Hemolytic Anemia in childrenHemolytic Anemia in children

Hematology-Oncology DivisionChild Health DepartementChild Health Departement Sumatera Utara University

Hemolytic anemia

Premature destruction of erythrocyte or red bloodPremature destruction of erythrocyte or red blood cells (RBC)

Anemia: rate of destruction exceeds the capacity of the marrow to produce RBC

RBC survival is shortened, RBC count falls erythropoetin is increasedfalls,erythropoetin is increased

Classification

1.Cellular: There are four main1.Cellular:- Intrinsic

abnormalities of the

There are four main types of Inherited Hemolytic anemia:

membrane- Enzymes 1.Hemoglobinopathies

- HemoglobinVirtually: Inherited

2.Thalassemia3.Enzyme defects4.Membrane defects

2.Extracellular Acqiured hemolytic2.Extracellular- antibodies- mechanical factors

Acqiured hemolytic anemia

Immune:- plasma factors

Virtually : Acquired- Direct complement

mediatedy q- Autoimmune HA

Warm ab IgGCold ab IgMCold ab IgM

….Classification

2.Non-Immune : 6.Oxydative drugs or

1.Mechanical trauma:HUS TTP DIC

6.Oxydative drugs or chemical

7.Severe burnsHUS, TTP,DIC

2.Thermal injury3.Acanthocytosis

8.Venom9.Infection: y

4.Severe hypophosphatemia

5 Wilson’s disease

Malaria,babesiasis, bartonellosis,Trypanosomiasis gram5.Wilson s disease,

Copper poisoningomiasis, gram negative/positive

Table 3. Some common drugs and chemicalsgthat can induce hemolytic anemia

AcetanilideDoxorubicin

NiridazoleNitrofurantoin

FurazolidoneMethylene blue

PhenazopyridinePrimaquine

Nalidixic acid Sulfamethoxazole

N Eng J Med 1991; 324;171

Mayor catagory

1.Immune mediated (alloimmune or1.Immune mediated (alloimmune or autoimmune)2.Membrane defects (spherocytosis, ( p y ,elliptocytosis)3.Enzym defects ( G6PD deficiency , pyruvate kinase deficiency)4.Hemoglobin defects ( sickle cell disease, th l i )thalassemia )

Approach to diagnosis

1 Clinical features suggesting hemolytic1. Clinical features suggesting hemolytic disease

2 Laboratory2. Laboratory3. Special hematologic investigation

Clinical features suggest a hemolytic process

1 Ethnic factors1. Ethnic factors2. Age factors3 History of anemia jaundice gallstones in3. History of anemia,jaundice.gallstones in

family4 P i t t t i i t d4. Persistent or recurrent anemia associated

reticulocytosis5 A i i t h ti i5. Anemia unresponsive to hematinics

6 Intermitent or persistent indirect6. Intermitent or persistent indirect hyperbilirubinemia

7 Splenomegaly7. Splenomegaly8. Hemoglobinuria9 M lti l ll t9. Multiple gallstones10. Chronic leg ulcers11. Exposure to certain drugs

Inherited Hemolytic Anemia

A.Red cell membrane defectA.1. Hereditary Spherocytosis

Essentials of diagnosis & typical featuresAnemia and jaundiceAnemia and jaundiceSplenomegalyPositive family history of anemia, jaundice

or gallstones.Spherocytosis with ↑reticulosytes↑Osmotic fragilility↑Osmotic fragilility Negative coombs test

A 2 Hereditary ElliptocytosisA.2. Hereditary Elliptocytosis

Autosomal dominant inheritanceMost are asymptomaticElevated reticulosyte Jaundice and splenomegalyJaundice and splenomegaly

No treatment is indicated :- folate suplementation- splenectomy

B. Enzyme Deficiencies

B.1. Glucose-6-phosphate Dehydrogenase(G6PD) Deficiency(G6PD) Deficiency

Essentials of diagnosis & typical features- Symptoms develop 24-48 hr after ingested a

substances has oxidant properties, such as aspirin, sulfonamides, and antimalarias

- African Mediterranean or Asian ancestry- African, Mediterranean or Asian ancestry- Neonatal hyperbilirubinemia- Sporadic hemolysis infection, oxidant drugs

fava beans- X- linked inheritance.

Acute : precipitous fall Hb + Ht- Acute : precipitous fall Hb + Ht- Heinz bodies in RBCs’ unstained/supravital

- Polychromatophilic cells, reticulocytosis- Enzymes activity < 10% normal- Reduction of enzymes activity more extreme in

Americans of European descent and in Asians than Americans of Africans descentthan Americans of Africans descent

- Screening tests : decoloration of methylene blue, reduction of methemoglobin, or fluorescence ofreduction of methemoglobin, or fluorescence of NADPH.

- After hemolytic episode reticulocytes and young RBCs predominate

- Dx suspected: G6PD activity is within low normal i th f hi h ti l trange in the presence of a high reticulocyte

count

Acquired Hemolytic Anemia

1 Microangiopathic Hemolytic Anemia1.Microangiopathic Hemolytic AnemiaHallmark: - schistocytes ( red cell fragments)on peripheral blood smear analysison peripheral blood smear analysis.Infection and sepsis microagiopathy ,

t ll d fib i i RBCuncontrolled fibrinogenesis RBC destruction

S RBC d t ti th b t iSevere RBC destruction , thrombocytopenia, coagulation factor consumption, DIC

Hemolytic Uremic Syndrome ( HUS)Hemolytic Uremic Syndrome ( HUS)- Microangiopathic- Decreased von Willebrand proteaseDecreased von Willebrand protease- Infection with enteric bacteria: Escherichia

coli O157:H7Thrombotic thrombocytopenic purpura

- Decreased von Willebrand proteaseDecreased von Willebrand protease- HUS + neurologic symptoms, inherited or

acquired q

2. Immune-Mediated Hemolytic Anemias2. Immune Mediated Hemolytic Anemias- Antibody againts one or more antigenson the

surface of RBC opsonization premature destruction: - erythocytes RES

- complement-mediated lysis of RBC in the bloodstream

- Antibodies come from patients: AIHA- Antibodies come from another source : Alloimmune

hemolytic anemia Hemolytic disease of the newbornnewborn

2.1.Autoimmune Hemolytic Anemia (AIHA)(AIHA)

History: previous viral or viral like illnessHistory: previous viral or viral like illness, fatigue, pallorUssually sudden severe anemiaUssually sudden, severe anemiaDark urine:acute intravascular hemolysis complement mediated red cellhemolysis complement mediated red cell lysisJaundice sclerae pruritusJaundice sclerae,pruritusMild splenomegaly

Autoimmune Hemolytic Anemia

2.1.1.Intravascular hemolysis

Complement mediated,IgM,complement-p , g , pfixing IgG direct against RBC antigen jaundice (hyperbilirubinemia) , LDH , low haptoglobin

2.1.2.Extravascular hemolysis

Mediated by IgGMediated by IgGNO increase LDH , bilirubinRBC destroyed in RES plasmaRBC destroyed in RES, plasma

Laboratory evaluation-Moderate to severe anemia-Brisk reticulocytosis-Spherocytosis,polychromasia,RBC clumpingp y ,p y , p g

-HemoglobinuriaHemoglobinuria-Direct Coombs test (antibody bound to the

patient’s RBC) : (+)patient s RBC) : (+)-Indirect Coombs test (test for free

antierythrocyte antibody in the patient’santierythrocyte antibody in the patient s serum

Primary AIHA :

1 Warm-reactive AIHA1.Warm reactive AIHAUsually : IgG binds RBC antigen at 37oC

2 Paroxysmal Cold Hemoglobinuria2.Paroxysmal Cold Hemoglobinuria3.Cold Agglutinin Disease:

Usually IgM binds erythrocyte antigens (typically red cell surface polysaccharide)

d fi l t t t b l 37oCand fixes complement at temp.below 37oC

Classification of autoimmune hemolytic anemia

Warm-reactive autoantibodiesprimary

Paroxysmal cold hemoglobinuria (PCH)

SecondaryLymphoproliferative disordersAutoimmune disorders (SLE)

Tertiary syphillisPost-viral infection

Infectious mononucleosisEvan’s syndromeHIV associated

Drug induced hemolytic anemiaHapten mediated (PCN)Immune complex type (quinidine quinine)

Cold-reactive antibodiesIdiopathic (cold aglutinin disease)

(quinidine, quinine)True autoimmune anti-RBC type ( methyldopa)

Metabolite drivend sease)secondaryAtypical or mycoplasma

pneumoniaI f i l i

Metabolite driven

Infectious mononucleosisLymphoproliferative disorders

Treatment of Acquired Hemolytic Anemia

Methyl-prednisolone 1 to 2 mg/Kg/day/ivMethyl prednisolone 1 to 2 mg/Kg/day/iv every 6 hours should be initiated promptly.Response (+) :increasingly stable p p y p ( ) g yHb,decreasing reticulocytosis,diminishing transfusion.After stabilization,prednisone 1 to p2 md /Kg /day can be substituted for methylprednisolone gradually tapered over several weeks to months

IV ImmunoglobulinIV ImmunoglobulinExchange transfusion/Plasmapheresis : limited efficacy effective for-IgMlimited efficacy, effective for-IgMSplenectomy: refractory IgG dependent chronic extravascular hemolysischronic extravascular hemolysisImmunosuppressive drugs: cyclophosphamide 6 mercaptopurine 6cyclophosphamide,6-mercaptopurine,6-thioguanine,azathioprine,cyclosporine A