HEREDITARYSPHEROCYTOSIS Defective or absent spectrin molecule Leads to loss of RBC membrane, leading tospherocytosis Decreased deformability of cell Increased osmotic fragility Extravascular hemolysis in spleen
HEREDITARYSPHEROCYTOSISOsmotic Fragility0204060801000.3 0.4 0.5 0.6NaCl (% of normal saline)%HemolysisNormal HS
Hereditary SpherocytosisUsually has an autosomal dominantinheritance pattern and incidence ofapproximately 1:1000 to 1:4500.In ~20% patients, the absence ofhematologic abnormalities in familymembers suggests either autosomalrecessive inheritance or spontaneousmutation.
Hereditary SpherocytosisSometimes clinically apparent in earlyinfancy but often escapes detection untiladult life.
Hereditary SpherocytosisClinical Manifestations– Prominent jaundice accounts for disorder’sprior designation as “congenital hemolyticjaundice” and is due to an increasedconcentration of unconjugated (indirect-reacting) bilirubin in plasma.
Hereditary SpherocytosisClinical Manifestations– Jaundice may be intermittent and tends to be lesspronounced in early childhood.– Due to increased bile pigment production,pigmented gallstones are common, even inchildhood.– Clinical course may be complicated by crisisHemolytic crisis (infection).Megaloblastic crisis (folate deficiency, especially inpregnancy).Aplastic crisis (parvovirus infection).
Hereditary SpherocytosisDiagnosis– Must be distinguished primarily from thespherocytic hemolytic anemias associated withRBC antibodies.– If present, family history of anemia and/orsplenectomy.– Immune spherocytosis positive directCoombs test.
Hereditary SpherocytosisDiagnosis– Splenomegaly can also be seenCirrhosis.Clostridial infections.G6PD deficiency.
Hereditary SpherocytosisTreatment– Splenectomy reliably corrects the anemia.– Splenectomy in children should be postponeduntil the age of 4-years.– Polyvalent pneumococcal vaccine should beadministered at least 2-weeks beforesplenectomy.– In patients with severe hemolysis folic acid(5-mg/d) should be administeredprophylactically.
Hereditary SpherocytosisTreatment– Acute, severe hemolytic crises requirestransfusion.
Hereditary ElliptocytosisHeterogeneous disorders in elliptocytic redcells.Functional abnormality of anchor proteinsin red cell membrane (alpha spectrin orprotein 4.1).Autosomal dominant or recessive.Less common than hereditary spherocytosis(1/10,000).
Red cell membrane has a lipid bilayer to which a‘skeleton’ of filamentous proteins is attached viaspecial linkage proteins.
Hereditary ElliptocytosisClinical presentation depends upon degreeof membrane defect.Asymptomatic diagnosed on blood film.Chronic compensated hemolytic state.
Hereditary ElliptocytosisTreatment– Same as hereditary spherocytosis only inchronic hemolytic anemia.Differential diagnosis includes– Iron deficiency anemia– Thalassaemia.– Mylofibrosis.– Mylodysplasia.– Pyruvate kinase deficiency.
Paroxysmal NocturnalHemoglobinuriaGPI Proteins GPI links a series of proteins to outer leaf of cellmembrane via phosphatidyl inositol bridge, withmembrane anchor via diacylglycerol bridge PIG-A gene, on X-chromosome, codes for synthesisof this bridge; multiple defects known to cause lackof this bridge Absence of decay accelerating factor leads to failureto inactivate complement & thereby to increased celllysis
HEMOLYTIC ANEMIAMembrane abnormalities -Enzymopathies Deficiencies in Hexose MonophosphateShunt– Glucose 6-Phosphate Dehydrogenase Deficiency Deficiencies in the EM Pathway– Pyruvate Kinase Deficiency
IMMUNE HEMOLYTIC ANEMIAGeneral Principles All require antigen-antibody reactions Types of reactions dependent on:– Class of Antibody– Number & Spacing of antigenic sites on cell– Availability of complement– Environmental Temperature– Functional status of reticuloendothelial system Manifestations– Intravascular hemolysis– Extravascular hemolysis
IMMUNE HEMOLYTIC ANEMIAGeneral Principles - 2 Antibodies combine with RBC, & either1. Activate complement cascade, &/or2. Opsonize RBC for immune system If 1, if all of complement cascade is fixed to red cell,intravascular cell lysis occurs If 2, &/or if complement is only partially fixed,macrophages recognize Fc receptor of Ig &/or C3bof complement & phagocytize RBC, causingextravascular RBC destruction
IMMUNE HEMOLYTICANEMIACoombs Test - Direct Looks for immunoglobulin &/or complement ofsurface of red blood cell (normally neither found onRBC surface) Coombs reagent - combination of anti-humanimmunoglobulin & anti-human complement Mixed with patient’s red cells; if immunoglobulin orcomplement are on surface, Coombs reagent will linkcells together and cause agglutination of RBCs
IMMUNE HEMOLYTICANEMIACoombs Test - Indirect Looks for anti-red blood cell antibodies in thepatient’s serum, using a panel of red cells withknown surface antigens Combine patient’s serum with cells from a panelof RBC’s with known antigens Add Coombs’ reagent to this mixture If anti-RBC antigens are in serum, agglutinationoccurs
DRUG-INDUCEDHEMOLYSISImmune Complex Mechanism Drug & antibody bind in the plasma Immune complexes either– Activate complement in the plasma, or– Sit on red blood cell Antigen-antibody complex recognized by RE system Red cells lysed as “innocent bystander” of destructionof immune complex REQUIRES DRUG IN SYSTEM
DRUG-INDUCEDHEMOLYSISHaptenic Mechanism Drug binds to & reacts with red cell surfaceproteins Antibodies recognize altered protein, ± drug,as foreign Antibodies bind to altered protein & initiateprocess leading to hemolysis
DRUG-INDUCEDHEMOLYSISTrue Autoantibody Formation Certain drugs appear to cause antibodiesthat react with antigens normally found onRBC surface, and do so even in the absenceof the drug
ALLOIMUNE HEMOLYSISHemolytic Transfusion Reaction Caused by recognition of foreign antigens on transfusedblood cells Several types– Immediate Intravascular Hemolysis (Minutes) - Due to preformedantibodies; life-threatening– Slow extravascular hemolysis (Days) - Usually due to repeatexposure to a foreign antigen to which there was a previousexposure; usually only mild symptoms– Delayed sensitization - (Weeks) - Usually due to 1st exposure toforeign antigen; asymptomatic
ALLOIMMUNE HEMOLYSISTesting Pre-transfusion ABO & Rh Type of both donor & recipient Antibody Screen of Donor & Recipient,including indirect Coombs Major cross-match by same procedure(recipient serum & donor red cells)
ALLOIMMUNE HEMOLYSISHemolytic Disease of the Newborn Due to incompatibility between mother negative foran antigen & fetus/father positive for that antigen.Rh incompatibility, ABO incompatibility mostcommon causes Usually occurs with 2nd or later pregnancies Requires maternal IgG antibodies vs. RBC antigensin fetus
ALLOIMMUNE HEMOLYSISHemolytic Disease of the Newborn -#2 Can cause severe anemia in fetus, witherythroblastosis and heart failure Hyperbilirubinemia can lead to severe brain damage(kernicterus) if not promptly treated HDN due to Rh incompatibility can be almost totallyprevented by administration of anti-Rh D to Rhnegative mothers after each pregnancy
AUTOIMMUNE HEMOLYSIS Due to formation of autoantibodies thatattack patient’s own RBC’s Type characterized by ability ofautoantibodies to fix complement & site ofRBC destruction Often associated with eitherlymphoproliferative disease or collagenvascular disease
AUTOIMMUNE HEMOLYSISWarm Type Usually IgG antibodies Fix complement only to level of C3,if at all Immunoglobulin binding occurs at all temps Fc receptors/C3b recognized by macrophages; Hemolysis primarily extravascular 70% associated with other illnesses Responsive to steroids/splenectomy
AUTOIMMUNE HEMOLYSISCold Type Most commonly IgM mediated Antibodies bind best at 30º or lower Fix entire complement cascade Leads to formation of membrane attack complex,which leads to RBC lysis in vasculature Typically only complement found on cells 90% associated with other illnesses Poorly responsive to steroids, splenectomy;responsive to plasmapheresis
HEMOLYTIC ANEMIASummary Myriad causes of increased RBC destruction Marrow function usually normal Often requires extra folic acid to maintainhematopoiesis Anything that turns off the bone marrow canresult in acute, life-threatening anemia