THROMBOSIS AND HEMOSTASIS
Abnormalities in the alternative pathway of complement in children
with hematopoietic stem cell transplant-associated thrombotic
Sonata Jodele,1Christoph Licht,2Jens Goebel,3Bradley P. Dixon,3Kejian Zhang,4Theru A. Sivakumaran,4
Stella M. Davies,1Fred G. Pluthero,2Lily Lu,2and Benjamin L. Laskin5
1Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH;2Division of Nephrology,
The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada;3Division of Nephrology and Hypertension and4Division of Human
Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; and5Division of Nephrology, The Children’s Hospital of Philadelphia, University of
Pennsylvania, Philadelphia, PA
• Genetic variations in the
alternative pathway of
complement may be
associated with thrombotic
microangiopathy in children
• These findings may guide the
development of novel
treatment interventions for
this poorly understood
Hematopoietic stem cell transplant (HSCT)-associated thrombotic microangiopathy (TMA)
is a complication that occurs in 25% to 35% of HSCT recipients and shares histomorpho-
logic similarities with hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic
purpura (TTP). The hallmark of all thrombotic microangiopathies is vascular endothelial
cell injury of various origins, resulting in microangiopathic hemolytic anemia, platelet
consumption, fibrin deposition in the microcirculation, and tissue damage. Although
significant advances have been made in understanding the pathogenesis of other
thrombotic microangiopathies, post-HSCT TMA remains poorly understood. We report an
analysis of the complement alternative pathway, which has recently been linked to the
Conversely, CFH autoantibodies were not detected in 18 children undergoing HSCT
who didnotdevelop TMA. Ourobservations suggest thatcomplement alternative pathway
dysregulation may be involved in the pathogenesis of post-HSCT TMA. These findings shed light on a novel mechanism of endothelial
injury in transplant-TMA and may therefore guide the development of targeted treatment interventions. (Blood. 2013;122(12):
Hematopoietic stem cell transplant (HSCT)-associated thrombotic
microangiopathy (TMA) shares histomorphologic similarities with
other small vessel diseases including diarrhea positive hemolytic
uremic syndrome (HUS), atypical HUS (aHUS), thrombotic throm-
bocytopenic purpura (TTP), and preeclampsia/HELLP syndrome
(hemolysis, elevated liver enzymes, and low platelets). These
disorders occur when endothelial injury leads to microangiopathic
hemolytic anemia, platelet consumption, fibrin deposition in the
microcirculation, and, ultimately, end-organ injury.1,2
Advances in understanding the pathogenesis of other micro-
angiopathies, such as the role of complement mutations in aHUS
and ADAMTS13 (a disintegrin and metalloproteinase with a
thrombospondin type 1 motif, member 13) deficiency in TTP, has
improvedoutcomes through earlydiagnosisandtheuseoftargeted
therapies.3-5In contrast, although TMA was recognized as a
complication of HSCT in the early 1980s and may occur in 25% to
35% of stem cell transplant recipients, we do not fully understand
the exact mechanisms of vascular endothelial injury in HSCT-
associated TMA.6-8Risk factors for HSCT-associated TMA include
chemotherapy, radiation, graft versus host disease, calcineurin
inhibitors, and viral infections.1,9The kidney is the most commonly
injured organ, but unrecognized and untreated HSCT-associated
TMA can evolve into a lethal multisystem disease.10In its most
severe form mortality rates are very high (;90%), especially when
dialysis is required. Milder cases may increase the risk of later
chronic kidney disease.11,12
Dysregulation of the complement alternative pathway has been
implicated in the kidney injury found in patients with Shiga toxin
mediated and aHUS, membranoproliferative glomerulonephritis
(MPGN), and preeclampsia/HELLP syndrome.13,14Inappropriate
complement activation or insufficient inhibition can result in vascular
endothelial injury and thrombotic microangiopathy. Deletions
in the complement Factor H (CFH)-related genes 3 and 1
(delCFHR3-CFHR1) have been associated with autoantibodies
Submitted May 10, 2013; accepted June 25, 2013. Prepublished online as
Blood First Edition paper, June 27, 2013; DOI 10.1182/blood-2013-05-
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against CFH in a subgroup of patients with aHUS called DEAP
HUS (Deficiency of CFHR plasma protein and Autoantibody
Positive) who respond to antibody depleting or complement
blocking therapy.15,16The role of complement in TMA occurring
after stem cell transplantation has not been defined. We present
our clinical observations suggesting the complement alternative
pathway is involved in the pathogenesis of HSCT-associated
Six consecutive patients who developed TMA after HSCT at Cincinnati
Children’s Hospital Medical Center (CCHMC) in 2009 were tested to
determine the potential role of the complement alternative pathway in HSCT-
associated TMA. TMA was diagnosed using current diagnostic criteria
including elevated lactate dehydrogenase (LDH) above normal for age,
haptoglobin below the lower limit of normal, evidence of schistocytes on
peripheral blood smear, anemia, thrombocytopenia, a negative Coombs test,
and acute kidney injury (AKI) defined as a doubling of the serum creatinine
relative to each subject’s pre-HSCT baseline.17,18Informed consent for
clinical genetic testing was obtained according to the requirements of the
Molecular Otolaryngology & Renal Research Laboratories (MORL) at the
University of Iowa. Research informed consent was obtained from patients
for CFHR protein testing on stored serum samples, and the CCHMC
Institutional Review Board approved data review and analysis. Study
subjects’ pre-HSCT plasma samples and control subjects’ plasma samples
were obtained from the CCHMC Bone Marrow Transplant repository. All
subjects in the repositories had previously consented to “future research
studies.” The control group included 10 consecutive allogeneic HSCT
recipients without any evidence of TMA or AKI during the first 100 days
post-HSCT, 5 consecutive allogeneic HSCT recipients with AKI of non-
TMA origin documented as doubling of serum creatinine from pre-HSCT
baseline, but without any laboratory evidence of TMA, and 3 patients
after autologous stem cell transplantation without any evidence of TMA
or AKI. This study was conducted in accordance with the Declaration of
Complement gene testing
Recipient DNA was extracted from blood samples collected before HSCT.
Direct gene sequencing analysis was used to identify single nucleotide
variations, small deletions, and small insertions in the protein coding
regions including intron/exon boundaries of CFH, Complement Factor I
(CFI), membrane cofactor protein (MCP), Complement Factor B (CFB),
and CFH-related-5 (CFHR5) genes.
Multiplex Ligation-Dependent Probe Amplification (MLPA) testing
procedure was used to examine CFH-CFHR5 in order to identify two
common, large deletions in the regulator of complement activation (RCA)
pre-HSCTsamples.All complement gene testingwasperformed at theMORL
laboratory according to their established laboratory techniques. Results were
reported as the presence or absence of alleles. The presence of both alleles was
considered a normal test. The absence of one allele was reported as a het-
erozygous gene deletion, and the absence of both alleles was reported as a
homozygous gene deletion. ADAMTS13 activity was tested in all patients to
rule out TTP by fluorescence resonance energy transfer (FRET) at CCHMC
Autoantibodies to CFH
In the six study subjects who developed TMA, CFH autoantibody was tested
on plasma collected before HSCT and after diagnosis of TMA. CFH
autoantibody testing for the control group without a diagnosis of TMA was
performed on plasma specimens collected at 100 days after HSCT, because
the highest risk time to develop TMA is during the first 100 days after
using an enzyme-linked immunosorbent assay (ELISA) at the MORL
laboratory for study subjects and CCHMC laboratory for control group
or “absent” CFH autoantibody.
Analysis of circulating CFHR1
In the six study subjects with TMA, serum was tested for the presence of the
CFHR1 protein on samples collected before HSCT. Testing was performed
by immunoblotting (western blot) as previously described at the Division of
Nephrology, The Hospital for Sick Children, Toronto, ON, Canada.14
Results were reported as “present” or “absent” CFHR1.
diagnosis of TMA are summarized in Table 1. Most of the patients
underwent HSCT for a malignant disorder (5 out of 6, 83%). Three
Table 1. Study patient demographics and disease characteristics
diagnosed TMA complications
14neuroblastoma autologousCEM (MA)
123HTN, PRES, seizures, polyserositis,
cardiac tamponade, acute dialysis
3 6.5neuroblastomaautologousCEM (MA)
147HTN, PRES, seizures, acute dialysis
53 acute lymphoblastic
allogeneic TBI/CY (MA)
135HTN, PRES, seizures, multiorgan
failure, acute dialysis
CEM, carboplatin-etoposide-melphalan; C-FM, Alemtuzumab(Campath)-Fludarabine-melphalan; Day1, day after stem cell transplantation; ESRD, end-stage renal
disease; HTN, hypertension; MA, myeloablative; PRES, posterior reversible encephalopathy syndrome; RIC, reduced intensity conditioning; TBI/CY, total body
irradiation-cyclophosphamide; TMA, stem cell transplant-associated; TPE, therapeutic plasma exchange.
2004JODELE et al BLOOD, 19 SEPTEMBER 2013 x VOLUME 122, NUMBER 12
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patients received an allogeneic HSCT from an unrelated donor, and
the remaining three received an autologous HSCT. TMA was
diagnosed clinically a median of 32.5 days post-HSCT (range 9-111
days). The diagnosis of TMA was also confirmed by kidney biopsy
in two subjects (patients 1 and 4).
received, and clinical outcome. All patients developed AKI and had
severe hypertension requiring 4 to 9 antihypertensive medications to
control their blood pressure. Three of the six patients (patients #1, #4,
and #6) required hemodialysis. Regarding potential triggers for TMA,
other documented infections. None of the three allogeneic recipients
had evidence of graft versus host disease.
Calcineurin inhibitor prophylaxis was stopped in the three
allogeneic recipients after TMA was diagnosed. Weekly rituximab
(375 mg/m2/dose) infusions were empirically initiated in all subjects
and 2 to 10 doses were administered.10Four patients with continued
clinical evidence of thrombotic microangiopathy despite rituximab
administration received daily therapeutic plasma exchange (TPE)
according to the institutional practices, as previously described.19
Four of the six patients (66%) had a positive response to rituximab
and/or TPE, whereas the remaining two progressed to end-stage
The results of the analysis of the complement alternative
pathway are shown in Table 2. Five of the 6 transplant recipients
(83%) had heterozygous CFHR3-CFHR1 gene deletions detected
by MLPA. On further testing, one of these five patients was shown
to have a heterozygous deletion spanning from CFHR1-CFHR4.
Three autologous transplant recipients with TMA were previously
reported, as part of a larger neuroblastoma cohort, as having no
detectable complement gene abnormalities, because they had no
but CFH-CFHR5 testing by MLPA was not available at that time,
publication.20One of the bone marrow donors (1 out of 3, 33%) also
had a heterozygous deletion in the CFHR3-CFHR1 gene detected by
autoantibodies. Two of these patients with CFH autoantibodies had
an associated heterozygous CFHR3-CFHR1 deletion, whereas the
remaining allogeneic transplant recipient didnot have any detectable
complement gene abnormalities that were tested. Patient #6 was
previously described as a clinical case report showing complete
resolution of hyperacute TMA with multiorgan involvement that
completely responded to prompt therapy with TPE and rituximab.
Patients#4 and #5arenewlyidentified caseswith CFH autoantibody
in our cohort of consecutive patients tested for complement system
had identifiable mutations in CFI, CFH, MCP, CFB, or CFHR5
genes by direct gene sequencing. By western blot, all patients had
detectable CFHR1 protein. There were no available tests to examine
C3 and C4 at TMA diagnosis. ADAMTS13 activity was normal to
slightly decreased, ranging from 59% to 96%, ruling out a diagnosis
of TTP (normal range .67% with ,10% being diagnostic for TTP).
Four of six patients (#2, #3, #4, #5) had pre-HSCT plasma sample
available in the BMT repository that had no detectable CFH
autoantibody before starting transplant chemotherapy. None of the
100 days after HSCT. Overall, 3 out of 6 (50%) of the patients with
TMA had detectable CFH autoantibodies, compared with 0 out of
18 (0%) of the controls (P 5 .01).
We examined the complement alternative pathway in 6 children
developing TMA after either autologous or allogeneic HSCT. We
identified a high prevalence (83%) of heterozygous CFHR3-CFHR1
deletions in HSCT recipients with TMA, whereas the same gene
variations in donors (33%) occurred at a frequency similar to that
HSCT recipients with TMA had detectable autoantibodies to CFH,
We speculate that CFH autoantibodies detected after HSCT are
pathogenic and can possibly trigger TMA, because 2 of these 3
allogeneic HSCT recipients, for whom pre-HSCT plasma samples
were available, were shown to have CFH autoantibody at TMA
diagnosis but not before transplantation. Also, none of the HSCT
recipients without TMA (control group) had any detectable CFH
autoantibodies at 100 days after transplantation, suggesting that CFH
The exact pathogenesis of TMA after HSCT remains incom-
pletely understood, limiting identification of the patients at highest
of targeted therapies.1Although TMA after HSCT may be triggered
by several factors, our preliminary observations suggest that TMA
may be associated with complement dysregulation at least in some
HSCT recipients, as evidenced by detectable CFH autoantibodies
and a positive response to antibody depleting therapy (rituximab,
TPE) in our patients.
Autoimmunity is a well-recognized complication after allogeneic
produced by host plasma cells as a response to recipient/donor CFH
genotype differences, as CFH autoantibodies were only observed in
allogeneic but not in autologous HSCT recipients in our cohort.
Table 2. Complement system analysis in patients with HSCT-TMA
CFHR1 protein analysis
1autologousnormal alleles*del(CFHR3-CFHR1)n/aabsent present
3autologous normal alleles*del(CFHR1-CFHR4) n/aabsent present
4allogeneic normal alleles*del(CFHR3-CFHR1) normal allelepresentpresent
5 allogeneicnormal alleles*del(CFHR3-CFHR1)*del(CFHR3-CFHR1) presentpresent
6 allogeneicnormal allelesnormal allelenormal allelepresentpresent
CFR, complement factor H-related gene 5.
*del refers to heterozygous deletions.
BLOOD, 19 SEPTEMBER 2013 x VOLUME 122, NUMBER 12COMPLEMENT ABNORMALITIES IN HSCT ASSOCIATED TMA2005
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Inhibitory autoantibodies to CFH, either alone or in combination
aHUS.22In aHUS, homozygous mutations in the CFHR3-CFHR1
genes have been associated with CFH autoantibody formation, an
entity termed DEAP-HUS (Deficiency of CFHR plasma protein and
Autoantibody Positive).23Homozygous CFHR3-CFHR1 deletions
are reported in 2% to 5% of the normal healthy white population, are
observed in 11% to 15% of patients with aHUS, and occur in .90%
of patients with DEAP-HUS. By contrast, heterozygous CFHR3-
CFHR1deletionsareidentified in 20% to 24% of whites and up to
35% of African Americans.21
Patients with aHUS lacking CFHR1, but not those lacking
CFHR3, present with CFH antibodies, suggesting that the generation
of these antibodies is associated with CFHR1 deficiency.15,16,22,24
Although CFH autoantibodies are reported in approximately 10% of
patients with aHUS, they are not specific for aHUS and have been
identified in 9% to 16% of patients with rheumatoid arthritis, 7% of
patients with systemic lupus erythematosus, 9% of patients with a
in patients with clinical disease, CFH autoantibody titers varied
among individual patients throughout time and were usually
detected during periods of more severe disease.25
CFH autoantibodies isolated from patients with aHUS bind to
the C-terminus of CFH. As in aHUS-related CFH mutations,
which also affect the C-terminal short consensus repeats (SCRs)
surfaces,thus resulting ina lack of normalcomplement control on the
endothelium. In contrast, epitope mapping experiments in patients
with rheumatic disease suggest that CFH autoantibodies bind to
several epitopes scattered throughout the CFH protein, possibly
explaining the more generalized inflammation observed in patients
with rheumatic conditions relative to aHUS in which the kidney is
identified in a high percentage of HSCT patients with TMA and were
associated with detectable CFH autoantibodies in allogeneic HSCT
recipients warrants further investigation. We speculate that heterozy-
gous deletions in CFHR3-CFHR1genes,even though common inthe
general population, may influence recipients’ susceptibility to direct
endothelial injury from high-dose chemotherapy or viral infections
after HSCT. It would therefore be of clinical interest to determine
whether recipient, donor, or both genotypes determine the suscepti-
bility to TMA after HSCT, potentially supporting baseline genetic
testing of the complement alternative pathway.
Because CFH autoantibodies were checked only once after the
diagnosis of TMA in our patients, we were not able to correlate the
if CFH autoantibodies were simply missed in autologous HSCT
recipients. Because autoimmunity is a well-documented phenome-
non after allogeneic HSCT, it remains possible that the presence of
autoantibodies to CFH may reflect immune dysregulation after
HSCT independent of the genetic abnormalities in the complement
system described in other types of thrombotic microangiopathies.
Clinically, two allogeneic and two autologous HSCT recipients
antibodies (rituximab, TPE). Even though CFHR1 was detected in
all patients by western blot, we were unable to determine whether
this protein is fullyfunctional in patientswith heterozygous CFHR3-
CFHR1 deletions. Since the CFHR1 protein is a presumed regulator
of the C5 convertase within the complement alternative pathway,
it would be important later to examine its function in individuals
with heterozygous CFHR3-CFHR1 deletion and to determine if TPE
offers therapeutic benefit by replacing defective protein in these
patients.26Recent studies showed that exogenous CFHR1 provided
during plasma exchange therapy for thrombotic microangiopathy
may neutralize anti-factor H autoantibodies and help in the treatment
of autoimmune aHUS.27Such knowledge would lead to a more
rational use of rituximab and TPE treatments in HSCT patients with
TMA for which we currently have no clear understanding of their
Along these lines, novel therapies such as the terminal com-
plement inhibitor eculizumab may offer another treatment option for
post-HSCT TMA. Eculizumab, which binds to C5 and prevents
generation of the membrane attack complex, has shown benefit in
patients with antibody-mediated kidney transplant rejection, aHUS,
and preeclampsia/HELLP syndrome28,29and was recently reported
to abrogate HSCT-associated TMA in an adult patient without a
documented complement genetic abnormality.30Targeted therapy
aimed at minimizing vascular endothelial damage in patients with
TMA may preserve kidney function and improve outcomes after
increased risk of developing chronic kidney disease after HSCT.
Future research is needed to examine further the role of complement
in the pathogenesis of TMA.
We thank the physicians, nurses, care managers, transplant coor-
dinators, and other care providers and staff at Cincinnati Children’s
Hospital, and we especially thank the patients and their families.
J.G. and S.M.D. performed research, edited the manuscript, and
provided vital conceptual insights; K.Z. and T.A.S. provided genetic
consultation and edited the manuscript; C.L. and F.G.P. provided
consultation for complement system analysis and manuscript editing;
F.G.P.andL.L.performed complementtestingon studysubjects;and
B.P.D. performed complement testing on the control group.
Conflict-of-interest disclosure: B.L.L. is supported by a Career
National Cancer Institute awarded to the University of Pennsylvania
(KM1CA156715-01). C.L. has a financial relationship with Alexion
Pharmaceuticals, Inc., via consultancy, paid speaking, and unre-
stricted research grants. S.J. has an Investigator Initiated Research
Grant (as PI) for complement gene testing in HSCT patients from
Alexion Pharmaceuticals, Inc., and is co-principal investigator on
National Institutes of Health grant P50DK096418 for AKI biomarker
testing in HSCT-TMA. B.P.D. has a financial relationship with both
Alexion Pharmaceuticals, Inc., and Novartis Pharmaceuticals via
consultancy and paid speaking. None of these funding sources had
any input in the study design, analysis, manuscript preparation, or
decision to submit for publication. The remaining authors declare no
competing financial interests.
Correspondence: Sonata Jodele, Division of Bone Marrow Trans-
plantation and Immune Deficiency, Cincinnati Children’s Hospital
Medical Center, 3333 Burnet Ave, MLC 11027, Cincinnati, OH
45229; e-mail: firstname.lastname@example.org.
2006JODELE et alBLOOD, 19 SEPTEMBER 2013 x VOLUME 122, NUMBER 12
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2013 122: 2003-2007
Sivakumaran, Stella M. Davies, Fred G. Pluthero, Lily Lu and Benjamin L. Laskin
Sonata Jodele, Christoph Licht, Jens Goebel, Bradley P. Dixon, Kejian Zhang, Theru A.
hematopoietic stem cell transplant-associated thrombotic
Abnormalities in the alternative pathway of complement in children with
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