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--heterogenous group of anemias with normal DNA metabolism and hemoglobin synthesis, and no common pathophysiology
--normocytic = MCV 80-100
--first Q: is there increased RBC production? check retics
--if high retics: if there hemolysis? if no, is there recent bleed?
--if low retics: is there renal failure, endocrine failure, chronic inflam, marrow prob?
--TYPES: ACD, acute blood loss, early IDA, hemolytic anemia, hereditary spherocytosis, aplastic anemia

--aka iron-reutilization anemia
--2nd most common form of anemia
--ETIO: inflam, cancer, infx: shortened RBC life, poor Fe metabolism, deficient erythropoiesis
--(exact mech: unknown)
--initial normo-normo-->micro/normo or micro/hypo
--if IDA also: low serum iron and low TIBC
--3 C'S:
--chronic infx (osteomyelitis, bacterial endocarditis, lung abscess)
--connective tissue diseases (RA, SLE, regional enteritis (Crohn's)
--cancer: Hodgkin lymphoma, lung and breast cancer
--ACD: low iron and TIBC but normal or elevated ferritin (IDA: low iron & ferritin, high TIBC)
--progression: normochromic, normocytic-->hypochromic, microcytic (25%)
--chronic inflam-->IL-1, TNF-alpha, TGF-beta (etio: RA, SLE, IBS, infx)
--MOI: defective iron utilization, impaired response to EPO, blunted increase in EPO dt kidney dz, mbdt iron or folate deficiency, shortened RBC survivial
--usu mild-moderate
--Dx: exclusion of all other causes, need BM biopsy
--Tx: treat underlying cause, EPO can work but costs $$$$, dialysis

--uncommon but correctable
--hypothyroid, hypogonadism, pan-hypopitutitarism

--very rare cause of normocytic anemia
--immune mediated destruction of RBC precursors in marrow
--low retic county
--Tx: immune suppression

--rate of RBC destruction exceeds that of replacement
--macrophages of RE, reticuloendothelia system remove RBC's, most in spleen, extravascular
--90% of normal RBC destrx occurs w/o release of HGB into circ
--is there hemolysis??? consider 1) damaged RBC's on blood film (spherocytes dt immune or hered), 2) marrow response to hemolysis (polychromasia on blood film, reticulocytosis, erythroid hyperplasia in marrow, 3) biochemical evidence (increased unconjugated bili, increased lactate dehydrogenase, decreased/absent haptoglobin)
--three main groups of causes: immune, congenital, and acquired
--extravascular: the spleen removes RBC's dt sickle cell anemia, hereditary spherocytosis (HS)
--intravascular: RBC's lysed by 1) mechanical trauma (mech heart valves, physical trauma such as marathon running, bongo drumming, malignant HTN) 2) immunologic: antibody fixation, auto- or allo- (idiopathic, mismatched blood transfusion, SLE, infx trigger, lymphoma, CLL) 3) toxic injury to RBC's (microangiopathic or infectious) (malaria, clostridium, septic shock-->disseminated intravascular coagulopathy [DIC]) 4) enzymopathy (G6PD)
--extrinsic causes are outside the RBC: RBC trauma dt cardiac prostheses, AV shunt, or narrowing/obstruction of microvasculature (DIC), autoimmune (usu IgG), SLE, malignant HTN, TTP, malaria, lead poisoning, hemolytic uremic syndrome (HUS), cancer, hypersplenism
--intrinsic: abnormality is genetic/hereditary with RBC itself: membrane, enzyme, or HGB issues, ex: sickle cell anemia, hereditary spherocytosis
--conditions assoc w/ hemolysis: TTP and HUS
--TTP = thrombocytic thrombocytopenic purpura = a rare life-threatening dz involving embolism and thrombosis of small BVs in the brain, characterized by platelet microthrombi, thrombocytopenia, hemolytic anemia, fever, renal abnormalities and neurologic changes: aphasia, blindness, convulsions, mortality w/ tx 10-20%, can be precipitated by antiplatelet drug clopidogrel (Plavix)
--DX: to discriminate extravascular from intravascular:
--extravasc-->elevated LD, elevated bili, haptoglobin normal to absent, NO hemoglobinuria, free HGB in plasma, or urine hemosiderin
--intravascular-->very elevated LD, elevated bilirubin, haptoglobin absent, hemoglobinuria, free HGB and urine hemosiderin present
--Dx of immune hemolytic anemia: Direct Antiglobulin Test = DAT = direct Coomb's test: detects IgG or complement on pts RBC's, majority of pts with active immune hemolysis with have a positive DAT. ALSO Indirect Antiglobulin Test = IAT = Indirect Coomb's test, detects Ab in pts serum, positive IAT does not mean hemolysis, it could mean allo-immunization due to previous exposure to foreign red cell antigens (past preg or transfusion), also check smear for spherocytes
--Tx of immune hemolytic anemia: tx cause, stop suspect drugs, prednisone, transfusions if needed


--dt a single point mutation in beta-blogin, resultant HGB called Hgb S
--sickles form at low pH-->low oxygen tension and HGB has lower affinity for O2-->HGB stacks up in cell
--also intracellular dehydration increases MCHC and facilitates sickling
--sickling is intially reversible but later the RBC is permanently deformed
--sickle cells live ~ 20 days
--8% of American blacks are carriers (heterozygotes) with ~60% normal hemoglobin, usu asymptomatic, or painless hematuria, or symptoms at very high altitudes or after marked exertion
--1/500 of American blacks are homozygous/have sickle cell disease
--1/100 in Africa have the dz
--alpha thalassemia DECREASES sickle cell symptoms when pt has both, because the lower globin synthesis reduces the MCHC
--chronic hemolysis (I would guess both intra- and extra- vascular)
--more bilirubin formed
--small vessel stasis and thrombosis (ischemia of extremities)
--hyperplastic bone marrow: prominent cheekbones and changes in skull to increase marrow
--splenic changes: enlargement at first but later shrinkage dt hypoxia, thrombosis, infarction-->fibrosis-->autosplenectomy
--pigmented gallstones dt breakdown of HGB and hyperbilirubinism
--loss of spleen fx-->increasing susceptibility to ENCAPSULATED ORGANISMS such as Streptococcus, Haemophilus influenza, and Salmonella
--pneumovax given to sickle pts before spleen damage to reduce pneumococcal pneumonia and salmonella osteomyelitis-->avascular necrosis
--Tx: EPO (increase RBC production-->decrease anemia) long term effects unknonw, butyrate "appears" to diminish sickling, studies ongoing on the use of L-arginine or Sildenafil (viagra) as vasodilators, another novel approach: hydroxyurea, chem agent that disrupts DNA replication
--3 mechanisms by which hydroxyurea helps sickle cell anemia: 1) anti-inflam: inhibits prod of WBCs, 2) increases mean RBC volume (MCV) and decreases concentration of HbS, 3) can be oxidized by heme groups to produce NO (vasodilator), converts some of the Hgb S to Hgb F, when Hgb F reaches 10-15% there is less incidence of vaso-occlusive complications
--approx half of all sickle cell patients live to be 50+
--usu causes of death: overwhelming infx, pulmonary emboli, renal failure

--both hereditary (70%) and acquired forms
--elevated retic (>9%) in 90% of pts wtih HS
--LABS: normal to decreased MCV, decreased HGB, normal to increased MCH, INCREASED MCHC
--DX: osmotic fragility test indicates ability of RBC to take up water w/o bursting, depends on surface/volume ration or shape, full/thick cells have increased fragility, spherocytes are more fragile in a hypotonic solution than normal RBC's
--RBC membrane defect makes RBC's less deformable in the vasculature, and increases its vulnerability to splenic sequestration and destruction
--population most affected by autosomal dominant HS (75% of cases): northern Europeans, 1/5000
--usu a defect in ankyrin, protein that anchors cytoskeleton
--three characteristic clinical features of HS: anemia, splenomegaly, jaundice
--dz highly variable in severity, some pts may suffer aplastic crisis dt parvovirus (B19) and show slapped cheeks or lacy rash on body
--S/Sx: gallstones (40-50%)
--more severe form of HS: autosomal recessive variant
--Tx: for HS, splenectomy, reduces extravascular hemolysis and reduces anemia

INTRAVASCULAR HEMOLYSIS: dt MECHANICAL (prosthetic heart valves, running, drumming), ANTIBODIES, TOXINS (malaria, septic->DIC)

--all have in common autoantibodies to RBC antigens resulting in immune mediated hemolysis and subsequent anemia
--categorized by responsible antibody: warm or cold agglutination, or drug induced
--most common: warm Ab Immunohemolytic anemia, WAIHA, IgG Ab's that bind at 37 degrees, idiopathic and mb fatal
--ETIO: (warm): 50% ideopathic, 50% dt SLE (collagen vascular dz), Ra, or neoplastic dz ie: lymphoma, carcinoma
--warm: usu IgG opsonizes RBC's-->monocytes and spleen Fc receptors bind-->RBC membrane busted
--S/Sx: splenomegaly (65%)
--ETIO: (cold) ? idiopathic IgM Ab's that bind just below 37 degress to 4 degrees C
--IgM; RBCs agglutinate at low temps 0-4 degrees C
--cold Ab's appear acutely during recovery phase of infectious dz: mycoplasma pneumo, mono, HIV, CMV, influenza
--ETIO of CHRONIC cold AIHA: certain lymphoid neoplasms, and ideopathic
--S/Sx: Raynaud's
--drug induced: antibodies formed against drug cross-react with red cell membranes
--PCH = paroxysmal cold hemoglobinuria: rare, assoc w/ measles, mono, chicken pox, IgG-->RBC's sensitive at cold temp-->hemolysis
--PNH = PAROXYSMAL NOCTURNAL HEMOGLOBINURIA = complement induced, complement activation rxn leads to hemolysis during night when body temp drops. Free HGB filtered by kidneys, produces mild-moderate anemia. New: Ham's test being replaced with flow cytometry.
--TRIGGERS OF AUTOIMMUNE DZ TARGETING RBC'S: lymphoma, carcinoma, sarcoidosis, collagen vascular dz (SLE or RA)

--ETIO: incompatible blood transfusions
--fetal maternal incompatibility

--fibrin formation in vasculature lyses RBC's
-->DIC, disseminated intravascular coagulopathy
--Tx: anticoagulants

-->hypoproliferation of RBC's dt low EPO
--assoc w/ uremia
--RBC's don't incorporate iron into RBC's?

--decrease in bone marrow mass-->pancytopenia or pure RBC aplasia
--ETIO: 1/2 ideopathic (young adults), 1/2 dt: chems, drugs, benzene, chemo, age, Fanconi's (genetic w/ microcephaly and dark pigmentation)
--ETIO: idiopathic, benzene, radiation, infx, chloramphenicol. Almost always environmental or chemical factor.
--decreased platelets
--increased risk of infx
--LABS: retic count of ZERO, elevated serum iron
--ETIO for pure RBC aplasia: infx, thymoma, immune sys injury, fertilizer, B2 deficient, CLL
--LABS: low RBC, WBC, PLT, Retic, high serum Fe, acellular bone marrow
--cellular depletion with fatty replacement of marrow
--increased serum iron (not enough RBC's to store iron)
--Tx: marrow transplant, must match HLA usu w/ family member
--pts kept alive by transfusions of WBC's and platelets but still die within 4-5 years of onset

--when marrow is replaced by tumor, granloma, lipid storage or fibrosis
--may see splenomegaly
--look for nucleated RBC's in PB, also immature myeloid cells (bands)

--G6P required for production of NADPH required for regeneration of reduced glutathione
--reduced ATP production-->decreased membrane flexibility-->increased oxidative damage to RBC-->hemolytic anemia
--sex linked: X chromosome (females can manifest if homozygous)
--more common in Kurdish Jews, African Americans
--selective advantage to malaria
--Dx: assay of G6PD enzyme most definitive
--susceptible persons exhibit hemolysis under oxidative stress, usudt drugs (antimalarials, sulfa, nitrofurantoins, aspirin), foods (fava beans), high dose intravenous vitamin C
--glucose-6-dehydrogenase = initial enzyme in HMPS pathway, hexose monophosophate shunt that generates reduced glutathione to protect hemoglobin and RBC membranes from oxidation
--Heinz bodies, use crystal violet or methylene blue stain, when RBC oxidatively damaged, denatured and precipitated hemoglobin can be seen as dark blue inclusion bodies
--infx can induce hemolysis in a person with G6PD: viral hepatitis, pneumonia, typhoid fever
--drugs can too: sulfonamides, antimalarials, nitrofurantoins
--favism = hemolysis in G6PD pt dt ingestion of fava beans, a component of which oxidizes older RBC membranes
--favism endemic in Middle East, Mediterannean and parts of Africa (could this be simply because those are the regions where fava beans are eaten, and G6PD occurence is more universal??)
--hemolytic anemia in G6PD usu mild and self-limiting because only the older RBC's fail

--Hemoglobin C is also found more in blacks and has a greater tendency to form aggregates with deoxygenated HbS and HbA => HbSC disease. 2-3% of US blacks are asymptomatic heterozygotes. About 1/1250 has HbSC dz.
--S/SX: hematuria, retinal hemorrhages, infarctions, aseptic necrosis of femoral head, leg ulcers, priapism, painful bone infarctions, "chest syndrome" incl: chest pain, fever, leukocytosis, lung infiltrates, possible pulmonary infarction
--"pain crisis" = vaso-occlusive crisis = bone ischemia and infarction
--sequestration crisis = spleen sequesters RBC's-->enlarges acutely-->hypovolemia and shock
--aplastic crisis = suppression of BM dt infx by Parvo B19 virus
--target cells might be the only sign that someone has HgBC trait
--S/Sx w/ homozygous (dz): anemia, abdominal pain, arthralgias, mild jaundice, splenic enlargement but no infarcts

--defined as peripheral blood pancytopenia without cytologic, BM abnormality or marrow replacement by fibrosis or malignancy
--peripheral pancytopenia
--marrow hypoplasia (devoid of hematopoietic elements, shows fat cells and fibrous stroma)
--activated T cells (activated by drugs, infx, envir) produce cytokines (TNF and IFNgamma) that prevent normal stem cell growth and development
--mortality dt infx and bleeding
--S/SX: pallor, headache, palpitations, dyspnea, fatigue, mucosal/gingival bleeding, petechial rashes, netropenia-->infx, ulcers in mouth/pharynx
--ETIO: 20% congenital
--ETIO: infx: hepatitis, EBC, HIV, parvovirus, mycobacterium
--ETIO: toxins, radiation

--replacement of marrow by fibrosis
--oft dt myeloproliferative dz such as leukemia or polycythemia
--BM may also be replaced by neoplasm



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