approach to congental hemolytic anemias
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APPROACH TO CONGENTAL HEMOLYTIC ANEMIAS
Dr. Somendra ShuklaFellow Neonatology
Other questions to guide you
Is this acute or chronic? Is this acute or chronic? Is there a family history? Is there a family history? Does the child appear ill, or have signs of Does the child appear ill, or have signs of systemic disease? systemic disease? Are the liver and spleen large? Are the liver and spleen large? (extramedullary extramedullary sites of sites of hematopoiesis hematopoiesis) Exposure to infectious disease: HIV, Exposure to infectious disease: HIV, malaria, dengue malaria, dengue
But first, is there really anemia?
• Anemia: Central venous hemoglobin < 13 g/dL or capillary hemoglobin < 14.5 g/dL in infant > 34 weeks and 0-28 days old
The Three Primary Measures
MeasurementA. RBC count (RCC) 5 million B. Hemoglobin 15 g%C. Hematocrit (PCV)45
A x 3 = B x 3 = C - This is the rule of thumbCheck whether this holds good in a given result
If not -indicates micro or macrocytosis or hypochro.
The Three Derived Indiceseasurement Normal
A. RCC 5 million B. Hemoglobin 15 g%C. Hematocrit 45 %
MCV C ÷ A x 10 = 90 flMCH B ÷ A x 10 = 30 pgMCHC (%) B ÷ C x 100 = 33%
Anemia – Second Test
RETICULOCYTE COUNT %
NormalLess than 2%
• ‘RBC to be’ or Apprentice RBC• Fragments of nuclear material• RNA strands which stain blue
Reticulocyte
No definite nucleus
Reticulum of RNA
Deep blue staining
Light blue cytoplasm
Cell size about 10 µ
Reticulocytes
Leishman’sSupravital
Reticulocyte Production IndexFor example, the RPI is calculated as follows
Reticulocyte count 9%Hb content 7.5 g%1. Correction for Anemia
= 9 x (7.5 ÷ 15) = 9 x 0.5 = 4.5 %2. Correction for life span
4.5 ÷ 2 = 2.25 %3. Thus, the RPI is 2.25
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Anemia
Hypoproliferative Hemolytic
RPI < 2 RPI > 2
The Reticulocyte production index (RPI, also called a corrected reticulocyte count)
•raw reticulocyte count is misleading in anemic patients. •reticulocyte count is not really a count but rather a percentage: it reports the number of reticulocytes as a percentage of the number of red blood cells. •In anemia, the patient's red blood cells are depleted, creating an erroneously elevated reticulocyte count
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Workup – Third Test
• The next step is ‘What is the size of RBC’ ?• MCV indicates the Red cell volume (size)• Both the MCH & MCHC tell Hb content of RBC• If the RPI is 2 or less• We are dealing with either
– Hypoproliferative Anemia (lack of raw material)– Maturation defect with less production– Bone marrow suppression (primary/ secondary)
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Mean Cell Volume (MCV)
• RBC size is measured indirectly by• The Mean Cell Volume (MCV) and RDW
Microcytic
< 80 fl
MCV
Normocytic Macrocytic
80 -100 fl > 100 fl
< 6.5 µ 6.5 - 9 µ > 9 µ
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Anemia Workup - MCV
Microcytic
MCV
Normocytic Macrocytic
Iron Deficiency (IDA)Chronic InfectionsThalassemiasHemoglobinopathiesSideroblastic Anemia
Chronic diseases, CKDEarly IDAHemoglobinopathiesPrimary marrow disordersCombined deficienciesIncreased destruction
Megaloblastic anemiasLiver disease/alcoholHemoglobinopathiesMetabolic disordersMarrow disordersIncreased destruction
Presentation of hemolytic anemia
• Jaundice is usually the first symptom• Compensatory reticulocytosis• Pallor presents after 48 hours of age• Unconjugated hyperbilirubinemia of > 10-12
mg/dL• Tachypnea and hepatosplenomegaly may be
present
Hemolytic Anemia
• Definition:– Those anemias which result from an increase in
RBC destruction
• Classification:– Congenital / Hereditary– Acquired
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)
URINEBilirubinHemosiderinHemoglobin
000
0++ severe cases
Inherited or acquired:
• Inherited HA are usually caused by intrinsic defect.• While acquired HA are caused by an extrinsic
defect.• However there are some exceptions: Paroxysmal
nocturnal haemoglobinuria (PNH) which is an acquired intrinsic defect, and severe hereditaryG6PD enz deficiency which requires the presence of an extrinsic trigger such as the antimalarial drug for the intrinsic defect to manifest.
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 HEMOLYSISBilirubin
LDHReticulocytes, n-RBC
Haptoglobulins+ve Urinary hemosiderin, Urobilinogen
Blood Film
Spherocytes No spherocytes Fragmentation
DCT +ve DCT –ve
AI Hemolysis H. Sherocytosis Malaria, Clostidium Hereditery enzymopathies Microangiopathic,
Traumatic
Red Cell Membrane Defects
1.Hereditary Spherocytosis– Usually inherited as AD disorder– Defect: Deficiency of Beta Spectrin or Ankyrin
Loss of membrane in Spleen & RES becomes more spherical Destruction in Spleen
RBC Membrane
– C/F:• Asymptomatic• Fluctuating hemolysis• Splenomegaly• Pigmented gall stones- 50%
Complications
• Clinical course may be complicated with Crisis:– Hemolytic Crisis: associated with infection– Aplastic crisis: associated with Parvovirus infection
• Inv:– Test will confirm Hemolysis– P Smear: Spherocytes– Osmotic Fragility: Increased
Screen Family members
Osmotic Fragility
• Management:– Folic Acid 5mg weekly, prophylaxis life long– Spleenectomy– Blood transfusion in Ac, severe hemolytic crisis
2.Hereditary Elliptocytosis• Equatorial Africa, SE Asia• AD / AR• Functional abnormality in one or more anchor
proteins in RBC membrane- Alpha spectrin , Protein 4.1
• Usually asymptomatic• Mx: Similar to H. spherocytosis• Variant:
3.SE-Asian ovalocytosis:• Common in Malaysia , Indonesia…• Asymptomatic-usually• Cells oval , rigid ,resist invasion by malarial parasites
Elliptocytosis
Red Cell Enzymopathies
• Physiology:– EM pathway: ATP production– HMP shunt pathway: NADPH & Glutathione
production
1. Glucose-6-Phosphate Dehydrogenase ( G6PD ) Deficiency– Pivotal enzyme in HMP Shunt & produces NADPH
to protect RBC against oxidative stress–Most common enzymopathy -10% world’s
population–Protection against Malaria–X-linked
(Oxidised form)(Reduced form)
• Clinical Features:– Acute drug induced hemolysis:
• Aspirin, primaquine, quinine, chloroquine, dapsone….– Chronic compensated hemolysis– Infection/acute illness– Neonatal jaundice– Favism
• Inv:– e/o non-spherocytic intravascular hemolyis– P. Smear: Bite cells, blister cells, irregular
small cells, Heinz bodies, polychromasia– G-6-PD level
• Treatment: – Stop the precipitating drug or treat the
infection– Acute transfusions if required
2. Pyruvate Kinase Deficiency– AR– Deficient ATP production, Chronic hemolytic
anemia– Inv;
• P. Smear: Prickle cells• Decreased enzyme activity
– Treatment: • Transfusion may be required
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