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\begin{document}

\title{Local territory-wide experience on challenges in management of
transplant-associated thrombotic microangiopathy in Hong Kong}



\author[1]{Wilson Chan}%
\author[2]{Alison LT Ma}%
\author[1]{Eugene Chan}%
\author[1]{Amanda Kan}%
\author[3]{Pamela PW Lee}%
\author[1]{Daniel Ka Leung Cheuk}%
\author[4]{Vincent Lee}%
\author[3]{Alan Chiang}%
\author[5]{Wing Leung}%
\author[6]{Godfrey Chan}%
\affil[1]{Hong Kong Children's Hospital}%
\affil[2]{Princess Margaret Hospital}%
\affil[3]{The University of Hong Kong}%
\affil[4]{CUHk}%
\affil[5]{University of Hong Kong}%
\affil[6]{Queen Mary Hospital}%


\vspace{-1em}



  
  \date{May 22, 2024}


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\selectlanguage{english}
\begin{abstract}
Transplant-associated thrombotic microangiopathy (TA-TMA) is an
under-recognized yet potentially devastating complication of
hematopoietic stem cell transplantation which had increased awareness in
recent years. This report summarizes territory-wide experience of
paediatric TA-TMA in the Hong Kong Children's Hospital from 1 April 2019
to 31 March 2021. Total six patients were identified among 73
transplants performed. Median duration of onset was 2.5 months
post-HSCT. Three patients died while all 3 survivors suffered from stage
2 to 5 chronic kidney disease despite administration of eculizumab. To
conclude, recognition and diagnosis of TA-TMA is challenging. Clinical
utility of complement blockage with eculizumab is limited.%
\end{abstract}%



\sloppy


\textbf{Brief report}

\textbf{Local territory-wide experience on challenges in management of
transplant-associated thrombotic microangiopathy in Hong Kong}

WYK Chan\textsuperscript{1}, ALT Ma\textsuperscript{2}, EYH
Chan\textsuperscript{2}, ANC Kan\textsuperscript{3}, PPW
Lee\textsuperscript{1}, DKL Cheuk\textsuperscript{1}, V
Lee\textsuperscript{1}, AKS Chiang\textsuperscript{1},

W Leung\textsuperscript{1}, GCF Chan\textsuperscript{1}

\begin{enumerate}
\tightlist
\item
  Paediatric Hematology and Oncology team, Department of Pediatrics and
  Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special
  Administrative Region, China
\item
  Pediatric nephrology team, Department of Pediatrics and Adolescent
  Medicine, Hong Kong Children's Hospital, Hong Kong Special
  Administrative Region, China
\item
  Department of Pathology, Hong Kong Children's Hospital, Hong Kong
  Special Administrative Region, China
\end{enumerate}

\textbf{Corresponding author:} Dr. Wilson Y.K. Chan

Telephone: (852) 5741 3367, Fax (852) 2459 9733; email: wykchan@hku.hk

\textbf{Main text word count:} 1,200

\textbf{Abstract word count:} 100

\textbf{Table:} 1

\textbf{Figure:} 0

\textbf{Running title:} Management of TA-TMA in HK

\textbf{Keywords (MeSH terms 2021):} hematopoietic stem cell
transplantation, thrombotic microangiopathy, morbidity, Hong Kong

\textbf{Author contributions}

(1) Concept or design: Wilson Chan, Alan Chiang, Daniel Cheuk, Vincent
Lee, Godfrey Chan

(2) Acquisition of data: Wilson Chan, Alison Ma, Eugene Chan, Amanda
Kan, Alan Chiang, Godfrey Chan

(3) Analysis or interpretation of data: Wilson Chan, Alison Ma, Amanda
Kan, Alan Chiang, Godfrey Chan

(4) Drafting of the article: Wilson Chan, Daniel Cheuk

(5) Critical revision for important intellectual content: Wilson Chan,
Alison Ma, Eugene Chan, Amanda Kan, Pamela Lee, Daniel Cheuk, Alan
Chiang, Wing Leung, Godfrey Chan



\textbf{Abbreviations}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
CKD & chronic kidney disease\tabularnewline
\midrule
\endhead
CNI & calcineurin inhibitor\tabularnewline
CSA & cyclosporine\tabularnewline
GFR & glomerular filtration rate\tabularnewline
GVHD & graft-versus-host disease\tabularnewline
HKCH & Hong Kong Children's Hospital\tabularnewline
HSCT & hematopoietic stem cell transplantation\tabularnewline
HUS & hemolytic-uremic syndrome\tabularnewline
LDH & lactate dehydrogenase\tabularnewline
TA-TMA & transplant-associated thrombotic microangiopathy\tabularnewline
TTP & thrombotic thrombocytopenic purpura\tabularnewline
\bottomrule
\end{longtable}



\textbf{ABSTRACT}

Transplant-associated thrombotic microangiopathy (TA-TMA) is an
under-recognized yet potentially devastating complication of
hematopoietic stem cell transplantation which had increased awareness in
recent years. This report summarizes territory-wide experience of
paediatric TA-TMA in the Hong Kong Children's Hospital from 1 April 2019
to 31 March 2021. Total six patients were identified among 73
transplants performed. Median duration of onset was 2.5 months
post-HSCT. Three patients died while all 3 survivors suffered from stage
2 to 5 chronic kidney disease despite administration of eculizumab. To
conclude, recognition and diagnosis of TA-TMA is challenging. Clinical
utility of complement blockage with eculizumab is limited.



\textbf{MAIN BODY TEXT}

\textbf{Introduction}

Transplant-associated thrombotic microangiopathy (TA-TMA) is an
under-recognized yet potentially devastating complication of
hematopoietic stem cell transplantation (HSCT) characterized by
endothelial damage, intravascular activation and platelet sequestration,
accumulation of microthrombi occluding microcirculation, and red blood
cells fragmentation causing non-immune microangiopathic hemolytic anemia
(1). Clinical and laboratory features include the triad of hypertension,
thrombocytopenia and elevation of lactate dehydrogenase (LDH); as well
as schistocytosis in peripheral blood smear, thrombocytopenia, decreased
haptoglobin level, and target organ damage such as renal impairment. It
had increasingly been identified in recent years (2-5) in both
autologous and allogeneic HSCT settings. Reported incidences of TA-TMA
vary widely from 0.5\% to 76\% due to different diagnostic criteria,
demographic characteristics, conditioning regimen, donor source, and
co-morbidities (6-22). TA-TMA carries a high mortality of 30\% to 90\%
(7, 12, 17, 20, 21, 23), depending on its severity and presence of
co-morbidities. This report summarized the experience of TA-TMA in the
Hong Kong Children's Hospital (HKCH), the only territory-wide paediatric
transplant centre in Hong Kong since its establishment in 2019,
highlighting challenges in management of TA-TMA in this locality.

\textbf{Methods}

All patients aged below 18 years of age who underwent HSCT in HKCH and
diagnosed to have TA-TMA during the 2-year study period from 1 April
2019 to 31 March 2021 were included. Data on basic demographics,
transplant details, potential risk factors for pathogenesis of TA-TMA,
clinical and laboratory presentations of TA-TMA, subsequent treatment
and outcomes were collected.

\textbf{Results}

Total 73 transplants (51 allogeneic, 22 autologous) had been performed
in 63 patients during the study period. Six patients (4 males and 2
females) developed TA-TMA at a median duration of 2.5 months post-HSCT.
Incidence rate was 9.52\%. For the six TA-TMA patients, five underwent
allogenic HSCT while one underwent autologous HSCT. Three out of six
cases of TA-TMA were histologically proven. Demographics and transplant
details are described in \textbf{Table 1a} . All five patients who
underwent allogeneic HSCT developed various degrees of acute
graft-versus-host disease (GVHD) and viral infections. Four used
calcineurin inhibitor (CNI) cyclosporine (CSA) as GVHD prophylaxis which
was stopped once TA-TMA was suspected. Three out of six patients
developed hepatic sinusoidal obstruction syndrome with defibrotide
given. Genetic predisposition had not been identified in local cohort
except identification of a variant of unknown significance in THBD gene
for \textbf{Case 6 (Table 1b)} . All six patients developed
hypertension, proteinuria, schistocytosis with elevated LDH. Five out of
six had anemia, thrombocytopenia, elevated creatinine, elevated d-dimer
and low haptoglobin level \textbf{(Table 1b)} . Median six doses (range
4 to 12 doses) of eculizumab were administered to four out of six
patients. Serum eculizumab level was not performed due to unavailability
of the test. Three patients died (2 due to fungal infection and one due
to acute-on-chronic renal failure) \textbf{(Cases 1 to 3)} and all
within 3 months upon diagnosis of TA-TMA. Mortality rate was 50\%. All
three survivors \textbf{(Cases 4 to 6)} suffered from chronic kidney
disease (CKD) and one \textbf{(Case 5)} required lifelong
dialysis\textbf{(Table 1c)} .

\textbf{Discussion}

\textbf{1. Challenges in recognizing and diagnosing TA-TMA}

TA-TMA is difficult to recognize as complex clinical picture post-HSCT
can mask or mimic TA-TMA, such as cytopenia due to marrow aplasia before
engraftment, drug-induced hypertension and immune-mediated hemolysis.
Besides, as not all features appear simultaneously and may evolve over
days to weeks, high index of suspicion is crucial to pick up subtle cues
of evolving TA-TMA such as persistent hypertension requiring multiple
anti-hypertensives, elevated LDH, or increased transfusion requirement
and platelet refractoriness. There has yet been a universally accepted
diagnostic criteria for TA-TMA. Histology is the most reliable modality
yet invasive and risky. Diagnostic triad of hypertension,
thrombocytopenia and elevated LDH proposed by Dvorak (2) provides useful
guidance in recognizing TA-TMA, though proteinuria instead of
thrombocytopenia is the third universal feature in local cohort
\textbf{(Table 1b)} .

\textbf{2. Challenges in assessment of therapeutic efficacy}

Management algorithm proposed by Jodele et al (24) stratifies high risk
TA-TMA patients as indication for eculizumab use with therapeutic drug
level monitoring. Clinical utility of this guideline is limited in local
setting as measurement of both soluble terminal complement complex
(sC5b-9) and eculizumab drug level are not readily available in local
laboratories. Long turnaround time due to transportation to overseas
accredited laboratories limits its use in facilitating timely clinical
decision making and management. Besides, eculizumab is currently
licensed only for treating atypical hemolytic-uremic syndrome (HUS) and
paroxysmal nocturnal hemoglobinuria. Off-label use of eculizumab for
TA-TMA costs USD\$6,700 per 300mg vial, which has great financial
implication on public healthcare system. Moreover, although decline in
glomerular filtration rate (GFR) and thus degree of kidney injury is
better evaluated by cystatin C (by Larsson formula) instead of serum
creatinine (by Schwartz formula) which is a late and insensitive
parameter particularly in young patients with low muscle mass and low
creatinine generation rates, cystatin C test is also not available in
local setting.

\textbf{3. Pathogenesis, risk factors and prevention}

Three-hit hypothesis proposed by Kosala et al (25) and Dvorak et al (2)
provide insights on pathogenesis of TA-TMA. For the ``first hit''
(initiation phase), patients either have an underlying predisposition to
complement activation (e.g., racial or genetic factors) or a
pre-existing endothelial injury (e.g., prior myeloablative conditioning
or prolonged use of calcineurin inhibitors). Genetic predisposition had
not been identified in local cohort except identification of a variant
of unknown significance in THBD gene for\textbf{Case 6 (Table 1b)} . For
the ``second hit'' (progression phase), delivery of conditioning regimen
mediates further endothelial injury. Injured endothelium exposes
damage-associated molecular patterns, which activates C3 to initiate
alternative pathway activity in the complement system. The ``third hit''
refers to complement activation by drugs, GVHD, infection or antibodies.
Usage of eculizumab in local cohort readily suppressed classical and
alternative complement pathway (the ``third hit''), normalized
haematological parameters, and resolved hypertension and proteinuria,
but damage to kidneys and decline in GFR are irreversible \textbf{(Table
1c)} .

Risk factors for development of TA-TMA include female sex (9, 17, 26,
27), older age (9, 16, 17, 26) , genetic variants in complement
activation (28), alternative donor transplant (16, 17, 22, 26), blood
group incompatibility (15, 26), intensive conditioning regimen (16, 18),
particularly those containing high dose busulphan (13) or irradiation
(17, 27), use of antithymocyte globulin (14), calcineurin inhibitor as
GVHD prophylaxis (13), infections (20, 27), and presence of GvHD (13,
15-18, 20, 22, 26, 27, 29). Vitamin D, eicosapentaenoic acid (EPA),
allopurinol, statin, and defibrotide are all potentially useful
compounds in preventing TA-TMA but their efficacy and safety has yet to
be elucidated.

\textbf{4. Prognostic factors}

Reported prognostic factors associated with poor outcome include
elevated LDH (20), acute kidney injury (20), proteinuria
(\textgreater{}30 mg/dL)(23), and raised plasma sC5b-9 at diagnosis
(23). Patients with proteinuria and elevated sC5b-9 at diagnosis had
84\% mortality while all patients without proteinuria or elevated sC5b-9
survived. Pulmonary hypertension is another poor prognostic factor with
80\% mortality (30). Elevated right ventricular pressure at day +7
post-transplant was significantly associated with subsequent development
of TA-TMA (25, 31).

\textbf{Conclusion}

In conclusion, recognition and diagnosis of TA-TMA is challenging.
Clinical utility of complement blockage with eculizumab is limited in
terms of therapeutic efficacy, response monitoring and financial
implications. Further prospective research studies on alternative agents
are warranted to improve treatment and outcomes of TA-TMA.

\textbf{Disclosure}

All authors have disclosed no conflicts of interest.

\textbf{Acknowledgement}

We would like to express our sincere gratitude to Dr Ng Wai Fu, retired
pathologist from Department of Pathology of the Hong Kong Children's
Hospital, for his contribution in the pathological diagnoses of
transplant-associated thrombotic microangiopathy of our patients
aforementioned.



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\textbf{Legend}

\textbf{Table 1a} Transplant details for local territory-wide cohort for
transplant-associated thrombotic microangiopathy (TA-TMA)

\textbf{Table 1b} Clinical and laboratory presentations of local
territory-wide cohort for transplant-associated thrombotic
microangiopathy (TA-TMA)

\textbf{Table 1c} Treatment and outcomes of local territory-wide cohort
for transplant-associated thrombotic microangiopathy (TA-TMA)

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