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Blood, 15 June 2001, Vol. 97, No. 12, pp. 3998-3999
CORRESPONDENCE
To the editor:
Granulocyte colony-stimulating factor-induced sickle
cell crisis and multiorgan dysfunction in a patient with compound
heterozygous sickle cell/ + thalassemia
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/ + 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
+ 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 al2
reported 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- , 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.
Andrew Wei and Andrew Grigg
Correspondence: Andrew P. Grigg, Department of Haematology,
Royal Melbourne Hospital, Grattan Street, Victoria, 3050, Australia
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