CASE DESCRIPTIONS
We report the cases of two pediatric patients with a diagnosis of TTP,
treated with the combination of PEX, Caplacizumab and immunosoppressive
therapy.
Case 1
A16-years-old overweight girl was admitted to our emergency department
due to fever and vomiting. Laboratory data showed mild renal impairment
(serum creatinine 1.16 mg/dL), hemolytic anemia (lactate dehydrogenase
2238 U/L, hemoglobin 5.4 g/dL, indirect bilirubin 1.54 mg/dL,
reticulocyte count 17%, negative Coombs Test), low platelet count
(7x109/L) and schistocytes (>1%) in the
peripheral blood smear. Autoimmune cytopenia and hematological
malignancies were ruled out. Hemolytic uremic syndrome (HUS) was
excluded due to the not suggestive history with negative stool cultures
and normal C3 complement fraction. During hospitalization she presented
a transient episode of dysarthria and confusion with negative cerebral
computed tomography scan. Clinical and laboratory data suggested the
diagnosis of acquired TTP, supported by the evaluation of the Plasmic
Score, which was 7 (high risk) [12]. The diagnosis was confirmed by
the reduction of the ADAMTS13 activity (0%) and by the presence of
anti-ADAMTS13 antibodies (66,9U/mL). We performed immunological tests
which showed an increase of the atypical B memory cells, according to
the autoimmune process. Daily PEX was immediately started associated
with intravenous high dose intravenous corticosteroids, immunoglobulins
and low molecular weight heparin. Caplacizumab (10 mg/day) was added
four days later. Three days after starting Caplacizumab, a progressive
increasing in platelet count was observed. Unfortunately, during the
following weeks, anti-ADAMTS13 antibodies remained persistently high, as
well as ADAMTS13 activity persistently low, thus a 4-dose course of
Rituximab (375mg/m2/week) was started. At the end of
the course, ADAMTS13 activity increased up to 64% and anti-ADAMTS13
antibodies levels concurrently decreased to 5.3 U/mL (Fig.1). To
the date, 42 weeks after withdrawal of the therapy, patient is in good
clinical conditions and her platelet count is within the normal range.
Case 2A 15-years-old obese girl was admitted to our hospital for
vomiting and petechial eruptions of the extremities. Blood exams showed
hemolytic anemia (Hb 7.3g/dL, indirect bilirubin 7.10 mg/dL, lactate
dehydrogenase 1953 U/L, reticulocyte count 24.3%, negative Coombs
test), schistocytes in the peripheral blood smear, a severe
thrombocytopenia (7x109/L) and a mild renal impairment
(creatinine 1.07 mg/dL). Hematological disorders, autoimmune cytopenia
and HUS were excluded. The immunological tests showed an expansion of
the CD19 cells. We considered the diagnosis of TTP, thus we performed
the Plasmic score which was 6 (high risk). The ADAMTS13 activity was 0%
and the level of the anti-ADAMTS13 antibodies was 130 U/mL. Patient was
treated with intravenous high dose immunoglobulin infusions, daily PEX,
oral prednisolone (1mg/kg/day) and low molecular weight heparin. In
contrast to the first case, Caplacizumab (10mg/day) was immediately
administered. A significant increase in platelet count was observed
after 2 administration and, in five days, her platelet count was normal.
Nevertheless, after 1 month of therapy, ADAMTS13 activity was
persistently low and ADAMTS13 inhibitors level was high. For this
reason, as in the previous case, a course of Rituximab
(375mg/m2/week) was administered. Once the Rituximab
course was completed, ADAMTS13 activity was 58% and ADAMTS13 inhibitors
were undetectable. Platelet count remained normal even when PEX and
Caplacizumab were discontinued. At present, 7 weeks after completing
Rituximab course, patient is in good health conditions with normal
platelet count.
DISCUSSION
TTP is included in the group of microangiopathic hemolytic anemias and
occurs predominantly in the adult population [3,13]. In children,
TTP is extremely rare and, at the onset, differential diagnosis from HUS
may be very challenging [14]. Nonetheless, its rapid identification
is critical to outcome, as treatment delay is potentially
life-threatening.
Here, we reported 2 cases of TTP in adolescents with a similar
successful therapeutic approach.
Current evidence suggests that conventional treatment with PEX can
improve survival rates from 20% to 80% [15] by removing
anti-ADAMTS13 antibodies, ADAMTS13 immune complexes, and replacing
ADAMTS13 activity. Most patients with acquired TTP receive
immunosuppressive therapy in addition to PEX. This practice is supported
by the autoimmune nature of the disease. Retrospective and prospective
studies employing Rituximab along with continued daily PEX reported
encouraging results [16,17,18]. Rituximab is an antiCD20-chimeric
monoclonal antibody, and its efficacy is due to B-cell depletion which
allows suppression of anti-ADAMTS13 autoantibodies production. In our
cases, immunological characterization is consistent with an autoimmune
process, and this fact strongly supported the use of an anti-CD20
therapy. Recently, Caplacizumab, a humanized monoclonal antibody
fragment, which binds the VWF and blocks the VWF interaction with the
platelet glycoprotein lb-IX-V, was approved for the treatment of TTP in
the adult setting [19,20]. It was initially used as a second-line
treatment [8,9,10,21], however a recent study showed that the use of
Caplacizumab during the acute phase is able to prevent unfavorable
outcomes [22], decreasing thromboembolic event rate and the number
of days of PEX [23]. Even though PEX is still considered crucial in
the treatment of TTP, successful outcomes with the use of multiple
treatment strategies without PEX were recently reported, suggesting the
possibility that PEX may be reserved to patients with very severe or
refractory disease [24,25], even though much more evidence from
specific clinical trials is needed to support this hypothesis.
Based on our experience, we could suggest that Caplacizumab is a safe
treatment in pediatric patients affected by TTP and that effectiveness
can be increased by the association with immunosuppressive therapy.
Although it does not modify the underlying immune pathophysiology of
TTP, a prompt administration appears to impact the timely recovery of
platelet count, as confirmed by the time to platelet count normalization
in our cases (Table1), and the risk of life-threatening events.
In conclusion, we speculate that the combined use of Caplacizumab and
immunosuppressive therapy in the acute phase may have a significative
impact on the prognosis. The combination of various therapeutic
approaches, such as blocking blood clotting, inhibiting the inflammatory
pathways and suppressing the production of anti-ADAMTS13 autoantibodies,
is crucial to obtain a significant response to treatment and a lasting
maintenance of clinical and laboratory remission. Although our
experience on a very limited number of patients does not allow drawing
any firm conclusions regarding a potential advantage in using a
Caplacizumab-based, PEX-free approach, in our opinion, this data might
suggest the efficacy and safety of this strategy in the pediatric
population, which could support further investigations on this topic.
Conflict of Interest statement: All the authors declared no
conflict of interest.
Acknowledgements: The authors thank the patients, their parents
and the Bambino Gesù Children’s Hospital staff for their participation
in this brief report.