Anemias

Type Wintrobe's Morphology Classification Epidemiology Unique Features Pathophysio Cause Etiology/ Pathogenesis CBC & Retic results Add'l Dx tests to confirm

Megaloblastic Anemia (vit B12/ cobalamin deficient)

macrocytic

Pernicious anemia (atrophic gastritis with failure of production of Intrinsic Factor, caused by autoimmune attack on gastric mucosa -> atrophy of stomach-> malabsorption) most common cause in Western countries (esp N. Europeans, occurs in families, females>males, peak at 60 yrs); other causes: vegan diet, congenital lack of IF, gastrectomy, diverticulosis, Crohn's, etc.

low serum vit B12, normal or raised serum folate, normal or low red cell folate; Schilling test (B12 vit B12 is coenzyme for methionine absorption +/- IF, synthase (needed to convert methyl distinguishes insidious onset, may low retic count, malabsorption from THF to THF), also assists in be mildly jaundiced, inadequate diet, conversion of CoA to succinyl CoA; leukopenia with diminished DNA low vit B12-> defective DNA synthesis glossitis, angular hyperclassic pernicious stomatitis, weight loss, segmented anemia = positive synthesis -> asynchronous maturation of neural tube defects in granulocytes, test, < 8% urinary (diminished nucleus & cytoplasm-> developing fetus, CV disease, excretion if no IF erythropoiesis) erythroblasts in bone marrow appear mild/moderate sterility, melanin thrombocytogiven, becomes megaloblastic (large); vit B12 pigmentation penia normal when IF absorption occurs in ileum, requires IF added), also diet secreted by parietal cells of fundic history, endoscopy, mucosa IF/parietal cell Ab's, abnormal f.a. incorp into neuronal lipids > neuro s/s (not seen in folate def)

Megaloblastic Anemia (folate deficient)

macrocytic

Nutritional (esp old age, institutions, poverty, special diets), Malabsorption (gastrectomy, Crohn's), Excess utilization (pregnancy, lactation, prematurity, hematological diseases, CA, inflamm diseases), Excess urinary folate loss (liver Dx, CHF), Drugs (anticonvulsants, sulfa), Mixed (liver Dx, alcoholism, ICU)

"

"

"

"

folate deficiency inhibits thymidylate synthesis (a rate-limiting step in DNA synthesis in which thymidine monophosphate is synthesized); all body cells receive folate from plasma as methyl THF (vit B12 is then needed to convert methyl THF to THF), lack of folate is the proximate cause of anemia in Vit B12 deficiency

"

"

normal or borderline serum vit B12, low serum folate, low red cell folate, diet history, tests for intestinal malabsorption, duodenal biopsy, underlying Dx

Anemias
Type Wintrobe's Morphology Classification Epidemiology Unique Features Pathophsio Cause Etiology/Pathogenesis CBC & retic results Add'l Dx tests to confirm

Iron Deficiency Anemia

hypochromic, microcytic (low MCV, low MCH, low MCHC)

may result from: 1) Dietary lack (esp elderly due to diet restrictions, poor, infants due to Pica, spoon nails small amt of iron in milk, children due (koilonychia), Plummerto growth & expansion of blood Vinson syndrome low Hb, low Hct, volume); (pharyngeal/ diminished Hb higher in developing low retic count in 2) Impaired absorption (diarrhea, esophageal webs, countries, but also common relation to the synthesis painless glossitis), steatorrhea, sprue, gastrectomy, other in US (esp toddlers, degree of (diminished dysphagia, angular dietary contents i.e. carbonates, adolescent girls, women of anemia, often erythropoiesis), or stomatitis; in kids get oxalates, phosphates which inhibit childbearing age) raised platelet increased loss irritability, poor absorption), count cognitive fxn, decline 3) Increased requirement (growing in psychomotor kids, adolescents, pregnant women), development 4) Chronic blood loss (from GI/GU tracts, most imp cause in Western world)

increased sTfR level, low serum iron, low serum ferritin, high TIBC, increased sTfR; deficiency in adult men and postmenopausal women is probably GI bleed, test stools for occult blood

most common cause of anemia among hospitalized pts in US, assoc with 3 categories of illnesses: may be 1) Chronic microbial normocytic & usually mild/nonnormochromic, or infections (osteomyelitis, Anemia of chronic progressive anemia, bacterial endocarditis, lung mildly dominant s/s are those inflamm/disease abscess), hypochromic of underlying Dx 2) Chronic immune (MCV rarely <75) & microcytic disorders (RA, regional enteritis), 3) Neoplasms (Hodgkin's, CA of lung & breast)

diminished erythroid production

assoc with reduced erythroid prolif, impaired iron utilization (due to block in the transfer of iron from storage pool to erythroid precursors) > may mimic iron deficiency; secretion of cytokines IL-1, TNF-a, IFN-g triggered by underlying chronic inflamm or neoplasm-> inadequate erythropoietin response to anemia

low Hb (rarely <9)

low serum iron, low TIBC, abundant stored iron in mononuclear phagos, serum transferrin WNL (presence of increased storage iron in marrow macs, high serum ferritin, and reduced TIBC rules out irondeficiency as cause); does NOT respond to iron therapy

Anemias
Type Wintrobe's Morphology Classification Epidemiology Unique Features Pathophsio Cause Etiology/Pathogenesis CBC & retic results Add'l Dx tests to confirm

alphaThalassemia

HbH disease = microcytic, hypochromic (low MCV, low MCH)

hereditary

4 gene deletions = incompat with life, hydrops fetalis, 3 gene deletions = anemia with splenomegaly, Hb H disease, 2 gene deletions = a-thalassemia trait, 1 gene deletion = silent carrier

diminished synthesis of alpha globin chains (diminished erythropoiesis)

caused by gene deletions on c'some 16, normally 4 copies of a-globin gene, severity classified acc to # of low Hb with Hb Hb electrophoresis is genes missing/inactive; get excess of H disease, o/w normal, need DNA b-chains -> aggregate into insoluble normal Hb with analysis to diagnose, inclusions in RBC precursors-> thalassemia normal a/b-synthesis premature destruction in marrow traits ratio is reduced (ineffective erythropoiesis), lysis of mature RBC's in spleen (hemolysis) but less severe than in b-Thalassemia

beta-Thalassemia

b-Thalassemia Major = homozygous, severe, transfusion dependent anemia; b-Thalassemia Intermedia = hereditary, esp hypochromic, heterozygous, severe Mediteranean countries, microcytic (low but doesn't require parts of Africa & SE Asia, MCV, low MCH, regular transfusions; incidence in US is highest in low MCHC) b-Thalassemia Minor these immigrants = 1 normal gene in the heterozygotes, asymp with mild/absent anemia, but see RBC abnormalities, most common type

diminished synthesis of beta globin chains (diminished erythropoiesis)

defects in transcription, processing, or translation of b-globin mRNA; get excess of a-chains-> aggretate into insoluble inclusions in RBC precursors -> premature destruction in marrow (ineffective erythropoiesis), lysis of mature RBC's in spleen (hemolysis); Hb ranges 3-6 in manifests at age 6-9 mos when Hb untransfused syntesis switches from HbF to HbA, pts, retic count kids suffer growth retardation & early elevated death unless supported by transfusions; if survive -> face becomes overlarge/distorted (Thalassemic facies), skull with "hair on end" on x-ray, iron overload unless chelation tx, hepatosplenomegaly, cardiac Dx, usually die by age 30

NOT helped by iron therapy, measure serum iron (high due to transfusions, need chelation tx), TIBC, serum ferritin to distinguish from irondef anemia, Hb electrophoresis shows absence of HbA (all is HbF), DNA analysis

Anemias
Type Wintrobe's Morphology Classification Epidemiology Unique Features Pathophsio Cause Etiology/Pathogenesis CBC & retic results Add'l Dx tests to confirm

Aplastic anemia

normochromic, normocytic or macrocytic

most cases idiopathic, but many causes: acquired = pancytopenia char stem cell defect, immune by: 1) anemia, 2) mediated, drugs, chemicals, neutropenia, and 3) irradiation, viruses; inherited thrombocytopenia = Fanconi anemia with defects in DNA repair

diminished erythropoiesis

failure/suppression of multipotent anemia, myeloid stem cells -> inadequate leukopenia, production/release of differentiated neutropenia, bone marrow sample cell lines; 2 major mechs: 1) thrombocytoimmuno mediated suppression by penia, low retic activated T cells (via IFN-g, TNF-a), 2) count intrinsic abnormality of stem cells

Anemia of Renal Failure

normochromic

see many hematological abnormalities in CRF: reduced erythropoietin production, aluminum excess, anemia of chronic disorders, iron def, folate def, abnormal platelet fxn, thrombocytopenia, increased risk of venous thrombosis

2 g/dl fall in Hb for every 10 mmol/l rise in blood urea

diminished erythropoiesis

impaired RBC production due to defective erythropoietin secretion; shortening of RBC lifespan in severe uremia, burr cells, spicules (spurs); get increased 2,3-DPG in response to anemia -> decreased O2 affinity, shift of Hb O2 dissoc curve to right (milder symptoms)

low Hb, low platelets

responds to Erythropoietin (EPO) tx

Anemia due to marrow damage

space-occupying lesions -> destroy/disturb bone marrow -> myelophthisic anemia; most common cause is metastatic CA, also multiple myeloma, leukemia, osteosclerosis, lymphomas, liver disease

diminished erythropoiesis

affects all formed elements of blood; infiltrative diseases destroy normal marrow envt -> reactive fibrosis -> inapprop release of erythroid & myeloid precursors into peripheral blood-> immature forms of RBC and WBC appear in peripheral blood (leukoerythroblastosis)

low Hb, low platelets, reticulocytosis

presence of thrombocytopenia in pt with known CA is always suspicious of extensive marrow replacement

Anemia due to leukemia

nomochromic, normocytic

ALL (kids esp age 3-7), AML (increases with age), CML (ages 40-60),

diminished erythropoiesis

ALL/AML: low ALL/AML: bone Hb, thrombomarrow hypercellular cytopenia, WBC with >30% leukemic may be low, blasts, LP shows normal, or high; accum of bone marrow blast cells -> CSF with leukemic CML: bone marrow failure -> anemia cells; leukocytosis, CML: bone marrow increased hypercellular with basophils, granulopoietic thrombocytopredominance penia

Anemias
Type Wintrobe's Morphology Classification Epidemiology Unique Features Pathophsio Cause Etiology/Pathogenesis CBC & retic results Add'l Dx tests to confirm

Intravascular immune hemolysis

Char of hemolytic anemias: 1) shortened RBC life 1 of the 2 main mechs of span (premature hemolytic anemia (depends destruction), on pathology involved); 2) accum of products RBC's broken down of Hb catabolism, directly in the circulation 3) marked increase in erythropoiesis in bone marrow to compensate

hemolytic

normal RBC's damaged by mech Main lab features: injury (ex: mech heart valves), 1)hemoglobinemia, complement fixation (ex: transfusion 2) hemoglobinuria (brown urine), of mismatched blood), or exogenous hemoglobin3) hemosiderinuria toxins (ex: malaria)-> free Hb emia (free Hb in (iron storage released -> saturates plasma blood), protein), haptoglobins, excess free Hb is reticulocytosis 4)methemalbuminfiltered by the glomerulus; if rate of emia, 5) jaundice, hemolysis saturates renal tubular 6) decreased serum reabsorp capacity, free Hb enters haptoglobin, urine, renal tubules loaded with 7)hyperbilirubin-emia hemosiderin

Extravascular immune hemolysis

1 of the 2 main mechs of hemolytic anemia (depends on pathology involved); excessive removal of RBC's by cells of the RE system

"

"

hemolytic

RBC's injured, rendered "foreign", or less deformable (ex: Sickle Cell Anemia)-> sequestration in splenic cords, -> phagocytosis

reticulocytosis

DO NOT SEE hemoglobinemia, hemoglobinuria; DO SEE anemia, hyperbilirubinemia, jaundice, reduced plasma haptoglobins, splenomegaly

Anemias
4 categories of Sickle Cell first manifests at age 5Crises 6 mos; sickling is (may overlap): initially reversible with 1) Vaso-occlusion oxygenation, repeat (pain, infarct of sickling-> irreversible; organs), precipitation of HbS 2) Hyperfibers -> upsets RBC hemolysis membrane even in (hypersplenism non-sickled cells -> > autolose K+ and H2O, gain splenectomy, or Ca2+-> probs splenomegaly), maintaining 3)Sequestration intracellular volume (mostly by -> dehydrated/dense spleen, also cell; fall in pH -> liver), 4) decreased affinity HbS Aplastic/ for O2 -> increased hypoplastic sickling (result of Parvovirus infection)

Sickle Cell Anemia

8% black Americans are heterozygous for HbS; heterozygous = 40% of Hb in RBC is HbS (rest is HbA), sickles only in severe hypoxia; homozygous = almost all Hb in the RBC is normochromic, HbS, full-blown sickle cell may see high anemia; 30% black Africans MCHC (due to in malaria-endemic areas dehydrated cells) are heterozygous (HbS in more severe affords slight protection cases against malaria); clinical course: severe anemia, crises of vaso-occlusive Dx, chronic hyperbilirubinemia, increased suscept to infections (impaired splenic fxn, defects in complement)

prototype hereditary hemoglobinopathy; point mutation-> substitution of Val for Glu at 6th position of b-globin chain -> HbS -> aggregation & polymerization when deoxygenated -> formation of HbS fibers -> distortion of RBC's -> 2 major consequences: 1) chronic hemolytic anemia (b/c low Hb, low Hct, sickled cells stuck in spleen, reticulocytosis destroyed), 2) occlusion of small BV (due to increased expression of adhesion molecules on altered membranes or non-sickled cells, increased transit time back to heart) -> ischemic tissue damage; septicemia & meningitis due to pneumococci and H. influenza most common causes of death in kids with SSA

hyperbilirubinemia, electrophoresis shows HbS, DNA analysis, splenic atrophy

Type

Wintrobe's Morphology Classification

Epidemiology

Unique Features

Pathophsio Cause

Etiology/Pathogenesis

CBC & retic results

Add'l Dx tests to confirm

G6PD deficiency

X-linked genetic variant (defect expressed in all RBC's of affected male-> more vulnerable); many variants, 10% black Americans; esp West Africa, Mediterranean, Middle East, SE Asia; protects against malaria

manifests after exposure to oxidant stress (due to primaquine, G6PD reduces NADP to NADPH-> chloroquine, sulfas, reducing power to reduce glutathione nitrofurantions, viral normal b/t > protects against oxidant injury; hepatitis, pneumonia, defective folding crises; low Hb, of G6PD protein, deficient G6PD -> abnormalities in typoid fever, fava low Hct with intravascular & glutathione metabolism -> beans)-> oxidation of oxidative stress, extravascular sulfhydryl groups of decreased ability of RBC to protect reticulocytosis globin chains -> itself against oxidatve injuries -> hemolysis on recovery denaturation of Hb, hemolytic disease; self-limiting after formation of Heinz only younger RBC's remain in circ bodies -> membrane damage, decreased deformability-> splenic destruction

Anemias

Acute hemorrhage

polychromatophilic when recovering (at ~7days)

if blood lost externally, adequacy of RBC recovery may be hampered by iron deficiency

increased blood loss

loss of blood volume -> shift of H2O from interstitial fluid compartment -> hemodilution-> lowered Hct

low Hb, low Hct, thrombocytosis, leukocytosis immed after blood loss, reticylocytosis as marrow regenerates

Anemias
Peripheral Blood Images

oval macrocytes, bone marrow is hypercellular with large erythroblasts & giant/ abnormally shaped metamyelocytes

"

"

Anemias
Perpheral Blood Images

hypochromic, microcytic cells with occasional target cells & pencil-shaped poikilocytes

Anemias
Perpheral Blood Images

marked hypochromic, microcytic cells, target cells, poikilocytosis, "golf ball" cells caused by precipitation of bglobin chains (cresyl blue stain)

severe abnormalities, marked anisocytosis, hypochromic, microcytic RBC's, target cells, basophilic stippling, fragments common, inclusions not seen (b/c removed by spleen), poorly hemoglobinized normoblasts

Anemias
Perpheral Blood Images

no abnormal cells; bone marrow shows hypoplasia, replacement of hemopoietic tissue with fat (75% of marrow)

burr cells, spurs

thrombocytopenia, nucleated RBC's, immature WBC's (presence of these distinguishes from multiple myeloma)

blast cells, myeloid cells

Anemias
Perpheral Blood Images

increase in # of normoblasts in marrow

"

"

Anemias

sickled cells, target cells

Perpheral Blood Images

Heinz bodies, bite cells

Anemias

polychromatophilic macrocytes (reticulocytes)