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SICKLE CELL DISEASE Michael L. Titzer, M.D. Oncology/Hematology Associates 2015 SICKLE CELL DISEASE • • • • • • • • • • • Molecular Biology Epidemiology Pathophysiology Laboratory Evaluation and Diagnosis Clinical Features Management Hydroxyurea Transfusion Therapy Surgical Considerations Bone Marrow Transplantation Prognosis Molecular Biology • RBC is a container for hemoglobin (Hb) • Hb made of four globin chains and four heme groups • Each heme group binds an oxygen molecule • Four types of globin chains (, , , ) • globin encoded by two genes on chromosome 16 • Non- chains encoded by genes on chromosome 11 • Hb consists of two chains and two non- chains • Three types of Hb Molecular Biology • Three types of Hb – Hb A (22) 97% – Hb A2 (22) 2% – Hb F (22) 1% • RBC contains Hb F throughout fetal life • After birth, -globin synthesis is suppressed, and -globin and -globin synthesis is activated Molecular Biology • Thalassemia – quantitative failure in globin chain production due to gene mutation or deletion • Sickle cell disease – qualitative/structural defect in globin involving single amino acid substitution Epidemiology • Black Africans and Americans, Mediterranean, East Indian, Latin America • 70,000 cases in US • 8% of Blacks carry trait • 0.25% have SS disease Pathophysiology • Substitution of val glu in -globin chain • AR • Sickle trait – – – – no sickling 40% Hb S and 60% Hb A normal lifespan no clinical disease Pathophysiology • Homozygotes present at age 6-12 months • Oxygenated Hb S has normal shape • Deoxygenation leads to distorted shape • Sickling/unsickling leads to hemolysis • Sxs result from hemolysis and vaso-occlusion • Also see increased blood viscosity, release of cytokines, changes in neutrophils, changes in endothelial cells Pathophysiology • Can inherit two different abnormal -globin genes – – – – – Hb SC Hb SDPunjab Hb SOArab Hb S-thal Hb SE • SC and S-thal have milder disease, although eye disease is more common Laboratory Evaluation and Diagnosis • CBC • MCV • MCHC • Peripheral smear • Reticulocyte count • Bilirubin and LDH • Iron and Folate • Hb electrophoresis Clinical Features • Vaso-occlusive complications • Complications of hemolysis • Infectious complications • Psychosocial issues Clinical Features painful episodes stroke acute chest syndrome priapism liver disease splenic sequestration pregnancy leg ulcers osteonecrosis proliferative retinopathy renal insufficiency pulmonary hypertension sudden death anemia cholelithiasis aplastic crises fever immunizations antibiotic prophylaxis psychosocial issues Management – Painful Episodes • • • • 90% of hospitalizations Ischemic tissue injury from vascular obstruction Ischemia → regional hypoxia and acidosis → ↑ sickling Typically last 4-7 days • Precipitants: hypoxia, infection, dehydration, acidosis, menses, OSA, cold, stress • Treat underlying cause • Usually no precipitating factors found Management – Painful Episodes • Frequency and severity are variable • Survival correlates with frequency • Chronic pain: avascular necrosis, arthritis, LE ulcers, vertebral body collapse • Acute pain: vaso-occlusion, acute chest syndrome, RUQ syndrome, dactylitis, priapism, splenic sequestration, gallstones Management – Painful Episodes • Immediate evaluation: – – – – – – – – – – – Fever ≥ 101 Lethargy Pallor Persistent emesis Acute pulmonary symptoms Acute neurologic symptoms Extremity weakness or loss of function Acute joint swelling Pain unrelieved with oral meds Priapism Acute flank or back pain Management – Painful Episodes • Labs nonspecific, can help determine underlying cause • Worsening anemia, low retic → aplastic crisis • Worsening anemia, low retic, low plts → splenic seques • Elevated WBC and left shift → infection Management – Painful Episodes • Standard eval: • • • • CBC, retic count, UA, chemistry, LFTs, CXR, oxygen saturation Blood cultures if T ≥ 101 KUB for abdominal pain Ultrasound if suspect RUQ syndrome X-ray/bone scan/MRI/biopsy/culture for osteomyelitis or septic joint Management – Painful Episodes • Five principles of treatment: – – – – – Analgesics Warmth Rest Hydration (3-4 liters/day) Treat precipitating event • Measure pain with verbal or visual analog scale • Believe the patient • Monitor for efficacy and side effects Management – Painful Episodes • • • • • • • • • • Acetaminophen NSAIDs Ketorolac (Toradol) Tramadol (Ultram) Opiods Long-acting morphine/oxycodone/fentanyl Avoid meperidine (Demerol) IV opiods with patient-controlled analgesia (PCA) Taper dosing Observe 12-24 hours on oral meds prior to discharge Management – Painful Episodes • Adjuvant medications: – – – – – – – Antihistamines (pruritus, nausea) Antiemetics (nausea) Laxatives (constipation) Benzodiazepines (anxiety) Tricyclic antidepressants (depression, pain, insomnia) Selective serotonin reuptake inhibitors (depression, pain) Anticonvulsants (pain) • Supplemental oxygen controversial • Transfusion controversial Management – Stroke • 10-15% of patients • Highest in ages 2-9 years • Sxs: seizure, somnolence, disorientation, HA, aphasia, sensory or motor loss, speech or vision disturbance • Risk of recurrence 50% • Risk decreases to 10% with transfusion • Can be hemorrhagic or thrombotic • Acutely treat with exchange transfusion to Hb S < 30% • Maintain for 3-5 years with simple transfusion Management – Stroke • Clinical trial of prophylactic transfusion • Those with flow velocity > 200 cm/sec randomized • Decreased risk of stroke from 16% to 2% • Screen with transcranial doppler q6mos ages 2-16 years • Simple transfusion to keep Hb S < 30% Management – Acute Chest Syndrome • • • • • • • 30% of patients 50% recurrence, 5-10% mortality Pleuritic CP, fever, cough, hypoxia, infiltrates on CXR Precipitated by infxn, fat embolism, pulmonary infarct Admit and monitor for rapid deterioration IVF, abx, oxygen, bronchodilators, analgesia Exchange transfusion for hypoxia, respiratory distress, or multi-lobar involvement • Steroids controversial – generally not used Management – Priapism • 10-40% of patients • Persistent painful erection • Pain medications • IV fluids • Nifedipine as vasodilator • Aspiration and epinephrine irrigation if > 24 hours Management – Liver Disease • Less than 2% of patients • Multiple etiologies: – – – – Iron overload from transfusions Hepatitis B and Hepatitis C Acute chest syndrome Multi-organ failure • Treat underlying cause Management – Splenic Sequestration • Seen in children under age 6 years • Acute onset of severe anemia and thrombocytopenia • Hypotension from pooling of blood in spleen • May be fatal • IV fluids • Transfusion • Splenectomy if recurs Management – Pregnancy • • • • • • Prenatal counseling 6% spontaneous abortion Folic acid supplementation Follow every 2 weeks until 36th week, then weekly Monitor fetal growth Transfuse prior to c-section – Hct 30% and Hb S < 50% • Most acute sickle cell problems treated the same as in the nonpregnant patient Management – Leg Ulcers • • • • • • • • • 20% of adults Small nonhealing sores on lower extremities Debridement Wet-to-dry dressings TID Skin graft or compression dressing (Unnaboot) Topical antibiotics Regranex gel BID Transfusion controversial, keep Hb S < 50% May take months or years to heal Management – Osteonecrosis • • • • • • • • 10-50% of adults Chronic hip or shoulder pain MRI best diagnostic test Rest Analgesics Osteotomy for children Core decompression may decrease pain in adults Joint replacement Management – Retinopathy • • • • • • • • • 3% in SS disease, 30-50% in SC disease Sickling in vascular bed of eye Retina exquisitely sensitive to oxygen deprivation Usually asymptomatic Visual field defects and eventually blindness Dilated fundoscopic exam yearly Laser photocoagulation Vitrectomy if hemorrhage does not clear spontaneously Surgery for retinal detachments Management – Renal Insufficiency • 5-20% of adults • Renal medulla is hypoxic, acidic, and hyperosmotic • Series of events: – – – – medullary blood flow / hyposthenuria / hyperfiltration papillary necrosis / RTA / proteinuria / hematuria glomerulonephritis / renal blood flow/nephrotic syndrome chronic renal failure • At age 3 years, monitor BP, UA, creatinine annually • Avoid diuretics • Hematuria – UA, coags, culture, US, IVP, cystoscopy Management – Pulmonary HTN • Most common cause of death in adulthood • Secondary to microvascular obstruction, acute chest syndrome, pneumonia, infarction, and fat emboli • Cor pulmonale and restrictive lung disease • Chronic hypoxia worsens sickling • Supplemental oxygen Management – Sudden Death • Reported in military recruits • Associated with extreme exertion Management – Anemia • Hemolysis from repeated sickling and unsickling • Hb 6-9 common baseline • Patients well-adapted • Folic acid 1-2 mg PO QD Management – Cholelithiasis • Seen in most adults • Many asymptomatic • Increased bilirubin from hemolysis • Ultrasound for diagnosis • Cholecystectomy if symptomatic Management – Aplastic Crises • Rapidly occurring, severe anemia • 85% associated with Parvovirus B-19 • Also seen with EBV, Streptococcus, and loss of erythropoietin in renal disease • Fatigue, DOE, pallor, anemia below baseline, low retic • Spontaneously resolves in 1-2 weeks • Support with simple transfusion • Recurrence of Parvovirus B-19 is rare Management – Fever • • • • • Infection most common cause of death in children Splenic dysfunction Panculture and start antibiotics immediately Lumbar puncture if signs/symptoms of meningitis Generally admit to hospital Streptococcus pneumoniae Hemophilus influenzae Staphylococcus aureus Escherichia coli Neisseria Salmonella Mycoplasma Management – Immunizations • Usual childhood immunizations: – HBV, DPT, Hib, IPV, MMR, OPV, Varicella • Age 2 years: – Pneumovax every 5 years – Flu shot yearly – Meningovax • Prior to surgical splenectomy: – Hib, Pneumovax, Meningovax Management – Antibiotic Prophylaxis • Oral Penicillin VK 125mg BID ages 3 months – 3 years • Oral Penicillin VK 250mg BID to age 18 years • Erythromycin if allergic to PCN Management – Psychosocial Issues • Growth retardation • Absenteeism from school or work • Frequent hospitalizations • Medical expenses • Fear of death Hydroxyurea (HU) Therapy • Mechanism of action • Indications • Side effects • Dosing Hydroxyurea – Mechanism of Action • • • • • • • • Exact mechanism unknown High Hb F associated with milder disease Hb F increases with sudden erythroid regeneration Cytotoxic agents trigger erythroid regeneration HU is oral and less toxic than other chemotherapeutics HU increases Hb F levels by 2-20% Randomized study stopped early due to benefit Decreased pain, transfusions, acute chest syndrome Hydroxyurea – Indications • Patients with end-organ damage • History of stroke • History of acute chest syndrome • Frequent pain episodes Hydroxyurea – Side Effects • • • • • • • • Mutagen and teratogen (no birth defects yet reported) Myelosuppression Thrombocytopenia Macrocytosis (elevated MCV) Increases Hb F and total Hb GI upset and diarrhea Rash Long-term adverse effects still unknown – Increased risk of leukemia, possible growth delay Hydroxyurea – Dosing • • • • No correlation between dose and clinical benefit Responses variable and may take several months Not all patients respond Proper contraception for women and men • • • • • 500-1500 mg PO QD Titrate dose q6-8 weeks based on response/tolerance Monitor CBC every 2 weeks initially Keep ANC > 2000 and platelets > 80,000 Look for elevation in MCV, Hb F, total Hb Transfusion Therapy • Simple transfusion – Can increase viscosity • Partial exchange transfusion – Manual phlebotomy before or during transfusion • Automated exchange transfusion (pheresis) – Rapid exchange without increasing viscosity or total Hb Transfusion Therapy • Indications for exchange transfusion – – – – – Acute stroke or transient ischemic attack Acute chest syndrome with hypoxia Severe RUQ syndrome Unresponsive priapism Cardiac failure or angina • Goal is to reduce Hb S < 30% Transfusion Therapy • Indications for acute simple transfusion: – – – – – Acute anemia (aplastic crisis/splenic sequestration/blood loss) Prior to surgery requiring general anesthesia Prior to any eye surgery Before injection of contrast materials Intractable acute pain syndromes • Goal is hematocrit of 30% Transfusion Therapy • Indications for chronic simple transfusion: – – – – – – Primary prevention of stroke (16% 2%) Secondary prevention of stroke (50% 10%) Chronic organ failure Complicated pregnancy Refractory leg ulcers Symptoms related to chronic anemia • Goal is Hb S < 30% (Hb S < 50% for leg ulcers) • Generally done every 2-4 weeks Transfusion Therapy • Transfusion generally NOT indicated for: – – – – – – Routine pain episodes Compensated anemia Uncomplicated pregnancy Local anesthesia/conscious sedation Minor infections Aseptic necrosis Risks of Transfusion Therapy • Alloimmunization – Hard to find compatible blood – Delayed hemolytic reactions – All blood products should be leukocyte depleted • Infections – HIV, HCV, HBV • Iron overload – Start iron chelation when ferritin > 2000 ng/ml – Deferoxamine prolonged SQ infusion daily Surgical Considerations • Pre-operative: – Admit 12-24 hours before surgery, IV fluids, bronchodilators, transfuse to hematocrit 30% • Intra-operative: – Monitor pulse oximetry, IV fluids, prevent hypothermia, replace blood loss • Post-operative: – Monitor pulse oximetry, IV fluids, incentive spirometry, observe 24-48 hours for acute chest syndrome Bone Marrow Transplantation • For children with severe complications • Need HLA-matched sibling donor • Only 1% of patients meet the above criteria • 10% treatment-related mortality • Full extent of toxicity is still unknown Prognosis • Hb SS median lifespan: – Female 48 years – Male 42 years • Those with sickle trait have normal lifespan