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sickle cell (hemoglobin SS) disease

Etiology: - point mutation in gene for hemoglobin beta chain* * first molecular disease identified Pathology: 1) precipitation of hemoglobin SS under low oxygen tension resulting in loss of erythrocyte structure & deformability - sickling & hemolysis due to polymerization of sickle hemoglobin upon deoxygenation [34] 2) microvascular occlusion & infarction 3) overactivity of SLC12A4 may contribute to erythrocyte dehydration 4) P-selectin may play a role in painful crises - it is released from endothelial cells & from platelets activated by inflammation or trauma - it mediates binding of erythrocytes & leukocytes to the endothelial cell surface - adherent masses of sickled red cells & leukocytes contribute to occlusive pain crises [25] Genetics: 1) point mutation in gene for hemoglobin beta chain 2) both allelles are affected (homozygous state) 3) mutation results in amino acid substitution of valine for glutamate at residue 6 of the beta chain Clinical manifestations: 1) symptomatic chronic anemia 2) sickle cell vaso-occlusive crisis or "painful crises" a) may be very painful & debilitating for the patient b) there are no objective findings to confirm the presence of pain 3) splenic atrophy in all patients by late adolescence 4) bone pain Laboratory: 1) complete blood count (CBC) a) anemia (Hgb 7-10 g/dL) normocytic b) leukocytosis c) thrombocytosis 2) peripheral smear - sickle cells 3) reticulocyte count a) usually elevated, especially during hyperhemolytic crisis b) diminished during aplastic crisis despite hemolytic anemia 4) hemoglobin electrophoresis establishes diagnosis -> Hgb S (80-98%), Hgb F (2-20%), Hgb A 0% 5) solubility testing 6) sickle cell disease genotyping - beta globin gene mutation 7) urinalysis for microalbuminuria [20] 8) serum ferritin to assess iron status Special laboratory: - echocardiography to assess pulmonary hypertension [1] Radiology: - transcranial Doppler ultrasound annually for children 2-16 years of age [20] - lifelong for patients with history of stroke [22] Complications: 1) vaso-occlusive painful crises, aplastic crises, hyperhemolytic crisis - may be due coexisting infection, especially parvovirus B19 - number of painful crises is inversely related to life expectancy [2] 2) complications of transfusion a) iron overload b) transfusion reactions (alloimmunization) - delayed hemolytic transfusion reactions 5-10 days after RBC transfusion result in jaundice, fever, & worsening painful crisis [2,14] c) transfusion-associated infections [2] 3) ischemic stroke - exchange transfusion or hydroxyurea [20] - IV alteplase can be helpful for adults [36] 4) bone marrow fat embolism 5) pulmonary complications a) acute chest syndrome with progressive respiratory failure - incentive spirometry in hospital to reduce risk [20] b) pneumonia 1] children: Streptococcus pneumonia is most common 2] adults: a] Staphylococcus aureus & Haemophilus influenzae b] majority of suspected pneumonias are due to pulmonary embolism c) pulmonary embolism d) pulmonary infarction e) pulmonary hypertension 6) renal complications (chronic renal failure) a) impaired urine concentrating ability (hyposthenuria) b) polyuria & nocturia c) microscopic & gross hematuria d) renal medullary ischemia resulting in infarction, necrosis, interstitial fibrosis & papillary necrosis e) focal segmental glomerulosclerosis f) nephrotic syndrome 7) cardiac complications [3] a) cardiomyopathy b) mitral regurgitation c) cardiac arrhythmias d) heart failure 8) splenic sequestration* 9) hepatobiliary a) gallstones (pigmented) 70%, cholecystitis b) choledocholithiasis c) hepatic crisis d) viral hepatitis 10) visual a) retinopathy b) blindness 11) skeletal (bone) a) bone infarcts b) avascular osteonecrosis - analgesics & physical therapy [20] c) oseomyelitis d) osteopenia/osteoporosis 12) skin (dermatologic) - ankle ulcers, foot ulcers 13) increased susceptibility to bacterial infections due to autosplenectomy* 14) priapism 15) multiorgan failure * hypersplenism & splenic sequestration may occur in children (> 5 years) prior to autosplenectomy from splenic infarction Management: 1) vaso-occlusive crisis (painful crisis) a) parenteral opioids for pain [2,20] - therapeutic management of the pain is a frequent source of conflict between the physician & patient or patient's family - do not use meperidine for treatment of painful crisis [2] b) general management principles include: - hydration with 3-4 L of oral fluid/day - intravenous fluids for dehydration or acute illness - lactated Ringer solution improves outcomes vs normal saline [43] - avoid iatrogenic fluid overload in patients with renal, cardiac or hepatic insufficiency - incentive spirometry to avoid acute chest syndrome - pregnant patients treated similarly to non-pregnant patients [2] c) agents used in combination with analgesics - antihistamines: diphenhydramine, hydroxyzine - tricyclic antidepressants - phenothiazines for nausea (ondansetron may be of benefit for nausea) d) nitric oxide of no benefit [8] e) systemic glucocorticoids increase risk for hospitalization due to vaso-occlusive crisis 4-fold [41] 2) aggressive evaluation is required for: a) fever > 38.5 C b) severe abdominal pain c) acute pulmonary complaints d) acute neurological events e) intractable pain unrelieved by oral medications 3) analgesia for chronic pain: a) non-steroidal anti-inflammatory agents (NSAIDs) b) acetaminophen c) relaxation, massage, biofeedback d) P-selectin inhibitor crizanlizumab (2.5-5 mg/kg q4 weeks) can decrease frequency of sickle cell painful crises [25] e) glutamine can also reduce frequency of painful crises [2] 4) avascular necrosis - analgesics & physical therapy [2] 5) renal complications - ACE inhibitor for microalbuminuria 6) ophthalmology referral for retinopathy 7) other pharmceuticals a) hydroxyurea - indications - > 2 painful crisis/year - acute chest syndrome - symptomatic anemia - pain or chronic anemia interfering with activities [20] - not for ischemic stroke or prophylaxis for ischemic stroke - chronic exchange transfusions treatment of choice [42] - contraindicated in renal failure & pregnancy - increases hemoglobin F - reduces frequency of acute chest syndrome, painful crises, hospitalizations, & blood transfusions [21] - as effective as chronic transfusion therapy for preventingstroke [24] - effective, but underused [7,21] - improves mortality & decreases painful crisis [2] - some patients may not respond favorably to hydroxyurea [24] b) glutamine powder (Endari) - FDA-approved for treatment of sickle cell disease [28] - 0.3 g/kg BID alone or with hydroxyurea reduces number of painful crisis [28] c) voxelotor (Oxbryta) reduces polymerization of hemoglobin upon deoxygenation thus sickling of erythrocytes [34] - voxelotor pulled from global markets, benefits no longer outweigh risks [44] d) folic acid can reduce need for transfusions e) iron only for documented iron deficiency - deferasirox (Exjade) for iron overload f) oxygen for all hypoxemic patients pO2 < 60-70 mm Hg g) erythropoietin for severe anemia, low reticulocyte count & chronic renal failure especially when cross-match compatible blood is difficult to find [2] h) aliphatic butyrate salts increase hemoglobin F i) prasugrel of no benefit [24] j) metformin use in patients with sickle cell disease & diabetes mellitus associated with fewer emergency deparment visits & fewer in-hospital adverse events [35] 8) blood transfusion/exchange transfusion a) indications - ischemic stroke (erythrocyte exchange transfusion) - history of ischemic stroke, history of transient ischemic attack, acute stroke [42] - monthly transfusions reduce risk of recurrent stroke in children [19] - acute chest syndrome [2] - surgery requiring anesthesia: - target blood hemoglobin = 10 g/dL [2,13,20] - exchange tranfusion with target of 30% Hgb S exposes patient to more blood products than transfusion [2] - reduces vaso-occlusive crisis - fat embolism - priapism - no role for routine RBC transfusion during pregnancy [2] b) contraindications - uncomplicated pregnancy - routine painful episodes - minor surgery not requiring anesthesia - asymptomatic anemia [2] c) RBC should be phenotypically matched whenever possible for - K antigen (Kell) - C antigen - E antigen - other antigens to which they have developed alloantibody [2,15] d) erythrocyte exchange - more effectively decreases hemoglobin S in blood than does packed RBC [2] - goal: hemoglobin S < 30% of total hemoglobin - greater exposure to blood & higher risk of transfusion reaction than target blood hemoglobin = 10 g/dL [2] - history of ischemic stroke, history of transient ischemic attack, acute stroke [42] 9) chelation therapy for iron overload 10) prophylaxis - Pneumovax is indicated for all patients with Hemoglobin SS disease - penicillin prophylaxis for children <= 5 years of age - 125 mg PO BID < 3 years of age, then 250 mg PO QD - ACE inhibitor for microalbuminuria [20] 11) stem cell transplantation - allogeneic hematopoietic stem cell transplantation from HLA-matched sibling (without myeloablation) for severe sickle cell phenotype [18] - indications: - overt stroke or abnormal transcranial Doppler - frequent pain with an inadequate response to standard therapies - recurrent acute chest syndrome [39] - for patients without a matched sibling donor, transplant from an alternative donor is suggested [39] - immunosuppression can be discontinued after 1 year in many patients [18] 12) gene therapy - antisickling beta-globin variant inserted into a lentivirus vector & transduced into bone marrow-enriched CD34+ cells followed by bone marrow ablation with busulfan & stem cell transplantation [26]

Interactions

disease interactions

Related

acute sickle cell chest syndrome; chest crisis; pulmonary sickle crisis hemoglobin S hemoglobin S/beta thalassemia + hemoglobin S/beta thalassemia 0 hemoglobin SC disease sickle cell sickle cell trait; hemoglobin S trait sickle cell vaso-occlusive crisis sickle screen; hemoglobin solubility

Specific

sickle cell disease during pregnancy

General

hemoglobinopathy hemolytic anemia

References

  1. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 790-91
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2022. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  3. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1038
  4. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 648
  5. Journal Watch 22(3):26, 2002 Miller et al Impact of chronic transfusion on incidence of pain and acute chest syndrome during the Stroke Prevention Trial (STOP) in sickle-cell anemia. J Pediatr 139:785, 2001 PMID: 11743502 - Wang WC et al A two-year pilot trial of hydroxyurea in very young children with sickle-cell anemia. J Pediatr 139:790, 2001 PMID: 11743503 - Powars DR Hydroxyurea in very young children with sickle cell anemia is not a cure-all. J Pediatr 139:763, 2001 PMID: 11743496
  6. Hanna J et al, Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 2007, Dec 6 PMID: 18063756 http://dx.doi.org/10.1126/science.1152092
  7. Brawley OW, Cornelius LJ, Edwards LR, Gamble VN, Green BL et al National Institutes of Health Consensus Development Conference Statement: Hydroxyurea Treatment for Sickle Cell Disease. Ann Intern Med. 2008 May 5. [Epub ahead of print] PMID: 1845827 http://www.annals.org/content/148/12/932.full
  8. Gladwin MT et al Nitric Oxide for Inhalation in the Acute Treatment of Sickle Cell Pain Crisis JAMA. 2011;305(9):893-902 PMID: 21364138 http://jama.ama-assn.org/content/305/9/893.full
  9. Field JJ, Knight-Perry JE, Debaun MR. Acute pain in children and adults with sickle cell disease: management in the absence of evidence-based guidelines. Curr Opin Hematol. 2009 May;16(3):173-8. PMID: 19295432
  10. Mayo Clinic Sickle cell anemia http://www.mayoclinic.com/health/sickle-cell-anemia/DS00324
  11. Wikipedia: Sickle-cell disease http://en.wikipedia.org/wiki/Sickle-cell_disease
  12. Arnold JL eMedicine (Medscape): Sickle Cell Anemia http://emedicine.medscape.com/article/205926-overview
  13. Howard J et al. The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: A randomised, controlled, multicentre clinical trial. Lancet 2013 Jan 23; PMID: 23352054
  14. Scheunemann LP, Ataga KI. Delayed hemolytic transfusion reaction in sickle cell disease. Am J Med Sci. 2010 Mar;339(3):266-9 PMID: 20051821
  15. Wahl S, Quirolo KC. Current issues in blood transfusion for sickle cell disease. Curr Opin Pediatr. 2009 Feb;21(1):15-21 PMID: 19242238
  16. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008 Mar 27;358(13):1362-9. PMID: 18367739
  17. Voskaridou E, Christoulas D, Bilalis A et al The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood. 2010 Mar 25;115(12):2354-63. PMID: 19903897
  18. Hsieh MM et al. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA 2014 Jul 2; 312:48 PMID: 25058217 http://jama.jamanetwork.com/article.aspx?articleid=1884578
  19. DeBaun MR et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med 2014 Aug 21; 371:699 PMID: 25140956 http://www.nejm.org/doi/full/10.1056/NEJMoa1401731
  20. Green D Managing Sickle Cell Disease: An Update NEJM Journal Watch. Sept 16, 2014 Massachusetts Medical Society (subscription needed) http://www.jwatch.org - Yawn BP et al. Management of sickle cell disease: Summary of the 2014 evidence-based report by expert panel members. JAMA 2014 Sep 10; 312:1033 PMID: 2520308
  21. Stettler N et al. Proportion of adults with sickle cell anemia and pain crises receiving hydroxyurea. JAMA 2015 Apr 28; 313:1671 PMID: 25919532
  22. Harb A, Saliba A A 5-Year-Old Girl With Headache and Vomiting. Medscape Case Challenges. May 14, 2015 http://www.medscape.com
  23. Ballas SK, Kesen MR, Goldberg MF et al Beyond the definitions of the phenotypic complications of sickle cell disease: an update on management. ScientificWorldJournal. 2012;2012:949535 PMID: 22924029
  24. Ware RE et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): A multicentre, open-label, phase 3, non-inferiority trial. Lancet 2015 Dec 4; [e-pub]. PMID: 26670617 - Heeney MM et al. A multinational trial of prasugrel for sickle cell vaso- occlusive events. N Engl J Med 2015 Dec 8; PMID: 26644172
  25. Ataga KI, Kutlar A, Kanter J et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med 2016 Dec 3; PMID: 2795970
  26. Ribeil JA, Hacein-Bey-Abina S, Payen E et al. Gene therapy in a patient with sickle cell disease. N Engl J Med 2017 Mar 2; 376:848 PMID: 28249145 http://www.nejm.org/doi/10.1056/NEJMoa1609677
  27. Piel FB, Steinberg MH, Rees DC. Sickle Cell Disease. N Engl J Med 2017; 376:1561-1573. April 20, 2017 http://www.nejm.org/doi/full/10.1056/NEJMra1510865
  28. FDA News Release. July 7, 2017 FDA approves new treatment for sickle cell disease. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm566084.htm - Niihara Y, Miller ST, Kanter J et al A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. N Engl J Med 2018; 379:226-235. July 19, 2018 PMID: 30021096 https://www.nejm.org/doi/full/10.1056/NEJMoa1715971
  29. Yawn BP, Buchanan GR, Afenyi-Annan AN et al Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014 Sep 10;312(10):1033-48. PMID: 25203083
  30. Kato GJ. New insights into sickle cell disease: mechanisms and investigational therapies. Curr Opin Hematol. 2016 May;23(3):224-32. Review. PMID: 27055046 Free PMC Article
  31. Novelli EM, Gladwin MT. Crises in Sickle Cell Disease. Chest. 2016 Apr;149(4):1082-93. Review. PMID: 26836899
  32. Gordeuk VR, Castro OL, Machado RF. Pathophysiology and treatment of pulmonary hypertension in sickle cell disease. Blood. 2016 Feb 18;127(7):820-8. Review. PMID: 26758918 Free PMC Article
  33. NEJM Knowledge+ Question of the Week. Feb 12, 2019 https://knowledgeplus.nejm.org/question-of-week/1668/
  34. Vichinsky E, Hoppe CC, Ataga KI et al. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med 2019 Jun 14; PMID: 31199090 - Thompson A. A targeted agent for sickle cell disease - Changing the protein but not the gene. N Engl J Med 2019 Jun 14; PMID: 31199089
  35. Badawy SM, Payne AB. Association between clinical outcomes and metformin use in adults with sickle cell disease and diabetes mellitus. Blood Adv 2019 Nov 1; 3:3297 PMID: 31698459
  36. Powers WJ, Rabinstein AA, Ackerson T et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 Update to the 2018 guidelines for the early management of acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 2019 Dec; 50:e344. PMID: 31662037 https://www.ahajournals.org/doi/10.1161/STR.0000000000000211
  37. Qureshi A, Kaya B, Pancham S et al. Guidelines for the use of hydroxycarbamide in children and adults with sickle cell disease: a British Society for Haematology guideline. Br J Haematol 2018 May; 181:460. PMID: 29732531
  38. Azar S, Wong TE. Sickle cell disease: a brief update. Med Clin North Am 2017 Mar; 101:375 PMID: 28189177
  39. Kanter J, Liem RI, Bernaudin F et al. American Society of Hematology 2021 guidelines for sickle cell disease: Stem cell transplantation. Blood Adv 2021 Sep 28; 5:3668 PMID: 34581773 https://ashpublications.org/bloodadvances/article/5/18/3668/476988/American-Society-of-Hematology-2021-guidelines-for
  40. Kavanagh PL, Fasipe TA, Wun T Sickle Cell Disease. A Review. JAMA. 2022;328(1):57-68. July 5. PMID: 3578879 https://jamanetwork.com/journals/jama/fullarticle/2793821
  41. Walter O, Cougoul P, Maquet J et al. Risk of vaso-occlusive episode after exposure to corticosteroids in patients with sickle cell disease. Blood 2022 Jun 30; 139:3771. PMID: 35471555 https://ashpublications.org/blood/article-abstract/139/26/3771/485065/Risk-of-vaso-occlusive-episode-after-exposure-to
  42. NEJM Knowledge+ Hematology
  43. Alwang AK, Law AC, Klings ES, Cohen RT, Bosch NA Lactated Ringer vs Normal Saline Solution During Sickle Cell Vaso-Occlusive Episodes. JAMA Intern Med. 2024 Sep 9:e244428. PMID: 39250114 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2823422
  44. Bassett M Sickle Cell Disease Drug Pulled From Global Markets. Benefits of voxelotor (Oxbryta) no longer outweigh the risks, Pfizer says. MedPage Today September 26, 2024 https://www.medpagetoday.com/publichealthpolicy/productalert/112123
  45. PubMed Health Sickle cell anemia http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001554/
  46. Sickle Cell Disease Association of America http://www.sicklecelldisease.org/

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