Sickle Cell Disease

Advances in disease management and new treatment models help patients live longer.

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Learning Scope #417
1 contact hour
Expires Jan. 21, 2015

You can earn 1 contact hour of continuing education credit in three ways: 1) Grade and certificate are available immediately after taking the online test. 2) Send the answer sheet (or a photocopy) to ADVANCE for Nurses, Learning Scope, 2900 Horizon Dr., King of Prussia, PA 19406. 3) Fax the answer sheet to 610-278-1426. If faxing or mailing, allow 30 days to receive certificate or notice of failure. A certificate of credit will be awarded to participants who achieve a passing grade of 70 percent or better.

Merion Matters is an approved provider of continuing nursing education by the Pennsylvania State Nurses Association (No. 221-3-O-09), an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation.

Merion Matters is also approved as a provider by the California Board of Registered Nursing (No. 13230) and by the Florida Board of Nursing (No. 3298).

The goal of this continuing education offering is to provide the latest information to nurses about sickle cell disease. After reading this article, you will be able to:
1. Review the epidemiology and pathophysiology of sickle cell disease.
2. Discuss the treatments and prevention of common sickle cell complications.
3. Identify new research directions and resources for caregivers.

The author has completed a disclosure form and reports no relationships relevant to the content of this article.

Sickle cell disease is a group of inherited hemoglobin disorders characterized by chronic hemolytic anemia, a heightened susceptibility to infections, end-organ damage and intermittent episodes of vascular occlusion causing both acute and chronic pain.
James Herrick, MD, first described sickle cell in the U.S. medical literature in 1910.1 Today, at least an estimated 100,000 Americans have sickle cell disease, one of the most common genetic diseases in the country.2

It is most common in African Americans and descendants of malaria-endemic areas of the world. It is also found in small numbers of U.S. Caucasians and Hispanics. Worldwide, sickle hemoglobin is found in Africans, Arabs, Turks, Greeks, Italians, North, South and Central Americans, and Asiatic Indians. More than 300,000 infants are born annually worldwide with sickle cell disease.3

Inheriting one sickle gene (i.e., sickle cell trait) provides some protection from the red cell parasite malaria. More than two million people in the U.S. have sickle cell trait and are usually asymptomatic, but hematuria and sickle complications including sudden death can occur under severe dehydration, hypoxia, increased altitude, increased or decreased temperature, or increase or decrease in pressure.4

This article will review the latest advances in sickle cell disease management and present the new treatment models needed for adults who are living longer but experiencing complications not seen in the past. Common medical problems in this population can be managed and prevented in primary care clinics, emergency rooms and public health centers.

Sickle Cell Variants

Sickle cell disease includes sickle cell anemia (SCD-SS), hemoglobin SC (SCD-SC) and hemoglobin S-beta-thalassemia (SCD 0-thal and SCD + thal). Sickle cell anemia, the most common variant, results when an individual inherits one hemoglobin sickle gene (Hb S) with a valine instead of glutamic acid at the beta six position from each parent.5 This substitution alters the hemoglobin molecule so it crystallizes and deforms the red cell into a sickle shape when the hemoglobin loses oxygen.

Sickle cell disease type SC occurs when a child inherits Hb S and hemoglobin C (Hb C), a substitution of lysine in the beta six position. Hemoglobin S-beta-thalassemia is caused by genetic mutations that abolish or reduce production of the beta-globin subunit of hemoglobin.6 Rarer variants include hemoglobin SD, SE and SO Arab.

Those with hereditary persistence of fetal hemoglobin (HPFH) in combination with Hb S (HbS-HPFH) have protective fetal hemoglobin levels of 15-30 percent and have mild clinical disease. The goal of new therapies is the induction of fetal hemoglobin production.7

Clinical Manifestations

The clinical manifestations of sickle cell disease result from increased blood viscosity, an activated clotting system, increased red cell adhesion, decreased circulating nitric oxide (NO) and vascular obstruction by deformed, sickled red cells.8 The disruption of blood flow causes vascular occlusions, hemorrhages, infarctions and ischemic necrosis in tissues and organs throughout the body.

The factors that favor sickle cell formation include deoxygenation of the hemoglobin molecule, increased percentage of Hb S in the red blood cell, increased mean cell hemoglobin concentration (which is a function of red cell hydration), low pH, increased temperature and blood stasis.9

The increased mechanical fragility and surface abnormalities of cells containing sickle hemoglobin reduce red cell lifespan from the normal 120 days to 14 days. This marked hemolytic anemia causes increased indirect bilirubin, lactate dehydrogenase (LDH) and elevated reticulocyte, platelet and white blood cell counts.10 Common complications, presentations, diagnostic workup and treatment options for sickle cell disease are outlined in Table 1.

Improving Outlook

In 1990, the reported average life expectancy for sickle cell patients was 15 years old. Four years later, data from the natural history study documented a mean survival of 44 years old for those with Hb SS and 64 years old for those with Hb SC.11 With improved pneumococcal vaccination, hydroxyurea preventive therapy and curative bone marrow transplant therapy, the life expectancy for all sickle cell patients is now more than 40 years old.

Preventive therapy for children with sickle cell disease includes annual health checks, daily supplemental folic acid, good hydration, rapid treatment of infections and avoidance of temperature extremes. Children should be placed on prophylactic penicillin from birth until age 5 to prevent fatal pneumococcal sepsis. The 13-valent pneumococcal polysaccharide-protein conjugate vaccine (Prevnar-13, marketed by Wyeth Lederle Vaccines) is used for all children aged 2-23 months and for adults with sickle cell disease.12

Adults should have annual health screening, including eye examinations, pulmonary function tests, cardiac echo for pulmonary hypertension and urine screening for microalbuminuria.13 Table 2 outlines ways to prevent complications.

The chemotherapeutic agent hydroxyurea stimulates the production of protective fetal hemoglobin within red blood cells. Children begin with low daily doses of 10 mg/kg/day and adults 15/mg/kg/day and are monitored with frequent complete blood counts (CBCs) for evidence of bone marrow suppression. Adult patients on hydroxyurea have 50% fewer pain episodes, 50% fewer blood transfusions and 50% less need for hospitalization.14 Studies in children as young as 9 months have shown the same efficacy and short-term safety.15

Adult patients taking hydroxyurea for frequent painful sickle cell episodes have reduced mortality after 9 years of follow-up.16 All Hb SS and S-beta-thalassemia patients with frequent pain events or complications should be considered for therapy. Children tolerate hydroxyurea therapy well and have reduced acute chest syndrome (ACS) and improved spleen function, cerebral blood flow and growth.17

Dealing With Pain

Intense pain - a common occurrence in sickle cell patients - is caused by the inflammatory response to bone marrow and muscle necrosis, ischemia and tissue infarction secondary to blood flow obstruction and sludging. Management of acute pain events includes performing a thorough history, physical examination, laboratory workup and radiological exam if necessary. Precipitating causes such as infection, dehydration, hypoxia and temperature exposure must be identified and corrected.18

General treatment measures include IV hydration with hypotonic D5W, multimodal pain medications and oxygen if the patient is dyspneic or hypoxic. If the patient has evidence of transient ischemic attack, stroke, chest infarction, multi-organ system failure or sequestration of red cells in the spleen or liver, phenotypic-packed red cell transfusions are indicated.19-22

The frequency of pain crisis varies with each individual and depends to some extent on their hemoglobin phenotype, physical condition, concurrent illness and psychological or social variables.23

Pain episodes should be managed as in any other severe, acute pain-producing disease: by tailoring the analgesic and dosage used to the level of the pain experienced by the patient.

Pain intensity should be assessed as a vital sign using a visual analog scale, or similar tool, at the beginning of treatment and at set intervals to document the response to treatment. Caregivers should believe patients' stated pain level. One question to ask the patient is, "Is this pain typical for your pain crisis?" If the pain is atypical, a search for other causes should be pursued. Headache, chest pain and abdominal pain should prompt a search for secondary causes and complications.23 See Table 3.

Oxygen only should be administered if the patient has an underlying pulmonary problem or hypoxia is documented by arterial blood gases or pulse oximetry. Pulse oximetry should be monitored as a vital sign, but it becomes less reliable when severe anemia is present. Low oxygen saturation in symptomatic patients must be investigated with arterial blood gases, chest X-rays and pulmonary testing.24

Pain medication should be administered on a fixed time schedule at an interval that equals the period of adequate analgesia. This will maintain a steady serum drug level, thereby improving control of pain, minimizing complications and decreasing anxiety in patients. Patient-controlled analgesia (PCA) pumps provide constant low-dose infusion with defined rescue doses.

The side effects of the narcotic analgesics include itching from histamine release, respiratory depression, nausea, vomiting, hypotension, constipation, increased bladder tone, urinary retention and decreased seizure threshold. The synthetic agonist-antagonist agents such as buprenorphine and nalbuphine are alternative choices for some patients, but they can cause withdrawal symptoms, similar to naloxone, in patients with opiate dependence.25

Patients with acute multi-organ failure syndrome present with pain that is typical in distribution but unusually severe for the patient. Deterioration on the third to fourth hospital day in spite of appropriate therapy for an acute pain episode is a warning sign.

The onset of organ failure is associated with fever, rapid fall in hemoglobin level and platelet count, non-focal encephalopathy and rhabdomyolysis. Bacterial cultures are negative in most cases. High baseline hemoglobin levels may represent a predisposing factor. Prompt, aggressive transfusion therapy is associated with survival and with rapid recovery of organ function in most episodes.26

Transplantation &Transfusion

Sickle cell disease can be cured by human leukocyte antigen (HLA)-matched bone marrow transplantation. This therapy now is accepted treatment in symptomatic SS and S beta 0-thalassemia children under 16 with stroke, ACS, avascular necrosis and frequent pain episodes. Most patients meeting the criteria for transplant lack a genotypically matched donor.27

At 47 participating sickle cell centers, with 9,198 patients, 627 (7 percent) met the criteria for bone marrow transplantation. A total of 188 patients were HLA-typed, and only 82 had HLA-matched siblings identified as donors. Forty-nine of these patients have been transplanted, two died of graft vs. host disease and four patients had their sickle cell disease return. The overall survival rate for HLA-identical sibling-donor stem cell transplantation is 93 percent, and event-free survival is 82%.28

Nearly one-quarter of sickle cell disease patients have cerebrovascular events including stroke. Transcranial Doppler ultrasound screening is now a standard-of-care, non-invasive method to detect children at risk for stroke. All Hb SS and S beta 0- thalassemia children should be screened annually beginning at age 2. Patients at risk should be treated with monthly red cell transfusions to prevent stroke, with hydroxyurea or bone marrow transplant being alternative therapy.29

Chronic transfusions can prevent serious sickle cell events, including central nervous system ischemia, acute chest syndrome, pain crises, growth failure and splenic dysfunction.30 The major side effects of transfusion therapy are iron overload and alloimmunization. However, red cell pheresis can prevent the iron overload, and the routine use of extended red cell matching limits transfusion reactions.30,31

Preoperatively, a conservative transfusion regimen can be used to increase the hemoglobin level to 10 g/dL. This is as effective as aggressive regimens to decrease the hemoglobin S level to less than 30 percent in preventing perioperative complications in patients with sickle cell anemia. The conservative approach resulted in only half as many transfusion-associated complications.32

Additional Complications

ACS, a syndrome with new chest X-ray infiltrates and cough, dyspnea, hypoxia, fever or chest pain, is an important cause of morbidity and mortality in sickle cell disease. The etiology of ACS includes viruses, atypical bacteria, bone marrow necrosis with fat embolism and bacteria. Young children (ages 2-4) present with fever, cough and a negative physical exam and rarely have pain. Adults often are febrile and complain of shortness of breath, chills and severe pain. Severe hypoxia occurs in 18% of adults and cannot be predicted by examination or laboratory findings. The death rate from ACS is four times higher in adults than in children.33

Bronchoscopy may be diagnostic and can be therapeutic (with removal of mucus plug casts) in cases of ACS. Patients should be treated with transfusions and antibiotics that cover atypical bacteria and pneumococci. ACS can be prevented by incentive spirometry for all hospitalized patients.34,35

Pulmonary hypertension is a common and severe finding in approximately 30 percent of adult patients screened by echocardiogram. Causes may be prolonged hemolysis, decreased NO and NO resistance. Pulmonary hypertension is present on 75 percent patients at autopsy. There is a 40 percent mortality at 22 months after detection of elevated pulmonary artery pressures and therapy should begin with hydroxyurea, monthly transfusions, anticoagulation and erythropoietin. Diagnosis is made with Doppler echocardiography with confirmation heart catheterization. Therapy with selective pulmonary vasodilator and remodeling drugs (bosentan and sildenafil) should be considered if the patient has symptomatic dyspnea on exertion that has progressed in recent months.35,36

Proteinuria is becoming a common finding in patients with sickle cell anemia and results from damage to the glomerulus (sickle cell glomerulopathy).37 It may occur in up to 27 percent of adults with hemoglobin SS and in 5-8 percent of adults with other sickle hemoglobinopathies.38 Despite the paucity of associated clinical findings, it may herald the development of progressive renal insufficiency and lead to end-stage renal disease; therefore, it should be thoroughly investigated.

Many sickle cell patients have a progressive nephropathy detected by microalbuminuria. All sickle cell patients should be screened annually for microalbuminuria by 24-hour urine collections. Several studies have demonstrated that ACE inhibitors may prevent renal disease by reducing proteinuria.38,39

The Future

Being investigated are additional therapies to prevent red cell dehydration, decrease red cell adhesion, increase NO, decrease the activation of the clotting system and increase protective hemoglobin F. Synergistic combination therapies are being sought.

Researchers have declared more than 200 patients cured by bone marrow transplantation, and they now experience normal daily life. The life expectancy of sickle cell patients and quality of life improves annually.40

References

1. Herrick, J.B. (1910). Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Yale Journal of Biology and Medicine, 74(3), 179-184.

2. CDC. (2011). Sickle cell disease data and statistics. Retrieved Nov. 9, 2012 from the World Wide Web: http://www.cdc.gov/NCBDDD/sicklecell/data.html

3. World Health Organization. (2011). Sickle-cell disease and other haemoglobin disorders. Retrieved Nov. 9, 2012 from the World Wide Web: http://www.who.int/mediacentre/factsheets/fs308/en/index.html

4. Goldsmith, J.C., Bonham, V.L., Joiner, C.H., et al. (2012). Framing the research agenda for sickle cell trait: Building on the current understanding of clinical events and their potential implications. American Journal of Hematology, 87(3), 340-346.

5. Serjeant, G. (2002). Sickle cell disease (3rd ed.). Oxford, England: Oxford University Press.

6. Steinberg, M.H. (1999). Management of sickle cell disease. New England Journal of Medicine, 340(13), 1021-1030.

7. Steinberg, M.H., & Sebastiani, P. (2012). Genetic modifiers of sickle cell disease. American Journal Hematology, 87(8), 795-803.

8. Malowany, J.I., & Butany, J. (2012). Pathology of sickle cell disease. Seminars in Diagnostic Pathology, 29(1), 49-55.

9. Bunn, H.F. (1997). Pathogenesis and treatment of sickle cell disease. New England Journal of Medicine, 337(11), 762-769.

10. Embury, S.H., Hebbel, R.P., Mohandas, N., Steinberg, M.H. (Eds.). (1994). Sickle cell disease: basic principles and clinical practice. New York: Raven Press.

11. Platt, O.S., Brambilla, D.J., Rosse, W.F., et al. (1994). Mortality in sickle cell disease. Life expectancy and risk factors for early death. New England Journal of Medicine, 330(23), 1639-1644.

12. Davies, E.G., Riddington, C., Lottenberg, R., & Dower, N. (2004). Pneumococcal vaccines for sickle cell disease. Cochrane Database of Systematic Reviews, (1), CD003885.

13. Lottenberg, R., & Hassell, K. (2005). An evidence-based approach to the treatment of adults with sickle cell disease. Hematology, 58-65.

14. Charache, S., Terrin, M.L., Moore, R.D., et al. (1995). Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. New England Journal of Medicine, 332(20), 1317-1322.

15. McGann, P.T., & Ware, R.E. (2011). Hydroxyurea for sickle cell anemia: what have we learned and what questions still remain? Current Opinion in Hematology, 18(3), 158-165.

16. Steinberg, M.H., Barton, F., Castro, O., et al. (2003). Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: Risks and benefits up to 9 years of treatment. JAMA, 289(13), 1645-1651.

17. Hankins, J.S., Ware, R.E., Rogers, Z.R., et al. (2005). Long-term hydroxyurea therapy for infants with sickle cell anemia: The HUSOFT extension study. Blood, 106(7), 2269-2275.

18. Ballas, SK. (1998). Sickle cell pain. IASP Press.

19. Benjamin, L.J. et al. (1999). Guideline for the management of acute and chronic pain in sickle cell disease. American Pain Society.

20. Eckman, J.R., & Platt, A.F. (2000). Problem oriented clinical guidelines. Accessed Nov. 9, 2012 from the World Wide Web: http://scinfo.org/problem-oriented-clinical-guidelines

21. Lane P., et al. (2001). Care paths and protocols: Children and adolescents. Accessed Nov. 9, 2012 from the World Wide Web: http://scinfo.org/care-paths-and-protocols-children-adolescents
22. Smith-Whitley, K., & Thompson, A.A. (2012). Indications and complications of transfusions in sickle cell disease. Pediatric Blood & Cancer, 59(2), 358-364.

23. Platt, O.S., Thorington, B.D., Brambilla, D.J., et al. (1991). Pain in sickle cell disease. Rates and risk factors. New England Journal of Medicine, 325(1), 11-16.

24. Embury, S.H., et al. (1984). Effects of oxygen inhalation on endogenous erythropoietin kinetics, erythropoiesis and properties of blood cells in sickle cell anemia. New England Journal of Medicine, 311(5), 291-295.

25. Platt, A., Eckman, J.R., Beasley, J., & Miller, G. (2002). Treating sickle cell pain: An update from the Georgia Comprehensive Sickle Cell Center. Journal of Emergency Nursing, 28(4), 297-303.

26. Hassell, K.L., Eckman, J.R., & Lane, P.A. (1994). Acute multiorgan failure syndrome: a potentially catastrophic complication of severe sickle cell pain episodes. American Journal of Medicine, 96(2), 155-162.

27. Smiers, F.J., Krishnamurti, L., & Lucarelli, G. (2010). Hematopoietic stem cell transplantation for hemoglobinopathies: current practice and emerging trends. Pediatric Clinics of North America, 57(1), 181-205.

28. Shenoy, S. (2011). Hematopoietic stem cell transplantation for sickle cell disease: current practice and emerging trends. Hematology, 273-279.

29. DeBaun, M.R. (2011). Secondary prevention of overt strokes in sickle cell disease: Therapeutic strategies and efficacy. Hematology, 427-433.

30. Smith-Whitley, K., & Thompson, A.A. (2012). Indications and complications of transfusions in sickle cell disease. Pediatric Blood & Cancer, 59(2), 358-364.

31. Rees, D.C., Williams, T.N., & Gladwin, M.T. (2010). Sickle-cell disease. Lancet, 376(9757), 2018-2031.

32. Vichinsky, E.P., Haberkern, C.M., Neumayr, L., et al, and the Preoperative Transfusion in Sickle Cell Disease Study Group. (1995). A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. New England Journal of Medicine, 333(4), 206-213.

33. Vichinsky, E.P., Neumayr, L.D., Earles, A.N., et al. (2000). Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. New England Journal of Medicine, 342(25), 1855-1865.

34. Bellet, P.S., Kalinyak, K.A., Shukla, R., et al. (1995). Incentive spirometry to prevent acute pulmonary complications in sickle cell diseases. New England Journal of Medicine, 333(11), 699-703.

35. Miller, A.C., & Gladwin, M.T. (2012). Pulmonary complications of sickle cell disease. American Journal of Respiratory and Critical Care Medicine, 185(11), 1154-1165.

36. Gladwin, M.T., & Kato, G.J. (2005). Cardiopulmonary complications of sickle cell disease: Role of nitric oxide and hemolytic anemia. Hematology, 51-57.

37. Guasch, A., Cua, M., & Mitch, W. (1996). Early detection and the course of glomerular injury in patients with sickle cell anemia. Kidney International, 49(3), 786-791.

38. Sharpe, C.C., & Thein, S.L. (2011) Sickle cell nephropathy -- a practical approach. British Journal Haematology, 155(3), 287-297.

39. Fitzhugh, C.D., Wigfall, D.R., & Ware, R.E. (2005). Enalapril and hydroxyurea therapy for children with sickle nephropathy. Pediatric Blood & Cancer, 45(7), 982-985.

40. Thompson AA. (2011). Primary prophylaxis in sickle cell disease: is it feasible? Is it effective? Hematology, 434-439.

Nurse Resources

1. CDC: www.cdc.gov/ncbddd/sicklecell/index.html

2. Harvard School of Medicine: http://sickle.bwh.harvard.edu/menu_sickle.html

3. International Association of Sickle Cell Nurses and Physician Assistants: www.iascnapa.org

4. National Institutes of Health: http://ghr.nlm.nih.gov/condition=sicklecelldisease

5. Sickle Cell Adult Provider Network: www.ucdenver.edu/academics/colleges/medicalschool/centers/sicklecell/SCAPN/Pages/SCAPNHome.aspx

6. Sickle Cell Disease Association of America (SCDAA): www.sicklecelldisease.org

7. Sickle Cell Information Center: www.scinfo.org

Patient Resources

1. Platt, A., Platt, S., & Hedrich, C. (2006). Overcoming pain: What it is, why it is, and successful ways to treat it. Munster, IL: Hilton Publishing.

2. Platt, A. Eckman, J., & Hsu, L. (2011). Hope and destiny: The patient and parent's guide to sickle cell disease and trait (3rd ed.). Munster, IL: Hilton Publishing.

Allan Platt is senior associate in medicine, physician assistant program, Emory University School of Medicine, Atlanta.




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