Sickle Cell Disease

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).

Laboratory findings 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

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

Major Clinical Manifestations 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 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