Colony-stimulating factors, in particular granulocyte colony-stimulating factor (G-CSF), are widely used for the amelioration of chemotherapy-induced neutropenia. There is a paucity of data regarding the safety of G-CSF in patients with sickle cell anemia. This is relevant, as neutrophil activation may be involved in the pathogenesis of sickle crises. Here we report a patient with sickle cell/β+ thalassemia who developed a sickle cell crisis and life-threatening multiorgan failure in close temporal relationship to administration of G-CSF.
A 58-year-old Greek female with stage II invasive ductal breast carcinoma underwent bilateral mastectomies and was scheduled to commence adjuvant chemotherapy with 150 mg cyclophosphamide orally alternating with 200 mg orally daily for a total of 14 days, 70 mg methotrexate intravenously on days 1 and 8, and 1050 mg 5-fluorouracil intravenously on days 1 and 8 (CMF). The cycle was to be repeated each 28 days. The patient's history included several episodes of lower back pain requiring narcotic analgesia in the preceding 2 years. Prior to starting chemotherapy, she had a normal hemoglobin (120 g/L; normal range, 115-150 g/L), microcytosis (mean corpuscular volume, 71 fL; range, 80-96 fL), and mild thrombocytopenia (platelets, 137 × 109/L; range, 140-400 × 109/L). An abdominal ultrasound revealed a bulky spleen. Liver function tests were normal. The serum ferritin level was 16 μg/L (range, 20-120 μg/L). Hemoglobin electrophoresis revealed an abnormal band migrating as Hb S amounting to 57% of the total hemoglobin. The solubility test for Hb S was positive. DNA testing revealed compound heterozygosity of Hb S with a β+ mutation involving intron 1, position 6. The only sibling, a sister, had an Hb S level of 36%, consistent with sickle cell trait. There were no other surviving first-degree relatives. The first chemotherapy cycle was administered without G-CSF and proceeded uneventfully except for mild chemotherapy-induced neutropenia (neutrophil nadir of 1.1 × 109/L on day 17). On day 9 of the second cycle, subcutaneous injections each morning of 480 μg r-metHuG-CSF (filgrastim, Neupogen, Amgen, Australia) were commenced. On the night after the fourth dose, the patient complained of severe lower back pain, along with dyspnea and drowsiness. Pain and respiratory distress worsened significantly following the next morning's dose, resulting in admission to the hospital. Severe hypoxia (arterial oxygen saturation, 70%), unresponsive to supplemental oxygen therapy, required endotracheal intubation and mechanical ventilation. A chest x-ray showed bilateral pulmonary infiltrates. A ventilation/perfusion lung scan demonstrated low probability for pulmonary embolism. Full blood examination revealed marked anemia: hemoglobin, 54 g/L; white cell count, 6.4 × 109/L; and platelets, 95 × 109/L. Blood film revealed a mild increase in the number of sickle cells compared to the prechemotherapy film. Anisopoikilocytosis, myeloid left shift, and toxic change were consistent with G-CSF. Blood cultures were repeatedly negative. There was widespread organ dysfunction with evidence of myocardial ischemia: troponin I level 28.9 μg/L (range, < 0.4 μ/L) and creatine kinase 333 IU/L (range, 20-160 IU/L); renal impairment: creatinine 0.22 mM (range, 0.05-0.09 mM); and abnormal liver function tests: alkaline phosphatase 880 IU/L (range, 0-120 IU/L), bilirubin 33 μmM (range, 0-19 μmM), and alanine transferase 92 IU/L (range, < 55 IU/L). The prothrombin time was 13.9 seconds (range, 8.3-9.9 seconds). The patient had a fluctuating conscious state with no focal neurological signs, consistent with encephalopathy. Bone marrow biopsy revealed extensive marrow necrosis and thrombosed, congested vessels consistent with infarction. Ventilatory support continued for a week. Fourteen units of packed red blood cells were transfused over the next 6 weeks with Hb S levels maintained between 4% and 10%. Neutropenia (< 1.0 × 109/L) persisted for 4 weeks after presentation, and the thrombocytopenia (< 50 × 109/L) persisted for 8 weeks. Organ dysfunction resolved within 2 weeks of admission, although recovery was delayed because of Candida glabrata septicemia, which responded to amphotericin B. Encephalopathy gradually resolved, and cerebral magnetic resonance imaging 3 weeks after admission revealed no gross structural abnormalities. The patient was discharged 8 weeks after admission.
The clinical presentation in this case was typical of acute multiorgan failure syndrome, a well-recognized complication of sickle cell anemia.1 It is characterized by hypoxia, pulmonary infiltrates, hepatic transaminitis, hyperbilirubinemia, renal impairment, and an elevated prothrombin time, and it may be accompanied by fever, encephalopathy, rhabdomyolysis, and a rapid fall in hemoglobin concentration and platelet count. Patients characteristically have an uneventful previous history and, notably, a relatively high baseline hemoglobin concentration.
Our patient, previously asymptomatic with respect to sickling (other than back pain of uncertain etiology), developed this syndrome concomitant with the introduction of G-CSF. Abboud et al2reported a patient with sickle cell anemia who developed acute chest syndrome and marked leukocytosis after receiving G-CSF to mobilize hemopoietic progenitor stem cells. Our patient did not have leukocytosis on presentation due to recent chemotherapy. Kang et al,3 however, safely administered G-CSF to patients with sickle cell trait (Hb S levels usually 35%-40%) to mobilize stem cells, suggesting the possibility of a threshold Hb S level that predisposes patients to developing G-CSF–induced sickle cell complications.
The pathophysiology of sickle cell crisis is complex and incompletely understood. Neutrophils are likely to be an important factor in causing microvascular sickle cell trapping and consequent vaso-occlusion. Studies show that patients with sickle cell anemia and elevated white cell counts are at greater risk for mortality and stroke.4,5 Lowering the white cell count with hydroxyurea may be beneficial in reducing the incidence of vaso-occlusive complications.6 Infection or systemic inflammation causing leukocytosis and enhanced neutrophil activation often precedes a sickle cell crisis and may be the critical process precipitating a vaso-occlusive episode.
Recent research has shed light on the pathophysiological process involved. Inflammation is characterized by an increase in circulating cytokines such as interleukin-1 and tumor necrosis factor-α, which increase endothelial expression of E-selectin. These molecules tether rolling neutrophils by binding to granulocyte Lewis x sialyated carbohydrate (CD15). This allows neutrophil integrins such as complement receptor 3 (CD11b) to adhere to the endothelium via interaction with its ligand intercellular adhesion molecule-1.7 The importance of CD64 (Fc-gamma receptor I) as a marker of endothelial adherence in patients with sickle cell disease and its notable increase during sickle cell crisis has been demonstrated. CD11b and CD64 expression on neutrophils is enhanced by G-CSF,8,9 providing further insight into mechanisms whereby G-CSF can enhance the trapping of neutrophils in the microcirculation, resulting in vascular occlusion, increased red cell transit time, and sickle cell polymer formation. In addition, sickle cells appear to be more adherent to neutrophils than to normal red cells.10 Sickle cells also increase neutrophil oxidative activity, which may be important in neutrophil-induced tissue damage during vaso-occlusive episodes.
G-CSF, both by increasing the number of circulating neutrophils and enhancing neutrophil activation and endothelial attachment, may serve to transform a relatively stable steady state into a catastrophic cascade of events resulting in a sickle cell crisis and, in severe cases, multiorgan dysfunction. G-CSF should be given with extreme caution in patients with sickle cell disease. Further study is required to delineate the critical Hb S level that predisposes patients to developing G-CSF–induced sickle cell complications.
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