Anemias of childhood. Haemopoiesis It is the process which maintains lifelong production of haemopoietic blood cells. The main site of haemopoiesis: –

Haemopoiesis

• It is the process which maintains lifelong production of haemopoietic blood cells.

• The main site of haemopoiesis:– in fetal life - the liver– throughout postnatal life - the bone marrow.

• All haemopoietic cells are derived from pluripotent haemopoietic stem cells

ErytropoiesisErytropoiesis begins with stem cell called hemocytoblast, which is begins with stem cell called hemocytoblast, which is then converted to proerythroblastthen converted to proerythroblastDevelopment and differentiation to stage of reticulocyte takes 4-5 Development and differentiation to stage of reticulocyte takes 4-5 daysdaysThen erythrocyte achieves its mature form in 45-70 hours in bloodThen erythrocyte achieves its mature form in 45-70 hours in blood

Characteristics of erythrocytes

• Diameter : 7,5 micrometer• No nucleus• Biconcave disk• 95% of its mass is haemoglobin• Function: Transport oxygen and carbon dioxide• Physical properties: soft, flexible, elastic

Normal red cells

Fetal hemoglobin (Hb F)

• Fetal hemoglobin has a higher affinity for oxygen – necessary for relatively hypoxic enviroment of the fetus.

Oxygen dissociation curve showing the left shift Oxygen dissociation curve showing the left shift of fetal hemoglobin compared with adult hemoglobinof fetal hemoglobin compared with adult hemoglobin..

Haematological values at birth and the first few weeks of life

• At birth, the Hb in term infants is high, 14-21.5g/dl, to compensate for the low oxygen concentration in the fetus.

• The Hb falls over the first few weeks, due to reduced erythropoiesis, reaching a nadir of 10 g/dl at 2 months of age

• Preterm babies have a steeper fall in Hb to 6.5-9 g/dl at 4-8 weeks of age.

• Normal blood volume at birth: 80 ml/kg; in preterm infants 100 ml/kg.

• White blood cell counts in neonates are higher than in older children (10-25 × 109/L).

• Platelet counts at birth – as in adults (150-400 × 109/L).

Anemias of childhood

• Anaemia is defined as a decrease of haemoglobin (Hb) level below the normal range for a child of that age and gender.

• The normal range varies with age, so that normal values in pediatrics must be correlated with the patient’s age.

Anemias of childhoodNormal values of the haemoglogin level in children

Anemia can be defined as:

• Neonate: Hb <14 g/dl

• 1-12 months: Hb <10 g/dl

• 1-12 years: Hb <11 g/dl.

AnemiaBasic mechanisms

• The type of anemia defines its pathophysiologic mechanism and its essential nature, allowing for appropriate therapy.

Three basic mechanisms: • Impaired/reduced red cell production - either due to ineffective

erythropoiesis (e.g. iron deficiency) or due to red cell aplasia • increased red cell destruction (excessive haemolysis) • blood loss - relatively uncommon cause in children unless

traumatic

AnemiaBasic mechanisms

• Blood loss should be the first consideration. Once it is ruled out, only the other two mechanisms need to be considered.

• RBC survival is 120 days - maintenance of RBC population requires daily renewal of 1/120 of the cells.

• Complete cessation of erythropoiesis results in a decline of about 10%/wk (1%/day) of RBCs. When RBC values fall >10%/wk without blood loss, hemolysis is a causative factor.

AnemiaClassification According to the Blood Film

Anemia can be classified according to the blood film (size and shape of the red cells):

• Microcytic - red blood cells have a low mean cell volume (MCV), appear small and pale

• Macrocytic - a large MCV, appear large and oval shaped• Normocytic - red blood cells may be normal in size and

shape but may be reduced in number

MicrocytosisAnything that impairs haemoglobin production

(Deficient or defective heme or globin synthesis)

Haemoglobin

Heme + Globin

ProtoporphyrinIron

Thalassemia(Abnormal Hb)

Sideroblastic

Iron DeficiencyACD

Anemias of childhoodHistory

• In the history is important to ask about duration and time of onset, family history, other subjacent illness, a dietary history, histories suggestive of chronic hemolysis, e.g. splenectomy or gallbladder disease, hemotransfusion, blood loss, and drug exposure.

Anemias of childhoodClinical Manifestations

• The clinical manifestations vary with the age, degree and rapidity of onset, presence of subjacent illness and other factors.

• Mild anemia is often asymptomatic (until Hb below 6-7 g/dL

Anemias of childhood Clinical Manifestations

• The main consequence of anemia is tissue hypoxia. If anemia has developed rapidly, there may not be adequate time for compensatory adjustments to take place, so there is a sudden marked contraction of intravascular volume, resulting in postural hypotension, fall in cardiac output, shunting of blood from skin to central organs, sweating, restlessness, thirst and air hunger.

• If anemia has slowly instalation, many adaptations for the oxygen mantainance occur, such as an increase of plasmatic volume and right shift of the oxygen-hemoglobin dissociation curve.

AnemiaSigns and Symptoms

The main symptoms are:• pallor (color of skin, palms, oral and conjunctival mucous membrane

and nail beds), • fatigue• apathy• dyspnea• anorexia• headache • pica (consumption of non-food substances such as ice, chalk, ashes

or clay, frequently found in iron deficiency anemia),• bowel disturbance• tachycardia• syncope (particularly following exercise)• wide pulse pressure, bounding pulse.

Anemias of childhoodClinical Manifestations

• Headache, syncope, tinnitus or vertigo, irritability, sleeping and concentration difficulties are more frequent in severe chronic anemia.

Anemia of ChildhoodComplications

• Pediatric anemia may result in life-long deficits 1. Negative effects persist despite correction of anemia

• Motor Effects 1. Decreased gross and fine motor coordination

• Cognitive effects 1. Lower scores on intelligence testing2. Longterm functional impairment in school

• Behavioral effects 1. Fearfulness and unhapiness2. Early fatique, less playful, clingy

Anemias of childhoodPhysical Examination

• Physical findings can include jaundice, splenic enlargement, neurologic symptoms (loss of vibration sensibility, abnormal march), tongue atrophy, lymphadenopathy, evidence of blood in feces or vomit, petechiae, and myriad signs of primary diseases that may cause a secondary anemia.

Anemias of childhoodBasic Laboratory Exams

• Complete blood count (with reticulocyte count, platelet count, mean cellular volume-VCM- and diferencial leukocyte count).

• Peripheral blood smear can confirm size and color of RBC, particularly important in evaluating a patient with hemolysis.

• Serum ferritin level, serum iron, and total iron binding capability (TIBC).

• Bone marrow aspiration is useful and critical in the workup of any unexplained anemia, specially in underproduction anemia.

Anemias of childhoodInitial Evaluation of Anemia

• The first test to analyze after detecting the anemia is reticulocyte count. If it is increased, it means anemia with increased red blood cell loss or destruction. If it is decreased, means anemia associated with decreased red blood cell production.

Anemias of childhoodInitial Evaluation of Anemia

Cause Reticulocyte Number (normal 50.000-100.000/ml, <10%o) -------------------------------------------------------------------------------

• Bone Marrow Failure Low or Normal • Hemolysis or Acute Blood Loss High

• Then, it is important to classify anemia based on mean cellular volume (microcytic, normocytic and macrocytic) with low, normal or high MCV, respectively).

Anemias Caused By Blood LossAcute posthemorrhagic anemia

Anemia caused by rapid massive haemorrhage. • Because marrow reserve is limited, anemia may result from

massive haemorrhage associated with spontaneous or traumatic rupture or incision of a large blood vessel, erosion of an artery by lesions (eg, peptic ulcer, neoplasm), or failure of normal haemostasis.

• Immediate effects depend on the duration and volume of haemorrhage. Sudden loss of 1/3 of blood volume may be fatal, but as much as 2/3 may be lost slowly over 24 h without such a risk. Symptoms are caused by a sudden decrease in blood volume (hypovolemic shock) and by subsequent haemodilution with a decrease in the oxygen-carrying capacity of the blood.


Symptoms and Signs • Faintness, dizziness, thirst, sweating, weak and

rapid pulse, and rapid respiration (at first deep, then shallow) may occur. Orthostatic hypotension is common. Blood pressure may at first rise slightly, because of reflexive arteriolar constriction, then it gradually falls. If bleeding continues, blood pressure may fall and death may ensue


Laboratory Findings • During and immediately after hemorrhage, the RBC count, Hb, and Hct

may be deceptively high because of vasoconstriction.• Within a few hours, tissue fluid enters the circulation, resulting in

hemodilution and a drop in the RBC count and Hb proportional to the severity of bleeding.

• The resultant anemia is normocytic. • Polymorphonuclear granulocytosis and a rise in platelet count may occur

within the first few hours.• Several days after the bleeding event, regeneration (ie, reticulocytosis) is

evident: Blood smears may disclose polychromatophilia and slight macrocytosis;

• If hemorrhage was massive and acute, occasional normoblasts and immature WBCs may be seen.

Anemias due to Abnormal RBC Production

• Microcytic anemias - Iron deficiency - Talassemia - Sideroblastic anemia• Macrocytic anemias (megaloblastic) - Folate and vitamin B12deficiency

• Normocytic anemias - aplastic and hypoplastic anemia - anemia of chronic disease

Reduced red cell production may be due to:

1. 'ineffective erythropoiesis'- red cell production occurs at a normal or increased rate but differentiation or survival of the red cells is defective (e.g. iron deficiency).

2. complete absence of red cell production (red cell aplasia). Diagnostic clues to ineffective erythropoiesis are:

normal reticulocyte count abnormal mean cell volume (MCV) of the red cells: low in iron

deficiency and raised in folic acid deficiency or myelodysplasia.

Anaemia due to reduced red cell productionAnaemia due to reduced red cell production

IRON – deficiency is the most common nutritional deficiency in children and is

worldwide in distribution

• 5.5 % school children aged from 5 to 8 years

• 2.6 % in preadolescent children • 25 % in pregnant teenage girls

REQUIREMENTS

• 1 mg/kg/day to a maximum of 15 mg/day is required in normal infants (mean 8 mg/day aat 1 year)

• 2 mg/kg/day to a maximum of 15 mg/day is required in low-birth-weight infants, infants with low initial hemoglobin values, and those who have experienced significant blood loss

Causes of Iron – Deficiency Anemia

I. Inadequate intake - dietary (milk) II .Increased demand : - Growth : * low birth weight * prematurity * low birth weith * multiple births

* high growth rate * adolescence, * pregnancy

-


III . Blood loss a) Perinatal - Placental * transplacental bleeding into maternal circulation * intraplacental * fetal blood loss at or before birth * fetofetal - Umbilicus * ruptured umbilical cord * inadequate cord tying * postexchange transfusion

Blood loss ...b) Postnatal : 1. Gut :

- primary anemia resulting in gut alteration with blood loss aggravates existing iron deficiency- hypersensitivity to cow milk protein; exudative enteropathy - anatomic gut lesions – varices, hiatus hernia, ulcer, ileitis Meckel’s diverticilum, hereditary teleangiectasia, - gastritis (from aspirin ingestion, adenocortical steroids)- Henoch – Schonlein purpura

Blood loss ...

2. Nose : recurrent epistaxis

3.Uterus : menstrual loss

4. Kidney : hematuria, nephrotic syndrome (urinary loss of transferrin), noctural hemoglobinuria

5. Hemodialysis 6. Trauma


IV . Impaired absorption :- Malabsorption syndrome - Celiac disease- Severe prolonged diarrhea - Inflammatory bowel diseases- Short bowel syndrome

Infants at High Risk for Iron Deficiency

Dietary factors - Early cow’s milk intake- Late solid food intake- Frequent tea intake (tannin inhibits absorption)- Low vitamin C intake - Low meat intake - Breast-feeding for more than 6 months without iron-

reach foods or supplements - Low socioeonomic status (frequent infections)

DIAGNOSIS - BLOOD

1. Hemoglobin is below the lower limit of normal for age 2. Red cell indices : Hypochromic, microcytic red cells (blood smear) MCV less than

acceptable normal for age; (<75 fL) - MCH less than 27 pg - MCHC less than 30%3. Reticulocyte count : - the reticulocyte count is usually normal - in severe iron-deficiency anemia associated with bleeding, a

reticulocyte count of 3-4% may occur

DIAGNOSIS - BLOOD

4. Platelet count : - thrombocytopenia is more common in severe iron-

deficiency anemia - thrombocytosis is present, when there is associated

bleeding from the gut 5. Low serum ferritin6. Serum iron and iron binding capacity : - decreased serum iron - increased iron binding capacity

DIAGNOSIS - BLOOD

7. Therapeutic response to oral iron a) Reticulocytosis with peak 5-10 days after institution of

therapyb) Following peak reticulocytosis hemoglobin level rises on

average by 0.25-0.4 g/dl/day or hematocrit rises 1%/day

Tissue Effects of Iron Deficiency

I . Gastrointestinal tract a) Anorexia common and early - Increased proportion of low-weight percentiles - Depression of growthb) Atrophic glossitis c) Dysphagiad) Reduced gastric aciditye) Leaky gut syndrome - Guaiac-positive stools - Exudative eneropathy: gastrointestinal loss of protein, albumin immuno-

globulins , copper , calcium, red cellsh) Malabsorption syndrome - Iron only - Generalized malabsprption: xylose, fat, vit. A, duodenojejunal mucosal atrophy


II. Central nervous systema) Irritabilityb) Fatiguec) Conduct disordersd) Lower mental and motor developmente) Papilledema


III. Cardiovascular system- Increase heart rate and cardiac output- Cardiac hypertrophy- Increase in plasma volume - Increased minute ventilations values

Tissue Effects of Iron DeficiencyV. Immunologic system: There is conflicting information as to the effect

on the immunologic system of iron-deficiency anemia a) Evidence of increased predisposition to infections - Reduction of acute illness in iron-deficient children by iron treatment and

improved rate of recovery - Increased frequency of respiratory infection in iron deficiency - Impaired leukocyte transformation - Impaired granulocyte killingb) Evidence of decreased predisposition to infections - Lower frequency of bacterial infection in iron-deficient children - Increased frequency of infection in iron overload

TREATMENT

I. Dietary advice!! 1. Maintain breast feeding for at least 6 months, if possible. 2. Infants should not be fed unmodified cow’s milk – iron poorly

absorbed! Restrict cow’s milk to 1 pint/day. 2. Use iron-fortified cereal from 6 months to 1 year 3. Use hydrolyzed formulas when iron deficiency is caused by

hypersensitivity to cow’s milk

TREATMENT 4. Provide supplemental iron for low birth weight infants a. Infants 1,5-2 kg : 2 mg/kg/day supplemental iron b. Infants 1-1,5 kg : 3 mg/kg/day supplemental iron c. Infants < 1kg : 4 mg/kg/day

supplemental iron 5. Facilitators of iron absorption such as vitamin C- rich foods

(citrus, tomatoes, potatoes), meat, fish and poultry should be included in the diet

Dietary sources of iron High in iron Red meat – beef, lamb Liver, kidney Oily fish – pilchards, sardines, etc.

Average iron Pulses, beans and peas Fortified breakfast cereals with added vitamin C Wholemeal products Dark green vegetables – broccoli , spinach, etc. Dried fruits – raisins , sultanas

Dietary sources of iron

Foods to avoid in exess toddlers Too much cow’s milk Tea – tannin inhibits iron uptake High-fibre foods – phytates inhibit iron absorption

TREATMENTII. Oral Iron Supplementation

1. Dose: 1.5 – 2 mg/kg elemental iron three times daily (4.5-6 mg/kg/day). Older children : ferrous sulfate (0.2 g) or ferrous gluconate (0.3 g) given three times daily to provide 100-200 mg elemental iron

2. Duration : 6-8 weeks after hemoglobin level is restored to normal (3-4 months)

3. Response : - Peak reticulocyte count on days 5-10 following initiation of iron therapy - Following peak reticulocyte level, hemoglobin rises on average by 0.25-0.4

g/dl/day or hematocrit rises 1% day during first 7-10 days - Thereafter hemoglobin rises more slowly : 0.1-0.15 g/dl/day

TREATMENT

4. Failure to respond to oral iron: the following reasons should be considered

- Failure or irregular administration of oral iron; administration verifiable by change in stool color to gray-black or by testing stool for iron

- Inadequate iron dose

- Ineffective iron preparation

- Persistent or recognized blood loss -the patient loses iron as fast as it is replaced

TREATMENT- Imparied GI absorption: malabsorption syndrom (coeliac

disease)(administration of antacids, which bind iron, as treatment of peptic ulcer)

- Coexistent disease that interferes with absorpion or utilization of iron (e.g. infection, malignant disease, hepatic or renal disease, concomitant deficiencies (vitamin B12, folic acid, thyroid), associated lead poisoning

-

TREATMENT

III. Parenteral therapy in malabsorption Iron-dextran complex for intramuscular use (Imferon) is safe,

effective, and well tolerated even in infants with:a) Variety of acute illnessesb) Including acute diarrheal disorders

Macrocytic (megaloblastic) anemia• Megaloblastic anemia may result from deficiencies of folate or

B12vitamin.• This deficiencies lead to impairment of DNA synthesis in rapidly

growing tissue and in concequence to disproportionate maturation in the cytoplasm and nucleus during erythropoiesis.

• Vitamin B12 deficiency occur very rare in children• Folate deficiency can occur as a result of inflammatory bowel

disease, celiac disease, anticonvulsant therapy• Bone marrow: - megaloblasts - ineffective erythropoiesis (intramedullary hemolysis)

Anemias of childhoodNormocytic Anemias

• Primary bone marrow disorders (aplasia and hypoplasia, myelodisplasia, myelofibrose, hematologic and solid tumors, HIV infection, granulomas)

• Chronic disease anemia • Secondary anemias (hepatic, renal or endocrine

disorders)

Aplastic and Hypoplastic Anemia

• Anemia resulting from a loss of RBC precursors, either from a defect in stem cell pool or an injury to the microenvironment that supports the marrow, and often with borderline high MCV values.

• The term aplastic anemia (bone marrow failure) commonly implies a panhypoplasia of the marrow with associated leukopenia and thrombocytopenia.

• The term pure RBC aplasia, defines the selective marked reduction or absence of erythroid precursors.

• Although both disorders are uncommon, aplastic anemia is more common.

• Both, aplastic and hypoplastic anemia may be acquired or congenital.

Acquired Aplastic AnemiaEtiology and Pathogenesis

• About 1/2 of the cases of true aplastic anemia are idiopathic.

• Recognized causes are : - chemicals (e.g. benzene, inorganic arsenic), - radiation - drugs (e.g. antineoplastics, antibiotics, NSAIDs,

anticonvulsants). • The mechanism is unknown, but selective (perhaps genetic)

hypersensitivity appears to be the basis.

Aquired Aplastic AnemiaSymptoms, Signs

• Signs vary with the severity of the pancytopenia.• General symptoms of anemia are usually severe. • Waxy pallor of skin and mucous membranes. Chronic cases may show

considerable brown skin pigmentation.• Severe thrombocytopenia, with bruising and bleeding. Haemorrhages into

the ocular fundi are frequent. • Agranulocytosis with life-threatening infections. • Splenomegaly is absent, unless induced by transfusion hemosiderosis.

Acquired Aplastic AnemiaLaboratory Findings

• RBCs are normochromic-normocytic (sometimes marginally macrocytic).

• A WBC count <= 1500/µL3 is common, the reduction occurring chiefly in the granulocytes.

• Platelets are often markedly reduced. • Reticulocytes are decreased or absent, even with coexistent

hemolysis. • The aspirated bone marrow is acellular. • Serum Fe is elevated.

Acquired Aplastic AnemiaTreatment

• Antithymocyte globulin (ATG) in dose 15 mg/kg infused intravenously over 4 to 6 h for 10 consecutive days has yielded responses in about 60% of patients. It has become the treatment of choice for patients without a compatible donor.

• Cyclosporine (5 to 10 mg/kg/day po) is as effective as ATG and has provided a response in about 50% of ATG failures, suggesting that its mechanism of action may be different.

• Combined ATG and cyclosporine is also effective. • Bone marrow transplantation from an identical twin or an HLA-

compatible sibling is a proven treatment for severe aplastic anemia,

Congenital Aplastic Anemia

• Fanconi's anemia - aplastic anemia with bone abnormalities (radius, thumbs), short stature, renal malforamtions, microcephaly, hypogonadism, and brown pigmentation of skin)

• A very rare congenital form of aplastic anemia (autosomal recessive)

• Presentation at 5-6 years of age • Transformation to acute leukaemia

Congenital Aplastic Anemia

• Schwachman-Diamond syndrome (bone marrow failure with signs of pancreatic exocrine failure and skeletal abnormalities)

• A rare congenital condition (autosomal recessive)• Mild pancytopenia or isolated neutropenia• Transformation to acute leukaemia

Red cell aplasia (Hypoplastic anemia)

Three main causes of red cell aplasia in children: • congenital red cell aplasia (Diamond-Blackfan

anemia) • transient erythroblastopenia of childhood • parvovirus B19 infection - only causes red cell

aplasia in children with inherited haemolytic anemias and not in healthy children.

The diagnostic clues to red cell aplasia

• low reticulocyte count despite low Hb • normal bilirubin • negative direct antiglobulin test (Coombs' test)• absent red cell precursors on bone marrow

examination

Blackfan-Diamond anemia• A rare congenital disaese• 80% sporiadic mutation• Presentation at 2-3 months, 25% at birth• Short stature and abnormalities of the thumbs or digits • RBC may have fetal Hb.• Treatment with steroids (60-70% responders) or monthly

RBC transfusions

Transient erythroblastopenia of childhood (TEC)

A brief reversible disappearance of RBC precursors in the marrow during various acute viral illnesses in young children. TEC is thought to be due to an abnormal response to infection, perhaps via an antibody that inhibits RBC progenitors. The RBC are normal in size and do not express fetal characteristics.

Recovery in several weeks

Parvovirus B19 infection

• Only in children with chronic hemolytic anemia, parvovirus B19 infection may cause aplastic crises (direct infection of the RBC progenitors?)

• Usually last 1-2 weeks, but prolonged aplasia has been described.

• Treatment of aplastic crises - blood transfusions.

Increased red cell distructions haemolytic anemias

• The essential feature of haemolytic anemia is a reduced RBC lifespan (normal - about 120 days), due to increased red cell distructions in the circulation (intravascular haemolysis) or liver or spleen (extravascular haemolysis)

• Haemolysis results in anaemia when bone marrow production can no longer compensate for the shortened RBC survival (eightfold increase possible)

Haemolytic anemias - causes• Immune haemolytic anemias – common in

neonates, uncommon in elder children• The main cause of haemolysis in children is intrinsic

abnormalities of the red blood cells: – red cell membrane disorders (e.g. hereditary

spherocytosis) – red cell enzyme disorders (e.g. glucose-6-phosphate

dehydrogenase deficiency) – haemoglobinopathies (abnormal haemoglobins, e.g. β-

thalassaemia major, sickle cell disease).

Haemolytic anemias

• Increased red cell breakdown leads to:

• anemia • reticuloendothelial hyperplasia - hepatomegaly and splenomegaly • elevated unconjugated bilirubin • excess urinary urobilinogen.

Haemolytic anemias - diagnosis• raised reticulocyte count (on the blood film this is called

'polychromasia' as the reticulocytes have a characteristic lilac colour)

• unconjugated bilirubinaemia and increased urinary urobilinogen

• abnormal appearance of the red cells on a blood film (e.g. spherocytes, sickle shaped or very hypochromic)

• positive direct antiglobulin test – Coombs’ test identifies antibody-coated red blood cells (positive only if an immune cause of haemolytic anaemia)

• increased erythropoiesis in the bone marrow.

Hereditary spherocytosis

• 1 in 5000 births in Caucasians• an autosomal dominant inheritance, 25% caused by new

mutations• mutations in genes for the skeletal proteins of the red cell

membrane (mainly spectrin, ankyrin or band 3). • reduction in red cells surface-to-volume ratio causes the

cells to become spheroidal• RBC are less deformable – what leads to their destruction in

the microvasculature of the spleen.

Hereditary spherocytosis The clinical manifestations are highly variable (even completely asymptomatic)The clinical features include: * jaundice - usually develops during childhood but may be intermittent; may cause severe haemolytic jaundice in the first few days of life

* anemia - mild anemia (haemoglobin 9-11g/dl), - the haemoglobin level may fall with an intercurrent infection; - many children have 'compensated' haemolysis with a normal haemoglobin

* mild to moderate splenomegaly - depends on the rate of haemolysis; this may be the mode of presentation in the first year of life

* aplastic crisis - uncommon, associated with parvovirus B19 infection

* gallstones - due to increased bilirubin excretion.

Hereditary spherocytosis

Diagnosis:• The blood film usually diagnostic • specific tests available (e.g. osmotic fragility,

Differetntial diagnosis:• Antibody-induced anaemia may be associated with

spherocytes. It must be excluded with a direct antiglobulin test especially in the absence of a family history.

Hereditary spherocytosisManagement:• Mild chronic haemolytic anemia requires only oral folic acid • Splenectomy - is only indicated for poor growth or troublesome

symptoms of anaemia (e.g. severe tiredness, loss of vigour)– usually after 7 years of age (the risks of post-splenectomy sepsis)– Prior to splenectomy all patients should be vaccinated against Haemophilus

influenzae (Hib), meningitis C and Streptococcus pneumoniae – In some cases lifelong daily oral penicillin prophylaxis is advised.

• Aplastic crisis from parvovirus B19 infection usually requires one or two blood transfusions over 3-4 weeks

• Gallstones - cholecystectomy if they are symptomatic

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

• The most common red cell enzymopathy • Over 100 million people are affected• High prevalence (10-20%) in central Africa, the

Mediterranean, the Middle East and the Far East. • Many different mutations - different clinical features


• G6PD is essential for preventing oxidative damage to red cells. Red cells lacking G6PD are susceptible to oxidant-induced haemolysis.

• X-linked inheritance – males predominantly affected (10-15% normal enzyme activity)

• Females - heterozygotes – 50% of the normal G6PD activity.


Clinical manifestations:• neonatal jaundice - in the first 3 days of life - it is the most

common cause of severe neonatal jaundice requiring exchange transfusion.

• acute haemolysis - precipitated by: – infection, the most common precipitating factor – certain drugs (antimalarials, sulphonamides, quinolones, high dose

aspirin) – fava beans (broad beans) – naphthalene in mothballs


Diagnosis:• measuring G6PD activity in red blood cells• misleadingly elevated enzyme level during

haemolytic crisis – Young red blood cells may have normal enzyme activity whilst older cells are deficient - a need for repeated assay

Management:• List of drug, food and chemicals to avoid• Transfusions rarely required

Haemoglobinopathies These are red blood cell disorders which cause haemolytic anaemia

because of:• reduced or absent production of HbA (α- and β-thalassaemias) or • production of an abnormal Hb (e.g. sickle cell disease).

• α-Thalassaemias are caused by deletions in the α-globin gene. • β-Thalassaemia and sickle cell disease are caused by mutations of the

β-globin gene. Clinical manifestations of the haemoglobinopathies affecting the β-chain are delayed until after 6 months of age when most of the HbF present at birth has been replaced by adult HbA

Sickle cell disease

• The most common genetic disorder in children in many European countries, (prevalence 1 in 2000 live births) - neonatal screening using the biochemical screening test (Guthrie test)

• Haemoglobinopathy in which HbS is inherited. HbS forms as a result of a point mutation in codon 6 of the β-globin gene

• Most common in patients from tropical Africa or the Caribbean, is also found in the Middle East and in low prevalence in most other parts of the world except for northern Europeans

Sickle cell disease • Pathogenesis:• HbS molecule becomes deformed (insoluble) in the deoxygenated

state. HbS polymerises within red blood cells forming rigid tubular spiral bodies which deform the red cells into a sickle shape.

• Irreversibly sickled red cells have a reduced lifespan and may be trapped in the microcirculation, resulting in thrombosis and therefore ischaemia in an organ or bone.

• This is exacerbated by low oxygen tension, dehydration, cold, excessive exercise or stress.

• The clinical manifestations vary widely between different individuals.

Sickle cell disease Clinical manifestations:• Anemia (6-8 g/dl)with jaundice • Infection (pneumococcical or H. influenze) due to hyposplenism

secondary to microinfarction in the spleen)• Painful vaso-occlusive crisis: in any organ (hand-foot syndrome with

dactylitis), cerebral and pulmonary infarction less comon but serious (stroke)

• Acute anemia: haemolytic, aplastic or sequestration crises from accumulation of sickled cells in spleen

• Priapism• Splenomegaly• Long term problems: cognitive problems, heart failure, cardiac

enlargemnet, renal disfunction, gallstones, leg ulcers, short stature and delayed puberty

Sickle cell disease Management :Prophylaxis to prevent infections: immunisation and twice daily penicillin throughout

childhoodOral folic acid because of the increased demand for folic acid Vaso-occlusive crises should be minimised by avoiding exposure to cold, dehydration,

excessive exercise, undue stress or hypoxia. Treatment of painful crises: oral or intravenous analgesia good hydration (oral or

intravenous as required); Infection – antibioticsOxygen - if the oxygen saturation is reduced. Exchange transfusion is indicated for acute chest syndrome, stroke and priapism. Recurrent painful vaso-occlusive crises or acute chest syndrome - hydroxyurea

(increases their HbF production) Bone marrow transplant – in the most severely affected children if possible

β-Thalassaemias • In people from the Indian subcontinent, Mediterranean and Middle East • As there is a deficiency of β-chains, γ-chain synthesis continues beyond the neonatal

period, producing an increased proportion of HbF, and δ-chain production increases the amount of HbA2. This results in precipitation of globin chains within the red cell membrane, bringing about cell death within the bone marrow (ineffective erythropoiesis) and premature removal of circulating red cells by the spleen.

• The disease severity of β-thalassaemia depends on the amount of HbA and HbF present: – β-Thalassaemia major - HbA (α2β2) cannot be produced because of the abnormal β-

globin gene. The most severe form. – β-Thalassaemia intermedia - the β-globin mutations allow a small amount of HbA and/or

a large amount of HbF to be produced. Milder, variable. – β-Thalassaemia trait - one normal and one abnormal β-globin gene. Asymptomatic

carrier

β-Thalassaemias

Clinical features: • severe anaemia and jaundice from 3-6 months of

age • failure to thrive/growth failure • extramedullary haemopoiesis, causing bone marrow

expansion (classical facies with maxillary overgrowth and skull bossing)

• marked hepatosplenomegaly (not seen in appropriately transfused children).

β-Thalassaemias

The condition is fatal without regular blood transfusions• RBC lifelong monthly transfusions • The complications of multiple transfusions:

• chronic iron overload: causes cardiac failure, liver cirrhosis, diabetes, infertility and growth failure - iron chelation therapy with subcutaneous desferrioxamine, given overnight from 2 to 3 years of age

• Allo-antibody formation – problems with compatible blood• Infections (HIV, Hepatitis A, B, C, malaria – rare)• Problems with venous access

• Bone marrow transplantation if possible

α-Thalassaemias• Helthy individuals have four α-globin genes. The

manifestation of α-thalassaemia syndromes depends on the number of functional α-globin genes.

• α-thalassaemia major (Hb Barts hydrops fetalis) - deletion of all four α-globin genes, so no HbA (α2β2) can be produced. It presents in mid-trimester with fetal hydrops (oedema and ascites) from fetal anaemia, which is always fatal in utero or within hours of delivery.

• When only three of the α-globin genes are deleted (HbH disease), affected children have mild-moderate anaemia

Anemia in neonatesEtiology

Increased blood loss may be the result of:Prenatal factors:• placenta praevia• cord rupture• feto-maternal or feto-placental bleeding• twin-twin transfusion Postnatally:• hemorrhage in the neonate, for example as a result of trauma or

coagulopathy• iatrogenesis - phlebotomy in sick neonates, lab testIncreased breakdown may be the result of:• hemolytic disease of the newborn

Hemolytic disease of the newborn

• Hemolytic disease of the newborn is diagnosed when hemolysis of a neonate's red blood cells is caused by antibody from the mother.

• This condition only occurs where there is incompatibility between the maternal and fetal blood.

Hemolytic disease of the newbornEtiology

• One of the most severe causes of this condition is rhesus (Rh) incompatibility.

• Other causes include, in descending order of frequency and severity: - AB0 system incompatibility - red blood cell metabolic disorders - for example, G-6-PD (glucose-6-

phosphate dehydrogenase) deficiency, pyruvate kinase deficiency - RBC morphology disorders - for example, hereditary spherocytosis, hereditary elliptocytosis• Rhesus incompatibility tends to be more severe than AB0 incompatibility

because anti-D antibodies are mainly IgG, which can easily cross the placenta, whereas anti-A and anti-B antibodies are mainly IgM, which cannot cross the placenta.

Hemolytic disease of the newbornInvestigations

If hemolytic disease of the newborn is suspected, the following investigations should be carried out:

• full blood count, with attention to hemoglobin, white cells and reticulocytes

• platelets• infant blood group and Coombs test• maternal blood group and hemolysins• red cell enzyme assay may be a helpful second line

investigation• blood film and osmolar fragility may diagnose

spherocytosis

Hemolytic disease of the newbornTreatment

• Preventative measures for Rhesus disease of the newborn was initiated in 1970. 500 IU of anti-D Rh gammaglobulin is administered to each Rhesus negative non-sensitized woman who delivers a rhesus positive child, has an abortion, or an amniocentesis. This removes fetal cells before they can sensitize.

• After birth, depending on the severity of the disease, the neonate might undergo phototherapy, exchange transfusion, or drugs to counter cardiac failure such as diuretics.

Anemia in neonatesClinical Features

Clinical features of neonatal anemia include:• pallor• air hunger• hypotension or shock• in extreme cases, heart failure and hydrops may

develop

Documents

Anemias of childhood. Haemopoiesis It is the process which maintains lifelong production of haemopoietic blood cells. The main site of haemopoiesis: –