GENERAL PRINCIPLES
Sickle cell disease (SCD) is a term for a group of genetic disorders characterized by the presence of at least one sickle gene and the predominance of hemoglobin (Hgb) S. Examples of SCD include sickle cell anemia (homozygous Hgb SS), sickle beta-thalassemia syndromes (Hgb S-beta+ or S-beta0), and Hgb SC disease.1 There is tremendous variability in clinical severity among disease groups and among individual patients with the same Hgb abnormalities. In the United States, these disorders are most commonly observed in African Americans and Hispanics from the Caribbean, Central America, and parts of South America and less commonly in Mediterranean, Indian, and Middle Eastern populations. In African Americans, the incidence of Hgb SS is 1:350 and that of Hgb SC is 1:835. The two hallmark pathophysiologic features of sickle cell disorders are chronic hemolytic anemia and vaso-occlusion, resulting in ischemic tissue injury.
Pathophysiology
· Normal Hgb is a tetramer consisting of two alpha and two beta chains. Hgb S results from the substitution of valine for glutamic acid at the sixth amino acid of the beta-globin gene. The change in the molecular structure of Hgb S results in the polymerization of the Hgb tetramers leading to the sickled shape of the RBC and increased whole-blood viscosity.
· Factors that contribute to Hgb S polymerization include decreased pH, RBC dehydration, and, most importantly, decreased O2 tension. The poor deformability of the RBC containing Hgb S results in occlusion of the microvasculature and ischemic tissue injury.
· It is now appreciated that pro-inflammatory interactions among the sickled cell, the vascular endothelium, and circulating leukocytes and reticulocytes contribute to vaso-occlusion. Sickled RBCs adhere to and activate vascular endothelium, causing further up-regulation of endothelial adhesion molecules and recruitment and activation of WBCs. Adherent WBCs and sickled RBCs form aggregates in the microvasculature, impede blood flow, and lead to continued hypoxia. Abnormal vasomotor tone favoring vasoconstriction also contributes to vaso-occlusion. Organs prone to venous stasis such as spleen and bone marrow are susceptible to frequent vaso-occlusion and infarction.
DIAGNOSIS
Clinical Presentation
The hallmarks of SCD are anemia due to decreased RBC lifespan and chronic hemolysis, and vaso-occlusion leading to acute and chronic complications secondary to end-organ dysfunction.2 The major causes of morbidity are acute vaso-occlusive pain crises, anemia, and infections. The clinical manifestations of SCD vary tremendously both within and among the major genotypes. Even within genotypes regarded as being the most severe for patients with SCD, some patients are entirely asymptomatic, whereas others are disabled by recurrent pain and chronic complications. SCD is associated with a shortened life expectancy due to multisystem failure from acute and chronic vaso-occlusion. One autopsy series3 reported causes of death in sickle cell patients, in decreasing order of frequency, as infection, stroke, therapy complications, splenic sequestration, pulmonary emboli/thrombi, renal failure, pulmonary hypertension, hepatic failure, red cell aplasia, and left ventricular dysfunction. Of note, death was sudden in 40% of the cases. In 1973, the mean survival was only 14.3 years. Currently, the life expectancy is 42 years for men and 48 years for women with sickle cell anemia. Risk factors for mortality in SCD are frequent pain crises, acute chest syndrome (ACS), and renal and pulmonary disease.
Sickle cell trait
Sickle cell trait (Hgb AS) has a prevalence of ~8% to 10% in African Americans. Sickle cell trait is a benign carrier condition with no hematologic manifestations. Red cell morphology, red cell indices, and the reticulocyte count are normal. Patients with sickle cell trait have a normal life expectancy. Clinical complications of sickle cell trait have been reported, most typically splenic infarction occurring at high altitudes; hematuria; increased frequency of urinary tract infection, especially in pregnancy; and a mild defect in ability to concentrate urine. Sickle cell trait is also associated with a 30-fold increased incidence of sudden death during basic training of African American military recruits, apparently related to exercise-induced vaso-occlusion and rhabdomyolysis. Risk factors include exertion under extreme conditions, and the risk of sudden death can be reduced with measures to prevent exertional heat illness. Sickle cell trait is not a contraindication to competitive sports and screening prior to participation is not required. In individuals who appear to have sickle cell trait but are symptomatic, the lab diagnosis must be verified. Hemoglobins other than S that polymerize may account for reports of “sickle cell trait” associated with clinical problems, and these patients should be further evaluated.
Hemoglobin SC disease
Hgb SC disease is approximately one-fourth as frequent among African Americans as Hgb SS. Although deoxygenated Hgb C forms crystals, Hgb C does not participate in polymerization with deoxy–Hgb S. This results in a disease that is less severe than homozygous Hgb SS disease, and the degree of anemia and leukocytosis is frequently mild. Splenomegaly may be the only physical finding, and clinical complications may be less frequent than in sickle cell anemia. The lifespan of Hgb SC and Hgb SS red cells is 27 and 17 days, respectively. The predominant red cell abnormality on the peripheral smear is an abundance of target cells and crystal-containing cells. The frequency of acute painful episodes is approximately one-half that of sickle cell anemia, and the life expectancy is two decades longer. However, there is a higher incidence of peripheral retinopathy in Hgb SC disease than Hgb SS disease. These patients may present with splenic sequestration and infarct in adulthood.
Diagnostic Testing
· Neonatal screening resulting in timely definitive diagnosis and appropriate comprehensive care has been shown to reduce the morbidity and mortality of SCD in early childhood. Forty-four states and the District of Columbia provide universal screening for newborns, and screening upon request is provided in the other six states. When a screening test indicates SCD, a definitive diagnosis is established through further blood testing. SCD is identified through lab testing alone. There are no findings on physical exam that suggest the presence or absence of Hgb S.
· The peripheral smear is normal in sickle cell trait (Hgb AS), but sickle cells are seen in each of the major SCD syndromes. Solubility testing is abnormal in all syndromes having at least one sickle cell gene and thus detects all carriers of the Hgb S gene, as well as those with the SS phenotype.
· Hgb electrophoresis is able to provide the clinician with the exact phenotype of SCD. Typical electrophoretic profiles are listed in Table 11-1.
TREATMENT4
Chronic Management
· Many patients can live for long periods without experiencing acute or severe exacerbations of SCD. Increased awareness of the disease and its long-term complications is contributing to the prolonged survival seen in sickle cell patients today.
· All patients with SCD should have routine office appointments to establish baseline physical findings, lab data, and a relationship between the patient and the treating physician. Patients with Hgb SS should have regular medical evaluations every 3 to 6 months, depending on the symptoms or manifestations of the disease.
· Preventive care should be initiated and maintained. A vaccination history should also be maintained. Adults should have seasonal influenza vaccines. If the patient has never received the pneumococcal vaccination, it should be offered and given at intervals based on the recommendations of the American Association of Family Physicians. Daily folic acid (1 mg PO daily) is given for the prevention of folate deficiency in the chronic hemolytic state. Retinal evaluation by an ophthalmologist is begun at school age and should be continued to monitor for evidence of retinopathy. Patients with relative hypertension are at increased risk for stroke and should be monitored and treated. Patients should be counseled during routine clinic visits about red flags for which they should seek further medical attention (Table 11-2).
· Hydroxyurea is a cytotoxic drug that has been shown to decrease the frequency of acute pain crisis, ACS, hospital admissions, and blood transfusions and to decrease mortality in adults with Hgb SS. It is generally indicated in patients with more severe manifestations of SCD. The mechanism by which hydroxyurea influences sickle cells and vaso-occlusion is likely multifactorial, including increases in Hgb F synthesis, improved red cell deformability, modulation of sickle cell adherence properties, increased nitric oxide production, and effects on WBCs. Hydroxyurea causes a decrease in the reticulocyte, platelet, and WBC counts. The dose is titrated to achieve clinical effect with minimal toxicity. However, not all patients respond to hydroxyurea. Of note, hydroxyurea has been shown to be teratogenic in mice, and should be avoided in pregnancy. Hydroxyurea has the potential to be carcinogenic, but the exact risk is unknown.
SPECIAL CONSIDERATIONS
Surgery and Anesthesia
Surgery and anesthesia are stress states that can provoke a painful sickle crisis. Currently, it is recommended that patients with SCD undergo simple transfusion to an Hgb of 10 mg/dL before elective surgery. Studies comparing aggressive transfusion (Hgb S levels <30%) versus conservative transfusion (Hgb S <60%, Hgb = 10 mg/dL) showed no benefit of the more aggressive regimen.5 Intraoperative overexpansion of blood volume should be avoided, particularly in patients with decreased cardiac function. Hypothermia must also be avoided in the OR to prevent sickling. After surgery, IV fluid management must ensure adequate hydration, with the avoidance of volume overload and pulmonary complications. Incentive spirometry should also be employed.
Dental Procedures
Procedures requiring local anesthesia can be performed in the dentist’s office. However, any dental procedure requiring general anesthesia warrants hospital admission.
Transfusion Therapy6
· Transfusion of RBCs has been used for almost every complication of SCD, although clinical trials have not been performed supporting efficacy for each complication. Indications for transfusion include the need to improve O2-carrying capacity (as in aplastic crisis or ACS), increase blood volume (as in splenic sequestration), or improve blood rheology (to prevent stroke recurrence, prior to surgery). Simple transfusion can be sufficient to improve O2-carrying capacity and blood volume and is generally indicated in aplastic crisis, acute splenic and hepatic sequestration, milder cases of ACS, and prior to surgery. Partial exchange transfusion has the advantage of decreasing the percentage of Hgb S without increasing the blood volume or causing hyperviscosity. It is generally recommended for acute indications such as ACS, acute ischemic stroke, retinal artery occlusion, and multiple organ failure and may be recommended for chronic transfusion programs, in which avoiding hyperviscosity and iron overload is important.
· Indications for chronic transfusion, which may be either simple or exchange, are primary stroke prevention for at-risk children and secondary stroke prevention in children; of note, many clinicians apply the same principles to adults with stroke. Patients with pulmonary hypertension and recurrent ACS may also benefit from chronic transfusion. The goal of transfusion is to raise the Hgb to a level of ~10 g/dL. Levels >10 g/dL can lead to hyperviscosity and increased vaso-occlusion. Transfusion is not indicated for compensated anemia, uncomplicated acute painful crises, uncomplicated pregnancy, avascular necrosis, infection, or minor surgery without anesthesia. Transfusion is controversial for priapism and leg ulcers.
· Transfusion complications in sickle cell patients are common and include the following:
o Alloimmunization in transfused sickle cell patients is due in part to minor blood-group incompatibilities (Rh, Kell, Duffy, and Kidd antigens) resulting from antigenic discrepancy in the donor (mostly Caucasian) and recipient (mostly African American) pool. Five to fifty percent of SCD patients who have received multiple transfusions develop alloimmunization, which is a risk for delayed hemolytic reactions and can make obtaining compatible blood difficult.
o Hyperviscosity syndrome is characterized by a posttransfusion elevation in blood pressure and congestive heart failure, mental status change, or stroke. Treatment is exchange transfusion.
o Iron overload and its complications of end-organ damage become a problem in those patients who are chronically transfused. Chelation is recommended when the total-body iron level is elevated, as measured by serum ferritin levels or, more reliably, serial liver biopsy. Chelation therapy with deferoxamine (Desferal), which requires subcutaneous overnight infusion, is an extremely time-consuming and inconvenient therapy for the patient, in addition to being very expensive. This is one of the motivating factors for a reduction in the number of transfusions and the use of exchange transfusion in patients with SCD. Oral iron chelators, such as deferasirox (Exjade), are now available, although not all patients can afford or tolerate this drug. Patients with iron overload on chelation therapy are at increased risk for infection with Yersinia enterocolitica.
COMPLICATIONS
Hematologic Complications
Acute exacerbations of anemia in the patient with SCD are a significant cause of morbidity and mortality. The most common causes of these exacerbations are splenic sequestrations and aplastic crises.
· Acute splenic sequestration of blood is characterized by an exacerbation of anemia, increased reticulocytosis, and a tender, enlarging spleen. Acute sequestration can progress to hypovolemic shock and death. It is associated with a 15% mortality rate, accounted for 6.6% of deaths in one autopsy series, and is common in children with SCD-SS. Patients susceptible to splenic sequestration are those whose spleens have not undergone fibrosis (i.e., young patients with sickle cell anemia and adults with Hgb SC disease or S-beta+ thalassemia). Treatment is simple transfusion to restore blood volume and red cell mass. Transfusion can lead to release of sequestered cells, and overtransfusion and resulting hyperviscosity should be avoided. Because splenic sequestration recurs in 50% of cases, splenectomy is recommended after the event has abated. Acute sequestration can also occur in the liver.
· Aplastic crises are transient arrests of erythropoiesis characterized by abrupt falls in Hgb levels and decreased reticulocytosis. Given the decreased lifespan of RBC in SCD, aplastic crises place patients at risk for severe anemia that is frequently symptomatic. Parvovirus B19 accounts for the majority of aplastic crises in children with SCD, but the high incidence of protective antibodies in adults makes parvovirus a less frequent cause of aplasia. Intravenous immune globulin can be used to treat parvovirus infection. Other infections have been reported to cause transient aplasia. Aplastic crisis can also be the result of bone marrow necrosis, which is characterized by fever, bone pain, reticulocytopenia, and a leukoerythroblastic response. The mainstay of treating aplastic crises is simple transfusion to correct severe anemia. SCD patients in the peri-infection period are at increased risk for complications, including pain crisis, ACS, and stroke. A useful guideline for transfusion is the reticulocyte count. In parvovirus B19 infection, reticulocytopenia lasts 7 to 10 days. A patient having an exacerbation of a chronic anemia with an elevated absolute reticulocyte count is less likely to require urgent transfusion than one with a normal or low absolute reticulocyte count.
· Hyperhemolytic crisis is the sudden exacerbation of anemia with increased reticulocytosis and elevated bilirubin level. The usual therapy for a hyperhemolytic crisis is simple transfusion. Most of these patients recover within 14 days. The diagnosis of a delayed hemolytic transfusion reaction should be considered in any patient receiving a recent blood transfusion.
· Subacute anemia: The gradual onset of worsening anemia may be due to developing renal insufficiency or folic acid deficiency. Chronic hemolysis results in increased use of folic acid stores and can lead to megaloblastic crises if nutritional supplementation is not used.
Acute Painful Crisis
· Acute pain is the first symptom of disease in >25% of patients. The acute painful episode is the most frequent reason for which patients with SCD seek medical attention. There is tremendous variability of painful episodes within genotypes and within the same patient over time. In one large study of patients with sickle cell anemia, one-third rarely had pain, one-third were hospitalized for pain approximately two to six times per year, and one-third had more than six hospitalizations per year. More frequent pain crises are associated with higher mortality rates. Pain episodes may be precipitated by temperature extremes, dehydration, infection, hypoxia, acidosis, stress, menses, and alcohol consumption. In addition, patients may cite that anxiety, depression, or physical exhaustion may be precipitants. In many instances, no precipitating factors can be identified. The painful episodes can occur in any area of the body, most commonly the back, chest, extremities, and abdomen. In ~50% of painful episodes, patients will present with objective clinical signs such as fever, joint swelling, tenderness, tachypnea, hypertension, nausea, and vomiting. There is no clinical or lab finding that is pathognomonic for painful crisis.
· In general, the management of acute painful crises includes the identification and treatment of possible precipitating factors, IV fluid hydration, and analgesics. When a patient presents complaining of pain, the physician is charged with ruling out etiologies other than vaso-occlusion. Acute painful episodes generally last 4 to 6 days but may vary in intensity and duration. The possibility that the pain is precipitated by a concurrent medical condition, such as an infection, should be considered, and the physician should search for a precipitating illness in every instance.
· Providing aggressive relief of pain often requires the use of parenteral narcotics. Patients will often be aware of the medications and dosages that have provided adequate relief in the past, and they are often undertreated for pain. Of note, patients with SCD do not respond to conventional doses of analgesia. They typically are on chronic oral narcotics and may have developed a tolerance to conventional doses of narcotics. Patient-controlled anesthesia (PCA) pumps are effective in the treatment of an acute painful crisis. Appropriate conversion between chronic PO medications and IV doses of narcotics must be used to ensure adequate and prompt pain relief. In cases in which there is no nausea or vomiting, patients are continued on the PO regimen prescribed for continuous relief at home, and PCA-demand-only doses can be added. Demerol may be used occasionally but should be avoided if possible. Patients should be monitored frequently and objective pain scores followed closely for titration of effective analgesia.
· Painful events are not commonly associated with changes in the patient’s Hgb levels, and transfusions are not indicated for simple acute painful crises. Hydroxyurea reduces the frequency of painful crises.
Infections
Infections are a leading cause of morbidity and mortality in SCD patients. Outcomes for children improved with the use of prophylactic penicillin to prevent Streptococcal pneumoniae sepsis. Although adults are less susceptible, all patients should receive the pneumonia vaccinations. Adults with Hgb SS disease are functionally asplenic and fever should be worked up aggressively with the appropriate cultures, imaging studies, and consideration of prompt antibiotic coverage. Patients with other geno-types are also at risk for infection, although they are not always functionally asplenic. Sources of fever include sepsis, meningitis, ACS, osteomyelitis, and urinary tract infection. In meningitis, empiric coverage should include Streptococcus pneumoniae and Haemophilus infl uenzae. Coverage for acute chest syndrome and osteomyelitis are discussed below.
Neurologic Complications
· Neurologic complications are common in patients with SCD, including transient ischemic attacks, cerebral infarction, cerebral hemorrhage, seizures, spinal cord infarction or compression, CNS infections, vestibular dysfunction, and sensory hearing loss. The risk for cerebral infarction, including clinical and silent infarctions, is as high as 30%. The highest stroke rates occur in children, and the risk of stroke by age 20 is 11%. Ischemic strokes7 are more common in children and those >30 years old, whereas hemorrhagic stroke is more common at between 20 and 30 years of age.
· Risk factors for strokes include severe anemia, low reticulocyte counts, low Hgb F levels, high WBC counts, the Hgb SS genotype, ACS within the previous 2 weeks, and systolic hypertension.
· Strokes are fatal in ~20% of initial cases, and 70% of patients will have a recurrence within 3 years. Patients with symptoms and signs of an acute stroke should be evaluated immediately. In those with hemorrhage, initial management depends on the site and amount of bleeding. In children with infarcts, prompt partial exchange transfusion is performed to reduce Hgb S to <30%.
· Chronic exchange transfusion therapy to maintain Hgb S levels below 30% has been shown to prevent recurrent thrombosis. At this time, it is unclear how long chronic transfusion should be maintained. Prophylactic transfusions to reduce Hgb S to <30% in children with abnormal transcranial Doppler velocity measurements in cerebral blood vessels have been shown to reduce the risk of first clinical stroke. Unfortunately, there are few systematic data on primary prevention of stroke in adults with SCD. It is unclear whether acute ischemic stroke in adults should be treated with immediate exchange transfusion as it is in children, or whether it should be approached as it is in adults without SCD (i.e., recombinant tissue plasminogen activator, aspirin, etc.) The role of chronic transfusion for secondary prevention in adults is unclear.
Pulmonary Complications
· One of the most feared acute pulmonary complications in SCD is acute chest syndrome.8,9 ACS is defined as a new infiltrate on chest x-ray (CXR) and one or more of the following: fever, cough, chest pain, dyspnea, tachypnea, and hypoxemia. Of note, the initial CXR may be negative. The definitive etiology of ACS is not known but infection, vaso-occlusion and infarct, fat embolism from necrotic marrow or a combination of these factors have been implicated. It has been reported to occur in 29% of patients with SCD and can progress to respiratory failure and death. ACS is the second most frequent cause of hospitalization and the most frequent complication of surgery in SCD. It should be noted, however, that nearly 50% of cases occur during hospitalization for other causes.
· Risk factors include prior episodes of ACS, Hgb SS, leukocytosis, hospitalization for acute pain crisis, and high-baseline Hgb concentrations.
· Atypical and typical bacterial pathogens and viruses, especially respiratory syncytial virus (RSV), have been found in patients with ACS. Antibiotics are indicated as initial therapy, preferably a cephalosporin and a macrolide or fluoroquinolone.
· Hypoxemia should be corrected by supplemental oxygen.
· Analgesics and incentive spirometry to correct splinting from chest pain should be initiated. Bronchodilators should be considered.
· Either simple or exchange transfusion should be considered promptly if there is a change in oxygen status from baseline. Simple transfusion can be used if there is a need for increased O2-carrying capacity such as mild hypoxemia or worsened anemia. Severe hypoxemia, clinical deterioration, or impending respiratory failure should lead to urgent consideration of exchange transfusion.
· Care in an intensive care unit and ventilator support may be required. ACS has a mortality rate of ~10%. Chronic therapy with hydroxyurea can reduce the frequency of episodes.
· Chronic pulmonary disease is an important cause of morbidity and mortality in patients with SCD. SCD patients may have restrictive and obstructive lung diseases, pulmonary fibrosis, and pulmonary hypertension. Pulmonary disease is more common in those with a history of ACS. Pulmonary hyper-tension occurs in up to 32% of SCD patients and carries a poor prognosis, even with mean pulmonary pressure elevations in the mild to moderate range.10 The etiology of pulmonary hypertension in SCD is unknown, although chronic intravascular hemolysis, which impairs normal vasodilation through its effects on the nitric oxide pathway, may contribute. Diagnosis is made with cardiac catheterization or echocardiogram-Doppler study. Patients presenting with exertional dyspnea and findings of right heart failure should be evaluated promptly. There are few data on the efficacy of different treatment modalities, and maximizing supportive care, treating comorbid conditions, and employing medications used in other patient populations with pulmonary hypertension may be of benefit. These patients may be considered for hydroxyurea, pulmonary vasodilators, anticoagulation, and home O2 therapy.
Hepatobiliary Complications
· The prevalence of pigmented gallstones in SCD is directly related to the rate of hemolysis. In sickle cell anemia, gallstones occur in children as young as 3 to 4 years and are eventually found in ~70% of patients. Patients presenting with fever, nausea, vomiting, and right upper quadrant pain should be evaluated for acute cholecystitis. Cholecystectomy should be considered even for asymptomatic gallstones.
· Hepatomegaly and liver dysfunction in SCD can be caused by multiple etiologies, including intrahepatic blood sequestration, transfusion-acquired hepatitis, transfusion-related iron overload, and very rarely autoimmune liver disease. Hepatic sequestration is characterized by a rapidly enlarging liver, decreased hematocrit, and rising reticulocyte count. Diagnosis is difficult, as CT and ultrasound show only a diffusely enlarged liver, liver function tests may be normal to moderately elevated, and the liver is variably tender. Both simple and exchange transfusions have been used to treat hepatic sequestration. As in splenic sequestration, care must be taken not to over-transfuse.
· Benign cholestasis of SCD results in severe, asymptomatic hyperbilirubinemia without fever, pain, leukocytosis, or hepatic failure. Progressive cholestasis with right upper quadrant pain, marked elevations in bilirubin and alkaline phosphatase, and progression to liver failure have been reported. These patients are treated with exchange transfusion and supportive care. Another serious complication is the hepatic crisis, in which hepatic ischemia results in fever, right upper quadrant pain, leukocytosis, severe hyperbilirubinemia, and abnormal liver function tests. It may progress to fulminant liver failure, which has a dismal prognosis. Because of the nearly uniform mortality of this type of hepatic crisis, exchange transfusion, plasmapheresis, and liver transplantation have been used as therapy, but no controlled data are available to support this approach.
Obstetric and Gynecologic Complications
· Delayed menarche, dysmenorrhea, ovarian cysts, pelvic infection, and fibrocystic disease of the breast are more common in women with SCD. However, the major reproductive concern in these patients is pregnancy. The improvement in fetal and maternal outcomes is largely due to improved prenatal and high-risk obstetric care. The incidence of spontaneous abortion, intrauterine growth retardation, pre-eclampsia, placental abruption, low birth weight, and intrauterine fetal death are higher in women with SCD.
· Maternal complications during pregnancy include increased rates of acute painful episodes, severe anemia, infections, and even death. The course of pregnancy is more benign in Hgb SC disease.
· Therapeutic interventions for painful crises in pregnant women should be identical to those in nonpregnant women, with IV hydration, attention to complications, and adequate pain control. Opiates can affect fetal movement and heart rate but are not teratogenic. Transfusions are generally reserved for patients with worsening anemia (Hgb <6 g/dL) and in anticipation of surgery. Hydroxyurea has been shown to be teratogenic in animals and should be stopped in pregnancy. There is a very high incidence of acute painful episodes associated with therapeutic abortions. Inpatient IV hydration immediately before the procedure and for the 24 hours after the procedure is recommended. Oral contraceptives containing low-dose estrogen are a safe, recommended method of birth control in women with SCD.
Renal Complications
· The kidney is particularly vulnerable to complications of SCD with manifestations that result from medullary, distal and proximal tubular, and glomerular abnormalities leading to the inability to concentrate the urine. Papillary infarction with hematuria, renal tubular acidosis, and abnormal potassium metabolism occur more commonly in patients with SCD or sickle cell trait. Patients with hematuria should be evaluated with ultrasound.
· Patients with SCD cannot excrete acid and potassium normally but usually do not develop systemic acidosis or hyperkalemia without an additional acid load, such as in the setting of renal insufficiency. Chronic renal insufficiency may be predicted by albuminuria and should be suspected in the setting of hypertension and worsening anemia.
· Risk factors for the development of chronic renal failure include hypertension and the use of anti-inflammatory drugs. The average age at onset of chronic renal failure is 23 years in sickle cell anemia and 50 years in Hgb SC disease.
· The use of ACE inhibitors was found to diminish proteinuria and pathological glomerular changes; it is unclear whether their use slows the progression of sickle nephropathy. Renal transplantation is recommended for patients with end-stage renal failure.
Priapism11
· Priapism affects 29% to 42% of males with SCD. It peaks in frequency at 1 to 5 and at 13 to 21 years of age. Priapism is most likely to develop in patients with lower Hgb F levels and reticulocyte counts, increased platelet counts, and the Hgb SS genotype.
· First-line therapy is conservative, including increasing PO fluid intake and anal-gesia. If the episode persists for 3 hours, the patient should seek medical care. IV fluids, parenteral narcotics, and a Foley catheter to promote bladder emptying are the initial treatments for acute priapism. If the episode lasts 4 to 6 hours, penile aspiration and irrigation as well as intracavernous injection of an alpha-adrenergic agonist by a urologist should be performed. Partial exchange transfusion can be considered, although efficacy has not been proved in randomized controlled trials and it can be associated with complications in this setting.
· ASPEN syndrome (association of SCD, priapism, exchange transfusion, and neurologic events), which involves headache, mental status change, neurologic deficits, and stroke, has been described in SCD patients with priapism undergoing exchange transfusion. It is important that initiation of transfusion does not delay more definitive treatment.
· If detumescence does not occur with nonsurgical management, a spongiosum–cavernosum or cavernosaphenous vein shunt may be recommended.
· Despite interventions, impotence remains a frequent complication of priapism. There is a paucity of clinical trials for the secondary prevention of priapism, although chronic transfusion according to stroke protocol, hydroxyurea, and vasoactive agents such as pseudoephedrine are used at some centers.
Ocular Complications
· Anterior chamber ischemia, retinal artery occlusion, and proliferative retinopathy with the risk of subsequent hemorrhage and retinal detachment can lead to vision loss in SCD. Sickle retinopathy is found most frequently between 15 and 30 years of age. Although found in all SCD, it is most frequent in Hgb SC.
· All patients who sustain eye trauma must be evaluated by an ophthalmologist urgently because they are at increased risk of visual loss. Patients should undergo a yearly retinal exam performed by an ophthalmologist. Sickle cell retinopathy may require vision-improving therapy with laser photocoagulation.
Bone Complications
· Bone and joint problems are a common cause of both acute and chronic pain in SCD. Erythroid hyperplasia secondary to chronic hemolytic anemia leads to widening of the medullary space and thinning of the trabeculae and cortices. This results in bony distortion, especially in the skull, vertebrae, and long bones. Vaso-occlusion and subsequent bone and marrow infarct are common, especially in the spine, ribs, and long bones.
· Dactylitis, painful swelling of the hands and feet, is caused by microinfarcts of the phalanges and metatarsals and usually occurs in early childhood.
· Osteonecrosis occurs in all SCD phenotypes but most frequently in sickle cell anemia with coexistent alpha thalassemia. Osteonecrosis occurs in both the femoral and the humeral heads, as well as in the vertebral bodies. The femoral heads more commonly undergo GS progressive destruction as a result of chronic weightbearing. MRI is the most accurate imaging study to diagnose avascular necrosis of the femoral head. Core decompression surgery to relieve increased intraosseous pressure can be used in early-stage osteonecrosis. A patient with more advanced disease is a candidate for total hip arthroplasty. This decision must take into account the likelihood that a second hip revision may be required and that there are more complications and a relatively high failure rate in patients with SCD compared to other patient populations. Vertebral infarction also occurs and leads to chronic back pain.
· Osteomyelitis must be differentiated from the more common bone infarction, because the two syndromes present with similar clinical and imaging findings but are treated very differently. Staphylococcus and salmonella are common pathogens for osteomyelitis in sickle cell patients. Increasing antibiotic resistance to salmonella is a major problem in SCD. Septic arthritis must also be distinguished from the more common joint effusion associated with acute painful episodes. Bone biopsy and culture are the most reliable tests to establish the diagnosis before starting long-term antibiotics.
Dermatologic Complications
Skin ulcers are major causes of morbidity in SCD. Ulcers occur commonly near the medial or lateral malleolus and are frequently bilateral. About 2.5% of patients age 10 and older develop leg ulcers. Ulcers may begin spontaneously or as a result of trauma. They are commonly infected with Staphylococcus aureus, Pseudomonas, streptococci, or Bacteroides species. Males have a threefold greater risk of developing leg ulcers. Therapy with gentle débridement, wet-to-dry dressings, and compression bandages is typically effective. Compression stockings may be used to prevent recurrence.
Cardiac Complications
An important cardiac consideration in the management of patients with SCD is the high cardiac output related to chronic anemia. Chronic high cardiac output can result in four-chamber enlargement and cardiomegaly. Age-dependent loss of cardiac reserve can lead to a greater risk of heart failure in adult patients during fluid overload, transfusion, or other reduced O2-carrying capacity states. Acute myocardial infarction in the absence of coronary disease has been reported but is rare.
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