Thrombotic Microangiopathy in Haematopoietic Cell
Transplantation: an Update
Evi Stavrou and Hillard M. Lazarus.
Department of Medicine,
University Hospitals Case Medical Center, Case Western Reserve
University, Cleveland, OH 44106
M. Lazarus, MD, FACP. Department of Medicine, University Hospitals Case
Center, 11100 Euclid Avenue, Cleveland, OH 44106. Telephone
216-844-5979. E-mail: email@example.com
Published: November 3, 2010
Received: October 9, 2010
Accepted: October 29, 2010
Medit J Hemat Infect Dis 2010, 2(3): e2010033, DOI
This article is available from: http://www.mjhid.org/article/view/6425
This is an Open Access article
distributed under the terms of
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0
which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited
hematopoietic cell transplantation (HCT) represents a vital procedure
for patients with various hematologic conditions. Despite advances in
the field, HCT carries significant morbidity and mortality. A rare but
potentially devastating complication is transplantation-associated
thrombotic microangiopathy (TA-TMA). In contrast to idiopathic TTP,
whose etiology is attributed to deficient activity of ADAMTS13, (a
member of the A Disintegrin And Metalloprotease with Thrombospondin 1
repeats family of metalloproteases), patients with TA-TMA have > 5%
ADAMTS13 activity. Pathophysiologic mechanisms associated with TA-TMA,
include loss of endothelial cell integrity induced by intensive
conditioning regimens, immunosuppressive therapy, irradiation,
infections and graft-versus-host (GVHD) disease. The reported incidence
of TA-TMA ranges from 0.5% to 75%, reflecting the difficulty of
accurate diagnosis in these patients. Two different groups have
proposed consensus definitions for TA-TMA, yet they fail to distinguish
the primary syndrome from secondary causes such as infections or
medication exposure. Despite treatment, mortality rate in TA-TMA ranges
between 60% to 90%. The treatment strategies for TA-TMA remain
challenging. Calcineurin inhibitors should be discontinued and replaced
with alternative immunosuppressive agents. Daclizumab, a
humanized monoclonal anti-CD25 antibody, has shown promising results in
the treatment of TA-TMA. Rituximab or the addition of defibrotide, have
been reported to induce remission in this patient population. In
general, plasma exchange is not recommended.
hematopoietic cell transplantation (HCT) is a useful therapeutic
modality for a wide range of hematologic and non-hematologic conditions.[1-3]
Peripheral blood progenitor cell collection, the new ‘gold standard’ in
hematopoietic cell harvesting, and non-myeloablative peripheral blood
progenitor cell transplantation, have reduced treatment-related
mortality and enabled an increasing number of patients with
comorbid conditions as well as older patients to receive therapy for
conditions such as acute leukemia, myelodysplastic syndrome, multiple
myeloma and lymphoma. The obstacles to successful HCT include the
development of acute and chronic graft-versus-host disease (GVHD),
opportunistic infections, and other complications, one of which is
transplantation-associated thrombotic microangiopathy (TA-TMA).[4-6]
The etiologies of this syndrome are diverse, and diagnosis of TA-TMA in
this patient population requires a high degree of clinical suspicion.
Moreover, management of TA-TMA remains a challenging task, mainly due
to the poor response to therapeutic modalities that are beneficial in
Pathologic and clinical features
TMAs are defined by the association of microangiopathic hemolytic
anemia, thrombocytopenia (platelet count < 100x109/L) and ischemic
manifestations related to the formation of platelet-rich thrombi in the
TMAs include thrombotic
thrombocytopenic purpura (TTP), and the hemolytic-uremic syndrome
(HUS), and variants of these, which are characterized by ischemic
manifestations involving the brain or gastrointestinal tract and/or
TMA may be primary, or occur
secondary to other disorders such as pregnancy, infections, autoimmune
diseases and the post-HCT state.
The clinical presentation of TMA invariably includes the presence of
schistocytes on the peripheral blood film and consumptive
thrombocytopenia. Surrogate markers include DAT (direct antiglobulin
test)-negative hemolytic anemia, an elevated serum lactate
dehydrogenase (LDH), decreased serum haptoglobin and indirect
hyperbilirubinemia. Coagulation studies are usually normal. A “pentad”
of signs and symptoms was traditionally associated with classic TTP:
thrombocytopenia, microangiopathic hemolytic anemia (MAHA), neurologic
abnormalities, renal abnormalities and fever. This complete set of
symptoms occurs in only 40% of patients, and more than 70% have only
the triad of MAHA, thrombocytopenia, and neurologic changes at the time
of diagnosis.10 In current clinical practice, thrombocytopenia,
schistocytosis, and an elevated serum LDH in the appropriate clinical
setting provide sufficient criteria for the diagnosis.
The clinical manifestations of HUS are similar to TTP, although renal
abnormalities, as opposed to neurologic dysfunction, often predominate.
Presentation of TA-TMA is similar to other forms of TMA; multiple
contributing pathogenic factors have been implicated.[4,11]
These include endothelial cell injury due to toxic conditioning
regimens (high-dose chemotherapy and total-body irradiation [TBI]),
cytomegalovirus (CMV) infection, the use of calcineurin inhibitors such
as cyclosporine, and a possible graft-versus-host effect on the
anemia, thrombocytopenia, renal impairment, and changes in mental
status are common and may have multiple causes in the transplant
population, diagnosis may be difficult.
observation currently is motivating experts in the field to reformulate
a classification of TMAs more focused on pathophysiologic mechanisms
rather than clinical symptoms.[16, 17]
Until recently, there were no widely accepted criteria for the
definition of hematopoietic progenitor cell TA-TMA. The Blood and
Marrow Transplant Clinical Trials Network (BMT CTN) and the
International Working Group separately formed toxicity committees to
develop a consensus formulation of criteria for diagnosing clinically
significant TA-TMA; these are listed in Table 1
Incidence and risk factors
The reported proportion of patients developing a clinically significant
TA-TMA syndrome has varied greatly. George and coworkers15 presented a
review of published reports on TMA after allogeneic HCT. Twenty-eight
different definitions of this syndrome have been used in the 35
reviewed reports. Reflecting the different definitions, the incidence
of TA-TMA varied in these reports from 0.5 to 63.6% of HCT recipients,
the median frequency of diagnosis being 7.9%. The mortality in the
different series ranged from 0% to 100%; the overall mortality rate was
61%. Of the deceased patients, 35 autopsy reports were identified.
Three of the autopsies attributed death to HUS due to observation of
isolated renal TMA. The remaining 32 deaths were attributed to other
causes, the most common being systemic infection, including CMV,
Aspergillus species, adenovirus and human herpesvirus-6 (HHV-6). Eleven
autopsies stated that there was no evidence of TTP-HUS.
In another review, Pettitt and Clark4 estimated that TA-TMA occurs in
14% and 7% of allogeneic and autologous transplant recipients,
respectively. A more recent report of more than 4000 HCT recipients
estimated the frequency of severe TA-TMA to be 0.5% and 0.13% of
allogeneic and autologous recipients, respectively.
This varying incidence of TA-TMA among reported series likely reflects
the level of physician awareness, the different diagnostic criteria,
and the heterogeneity of the transplant population.
A variety of potential risk factors for the development of TA-TMA have
been proposed (Table 2
the earliest reports, the use of
cyclosporine (CsA) for the prevention of GVHD was recognized as a
with other inhibitors of the Ca2+-activated phosphatase, calcineurin
have been associated with TA-TMA as well. In the following section we
examine the pathophysiology and clinical characteristics of both
primary and secondary TMAs. The heterogeneity in clinical background
(idiopathic TTP vs. disease-associated TMA, including TA-TMA) and
plasma concentration of markers (normal vs. decreased ADAMTS13
activity) is well emphasized and represents a barrier to the
development of clear treatment guidelines.
Moake and colleagues 
were the first to describe the presence of very high molecular
weight [so-called ultralarge (UL)] multimers of von Willebrand factor
(vWF) in the plasma of a patient with recurrent TTP. Once released from
stimulated endothelial cells, UL-vWF, not present in plasma from
healthy individuals, promote excessive aggregation of platelets,
primarily in the microvasculature. Some ULvWF multimers remain on the
endothelial cell surface as long strings that adhere to platelets. The
molecules responsible for the binding of UL-vWF to endothelial cells
and platelets are believed to involve integrin αvβ3 and glycoprotein Ib
and hemolytic anemia occur particularly in high shear stress locations,
such as the microvasculature, that results in unfolding of ULvWF
multimers and exposure of platelet binding sites.[7,28]
Moake hypothesized that a deficiency of a vWF cleaving protease might
be responsible for the presence of ULvWF, 
it was Furlan and colleagues 
et al., Tsai and
who first isolated a plasma metalloprotease that cleaved the peptide
bond between the tyrosine 1605 and methionine 1606 in the central A2
domain of vWF. These investigators subsequently found a deficiency of
this vWF-cleaving protease in a retrospective cohort of patients
clinically diagnosed as having TTP.[29,30]
protease was characterized in 2001 by Zheng and coworkers31 as a new
(the thirteenth) member of the ADAMTS (A Disintegrin And
Metalloprotease with Thrombospondin 1 repeats) family of
metalloproteases and was thus called ADAMTS13.[16,31-34]
The primary role of ADAMTS13 is to regulate the multimeric structure of
vWF by cleaving the most hemostatically active ULvWF multimers.
Failure of this regulatory mechanism causes the highly adhesive,
unusually large multimers of vWF to accumulate in plasma, which may
lead to the microvascular thrombosis, tissue ischemia and infarction
which are characteristic of TTP.
The estimated annual incidence of idiopathic TTP is 3.7 to 11 cases per
In extremely rare cases, severe deficiency of ADAMTS13 (defined as
<5% serum activity) is related to compound heterozygous or
homozygous mutations of the ADAMTS13 gene (Upshaw-Shulman syndrome).[37-39]
Defects in coding of the metalloprotease gene, located on chromosome
9q34, result in functionally deficient enzyme. In the vast majority of
cases, severe ADAMTS13 deficiency is secondary to the development of
anti-ADAMTS13 autoantibodies that can be detected in vitro.[29,30]
Functional testing often is employed in which anti-ADAMTS13
autoantibodies are detected by their inhibitory effect on ADAMTS13
enzymatic activity. More recently, physical methods of detection
have been used and identify either immunoglobulin G (IgG) or IgM
species via enzyme-linked immunosorbent assay (ELISA).[41,42]
In more than 80% of acquired TTP, anti-ADAMTS13 antibodies are
Less frequently, the mechanism
for acquired TTP may be different, involving anti-ADAMTS13
noninhibitory IgG or IgM [41,42]
promote the clearance of ADAMTS13 from blood without inhibiting its
Adults with acquired idiopathic TTP require daily plasma exchange
until neurologic symptoms have resolved and both a normal serum LDH and
platelet count have been maintained for at least 2 to 3 days.[43-46]
Plasma exchange is thought to remove antibodies
against ADAMTS13, while replacing the deficient protease.[47,48]
Plasma exchange results in the remission of TTP, which is usually fatal
when untreated, in approximately 80%-90% of cases,[49-52]
generally without persistent organ damage. Production of ADAMTS13
autoantibodies may also be suppressed by high-dose corticosteroid
although there is very little
controlled data that demonstrates efficacy of steroids in the treatment
of idiopathic TTP. Other therapies include use of the monoclonal
antibody rituximab that is directed against the CD20 epitope on B
lymphocytes; given weekly for 4-8 weeks, this agent will eliminate
antibody-producing cells [53-57]
and has been shown
to induce remission in refractory TTP, and to reduce the otherwise high
incidence of relapse in these patients.[56,58]
Finally, splenectomy also has been shown to be effective in anecdotal
cases of refractory TTP, and to reduce the incidence of relapse in
HUS refers to TMA that primarily affects the
kidney, often causing oliguric or anuric renal failure.
HUS may present with a variety of manifestations, with one variant
occurring after Escherichia coli O157:H7 gastroenteritis, primarily in
In adults, however, HUS occurs most
commonly in association with pregnancy, with more than 90% of cases
developing in the postpartum period.
characteristic histologic lesion of HUS consists of vessel wall
thickening, with swelling and detachment of the endothelial cells from
the basement membrane. In HUS, microthrombi are rich in fibrin and
contain relatively little vWF.[62
] Their location is
confined primarily to the kidneys and thus, renal failure is the
dominant feature. HUS associated with renal failure in the absence of a
diarrheal illness or other predisposing condition is commonly referred
to as atypical HUS. It has been proposed that this group may, in part,
consist of patients with complement system dysfunction owing to either
a mutation of a complement-regulatory protein,
antibody directed at one of these proteins,
or an activating mutation of a complement protein such as C3. Study of
families with a history of HUS has implicated mutations in several
proteins responsible for regulating the alternative complement pathway,
namely complement factor H,
protein (MCP), and factor I (IF),
as well as
Exposure to agents potentially toxic to the vascular endothelium (such
as certain viruses, bacteria, toxins, immunocomplexes, and cytotoxic
drugs) may initiate local intravascular thrombosis.
This action promotes C3bBb convertase formation and complement
deposition within capillary vessels. Under normal conditions,
however, factor H may effectively limit complement deposition and
further extension of the process by modulating C3bBb activity.
In contrast, when the factor H bioavailability is reduced due to
decreased activity or is congenitally defective, C3bBb convertase
formation and complement deposition may become uncontrolled. As a
result, the microangiopathic process is extended, leading to full-blown
manifestations of the disease.
Secondary forms of TMA refer to a diverse group of
disorders with frequently overlapping clinical features (Table 3
alternative classification that takes into consideration the underlying
pathophysiologic mechanisms (immune-mediated vs. nonimmune-mediated) is
presented here (Table 4
Immune-mediated forms result from
autoantibodies against ADAMTS13.[41,42,70]
The second category (nonimmune-mediated) occurs from massive
endothelial cell stimulation with consequent release of ULvWF multimers
in amounts exceeding the system’s degradative ability, despite the
presence of normal or only mildly reduced concentrations of ADAMTS13.
Distinction between these forms should limit diagnostic uncertainty and
assist with management strategies, namely implementation of plasma
exchange and use of immunosuppressive therapy.
Table 4: Pathophysiologic
classification of primary and
secondary thrombotic microangiopathies.
The most common physiologic
condition present in the immune-mediated
forms, which is often associated with severe ADAMTS13 deficiency, is
Immune-mediated TMA in pregnancy should be distinguished from a number
of pregnancy-associated TMAs such as preeclampsia, hemolysis with
elevated liver enzymes and low platelets (HELLP) syndrome, acute fatty
liver of pregnancy, and antiphospholipid syndrome.[74,75]
Accurate diagnosis is essential since plasma exchange is indicated for
pregnancy-associated TTP while fetal-placental delivery is therapeutic
for HELLP syndrome.
The association between TTP and SLE has been well recognized in
clinical and histologic reports.
deficiency of ADAMTS13 activity is predominantly associated with the
presence of inhibitory anti-ADAMTS13 IgG.
ADAMTS13 levels are not generally decreased with infections such as
HIV, suggesting an alternative mechanism for TMA in these patients.[77,78]
Cases of TMA associated with severe ADAMTS13
deficiency and inhibitory anti-ADAMTS13 IgG have been reported with
legionella pneumonia 
Antibodies that inhibit plasma ADAMTS13 have also been demonstrated in
patients with ticlopidine 
The immune dysregulation by these thienopyridine compounds might be
analogous to the anti-RBC antibody ‘escape’, associated with the
antihypertensive medication α-methyldopa.
The most frequent concomitant conditions associated with TMA forms
presenting with normal or mildly reduced levels of ADAMTS13 (greater
than 10% serum activity) are malignant hypertension,17 metastatic
tumors,85 solid organ transplantation, HCT (particularly allogeneic
transplants), and the use of drugs such as cyclosporine, mitomycin, and
Despite having some features in common, TA-TMA differs from de novo TTP
in many aspects including the absence of severe ADAMTS13 deficiency, a
different spectrum of clinical symptoms, poor response to plasma
exchange, and the lack of evidence of systemic microthrombus formation.
Several small retrospective studies of TA-TMA encompassing a total of
33 HCT recipients also suggest that severe ADAMTS13 deficiency may be
rare among this patient population.[86-88]
other prospective reports in HCT recipients suggest that the majority
of these patients experience only a mild decrease in ADAMTS13 activity
(usually after the cytotoxic conditioning) that can persist for weeks;
however, severe ADAMTS13 deficiency was rare.[89,90]
These data suggest that, unlike idiopathic TTP, ADAMTS13 deficiency is
not the primary component of the pathophysiology of TA-TMA and other
factors may play a more central role.
endothelial cell injury:
long time, many authorities have considered endothelial cell injury as
central and likely inciting factor that sustains the microangiopathic
in TMA, including the post-transplantation state.
early as 1942, Altschule 
suggested that microvascular endothelial cell activation was the
causing platelet deposition in arterioles and capillaries with
“clearance of enormous numbers of platelets from the circulation”.
cells synthesize many substances involved in coagulation and
including vWF, thrombomodulin, tissue-type plasminogen activator (tPA),
plasminogen activator inhibitor (PAI-1), protein S, prostacyclin
nitrous oxide (NO). Alterations in the concentration of these
been reported in idiopathic TTP and TA-TMA.[92,93]
alterations represent an initiating effect or simply are reflective of
endothelial cell injury, remains elusive. Levels of vWF antigen and
thrombomodulin were measured in patients with idiopathic TTP and TA-TMA.
vWF antigen and thrombomodulin levels were elevated in both patient
compared to controls. Thrombomodulin concentrations were significantly
in TA-TMA compared to idiopathic TTP, supporting a role for endothelial
damage in the former. Gordon and colleagues 
protein C deficiency correlated with thrombotic complications in
Several groups have
reported elevated plasma levels of fibrinogen, tPA, PAI-1, vWF antigen,
thrombomodulin, and intercellular adhesion molecule 1 (ICAM-1).[96-100]
Kanamori et al.
proposed that measurement of
levels on day 14 post-HCT may be useful in surveillance for TA-TMA.
proposed that endothelial cell
injury is pathognomonic
of TA-TMA as well after they demonstrated absent endothelial cell PGI2
release and scanning electron microscopy (EM) evidence of endothelial
damage with TMA after allogeneic HCT.
1996, Laurence and co-workers 
from four acute TTP patients could induce apoptosis of cultured
cells of microvascular but not of large-vessel origin. Ultrastructural
became apparent within 30 minutes after exposure of endothelial cells
sera and fresh complement; virtually every cell quickly developed
cytoplasmic inclusions, followed by complete cytoplasmic and nuclear
degeneration. Apoptosis was independent of tumor necrosis factor-α
(TNF- α) or
the presence of CD36 on microvascular endothelial cells, but was linked
rapid induction effect of Fas (CD95) on these cells. Use of soluble
antibodies suppressed the endothelial cell apoptosis mediated by TTP
The presence of
circulating endothelial cells (CEC) recently has been
recognized as a useful marker of vascular damage. Usually absent in the
of healthy individuals, CEC counts are elevated in diseases marked by
presence of vascular insult.
marker linked with vascular dysfunction has been identified.
microparticles (EMP) are vesicles formed by the endothelial cell
injury or activation. The phenotypic profile of EMP can vary
depending on whether parent cells have undergone either activation
) or apoptosis (predominantly CD31+
(MP) formation has been demonstrated using in
endothelial cell activation by cytokines such as TNF-α and
It has also been
demonstrated that EMP have
procoagulant activity, defined by platelet factor 3 activity and tissue
In prothrombotic states, Shet et al.
raised tissue-factor (TF)-positive EMP in patients compared with
controls and a
strong correlation with procoagulant activity. Increased production of
been demonstrated in idiopathic TTP.
concerning the release of EMP in the course of HCT exist; however, a
report suggests that EMP increase in the setting of acute GVHD, but not
immediately after non-myeloablative conditioning regimens.
in circulating platelet- and monocyte-derived MP have also been
observed in the
post-transplantation period, including in one case of TA-TMA.[109
In the HCT setting, proposed
mechanisms of endothelial cell injury
include toxic conditioning regimens with high-dose chemotherapy, [110-114]
infections (CMV, HHV-6), [116,117
Evidence of TA-TMA was found in one analysis of allogeneic HCT
receiving cyclosporine as GVHD prophylaxis but not in those treated
In addition, other
(e.g., tacrolimus) used for GVHD prophylaxis have been associated with
increased production of thromboxane (TX) A2
Addition of sirolimus
to a calcineurin
inhibitor has been associated with potentiation of these effects.
Data from renal transplant recipients developing TA-TMA on an
regimen of cyclosporine and sirolimus suggest that the combination of
agents concomitantly targets the molecular control of cell death and
the EC level.
The end result is loss of
integrity, and generation of a proinflammatory, procoagulant state
leading to predilection for secondary TMA.
factors and prognosis:
risk factors for development of TA-TMA include female
gender, African American race, and older age.[36,122,123]
history of severe hepatic dysfunction and advanced primary disease also
increase the risk of developing TA-TMA.[124,125]
factors include: unrelated donor transplants; [88
HLA-mismatched donors;124 fludarabine-based non-myeloablative
conditioning regimens;88,129 busulfan and TBI myeloablative
The incidence of TA-TMA did not differ
according to graft source, e.g. bone marrow versus peripheral blood.122
As mentioned above, use of calcineurin inhibitors such as
associated with the development of
TA-TMA. Infections and the development of GVHD also increase the risk
of developing TA-TMA.[14,21,123,124,128]
In the HCT patients,
non-transplantation etiologies of TMA such as idiopathic TTP and HUS
should always be considered in the differential diagnosis, as they may
coexist with the primary hematologic disease. In TA-TMA, poor
prognostic indicators include: patient age > 18 years, a graft
source from an unrelated or haploidentical donor,
at least five
schistocytes per high-power field on peripheral film,
TA-TMA in the
absence of sirolimus,
Specifically, Uderzo and
reported three factors statistically
predicting outcome of TA-TMA: adult age, unrelated or haploidentical
graft source, and high TMA index (elevated LDH-platelet ratio). A
retrospective cohort analysis of myeloablative allogeneic HCT
recipients showed that sirolimus exposure constitutes a risk factor for
the development of TA-TMA (10.8% in the sirolimus-exposed subjects vs.
4.2% in the non-sirolimus group)
but is also a
indicator in terms of TA-TMA overall survival (58.3% for TA-TMA related
to sirolimus exposure vs. 11.1% in the non-sirolimus group)134 and
renal recovery (92% vs. 78% respectively).
colleagues136 reported lower one-year survival in patients with TA-TMA
than in patients without TA-TMA (27 ± 18.1% for TA-TMA with high
schistocyte counts; 53 ± 15% for TA-TMA with low schistocyte counts;
vs. 78 ± 7% in patients without TA-TMA, p< 0.0001). A survey of the
European Group for Blood and Marrow Transplantation (EBMT)122 conducted
among forty-five centers included 406 patients transplanted, and
reported an incidence of TA-TMA of 6.7%. The only factor predictive of
resolution of TA-TMA was the absence of nephropathy.
At the present time there is no consensus on what
appropriate therapy for patients with TA-TMA. Initial attempts should
focus on the following: i) eliminating possible causative conditions
such as treating underlying infections and controlling acute GVHD; and
ii) pharmacologic therapy with medications such as daclizumab,
defibrotide and rituximab. The rationale for use of these agents is
based on empirical benefit.
Risk Factors and Consideration of Plasma Exchange:
tacrolimus and sirolimus should be discontinued
immediately and replaced with alternative immunosuppressive
medications. Corticosteroids, mycophenolate mofetil, azathioprine and
methotrexate can be used as appropriate alternatives. Withdrawal of
cyclosporine with initiation of plasma exchange/apheresis has shown
response rates of up to 63%.
In all reported
cases cyclosporine was
discontinued at the time of diagnosis of TA-TMA, and the effect of this
intervention in isolation cannot be determined as patients went on to
have therapeutic plasma exchange.
Unlike the situation in idiopathic TTP, responses to plasma exchange
alone are suboptimal in TA-TMA. Reported response rates vary between
compared with 78-91% in patients
Further, rise in
platelet count, the usual marker for
response to plasma exchange, cannot be relied upon in TA-TMA because
platelet engraftment may not yet have occurred. In addition, plasma
exchange procedures are associated with a significant number of
complications, including systemic infections, catheter thrombosis,
bleeding, pneumothorax, pericardial tamponade, and with plasma
infusion, serum sickness and anaphylaxis.
Based on the incomplete responses and high complication rates, we do
not advocate use of this procedure but rather alternative therapeutic
approaches as discussed below.
Daclizumab is a humanized monoclonal anti-CD25 antibody, which targets
the chain of the IL-2 receptor.
This agent is
retaining only 10% of the original murine compartments in the critical
hypervariable segments for binding specificity. Daclizumab has been
used to decrease the incidence of acute rejection in solid organ
transplants including renal,
Daclizumab also has been used successfully in
T-cell mediated autoimmune diseases such as multiple sclerosis,[146-148]
pure red cell aplasia,
and aplastic anemia.
In the HCT setting, intravenous daclizumab (with a serum half-life of
20 days) has been used to prevent or treat acute GVHD;
recently, this agent has been used for the treatment of TA-TMA. Adverse
effects include an increased risk for bacterial, candida and
aspergillosis infections, as well as CMV reactivation. Through its
effect on depleting alloreactive T-cells, daclizumab can substitute for
a calcineurin inhibitor. Wolff et al.
daclizumab at an initial
loading dose of 2mg/kg and then 1mg/kg weekly. Nine of 13 affected
patients attained complete remission after therapy.[132
Four of the
patients who had a complete remission from TMA also had complete
resolution of active GVHD. A fifth, complete remitter patient from both
TMA and GVHD died of primary disease relapse; the remaining eight
patients died from infections, GVHD or multiorgan failure.
half-life and potent immunosuppressive effect make this agent a
promising treatment modality that merits further investigation.
Defibrotide is a large, single-stranded polydeoxyribonucleotide,
derived from porcine mucosa by controlled depolymerization. It has been
found to have potent anti-thrombotic, anti-ischemic, anti-inflammatory,
and thrombolytic properties, without significant systemic anticoagulant
This drug exerts its properties by inhibition of
TNFα-mediated endothelial cell apoptosis in vitro,148 decreasing the
activity of PAI-1 and increasing endogenous tissue plasminogen
activator (tPA) function.
Hepatic veno-occlusive disease (VOD) is a potentially lethal
complication of both allogeneic and autologous HCT,[156,160,161]
especially after prior exposure to the immunoconjugate gemtuzumab
In some studies, the incidence of
hepatic VOD after HCT
approaches 20% with mortality ranging from 7% to 50%.
pathogenesis of VOD involves injury to the sinusoidal endothelial
cells, leading to occlusion of small vessels with fibrin deposition and
disruption of hepatic function. Previous attempts at therapy using
either heparin or tPA have been unsuccessful.[164,165]
therapy has improved outcomes for hepatic VOD that develops after HCT
(30% to 60% CR rate).[166-170]
similarities in pathophysiology
with TA-TMA, including loss of small vessel endothelial cell integrity,
Corti and coworkers
reported that 3 of 12
affected patients with
TA-TMA given oral defibrotide achieved partial remission, while 5 of 12
patients achieved a complete response.
the effects of
defibrotide are exerted locally within the vascular bed, it is usually
well tolerated with no significant systemic effects on coagulation such
as seen during treatment with tPA.
Rituximab, discussed above, has been used with increasing frequency for
the treatment of various hematologic and rheumatologic disorders
including idiopathic TTP,[171-173]
lupus erythematosus176 and rheumatoid arthritis.[177,178]
in relapsed, refractory TTP is linked to its ability to eliminate
antibodies to ADAMTS13.171 Au et al.
five TA-TMA patients
refractory to a week of plasma exchange and prednisolone with rituximab
375mg/m2/week for four doses. Four attained complete remission; two
patients recovered after receiving two weeks of rituximab.
median follow-up of 305 days, 3 of 4 responders remained in
but the fourth responder died of
sepsis. The only
non-responder died of multi-organ failure after three weeks.
ADAMTS13 antigen levels were marginal or low either post-HCT or at the
onset of TMA and did not change significantly after rituximab-induced
It remains unclear whether these
patients actually had
TA-TMA (or TTP), thus making the use of rituximab in this setting
uncertain. In addition, there are no established guidelines for
recommending duration of rituximab treatment. Given the lack of
reliable markers for remission (serum ADAMTS13 activity and
anti-ADAMTS13 antibody levels), maintenance rituximab therapy cannot be
modalities and future directions:
Single agent response rates
for the antiplatelet agents aspirin and
dipyridamole approximate 10%,[49,180]
a result indistinguishable from the
natural history of TTP. Antiplatelet agents have not been convincingly
shown to increase the response to plasma exchange [45,51,181]
promote bleeding in the setting of acute thrombocytopenia and invasive
use as first-line treatment of TMA,
including TA-TMA, cannot be recommended. Although not verified in vivo,
intravenous immunoglobulin (IVIG) has been used therapeutically based
on a report that IgG from healthy individuals inhibits the capacity of
TTP plasma to agglutinate platelets in vitro.
described a response to the combination of plasma exchange and IVIG in
a patient who was refractory to plasma exchange alone.
anecdotal reports of favorable responses of TTP to
as other immunosuppressive therapies
such as azathioprine, cyclophosphamid, and staphylococcal protein A
By analogy, there are
case series of use of
these agents in the setting of TA-TMA. Results were disappointing and
difficult to interpret since all of the patients received concurrent
therapy with plasma exchange.[128,139,189]
On-going studies for further investigation of the pathogenesis of
TA-TMA involve medications that modulate the endothelial cell
These agents include
an endothelin receptor antagonist
with protective effects
in in vivo ischemia-reperfusion injury models. Anti-oxidant agents,
such as nitric oxide donors which limit vascular injury caused by
free-radicals, also may alter the course of the
TA-TMA is an uncommon but devastating complication of HCT. Evidence
suggests that it represents the final common pathway of multiple,
frequently confounding variables such as conditioning regimens, use of
calcineurin inhibitors, acute GVHD and opportunistic infections. The
elevated blood concentrations of vWF antigen confirm endothelial cell
injury. The typically incomplete responses and high mortality rates
call for better therapeutic approaches. An alternative classification
that takes into consideration the underlying pathophysiologic
mechanisms is presented here and should limit diagnostic uncertainty.
Accurate diagnosis is instrumental in designing future studies
comparing management strategies and outcomes among different series.
Treatment of TA-TMA consists of discontinuing offending agents and
substituting calcineurin inhibitors with daclizumab or other
immunosuppressives. Due to questionable efficacy and significant
associated adverse events, plasma exchange, in general, is not
recommended. Finally, monitoring production of endothelial cell
microparticles or protein concentration changes of vWF, soluble
thrombomodulin, and PAI-1, which occur in the setting of endothelial
cell injury, may be useful in detecting early onset of TA-TMA. In line
with these considerations, interventions directed at improving
endothelial cell function, accelerating endothelial cell recovery from
injury and preventing apoptosis of these cells are potential goals for
future developmental therapies.
The authors thank Keith R. McCrae M.D. for his thorough review of the
manuscript and excellent suggestions.
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