¹Department of Hematology, Yinzhou People's Hospital, Ningbo, China. E-mail: peirz@163.com

PBSC are now widely used as a source of progenitor cells for allogeneic transplantation. Recombinant human G-CSF (rhG-CSF) is used to mobilize PBSC for collection by leukapheresis. Although side effects of mobilization are generally benign, adverse effects have been reported. We present a case of intracranial hemorrhage caused by cerebrovascular malformation in a sibling donor undergoing PBSC mobilization.

A healthy 42-year-old Chinese male patient was selected as a hematopoietic stem cell donor for his brother. The donor passed a medical history check, physical examination and laboratory testing that met National Marrow Donor Program criteria. Informed consent was obtained for the donation process. He had only suffered from hypertension for 6 years and he maintained his blood pressure at 140/80 mm Hg by taking 5 mg oral amlodipine besylate tablets once a day. Treatment with the amlodipine besylate tablets was not interrupted. The donor received rhG-CSF (filgrastim) 6 g/kg/day given s.c. for 5 consecutive days. Anticoagulation with acid-citrate-dextrose was used during the two apheresis procedures in which 7.03 10⁶/kg of CD34⁺ progenitor cells were collected on the fourth and fifth day. The transplantation was successful in his brother. The blood pressure was monitored every hour during and after the two apheresis procedures and it remained stable, at around 134–146/78–85 mm Hg. Routine blood coagulation tests and electrolytes were monitored before and after the apheresis procedures and they were normal. The number of WBC reached 45.4 10⁹/l, hemoglobin 132 g/l and platelet count 185 10⁹/l before the two apheresis procedures. The platelet count dropped to 119 10⁹/l 5 days post apheresis. On the evening of the fifth day, the donor developed a headache, which was intermittent and of mild intensity, accompanied by nausea and vomiting. The blood pressure was 134/84 mm Hg. Five hours later, head computerized tomography scanning was performed and showed a half-moon high-density shadow indicating the existence of a subdural hematoma at the left temporal lobe. The symptoms were increasing in intensity and the donor gradually became unconscious. The second head computerized tomography scan was performed after 16 h of symptomatic treatment and it revealed that the subdural hematoma was gradually enlarging (Figure 1). The donor was operated on the following day. A ruptured blood vessel and active bleeding was discovered during the operation subdural to the left temporal lobe. The histopathologic diagnosis after the operation was consistent with vascular malformation and subdural hemorrhage at the left temporal lobe (Figure 2). The donor recovered well after the operation and has been attending follow-up checks for 2 years. So far, he has not experienced sensory disability or limb dyskinesia and only a little allolalia.

Figure 1.

The second head computerized tomography scanning showing the enlarged subdural hematoma.

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Figure 2.

The histopathologic diagnosis after operation showing vascular malformation and subdural hemorrhage.

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The number of allogeneic transplantations of rhG-CSF-mobilized PBSC is increasing. Although PBSC donation is a reasonably safe procedure, adverse events do occur. The symptoms reported in most PBSC donors are related to hematopoietic growth factors, usually rhG-CSF. According to the survey results from 1080 PBSC donors reported by National Marrow Donor Program,¹ bone pain was the most common cytokine-associated symptom. Headache was also common. Pain was usually manageable with non-narcotic analgesics. Other symptoms such as nausea, vomiting, myalgia, fatigue, insomnia and injection site reactions were often observed. The apheresis procedure was also a source of adverse events. Anticoagulation with acid-citrate-dextrose solution may elicit symptoms of hypocalcemia—perioral numbness, paresthesias and carpopedal spasms—requiring oral or i.v. calcium supplementation. Important hematologic changes were also expected to occur with growth factors and the apheresis procedure. WBC, in particular neutrophils, increased dramatically. At daily filgrastim doses of 10 g/kg or greater, the total WBC count may reach 70–80 10⁹/l. Although clinically significant, leukostasis was not reported and it was generally recommended that the filgrastim dose can be reduced if the count exceeds 70–75 10⁹/l. Concomitant with leukocytosis, platelet counts decline although usually the reduction is modest. Thrombocytopenia was the most significant finding post-apheresis. The platelets did not begin to recover until 3–4 days after the last collection. Some serious complications had been reported, but serious hemorrhage secondary to thrombocytopenia had not been reported. Filgrastim administration may precipitate severe sickle crisis in persons with sickle cell anemia or complex sickle cell hemoglobinopathies.² Spontaneous splenic rupture was reported in three normal hematopoietic PBSC donors.³

Cerebral arteriovenous malformations (AVMs) are congenital anomalies that consist of abnormal arteries and veins without an intervening capillary bed. A large autopsy series has shown the incidence of AVMs to be between 0.04 and 0.52%.⁴ Although the majority of AVMs were discovered after an intracerebral hemorrhage, others were diagnosed in patients with seizures, headaches and progressive neurologic deficits. Natural history studies of untreated AVMs have demonstrated an overall 2–4% annual rate of hemorrhage, with approximately 3% of combined annual morbidity and mortality. Risk factors believed to predispose AVM patients to hemorrhage include a history of a prior bleeding, small AVM size, deep venous drainage and higher feeding artery pressures. The relative importance of these factors is unknown. To our knowledge, our patient represents the first case of cerebrovascular malformation hemorrhage in a previously healthy donor undergoing an rhG-CSF-mobilized PBSC collection. Our patient had a high WBC count, which could lead to leukostasis. Subsequently, the leukostasis produced a high venous pressure, which could be a risk factor that precipitated the bleeding of AVMs. While the blood coagulation action was normal, anticoagulation with acid-citrate-dextrose and thrombocytopenia may be the two causes of bleeding.

Most donors go through the stem cell collection process without any serious side effects, but potentially severe outcomes must be kept in mind, and donors should be warned. Death occurring in PBSC donors has been reported in only three cases. The three deaths after peripheral blood donation were from sickle crisis, stroke and cardiac arrest. Given the relatively limited experience with allogeneic peripheral blood donations, the risk of death cannot currently be estimated. It is essential that donors should be assessed to detect conditions that might increase the risk of donation to unacceptable levels. All donors must be carefully evaluated and fully informed before hematopoietic stem cell donation by clinicians with good understanding of the potential physical and psychological complications and factors that may increase the risks. It is necessary to understand the most common and the most serious potential adverse events.