.1 Midterm

RBC structure + function?

• biconcave, anucleate (glycolysis for ATP), central pallor on smear, lipid bilayer membrane, cytoskeleton (deform)

  • loss of deform → splenic sequestration

  • membrane defect → hemolysis

• O2 delivery via hemoglobin

  • dec. ATP → membrane fragile → hemolysis

RBC lifespan? recycling?

• 120 days, loss of membrane + enzyme depletion = tag for removal via RES (spleen + liver MO)

  • erythropoiesis in BM (DNA, globin, heme synthesis; Fe) via EPO in kidney stroma → reticulocytes (bluish, larger) w/ residual RNA = indicator of BM response

• in MO = globin → aa, heme → Fe (stored w/ ferritin or transported w/ ferritin) + protoporphyrin (bilirubin → liver → bile)

hemoglobin synthesis requirements?

• globin chain (in cytoplasm of developing red nuclei)

  • Chr. 16 (a-like), Chr. 11 (B-like)

• heme synthesis (in RBC mitochondria, O2 binds + relies on Fe)

• Fe availability (absorbed in duodenum via ferroportin; transport via transferrin)

hemoglobin types?

• HgbA → 2a + 2B chains (a2B2)

  • HgbA2 → 2a + 2o chains (a2o2); inc. B thalassemia

• HbF (fetal) → 2a + 2y chains (a2y2)

  • inc. O2 affinity, tissue hypoxia in adult

iron metabolism? iron absorption location + regulation? transport? storage?

• plasma Fe → BM → RBC

• duodenum, upper jejunum via ferroportin (low Fe = high FP) → regulated via hepcidin (high Fe = high hepcidin → dec. FP/ (-) feedback)

  • inactivating HPE mut. = Fe overload (bronze skin, arthralgia, amenorrhea, weight loss, organ damage (liver, pancreas, heart))

• transferrin → blood to liver + BM (via low hepcidin/ no Fe absorption downregulation)

• IC Fe bound to ferritin = prevent free radicals

anemia mechanism? symptoms? smear?

• RBC or Hb loss/destruction/impaired production → deficiency → dec. O2 carrying capacity of blood

• weakness, dyspnea, fatigue, pale skin, headache, lightheadedness, MI, reticulocytosis, splenomegaly, Hx pigmented gallstones

types of microcytic anemia?

• thalassemia, anemia of chronic disease, iron def., lead poison (TAIL)

• dec. production of Hb = RBC progenitor cells undergo extra division to maintain Hb (e.g conserve)

thalassemia mechanism? geographic distribution?

• defective globin synthesis → imbalanced globin chain → insoluble unpaired/individual chains precipitate → RBC destruction → inadequate Hb → hypoxia

• mediterranean, middle east, african, southeast asian

• absence/mut of a/B globin = dec. HbA → tissue hypoxia → EPO inc

a-thalassemia mechanism? B- thalassemia mechanism?

• gene deletion on Chr. 16 = absent a chains

• absent (B0) or mutated (B+) B chains affecting HBB on Chr. 11

silent a-thalassemia? a-thalassemia minor?

• ¾ a globin gene normal → asymptomatic, slight microcytosis (-a/aa)

• loss of 2/4 a globin genes (- -/aa) or (- a/- a)

  • microcytosis w/ minimal or absent anemia, HbF levels low or normal

  • affected parents w/ (-/-) haplotype = risk

  • peripheral smear → target cell, spherocytes, hypochromasia

hemoglobin H disease (HbH)?

• loss of ¾ a globin genes (- -/-a)

• B tetramers (4 B subunits) form w/ very high affinity for O2 → tissue hypoxia disproportionate to Hb level

• HbH prone to oxidation → splenic red cell sequestration + phagocytosis → moderate severe anemia

• peripheral smear → hypochromic, microcytic erythrocytes

homozygous/Bart’s hemoglobin (hydrops fetalis)?

• loss of all 4 globin genes (- -/ - -)

• y-tetramers (4 y-subunits) form w/ extremely high affinity for O2 → anoxia → fetal IU death

• if baby born → severe pallor, generalized edema, massive hepatosplenomegaly

• peripheral smear → severe hypochromic microcytic anemia, anisopoikilocytosis, nucleated erythroid forms (normoblasts), target cell

B-thalassemia minor/trait (heterozygous)? B-thalassemia intermedia?

• 1 absent + 1 normal (B0/B) OR 1 mutated + 1 normal (B+/B)

  • peripheral smear → hypochromasia, microcytosis, basophilic stippling, target cells, nucleated RBC

  • BM → mild erythroid hyperplasia

• mutation on both B chains (B+/B+) OR 1 mutated + 1 absent (B+/B0)

  • variable, ranges form mild/asymptomatic to severe/transfusion dependent

B-thalassemia major (homozygous)?

• loss of both B chains (B0/B0)

• severe transfusion-dependent anemia → associated 2ndary hemosiderosis + hemochromatosis organ damage (heart, endo, liver, pancreas)

• marked hemolysis, erythroid hyperplasia w/ marrow expansion + extramedullary hematopoiesis → cortical bone remodel (maxillary, frontal facial) + organomegaly

• peripheral smear → marked anisocytosis, poikilocytosis, microcytosis, hypochromia, target cell, basophilic stippling, fragmented red cell, nucleated red cell (poorly hemoglobinized)

anemia of chronic disease mechanism? effect of inflammatory mediators? how can iron be trapped? what chronic conditions contribute to iron deficiency?

• chronic disease → APR prod. (hepcidin) → traps Fe in storage → high ferritin + low serum Fe/ TIBC

• e.g IL6 → trigger hepcidin prod. → inhibit ferroportin (no uptake)

• Fe trapped via limiting Fe transfer from MO to erythroid precursor OR suppress EPO → no erythropoiesis

• TNF-a, IL1, INF → suppress erythroid colony formation (EPO resistance) → no erythropoiesis

• HF, CKD, ACE I or angiotensin R blocker (inhibit EPO)

  • chronic blood loss → via menorrhagia, GI bleed, intestinal parasites

iron deficiency populations? iron absorption inhibitors? stages? bone marrow? blood smear?

• nursing infants, ppl w/ poor diet/absorption issues, plummer-vinson syndrome, inc. requirement, hypothyroidism, chronic blood loss

• tannates (tea), carbonates, oxalates, phosphates

• low Fe, + TSAT, Hb, serum ferritin; high TIBC, soluble transferrin receptor + platelets

• stainable Fe from MO gone

• poikilocytes (pencil cell), anisocytosis, microcytic/hypochromic RBC → enlarged pallor zone

lead poisoning (sideroblastic anemia) mechanism? heme pathway? causes? labs?

• defective heme/protoporphyrin synthesis → Fe trapped in mit. → high TSAT

• SCA (via B6 + ALAS) → a-ALA ( via ALAD) → porphobilinogen → hydroxymethylbilane → uroporphyrinogen III → coproporphyrinogen III → protoporphyrin (via ferrochelatase) → heme

• lead (inhibits ALAD + ferrochelatase) + ALAS2 mut., alcoholic damage to mit., vit B6 def. (via TB isoniazid)

• basophilic stippling (pappenheimer bodies), high serum Fe, ferritin, TSAT (Fe overload), microcytic hypochromatic RBC

• BM → erythroid hyperplasia + rigned sideroblasts (from Fe PO4-enorged mit.)

normocytic anemias (MCV = 80-100)?

• non hemolytic → aplastic, acute blood loss

• hemolytic

  • intrinsic → damage affecting RBC membrane, metabolism, of Hb

  • extrinsic → RBC damaged externally via mechanical, immunological, infectious or metabolic/oxidant damage

aplastic anemias?

• renal failure (low EPO prod.), hepatocellular disease (folate + Fe def.), damage to BM RBC precursor cell

• parvovirus B19 → attaches to P antigen on erythroid progenitor cell → lysis → reticulocytopenia (slapped cheek, arthralgia)

• chronic conditions contributing to aplasia → thymoma, glandular lymphocytic leukemia, neutralizing Ab against EPO, autoimmune

acute blood loss mechanism? RBC appearance?

• internal blood loss = Hb recycled

• external blood loss = Hb lose = iron deficiency

• RBC → normocytic + normochromic initially → production inc. → reticulocytosis

hemolytic intrinsic anemias?

• RBC membrane or cytoskeleton defect → hereditary spherocytosis, hereditary elliptocytosis, end-stage liver or kidney disease (burr cells), PNH

• metabolic abnormalities → G6PD deficiency + pyruvate kinase deficiency

• defects of hemoglobin → sickle cell + hemoglobin C

hereditary spherocytosis mechanism? complication? lab? blood smear?

• mut. of spectrin, ankyrin, band 3 or 4.2 → affects assembly of inner cytoskeleton to outer lipid layer

• aplastic crisis (parvovirus kills all RBC progenitor cells), folate deficiency, pigmented gallstones

• anemia, reticulocytosis, serum bilirubin, LDH, urine urobilinogen, +osmotic fragility test, -direct coombs test

• spherocytes small, dark-stain, spherical cells lacking central pallor, polychromasia

paroxysmal nocturnal hemoglobinuria mechanism? how to test for it? findings?

• acquired spontaneous mutation in phosphatidylinositol glycan complementation group A gene (PIGA)

  • PIGA → enzyme for synthesis of membrane-associated complement regulatory proteins (GPI-linked protein)

    • deficient = RBC susceptible to complement induced lysis (C5b-C9 MAC)

• test via flow cytometry → check CD55 + CD59 deficiency

• paroxysmal ep. dark urine at night (hemoglobinuria), partial clearing during day, vasospasm, thrombosis

• lab → inc. bilirubin, LDH, hemosiderinuria; dec. Hgb, serum Fe, ferritin or folate

• peripheral smear → schistocytes (IV hemolysis)

G6PD deficiency-related hemolysis mechanism? geographic distribution? triggers? labs?

• deficient G6PD = dysfunctional hexose monophosphate path → rigid spectrin + oxidation of Hgb

• african, mediterranean or middle eastern

• asymptomatic until trigger → acute episodes, self-limited, 2-4 days after exposure

  • oxidative stress (fava beans), infections, meds (ciprofloxacin, metronidazole)

• labs → inc. bilirubin, urobilinogen, LDH; reticulocytosis, hemoglobinuria, pallor, scleral icterus; dec. Hgb, haptoglobin

• peripheral smear → bite cell, blister cell, heinz bodies, polychromasia, anisocytosi, spherocytes

hemoglobin C disease cause? sickle cell disease mechanism? geographic distribution?

• hereditary B globin (HBB) gene pt. mut. (G → A; Glu → Lys) on Chr. 11 → HbC production = HbC crystallization in RBC → hemolysis, target cells, dec. flexibility

• hereditary B globin (HBB) gene pt. mut. (A → T; Glu → Val) on Chr. 11 → HbS

• west + central africa, w/ mediterranean, middle east, india

sickle cell disease mechanism? higher expression of what?

• alignment/polymerization of deoxygenated HbS → sickling (dehydrated, dense, rigid RBCs)

• higher level adhesion molecules → microvascular occlusions + thrombosis → hypoxia (affects bones, lungs, liver, brain, spleen, penis; e.g acute chest syndrome)

• peripheral smear → sickled cell, reticulocytes, target cells, howell-jolly bodies, small nuclear remnants

sickle cell disease symptoms? treatments?

• severe hemolytic anemia, marrow expansion (erythroid hyperplasia), hyperbilirubinemia (jaundice, pigmented gallstones)

  • adults → leg ulcers; children → dactylitis + priapism

• Tx = hydroxyurea → inc. HbF production to interfere w/ polymerization of HbS + dec. sickle cell formation

sickle cell disease genotype? sickle cell trait? sickle cell anemia? HbSC disease? HbSB-thalassemia?

• both HBB alleles mut. + at least 1 BS allele

• HbAS → HBB/BS

• SCA → BS/BS

• BS/BC

• BS/HbB0

non-immune mediated anemias?

• oxidant injury, mechanical trauma, infectious disease, toxin/poison, hypertonic saline, hypersplenism, thrombi

  • mechanical → prosthetic valve, microangiopathies (TPP, HUS, DIC)

  • infectious → malaria (RBC rupture), clostridium perfringens (release enzymes that digest RBC membrane)

immune mediated anemia?

• Ab and/or complement bind to RBC membrane components, flagging RBC for destruction via extra or intravascular hemolysis

• types of immune mediated hemolysis → autoimmune, alloimmune, drug induced

intravascular hemolysis mechanism? labs?

• complement mediated lysis in circulation → free Hbg released w/in circulating plasma

• unique labs → hemoglobinuria, hemosiderinuria, fragmented RBCs (schistocytes)

• both IV + EV hemolysis → inc. reticulocytes, LDH, bilirubin; dec. haptoglobin

extravascular hemolysis mechanism? complications? labs?

• MO in reticuloendothelial system of spleen, liver, BM recognize C3b opsonized RBC

  • incomplete phagocytosis results in spherocyte

• splenomegaly via inc. MO + damaged/deformed RBC → inc. congestion in splenic cords of billroth

• indirect hyperbilirubinemia, risk of gallstones (chronic hemolysis)

autoimmune hemolysis types? mechanism?

• warm AIHA: IgG Ab → (+) indirect coombs = detectable circulating Ab directed against RBC

• cold AIHA: IgM Ab → (+) direct coombs = detectable Ag bound on RBC surface

  • ass. w/ mycoplasma pneumonia, EBV, CMV

• paroxysmal cold hemoglobinuria

alloimmune hemolysis types?

• hemolytic disease of fetys/newborn: Rh(D) incompatibility → maternal IgG cross placenta + attack fetal RBC = anemia, hydrops, kernicterus

  • prevent w/ Rh(D) immunoglobulin prophylaxis + kelihauer-betke test (fetal-maternal hemorrhage)

• hemolytic transfusion rxn: rapid IV hemolysis; IgM-mediated complement fixation

  • fever, renal failure (=flank pain + hematuria), hypotension, DIC

• delayed hemolytic transfusion rxn: IgG mediated EV hemolysis; dys-wks post transfusion

  • anemia, jaundice, spherocytosis

drug induced hemolysis mechanism?

• direct toxicity

• hapten mediated production

• autoantibody induction

• complement fixation or opsonization

folate processes? megaloblastic anemia (folate deficiency) cause? findings?

• leafy greens + absorbed in jejunum

• purine synthesis, conversion of homocysteine to methionine, dTMP synthesis (req for DNA syn)

• dec. intake (diet, hemodialysis), impaired absorption (tropical sprue), inc. reqs (pregnancy), anticonvulsant phenytoin + OOC, folate antagonist (methotrexate)

• macrocytic RBC w/ hypersegmented neutrophils, normal methylmalonic acid, glossitis, low serum folate, high serum homocysteine

megaloblastic anemia (cobalamin/B12 deficiency) cause? labs?

• impaired division + enlarged RBC precursor

• impaired gastric absorption (gastrectomy, ZES), ileal damage (fish, tapeworm, IBD), pancreatic insufficiency, low intake (vegans)

• B12 binds intrinsic factor (parietal cells), absorbed in ileum → pernicious anemia = parietal cell destruction

• Vit B12 needed for CNS dev/myelination/fxn, healthy RBC formation, DNA syn. → B12 injection cause inc. MMA

• macrocytic RBC w/ hypersegmented neutrophils, low reticulocytes, BM hyperplasia, inc. MMA + homocysteine