Patients with homozygous sickle cell disease as well as those with Hb S/β-thalassemia and Hb SC disease have a variety of clinical problems, outlined in Table 9-2. Among the constitutional manifestations are delayed growth and development. In addition, sickle cell patients are at increased risk of developing serious infections, due to pneumococcus as well as a broad range of other bacterial pathogens. Repeated splenic infarctions lead to loss of organ function and therefore defective clearance of circulating bacteria. Occasionally infarcts in the spleen or other sites of vaso-occlusion become infected, leading to abscess formation.
TABLE 9-2Clinical Manifestations of Sickle Cell Disease
Hb SS homozygotes have severe hemolytic anemia with hemoglobin values between 6 and 9 g/dL and elevated reticulocyte counts. The mean red cell lifespan is 10 to 15 days. As a result of accelerated red cell destruction, sickle cell patients have laboratory test findings characteristic of hemolysis, as described in Chapter 3. Patients with Hb S/β+-thalassemia and Hb SC disease have less severe hemolysis. In Hb SS patients, infection will suppress erythropoiesis and cause a fall in hemoglobin level (Table 9-2). In particular, parvovirus B19 has a tropism for erythroid progenitors and therefore can trigger a drop in the hemoglobin levels of sickle cell patients to extremely low levels.
The morbidity and mortality of sickle cell disease are due primarily to recurrent vaso-occlusive phenomena. As outlined in Table 9-2, these can be divided into microinfarctions, which manifest as acute, episodic attacks of pain, and macroinfarctions, which cause progressive and usually irreversible damage to a wide range of organs.
Throughout their lives, most sickle cell patients are plagued with recurrent attacks of acute pain caused by vaso-occlusion. These episodes account for most of the hospital admissions of sickle cell patients. Pain crises are sporadic and highly unpredictable. Usually, they appear suddenly and are localized to a limited area, particularly the abdomen, chest, back, or joints. As mentioned earlier and in Table 9-2, pain crises are often preceded by a viral or bacterial infection. Most patients are able to distinguish sickle cell pain from pain due to some other type of acute process such as biliary colic, a perforated viscus, or abscess.
The acute chest syndrome, a pulmonary vaso-occlusive crisis, is the most common cause of death in both children and adults with Hb SS disease. The diagnosis is based on the combination of acute chest pain, pulmonary infiltrate(s) and arterial hypoxemia. Because it is often difficult to distinguish between pulmonary vaso-occlusion and pneumonia, all patients should be treated with antibiotic therapy. If there is rapid expansion in the size of the infiltrate(s) or deterioration of pulmonary function, progressive vaso-occlusion is likely, and prompt intervention is necessary. As shown in Figure 9-9, replacing at least half of the patient's Hb SS red cells with normal (Hb AA) red cells (so-called exchange transfusion) can result in surprisingly rapid clinical improvement and resolution of pulmonary infiltrates. In some patients, acute chest syndrome is triggered by fat emboli shed into the circulation from infarcted bone marrow, a common site of painful vaso-occlusion.
Acute chest syndrome. A) The chest radiograph on the left is from an acutely ill, hypoxemic patient with pulmonary infiltrates, most prominent in the right lower lobe. B) Forty-eight hours after treatment with exchange transfusion, the infiltrates have cleared.
Over time, most sickle cell patients sustain damage to various organs due to the cumulative effect of recurrent vaso-occlusive episodes.
Roughly one-fourth of sickle cell patients develop a central neurologic complication at some point in their lifetimes. Noninvasive studies in children have revealed a surprising and sobering frequency of abnormalities of cerebral blood flow that are associated with subclinical impairment of cognition along with increased risk of vaso-occlusive stroke. As patients get older, hemorrhagic strokes may occur. A rigorous and sustained program of red cell transfusions has proven effective in preventing strokes during childhood. It is not known yet whether hydroxyurea therapy (discussed later in the prevention Sickling section) will be as effective.
Sickle cell patients commonly have impairment of pulmonary function. Resting arterial PO2 is usually low, in part because of intrapulmonary arterial-venous shunting. Repetitive bouts of acute chest syndrome, described earlier, and chronic hypoxemia can lead to pulmonary hypertension and occasionally to cor pulmonale. In addition, many sickle cell patients have left ventricular dilatation and decompensation, probably due to a combination of chronic anemia, hypoxia, and iron overload.
Like other patients with chronic hemolytic anemia, those with sickle cell disease are very likely to develop gallstones. Nearly all Hb SS patients and many with Hb S/β-thalassemia and Hb SC disease have abnormal liver function, owing to a combination of hepatic vaso-occlusion, hepatitis transmitted via blood transfusions, and iron overload.
The hypertonic milieu of the renal medulla dehydrates red cells and increases the intracellular hemoglobin concentration, thereby promoting sickling. Therefore, all individuals with Hb S, even Hb AS heterozygotes, develop hyposthenuria (the inability to concentrate urine) and some have episodes of painless hematuria. Hyposthenuria has little deleterious effect on its own, but makes patients (and thus their red cells) prone to dehydration, which can increase the risk for vaso-occlusion. In addition, Hb SS patients develop progressive impairment of glomerular function. As they survive into the fifth and sixth decades of life, renal failure becomes an important contributor to morbidity and mortality. Males with sickle cell disease occasionally develop episodes of priapism, acute painful engorgement of the penis, due to vaso-occlusion in the sinuses of the corpus cavernosum.
Vaso-occlusion within a bony matrix leads to aseptic necrosis, particularly of the hips and shoulders, and may cause sufficient disability to require joint replacement. Figure 9-10 shows the characteristic deformity of the lumbar spine due to vaso-occlusion in the interior of the vertebral body.
A deformity of the lumbar vertebrae in a patient with sickle cell disease. Lateral radiographic view showing biconcave or "fish mouth" vertebrae. The collapse of the inner part of the vertebral body occurs because the corners are well-perfused with blood vessels, whereas the inner portion is at the mercy of a single blood vessel.
Many sickle cell patients are plagued by chronic ulceration of the skin overlying the ankle bones (Fig. 9-11). These lesions probably arise from a combination of minor trauma, local infection, and circulatory compromise by vaso-occlusion. These ulcers are often extremely refractory to treatment.
Ankle ulcers in patients with sickle cell disease.
Sickle cell disease is the leading cause of monocular blindness among people of African ancestry. The retina can be damaged by a variety of events including arterial occlusion, hemorrhage, and proliferation of blood vessels in response to ischemia. Figure 9-12 shows the retina of a patient who sustained a localized hemorrhage, the resolution of which led to the accumulation of hemosiderin-laden macrophages. Proliferative retinopathy is the most commonly encountered ocular complication, surprisingly affecting patients with Hb SC disease and Hb S/β+-thalassemia about twice as often as those with Hb SS and Hb S/β0-thalassemia.
Sickle cell retinopathy. The "black sunburst" is essentially an accumulation of hemoglobin-laden macrophages in the aftermath of a retinal hemorrhage.