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Hemolytic anemia. Rakesh Biswas MD, Professor, Department of Medicine, People's College of Medical Sciences, Bhanpur, Bhopal, India. Young man of 19 Complains of giddiness weakness, pallor Examination reveals a spleen mild lemon yellow sclera. - PowerPoint PPT Presentation
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Hemolytic Hemolytic anemiaanemia
Rakesh Biswas
MD, Professor, Department of Medicine, People's College of Medical Sciences,
Bhanpur, Bhopal, India
Young man of 19
Complains of giddiness weakness, pallor
Examination reveals a spleenmild lemon yellow sclera
How shall you investigate to find out the cause of the problem?
Laboratory investigations:
Severe normochromic, normocytic anemia (hemoglobin level of 6.4 g/dL
Reticulocyte count of 12.2%.
Blood film:
Bilirubin level of 2.5 mg/dL,
Lactate dehydrogenase (LDH) of 2140 IU/L,
Haptoglobin below 7 mg/dL
Introduction
Mean life span of a RBC-120daysMean life span of a RBC-120daysRemoved Extravascularly by- Macrophages Removed Extravascularly by- Macrophages
of RE system of RE system
Hemolytic Anemia
Definition:Definition:Those anemias which result from an increase Those anemias which result from an increase
in RBC destructionin RBC destruction
Classification:Classification:Congenital / HereditaryCongenital / HereditaryAcquiredAcquired
Laboratory Evaluation of HemolysisExtravascular Intravascular
HEMATOLOGIC
Routine blood filmReticulocyte countBone marrow examination
Polychromatophilia
Erythroid hyperplasia
Polychromatophilia
Erythroid hyperplasia
PLASMA OR SERUM
BilirubinHaptoglobinPlasma hemoglobinLactate dehydrogenase
Unconjugated , Absent N/ (Variable)
UnconjugatedAbsent (Variable)
URINE
BilirubinHemosiderinHemoglobin
000
0++ severe cases
Hemoglobinuria
Classification of Hemolytic Anemias
Hereditary 1. Abnormalities of RBC interior a.Enzyme defects: G-6-PD def,PK def b.Hemoglobinopathies 2. RBC membrane abnormalities a. Hereditary spherocytosis etc. b. PNH
Acquired c. Spur cell anemia3. Extrinsic factors a. Hypersplenism b. Antibody: immune hemolysis c. Mechanical trauma: MAHA d. Infections, toxins, etc
Ref : Harrison’s
Features of HEMOLYSISBilirubinBilirubin
LDHLDHReticulocytes, n-RBCReticulocytes, n-RBC
HaptoglobulinsHaptoglobulins+ve Urinary hemosiderin, Urobilinogen+ve Urinary hemosiderin, Urobilinogen
Blood FilmBlood Film
Spherocytes No spherocytes FragmentationSpherocytes No spherocytes Fragmentation
DCT +ve DCT –veDCT +ve DCT –ve
AI Hemolysis H. Sherocytosis Malaria, AI Hemolysis H. Sherocytosis Malaria, Clostidium Clostidium Hereditery enzymopathies Microangiopathic, Hereditery enzymopathies Microangiopathic,
Traumatic Traumatic
Red Cell Membrane Defects
1.Hereditary SpherocytosisUsually inherited as AD disorderUsually inherited as AD disorderDefect: Deficiency of Beta Spectrin or Ankyrin Defect: Deficiency of Beta Spectrin or Ankyrin
Loss of membrane in Spleen & RES Loss of membrane in Spleen & RES becomes more sphericalbecomes more spherical Destruction in Destruction in SpleenSpleen
RBC Membrane
C/F:C/F:AsymptomaticAsymptomaticFluctuating hemolysisFluctuating hemolysisSplenomegalySplenomegalyPigmented gall stones- 50%Pigmented gall stones- 50%
Complications
Clinical course may be complicated with Clinical course may be complicated with Crisis:Crisis:Hemolytic Crisis: associated with infection: associated with infectionAplastic crisis:: associated with Parvovirus associated with Parvovirus
infectioninfection
Inv:Inv:Test will confirm HemolysisTest will confirm HemolysisP Smear: SpherocytesP Smear: SpherocytesOsmotic Fragility: IncreasedOsmotic Fragility: Increased
Screen Family membersScreen Family members
Osmotic Fragility
Management:Management:Folic Acid 5mg weekly, prophylaxis life longFolic Acid 5mg weekly, prophylaxis life longSpleenectomySpleenectomyBlood transfusion in Ac, severe hemolytic crisisBlood transfusion in Ac, severe hemolytic crisis
2.Hereditary Elliptocytosis Equatorial Africa, SE AsiaEquatorial Africa, SE Asia AD / ARAD / AR Functional abnormality in one or more anchor Functional abnormality in one or more anchor
proteins in RBC membrane- Alpha spectrin , proteins in RBC membrane- Alpha spectrin , Protein 4.1Protein 4.1
Usually asymptomaticUsually asymptomatic Mx: Similar to H. spherocytosisMx: Similar to H. spherocytosis Variant:Variant:
3.SE-Asian ovalocytosis:Common in Malaysia , Indonesia…Common in Malaysia , Indonesia…Asymptomatic-usuallyAsymptomatic-usuallyCells oval , rigid ,resist invasion by malarial Cells oval , rigid ,resist invasion by malarial
parasitesparasites
ElliptocytosisElliptocytosis
Red Cell Enzymopathies
Physiology:Physiology:EM pathway: ATP productionEM pathway: ATP productionHMP shunt pathway: NADPH & Glutathione HMP shunt pathway: NADPH & Glutathione
productionproduction
1. Glucose-6-Phosphate Dehydrogenase ( G6PD ) DeficiencyPivotal enzyme in HMP Shunt & produces Pivotal enzyme in HMP Shunt & produces
NADPH to protect RBC against oxidative NADPH to protect RBC against oxidative stressstress
Most common enzymopathy -10% Most common enzymopathy -10% world’s populationworld’s population
Protection against MalariaProtection against MalariaX-linkedX-linked
(Oxidised form)(Reduced form)
Clinical Features:Clinical Features:Acute drug induced hemolysis:Acute drug induced hemolysis:
Aspirin, primaquine, quinine, chloroquine, Aspirin, primaquine, quinine, chloroquine, dapsone….dapsone….
Chronic compensated hemolysisChronic compensated hemolysis Infection/acute illnessInfection/acute illnessNeonatal jaundiceNeonatal jaundiceFavismFavism
Inv:Inv:e/o non-spherocytic intravascular e/o non-spherocytic intravascular
hemolyishemolyisP. Smear: Bite cells, blister cells, P. Smear: Bite cells, blister cells,
irregular small cells, Heinz bodies, irregular small cells, Heinz bodies, polychromasiapolychromasia
G-6-PD levelG-6-PD level
Treatment: Treatment: Stop the precipitating drug or treat the Stop the precipitating drug or treat the
infectioninfectionAcute transfusions if requiredAcute transfusions if required
2. Pyruvate Kinase DeficiencyARARDeficient ATP production, Chronic Deficient ATP production, Chronic
hemolytic anemiahemolytic anemiaInv;Inv;
P. Smear: Prickle cellsP. Smear: Prickle cellsDecreased enzyme activityDecreased enzyme activity
Treatment: Treatment: Transfusion may be requiredTransfusion may be required
Hemolobinopathies…Hemolobinopathies…
Autoimmune Hemolytic Anemia
Result from RBC destruction due to RBC Result from RBC destruction due to RBC autoantibodies: Ig G, M, E, Aautoantibodies: Ig G, M, E, A
Most commonly-idiopathicMost commonly-idiopathicClassificationClassification
Warm AI hemolysis:Ab binds at 37degree Warm AI hemolysis:Ab binds at 37degree CelsiusCelsius
Cold AI Hemolysis: Ab binds at 4 degree Cold AI Hemolysis: Ab binds at 4 degree CelsiusCelsius
1.Warm AI Hemolysis:Can occurs at all age groupsCan occurs at all age groupsF > MF > MCauses:Causes:
50% Idiopathic50% IdiopathicRest - secondary causes:Rest - secondary causes:
1.Lymphoid neoplasm: CLL, Lymphoma, 1.Lymphoid neoplasm: CLL, Lymphoma, MyelomaMyeloma
2.Solid Tumors: Lung, Colon, Kidney, Ovary, 2.Solid Tumors: Lung, Colon, Kidney, Ovary, ThymomaThymoma
3.CTD: SLE,RA3.CTD: SLE,RA4.Drugs: Alpha methyl DOPA, Penicillin , 4.Drugs: Alpha methyl DOPA, Penicillin ,
Quinine, ChloroquineQuinine, Chloroquine5.Misc: UC, HIV5.Misc: UC, HIV
IMMUNOHEMOLYTIC ANEMIA
MACROCYTE
SPHEROCYTE
Direct antiglobulin test demonstrating the presence of autoantibodies (shown here) or complement on the surface of the red blood cell.
complement
Inv:Inv:e/o hemolysis, MCV e/o hemolysis, MCV P Smear: Microspherocytosis, n-RBCP Smear: Microspherocytosis, n-RBCConfirmation: Coomb’s Test / Antiglobulin testConfirmation: Coomb’s Test / Antiglobulin test
TreatmentTreatmentCorrect the underlying causeCorrect the underlying causePrednisolone 1mg/kg po until Hb reaches Prednisolone 1mg/kg po until Hb reaches
10mg/dl then taper slowly and stop10mg/dl then taper slowly and stopTransfusion: for life threatening problemsTransfusion: for life threatening problems If no response to steroids If no response to steroids Spleenectomy or, Spleenectomy or, Immunosuppressive: Azathioprine, Immunosuppressive: Azathioprine,
CyclophosphamideCyclophosphamide
2. Cold AI HemolysisUsually Ig MUsually Ig MAcute or Chronic formAcute or Chronic formChronic:Chronic:
C/F:C/F:Elderly patients Elderly patients Cold , painful & often blue fingers, toes, Cold , painful & often blue fingers, toes,
ears, or nose ( Acrocyanosis) ears, or nose ( Acrocyanosis) Inv:Inv:
e/o hemolysise/o hemolysisP Smear: MicrospherocytosisP Smear: Microspherocytosis Ig M with specificity to I or I AgIg M with specificity to I or I Ag
Other causes of Cold Agglutination:Other causes of Cold Agglutination: Infection: Mycoplasma pneumonia, Infec Infection: Mycoplasma pneumonia, Infec
MononucleosisMononucleosisPCH : Rare cause seen in children in PCH : Rare cause seen in children in
association with cong syphilisassociation with cong syphilis
Treatment:Treatment:Treatment of the underlying causeTreatment of the underlying causeKeep extremities warmKeep extremities warmSteroids treatmentSteroids treatmentBlood transfusionBlood transfusion
Non-Immune Acquired Hemolytic Anemia
1. Mechanical TraumaA). Mechanical heart valves, Arterial grafts: A). Mechanical heart valves, Arterial grafts:
cause shear stress damagecause shear stress damage
B).March hemoglobinuria: Red cell damage in B).March hemoglobinuria: Red cell damage in capillaries of feetcapillaries of feet
C). Thermal injury: burnsC). Thermal injury: burns
D). Microangiopathic hemolytic anemia D). Microangiopathic hemolytic anemia (MAHA):(MAHA): by passage of RBC through fibrin strands by passage of RBC through fibrin strands deposited in small vessels deposited in small vessels disruption of disruption of RBC eg: DIC,PIH, Malignant HTN,TTP,HUSRBC eg: DIC,PIH, Malignant HTN,TTP,HUS
TRAUMATIC HEMOLYSIS
Acquired hemolysis
2.Infection
F. malaria: intravascular hemolysis: severe F. malaria: intravascular hemolysis: severe called called ‘Blackwater fever’
Cl. perfringens septicemiaCl. perfringens septicemia
3.Chemical/Drugs: oxidant denaturation of oxidant denaturation of hemoglobinhemoglobin
Eg: Dapsone, sulphasalazine, Arsenic Eg: Dapsone, sulphasalazine, Arsenic gas, Cu, Nitrates & Nitrobenzenegas, Cu, Nitrates & Nitrobenzene
The direct antiglobulin test was positive for complement (C3d) (++), and IgG (++-).
Also was positive for agglutinins of IgM type and had a titer of 1:1024.
Serologies for human immunodeficiency virus, hepatitis B and C viruses, and Mycoplasma pneumoniae were negative.
Rheumatoid factor and antinuclear antibodies were undetectable.
Prednisone therapy was started at a dose of 1 mg/kg intravenously, daily. Hemoglobin level rose to 11 g/dL, concomitantly with the
improvement of hemolytic signs.
A reduction of positivity of both direct and indirect antiglobulin tests (polyvalent serum + ; C3d + ; IgG+ ), as well as a reduction of cold agglutinin titers (1:128), was observed 8 weeks after corticosteroid therapy.
Three months later, corticosteroids were tapered to a maintenance dose of 25 mg daily.
Hemolysis recurred again with the fall of hemoglobin to 7 g/dL.
The direct antiglobulin test recurred positive for polyvalent serum (+++), complement (+++), and IgG (+++), while cold agglutinin titers again became strongly positive (1:256).
Immunophenotyping of bone marrow cells showed that 10% of all the cells were CD20 and CD19 positive.
CD20 is widely expressed on B-cells.
CD20 could play a role in Ca2+ influx across plasma membranes, maintaining intracellular Ca2+ concentration and allowing activation of B cells.
Rituximab is a monoclonal antibody that binds to CD 20
Rituximab was started at the dose of 375 mg/mq once weekly, for a total of 4 doses
Hemoglobin value reached 13.5 g/dL just before the third dose, although biochemical signs of hemolysis remained substantially unaltered.
At the end of therapy, the hemolytic signs disappeared, the direct and indirect antiglobulin tests became negative, and cold agglutinin titers
fell to 1:32
Immunophenotyping of bone marrow cells showed the absence
of CD20 and CD19 B cells.
Summary of lecture
Learning points