Sickle Cell Disease: Pathogenesis, Diagnosis & Interventions

Patients with sickle cell disease (SCD), a potentially life-threatening hemolytic anemia, represent an important subpopulation of chronically ill people whose disease significantly influences their physical, psychological and social health from early childhood through adulthood. Nurses are important in caring for these patients during the acute phases of their illnesses and, perhaps more significantly, in helping them achieve their optimal wellness potentials.

Although SCD is the most common genetic disorder in the world,1 most nurses are under-informed about this condition, the rationale for care given to patients in "crisis," and our role as teacher of patients, their families and their schools.

Case Study
T.G., an 18-year-old Hispanic female, presented with 1-2 day history of upper respiratory infection with symptoms including cough and fever. Pain started in the lower back and legs. She increased her fluid intake and took oral ibuprofen and meperidine, as prescribed on an around-the-clock schedule, without relief. She presented to the emergency department writhing in pain. She had a temperature of 38.5° C, and her pulse-oximetry was 91 percent on room air. After assessment (verbal pain scale 10/10), peripheral access was established and a dose of morphine 6 mg (0.1 mg/kg) was given IV, and a fluid bolus of 500cc of 0.9 percent sodium chloride was given over 30 minutes.

T.G. has SCD with beta-zero-thalassemia (HbSß0-thalassemia), an inherited hemoglobinopathy (impaired red cell production due to altered hemoglobin synthesis) characterized by chronic hemolysis (increased red cell destruction), frequent infections and recurrent blockage of the microcirculation (vaso-occlusion) that leaves patients susceptible to a variety of debilitating manifestations requiring numerous hospitalizations.

Anemia
Anemia, a reduction in red cells to levels below normal, is not a specific disease state but a sign of an underlying disorder.2 Anemia may be the result of: 1) impaired red cell production, 2) blood loss, 3) increased red cell destruction, or 4) some combination of the previous three.3 Significant reductions in the number of circulating red cells may result in anemic hypoxia caused by the decrease in oxygen-carrying capacity of the blood. Since the underlying problem in sickle cell disease is the production of abnormal hemoglobin, an understanding of the normal hemoglobin molecule is important.

Hemoglobin is the oxygen-transport protein contained in red blood cells. A normal hemoglobin molecule has two parts: the globin portion, a protein made up of four highly folded polypeptide chains; and four iron-containing heme groups, each of which is bound to one of the peptide chains. Heme contains iron (Fe) that binds reversibly with oxygen. There are several variations in the hemoglobin chains, depending on the amino acid composition of the globin portion. The different types of chains are designated alpha, beta, gamma and delta. Fig. 1 illustrates normal, adult hemoglobin (HbA).

Normal red cells (after age 6 months) contain three types of hemoglobin (see Table 1). Hemoglobin A (HbA), formed by two alpha and two beta chains, makes up approximately 95-98 percent of the total hemoglobin concentration. HbA2, formed by two alpha chains and two delta chains, accounts for 2-3 percent of the total hemoglobin, and fetal hemoglobin (HbF), the combination of two alpha chains and two gamma chains, makes up less than 1 percent of hemoglobin. Fetal hemoglobin makes up to 60-90 percent of the red cell hemoglobin concentration until 8-10 weeks after birth; thereafter, HbA predominates.

Sickle Hemoglobin
Sickle hemoglobin (HbS) is formed through the substitution of valine for glutamic acid in position six of the beta chain of HbA. Fig. 2 shows the first eight of the 146 amino acids in the beta globin subunit of the hemoglobin molecule. The letter G represents the normal amino acid, glutamic acid, at position 6 and the letter V represents the valine in substitution sickle cell hemoglobin. The other amino acids in sickle and normal hemoglobins are identical.

Genetics
Sickle cell disease is a generic term for a group of disorders characterized by the predominance of HbS.4 It is an inherited condition; therefore, the genes received from each parent will determine whether a person will have SCD.

Most human cells (except germ cells) contain 23 pairs of comparable (homologous) chromosomes. The paired state of the homologous chromosomes results from the union of a sperm cell containing 23 chromosomes with an egg cell that contains the homologous 23 chromosomes. Each chromosome contains thousands of genes coding for many different types of proteins. A single gene located on chromosome 11 controls the production of the beta protein chain of hemoglobin. A defect in this gene is responsible for the production of HbS.

Sickle cell anemia (HbSS), accounting for 60-70 percent of the sickle cell diseases, occurs when two defective hemoglobin genes producing HbS are inherited (one HbS from each parent). If a defective gene (HbS) is inherited from one parent and a non-defective gene (HbA) is inherited from the other, a carrier state exists (sickle cell trait, HbAS) but not the disease. Usually, individuals with sickle cell trait are not anemic and do not need treatment or work limitations. About 5 percent have hematuria at some time and most cannot concentrate their urine, but these are clinically unimportant.5 If both parents are carriers (HbAS), each of their children have a 1-in-4 chance for sickle-cell anemia (HbSS), a 1-in-4 chance of normalcy (HbAA), and a 2-in-4 chance for sickle cell trait (HbAS).

In this case study, T.G. inherited a ß-mutated gene for HbS from one parent and a ß-mutated gene for thalassemia from the other parent (Hbß). ß thalassemias are inherited disorders of ß globin synthesis. In most, ß globin structure is normal but the rate of production is reduced, a condition referred to as ß+-thalassemia. However, T.G. has ß0-thalassemia, a severe form of thalassemia in which there is no ß globin production.

One gene is making HbS and the other gene is defective and cannot make anything. Therefore, the only hemoglobin produced is HbS with minor amounts of HbA2 and HbF.

Pathophysiology
The pathophysiology of this disorder involves the following sequential steps that occur in the microcirculation and cause acute painful episodes leading to organ damage, organ failure and premature death: 1) polymerization of HbS, 2) deleterious effects on the red blood cell membrane, 3) microvascular occlusion, 4) hypoxia of the tissue supplied by the occluded microvascular network, and 5) tissue damage causing painful stimuli.6

Polymerization of HbS-When red cell deoxygenation occurs in peripheral tissues (cellular respiration), sickle hemoglobin polymerizes, forming rigid crystal-like rods that distort the red cell from a biconcave disc to an irregular, brittle, sickle-shaped cell.7 Polymerization is a process wherein "units" link together, forming long, chain-like molecules; in sickle cell disease, the units that are linked are hemoglobin molecules. When red cells re-oxygenate in the lungs, the hemoglobin molecules depolymerize and return to the normal, biconcave disc shape. This change in shape is illustrated in Fig. 3.

Among the numerous factors influencing the intracellular polymerization of HbS, the most dramatic is the HbS concentration. A small increase significantly shortens the time and lessens the extent of deoxygenation required to initiate polymerization.8 Factors affecting polymerization of HbS are summarized in Table 2.

Deleterious Effects on the Red Cell Membrane-Although polymerization of deoxy HbS is reversible, repeated cycles of deoxygenation/oxygenation can have deleterious effects on red cell membranes.9 The three effects are: 1) more rigid and less deformable membrane, resulting in a greater risk of being trapped in the microcirculatory beds; 2) increase in fragility; and 3) change in permeability leading to intracellular water and potassium loss generating dehydrated, dense red cells.9,10

Red cell membrane damage also causes the life span of sickle cells to be significantly shortened. (The average life span of a sickle red cell is 7-14 days compared with the 120-day life span of normal red cells.) Reduced deformability is a major determinant for hemolysis and red cell life span.11

Vaso-occlusion-Vaso-occlusion, which is responsible for most of the severe complications of sickle cell disease, can occur wherever blood flows.5 These episodes, characterized by tissue infarction and often accompanied by pain, can affect nearly all organs or tissues.4 The incidence and severity of vaso-occlusive episodes and the development of chronic organ damage varies greatly among different individuals and even within a given patient.12

No single mechanism explains vaso-occlusion but several hypotheses exist. Increased evidence supports the hypothesis that deformable, less dense red cells initiate vascular obstruction by adhering to endothelial cells, forming a vascular plug.12 Reticulocytes may also contribute to adhesion and the slowing of blood flow, according to Carlton Dampier, MD, chief of hematology/oncology at St. Christopher's Hospital for Children in Philadelphia. Adherence of red cells to endothelial cells slows blood flow and increases the time red cells spend in the microvasculature accelerating HbS polymerization.11 The enhanced polymerization with resultant sickling prior to exiting the microvasculature, results in the trapping of sickled cells behind the adherent cells, causing vaso-occlusion and hypoxia to the area supplied by these vessels (see Fig. 4).

Past Medical History
T.G.'s sickle cell disease was first diagnosed when she was 2-1/2 years old. At that time, she presented with fever and cervical adenopathy and was found to be anemic with an enlarged spleen. She has been admitted 4-6 times a year either for pain or infectious complications, particularly pneumonias. Asthma was diagnosed at age 7 years, and she has been treated intermittently with albuterol and inhaled steroids. Surgeries include tonsilectomy and adenoidectomy with myringotomy tubes at age 5 and adenoidectomy at age 16 for obstructive sleep apnea. She has received numerous blood transfusions but has no evidence of alloimmunization.

Electrophoresis is a process performed in the laboratory that utilizes properties of charge and size to differentiate among substances. In hemoglobinopathies, it is used to identify and quantify molecules, such as, HbA, HbS, HbF and HbA2.

T.G.'s latest electophoresis at age 14 years indicated: HbS 74.8 percent, HbA2 5.2 percent, HbA 0 percent, HbF 20 percent. Chest X-ray showed a left lower lobe infiltrate.

Laboratory studies showed CBC as follows: WBC 20.2 mg/dL (4.8-10.8), RBC 3.17 mg/dL (4.7-6.1), HGB 7.6 g/dL (14.0-18.0), HCT 22.4 percent (42.0-52.0), MCV 70.5 fL (80-94), MCH 24.1 pg/fL (27-31), MCHC 34.1 g/dL (33-36), RDW 21.4 percent (11-14.5), PLT 290/mm3 (150-450); reticulocytes 7.8 percent (0.5-1.5). The peripheral blood smear showed 2+ targets, sickle cells and occasional spherocytes.

Diagnosis
T.G.'s diagnosis, HbSß0-thalassemia, is based on hemoglobin electrophoretic patterns, blood analysis and red cell morphology in peripheral blood smears. The presence of HbS (74.8 percent) with the absence of HbA (0 percent) denotes HbSS or HbSß0-thalassemia. ß0-thalassemia is differentiated by the presence of an elevated HbA2 level (5.2 percent) and a decrease in mean corpuscular volume (70.5 percent). Measurements of HbF (20 percent) will further distinguish between these conditions because HbF levels are generally higher in HbSß0-thalassemia than in HbSS.

Furthermore, sickle cell anemia is typically normochromic (normal MCHC) and normocytic (normal MCV) with a mean hemoglobin between 7.0 and 8.0 g/dL and a MCV of 90 fL.13 T.G. has a hematologic picture characterized by microcytosis (reduced MCV) and hypochromia (below normal MCHC), which is indicative of ß0-thalassemia.13 T.G.'s white cell count is elevated owing to increased marrow activity secondary to chronic hemolysis.13

Table 3 summarizes the relationship among the clinical severity, blood counts, peripheral smear and levels of HbS, HbF and HbA2 for HbSS and HBSß0-thalassemia.

In addition to having an acute and painful episode, T.G. is diagnosed with acute chest syndrome based on the appearance of a new pulmonary infiltrate as seen in X-ray.

Clinical Manifestations
Clinical manifestations of SCD differ significantly with the various disorders and even among patients with the same disorder.14 HbSß0-thalassemia presents a clinical picture virtually indistinguishable from that of HbSS.7

Although disease attributed to HbS has been observed in early infancy, affected individuals characteristically are without signs and symptoms until age 6 months.4 The lack of clinical expression of the HbSS genotype during fetal and early postnatal life is explained by the production of a sufficient quantity of HbF to limit clinically important sickling.

The clinical course of affected individuals is typically associated with long periods of wellness interspersed with recurrent symptomatic episodes referred to as "crisis."15 Precipitating factors can include infection, stress, dehydration or changes in temperature, but precipitants may be unidentifiable.

Precipitating Factors: Infections-Serious bacterial infections are a major cause of morbidity and mortality for patients with sickle cell disease.4 The spleen, part of the lymphatic system, is an important "infection-fighting" organ whose functions include phagocytosis of bacterial organisms. Infections are common in this patient population because most develop functional asplenia (auto-spleenectomy) as a result of multiple infarcts. Infections are most frequent and more serious in preschool-age children and are associated with a 30 percent mortality rate.15 The risk of infection is highest with encapsulated organisms such as Streptococcus pneumoniae, Haemophilus influenzae, meningococci and Salmonella sp.

For patients with SCD, prevention and early, aggressive treatment of infection are paramount.4 Oral penicillin, given twice a day, has been successful in reducing morbidity and mortality from pneumococcal infections in infants. For patients allergic to penicillin, erythromycin ethyl succinate given bid can provide adequate prophylaxis.4 Antibiotic prophylaxis should be addressed at all patient contacts. Parents must learn to administer antibiotics accurately and faithfully to help prevent serious illness. During T.G.'s acute episode, IV Unasyn® (ampicillin sodium/sulbactam sodium, Pfizer) was administered. Her long-term management included 250 mg amoxicillin bid as prophylactic antibiotic.

A strong ally of infection prevention is immunization. As with other children, immunizations should be administered according to schedules recommended by the American Academy of Pediatrics. Children with SCD should be immunized against hepatitis B virus and should receive the polyvalent pneumococcal vaccine at age 2 years, with a booster at age 5. Until February 2000, children under 2, the age group at highest risk for infection, did not have an anti-pneumococcal vaccine option. However, on Feb. 17, 2000, the FDA granted approval to a new vaccine, PrevnarT (diphtheria CRM197 protein, Wyeth Lederle). Prevnar, a 7-valent conjugate vaccine, has proven effective in preventing pneumococcal bacteremia and meningitis in children in this vulnerable age group. Children should receive four doses of the vaccine, at 2, 4, 6 and 12-15 months of age. In addition, it is recommended that individuals with SCD receive seasonal influenza vaccines.4

Dehydration-Typically, patients with SCD are dehydrated, a problem that contributes to the polymerization of HbS. At the cellular level, damaged red cell membranes allow potassium and water to leak from the cell, leaving them too dense. Systemically, patients are "dry" because of excessive urination secondary to their inability to concentrate urine (hyposthenuria). Frequent urination can also cause bedwetting. This is common for most children with SCD and is not caused by a psychological problem. Systemic dehydration is aggravated by additional fluid losses, such as vomiting, diarrhea or fever. Signs of dehydration include tiredness; decrease in usual amounts of urination; dry, sticky mouth and lips; and sunken eyes or anterior fontanelle. During her crisis, T.G. was given IV fluids, D5W.45 NS (normal saline) plus 10 meq KCl/L at 100 cc/hour for hydration.

Complications: Acute Painful Crisis-The acute painful crisis is the most frequent manifestation of SCD and can include acute chest syndrome, stroke and splenic sequestration.7,13 The frequency of pain crisis varies directly with the hematocrit and inversely with HbF.13 Pain is commonly the result of infarctions of bone marrow and cortical bone.15 The exact cause of the intense pain is unknown but believed to be due to the inflammatory response to bone marrow necrosis, ischemic muscle and ischemic bowel resulting from the obstruction and sludging of blood flow. In young children, pain often involves the small bones of the hands and feet (hand-foot syndrome); in older patients, head, chest, abdomen and back pain occur more commonly.7

Severity of pain has been reported to range from mild transient attacks of 5 minutes to pain lasting days or weeks requiring hospitalization. Cumulative ischemic tissue damage and fibrosis can lead to chronic pain.

Acute Chest Syndrome-Acute chest syndrome is a descriptive term for an acute episode of chest pain in conjunction with the appearance of a new pulmonary infiltrate and varying degrees of chest pain, dyspnea, hypoxemia, fever and prostration.4 Acute chest syndrome is the second most common cause of hospital admission in patients with SCD and, in some cases, constitutes a medical emergency.4

In adults, acute chest syndrome commonly results from pulmonary infarction, bacterial or viral infection, fat/bone marrow embolism, intrapulmonary sickling and emboli of sickled red cells. In children, it is better to assume an infectious etiology.4

Although the illness is frequently self-limited, particularly when it involves a small area of pulmonary parenchyma, it can rapidly progress and may be fatal. Frequent chest syndrome episodes indicate severe sickle cell disease and predict early mortality in adults.

Stroke-Stroke is a catastrophic complication of SCD and should be regarded as a medical emergency. Strokes are more common in children than in adults.14,16 Approximately 10 percent of children with SCD have a stroke.17 The etiology of most strokes in pediatric patients is cerebral infarction caused by complete occlusion or narrowing of large cerebral vessels such as the internal carotid, middle cerebral and anterior cerebral arteries.18 Strokes usually occur without warning but may accompany painful episodes, aplastic anemia or infections.14 Presenting symptoms vary, but hemiparesis, aphasia and seizures are the most common.18

Exchange transfusion is the standard therapy. Exchange transfusion is followed by monthly transfusions to maintain levels of HbS to less than 30 percent. The risk for a recurrent stroke in untreated patients is approximately 70 percent during the first 3 years following the initial event. Maintenance transfusion therapy reduces this risk to 10 percent.14 The need for transfusions may be life-long, and complications such as alloimmunization, iron overload and exposure to infectious diseases may occur.

The risk of stroke can be assessed by transcranial Doppler ultrasound examinations. High-flow values are associated with an increased risk.17 In adults aged 20-29 years, hemorrhagic strokes occur more frequently than arterial occlusive strokes with subarachnoid hemorrhages being the most common.14,16 In hemorrhagic stroke, more generalized phenomena such as coma, headache and seizures occur.4

Splenic Sequestration-This is an acute trapping of blood in the spleen caused by impaired egress of blood due to clogging by sickled cells.15 The spleen is uniquely susceptible to damage by sickled cells because its slow microcirculation provides a conducive environment for polymerization of HbS.4,18

As early as 3-6 months, congestion by sickled red cells causes functional asplenia that predisposes children with HbSS or HbSß0-thalassemia to life-threatening infection.18 The risks of splenic sequestration are greater in the first 3 years of life and become less frequent after age 5.

During severe splenic sequestration, the spleen greatly enlarges. The signs and symptoms include weakness, abdominal pain, fatigue, dyspnea, tachycardia and pallor. Anemia can be profound, thrombocytopenia due to splenic entrapment is common, and the reticulocyte count is often markedly elevated. Sequestration events may be triggered by infection or occur with no apparent antecedent.

Aplastic Crisis-Aplastic crisis is the result of diminished red cell production in addition to the underlying chronic hemolytic anemia.14 Aplastic crisis is often secondary to infection with human parvovirus B19 infection, which destroys erythrocyte precursors.14

Since the life span of a red cell is decreased from the normal 120 days to 10-14 days, bone marrow compensates with an increase in activity. In the wake of parvovirus or other infections, the imbalance between red cell production and destruction is significantly worsened.

The signs and symptoms of aplastic crisis include a falling hemoglobin and hematocrit, along with a falling reticulocyte count, weakness, pallor, dyspnea and dizziness.

Nursing Considerations
In treating and caring for patients through the clinical manifestations of SCD, it is important for nurses to provide culturally competent care and to recognize that not all patients with SCD are African-Americans. In addition to its presence in African-American populations, there are significant occurrences of the sickle gene in Hispanic populations, particularly from the Caribbean and Central America, and in people from southern Europe and the Middle East.4

Nurses must avoid stereotyping patients by culture, in general, and most importantly when assessing and treating pain.2 Dr. Dampier expressed his desire for nurses to know that "many/most patients with SCD have supportive families and resilient coping styles and attempt to lead as normal a life as possible. The patients most nurses see frequently on an inpatient service are those with very severe disease and poor coping mechanisms and/or poor support systems. None of these are the patient's fault."

According to the National Institutes of Health, the core of effective health maintenance for patients with SCD lies in a strong patient-provider relationship built on trust, respect, honest communication and mutual understanding.

Care During Acute Crisis
When T.G. arrived at the hospital in crisis, relieving his pain was a nursing priority.

The responsibilities of RNs in pain management include administering pain-relieving interventions, both pharmacologic and non-pharmacologic, assessing the effectiveness of those interventions, monitoring for adverse responses, and acting as an advocate for the patient when the ordered intervention fails to adequately relieve pain.2

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. The treatment of pain crisis includes administration of analgesics, intracellular hydration with hypotonic oral or intravenous fluids, bed rest, treatment of underlying infection and other precipitants.

The nurse should know that the patient's experience is both personal and multi-factorial. There are always various degrees of tissue damage leading to the sensory component of pain, which will be subsequently altered (either magnified or diminished) by psychological, emotional and cognitive factors, which result in the ultimate perception of pain. This pain should be judged in the context of the patient's experience of pain, not from the nurse's own experience, which is likely to be significantly different.2,4

Culture and ethnicity have an influence on how people describe their pain and how they behave when in pain. Research findings demonstrate that pain perception varies by individual rather than by ethnicity.2 Nurses should know that despite these findings, people of nonwhite ethnic groups are prescribed and receive significantly less analgesia in emergency departments, after surgery,19-22 and for cancer-related pain.23

Current practice in pain management has moved away from the notion of taking the patient to a level of "tolerable" pain to a preventive approach using analgesics given at set intervals so that the medication acts before the pain becomes severe and serum opioid level falls to a subtherapeutic level.

For T.G., her crisis pain was managed with IV Toradol® (ketoorolac tromethamine injection, Roche Laboratories) and IV morphine via PCA and her long-term pain management at home included prn analgesics, ibuprofen and Percocet® (oxycodone, acetaminophen; Endo Pharmaceuticals).

The Nurse as Teacher
The role of the nurse as teacher is important to patients with SCD, their families and their schools. Throughout their lives, these individuals will need care and information and so will those who teach and work with them.

Parents of children with SCD will need to learn specific physical assessment skills and at-home interventions for treating mild to moderate pain episodes. At-home treatments include fluid intake (clear liquids), rest and quiet play, warm baths, heating pad or warm moist towels, massage, distraction and acetaminophen or prescription analgesic.2,4 In addition, parents must be instructed to seek immediate medical attention if they notice their child has signs or symptoms that suggest a serious problem. These include fever (>= 101°F/38.1°C); increased pallor; abdominal pain or enlargement; rapid increase in the size of the spleen; chest pain; shortness of breath; pain with swelling or redness; severe headache; seizure; fainting; sudden weakness of an arm or leg or the whole body; difficulty speaking; a difference in movement of one side of the face from the other; priapism; and pain that is not relieved by at-home interventions. Educating parents is an essential component of newborn screening follow-up and has resulted in reduced mortality from splenic sequestration.4

School Nurses
The school nurse is in an excellent position to be a valuable resource to student/ patients, teachers, school administrators and parents about the needs of children with SCD. Parents and educators should be encouraged to treat these children as normally as possible and to encourage them to engage in activities that foster self-esteem and self-reliance. As with other chronic disorders, a positive self-image and a feeling of self-worth will help them to cope more effectively with their illness.4

The school nurse should be knowledgeable about precipitating factors for sickle cell crisis, signs and symptoms of complications and the treatments for them. Teachers should be informed that individuals with sickle cell disease need to drink water or other clear liquids often and that they will need to be excused to the bathroom often. Absences are expected due to pain or other complications. SCD does not affect one's intelligence but events associated with this illness may impair academic performance. Establishing a timely mechanism for providing homework and instruction at home/in hospital can help these students keep up academically.

Physical fitness instructors can help protect this vulnerable population by selecting physical activities with care. These children have a decreased ability to oxygenate their bodies due to chronic anemia and are likely to need to rest periodically. They are also at risk when exposed to temperatures that are too hot or cold, making cold winter and hot summer weather a potential problem, especially when accompanied with rigorous physical exertion. Patients with SCD should dress warmly for cold weather and avoid direct exposure to cold temperatures, including cold water (pools and showers).4

Treatments, Preventive Therapies
New treatments and preventive therapies offer promise for improving the lives of patients with SCD. Hydroxyurea, a chemotherapeutic agent, is reported to be beneficial in treating SCD. Hydroxyurea stimulates the production of protective HbF, reduces the number of neutrophils, monocytes and reticulocytes, and raises the total hemoglobin concentration slightly.5 In adults, a 50 percent decrease in pain episodes, transfusions and hospitalizations has been reported.24 Studies in children have shown benefit and short-term safety but long-term safety has not been established yet. T.G.'s physicians are considering using hydroxyurea in her treatment in the future.

Bone marrow transplantation, full or partial, is a treatment that holds the promise of cure. Currently, the lack of human leukocyte antigen (HLA) matched donors and the risk of morbidity and mortality associated with transplants are obstacles. Because of problems in predicting which patient will express severe disease, choosing an appropriate candidate to transplant is difficult. The use of umbilical cord blood as the source of progenitor cells may increase the number of HLA acceptable matches and improve the odds for finding a suitable donor. As transplant protocols continue to improve, so do the chances for this therapy to become a standard therapy for SCD cure.

There are new therapies appearing on the horizon. Nitric oxide has been used in the treatment of painful crisis because when inhaled, it causes smooth muscle in blood vessel walls to relax and allows the vessel to dilate, improving blood flow.25,26 A drug, CPC-111 (Cypros Pharmaceutical Corp.) is reported to reduce red cell sickling and will also be used to treat SCD pain crisis. RheothRx (purified poloxamer 188, CytRx Corp.) is an intravascular agent with anti-adhesive/antithrombotic properties, approved for the treatment of acute myocardial infarction. It's expected to be used in the treatment of vaso-occlusive events because through its action, blood cells "slip over" one another, improving blood flow and restoring O2 delivery.27 Clotrimazole, an oral antifungal that blocks the loss of K+ from red cells, prevents the increase in HbS concentration and reduces sickling. ACE inhibitors may prevent renal disease by reducing proteinuria.28,29 Finally, researchers at Duke University Medical Center, Raleigh, NC, have reported on a new type of gene therapy to correct the HbS defect in human blood cells.

Marilyn Slavin Blumenstein directs the therapeutic and stem cell apheresis programs for the Penn-Jersey Region of the American Red Cross, Philadelphia. Robert Blumenstein is dean of the graduate programs and chairman of the natural sciences department, DeSales University, Center Valley, PA.

Table 1: Normal Hemoglobins After Age 6 Months
Two alpha and two beta chains Two alpha and two delta chains Two alpha and two
gamma chains
95-98 2-3 < 1

Table 2: Factors Influencing the Rate of Hemoglobin Polymerization and Sickling
High % HbS

Oxygen tension < 40 mm Hg

Low temperatures (vasoconstriction); increased temperature (fever)

Increase in red cell HbS concentration (MCHC)

Dehydration (promotes vascular stasis & increases concentration of HbS)

Low pH

Table 3: Clinical Severity and Hemoglobin Patterns of HbSS and HBSß0-thalassemia4
HbA Normal None 0 <2 <3.5 12-16 <2 80-95
HbSS Sickle cell anemia Marked >90 <10 <3.5 6-11 5-20 >80
HbSß0 Sickle cell-ß0-thalassemia Marked to Moderate >80 <20 >3.5 6-10 5-20 <80


Sickle Cell Disease: Pathogenesis, Diagnosis & Interventions

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