Pathology(Anemia)*

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2 major mechanisms in w/c anemia is caused

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1)Dec. red cell production: hematopoietic cell damage due to infxn.,drugs,radiation;def. of factors for heme synthesis(iron) or DNA synthesis(vit.B12,folate) 2)Inc. red loss:external loss;red cell destruction(hemolytic anemia)

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Signs & symptoms of acute post hemorrhagic anemia

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Clinical symptoms related to hypovolemia;prior to hemodilution(compensatory inc. in plasma vol.),there is no dec. in hemoglobin, hematocrit,& RBC due to parallel loss of both red cells & plasma;marked inc. in platelet count

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Types of anemia due to dec. RBC production

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Iron def. anemia(impaired heme synth.),Pernicious anemia(vit.B12 def.) Folate def(delayed DNA replication), Aplastic anemia(dec. hematopoiesis), Anemia of chronic dse.,Myeloplastic anemia(bone marrow replacement by a malignant tumor)

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Anemia w/ charact. hypochromia & microcytosis,dec. iron ,inc. TIBC,& dec. serum ferritin;due to dietary def. in infants & preadolescents,excess menstrual bleeding, & chronic bld. loss from GIT

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Iron Def. Anemia
-impaired heme synthesis

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Anemia w/ charact. pancytopenia,oval macrocytes,hypersegmented neutrophils, megaloplastic hyperplasia,achlorhydria, anti-intrinsic factor antibodies, hyperreflexia,absent position & vibration sensatio,impaired vit.B12 absorption corrected by intrinsic factor(abnormal Schilling test)

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Pernicious Anemia
-autoimmune gastritis~lack of gastric intrinsic factor~failure to absorb Vit.B12~delayed DNA replication

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Anemia charact. by pancytopenia,oval macrocytes,hypersegmented neutrophils & megaloblastic hyperplasia;due to dietary def. & malabsorption synd. resulting in delayed DNA replication

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Folate Def.

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Anemia charact. by pancytopenia, reticulocytopenia, & marked hypocellularity of the bone;due to toxic drugs & chemicals;often idiopathic;greatly diminished hematopoiesis

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Aplastic Anemia

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Causes of iron def. anemia

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Chronic bld. loss(most common, menorrhagia,GIT bleeding),dietary def.(rare,usually occurs in infants w/ in 1st 6mos),inc. iron requirement(pregancy,infants & preadolescent who outgrow borderline iron stores)

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Clinical manifestations of iron def. anemia

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Pallor,fatigue,dyspnea on exertion, angina pectoris(people w/ coronary artery narrowing);when extreme(glossitis,gastritis,koilonychia, Plummer-Vinson synd.)

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Laboratory findings in iron def. anemia

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Dec. hemoglobin,hematocrit,& RBC count; hypochromic microcytic erythrocytes on peripheral smear;dec. serum iron & inc. TIBC;dec. body iron stores(measured by bone marrow examination for hemosiderin or dec. serum ferrit)

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Differential diagnosis for iron def. anemia

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Anemia of chronic dse. & B-thalasemia minor(both also hypochromic microcytic);in anemia of chronic dse.(dec. serum iron & TIBC);in B-thalasemia minor(inc. A2 hemoglobin)

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Type of anemia defined by large abnormal erythroid precursor cells(megaloblast)in bone marrow;caused by vit.B12 & folate def.;charact. by dec. DNA synth.~impaired red cell synth. & destruction w/in bone marrow(ineffective erythropoiesis)

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Megaloblastic Anemia
-lab findings:peripheral bld.(pancytopenia,oval macrocytosis, hypersegmented neutrophils),bone marrow(megaloblastic hyperplasia)

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General features of pernicious anemia(most common form of vit.B12 def. megaloblastic anemia)

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Autoimmune disorder(autoimmune gastritis~failure of prod. of intrinsic factor w/c is needed for absorption of Vit.B12);achlorhydria(absent gastric free HCl acid);anti-intrinsic factor & antiparietal cell antibodies;inc. incidence of gastric carcinoma

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Clinical findings in pernicious anemia

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Insidious onset,lemon-yellow skin color,stomatitis & glossitis,subacute combined degeneration of spinal cord(demyelination of post. & lat. columns;ataxic gait,hyperreflexia w/ extensor plantar reflexes,impaired position & vibratory sensation)

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Laboratory findings in pernicious anemia

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Pancytopenia,hypersegmented neutrophils,megaloblastic hyperplasia of bone marrow,anti-intrinsic factor antibodies,antiparietal antibodies, abormal schilling test(impaired vit.B12 absorption corrected by intrinsic factor;if not corrected,charact. of intestinal malabsorption such as Crohn dse.,blind-loop synd.,tapeworm infestation)

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Second most common form of anemia w/c is due to a wide variety of primary disorders(rheumatoid arthritis,renal dse.,chronic infxn.);normochromic & normocytic;dec. TIBC(unlike iron def. anemia)

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Anemia of Chronic Dse.
-dec. serum iron,hypochromia & microcytosis when assoc. w/ chronic inflam. states

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Other forms of vit.B12 def. megaloblastic anemia other than pernicious anemia

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Total gastric resection,Disorder of the distal ileum,Strict vegetarian diet, Intestinal malabsorption synd.,Blind-loop synd.(bact. overgrowth in surgically induced blind-loops),Broad spectrum antibiotic therapy(result in intestinal bact. overgrowth), Diphyllobothrium latum infestation(tapeworm infestation from eating freshwater fish)

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Megaloblastic anemia w/ no neurological sympt.,unlike vit.B12 def.

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Folate Def.
-due to severe dietary deprivation(common in chronic alcoholics & fad dieters),pregnancy,dilantin(phenytoin) or oral contraceptive therapy,folic acid antagonist chemotherapy,relative folate def.(inc. demand due to accel. erythropoeisis in hemolytic anemia), intestinal malabsorption(sprue,gardia lamblia)

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Immune hemolytic anemia due to maternal alloimminization to fetal red cell D antigen of the Rh bld. group system;can result from ABO incompatibility

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Hemolytic dse. of the newborn(erythroblastosis fetalis)
-results in fetal hemolytic anemia, hydrops fetalis(fetal heart failure w/ massive edema),kernictterus(most significant long-term consequence)

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Anemia charact. by hypocellular bone marrow w/ loss of hematopoietic, erythroid & myeloid precursor cells, megakaryoctes;peripheral pancytopenia(anemia,leukopenia,thrombocytopenia), reticulocytopenia;2nd to toxic exposure

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Aplastic Anemia
-caused by autoimmune dysfunction of cytotoxic T cells;induced by chemicals(benzene),radiation,therapeutic drugs(chloramphenicol,chlorpromazine,anti-malarial drugs,alkylating agents,viral infxn.(HPV,HCV)

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Anemia caused by bone marrow failure due to replacement by malignant neoplasm

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Myelophthisic Anemia
-less commonly due to bone marrow destruction from non-neoplastic causes(marrow fibrosis)

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Anemia charact. by inc. red cell destruction~inc.unconjugated bilirubin~ acholuric jaundice(jaundice w/o bilirubinuria)~pigment containing gallstones~inc. urine urobilinogen~ hemoglobinemia, hemoglobinuria, disappearance of serum haptoglobin, hemosiderosis

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Hemolytic Anemia
-inc. erythropoiesis(compensation for shortened red cell survival)

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Compensation in hemolytic anemia

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Inc. erythropoeisis:Normoblastic erythroid hyperplasia(bone marrow), Reticulocytosis(inc. # of newly formed red cells~inc. MCV),Polychromatophilia(inc. # of larger red cells equal to inc. reticulocyte count)

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2 types of hemolytic anemias, one genetically determined & other acquired

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Intracorpuscular(defect in the red cell itself) & extracorpuscular(defect in the extraerythrocytic env.-antibodies, enlarge spleen)

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Hemolytic anemia charact. by maternal aloimmunization to fetal red cell antigens(Rh system);caused by alloimmunization to ABO blood group antigens;diagnosed by inc. maternal anti-Rh antibodies later in preg.,cord bld. contains immature red cell precursor w/ (+)direct Coombs test, postnatal inc. in indirect bilirubin

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Hemolytic Dse. of the newborn(erythroblastosis fetalis)

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Prevention & treatment of erythroblastosis fetalis

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Administration of anti-Rh antibody(anti-D IgG)to mother at time of delivery, removing Rh(+)red cells from maternal circulation,exchange transfusion to remove unconjugated bilirubin from infant to prevent kernicterus

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An autosomal dominant hemolytic anemia charact. by red cell membrane skeletal protein abnormality due to def. of spectrin due to diverse mech.

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Hereditary Sperocytosis
-diagnosed by anemia,spherocytosis, reticulocytosis,inc. mean corpuscular hemoglobin conc.,unconjugated hyperbilirubinemia,acholuric jaundice, splenomegaly,inc. erythrocyte osmotic fragility to hypotonic saline

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An X-linked hemolytic anemia charact. by failure of erythrocyte hexose monophosphate shunt under oxidative stress;self-limited

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Glucose-6-phosphate dehydrogenase(G6PD)def.

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Hemolytic anemia charact. by severe anemia,recurrent painful & aplastic crises,nonhealing ulcers,recurrent splenic infarcts w/ progressive fibrosis~autosplenectomy

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Sickle Cell Anemia
-Beta-globin hemogloinopathy(mutation in coding sequence of B-globin gene,GAG[glu] to GTG[val]

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Diagnostic feautures of sickle cell anemia

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Anemia,reticulocytosis,sickle shape erythrocytes demonstrable on peripheral blood smear,homozygosity for hemoglobin S demonstrable by electrophoresis

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Hemolytic anemia due to mutations in B-globin gene~dec. synthesis of B-globin chains;aggregation of excess alpha-chains~hemolytic anemia & ineffective erythropoiesis;diagnosed by severe anemia,thalassemic red cell morphology, & inc. hemoglobin F

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B-Thalassemia major(Cooley anemia, Mediterranean anemia)

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Immune hemolytic anemia mediated by IgM antibodies(active <30°C);assoc. w/ lymphoid neoplasms;mediated by anti-i antibodies

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Chronic cold agglutinin dse.
-assoc. w/ Raynaud phenomenon; exacerbated by cold weather~puctuated by jaundice,hemoglobinemia & hemoglobinuria

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Hemolytic anemia charact. by deletion of 1 or more of the four alpha-globin genes(alpha-globin gene is reduplicated in tandem on each chromosome 16);differ according to the # of deletions

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Alpha-Thalassemia
-1 gene deletion(no clinical abnormalities),2 or 3(mild-to-mod. thalassemic states),4(intrauterine death);hemoglobin Barts(omega4)in fetal death;hemoglobin Barts(B4)in adult life

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Most common form of immune hemolytic anemia;mediated IgG autoantibodies that react w/ red cell surface antigens; charact. by classic features of hemolytic anemia,spherocytosis,(+)direct combs test

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Warm antibody autoimmune hemolytic anemia
-often 2nd to SLE,Hodgkin dse.,non-Hodgkin lymphoma

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Immune hemolytic anemia mediated by IgM antibodies(active <30°C) w/ specificity for I blood group antigens;complication of infectious mononucleosis or mycoplasma pneumoniae

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Acute cold agglutinin dse.

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Hemolytic anemia w/ acquired intracorpuscular defect arising from somatic mutations in PIG-A gene~impaired synthesis of the glycosylphosphatidylinositol(GPI)anchor(reqired for fixation of CD55,CD59,C8 binding protein to cellular surface for protection of red cells,granulocytes,& platelets from complemented-mediated lysis)

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Paroxysmal Nocturnal Hemoglobinuria
-charact. by inc. sensitivity to complement-induced red cell lysis~intravascular hemolytic anemia, pancytopenia,inc.venous thrombosis; hemoglobin-containing urine on awakening

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Test used to diagnose paroxysmal nocturnal hemoglobinuria

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Positive Ham(acid serum)test
-can also be diagnosed by flow cytometry demonstrating a population of CD59-neg. erythrocytes

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Autosomal dominant hemolytic anemia due to memb. skeletal protein abno°(def. in spectrin)charact. by spherocytes(trapped in the spleen~splenomegaly), inc. erythrocyte osmotic fragility to hypotonic saline,inc. mean corpuscular hemoglobin conc.(MCHC)

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Hereditary Sperocytosis
-most common intracorpuscular inherited hemolytic anemia in whites

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Hemolytic anemia caused by memb. skeletal protein abno° charact. by elongated,oval red cells;does not always cause anemia

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Hereditary elliptocytosis(ovalocytosis)

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Most common form of enzyme def. hemolytic anemia due to oxidative stress induced infxn.(primaquine, sulfonamides,fava beans)suggested by presence of "bite cells"on peripheral bld.

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Glucose-6-phosphate dehydrogenase(G6PD)def.
-X-linked disorder(10% of african americans & mediterranean origin)

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Second most common enzyme def. hemolytic anemia charact. by hereditary non-spherocytic hemolytic anemia; chronic & sustained anemia(in contrast to G6PD w/c is episodic & self-limited)

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Pyruvate Kinase Def.

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Hemolytic anemia due to genetic abno° of the hemoglobin structure:hemoglobin S(most common),hemoglobin C,hemoglobin E(urban centers)

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Hemoglobinopathies

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Hemoglobinopathy w/c affects 7% of african americans,confers resistance to falciparum malarial infxn.;due to mutation in codon 6 of B-globin gene~subst. of valine for glutamic acid;polymerizes at low 02~elongated, sickle shape red cells(sickle cell anemia)~hemolysis & obstruction of microvasculature

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Hemoglobin S disorder
-charact. by (+)sickle cell preparation

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Hemoglobin S disorder charact. by severe hemolytic anemia,chronic leg ulcers,vaso-occlusive painful crises precipitated by infxn. or dehyd., repeated infarction in lungs & spleen(autosplenectomy),aplastic crises(fall in hemoglobin conc. due to viral infxn.,human parvovirus),infectious complications(salmonella osteomyelitis)

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Sickle Cell Anemia
-homozygous form of hemoglobin S

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Heterozygous form of hemoglobin S w/c leads to sickle cell trait;w/o clinical consequence

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Sickle Cell trait

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Hemoglobinopathy disorder;if homozygous characterized by mild hemolytic anemia, splenomegaly,target cells,& intraerythrocytic crystals;if heterozygous,results in dse. if coinherited w/ other abno° hemoglobin

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Hemoglobin C disorder

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Hemoglobin disorder prevalent in southeast asia;common than hemoglobin S in urban areas;similar clinical & laboratory results to hemoglobin C disorder

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Hemoglobin E disorder

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Heterogenous group of genetic disorders charact. by def. prod. of alpha or beta globin chains of hemoglobin;heme synthesis is unaffected

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Thalasemias
-B-Thalasemia(most common form in Mediterranean & U.S);Alpha-Thalassemia(most common form in Southeast Asia)

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Thalasemia charact. by anemia(due to dec. in hemoglobin synthesis,dec. in red cell life span due to aggregation of insoluble excess alpha-chains, ineffective erythropeisis,folate def.), splenomegaly,distorted skull,facial bones,& long bones(erythroid marrow expansion),thalassemic red cell morphology(microcytosis,hypochromia, target cells,changes in size & shape), inc. hemoglobin F,hemosiderosis(due to hemolysis,ineffective erythropoiesis,& repeated transfusion)

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B-Thalasemia Major
-also known as Mediterranean anemia or Cooley anemia

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Results from compound heterozygosity or homozygosity for thalasemic variants of the B-globin gene

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B-Thalassemia Major

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Results from heterozygous inheritance of thalassemic variants of the B-globin gene;manifest as minimal hypochromic microcytic anemia,inc. hemaglobin A2(usefull in distinguishing from iron def. anemia & anemia of chronic dse.)

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B-Thalassemia minor

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Results from coinheritance of hemoglobin S gene & thalassemic variant of the B-globin gene;clinically similar to but less severe than sickle cell anemia

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Sickle Cell Thalassemia

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Thalassemia caused by defects in the promoter sequence,in introns, or in coding regions of the B-globin gene

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B-Thalassemias

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Thalassemia caused by deletions of one or more of the four alpha globin genes;may be charact. by inc. conc. of hemoglobin Barts(B4) or hemoglobin H(delta4)

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Alpha-Thalassemias

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Pathogenesis of microangiopathic hemolytica

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Assoc. w/ DIC & thombotic thrombocytopenic purpura in w/c partial occlusion of small vessels~mechanical disruption of erythrocytes~circulating red cell fragments(schistocytes or helmet cells)