4. DISCUSSION
TA-TMA is a serious complication following hematopoietic stem cell transplantation, with incidence varying widely from 0.5% to 76%5. In recent years, as the number of patients with TA-TMA has increased, Epperla6 concluded that the one-year incidence in a single center was highest at 12% (95% CI = 9%–15%), while the incidence of the disease in the first year after transplantation in our center was slightly lower at 9.60% (95% CI = 5.5%–13.6%).
The onset time of TMA was approximately 27 days and 303 days after transplantation7, stratified by early-onset TA-TMA and late-onset TA-TMA, respectively. The time of onset of TA-TMA patients in our center was also distributed in two groups, with a similar number of patients with early-onset and late-onset, and 6 of the 9 late-onset patients (66.6%) had combined grade III-IV°GVHD while 3 of the 11 early-onset patients(27.3%). The differences did not reach statistical significance, potentially due to the limited sample size of this small cohort. For patients receiving long-term, continuous use of cyclosporine and tacrolimus, clinicians need to be alert to the occurrence of late-onset TA-TMA, as these appear to be risk factors for TA-TMA. This conclusion needs to be confirmed by studies with larger sample sizes.
The existing diagnostic criteria5,8,9 have been continuously improved in the last few years. In 2014, sC5b-9 detection was incorporated into the TA-TMA diagnostic criteria10. In our study, sC5b-9 was monitored in 15 cases, of which 13 cases had levels exceeding the normal range, while the other two cases were elevated before the diagnosis of TA-TMA. A single sC5b-9 value may not corroborate diagnosis, and iterative testing of sC5b-9 may be instructive in the diagnosis and treatment of TA-TMA.
Schistocytes visible on peripheral blood smears were included in multiple diagnostic criteria. However, one case was reported without peripheral blood schistocytes but with evidence of microthrombosis in pathological examinations of the tissue11. It should be noted that expert consensus across China has broader diagnostic criteria3, with pathological diagnosis or the presence of 5 of the 7 markers being the minimum required for diagnosis. Dvorak, C. C12 believe that elevated LDH, proteinuria, and hypertension may be enough for consideration of TA-TMA diagnosis. In our study, only two patients had peripheral blood schistocytes, which is similar to Young13 who proposed that peripheral blood schistocytes were not an early predictor of TA-TMA.
Fifteen patients had early clinical manifestations such as platelet transfusion without therapeutic response, skin petechiae and ecchymosis. Platelet monitoring is a routine blood test for pediatric patients within 1 year of transplantation. The appearance of ecchymosis and petechiae is more intuitive than that of proteinuria and hypertension. Unexplained platelet transfusion ineffectiveness and new petechiae may emerge as one of the early diagnostic indicators for the diagnosis of TA-TMA. However, the number of cases in the current study is small, which still needs to be verified by more centers in order to confirm sensitivity and specificity for TA-TMA.
Withdrawal of the calcineurin inhibitors such as cyclosporine and tacrolimus seems to be involved in the treatment of TA-TMA14, but patients with GVHD need to be evaluated for replacement or reduction of anti-rejection drugs. Plasma exchange is one of the most common methods for the treatment of patients with thrombotic thrombocytopenic purpura at present, but it has poor efficacy in TA-TMA15. In recent years, Jodele demonstrated through a retrospective study that early use of plasma exchange may be beneficial for patients with multiple organ failure caused by TA-TMA16. Yang17 has shown that plasma exchange was effective in TA-TMA patients without gastrointestinal bleeding, and it is possible that the frequency and duration of plasma exchange might achieve better efficacy. Plasma exchange was used in 17 patients in this study, where clinical symptoms improved and disease progression slowed down. However, only six patients survived. In particular, the effect of plasma exchange was not good in patients with bleeding.
McFadyen18 has proposed that endothelial cell damage caused by an immune response to infection could resolve microthrombosis through an anticoagulant pathway. The pathogenesis of TA-TMA is also influenced by the development of microthrombi caused by endothelial injury. Tissue plasminogen activator and low-molecular-weight heparin may be future treatments for TA-TMA. Low-molecular-weight heparin-calcium infusion was used in 19 patients, but its exact efficacy was unclear due to the combination of other treatments. Rituximab is a CD20 monoclonal antibody whose role in TA-TMA is unclear. In the review by Kim19, 12 of 15 patients (80%) who received rituximab resulted in therapeutic efficacy. In our study, twelve patients were treated with rituximab, of which four experienced ineffective response. However, rituximab is often used in combination with plasma exchange, and the exact effect is not clear in TA-TMA. Defibrotide has been shown to exhibit antithrombotic and fibrinolytic activities. Higham20 demonstrated that defibrotide may reduce the risk of TA-TMA in pediatric patients. One patient in our center was given defibrotide but it did not work. Eculizumab is a recombinant human monoclonal antibody that inhibits terminal complement C5. The antibody has high affinity for C5, blocks the formation of C5a and C5b-9, and protects vascular endothelial cells from C5b-9-mediated damage. In a study of 64 pediatric patients with high-risk TA-TMA21, 36 (56%) patients treated with eculizumab achieved complete remission and 5 (8%) achieved a partial response. The remaining 23 (36%) had no response at the end of treatment. Eculizumab improved 1-year post-HSCT survival. Two patients in our center were treated with eculizumab and both achieved remission, but both patients also developed serious infections after its use. Further research is needed for the prevention of treatment complications arising from eculizumab.
In conclusion, TA-TMA is a serious complication after allo-HSCT, with a high mortality rate. Early identification and prompt treatment are key to saving lives. TA-TMA in pediatric patients may occur without evidence of peripheral blood schistocytes. Unexplained precipitous thrombocytopenia or ineffective platelet transfusions may be the earliest signs of TA-TMA in pediatric patients and could be early diagnostic indicators. However, multi-center studies are needed to provide sufficient patient numbers in confirming our observations.