Epidemic hemolytic-uremic
syndrome related to bleomycin
Santiago Albiol, Juan J Grau, Antonio Pereira, Noemi Reguart,
Pere Gascon
Institut de Malalties Hemato-Oncologiques (IMHO). Hospital Clinic
of Barcelona, Spain.
Correspondence: Santiago Albiol, MD, Medical Oncology Depart.
IMHO. Hospital Clinic. Villarroel 170-03036. Barcelona. Spain
E-mail: salbiol@teleline.es
Hemolytic-uremic syndrome (HUS) has been described as a rare
complication of cancer chemotherapy. This chemotherapy-related HUS
is mainly associated with mitomycin C but has also been described
with several other antineoplastic agents, particularly cisplatin
and bleomycin-containing combinations.1 Between April,
1995 and January, 1996, seven consecutive patients with squamous
carcinoma (6 cases with head and neck cancer and 1 case with
esophageal cancer) developed HUS after treatment with cisplatin
120 mg/m2 iv, day 1, and bleomycin 20
mg/m2/day iv, the days 1 to 5 in continous perfusion.
The first four patients also received mitomycin C 10
mg/m2 iv, day 1. Mitomycin was suppressed but three
more patients developed HUS. All seven patients had a normal serum
creatinine level, hematocrit, and platelet count before initiation
of chemotherapy. Six patients received two courses of
chemotherapy. One patient developed HUS in the first course. The
diagnosis of this syndrome was based on the findings of
microangiophatic hemolytic anemia, thrombocytopenia and renal
insufficiency. In addition to the development of anemia and
thrombocytopenia, a microangiophatic blood smear with
schistocytosis, elevation in serum lactate dehydrogenase,
reduction in serum haptoglobin and elevation in serum creatinine
was seen in all 7 patients. There was no laboratory evidence of
disseminated intravascular coagulation in any of the patients. The
clinical characteristics of seven patients are shown in
Table
1. The median time from
the beginning of therapy to the onset of HUS was 8.3 days (range 4
to 16 days). No patients experienced Raynaud's phenomena.
Digestive bleeding was seen in two patients. Severe dyspnea and
hypoxemia with bilateral interstitial infiltrates on x-ray
examination occurred in six patients All patients were treated
with steroids. In six patients plasmapheresis were performed and
four patients required supportive hemodialysis. Only one patient
improved in platelet count and anemia after plasmapheresis, but no
change in renal function was observed. All 7 patients died for
HUS-related complications. Intercurring infections were ruled out
and no patients received immunosuppresants. Although disseminated
adenocarcinoma has been associated with HUS, rarely occurs in
squamous carcinoma. Chemotherapy-related HUS has also been
described with the use of cisplatin and bleomycin combination
regimens. Several findings suggest that the bleomycin was probably
the responsible factor of HUS in our patients, specially the
epidemiological finding. From 1996 to 1999, bleomycin was changed
by 5-fluorouracil (5-FU). In this period, 50 patients received
treatment with 87 courses of cisplatin and 5-FU; no other patient
developed HUS. In our cases, it can not be completely excluded
that the effects of the cisplatin and bleomycin combination,
rather than bleomycin alone, were responsible for the development
of HUS. Bleomycin is not a pure product, it is a combination of
glicoproteins isolated of Streptomyces verticillus cultures.
Activity and toxicity are different for each fraction, but if risk
of microangiophatic toxicity is increased for changes in one or
several fractions, it is unknown. Although, no differences in
bleomycin composition were informed from the analysis of the batch
performed by the pharmaceutical company, a little variability in
bleomycin composition into therapeutically range may be possible.
The pathogenesis of chemotherapy-related HUS has not been
determined. Recently, stimulated blood monocytes and
polymorphonuclear granulocytes (PMN) have been involved in some
microangiopathic syndromes by interacting and activating both
vascular endothelium and platelets.2 Cisplatin
stimulates blood phagocytes, increasing their procoagulant
activity and their interaction with platelets, whereas bleomycin
can induce intracellular oxidation in alveolar macrophages, which
seem to be the first step in the lung fibrosis related to this
drug.3 We have studied the ability of bleomycin and
cisplatin to stimulate the oxidative burst in PMN and monocytes
obtained from healthy donors by luminol- and lucigenin-enhaced
chemyluminiscence.4 Two sources of bleomycin were
analyzed, one from the bath currently in use and another from a
previous batch that was not associated with microangiophatic
toxicity. Bleomycin and cisplatin, tested either individually or
simultaneously, failed to stimulate the oxidative burst of PMN and
monocytes. Addition of bleomycin or cisplatin after previous cell
stimulation with formyl-peptide (fMLP) or opsonized zymosan did no
increase the production of reactive-oxigen species over that seen
with fMLP or zymosan alone. No difference was seen between both
batchs of bleomycin. These findings suggest that, in our case, the
activation of PMN and monocytes by bleomycin and/or cisplatin was
not incriminated in the microangiophatic toxiticy of these
chemotherapeutics agents. There is evidence that bleomycin may
directly damage the vascular endothelial cell and the equilibrium
between the synthesis and metabolism of endothelial products that
control clot formation o degradation may be altered.1
On the other hand, chemotherapy may stimulate intravascular
platelet aggregation perhaps resulting from a decrease in
prostacyclin synthesis.1 The role that any of these
factors play in the pathogenesis of HUS in our patients remains to
be determined. Further investigation into the pathogenesis and
therapy of HUS after de use of bleomycin and cisplatin-containing
combination regimens is indicated.
