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.