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.