Sickle cell anaemia ver 1.0

Sickle cell anaemia

1. Sickle Cell Anaemia (SCA)

2. What Is Sickle Cell Disease? Term sickle cell disease (SCD) describes a group of inherited red blood cell disorders People with SCD have abnormal hemoglobin, called hemoglobin S or sickle hemoglobin, in their red blood cells

3. Forms of Sickle Cell Disease Hemoglobin SS Hemoglobin SC Hemoglobin S β0 thalassemia Hemoglobin S β+ thalassemia Hemoglobin SD Hemoglobin SE Sickle Cell Anemia

4. Sickle Cell Disease: Global Issue One of the most common monogenic disorders globally with an autosomal recessive inheritance Prevalence of sickle cell trait varies greatly between different regions but reaches levels as high as 40 percent in some areas of sub-Saharan Africa, eastern Saudi Arabia, and central India In resource-poor countries more than 90 percent of children with SCD do not survive to adulthood

5. Sickle Cell Disease: Global Issue Approximately 1,000 children in Africa are born with SCD every day and more than half will die before they reach five. SCD has a high prevalence in India, especially in the central and western regions. Approximately 20 percent of children with SCD die by the age of two.

6. Origin of Sickle Cell Anaemia A single mutation in hemoglobin results in a binding of one protein to another. Hemoglobin A Hemoglobin S Biswal , B. K et al, Acta Crystallogr ., Sect.D 58 pp. 1155 (2002) Padlan , E. A et al, J Biol Chem 260 pp. 8272 (1985)

7. Normal and Sickled Red Blood Cells in Blood Vessels Figure A shows normal red blood cells flowing freely in a blood vessel. The inset image shows a cross-section of a normal red blood cell with normal hemoglobin. Figure B shows abnormal, sickled red blood cells clumping and blocking the blood flow in a blood vessel. The inset image shows a cross-section of a sickled red blood cell with abnormal strands of hemoglobin.

8. Inheritance of Sickle Cell Anaemia

9. Pathophysiology of Sickle Cell Anaemia (Modified from Steinberg, M., Cecil Medicine 2007)

10. Factors that Increase Hgb S Polymerization Decreased oxygen Increased intracellular hemoglobin S concentration (SS > SC, S- thal ) Increased 2,3-DPG Decreased pH Slowed transit time through the circulation Endothelial adhesion

11. Factors that Decrease Hgb S Polymerization Lower concentration of Hb S (compound heterozygosity for α thal ) Increased HbF levels Genetic basis Hydroxyurea

12. Clinical Features of Sickle Cell Anaemia Painful episodes Pneumococcal disease Acute chest syndrome Splenic infarction Splenic sequestration Stroke Osteonecrosis Priapism Retinopathy Leg ulcers Gallstones Renal abnormalities Osteopenia Nutritional deficiencies Placental insufficiency Pulmonary hypertension

13. Clinical Features of Sickle Cell Anaemia Associated with higher hemoglobin Associated with lower hemoglobin Painful episodes Stroke Acute chest syndrome Priapism Osteonecrosis Leg Ulcers Proliferative retinopathy

14. Screening & Diagnosis

15. Screening Tests Indicate presence of HbS but do not define the Hb genotype e.g. Solubility test Sickle solubility test Mixture of HbS in a reducing solution Gives a turbid appearance (Precipitation of HbS ) Normal Hb gives a clear solution

16. Hb electrophoresis Most common for definitive diagnosis Based on differential protein mobility in an electrical field Uses cellulose acetate or citrate agar buffers

17. Prenatal Diagnosis Usually in the first trimester of pregnancy Samples are taken from amniotic cells or chorionic villus and DNA analysis done by PCR and DNA sequencing

18. Laboratory Findings Laboratory examinations results Values in this disease Values in health WBC count increased 10000 -30000 5000 -10000 RBC count decreased 1 -4 million/mm 3 4 -6 million/mm 3 Hb count decreased 6 -8g/100ml Male=13.5-17.5g/dl Female=11.5-15.5g/dl Haematocrit reading decreased 10 -30% 45% Reticulocyte count increased 10-40% 1-2% Hb electrophoresis positive HbS & HbF HbA Urine analysis Albumin casts positive negative Serum bilirubin increased 1-3 mg/100ml 0.2-0.8mg/100ml Platelet count increased 40000-50000/mm 3 150000-400000/mm 3 Bone marrow exanination Increased red cells 40-70% 8-30%

19. Laboratory Findings The blood film is microcytic and hypocromic Sickle cell Anaemia Normal

20. Differential Diagnosis Acute Anemia Carotid Cavernous Fistula Hemoglobin C Disease Hemolytic Anemia Legg-Calve- Perthes Disease Imaging Ophthalmologic Manifestations of Leukemias Osteomyelitis in Emergency Medicine Pulmonary Embolism Rheumatoid Arthritis Hand Imaging Septic Arthritis

21. Management

22. Goals Management of vaso -occlusive crisis Management of chronic pain syndromes Management of chronic hemolytic anemia Prevention and treatment of infections Management of the complications and the various organ damage syndromes associated with the disease Prevention of stroke Detection and treatment of pulmonary hypertension

23. Hydroxyurea Therapy Only drug currently approved by the US Food and Drug Administration (FDA) for the treatment Increases total and fetal hemoglobin in children Effects of therapy with hydroxyurea

24. Indications for hydroxyurea Frequent painful episodes (six or more per year) History of acute chest syndrome History of other severe vaso -occlusive events Severe symptomatic anemia Severe unremitting chronic pain that cannot be controlled with conservative measures History of stroke or a high risk for stroke Patients receiving hydroxyurea require frequent blood testing and monitoring, with special attention to development of leukopenia and/or thrombocytopenia.

25. Transfusion Acute red cell exchange transfusion is indicated in the following situations: Acute infarctive stroke Severe acute chest syndrome Multiorgan failure syndromes Right upper quadrant syndrome Priapism that does not resolve after adequate hydration and analgesia Transfusion-related complications include alloimmunization, infection, and iron overload

26. Vaso -Occlusive Crisis Management Treated with vigorous intravenous hydration and analgesics Normal saline and 5% dextrose in saline may be used

27. Control of Acute Pain Pain control is best achieved with opioids Morphine is the drug of choice National Institute for Health and Care Excellence (NICE) guidelines recommendations 2014 Tailor the analgesic drug, dose, and administration route to the severity of the pain, the age of the patient, and any analgesia the patient has already taken for the current episode

28. Control of Acute Pain Offer a bolus of a strong opioid to all patients with severe pain and all patients with moderate pain who have already taken an analgesic Consider a weak opioid for patients with moderate pain who have not yet had any analgesia Offer all patients regular paracetamol ( acetaminopen ) and non-steroidal anti-inflammatory drugs (NSAIDs) by a suitable administration route, in addition to an opioid, unless contraindicated Do not offer pethidine (meperidine) for pain relief When opioids are used, offer laxatives and, as needed, antiemetics and antipruritics

29. Treatment of Acute Chest Syndrome British Committee for Standards in Haematology (BCSH) 2015 guidelines for treatment of acute chest syndrome (ACS) recommend use of the following measures Prompt and adequate pain relief Incentive spirometry – In patients with chest or rib pain, to prevent ACS; should be considered in all patients with ACS Antibiotics, with cover for atypical organisms, even if blood cultures and sputum cultures are negative

30. Treatment of Acute Chest Syndrome Anti-viral agents– If there is a clinical suspicion of H1N1 infection Early simple transfusion should be considered early in patients with hypoxia; however, exchange transfusion is necessary in patients with severe clinical features or evidence of progression despite initial simple transfusion Transfused blood should be sickle-negative and fully matched for Rh (C, D, and E type) and Kell antigens; a history of previous red cell antibodies should be sought and appropriate antigen-negative blood given Bronchodilators - In patients with clinical features suggesting a history of asthma or evidence of acute bronchospasm

31. Control of Chronic Pain Chronic pain is managed with long-acting oral morphine preparations and acetaminophen and NSAIDs NSAIDs are particularly effective in reducing deep bone pain Weak agents, codeine and hydrocodone, are used first Meperidine should be avoided Hydroxyurea may decrease the frequency and severity of pain episodes

32. Control of Chronic Pain Nonpharmacological approaches are also useful Physical therapy Heat and cold application Acupuncture and acupressure Hypnosis Transcutaneous electric nerve stimulation (TENS)

33. Management of Chronic Anemia Anemia is usually well tolerated Folic acid (1 mg/d) Commonly prescribed for adults to prevent development of megaloblastic anemia due to increased folate requirements caused by hemolysis May raise the Hb level and support a healthy reticulocyte response Initiation of folic acid therapy For patients younger than 6 months, the usual dose is 0.1 mg per day

34. Management of Chronic Anemia For infants aged 6 months to 1 year, 0.25 mg per day For children aged 1-2 years, 0.5 mg per day For patients older than 2 years, 1 mg per day Blood transfusion Indicated In Acute chest syndrome Stroke Abnormal findings on transcranial Doppler in children (for stroke prevention) Pregnancy General anesthesia For anemic crisis with splenic sequestration, give early red cell transfusions because the process can rapidly progress to shock

35. Management of Infections Common organisms…….H. infl., pneumococcus, salmonella spp., S. aureus. Choice of antibiotics: Chloramphenicol + Erythromycin Xtalline pen + Chloramphenicol Chloramphenicol + Cloxacillin Cephalosporins

36. Priapism Sedatives/anxiolytics. Analgesics. Intracavernous injection of adrenergic agonists…e.g. Etilefrine. E.B.T Surgery, if ICI fails: caverno-spongiosum anastomosis.

37. Haematuria Usually stops spontaneously Conservative treatment: Liberal fluids, to reduce clot formation Correct anaemia Epsilon amino caproic acid, an antifibrinolytic agent, is useful in mgt

38. Bone Marrow Transplantation Has curative potential Problems: GVHD Acute effects of total body irradiation Lack of suitable stem cell donors. Limited access to normal HLA identical

39. Diet and Activity Restrictions General well-balanced diet Patients with avascular necrosis of the femur may not be able to tolerate weight bearing and may be restricted to bed rest Patients with chronic leg ulcers may need to restrict activity that involves raising the legs

40. References American Society Of Hematology, State Of Sickle Cell Disease 2016 Report Roshan B. C, Malay B. M, Snehal M, Ghosh K, Sickle cell disease in tribal populations in India, Indian J Med Res 141, May 2015, pp 509-515 Sickle cell disease in India: A perspective, Indian J Med Res 143, January 2016, pp 21-24 Maakaron J E, et al, Sickle Cell Anemia, www.Medscape.com, http://emedicine.medscape.com/article/205926 Assessed on 18.12.16 Sickle cell Anaemia , www.nhlbi.nih.gov, https://www.nhlbi.nih.gov/health/health-topics/topics/sca Assessed on 20.12.16

41. Thank You