Sickle Cell Information - Clinician Summary

Sickle cell diseases are 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. It is estimated that 70,000 Americans of different ethnic backgrounds have sickle cell disease. In the U.S., sickle cell syndromes are present in 1 in 400 African Americans. The disease is also found in high frequency in individuals from certain areas of the Mediterranean basin, the middle east, and India.

Sickle cell syndromes include sickle cell anemia (HbSS), hemoglobin SC (HbSC), and hemoglobin S beta thalassemia (HbSBeta-thal). Sickle cell anemia, the most common variant, results when an individual inherits a substitution of valine for the normal glutamic acid in the 6th amino acid position of the beta globin chain of hemoglobin from both parents. (2) This substitution alters the hemoglobin molecule so it crystallizes and deforms the red cell into a sickle shape when the hemoglobin loses oxygen. Hemoglobin C is caused by a substitution of lysine in the same location. Beta thalassemias are caused by genetic mutations that abolish or reduce production of the beta globin subunit of hemoglobin.

Diagnosis

The definitive test used to diagnose sickle cell syndromes is the hemoglobin electrophoresis. Because the HbS and HbC amino acid substitutions change the electrical charge of the protein, the migration pattern of the hemoglobin with electrophoresis or isoelectric focusing results in diagnostic patterns with each of the different hemoglobin variants. Diagnosis of HbSBeta-thal requires careful evaluation of the red cell count and mean corpuscular red cell volume (MCV) and specifically quantifying HbA, S, A2, and F. A five minute solubility test, named the Sickledex, has been used to detect the presence of HbS in the emergency setting. This test is of little diagnostic value because it does not differentiate sickle syndromes from the benign carrier state (HbAS or A sickle trait). False negatives are also frequent in newborns and with severe anemia.

Clinical Manifestations

The clinical manifestations of sickle cell anemia result from increased blood viscosity and vascular obstruction by deformed, sickled red cells. The disruption of blood flow causes vascular occlusions, hemorrhages, infarctions, and ischemic necrosis is 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, and increased temperature, and blood stasis. The increased mechanical fragility and surface abnormalities of cells containing sickle hemoglobin reduce red cell life span from the normal 120 days down to 10 to 30 days. This marked hemolytic anemia causes increased indirect bilirubin, LDH, and a high reticulocyte count.

The common complications seen in individuals with sickle cell disease are summarized by the mnemonic "HBSS PAIN CRISIS":

H - Hemolysis, Hand-Foot syndrome

B - Bone Marrow Hyperplasia/Infarction

S -Stroke: Thrombotic or hemorrhagic, Subarachnoid bleeds

S - Skin ulcers (primarily leg)

P - Pain episodes, Priapism, Psychosocial problems

A - Anemia, Aplastic crisis, Avascular necrosis

I - Infections: CNS, Pulmonary, GU, Bone, Joints

N - Nocturia, urinary frequency from hyposthenuria

C - Cholelithiasis, Cardiomegaly, Congestive heart failure, Chest syndrome

R - Retinopathy, Renal failure, Renal concentrating defects

I - Infarction: Bone, Spleen, CNS, Muscle, Bowel, Renal

S - Sequestration crisis involving spleen or liver

I - Increased fetal loss during pregnancy

S - Sepsis

Pain Episodes

The most common problem for sickle cell patients is the pain episode, a self limiting and reversible pain in the extremities, back, chest, and abdomen. Severity of pain has been reported to range from mild transient attacks of five minutes to pain lasting days or weeks requiring hospitalization. The exact cause of the intense pain is unknown but believed to be caused by the inflammatory response to bone marrow necrosis, ischemic muscle, and ischemic bowel resulting from the obstruction and sludging of blood flow produced by sickled erythrocytes. Cumulative ischemic tissue damage and fibrosis can lead to chronic pain. 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.

Pain episodes should be managed as in any other severe, acute pain-producing disease, tailoring the analgesic used and dosage to the level of 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. A detailed history and physical examination is important to identify correctable precipitating factors such as infection, dehydration, increased anemia, acidosis from any cause, emotional stress, extreme temperature exposure, or ingestion of other substances such as alcohol or other recreational drugs. The treatment of pain crisis includes administration of analgesics including narcotics and NSAIDs, intracellular hydration with hypotonic oral or intravenous fluids, bed rest, treatment of underlying infection, and other precipitants.

Oxygen should be administered if the patient has an underlying pulmonary problem and 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. Oxygen therapy, when hypoxia is not present, has been shown to reduce red blood cell production.

Managing acute pain episodes requires controlling pain appropriately, excluding correctable precipitating causes, detecting life threatening complications, and diagnosing causes of pain unrelated to sickle cell complications. Pain therapy requires choosing agents that are safe and provide rapid analgesia. 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. The oral route of administration is safest. The oral dose needed is always greater than the dosage needed using the parenteral route. The ratio of oral to a parenteral dose varies with each of the narcotic analgesics and must be based on the pharmacology of the drug. Patient controlled analgesia (PCA) pumps that provide constant low dose infusion of morphine with defined rescue doses is gaining favor. 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 (Buprenex) and nalbuphine (Nubain) are alternative choices for some patients, but they can cause withdrawal symptoms similar to naloxone in patients with very frequent narcotic usage.

Hydration with intravenous hypotonic solutions such as D5W is a treatment that may slow or stop the sickling process by lowering the serum sodium and thus the serum osmolality. Reduced serum osmolality moves water into the red blood cell, reducing the concentration of the sickle hemoglobin in the cell. This reverses sickling because the tendency for sickle hemoglobin to polymerize increases with the thirtieth power of the hemoglobin concentration. Fluid should be administered to adults at the rate of 250 cc/hr for eight hours, then reduced to 125 cc/hr if there are no signs or past history of congestive heart failure, renal failure, or hyponatremia.

Other Complications

Bacterial infection is one of the main causes of morbidity and mortality in patients with sickle cell disease. Children less than three are at the greatest risk for fatal sepsis but patients of any age are at risk for rapid death from sepsis. Splenic function is markedly decreased or absent in sickle cell anemia, leaving the individual at great risk for infection within encapsulated organisms such as streptococcus pneumoniae, Hemophilus influenza, salmonella, meningococcus, and others. Serious infections such as meningitis, pneumonia, sepsis, and osteomyelitis must be aggressively excluded and treated empirically early to prevent morbidity and mortality. Preventive measures such as pneumococcal and Hemophilus influenzae vaccine should be administered to all sickle cell patients starting at two years old. Prophylactic penicillin should be instituted immediately and should continue until the child is six years old.

Splenic sequestration crisis is one of the most serious complications and is second only to infections as a cause of death in infants with sickle cell disease. This event usually occurs between the ages of four months and three years, but may occur at any age with hemoglobin SC or S-$thal disease. During sequestration episodes sickle cells are trapped in the spleen, causing rapid fall in the hemoglobin level and enlargement of the spleen. Sequestration events may be triggered by infection or occur with no apparent antecedent. The onset of signs and symptoms is very rapid and consists of weakness, abdominal pain, fatigue, dyspnea, and pending shock, tachycardia, pallor, enlarging spleen, and a falling hemoglobin hematocrit with a reticulocyte count equal and usually higher than the patient's baseline. Treatment consists of admission to an ICU with aggressive blood transfusions. Emergent splenectomy is occasionally required.

Hepatic sequestration may occur later in life with similar signs and symptoms including a rapidly enlarging liver and a falling hematocrit. The treatment consists of aggressive simple transfusion or red cell exchange transfusion.

Aplastic crisis occurs when the bone marrow slows or stops new red blood production. Signs and symptoms are a falling hemoglobin, and hematocrit, along with a falling reticulocyte count, weakness, pallor, dyspnea, and dizziness. In sickle cell disease, the absolute reticulocyte count is three to four times the upper limit of normal in compensation for the shortened red cell survival. Treatment for aplastic crisis includes immediate hospitalization and blood transfusions to support the hemoglobin level. Sources of the aplastic event such as infection with parvo virus or folate deficiency should be sought.

Preventive Care

Folate should be administered daily to most sickle cell patients because dietary intake of folate may not meet the increased requirements for red cell production. Hemoglobin, hematocrit and reticulocyte counts should be checked periodically to determine a normal baseline for each patient so significant changes can be identified early. Iron preparations are to be avoided unless serum ferritin, iron, and TIBC levels establish a diagnosis of iron deficiency. Iron is recycled in the reticuloendothelial cells and reused for the production of hemoglobin in new red cells. Iron overload may become a problem later in life for the sickle cell patient treated with repeated blood transfusion and aggressive oral or parenteral iron supplementation.

Those with sickle cell disease should be evaluated periodically to identify chronic problems, update immunizations, maintain folate acid therapy, and provide patient education and support. Patients and parents should be educated how to read a thermometer and how to seek immediate medical attention when a fever develops or signs of infection appear. Smoking and excessive alcohol intake should be discouraged. Patients should be educated about the importance of drinking eight to 10 glasses of water or fluid per day. They should avoid extreme temperature changes, dressing properly in hot and cold weather. Excessive physical exertion that repeatedly leads to complications should be avoided. The patient should be encouraged to find and not exceed their personal physical limits in sports and outdoor activities. Educational and vocational goals should be set and actively pursued with positive reinforcement. Over-protectiveness, family and health care over-dependence, and chronic illness behavior should be discouraged.

In patients with chronic pain, NSAIDs with renal sparing properties should be administered continuously to maintain analgesic blood levels. Transcutaneous nerve stimulation units, relaxation techniques, occupational and physical therapy may be used to maintain a functional lifestyle. Vocational rehabilitation and outside activities are critical in maximally coping with the chronic pain of sickle cell disease. Severe pain can be cautiously managed using the long acting narcotics such as sustained release oral morphine, sustained release oxycodone, or methadone.

Patients with sickle cell disease may be followed by primary care practitioners. Complicated cases should be managed with input from comprehensive sickle cell centers where specialized medical resources can be obtained. Comprehensive sickle cell centers should have facilities to evaluate, treat, and counsel those with any of the complications of the disease. Centers should have support staffs including patient educators, genetic counselors, psychiatric support, vocational rehabilitation, occupational therapy, physical therapy, and health care providers all working together as a multidisciplinary team to solve the complex medical, psychological, and social problems associated with these diseases.

New Treatments

Daily administration of oral hydroxyurea (Hydrea) is the first effective pharmacologic intervention documented to provide clinically significantly prevention of complications in sickle cell disease. Treatment with Hydrea has recently been shown to reduce pain events, hospital admissions and the need for blood transfusions by 50%. When used in doses starting at 15-20 mg/kg/day and increased slowly until a favorable response is obtained or toxicity signs appear (neutrophil count < 2,000/mm³, platelets < 80,000/mm³, hemoglobin drop of 2 g/dl, or absolute reticulocyte count < 80,000/mm³), or a total dose of 35 mg/kg is reached. When a good clinical response is observed, the patient=s fetal hemoglobin increases and total hemoglobin increases an average one gram/dl. The patient must be monitored with CBCs every two weeks for evidence of bone marrow suppression and only a two-week supply of hydrea with no refills should be given to the patient at each visit. Once a stable or maximally tolerated dose is obtained, the patient can be monitored monthly. The long term benefits of hydroxyurea and toxicities are unknown. Studies of safety and efficacy are being initiated in children and this treatment cannot presently be recommended for children.

A recent cooperative study of preoperative transfusion demonstrates that sickle cell patients should have simple transfusions to raise the patient's hemoglobin to 10 gm/dl before surgery. These simple transfusions are safer and as effective in preventing postoperative complications as are exchange or aggressive transfusions to decrease the hemoglobin S level below 30%. Postoperative complications such as chest syndrome, fever, and alloimmunization with delayed transfusion reactions are common. Alloimmunization can be minimized by giving antigen matched blood ( matched for K, C, E, S, Fy, and Jk antigens). All patients should receive incentive spirometry, given adequate hydration and oxygenation. Transfusions are still the best acute treatment for life threatening complications such as stroke, acute chest syndrome, sequestration and aplastic events. Chronic transfusions are necessary for life to prevent recurrent strokes. Transfusion to hemoglobin levels above 10 may cause hyperviscosity, increased sludging and complications like stroke.

New methods for screening for CNS ischemia including transcranial doppler and MRI-MRA have uncovered a 15% incidence of CNS ischemic injury in asymptomatic sickle cell patients. A prospective trial of chronic transfusion therapy is underway to determine if strokes can be primarily prevented. All patients with CNS symptoms should be screened immediately and treated with acute exchange therapy if an infarctive stroke is documented. Strokes and transient ischemic attacks are associated with a 50% or greater recurrence rates unless chronic transfusion therapy is maintained for life. Because of the problems of alloimmunization, blood-born infection and chronic iron overload, bone marrow transplantation is considered in young children with strokes.

Bone marrow transplantation has been used to successfully convert 27 patients in the United States from hemoglobin SS to normal AA or AS, depending on the phenotype of the related marrow donor. Bone marrow transplantation is an experimental therapy limited to patients who have enough complications from sickle cell disease to warrant the risk death and long-term complications from bone marrow transplantation and who also have a sibling with an identical HLA match. Patients face a 10% mortality from the procedure, and several months in the hospital in preparation and care after transplantation. Successful transplantation has resulted in the first cures of this genetic disorder. Eligible patients can be referred to one of 25 participating transplant centers across the nation including the Sickle Cell Center in Atlanta.

Specialty Center's role in Sickle Cell Management

The Georgia N.I.H. Comprehensive Sickle Cell Center at Grady Health System in Atlanta, Georgia, a 24-hour acute care center for those with sickle cell disease, was established in the fall of 1984. The unit is staffed by physician assistants supervised by staff hematologists and third year medical residents. In addition to acute care, there is health maintenance care provided by the above-mentioned staff as well as LPNs, RNs, social workers, and a psychiatric clinical nurse specialist. This comprehensive approach to sickle cell disease promotes a positive patient/health care provider relationship as well as early detection of complications and early intervention. The 24 hour phone number for sickle cell information is (404) 616-3572.

Physician assistants, under supervision of the attending hematologists, function as primary care providers for the patients giving them consistent family practice type care in a teaching institution environment. In a large teaching hospital where resident physicians frequently rotate, PAs provide a stable health care provider relationship for the patient. Providing emergency care and primary services in the same area by the same staff gives the patient quick and efficient evaluations and treatment. Currently, there are five PAs on the center team providing primary and emergency care to children and adults, research support and administrative duties. The center is a prototype model for what can be done across the nation as well as the world in areas where sickle cell disease is prevalent. Physician assistants and nurse practitioners are a cost-effective way of establishing such centers.

The International Association of Sickle Cell Nurses and Physician Assistants is an organization of heath care providers involved in improving the care of the sickle cell patient. For further information contact: IASCNPA, Box 3939, Duke University Medical Center, Durham, N.C. 27710.

REFERENCES

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2. Sergeant G. Sickle cell disease. Oxford: Oxford University Press 1985.

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8. Reid CD, Charache S, Lubin B, et al. Management and Therapy of Sickle Cell Disease. N.I.H. Publication No. 95-2117, 1995.

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11. Sergeant G. Sickle cell disease. Oxford: Oxford University Press 1985.

12. Diggs L. Anatomic lesions in sickle cell diseases. In Abramson H, Bertles JF, Wethers DL, eds. Sickle cell disease diagnosis, management education, and research. Saint Louis: The C.V. Mosby Company, 1973:189.

13. Powars D, Overturf G, Weiss J, Lee S, Chan L. Pneumococcal septicemia in children with sickle cell anemia. JAMA 1981;245:1839-42.

14. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. N Engl J Med 1986;314:1593-99.

14. Charache S, Terrin M, Moore R, Dover G, et al. Effect of Hydroxyurea on the frequency of painful crises in sickle cell anemia. NEJM 1995:332:1317-22.

15. Vichinsky EP, Haberkern CM, Neumayr L, et al: A comparison of conservative and aggressive transfusion regiments in the perioperative management of sickle cell disease N Engl J Med 222:206-213, 1995.

16. Haberkern CM, Neumayr L, Earles AN, Robertson S, et al. Cholecystectomy in sickle cell anemia patients:Report of 364 patients from the preoperative transfusion study. Blood 1995:86:142a

17. Vichinsky EP, Earles A, Johnson RA, et al: Alloimmunization in sickle cell anemia and transfusion of racially unmatched blood. N Engl J Med 322:1617-1621, 1990.

18. Adams R, McKie V, Nichols F et al. The use of transcranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med 1992:326:605-610.

19. Walters MC, Patience M, Leisenring W, Eckman JR, et al: Marrow transplantation for sickle cell disease: Results of a multicenter collaborative investigation. New Engl J Med 355:369-76, 1996.

20. Walters MC, Patience M, Leisenring W, Eckman JR, et al: Barriers to bone marrow transplantation for sickle cell anemia. Biol Blood Marrow Transplant 2:100-104, 1996

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Last modified: October 16, 1997