Key-words:
Cerebral infarction - cisplatin - vascular toxicity - von Willebrand factor
Introduction
Chemotherapy-associated cerebral infarction, such as that induced by cisplatin, is
rare and poorly understood.[[1]],[[2]],[[3]] Despite its reputation as an effective chemotherapeutic drug, cisplatin has been
shown to induce vascular toxicity and be associated with cerebral infarction;[[4]],[[5]] however, its mechanism of action remains unknown. Here, we describe a case presenting
with cisplatin-associated cerebral infarction.
Case Report
A 59-year-old male was diagnosed with stage III carcinoma of the external auditory
canal, with no apparent brain metastases. The patient had no previous medical history
of atrial fibrillation, ischemic heart disease, or stroke. After cancer was removed,
the patient was treated with cisplatin to prevent cancer recurrence. Seven days after
cisplatin administration, he suddenly presented with a disturbance of consciousness.
Head magnetic resonance imaging showed basilar artery occlusion, which was associated
with chemotherapy administration [[Figure 1]]a. Once diagnosed, an endovascular stent retrieval thrombectomy was performed [[Figure 1]]b and [[Figure 1]]c. The patient recovered consciousness after thrombectomy, although there were some
ischemic lesions visible on diffusion-weighted images [[Figure 1]]d. The patient then began taking a direct oral anticoagulant to prevent thrombosis.
Serum von Willebrand factor (vWf) activity increased during the occurrence of cerebral
infarction. This vWf activity gradually decreased after the cerebral infarction and
normalized 5 months after cisplatin administration [[Figure 2]]. The patient did not experience a recurrence of cerebral infarction after cisplatin
administration.
Figure 1: (a) Magnetic resonance angiography shows basilar artery occlusion (b) Preoperative
cerebral angiography also shows basilar artery occlusion (black arrow) (c) Postoperative
cerebral angiography shows the recanalization of the basilar artery (d) Diffusion-weighted
image shows ischemic lesions on the cerebellum and brainstem
Figure 2: Time-course measurement of serum von Willebrand factor activity
Discussion
A previous study reported an incidence rate of 0.137% for chemotherapy-associated
ischemic stroke and observed that most of the patients exhibited a latency period
of ≤10 days after the latest chemotherapy session.[[6]] Regarding cisplatin usage specifically, a previous study of 108 patients with non-small
cell lung carcinoma who received cisplatin and gemcitabine treatment concluded that
chemotherapy is a powerful risk factor for arterial thrombosis, including cerebral
infarction.[[7]] The findings of that and other previous studies are consistent with our findings
demonstrating that one patient experienced ischemic stroke combined with the reported
occurrence of cerebral infarction.[[1]],[[4]],[[5]],[[6]]
The mechanism of chemotherapy-associated cerebral infarction is multifactorial. Cancer-induced
hypercoagulation can cause a thrombus. Possible mechanisms, including platelet activation,
alteration of the clotting cascade (including hyperfibrinolysis), and disturbances
of prostacyclin–thromboxane homeostasis, could explain the 4- to 6-fold increased
risk of thrombosis in cancer patients relative to the general population.[[8]] All patients in the current study exhibited increased D-dimer levels, which can
indicate the presence of a thrombus.
Cisplatin-associated vascular toxicity can also increase the risk of stroke. Moore
et al. showed that when diagnosing cisplatin-induced cerebral infarction, risk factors
for thromboembolism such as atherosclerosis and preexisting cardiovascular diseases
can be excluded from consideration.[[1]] Lajer andDaugaard reported that cisplatin induces hypomagnesemia in 76%–87% of
treated patients.[[9]] Low magnesium levels increase the intracellular calcium concentration, which initiates
smooth muscle contraction and causes vasospasm and tissue ischemia. Other possible
mechanisms could include cisplatin-associated damage of the endothelium and basement
membrane, which could cause a thrombotic effect that leads to ischemic cerebrovascular
disease. Nuver et al. showed that human endothelial cells exposed to cisplatin in
vitro upregulated the production of inflammatory proteins, which are assumed to initiate
vascular inflammation and endothelial dysfunction.[[10]] Moreover, since vWf is produced by endothelial cells, it is considered to be a
suitable biomarker of endothelial cell activation and vascular damage.[[11]] Physiologically, vWf mediates the mechanisms of endothelial injury repair, which
is achieved mainly through the platelet adhesion and aggregation. Furthermore, Uchiyama
et al. reported that platelet aggregation is increased in patients with atherothrombotic
stroke and transient ischemic attacks, and this event is correlated with an increase
in large vWf multimers, defined as those with molecular weights of ≥13–14 × 106 kDa.[[12]] One noteworthy aspect of the afore-mentioned case study was the increase in serum
vWf activity at the onset of cerebral infarction and then normalized within several
months, suggesting endothelial injury. The previous reports showed that the vWf level
normalized approximately 4 months after endothelial injury.[[11]],[[13]] Taken together, these data suggest that serum vWf can be a useful biomarker for
predicting cisplatin-associated cerebral infarction. However, confounding factors
such as malignancy and concomitant medication cannot be excluded from the study.
Moreover, cisplatin-associated cerebral infarction is likely suspected in cases, in
which this cerebrovascular event occurs shortly after chemotherapy administration.
Alternative chemotherapy programs that exclude cisplatin administration may reduce
the occurrence of cerebral infarction. One limitation of this study was our inability
to measure the serum activity of vWf in all cases. In addition, a comparison of the
baseline vWF activity before chemotherapy administration with the posttreatment level
would have been ideal. Second, vWf is not specific for cisplatin-induced cerebral
infarction because vWf activity may increase in noncancer patients who experienced
a stroke. Some animal models have shown that serum vWf activity increased in an ischemic
model.[[14]] Our observations regarding serum vWf activity thus require further analysis. In
conclusion, patients who underwent cisplatin-based chemotherapy exhibit an increased
risk for the rare complication of cerebral infarction. Moreover, we observed an increase
in vWf activity during the onset of cerebral infarction, which was later normalized
within several months. Taken together, serum vWf activity could be a potentially useful
biomarker for predicting cisplatin-associated cerebrovascular diseases.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form the patient(s) has/have given his/her/their consent for his/her/their
images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
be made to conceal their identity, but anonymity cannot be guaranteed.
