Dr. Salma AL-HadadApril 11th 2016 Childhood Hemolytic Anemia5th Year Medical Student
Objectives Describe the presentation & management of G6PD, AIHA, Thalassemia major & Sickle cell disease. Describe the presentation & management of Bone marrow failureCase scenario 7 year old boy, otherwise healthy presented with sudden pallor, malaise, fatigue, he mentioned that he passed tea color urine. His mother noticed that he is jaundiced too.He was pale, jaundiced, inactive, PR 120 beats/minute, no organomegaly. *
Action What is the differential diagnosis?What investigation will you order?What is your action? *
G6PD Deficiency Most common RBC enzyme defect; Sex linked, affecting males & carried by females who show half normal RBC G6PD values. Associated with potentially life-threatening hemolytic disease because of severe deficiency.Results from oxidative damage to RBCs as a consequence of the loss of the protective effect of the enzyme G6PD, so the cells can’t convert the oxidized substrate to a reduced state.
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G6PD Deficiency Clinical presentationsI. Neonatal jaundice: Jaundice usually appears by age 1-4 days.II. Acute hemolytic anemia beyond the neonatal period: Typically; most patients are asymptomatic until exposed to an exciting agent (such as oxidative drugs or chemicals, infection, or ingestion of fava beans).The onset of hemolysis usually is within 24 to 48 hours of exposure. Non specific symptoms; acute abdominal pain, vomiting or diarrhea, Hemoglobinuria (cola-colored urine)---- jaundice------symptoms of anemia such as lethargy and irritability----cardiovascular decompensation may occur.
G6PD Deficiency Clinical presentations Most acute hemolytic episodes are mild & self-limiting, even if continuing exposure, because there is an increased level of enzymes in the remaining younger population of cells, anemia usually resolves in 3 to 6 weeks. Possible Complications; renal failure or death following a severe hemolytic event.Outside of these episodes; no evidence of chronic hemolysis exists.Chronic hemolysis (congenital non-spherocytic hemolytic anemia) is rare
Diagnosis of G6PD deficiency During an attack, the following lab. findings are present: AnemiaPeripheral Blood film (smear) shows; Normochromic normocytic anemia of varying degrees Small cells (poikilocytes), some of which are spherocytic or fragmented. Characteristic findings include “bite” cells,Reticulocytosis .
Diagnosis of G6PD deficiency Heinz bodies (inclusion bodies) detected by using special (supravital) stains There is evidence of intravascular hemolysis; Serum haptoglobin is reduced, Increased unconjugated hyperbilirubinemia, In severe cases, hemoglobinemia and hemoglobinuria.
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Hienz bodies in G6PD deficiency
Diagnosis of G6PD deficiency G-6-PD enzyme deficiency can be detected using several screening tests. The blood count is normal between attacksTreatment of G6PD deficiency During the attack:Remove offending drug & treat any underlying infectionBrisk hydration to ensure adequate urine output that will prevent clogging of renal tubules. Transfusion may be necessary in severe hemolysis.Teaching to avoid oxidant drugs, chemicals, & fava beans
Auto Immune hemolytic anemia (AIHA) Production of Antibodies against an individual’s own RBC membrane Antigens, which leads to hemolysis.Acquired form of hemolysis with a defect arising outside the red cell. Divided into ‘warm’ and ‘cold’ types depending on whether the antibody reacts better with red cells at 37°c or 4°c.The peak incidence occurs in the preschool age group.The hemolysis is largely extravascular, usually involves IgG, and occurs primarily in the liver and spleen.
AIHA Clinical features Pallor, Jaundice, Non specific: lethargy, abdominal pain, or low-grade fever. If hemolysis is severe, the urine may be dark. Hyperdynamic circulation Enlarged spleen and liver.
AIHA Laboratory findings Anemia; Hemoglobin level—very lowPeripheral blood smear; prominent spherocytes, polychromasia, macrocytes, autoagglutination (antibodies best detected at 37°C)Reticulocytosis—commonEvidence of hemolysis: HyperbilirubinemiaHaptoglobin level—markedly decreasedHemoglobinuriaIncreased urinary urobilinogen Direct coomb’s test—positive
AIHA TreatmentMost patients who have AIHA exhibit mild anemia of limited duration and, therefore, do not need therapy. Compensated hemolysis – observation and folic acid at an oral dose 1mg/dayDecompensated hemolysis (definitive therapy depends on the cause): Steroid therapy Immunoglobulins Splenectomy Blood transfusion: only in life-threatening situations as a temporary solution while waiting for other modalities to begin working. The “least incompatible” blood.
Thalassemia syndromes Inherited disorders of Hb synthesis that result from an alteration in the rate of globin chain production. Their clinical severity widely varies, ranging from asymptomatic forms to severe or even fatal entities.
B-Thalassemia I. Thalassemia minor; Deficiency of one beta genes leads to essentially no significant hemolysis and no unusual signs or symptoms are encountered.II. Thalassemia major; Deficiency of both genes leads to significant hemolytic anemia. III. Thalassemia intermedia is a condition in which the degree of hemolysis is milder even though the patient may have a deficiency of both beta genes. It is essentially a descriptive term that refers to minimal or no need for transfusions.
Case Scenario A 7-month old boy brought by family after they noticed a progressive pallor, with abdominal distension. Feeding history is normalFamily history positive for a sibling with B-Thalassemia major O/E pale, liver 3cm BCM, spleen 3cm BCM *
Я -thalassaemia major Clinical features:Anemia first becomes apparent between 3-6 months when production of HbF declines, the infant clinically normal at birth (as fetal Hb does not contain Я chains) then during first year of life; Progressive anemia will occur. Failure to thriveHepatosplenomegaly & jaundice.The severity of this anemia results from a combination of ineffective erythropoiesis and shortened survival of the red blood cell in circulation.
Я -thalassaemia major ComplicationsHemolysis include expansion of bones leads to thinning of cortex & tendency to fractures, bossing of skull & specific facies with hair-on-end appearance on x-ray, gallstones & chronic leg ulcers. Iron overload caused by repeated transfusion, increased iron absorption due to ineffective erythropoiesis; The complications of iron overload affect all organs of the body, including the heart (failure), liver (cirrhosis), thyroid (hypothyroidism), pancreas (diabetes), and (delayed growth and sexual maturity) unless chelation therapy is given.Infections secondary to splenectomy & blood transfusion transmitted viruses
B-Thalassemia Major 40
Hair on End Appearance *Я -thalassaemia major Laboratory diagnosis Complete blood picture:The Hb level ranges from 2-8 g/dL.Microcytic hypochromic anemia.Blood film: nucleated RBCs, target cells, polychromasia, anisopoikilocytosis, basophilic stipplingMCV and MCH are significantly low.Hemoglobin electrophoresis: elevated HbF (>50%) with variable HbA2.Evidence of hemolysis: Unconjugated hyperbilirubinaemia.Iron studies show high serum iron & ferritin levelsDNA analysis. detect deletions & mutations in the β globin producing genes. Both parents will have β -thalassemia trait
Diagram of apparatus for performing Hb electrophoresis *
Patterns of Hb electrophoresis *Я -thalassaemia major Management Blood transfusion: every 4-6 weeks with fresh, filtered blood to maintain the Hb > 10g /dlIron chelation: start after 10-15 units of blood, Desferioxamine by s.c infusion over 8-12 hours, 5-7 days weekly, Deferasirox (Exjade) a new oral chelator with few side effectsSplenectomy; indicated if the spleen is enlarged substantially or there is evidence of hypersplenism leading to pancytopenia, it can reduce the transfusion frequency.Stem cell transplantation (SCT), the probability of survival exceeds 90%.Gene therapy: Stimulation of fetal hemoglobin production and somatic gene therapy
Sickle Cell Disease Pathogenesis:In HbS, glutamic acid has been replaced by Valine at the 6th amino acid of the B globin chain In the deoxygenated state the red cell loses its normal deformability and becomes characteristically sickle shaped.Hemolysis - because sickle RBCs are too fragile to withstand the mechanical trauma of circulationOcclusion in microvascular circulation caused by distorted, inflexible RBCs adhering to vascular endothelium
Sickle Cell Disease Clinical features Most patients have asymptomatic periods alternates with recurrent symptomatic episodes.Vaso-occlusive episodes; The most common complaint is of pain & recurrent episodes may cause irreversible organ damage. It can affect nearly all organs. It may occur early in the first year of life as “dactylitis” that involves the small bones of the hands and feet (hand-foot syndrome), but more commonly it occurs later. Most common sites are bones, lungs, spleen, liver, penis, and brain. Precipitating events; infection, stress, dehydration, or changes in temperature.
Sickle Cell Disease Clinical features Transient red blood cell aplastic episode; Acute infection with Parvovirus B19 is usually associated with red cell aplasia, fever, and pain.Acute sequestration episode; This is an acute trapping of blood in the spleen and less frequently in the liver caused by impaired egress of blood out of these organs due to clogging by sickled cells.
Sickle Cell Disease Clinical featuresInfection; due to functional asplenia which can appear as early as 6 months of age up to 5 yr of age in most children. The risk of infection is highest with encapsulated organisms such as pneumococci, Haemophilus influenzae, meningococci & Salmonella sp.Others; Gall stones, chronic osteomyelitis, chronic leg ulcers, Lung disease (acute chest syndrome), Renal disease, Recurrent priapism, etc..
Sickle Cell Disease Diagnosis of SCA Blood film: sickled cells, marked poikilocytosis, target cells. Screening tests for sickling: the blood sample is deoxygenated to induce sickling Hemoglobin electrophoresis: in sickle cell anemia (HbSS)
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Long term result of dactylitis in sickle cell anemia X-ray of his hand *
Hand of 18-year old boySickle Cell Disease TreatmentTreatment of vaso-occlusive crisis include: Hydration Pain control Empirical antibiotics Blood transfusion (simple or exchange transfusion)II. Chronic transfusion therapy.
Sickle Cell Disease TreatmentProphylactic oral penicillin at least until 5 years of ageRoutine childhood immunizations & annual administration of influenza vaccine are highly recommended.Medical intervention; Stimulation of increased hemoglobin F production (hydroxyurea)Cellular and genetic levels includeStem cell transplant Gene therapy
Bone Marrow Failure
Acquired Bone Marrow Failure The majority of cases in childhood are “idiopathic” in that no causative agent is identifiedDrugs, chemicals, toxins, infectious agents, radiation, and immune disorders can result in pancytopenia.Pathology & Pathogenesis The hallmark of Aplastic anemia is peripheral pancytopenia, coupled with hypoplastic or Aplastic bone marrow Acquired pancytopenia is typically characterized by anemia, leukopenia, and thrombocytopenia.
Laboratory findings Bone marrow examination should include both aspiration and a biopsy, and the marrow should be carefully evaluated for morphologic features, cellularity, and cytogenetic findings
Complications The major complications of severe pancytopenia are related to the risk of life-threatening bleeding from prolonged thrombocytopenia or to infection secondary to protracted neutropenia.
Treatment Supportive care coupled with an attempt to treat the underlying marrow failureFor patients with HLA–identical sibling marrow donor, allogeneic bone marrow transplantation offers a 90% chance of long-term survivalFor patients without a sibling donor, the major form of therapy is immunosuppression, with a response rate of 60–80%
Fanconi’s Anemia Clinical presentation:Hyperpigmentation of the trunk, neck, as well as cafй-au-lait spots and vitiligo. Short stature & growth failure may be associated with abnormal growth hormone secretion, or with hypothyroidism. Absent radii and hypoplastic, bifid, or absent thumbs are common.Many patients have a Fanconi “facies,” including microcephaly, small eyes, epicanthic folds. Approximately 10% of patients are mentally retarded. Ectopic, pelvic, or horseshoe kidneys are detected by imaging
Fanconi anemia
Fanconi anemia Chromosomal breakageFanconi anemia-Syndactyly
Fanconi anemia- Absent radius
Fanconi anemia-absent thumbLaboratory Findings Marrow failure usually ensues in the 1st decade of life The marrow becomes progressively hypocellular and fatty, similar to severe acquired aplastic anemia. Chromosome fragility is due to spontaneously occurring chromatid breaks
Treatment If the hematologic findings are stable and there are no transfusion requirements, observation is indicatedHematopoietic stem cell transplantation is the only curative therapy for the hematologic abnormalities.