Introduction • Vaso-occlusive phenomena and hemolysis are the clinical hallmarks of Sickle Cell Disease (SCD) • Inherited disorder due to homozygosity for the abnormal hemoglobin, hemoglobin S (HbS)
HbS results from substitution of valine for glutamic acid as sixth amino acid of the beta globin chain, which produces a hemoglobin tetramer that is poorly soluble when deoxygenated. • Polymer assumes elongated rope-like fiber form in the classic sickle shape
Sickle cell shape results in decrease cell deformability. • Changes also occur in red cell membrane structure and function, disordered cell volume control and increase adherence to vascular endothelium.
Overview • Disorder most severe in patients with SCD (homozygosity for HbS), of intermediate severity in hemoglobin SC disease (HbSC, combined heterozygosity for hemoglobin S & C), and generally benign in those with sickle cell trait (heterozygosity for Hbs).
Patients with homozygous SCD are typically anemic and often lead a life of painful episodes. • Clinical signs and symptoms begin at an early age.
Prevalence of symptoms at age • Six month of age - 6% • Twelve months of age - 32% • Two years of age - 61% • Six years of age - 92% • eight years of age - 96%
Predictors of adverse outcome • Dactylitis before age one • Hemoglobin concentration < 7 g/dl • Leukocytosis in absence of infection • An adverse outcome, defined as stroke, frequent episodes of pain, recurrent acute chest syndrome or death occurred in 18% with these predictors,(392 infants/10yrs).
Moderate anemia Reticulocytosis 3-15% High MCV Unconjugated hyperbilirubinemia Elevetaed LDH Low haptoglobin Folate & iron deficit Peripheral smear shows sickle cells Polychromasia Howell-jolly bodies Elevated WBC Elevated Platelets Low than after 18 yrs high creatinine Laboratory findings
Acute Severe Anemia • Acute fall in haptoglobin. • Patients present with pallor, weakness and lethargy. • Fatalities not uncomon. • Due to the Splenic sequestration crisis, aplastic crisis or hyperhemolytic crisis.
Splenic sequestration crisis • Vaso-occlusion in the spleen and pooling of blood in the spleen produce fall in hemoglobin, reticulocytosis and rapidly enlarging spleen. • Risk of hypovolemic shock and 10-15% mortality. • Recurrent in 50% of survivors.
Aplastic crisis • Arrest of erythopoiesis with falling hemoglobin levels and absence of reticulocytes. • Associated with infection namely Parvo-B19, EBV, Streptococcus and salmonella. • Reticulocytes usually reappear in 2-14 days.
Hyperhemolytic crisis • Sudden exacerbation of anemia with reticulocytosis. • Cause unknown. • Rare
Acute painful episodes Multiorgan failure Psychosocial issues Growth & development Infection Bacteremia Meningitis Bacterial pneumonia Osteomyelitis CVA Bone complcations Infarct and necrosis Marrow infarct Orbital compression Arthritis Major Clinical Manifestations
Cardiac complications Myocardial infarct Dermatologic complications Leg ulcers Hepatobiliary complications Cholelithiasis Chronic liver disease Acute hepatic episodes Pregnancy complications Fetal complications priapism Pulmonary complications Major Clinical Manifestations
Major Clinical Manifestations • Renal complications • Retinopathy • Take a deep breath!
Acute painful crisis • Precipitated by cold, infection, dehydration, infection, stress, menses, hypoxemia, alcohol or no identifiable cause. • Can affect any area, but back, chest, extremities and abdomen most frequent. • Usually last 2-7 days. • Frequency- 1/3 rarely, 1/3 2-6yr, 1/3>6yr
Acute chest syndrome • Due to pneumonia, infarct due to in situ thrombosis and embolic phenomena due to fat embolism and bone marrow infarct. • Manifestations are chest pain, infiltrate on CXR and fever. • Treat with O2, antibiotics, and exchange transfusion to lower HbS to below 30%.
Management • Treatment and prevention of the acute manifestations of SCD. • Therapies designed to interfere with the polymerization process at different levels
General principals • Regular Physician follow up. • Establish base line labs and Physical findings. • Education regarding nature of disease, genetic counseling and psychosocial assessment. • Immunize for Strep, influenza and Hep B
Prophylactic penicillin until five years. • Folic acid 1md/day • TCD • Retinal evaluation • BCP • Hydroxyurea
Hdroxyurea • Increases production of hemoglobin F. • Reduces median crisis rate by 50%, decreased acute chest syndrome and transfusion. • 40% reduction in mortality. • Mild increase in acute myeloid leukemia
Pain management • Narcotics - Morphine or dilaudid • Toradol • Inhaled nitric oxide • anticoagulation low dose INR 1.5 • Poloxamer 188
Management of infection • Prophylactic fever - Ceftriaxone • Acute chest syndrome - Cefuroxime & Erythromycin. • Osteomyelitis - Cover salmonella and staph until cultures available.
Transfusion therapy • Aplastic crisis • Acute chest syndrome or sepsis • CVA • Priapism • Perioperative • Simple vs exchange • Do not raise Hgb > 10
Prophylactic preoperative transfusion • Increase hemoglobin to 10g/dl • Reduces serious complications • Orthopedic surgery still has 67% serious complications and 17% sickle-related Complications ( acute chest syndrome and vaso-occlusive crises )
Transfusion complications • Alloimmunization • Iron overload • Infection
Prognosis • Median age of death for SCD in males is 42 for men and 48 for women • Median age of death for Hb SC is 60 for men and 68 for females
Causes of death • Infection - 48% • Stroke - 10% • Complications of therapy - 7 % • Splenic sequestration - 7 % • Thromboembolism - 5% • Renal failure - 4 % • Pulmonary hypertension - 3 %
The future • Gene therapy • Increase expression of Hb F • RNA repair • Hematopoietic cell transplantation