Hematology and Immunology A concise update Adlette Inati MD Pediatric Hematology Oncology Lebanese American University and Rafik Hariri University Hospital
Lebanese University Oct 25, 2013 Learning Objectives Concisely Review Anemia Hematopoietic and Stromal Cell Differentiation Erythropeisis Main players
Pluripotent stem cells
Chemical regulators Cytokines Erythroid specific growth factor Erythropoietin (EPO) Thyroid hormones, estrogens and androgens
Nutritional requirements Proteins and amino acids
Vitamin B12 and folic acid Vitamin B6 (pyridoxine) Iron Other nutrients (Vitamin C, cupper, cobalt) Anemia Diagnosis
History Physical Examination Blood count Blood smear Reticulocyte count Medical History
Sudden onset of pallor, fatigue or exercise intolerance?
Blood loss, easy bruisability?
Cold intolerance, constipation, lethargy, poor growth
Recent drug or fava bean intake or viral infection?
Neonatal jaundice or episodes of jaundice or dark urine in the past?
The child’s diet? Any iron supplements? Any history of pica?
Any history of recurrent bone or joint pain or diarrhea? Family History
Anemia or low blood counts?
Excessive bleeding, transfusion requirements ?
Splenectomy ,cholecystectomy, hystereectomy at an early age?
Autoimmune diseases ?
Consanguinity?
Ethnic / geographical origin? Physical Examination
Is the child active and playful or fatigued?
Look for pallor, signs of heart failure, icterus, jaundice, glossitis
Look for petechiae, bruises, splenomegaly, pathologic lymphadenopathy, abdominal masses, skeletal abnormalities and abnormal facies Complete blood count (CBC)
Automated counter Provides a panel of tests:
Red Blood Cells (RBCs) Number of RBCs per volume of blood Hemoglobin (Hb) – amount of Hb in the blood Red cell Indices
White Blood Count (WBCs) Number of white blood cells per volume of blood WBC differential - types of WBCs present
Platelets (Plts) Number of platelets per volume of blood MPV Normal values are age and sex dependent Blood Smear
Shows specific morphologic abnormalities Reveals polychromatophilia which is a reflection of reticulocytosis Recognizes abnormal cell morphology Reticulocyte Count An Underutilized Parameter
Immature mononucleated RBCs indicating active erythropoiesis
Elevated in blood loss or hemolysis
Low to NL in bone marrow failure or ineffective erythropoiesis
Oski FA, Brugnara C, Nathan DG: A diagnostic approach to the anemic patient. In: Nathan and Oski’s Hematology of Infancy and Childhood. 5th ed. Harcourt Health Sciences; 1998:375-384 Polycythemia Anemia Lymhocytes(Increased Hb) (Decreased Hb) Decreased blood volume (dehydration, burns, diuretics) Decreased production
Increased RBC mass (polycythemia) Increased destruction - Chronic hypoxia (hemolysis) - Erythropoetin secreting Tumors - Primary (polycythemia vera)
Blood loss -
Sequestration Anemia Diagnostic Algorithm
History, Physical exam Hb, WBC, Platelets Microcytic Red cell indices Macrocytic Reticulocyte count Blood film Iron deficiency Thalassemia Folic acid deficiency Lead poisoning Vit. B12 deficiency Sideroblastic anemia Normocytic Hypothyroidism Unstable hemoglobins Liver disease Anemia of chronic Drugs disease
Low Reticulocyte count Nl reticulocyte count High reticulocyte count R/O Bone Marrow Chronic inflammation R/o hemorrhage Failure/Red Cell Aplasia Adlette Inati. Iron curriculum R/O hemolysis ESH, Webcast 2010 Iron-deficiency anemia (IDA) • • • • • • • • • •
• absent globinchainsynthesis Inherited anemias characterizedby Thalassemias Severe transfusion dependent Severe dependent anemia transfusion If Significant Significant Mild anemia, diagnosed usually in late childhood inlate usually diagnosed Mild anemia, Occasional blood transfusions may be required be may transfusions Occasional blood impaired moderately production chain Globin Various interactions genetic May require genetic counseling counseling May genetic require Asymptomatic Heterozygous condition Homozygous disorder Homozygous untreated, leads to death usually in usually death tountreated, leads imbalance of imbalance b a globin globin chains first decade decade first presenting early life early presenting in b b b d - - - intermedia thalassemia thalassemia thalassemia ecreased minor major or
Severity of disease Thalassemia Diagnosis Beta thalassemia blood smear Normal blood smear
Lab diagnosis
Low Hb / Hct Low MCV / MCH High HbF / HbA2 β -Thalassemia Major Management
Several ongoing thalassemia trials in Lebanon and the ME Macrocytic Anemias
Large RBC s with high MCV > 100 Common in adults Hypersegmented neutrophils
Megaloblastic: Impaired DNA synthesis and assembly resulting in delayed nuclear maturation with normal cytoplasmic development Vit B12 deficiency Folate deficiency Drug induced Myelodysplasia Non-megaloblastic: abnormal RBC maturation Alcohol Liver disease Hypothryroidism chemotherapy/drugs Megaloblastic anemia Symptoms
Folic Acid Vitamin B12 deficiency deficiency No neurologic symptoms Neurologic symptoms Pallor, lethargy, weakness Anorexia, diarrhea Light headedness Papitations, angina Macrocytic anemias Hemolytic anemias
A group of inherited or acquired disorders characterized by premature RBC destruction and inability of the marrow to have sufficient erythrocyte production to keep up with accelerated RBC destruction, thus producing anemia
Presentation ranges from an asymptomatic to a severe life threatening state with angina and cardiopulmonary decompensation in severe cases
Usual symptoms and signs: pallor, lethargy, jaundice, icterus and dark urine, fever and sometimes back and abdominal pain Classification of Hemolytic Anemias Intra versus extra vascular hemolysis Intravascular Hemolysis Extravascular Hemolysis
Severe clinical course Mild to moderate course
↑ Free plasma hemoglobin No free plasma hemoglobin
↑ Free urinary Hb / hemosiderin Absent urinary Hb / hemosiderin
Schistocytes Spherocytes
Decreased serum haptoglobin Normal serum heptaglobin
↑ Indirect bilirubin reticulocytosis Urobilinogen in stool and urine Intra versus extra corpuscular hemolysis
INTRACORPUSCULAR EXTRACORPUSCULAR
•Membrane abnormalities •Immune Hereditary spherocytosis •Allo immune •Autoimmune •Enzyme abnormalities •Non Immune G6PD deficiency •Microangiopathic (TTP) •Infection(malaria) •Chemical agents (spider venom •Hb abnormalities Sickle cell disease/ Thalassemia Membrane Abnormalities Hereditary Spherocytosis Enzyme abnormalities Favism
Adlette Inati, et. J Med Screen. 2012;19 (2):103-4 Hemoglobinopathies Pathophysiology of SCD
β-Globin Gene
Glutamic acid HbS Valine (ɑ2βˢ2) Deoxygenated Hb polymers Low oxygen tension
Sickle erythrocyte
Haemolysis Vaso occlusion
Pain, acute chest syndrome, joint necrosis, Anaemia, gallstones, priapism, stroke acute splenic sequestration, increased leg ulcers, pulmonary hypertension infections, multi-organ damage
Adapted from Inati A, et al. Pediatr Ann. 2008;37:311-25. SCD diagnosis SCD blood smear Normal blood smear
HPLC. Sickle Cell Disease Preventive strategies
Neonatal Screening, Penicillin prophylaxis and Vaccination
Disease Modifying Comprehensive Therapies Care and family (hydoxyurea, transfusions education and stem cell transplant)
Transcranial Screening for doppler pulmonary hypertension screening for
stroke risk Inati A etal. Pediatr Ann. 2008;37:311-25 Vichinsky et al. Pediatrics 1988; 81: 749-755 Sickle cell disease in Lebanon
Evelyne Khoriaty etal. & Adlette Inati. EHA 2012, Abstract no. 2021 Hemoglobinopathies Treatment Options in Development Treatment Option Clinical Effect Arginine es production of nitric oxide a potent vasodilator Decitabine es HbF
Butyrates short-chain FAs that inhibit histone deacetylase (HDAC), HbF production Clotrimazole Inhibits cation transport channels in RBC membranes thereby reducing cellular dehydration Gene Therapy Clinical evidence not yet available. Early promise shown in a transgenic mouse model
Several ongoing trials in Lebanon on HbF modulation Bone marrow failure syndromes (BMFSs) Bone marrow failure syndromes Hereditary Acquired
Diamond Blackfan anemia Idiopathic
Fanconi’s anemia Drugs: chemotherapy, chloramphenicol, benzene, sulfas…. Dyskeratosis congenita Radiation, chemicals Schwackman – Diamond anemia Viruses: EBV, HIV, parvovirus, hepatitis
Amegakaryocytic thrombocytopenia Malnutrition
Thrombocytopenia with absent radius Paroxysmal nocturnal hemoglobinuria syndrome (PNH)
Severe congenital neutropenia Disorders of immune system
Myelodysplastic syndromes (MDS) Bone marrow failure syndromes Symptoms Bone marrow failure Treatment Options
Hematopoetic growth Bone Marrow factors Transplant
Immune Suppressive Supportive Care Therapy White blood cells disorders
Benign disorders Proliferative disorders
Quantitative Leukemia Leukopenia Leukocytosis Lymphoma
Qualitative abnormalities Myeloma Leucocytosis Leucopenias Increased WBCs Decreased WBCs
Infections Bone marrow failure Inflammations and or suppression Cancers Increased (leukemias….) destruction Shift of neutrophils Sequestration from marginating Shift of neutrophils pool to circulating from CP to MP pool (margination) Neutropenia
Classification Neutrophil Count
Mild 1.0- 2.0 x 10⁹/L
Moderate 0.5-1.0x 10⁹/L
Severe <0.5 x 10⁹/L
Very severe <0.1 x 10⁹/L (agranulocytosis) Fever and Neutropenia