Approach to Congental Hemolytic Anemias

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