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RBCs and Anemia, Red Blood Cells & Anemia Polycythemia/Erythrocytosis Inc. [RBC] -"Relative" if dec. MCV-from dehydration -ass'd w/ Gaisbock syn-'stress polycythemia' -"Absolute" if inc in total RBC mass -'Primary' when intrinsically ABNL myeloid stems -Polycythemia vera -Congenital polycythemia-very sensitive EPO receptors -'2ndary' when stems NL but excess, inappropriate EPO, Acquired-extrinsic factors RBC Trauma Cardiac Valve Prostheses, Vasc. Obstruction -worse w/ mechanical, not porcine valves -dmged by shear stresses from turbulence Microangiopathic=narrowed vasc -most often via DIC->fibrin deposition -also malignant HTN, SLE, TTP, HUS, CA ->schistocytes=burr, helmet, triangle cells -only major condition in Thrombotic Thrombo- cytopenic Purpura, Hemolytic-Uremic Syn, Thalassemias-alpha, beta -lack or dec. synth of alpha or beta globins of HbA ->low concentration of alpha or beta ->high relative concentration of beta or alpha ->aggregate->premature blast, RBC destruction beta-Thalassemias 2 beta-globin genes on one of chrom 11 -Med. countries, Africa, SE Asia-trait protects against malaria beta^0-thal=no beta chains in homozygous beta+-thal=reduced beta chains in homo -100 point mutations -promoter region->reduce xscript rate->beta+ -chain terminator->stop codons early->beta0 -SPLICING-most affect introns -if at splice jcn->beta0, if in intron->beta+ MECHANISMS OF ANEMIA 1. Inadequate HbA formation->low MCHC, hypochromic 2. alpha aggregate-MORE IMP'T->memb dmg, inclusions ->K+ loss, impaired DNA synth -ineffective erythropoiesis=70-80% RBC precursors apop -survivors suscep to hemolysis in spleen (inclusions) Severe->marked anemia->erythropoietin secreted ->severe erythroid hyperplasia in marrow, extramed. ->impedes bone ->excess dietary Fe absorption->iron-laden liver SYNDROMES beta-thal MAJOR-homozygous beta+/beta+ or beta0/beta0 -severe, transfusion-dependent, "crew-cut", anisocytosis, fragmented RBCs, agg. alpha chains removed in spleen beta-thal MINOR/TRAIT-heterozygous-one NL gene, eg beta0/beta -only mild anemia-need to diff'ate from Fe-deficiency beta-thal INTERMEDIA-severe anemia, not enough for xfusions -can be beta+/beta0, or severe MINOR, or mild MAJOR MORPHOLOGY-hypochromic, target cells, microcytic, baso. stippling, Acquired-extrinsic factors Immunohemolytic Anemia Warm AB Hemolytic Anemia -most common - in many cases AB against Rh factor -50% idiopathic, 50% underlying condition,drugs -mostly IgG, little IgA -Fc binds splenic macs, monos->spheroidal xform -leads to spherocytes->removal in spleen ->splenomegaly DRUG-INDUCED Hapten Model-PCN, cephalosporins act as haptens -combine w/ RBC memb, AB against drug -1-2 wks after Tx of large IV dose PCN-binds only to drug Quinidines-bind drug:protein complex BOTH-intra-, or extravascular hemolysis AutoAB model-anti-HTN alpha-methyldopa -drug initiates auto-ABs against RBC Ags -10% users w/ auto-ABs (Coombs), 1% manifest, -reduction of O2 carrying capacity of blood -in most cases due to RBC def. Significant anemia->pallor, weakness, malaise -dyspnea on mild exertion,koilonychia -fatty changes in liver, kidney, myocard->failure -anuria,oliguria,angina -CNS hypoxia->headache,dimness,faintness Anemias of Blood Loss Acute-trauma, hemorrhage -loss of volume, not Hgb (CBC might look NL) -can ->shock,death -rapid restoration of volume from interstitium ->lowers Hct (via hemodilution) -immediate de-margination ->leukocytosis,thrombocytosis -erythropoietin released->marrow makes RBCs If internal blood loss-can recycle Fe If external-RBC production can be Fe-limited RBCs normocytic/normochromic -but 10-15% reticulocytes after 7 days Can be mistaken for hemolytic process, -reduction of O2 carrying capacity of blood -in most cases due to RBC def. Significant anemia->pallor, weakness, malaise -dyspnea on mild exertion,koilonychia -fatty changes in liver, kidney, myocard->failure -anuria,oliguria,angina -CNS hypoxia->headache,dimness,faintness Hemolytic Anemias Hereditary-interior cell defects, Red Blood Cells & Anemia Development Blood Islands in yolk sac at 3rd week -clusters of stem cells 3rd month-cells migrate to liver -primary site of RBC production til birth 4th month-start production in marrow Birth-marrow takes over for production -significant extramedullary hematopoiesis-ABNL in fullterm 18yo-only vert,ribs, skull,sternum,pelvis,hum/femur -all else become fatty marrow (about half) -can revert to red marrow if RBCs needed -also extramedullary hematopoiesis can compensate, Hereditary-interior cell defects Types Sickle Cell Disease -hereditary hemoglobinopathy -mutations in beta-globin gene POINT MUTATION: Glu->Val at 6th position -slight protection against falciparum malaria -8% AA males heterozygous for HbS-40% HbS -"sickle cell TRAIT" - HbS and HbA -homozygous for HbS-almost all Hgb is HbS MECHANISM -deox->HbS aggregate, polymerize->HbS fibers ->distort RBCs->sickle shaped -reversible to a point-too much dmg->sickled -HbS fibers also->membrane dmg- -even if appear NL ->lose K, H2O,gain Ca->dehydration->inc. MCHC HbF (fetal) disallows ppt->manifests after 6mo HbC aggregates better than HbA -HbSC individuals more severe than "trait" Higher MCHC (via dehydration)->inc. ppt pH fall->reduce O2 affinity->worse dz MANIFESTATIONS 1. Chronic Hemolytic Anemia-of irrev sickled -some intravasc. due to memb dmg -some extravasc, in spleen via macs -20 day RBC life span 2. Microvascular Occlusion-HbS,NON-SICKLED -inc. adhesion molecs->sticky->narrow vessel ->more rigid cells plug narrowed vessel Hyperplastic marrow w/ normoblasts->bone resorbs ->"crew haircut", also extramed. hematopoiesis Splenomegaly in kids, then atrophy w/ ischemia -autosplenectomy by teenage years -infarction also in bones, brain, kidney, liver, retina Pigment gallstones, hyperbilirubinemia during lysis Increased susceptibility to infx, H. influenzae, pneumo ->septicemia, meningitis-most common cause of death Vaso-occlusive crises, Hand-foot syndrome, leg ulcers Acute chest syndrome due to infarction of lung caps Aplastic crises(B19), Chronic hypoxia->seizure/stroke Sx Hydroxyurea increases HbF->less vaso-occlusion, Hereditary-interior cell defects Types Hereditary Spherocytosis -intrinsic membrane defect -spheroidal, less deformable cells -vulnerable to splenic destruction 1 in 5000 N. European descent Mostly auto. dominant-ankyrin most mutated ->spectrin defective too Auto. recessive form more dangerous -SPECTRIN, band 3, protein 4.1, ankyrin -all possibly defective -spectrin responsible for instability, fragment loss ->reduces SA:volume->sphere -spheres can't deform out of cords of Billroth ->trapping, stagnation->osmotic injury ->phagocytes eat cells Remove spleen->no anemia even w/ sphere cells Signs-Splenomegaly,cholelithiasis, jaundice spheres also in autoimmune hemolytic anemia Aplastic crisis(stops making RBCs)>hemolytic crisis Increased MCHC w/ cell dehydration (MOST pts) Spherocytes vulnerable to osmotic lysis, Thalassemias-alpha, beta -lack or dec. synth of alpha or beta globins of HbA ->low concentration of alpha or beta ->high relative concentration of beta or alpha ->aggregate->premature blast, RBC destruction alpha-Thalassemias alpha+ or alpha0 -NL-4 alpha genes (2 pairs on each chrom 16) -excess beta, gamma, delta chains Bart Hgb=gamma_4 tetramers in newborn HbH=beta aggregates -both more soluble, less toxic than alpha aggs ->hemolytic anemia/ineff. hematopoie less severe Mostly caused by DELETIONS (not pt mutations) SYNDROMES: Silent Carrier State-single alpha deletion, no anemia -completely asymptomatic alpha-Thal Trait-2 alphas deleted-same chrom in Asians -diff chrom in Africans-better outcome for offspring -both clinically like beta-thal MINOR Hgb H Dz-3 deletions, mostly in Asians, excess beta -beta-tetramers=HbH->high O2 affinity->no O2 xchange -HbH can't w/stand oxidative stress->ppt ->older RBCs removed by spleen -clinically like beta-thal-INTERMEDIA Hydrops Fetalis-4 deletions->Bart Hgb in fetus-HIGH O2 aff. ->no O2 to tissues->SEVERE ANOXIA-intrauterine death