A Sickle Cell Primer

Sickle cell anemia is a prototypical single gene deletion disorder familiar to medical students everywhere. Most physicians recall that it is a devastating disorder that starts with a single substitution of valine for glutamic acid in the beta-globin gene of the hemoglobin molecule, rendering the hemoglobin molecule unstable in its de-oxygenated state. This leads to polymerization of hemoglobin molecules within the red cell, deformation of the cell membrane, and sickling. Sickling, in turn, causes blood vessel damage, vaso-occlusion, and various other physiologic effects, which lead to both micro- and macro-vascular protean complications.1

Despite extensive basic research in sickle cell disease (SCD), clinical research into the optimal management of this complex disease has lagged behind. Many adult hospitalists may be unfamiliar with the care of adult SCD patients because most of these patients are cared for in academic centers by hematologists.

In this article we review the common complications of sickle cell anemia in adult patients, the management of associated conditions, and the evidence base for treatment guidelines.

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Overview

Sickle cell anemia is not just one disorder, but is, rather, a collection of related disorders involving mutations of the hemoglobin molecule. (These disorders are categorized in Table 1, p. 40) In the United States, SCD primarily affects black Americans, with about 9% of this population having sickle trait.2 One in 600 black Americans has sickle cell anemia, also known as hemoglobin SS disease, and there are an estimated 72,000 patients with SCD in the United States.2

In the early 1970s, the average life expectancy for patients with SCD was estimated to be 14.3 years.3 At that time, more than half of SCD patients died before age five, primarily from infectious complications such as pneumococcal sepsis. Twenty years later, the Cooperative Study of SCD documented a much better life expectancy: an average of 42 for males and 48 for females with homozygous S disease (the set of patients with two copies of the defective hemoglobin S mutation).

On average, patients with hemoglobin SCD routinely survive into their 60s. Many factors, including earlier diagnosis of SCD through universal screening programs, better vaccines and vaccination rates, prophylactic antibiotics in infancy and young childhood, and aggressive treatment of fever in infants, as well as other advances in care, have contributed to this progress. A longer life expectancy in this population has heralded the extension of common complications into adulthood, however, along with the emergence of other adult-specific complications of SCD. (See Table 2, p. 40.) In order to best treat adults with SCD, hospitalists should be aware of these complications, as well as of the advances that have been achieved.

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Extension of Pediatric Complications

Perhaps the most common manifestation of SCD in children and adults is the painful crisis. This manifests in infants as a painful swelling in the digits of the hands and feet known as dactylitis. In older children and adults, pain occurs more often in the long bones of the arms and legs and in the sternum, vertebrae, and pelvic bones. Risk factors for painful crises include higher hematocrit values and higher sickle fractions, typically greater than 30%.4 Frequent painful crises are a marker of disease severity and an independent risk factor for death in SCD.

Hospitalists who regularly admit SCD patients are familiar with a subset of “frequent flyers” who experience recurrent painful crises. Remember that this is a small fraction of the total SCD population. In fact, 40% of SCD patients don’t suffer any painful crises requiring medical attention in a given year, and only 1% face more than six such events.5 Pain management in SCD is perhaps beyond the scope of this article, and there are no widely accepted guidelines. A few expert reviews are available for guidance, however.6,7

Treatment Options for Painful Crises

The most beneficial new treatment for painful crisis in the past two decades has been the use of hydroxyurea. After early studies showed promise, a phase III clinical trial in adults with SCD who suffered frequent painful crises (i.e., more than four per year) and who were given doses of up to 35 mg/kg/day of hydroxyurea showed a dramatic decrease in painful episodes. These patients also endured fewer episodes of acute chest syndrome, with a relative risk of 0.44, and experienced a reduced need for transfusions, with a relative risk of 0.64. This trial was stopped early (at 21 months average follow-up) due to the striking findings.8 Subsequent longer-term trials have not shown any of the feared theoretical complications of hydroxyurea, including cytopenias (when the production of one or more blood cell types ceases or is greatly reduced) or secondary malignancies.9 (See Table 3, p. 40.)

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Childhood Complications

Some SCD complications are more prominent or more severe in early childhood than in adulthood. Two examples of this phenomenon are infectious complications and splenic sequestration. Pediatricians and parents of children with SCD live in fear of febrile illness because overwhelming infections such as pneumococcal sepsis remain the primary reason for death in children with SCD. This was especially true before Hemophilus influenza type b (Hib) and pneumococcal conjugate vaccines were introduced and before penicillin prophylaxis from birth through age five became universal.

Though functionally asplenic, adult patients are at a relatively low risk for overwhelming infections because their immune systems have matured enough to allow type-specific antibody production to polysaccharide antigens.7 Still, adults with SCD should be aggressively evaluated for infectious etiology of any febrile illness and routinely administered empiric antibiotics to cover strep species.

Splenic sequestration occurs when sickled cells are caught up in the spleen; this causes massive hemolysis, splenic enlargement, and cardiovascular compromise, and it is most common in SCD patients younger than five. Thankfully, this is rare in adults with SS and SB0Thal; however, the notable exception to this rule is in patients with hemoglobin SC disease or SB+Thal, where complete splenic infarction does not routinely occur.

Acute chest syndrome (ACS) is perhaps the most feared complication in both children and adults with SCD—and with good reason. It is the second most common cause for hospital admission in SCD patients, and it is an independent risk factor for death in SCD.7,10 Occurring more often in children, ACS is typically more severe in adults, in whom ACS can progress rapidly to an acute respiratory distress syndrome (ARDS)-like picture, with mortality reaching 5%-9%.11

ACS involves a classic triad of fever, chest pain, and new pulmonary infiltrates on chest X-ray, but patients are invariably hypoxic and dyspneic as well. The etiology of ACS varies. In one series, 54% of patients had an identified infectious pathogen, most commonly chlamydia or mycoplasma. Bronchoalveolar lavage (BAL) showed lipid-laden macrophages in about 16%, suggesting fat embolism after bony infarcts. The remainder of patients were presumed to have primary pulmonary infarctions.11 The treatment of ACS involves broad-spectrum antibiotics, especially atypical coverage, along with transfusion (simple versus exchange), supplemental oxygen, pain control, and judicious use of IV fluids.

The second most feared complication in SCD is stroke, which can be devastating in both children and young adults. Eleven percent of patients younger than 20 have ischemic strokes, with a risk of stroke that is 200 times higher than that of age-matched peers.9,12 The peak incidence of ischemic stroke occurs before 10 and after 30. These patients are also susceptible to hemorrhagic strokes, the incidence of which peaks in the third decade, for reasons that are unclear.13

Management of acute ischemic stroke in patients with SCD is similar to that used with general patients: antiplatelet therapy, careful attention to normo-glycemia and normovolemia, and maintenance of cerebral perfusion pressure. In addition, SCD patients should receive emergent transfusion to reduce the sickle fraction to less than 30%. Patients with prior transient ischemic attack (TIA) or stroke should be on a chronic monthly transfusion regimen. Also, based on the results of the 1997 STOP I trial (Stroke Prevention Trial in Sickle Cell Anemia), children with SCD should be screened with transcranial Doppler for high velocity flow (>200 cm/second) in the internal jugular and vertebral arteries.14 Children with high velocity flow who were treated with preventative transfusion regimens had a 90% absolute risk reduction in the incidence of first stroke.

In 2001-2006, a follow-up trial (STOP 2) revealed that among patients receiving at least 30 months of chronic transfusion to prevent a first stroke 39% of those randomized to discontinue transfusion had a reversion to high risk Doppler or suffered a stroke within an average of 4.5 months. This has led many to believe that prophylactic transfusion should be a lifelong treatment.15

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Complications Seen Primarily in Adults

As the SCD population in this country has grown older, some previously uncommon complications have become more prominent. One predominantly adult complication of SCD is avascular necrosis of the femoral and humeral heads. Though clearly recognized in younger children in whom the incidence is estimated at about 3%, the major burden of femoral osteonecrosis is seen in adults older than 35, in whom prevalence reaches 50%.16 Necrosis of the humeral head can affect nearly 20% of SCD adults as well.17

It is important to recognize this complication as a new or different type of pain, separate from the vaso-occlusive pain usually experienced by SCD patients because it benefits from different therapies. Diagnosis by plain radiography is possible in the late stages, when evidence of remodeling, cystic changes, and sclerosis can be seen, but MRI has become the gold standard, with an estimated diagnostic accuracy of 90%.16 Conservative treatments include NSAIDs and steroid joint injections, but many afflicted patients may need orthopedic referral for joint replacement.

While acute chest syndrome remains a primary cause of mortality in SCD, adults with SCD are also at high risk for the chronic effects of pulmonary arterial hypertension (PAH). Thought to be uncommon in children, PAH affects up to one-third of adult SCD patients.18 Suspicion of this condition can be based on worsened fatigue, new resting hypoxemia, or increased painful crises, but experts advocate universal screening using transthoracic echocardiography. Patients with a tricuspid regurgitant jet velocity of 2.5 m/sec meet diagnostic criteria, and it is notable that the relative risk of death is 7.4 compared with SCD patients without PAH. This correlates with only moderate elevation of pulmonary pressures, suggesting that SCD patients tolerate PAH less well than other populations. Treatment options advocated include hydroxyurea, chronic transfusions, oxygen, pulmonary vasodilators such as prostacyclin and bosentan, and phosphodiesterase inhibitors such as sildenafil.

As SCD patients age, kidney disease is seen with increasing frequency, and three primary mechanisms are recognized. First, ischemic damage in the tubules causes tubular necrosis, which leads to hematuria.19 This condition can range from microscopic to severe gross hematuria, threatening urinary obstruction. Second, damage in the collecting duct impairs the body’s ability to concentrate urine, a condition that is called hyposthenuria. This condition makes SCD patients susceptible to dehydration, especially during physical exertion or in hot weather.

Interestingly, these first two mechanisms of kidney damage are also seen in patients with sickle cell trait. Finally, and most importantly, medullary interstitial fibrosis damages the glomerulus. Clinically, this is the most important mechanism because it leads to nephritic syndrome and chronic kidney disease as well as end-stage renal disease (ESRD).19

Priapism is the persistent, painful erection of the penis in post-pubertal SCD males not associated with sexual desire or relieved by orgasm; this condition is typically defined as lasting more than four to six hours.20 It is particularly common in younger males, with a yearly incidence of 6%-27%; the incidence of priapism in adults approaches 42%. In addition to being extremely painful, prolonged or repeated episodes can lead to impotence. Unfortunately, there are few well-studied treatment options; expert opinion suggests supportive care, including IV fluids, oxygen, ice, elevation, narcotic pain control, and even red cell transfusion in selected cases. Medications used include oral terbutaline, pseudoephedrine, and even stilboestrol, as well as injected phenylephrine, epinephrine, methylene blue, and tenecteplase (TNK-tPA). Surgical procedures attempted have included dorsal penile nerve block, cavernous aspiration, and the Winter procedure, which involves creating a vascular shunt from the corpora cavernosa to the glans penis. Urology consultation is often required for severe cases.

Several forms of eye disease occur in SCD patients. They can be broadly grouped into non-proliferative and proliferative diseases. In the former group, ocular trauma should be recognized as a visual emergency because patients are at risk for developing hyphema, occlusion of the trabeculae in the anterior chamber, and acute glaucoma. SCD patients of all ages are also at risk for acute retinal artery occlusion. Older SCD patients are at greatest risk, however, for a proliferative retinopathy similar to that seen in diabetes.21

Though red blood cell transfusions are helpful in many SCD patients, repeated transfusions can result in infections, immunologic consequences, and iron overload. (See Table 4, p. 41.) Infections that may result include parvovirus B19, HIV, human T-lymphotropic viruses (HTLV) I and II, and viral hepatitides. Immunologic consequences include alloimmunization, which occurs in up to 50% of SCD patients, and potentially fatal acute hemolytic reactions.22 Finally, patients who require frequent transfusions develop iron overload, which in turn causes fatigue, cardiomyopathy, diabetes mellitus, and cirrhosis. This necessitates iron chelators such as deferoxamine, which are disappointingly difficult to administer, requiring either IV or subcutaneous infusion over 12-24 hours daily. One bright note is the recent approval of deferasirox, an iron chelator that is taken orally once daily.

Conclusion

SCD is a complex genetic disease that affects multiple organs. Advances in medical care have increased longevity for SCD patients, and there are currently more adults living with the disease than ever before. Though patients often receive their care in academic centers, hospitalists may encounter them in routine practice. It is useful to have an understanding of the complications of SCD commonly seen in adults and to review the evidence base for care. TH

References

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