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\begin{document}

\title{Clinical characteristics of pediatric allogeneic hematopoietic stem cell
transplantation-associated thrombotic microangiopathy (TA-TMA): A
retrospective single-center analysis}



\author[1]{Linlin Luo}%
\author[2]{hao xiong}%
\author[2]{Zhi Chen}%
\author[2]{Li Yang}%
\author[2]{Ming Sun}%
\author[2]{Wenjie Lu}%
\author[2]{Fang Tao}%
\author[2]{Zhuo Wang}%
\author[2]{Jianxin Li}%
\author[3]{Zuofeng Li}%
\author[1]{Sujie Tang}%
\affil[1]{Jianghan University School of Medicine}%
\affil[2]{Wuhan Women and Children Medical Care Center}%
\affil[3]{Wuhan University of Science and Technology School of Medicine}%


\vspace{-1em}



  
  \date{June 13, 2024}


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\selectlanguage{english}
\begin{abstract}
Transplantation-associated thrombotic microangiopathy (TA-TMA) is one of
the most serious complications of allogeneic hematopoietic stem cell
transplantation (allo-HSCT) and is characterized by microvascular
hemolytic anemia and thrombocytopenia. To further our understanding of
the clinical characteristics of TA-TMA in pediatric patients, we
retrospectively analyzed 20 pediatric patients with TA-TMA from August
1, 2016 to December 31, 2021 in our center. During this period, 209
patients received allo-HSCT in our department, 20 (9.6\%) of whom
developed TA-TMA. TA-TMA was diagnosed at a median of 94 (7--289) days
post-HSCT. Eleven (55\%) patients had early TA-TMA within 100 days
post-HSCT, while the other 9 (45\%) patients had TA-TMA thereafter. The
most common symptom of TA-TMA was ecchymosis (55\%), while the main
signs were refractory hypertension (90\%) and multi-cavity effusion
(35\%). Five (25\%) patients had central nervous system symptoms
(convulsions and lethargy). Median follow-up time was 8 (1--26) months.
All 20 patients had progressive thrombocytopenia, with 16 patients
receiving transfusion of platelets that was ineffective. Ruptured red
blood cells were visible in only two patients with peripheral blood
smears. Cyclosporine A or Tacrolimus (CNI) dose was reduced once TA-TMA
was diagnosed. Nineteen cases were treated with low-molecular-weight
heparin, 17 patients received plasma exchange, and 12 patients were
treated with rituximab. TA-TMA-related mortality percentage in this
study was 45\% (9/20). Of the 11 patients who were effectively treated
initially, 4 died of sepsis and acute respiratory failure. In
conclusion, platelet decline and/or ineffective transfusion post-HSCT
should be considered an early indicator of TA-TMA in pediatric patients.
TA-TMA in pediatric patients may occur without evidence of peripheral
blood schistocytes. Aggressive treatment is required once diagnosis is
confirmed, but the long-term prognosis is poor.%
\end{abstract}%



\sloppy


\textbf{1. INTRODUCTION}

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the
most effective curative therapy for several hematological malignancies
and bone marrow failure disease in pediatric patients. However,
transplantation-related complications provide a serious threat to the
long-term survival of patients, one of which is
transplantation-associated thrombotic microangiopathy (TA-TMA). TA-TMA
is characterized by microvascular hemolytic anemia and
thrombocytopenia\textsuperscript{1}. The fundamental trigger to onset of
TA-TMA is vascular endothelial injury. In addition to the widening of
the sub-endothelial space and platelet thrombosis, multiple organ
dysfunction also tends to occur particularly of the kidney, heart,
intestine, lungs, and brain\textsuperscript{2}. Currently, the diagnosis
and treatment of TA-TMA in pediatric patients is still in the
exploratory stage. In this paper, we retrospectively analyzed the
clinical characteristics of 20 pediatric patients with TA-TMA, and
hereby present the diagnosis, clinical sequelae, and outcomes.

\textbf{2. METHODS}

\textbf{2.1 Study design, patients, and treatment}

This study retrospectively analyzed 20 patients who underwent allogeneic
HSCT and were confirmed as having TA-TMA in the Department of Hematology
and Oncology, Wuhan Children's Hospital from August 2016 to December
2021. TA-TMA was diagnosed according to the criteria proposed by the
Hematopoietic Stem Cell Application Group, Chinese Society of
Hematology, Chinese Medical Association\textsuperscript{3}. The criteria
for inclusion were: lactate dehydrogenase (LDH) levels increased to
upper normal limit, proteinuria, hypertension, thrombocytopenia
\textless{}50 \selectlanguage{ngerman}× 10\textsuperscript{9}/L or a 50\% decrease in platelet
count, decreased hemoglobin, evidence of microangiopathy, and plasma
sC5b-9 values above the upper limit of normal. If 3 of the 7 laboratory
or clinical indicators were met, or if tissue biopsy indicators had
evidence of microthrombosis, then a diagnosis of TA-TMA was confirmed.

Once diagnosis of TA-TMA was established, the dose of cyclosporine and
tacrolimus (CNI) was immediately reduced. Plasma exchange, rituximab,
low molecular weight heparin, calcium, defibrotide, eculizumab, and
other supportive treatments were administered.

\textbf{2.2 Follow-up endpoints and laboratory metrics}

The follow-up endpoint was either June 30, 2022, or patient death. This
was achieved by reviewing hospital medical records, laboratory data,
conducting telephone interviews, and outpatient reviews. Clinical
indicators included clinical manifestations, routine blood tests,
platelet transfusion refractoriness (PTR), proteinuria, ruptured red
blood cells in peripheral blood, LDH, soluble terminal complement
complex sC5b-9, and pathological diagnosis. We define a platelet
transfusion--refractory patient as an individual who has received two
recent (but not necessarily consecutive) platelet transfusions within a
24 hour window, and where corrected count increment (CCI) was lower than
4500/\selectlanguage{greek}μ\selectlanguage{english}l.\textsuperscript{4}

\textbf{2.3 Statistical analysis}

Statistical analyses were performed using SPSS, version 24.0 (IBM,
Chicago, IL). Continuous variables were expressed as median and range,
and the categorical variable was expressed as count with percentage.
Hierarchical cluster analysis was used in the clustering.

\textbf{3. RESULTS}

\textbf{3.1 Clinical data}

A total of 209 pediatric patients underwent allo-HSCT, of which 20 were
diagnosed with TA-TMA. This equates to 9.60\% (95\% CI = 5.5\%--13.6\%).
The gender split was 11 males (55\%) and 9 females (45\%), with a median
age of 146 (10--190) months. Basic clinical and demographic information
for the 20 patients with TA-TMA is shown in Table 1. Primary diseases
included aplastic anemia (30\%), acute myeloid leukemia (20\%),
hemophagocytic lymphohistiocytosis (15\%) acute lymphoblastic leukemia
(5\%), Fanconi anemia (5\%), myelodysplastic syndrome (5\%),
mixed-phenotype acute leukemia (5\%), mucopolysaccharidosis (5\%), and
myeloid sarcoma (5\%). According to routine clinical practice in our
center, haplo-identical donors were a common source of stem cells, with
peripheral blood being the main source. The majority of recipients
received busulfan (BU)-cyclophosphamide (CY) and anti-thymocyte globulin
(ATG) therapy for myeloablative conditioning. Almost all transplant
recipients received CNI-based GVHD prophylaxis, and only one case used
sirolimus. Nineteen patients (95\%) achieved neutrophil and platelet
engraftment. The median neutrophil engraftment time was 15 (10--22) days
and the median platelet engraftment time was 16 (7--39) days following
allo-HSCT. The median count of graft mononuclear cells was 8.335
(0.821-39.6) \selectlanguage{ngerman}× 10\textsuperscript{8}/kg and the CD34+ cell count was
7.95 (0.353--23.6) × 10\textsuperscript{6}/kg.

\textbf{3.2} \textbf{Clinical features of pediatric patients with
TA-TMA}

TA-TMA was diagnosed at a median of 94 days (7--289) post-HSCT. Eleven
(55\%) patients had early-onset TA-TMA, which happened within 100 days
post-HSCT, while the remaining 9 (45\%) patients had late-onset TA-TMA,
which happened at \textgreater{}100 days post-HSCT. Early-onset TA-TMA
occurred at a median of 56 (7--94) days, and late-onset TA-TMA occurred
at a median of 157 (104--297) days. Nine cases were combined stage
III-IV-GVHD, of which 6 were late-onset TA-TMA.

The most common symptom of TA-TMA was ecchymosis. Seventeen cases had
varying degrees of bleeding, mainly in the skin and mucous membranes,
with black-purple petechiae as a typical manifestation, while the
gastrointestinal tract and urinary system were also involved. Case ''5''
showed diffuse alveolar hemorrhage. Seven cases suffered from dyspnea,
which was manifested as high-flow oxygen inhalation of 3 L/min and above
mask oxygen inhalation, CAPA-assisted ventilation, and even mechanical
ventilation with other advanced support, where transcutaneous oxygen
saturation could be maintained at approximately 95\%. Five cases had
central nervous system symptoms, which manifested as convulsions and
lethargy. The main clinical signs of TA-TMA were hypertension and
effusion. The blood pressure of 18 cases was higher than the higher
blood pressure values typically observed in children with hypertension
of the same age. Furthermore, seven cases had serous cavity effusion,
mainly manifesting as pleural effusion and pericardial effusion.

The median platelet counts, hemoglobin, and LDH levels were 21 (1--79)
×10\textsuperscript{9}/L, 79 (41--106)g/L, and 715 (350--4034) U/L,
respectively. All 20 patients had a progressive decrease in platelets,
of which 16 patients received transfusion that was ineffective.
Proteinuria was positive in 16 cases and 2 patients showed ruptured red
blood cells in peripheral blood smears. Fifteen patients were monitored
for sC5b-9, of which 13 patients displayed higher levels than the normal
range. Pathological examination was performed in 13 cases, and
microthrombosis was evident in the microvascular pathological films of 7
of them.

\textbf{3.3 Treatment and Outcomes}

The dose of CNI was reduced once TA-TMA was formally diagnosed. Nineteen
patients were treated with low-molecular-weight heparin, 17 patients
were treated with plasma exchange, and the median number of plasma
exchanges was 4 (3--18). Rituximab was used in 12 patients with a median
of 1.5 (1--3) administrations. Two patients were treated with eculizumab
and one was treated with defibrotide.

Among the 20 patients, 11 responded well to treatment, with hemoglobin
and platelets both increasing, LDH levels and blood pressure decreasing,
and no new ecchymosis or petechiae on the skin. Nine patients had a poor
response to treatment and unfortunately died (45\% mortality from
diagnosis). The median time of death was 16 (5--77) days after
diagnosis, and the main cause of death was disseminated intravascular
coagulation and multi-organ failure. Of the 11 patients who were
effectively treated, 4 eventually died of sepsis and acute respiratory
failure within 136, 177, 279, and 602 days after diagnosis,
respectively. Only seven patients survived to the end of the follow-up
period and were reported to be healthy.

\textbf{4. DISCUSSION}

TA-TMA is a serious complication following hematopoietic stem cell
transplantation, with incidence varying widely from 0.5\% to
76\%\textsuperscript{5}. In recent years, as the number of patients with
TA-TMA has increased, Epperla\textsuperscript{6} 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
transplantation\textsuperscript{7}, 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 criteria\textsuperscript{5,8,9} have been
continuously improved in the last few years. In 2014, sC5b-9 detection
was incorporated into the TA-TMA diagnostic
criteria\textsuperscript{10}. 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 tissue\textsuperscript{11}. It should
be noted that expert consensus across China has broader diagnostic
criteria\textsuperscript{3}, with pathological diagnosis or the presence
of 5 of the 7 markers being the minimum required for diagnosis. Dvorak,
C. C\textsuperscript{12} 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 Young\textsuperscript{13} 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-TMA\textsuperscript{14}, 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-TMA\textsuperscript{15}. 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-TMA\textsuperscript{16}. Yang\textsuperscript{17} 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.

McFadyen\textsuperscript{18} 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 Kim\textsuperscript{19}, 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. Higham\textsuperscript{20} 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-TMA\textsuperscript{21}, 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.

\textbf{ETHICS STATEMENT}

Ethical approval was obtained from the Ethics Committee of Wuhan
Children's Hospital (2022R017-E01).

\textbf{Data availability statement}

The data that support the findings of this study are available on
request from the corresponding author. The data are not publicly
available due to privacy or ethical restrictions.

\textbf{ACKNOWLEDGEMENTS}

The authors thank the participating patients and their caregivers, and

the study centers and investigators for their contributions to the

study. This study was funded by Wuhan Clinical Medical Research Project
(WX20D20, WZ20Y04, WX21Z48)\textbf{References}

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Table 1 Clinical and demographic characteristics of pediatric patients
with TA-TMA\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllllllll@{}}
\toprule
NO. & Gender & Underlying diseases & Age at transplant, months & Graft
type & Age at donor, months & donor-recipient ABO blood group &
Conditioning regimen & GVHD prophylaxis & Graft source & donor-recipient
HLA match & MNC counts(X10\^{}8/KG) & CD34+ counts(X10\^{}6/KG) &
neutrophil engraftment time & platelet engraftment time\tabularnewline
1 & F & AA & 63 & HLA-matched sibling & 5 & O+/O+ & Bu/Cy/Flu/ATG & CsA
& PBSC & 10 & 8.38 & 5.17 & 11 & 25\tabularnewline
2 & F & AML & 167 & Haploidentical & 28 & O+/O+ & Bu/Cy/ATG & PTCy &
PBSC & 5 & 17.7 & 20.05 & 19 & 14\tabularnewline
3 & M & MPS & 39 & (9/10)HLA-matched unrelated & 0 & O+/A+ &
Bu/Cy/Flu/ATG & CsA/MMF & CB & 9 & 0.821 & 0.353 & 22 &
39\tabularnewline
4 & M & AML & 174 & (9/10)HLA-matched unrelated & 29 & O+/B+ & Bu/Cy/ATG
& CsA/MMF/MTX & PBSC & 9 & 7.4 & 7.1 & 12 & 12\tabularnewline
5 & M & ALL & 72 & Haploidentical & 27 & A+/O+ & Bu/Cy/Flu/ATG & PTCy &
PBSC & 5 & 26.06 & 23.6 & 14 & 9\tabularnewline
6 & M & HLH & 35 & Haploidentical & 32 & A+/O+ & Bu/Cy/Flu/ATG/VP-16 &
CsA/MMF/MTX & PBSC & 7 & 7.97 & 4.64 & 19 & 37\tabularnewline
7 & F & MDS & 159 & Haploidentical & 6 & B+/B+ & Bu/Cy/Flu/ATG & PTCy &
PBSC & 5 & 27.04 & 14.27 & 16 & 11\tabularnewline
8 & M & HLH & 153 & Haploidentical & 39 & B+/O+ & Bu/Cy/Flu/ALG &
CsA/MMF/MTX & BM+PBSC & 8 & 8.25 & 7.25 & Non-engraftment &
Non-engraftment\tabularnewline
9 & F & AA & 50 & Haploidentical & 33 & A+/A+ & Bu/Cy/Flu/ATG &
CsA/MMF/MTX & PBSC & 9 & 8.29 & 3.62 & 15 & 15\tabularnewline
10 & F & AA & 146 & Haploidentical & 39 & A+/AB+ & Bu/Cy/Flu/ATG &
CsA/MMF/MTX & PBSC & 7 & 7.5 & 8.65 & 12 & 17\tabularnewline
11 & F & AA & 29 & (9/10)HLA-matched unrelated & 22 & O+/AB+ &
Bu/Cy/Flu/ATG & CsA/MMF/MTX & PBSC & 9 & 7.4 & 9.4 & 15 &
34\tabularnewline
12 & M & HLH & 163 & Haploidentical & 5 & A+/O+ & Bu/Cy/Flu/ATG/VP-16 &
KF506/MMF/MTX & PBSC & 5 & 7.85 & 5.8 & 18 & 23\tabularnewline
13 & M & MPAL & 105 & Haploidentical & 42 & A+/O+ & Bu/Cy/Flu/ATG & PTCy
& PBSC & 6 & 31.89 & 13.52 & 15 & 15\tabularnewline
14 & F & FA & 10 & (9/10)HLA-matched unrelated & 28 & B+/0+ &
Bu/Cy/Flu/ATG & CsA/MMF & PBSC & 9 & 7.4 & 6.2 & 10 & 7\tabularnewline
15 & F & AML & 182 & Haploidentical & 38 & B/AB & Bu/Cy/Flu/ATG & PTCy &
PBSC & 5 & 33.9 & 13.25 & 17 & 15\tabularnewline
16 & M & AML & 145 & Haploidentical & 34 & AB/A & Bu/Cy/Flu/ATG & PTCy &
PBSC & 5 & 39.6 & 14.17 & 19 & 22\tabularnewline
17 & M & AA & 190 & Haploidentical & 41 & A+/A+ & Bu/Cy/Flu/ATG &
CsA/MMF/MTX & PBSC & 5 & 7.98 & 5.12 & 15 & 17\tabularnewline
18 & M & MS & 100 & Haploidentical & 39 & B/AB & TBI/Bu/Cy/Flu/ATG &
PTCy & PBSC & 6 & 35.99 & 17.92 & 13 & 11\tabularnewline
19 & F & AA & 170 & Haploidentical & 19 & O+/O+ & Bu/Cy/Flu/ATG &
CsA/MMF & PBSC & 5 & 8.38 & 4 & 16 & 17\tabularnewline
20 & M & AML & 175 & Haploidentical & 42 & A+/O+ & Bu/Cy/Flu/ATG & PTCy
& PBSC & 6 & 32.2 & 14.1 & 16 & 16\tabularnewline
\bottomrule
\end{longtable}

M, male; F, female ;AA, aplastic anemia; ALL, acute lymphoblastic
leukemia; AML, acute myeloblastic leukemia; FA, Fanconi anemia; HLH,
hemophagocytic lymphohistiocytosis; MDS, myelodysplastic syndrome; MPAL,
mixed-phenotype acute leukemia; MPS, mucopolysaccharidosis; MS, myeloid
sarcoma; HLA, human leukocyte antigen; Bu, busulfan; Cy,
cyclophosphamide; Flu, fludarabine; ATG, anti-thymocyte globulin; ALG,
anti-lymphocyte globulin; VP-16, etoposide; TBI, total body irradiation;
GVHD, graft-versus-host disease; CsA, cyclosporin A; MMF, mycophenolate
mofetil; MTX, methotrexate; FK506, tacrolimus; PTCy, post-transplant
cyclophosphamide; MNC, mononuclear cells.

Table 2 Clinical features of pediatric patients with TA-TMA\selectlanguage{english}
\begin{longtable}[]{@{}llllllllllll@{}}
\toprule
NO. & TA-TMA diagnosis day post-HSCT & Signs and symptoms & With III-IV
GVHD & Hb (g/L) & PLT (10\^{}9/L) & PTR & Proteinuria(+) &
Schistocytes & LDH & sC5b-9 & Pathological examinations\tabularnewline
1 & 36 & neurological
symptoms\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}hematochezia\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}dyspnea\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}pericardial effusion & No
& 87 & 17 & Yes & 3 & + & 912 & - & No thromboembolic\tabularnewline
2 & 46 & hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}dyspnea\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}DAH & No & 79 & 14 & Yes & 0 & - & 451 &
354 & No thromboembolic\tabularnewline
3 & 94 & neurological symptoms\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}dyspnea & Yes & 83 & 31 &
Yes & 1 & - & 1174 & - & -\tabularnewline
4 & 94 & hematuria\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}edema & Yes & 60 & 75 & No & 3 & -- & 367 & 439 & No
thromboembolic\tabularnewline
5 & 72 & neurological symptoms\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}mucocutaneous bleeding &
Yes & 80 & 34 & Yes & 2 & - & 679 & 245 & thromboembolic\tabularnewline
6 & 7 & neurological symptoms\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}mucocutaneous
bleeding\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}hematochezia\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}ascites & No & 123 & 32 & Yes & 2 & - & 1463 & -
& -\tabularnewline
7 & 157 & hypertension & Yes & 78 & 62 & No & 1 & - & 660 & 329 &
thromboembolic\tabularnewline
8 & 13 & neurological
symptoms\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}hematochezia\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}hematuria\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}ascites & No & 79 & 25
& Yes & 2 & - & 1516 & - & -\tabularnewline
9 & 121 & neurological symptoms\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}mucocutaneous
bleeding\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}dyspnea\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}pleural effusion & Yes & 79 & 17 & Yes & +- & - & 761
& 421 & thromboembolic\tabularnewline
10 & 111 & hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}mucocutaneous bleeding & No & 72 & 33 & Yes &
+- & - & 533 & 407 & -\tabularnewline
11 & 43 & hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}mucocutaneous bleeding & No & 76 & 15 & No & 0 &
- & 958 & 648 & thromboembolic\tabularnewline
12 & 83 & hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}dyspnea\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}pleural effusion & No & 49 & 13 & Yes &
2 & - & 4034 & 410 & No thromboembolic\tabularnewline
13 & 209 & hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}dyspnea\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}hematochezia & Yes & 72 & 34 & Yes & 2
& - & 696 & - & No thromboembolic\tabularnewline
14 & 178 & hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}mucocutaneous bleeding\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}hematochezia & Yes & 61
& 22 & Yes & 0 & - & 528 & 392 & No thromboembolic\tabularnewline
15 & 289 & hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}hematochezia & Yes & 65 & 1 & Yes & 2 & - & 606
& 937 & thromboembolic\tabularnewline
16 & 75 & mucocutaneous bleeding & No & 74 & 3 & Yes & 2 & - & 350 & 416
& -\tabularnewline
17 & 56 & hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}mucocutaneous bleeding & No & 90 & 22 & No & 1 &
+ & 734 & 358 & -\tabularnewline
18 & 203 & hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}mucocutaneous
bleeding\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}hematochezia\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}dyspnea\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}pleural effusion & No & 41 & 15 & Yes &
2 & - & 1878 & 402.45 & thromboembolic\tabularnewline
19 & 104 & hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}mucocutaneous bleeding & No & 89 & 47 & Yes & 1
& - & 837 & 203 & -\tabularnewline
20 & 131 & hypertension\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}mucocutaneous bleeding & Yes & 75 & 28 & Yes &
0 & - & 599 & 651 & thromboembolic\tabularnewline
\bottomrule
\end{longtable}

DAH, diffuse alveolar hemorrhage; PTR, platelet transfusion
refractoriness.

Table 3 Treatment and outcome of pediatric patients with TA-TMA\selectlanguage{english}
\begin{longtable}[]{@{}llllllllll@{}}
\toprule
NO. & CNI & Withdrawal of CNI & Episodes of TPE & Episodes of Ritux &
Other treatments & Efficacy & Outcome & Died of TMA & Time from
diagnosis to death (days)\tabularnewline
1 & CsA & Yes & 5 & 0 & LMWH & invalid & died & Yes & 14\tabularnewline
2 & CsA & Yes & 4 & 0 & LMWH & Valid & survival & - & -\tabularnewline
3 & CsA & Yes & 4 & 1 & LMWH & invalid & died & Yes & 20\tabularnewline
4 & CsA & Yes & 5 & 2 & LMWH & Valid & survival & - & -\tabularnewline
5 & CsA & Yes & 4 & 0 & LMWH & Valid & died & No & -\tabularnewline
6 & CsA & Yes & 0 & 0 & LMWH & invalid & died & Yes & 59\tabularnewline
7 & CsA & Yes & 4 & 1 & LMWH & Valid & died & No & -\tabularnewline
8 & CsA & Yes & 4 & 0 & Defibrotide & invalid & died & Yes &
16\tabularnewline
9 & CsA & Yes & 18 & 3 & LMWH/Eculizumab & Valid & survival & - &
-\tabularnewline
10 & CsA & Yes & 14 & 3 & LMWH & invalid & died & Yes &
77\tabularnewline
11 & CsA & Yes & 3 & 1 & LMWH & Valid & died & No & -\tabularnewline
12 & FK506 & Yes & 3 & 1 & LMWH & invalid & died & Yes &
7\tabularnewline
13 & CsA & Yes & 13 & 0 & LMWH & invalid & died & Yes &
45\tabularnewline
14 & CsA & Yes & 4 & 1 & LMWH/Eculizumab & Valid & died & No &
-\tabularnewline
15 & CsA & Yes & 4 & 0 & LMWH & invalid & died & Yes & 11\tabularnewline
16 & CsA & Yes & 4 & 0 & LMWH & Valid & survival & - & -\tabularnewline
17 & CsA & Yes & 4 & 2 & LMWH & Valid & survival & - & -\tabularnewline
18 & CsA & Yes & 0 & 1 & LMWH & invalid & died & Yes & 5\tabularnewline
19 & CsA & Yes & 3 & 3 & LMWH & Valid & survival & - & -\tabularnewline
20 & CsA & Yes & 0 & 3 & LMWH & Valid & survival & - & -\tabularnewline
\bottomrule
\end{longtable}

CNI, calcineurin inhibitor; TPE, therapeutic plasmatic exchange; Ritux,
rituximab; LMWH, low-molecular-weight heparin.

\selectlanguage{english}
\FloatBarrier
\end{document}

