Sickle Cell Disease

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2. Sickle Cell Disease

3. Common Genotypes of Sickle Cell Disease • Sickle cell trait (“HbAS”) • Person carries sickle hemoglobin gene (HbS) and also has some normal hemoglobin (HbA) • HbS ≤40% total hemoglobin; usually no symptoms • Cells don’t deform when deoxygenated • Sickle cell anemia (sickle-cell disease, “HbSS”) • HbShomozygosity; most / all HbA replaced with HbS • Most common + most severe of sickle cell variations • Complications due to sickled cells shape + thickness

4. Other Common Genotypes of Sickle Cell Disease • HbSC disease • Compound heterozygosity for HbS and HbC genes • HbSE disease • Compound heterozygosity for HbS and HbE genes • HbS-β-thalassemia disease • Compound heterozygosity for HbS and a β0- or β+-thalassemia gene • HbSO Arabia • Compound heterozygosity for HbS and HbO Arabia • HbSD Los Angeles (Punjab) • Compound heterozygosity for HbS and HbD

5. Who should be screened for sickle cell anemia and sickle cell trait? • All U.S. newborns • Test also detects sickle cell trait carriers • At risk individuals pregnant or planning pregnancy • Determining who is at risk can be difficult • Maternal & paternal family history: best guide for determining individual HbS screening • Individuals with hyphema or hematuria

6. What screening and diagnostic tests are available? • To detect HbS: high-performance liquid chromatography • In newborns, children, adults • Some labs use isoelectric focusing • When genetic counseling needed: DNA-based test • Establishes parental globin gene mutations • If positive: DNA-based testing of chorionic villus samples or amniotic fluid cells • Before considering prenatal Dx, counsel parents: • On risks of procedure and consequences of positive Dx • On likelihood of affected fetus and options for termination

7. Pathophysiology includes: • Abnormal erythrocyte volume regulation • Impaired nitric oxide bioavailability • Reperfusion injury • Inflammation and oxidant damage • Abnormal intercellular interactions • Endothelial injury • Leukocyte and platelet activation • HbS gene most prevalent in persons of African, Arabian, and Asian-Indian ancestry

8. CLINICAL BOTTOM LINE: Screening… • Screening can lead to prompt diagnosis • Screening helps prevent serious complications • Screening provides information for family planning

9. What should prompt consideration of undiagnosed sickle cell disease? • Suspicious symptoms • Frequent, unexplained pain • Splenomegaly • Stroke at young age • Pneumonia with anemia requiring transfusion • Osteonecrosis in femur heads and humerus • Rare complications • Leg ulcers, priapism, nephropathy+renal failure, severe anemia • Complications occurring with advancing age • Sickle retinopathy, liver disease • Infections • Major cause of death in children and adults

10. What should be looked for on the physical exam when sickle cell disease is suspected? • Swelling and tenderness over affected areas and low-grade fever (in acute, painful episodes) • Consolidation, rales, rhonchi, wheezing (acute chest syndrome) • Cardiac enlargement and systolic murmurs (common) • Enlarged liver • Asplenia, nosplenic dullness on percussion • Splenomegaly (in HbSC disease and HbS–β-thalassemia) • Sickle retinopathy

11. What lab tests should be ordered in the evaluation of possible sickle cell disease? • Erythrocytes (normocytic or macrocytic); microcytosis • Sickle solubility test • High-performance liquid chromatography • In untreated sickle cell anemia • After diagnosis established • Baseline CBC and reticulocyte counts • Red cell antigen phenotyping • Blood urea nitrogen, creatinine, urine albumin, electrolytes, bilirubin, lactate dehydrogenase, serum ferritin, alaninetransaminase, aspartatetransaminase, alkaline phosphatase • Chest radiographs and pulmonary function tests • Pulse oximetry • Echocardiography to estimate the TRV

12. What are complications of sickle cell trait? • Most carriers can’t concentrate urine normally • Due to renal medullary abnormalities • Important to hydrate adequately • Increased risk hematuria • Due to papillary necrosis (usually benign and self-limited) • 2-fold higher risk thromboembolic disease • 4-fold higher risk pulmonary embolism • Splenic infarction rare • Preop screen: needed w/ open-heart or complicated intra-thoracic procedures where hypoxia intrinsic to procedure

13. Which patients with sickle cell disease should be referred to a specialist? • General internist, pediatrician, or family physician can manage routine maintenance + common complications • Consult appropriate specialists as needed • All patients with sickle cell disease: hematologist with expertise in hemoglobinopathies (annually) • Pulmonary complications: pulmonologist or cardiologist • Severe acute chest syndrome:hematologist and critical care specialist • Pregnancy: high-risk obstetrician and hematologist

14. CLINICAL BOTTOM LINE: Diagnosis and evaluation… • Suspicious symptoms: undiagnosed sickle cell disease • Frequent, unexplained pain • Splenomegaly • Stroke at young age • Pneumonia with anemia requiring transfusion • Osteonecrosis in femur heads and humerus • H&P and lab tests used to confirm diagnosis and evaluate patient

15. What drugs should be considered for the primary treatment of sickle cell anemia? • Hydroxyurea • Only FDA-approved drug for primary Rx • Begin early, before irreversible vasculopathy and organ damage develop • Reduces of acute painful events and acute chest syndrome • Reduces mortality 40% and reduces hemolysis • Fewer hospitalizations, reduced medical costs • Improved physical capacity

16. What is the role of blood transfusion? • Simple transfusions reduce HbS levels more gradually • Require only peripheral venous access and rapidly available • Lower alloimmunization risk; greater hyperviscosity risk • Exchange transfusions reduce HbS levels more rapidly • Take more time to start and more complicated venous access • Lower hyperviscosity risk; higher alloimmunization risk • Preop: simple transfusion can reduce postop complications • Stroke: exchange transfusion can reduce recurrence • Acute chest syndrome • Patient may not need transfusion if no hypoxia + chest infiltrates minor, fever minimal, blood count changes small • Don’t use repeated transfusion to manage routine crisis

17. What is the role of bone marrow transplantation in sickle cell anemia? • Transplantation mortality rate: ≈5% • Event-free survival: 84% • Rejection or disease recurrence: ≈10% • When successful, disease is “cured” • Patient no longer anemic • Long-term, stable engraftment sufficiently eliminates the phenotype of sickle cell disease • Myeloablative stem cell transplantation largely limited to children <16 yrs old with severe disease

18. What are the features of sickle cell anemia over a patient's lifetime? • Major clinical features in the first decade… • Severe life-threatening infection • Acute chest syndrome • Splenic sequestration • Stroke; pain; dactylitis • Major clinical features in young adulthood and beyond… • Sicklevasculopathy likely to progress despite few symptoms • Chronic organ damage leads to pulmonary vasculopathy • Deteriorating pulmonary function and renal failure • Late effects of cerebrovascular disease

19. How does pain manifest in sickle cell disease? • Clinical Features of the Acute Painful Episode • Some patients always in pain; others rarely • Pain distribution and duration varies • Pain most often occurs in back, chest, extremities, joints • Cause unclear: unrelated to “new sickling”; blood film unhelpful • Physical findings limited • Frequent episodes associated with poor prognosis • Directly related to packed cell volume; indirectly related to HbF

20. How should pain be managed? • Most pain successfully managed at home • Many patients can sense the beginning of an episode • Use nonopioid analgesics, then oral opioids if needed • Up fluid intake, use rest, warm baths, heating pads, massage • Pain requiring medical intervention • Usually treated in the hospital ED • Initiate parenteralopioids and adjust dosage as needed • Individualize Rx (analgesic doses can vary considerably) • Monitor for oversedation, hypoxia, and low respiratory rate

21. How are episodes requiring further treatment and continuously increased use and dose of opioids managed? • Decision to initiate long-term opiate therapy • Define cause of pain • Determine pain intensity + effect on functioning, QOL • Document evaluation and treatment plan • Monitor closely • Causes of Persistent Severe Pain • Progressive tissue damage • Inadequate treatment • Tolerance • Hyperalgesia • Changes at receptors • Maladaptive behavior

22. How common is the acute chest syndrome in sickle cell disease? • Affects >50% • Mortality higher in adults than children (<10% cases fatal) • Second most common reason for hospitalization • Features: fever, chest pain, cough, and lung infiltrates • Causes: infarction, pulmonary infection, atelectasis, embolism, in situ thrombosis • Frequent postop complication, even after preop transfusion • Fat embolism from necrotic bone marrow causes most severe acute chest events

23. How is the acute chest syndrome in sickle cell disease managed? • Transfusions • Antibiotics • Hydration (avoid overhydration) • Respiratory therapy with bronchodilators • Incentive spirometry • Maintenance of tissue oxygenation • Oxygen: if hypoxic or tachypneic; in respiratory distress • Opioids: balance pain relief w/ respiratory suppression risk • Patients who deteriorate rapidly: admit to ICU

24. What other conditions complicate sickle cell anemia? • Pulmonary vasculopathy & abnormal pulmonary function • Infection • Retinopathy • Anemia • Leg ulcers • Priapism • Renal disease • Digestive system disease • Neurocognitive dysfunction

25. As patients with sickle cell disease live longer, what new health issues are emerging? • Cardiomegaly and heart murmurs • Contractility usually normal and overt CHF uncommon • Hypertension • Cause of ventricular hypertrophy and HF • May contribute to sickle nephropathy and renal failure • Chest pain • Very common but MI unusual

26. Is pregnancy more complicated in women with sickle cell disease? • Most managed without regular transfusions • Identify red cell phenotype & alloantibodies: so pheno-typically matched blood can be used if needed • Multiple-birth pregnancies benefit from transfusion • Obstetric complications and C-section more common • Prenatal testing needed • Establish Hb phenotype and HbF level • Blood counts; serum chemistries; hepatitis A,B,C; HIV testing • Urinalysis; urine culture; rubella antibody titer; serum ferritin

27. Are patients with sickle cell disease at particularly high risk during surgery? • Surgery and anesthesia safe but not complication-free • Blood transfusion: major issue preoperatively • Preparation: hydration; optimization of pulmonary status • Be vigilant toward detecting acute chest syndrome

28. How should end organ damage be monitored, treated, and prevented? • If patient stable  follow every 4 to 6 months • Perform blood counts • Monitor renal and liver function • Test for baseline pulmonary function • Obtain baseline and periodic estimation of TRV • Periodically evaluate for sickle retinopathy • Ophthalmologist visit

29. CLINICAL BOTTOM LINE: Treatment and management… • Sickle cell disease has protean manifestations • Optimum care consists of: • Direct drug therapy with hydroxyurea • Prompt diagnosis • Prompt treatment of complications

30. What should patients be taught about preventing disease complications? • Good self-management can help prevent complications • Awareness of acute pain episode beginning • Use rest, hydration, warm baths to arrest development • Avoidance extremes of temperature • Cold, windy conditions associated with painful episodes • Maintenance of good hydration • Lower legs: protect from trauma, keep well-moisturized • To avoid leg ulcers

31. What should patients be taught about prenatal screening and management of pregnancy? • Discuss prenatal screening and its implications • Preferably during planning • At least in the first weeks of pregnancy • Manage pregnancies in a high-risk obstetrics clinic • Consult with a hematologist

32. CLINICAL BOTTOM LINE: Patient education… • Teach patients to recognize the early signs of an acute crisis • Encourage regular medical follow-up from a primary care provider with access to a sickle cell center