We summarize here a case involving a fatal sickle cell crisis in a patient with previously very mild hemoglobin sickle cell (Hb SC) disease. With granulocyte colony-stimulating factor (G-CSF) priming for peripheral stem cell collection, a crisis developed, followed by death within 36 hours. The case strongly suggests a role for granulocytes in acute sickle cell complications and a need for cautious use of G-CSF in this disease.
The patient was a 47-year-old African American woman who 6 weeks earlier learned that she had Hb SC disease. She had no history of sickle cell crises, although she occasionally had some joint pains that always resolved within a few hours after 1 or 2 doses of aspirin. She had pneumonia as a child, but no history of strokes, lower extremity ulcerations, gallstones, splenic infarctions, hypersplenism, bone infarcts, hip necrosis, blood transfusions, or ophthalmologic problems.
Hb SC disease was diagnosed after a hemoglobinopathy evaluation at the time of HLA typing, done in preparation for her to become a stem cell donor for her sister, who had chronic myeloid leukemia (CML) and mild Hb SC disease. The patient was the only sibling and had a 6 of 6 antigen match. After transplantation committee and ad hoc member reviews and careful discussions with donor and recipient, the patient proceeded with treatment to donate stem cells. She started daily G-CSF injections (400 μg/M2) and dexamethasone (10 mg/M2, starting on day 3) and noted some aches and pains in her back, legs, and shoulders. But on the fourth day of treatment, she awoke with the worst pain of her life, primarily affecting her lower back and thighs. She had no associated fevers, chills, dyspnea, cough, nausea, vomiting, diarrhea, or neurologic symptoms.
The admission physical exam revealed a well-developed and well-nourished woman writhing in pain. The vital signs included a temperature of 37.0°C (98.6°F), a pulse rate of 85, a respiratory rate of 24, and blood pressure of 138/94. The eyes had no scleral icterus. Results of the lung and heart exams were normal. The abdomen was nondistended with normal bowel sounds and flexed muscles but no obvious guarding or tenderness. No masses were noted. Lumbar and sacral spine regions, posterior pelvis, and both femurs were markedly tender. The skin and neurologic exams were normal. Table1 shows the remarkable admission studies: the white blood cell (WBC) count differential had 72% segmented neutrophils, 21% band forms, 2% metamyelocytes, 2% lymphocytes, and 3% monocytes.
Intravenous hydration, scheduled morphine, and a single dose of ketorolac achieved good pain control. The next morning, the patient felt much improved and easily sat in a chair with only mild back pain remaining. But laboratory evaluation showed evidence of multiorgan injury and profound anemia (see “Hospital day 2” in Table 1). Packed red blood cell transfusions were given. Reevaluation of the abdomen showed the development of massive splenomegaly. The oxygen saturation dropped (95%), with a respiratory rate of 20. The patient received platelet transfusions followed by leukophoresis for both stem cell collection and the potential benefit of leukoreduction. The patient had a marked worsening of her respiratory status and arrested. Although the patient was revived, disseminated intravascular coagulation (DIC) developed and adequate oxygenation became impossible over the next several hours. She arrested a second time and ultimately expired. A postmortem bone marrow stem cell collection was performed to complete the harvest and achieve an adequate number of CD34 cells for transplantation to her sister the next day. The patient's sister has no evidence of CML 12 months after transplantation.
Microbiology cultures and parvovirus studies remained negative. The autopsy showed an enlarged spleen (weight, 1200 g) with infarctions and lacerations and a 1000 mL hemoperitoneum. The lungs were congested (weight, 1540 g), having vascular engorgement by red blood cells and neutrophil infiltrates. The liver had acute centrilobular congestion. No fat emboli were present.
Two other publications describe sickle cell disease complications after growth factor administration. One reports a vaso-occlusive pain crisis hours after topical administration of GM-CSF on a leg ulcer,1 and another, the development of acute chest syndrome following administration of G-CSF before peripheral stem cell collection in a patient with homozygous sickle hemoglobin (hemoglobin SS) disease and a history of multiple sickle cell complications.2 The latter case shares many similarities with the one presented here. But because the current case involves a patient with no prior history of sickle cell complications, it even more strongly implicates a role for the G-CSF and/or elevated WBC count in precipitating sickle cell complications.
Steady-state elevations of the WBC count have been linked with a worse clinical course.3 But few data exist regarding the relationship between acute leukocytosis and a sickle cell crisis, even though granulocytes may play an active role in vaso-occlusion.4 In part, the difficulty in determining the significance reflects the complexity of a sickle cell crisis that may include a concurrent infection and frequent increases in multiple cytokines that can affect inflammation.5,6 In contrast to the usual clinical situation, these 2 reports involving G-CSF administration present simpler backgrounds upon which to evaluate the effect of the WBC count. In both cases, complications occurred with the development of marked WBC count elevations a few days after initiating the cytokine treatment in clinically well individuals. These cases suggest that an acute elevation in the polymorphonuclear leukocyte count can promote acute sickle cell complications. Alternatively or additionally, G-CSF–induced changes in granulocyte function, such as increased adhesiveness, might have played a major pathogenic role in the above cases since leukocyte adhesion appears to contribute to the pathophysiology of sickle cell vaso-occlusion.7 Thus, in the absence of infection, dehydration, or other clinically important conditions, a large number of adherent polymorphonuclear leukocytes might have precipitated the fatal vaso-occlusive event described above.
The present case supports the concept that granulocytes play, or can play, an important role in acute complications of sickle cell disease. The importance of granulocyte number, versus functional characteristics, remains unknown, but understanding the role of granulocytes in acute sickle cell events might provide insights for new therapeutic intervention in this disease. Pending a better understanding of the pathophysiology of vaso-occlusion, patients with sickle cell disease should receive G-CSF with great caution.
