Congenital Haemoglobinopathies L. DEDEKEN, MD H O P I T A L U N I V E R S I T A I R E D E S E N F A N T S R E I N E F A B I O L A U N I V E R S I T E L I B R E DE B R U X E L L E S Red Blood Cell Disorders BHS training course 2013
Introduction ~ 5% of the world s population carries trait genes for haemoglobin disorders Carriers ~ 25% in some regions > 300.000 new births with severe haemoglobin disorders each year Lopez et al. Gene 2010
Sickle cell disease
Epidemiology Rees et al. Lancet 2010 In Brussels 1 st genetic disorder 1/1600 birth Harteveld et al. Orphanet J Rare disease 2010
Genetics Autosomal recessive disorder Mutation on β-globin gene sixth aminoacid becomes valine instead of glutamic acid (HbS) Sickle cell trait Hb AS Sickle cell syndrome Hb SS (sickle cell anemia) Hb SC Hb Sβ-thalassemia Hb SD Punjab Hb SO Arab
Physiopathology Rees et al. Lancet 2010
Subphenotypes of SCD Kato et al. Blood Rev 2007
Diagnostic tools Blood cell count Peripheral blood smear Hemoglobin electrophoresis Genetic
Survival Quinn. Blood 2010 Platt. NEJM 1994
Clinical features
Anemia Chronic hemolytic anemia Hemoglobin level AA : 10-13 g/dl SS : 6-10 g/dl SC : 10-12 g/dl Acute event Erythroblastopenic anemia < B19 Parvovirus Infection Splenic sequestration G6PD deficiency, folate deficiency, malaria, allo-immunisation,
Infections
Vaso-occlusive crisis Painful event Increased occurence whith Hypoxia, dehydratation, acidosis, cold exposure, Dactylitis Osteo-articular manifestations Pain Swelling Functional impact Differential diagnosis : Osteomyelitis or arthritis
Acute chest syndrome Fever OR tachypnea OR decreased O 2 saturation with Abnormal pulmonary exam New infiltrate on RX Etiology Infections (30-40%) Fat embolism (7%) No identify cause (40-50%) Differential diagnosis Pulmonary embolism Lancet 2010
Cerebral vasculopathy
Lancet Neurol 2006 Blood 1998 Stroke Ischemic or hemorragic Seizures Cognitive impairement Blood 2009
How to assess the risk? Blood 2009
Chronic complications Retinopathy Leg ulcer Osteonecrosis Pulmonary hypertension
Management Education and information Good lifestyle To avoid risk factors (hypoxia, dehydratation, cold exposure, ) To recognize a acute event Folic acid Infection prevention Prophlyactic antibiotics Vaccination Streptococcus pneumonia, Haemophilus influenzae, Flu Emipiric antibiotherapy
Symptomatic management Vaso-occlusive crisis Adapted pain management Good hydratation Acute chest syndrome Exchange transfusion Antibiotics Stroke or unexplained neurological symptom Exchange transfusion
Intensification Chronic (exchange) transfusion program Primary or secondary prevention of stroke Recurrent ACS or VOC despite HU Organ failure (hepatic, renal, ) Hydroxyurea The only efficient drug Well tolerated Up to maximal tolerated dosis if needed Ware. Blood 2010
Voskaridou. Blood 2010 Lopes de Castro Lobo. BJH 2013
Hematopoietic stem cell transplantation The only curative treatment Severe disease and intra-familial HLA donor Survival Overall survival 92-96% Event free survival 82-86% Death 3-9% In development Matched unrelated donor Halpoidentical transplantation High risk of rejection and GVHD Gene therapy
Thalassemia
Lancet 2012
β-thalassemia
Physiopathology http://calgaryguide.ucalgary.ca/hematology.aspx
Clinical outcome Severe anemia Without appropriate chronic transfusion Asthenia Dilated cardiomyopathy Hepatosplenomegaly Jaundice Bone deformities Specific facial deformation (frontal bossing, maxillary overgrowth,...) Osteoporosis Growth and development delayed Hypermetabolic state Recurrent infections
Treatment Chronic transfusion Monthly To keep Hb 9-11 g/dl Hb F inducer (HU) Iron overload Evaluation Ferritine Liver biopsy MRI T2* Clinical outcome
Iron chelators Neufeld. Blood 2006
Survival Adapted from Ladis et al. Ann N Y Acad Sci. 2005
HSCT & β-thalassemia Sabloff. Blood 2011
α-thalassemia Harteveld & Higgs. Orphanet J Rare Diseases 2010
Pathogenesis http://calgaryguide.ucalgary.ca/hematology.aspx
Clinical features Absence of 1 or 2 α chain(s) -α/αα ; --/αα ; -α/-α Absence of 3 α chains (HbH disease) --/-α Absence of 4 α chains (Hb Bart s Hydrops Fetalis) --/-- Common Asymptomatic or moderate microcytic anemia Does not requires therapy Hemolytic feature (gallbladder lithiasis, HSM) Microcytic anemia (Hb 7-10g/dl) Folic acid, infrequent transfusion Hydrops fetalis Non viable
CONCLUSION
References Stuart MJ, Nagel RL. Sickle cell disease. Lancet. 2004; 364: 1343-60 Rees DC, Williams TN, Gladwin MT. Sickle cell disease. Lancet. 2010; 376: 2018-31 The management of sickle cell disease. http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassaemia. Lancet. 2012; 379: 373-83. Harteveld CL, Higgs DR. Alpha-Thalassaemia. Orphanet J Rare Dis. 2010 May 28;5:13