Thrombotic Thrombocytopenic Purpura:

A Moving Target
J. Evan Sadler
Almost 80 years after Eli Moschcowitz published the
first description of the disease, most patients with
idiopathic thrombotic thrombocytopenic purpura (TTP)
were found to have acquired autoantibody inhibitors of
the ADAMTS13 metalloprotease. Plasma ADAMTS13
normally cleaves von Willebrand factor within nascent
platelet-rich thrombi, and ADAMTS13 deficiency
allows unchecked thrombus growth to cause
microangiopathic hemolysis, thrombocytopenia, and
tissue infarction. At present, ADAMTS13 deficiency
with a high-titer inhibitor level appears to be associ-

ated with an increased risk of early death and subsequent relapse. Thus, acquired ADAMTS13 deficiency
identifies a specific mechanism of TTP and is a
potential biomarker of disease activity or risk. At
present, two major clinical questions in the field may
be summarized as follows. First, by emphasizing TTP
caused by ADAMTS13 deficiency, are we in danger of
neglecting other causes that should be treated with
plasma exchange? Second, should we treat asymptomatic patients who have severe ADAMTS13 deficiency to prevent future disease, and if so, how?

The last few years have set the stage for a new approach to
the management of thrombotic thrombocytopenic purpura
(TTP). The criteria for idiopathic TTP have remained approximately constant, and plasma exchange is still the standard therapy. But the discovery of the ADAMTS13
metalloprotease has revolutionized our understanding of
TTP and initiated a period of experimentation with regard
to diagnosis and treatment. The management of TTP has
been reviewed recently,1 and I will not discuss it comprehensively. Instead, I will try to integrate the new knowledge about ADAMTS13 into a model for the pathogenesis
of TTP, relate it to our experience in caring for these patients, and suggest where we may look for further advances
during the next few years.

The entry criteria for this study included microangiopathic hemolytic anemia (Coombs negative), thrombocytopenia (< 100,000/L), and no alternative (secondary) explanation such as cancer, disseminated intravascular coagulation (DIC), or eclampsia. There was no requirement for neurological deficits, fever, or renal involvement.
In fact, subjects with oliguria were excluded because they
could not tolerate plasma infusion.2
Today we still diagnose idiopathic TTP using essentially the same criteria (Table 1): unexplained microangiopathic hemolytic anemia and thrombocytopenia.
However, the spectrum of associated symptoms has changed.
In contrast to case series from the era before plasma exchange, patients often do not have fever, significant renal
impairment, or obvious neurological involvement at diagnosis.2 This shift toward earlier diagnosis follows naturally
from the desire to provide plasma exchange therapy to every patient who may benefit. However, there has been little
further improvement in prognosis. Approximately 20% of
patients with idiopathic TTP still die during the first month
of acute illness, and at least 30% experience one or more
relapses within 2 years.3-5 Practically speaking, will we ever
be able to predict who will respond to plasma exchange, or
who will relapse? If so, can we offer effective alternative
therapy?

I. Plasma Exchange for Idiopathic TTP

The modern era in the management of TTP began with a
randomized trial, published in 1991, which established that
plasma exchange is superior to plasma infusion for the treatment of TTP.2 During the decade before these results were
reported, anecdotal experience indicated that plasma
therapy could cure patients who otherwise had an expected
survival of < 10%. By demonstrating that plasma exchange
increased survival to > 80%, this key trial simultaneously
established a standard of care and an enduring clinical definition of idiopathic TTP.2

Departments of Medicine and Biochemistry and Molecular

Biophysics, and Howard Hughes Medical Institute, Washington
University School of Medicine, St. Louis, MO
Correspondence: J. Evan Sadler, Howard Hughes Medical
Institute, Washington University School of Medicine, 660 South
Euclid Avenue, Box 8022, St. Louis, MO 63110; Phone 314362-9029, Fax 314-454-3012; Email esadler@im.wustl.edu.

Hematology 2006

II. ADAMTS13 Changed the Landscape

Before 1998, our ability to make such predictions was hampered by a fundamental lack of knowledge about the pathophysiology of TTP. In that year, adults with idiopathic TTP
were reported to have acquired autoantibodies that inhibit
a von Willebrand factor (VWF) cleaving protease, which is
normally present in plasma.6,7 In 2001, the VWF cleaving
protease was purified and cloned by several groups, shown
to be a new member of the a disintegrin and metalloprotease with thrombospondin type 1 repeats family, and
415

Table 1. Classification and characteristics of thrombotic microangiopathy syndromes.

Category

Clinical Features*

Mechanism

Treatment

Idiopathic TTP

Coombs negative, without DIC or

other conditions associated with
secondary TTP. Severe renal failure
is uncommon. Specific conditions**
that may coexist with idiopathic TTP
are discussed in the text.

Autoimmune ADAMTS13 deficiency

in a majority of patients.

> 80% response to plasma

exchange. May benefit from
immunosuppression.

Secondary TTP

Associated conditions include

cancer, infection, hematopoietic
stem cell transplantation, solid organ
transplantation, chemotherapy,
certain drugs.

Mechanisms are mostly unknown.

ADAMTS13 deficiency is rare.

With few exceptions, responses

to plasma exchange are unlikely.
Treatment and prognosis are
dictated by the specific associated conditions.

Diarrheaassociated HUS
(D+HUS)

Acute renal failure, often oliguric,

preceded by bloody diarrhea.

Endothelial damage by Shiga toxin

producing E. coli. ADAMTS13
deficiency is rare.

No demonstrated efficacy of
plasma exchange.

Atypical HUS

Acute renal failure, often oliguric,

without a prior diarrheal illness.

Complement regulatory protein

defects in at least 50% of patients;
ADAMTS13 deficiency is rare.

No demonstrated efficacy of
plasma exchange, except
possibly for factor H deficiency.

*Clinical features listed are in addition to microangiopathic hemolytic anemia and thrombocytopenia.
**Conditions associated with autoimmune ADAMTS13 deficiency and idiopathic TTP include certain autoimmune disorders, pregnancy, and ticlopidine.

named ADAMTS13.8-12 Thanks to these discoveries, we now

have a plausible model for the pathogenesis of TTP (Figure 1): autoantibodies inhibit the activity of ADAMTS13.
The absence of ADAMTS13 allows VWF and platelets to
accumulate unchecked in microvascular thrombi, which
leads to platelet consumption, hemolysis, and microvascular occlusion. Plasma exchange is efficacious because it
removes pathogenic autoantibodies and replenishes the
missing ADAMTS13 protease, restoring the normal regulation of VWF-dependent platelet adhesion. As we will see,
this is a reasonable model but it may not explain everything about idiopathic TTP.

III. Clinical Correlations of ADAMTS13 Deficiency

III.A. Specificity and sensitivity for idiopathic TTP
Subsequent studies have begun to demonstrate the potential and also the limitations of ADAMTS13 testing. Modest decreases in plasma ADAMTS13 activity occur in a
variety of acute and chronic illness, but rarely are the values < 25% of normal. ADAMTS13 is synthesized mainly in
the liver, and severe ADAMTS13 deficiency (< 5%) has
occurred with hepatic failure from various causes. Severe
ADAMTS13 deficiency appears to be more frequent in sepsis-induced DIC. In a retrospective study of 109 patients,
ADAMTS13 levels were < 5% in 17 patients and < 20% in
51 patients.13
Figure 1. Pathogenesis of idiopathic
thrombotic thrombocytopenic purpura
(TTP) caused by ADAMTS13 deficiency.
Multimeric von Willebrand factor (VWF)
adheres to endothelial cells or to connective
tissue exposed in the vessel wall. Platelets
adhere to the VWF through platelet
membrane glycoprotein GPIb. In flowing
blood, VWF in the platelet-rich thrombus is
stretched and cleaved by the
metalloprotease ADAMTS13, limiting
thrombus growth. If ADAMTS13 is absent,
VWF-dependent platelet accumulation
continues, eventually causing microvascular thrombosis and TTP.

416

American Society of Hematology

In contrast, studies of patients with thrombotic

microangiopathy have confirmed the specificity of severe
ADAMTS13 deficiency (undetectable, or < 5%) for idiopathic TTP, although the sensitivity remains controversial.
Severe ADAMTS13 deficiency rarely occurs in secondary TTP associated with cancer, hematopoietic stem cell
or solid organ transplantation, preeclampsia, systemic infections, drug toxicity, or other predisposing conditions.
Also, severe ADAMTS13 deficiency is almost unheard of
in diarrhea-associated hemolytic uremic syndrome caused
by Shiga toxinproducing E. coli (D+HUS) or other thrombotic microangiopathy accompanied by oliguric renal failure (atypical HUS). The Oklahoma TTP-HUS registry
provides representative data: none of 92 patients with these
varieties of secondary TTP or D+HUS had severe
ADAMTS13 deficiency.4 Similarly, a major referral laboratory in Switzerland reported that 3 of 188 subjects (1.6%)
with secondary TTP and none of 130 subjects with HUS
had severe ADAMTS13 deficiency.14
On the other hand, when patients with idiopathic TTP
are stratified by plasma ADAMTS13 activity level, the incidence of severe ADAMTS13 deficiency (< 5% of normal
pooled plasma) has varied from 33%4 to 100%,6,7,15 with
intermediate values of 52% to 94% in other studies.3,14,16-18
Some of this variation probably reflects differences in case
definitions for idiopathic TTP or assay methodology. In
any case, some patients diagnosed with idiopathic TTP do
not have severe ADAMTS13 deficiency, at least in vitro.
Whether the short-term prognosis differs for idiopathic TTP
with or without ADAMTS13 deficiency is not yet clear.
One study suggests that the initial response to plasma exchange is similar for the two groups.4
As an aside, the recent progress in understanding familial and idiopathic TTP has been matched by similar
advances regarding atypical HUS. In a study of 156 patients, mutations in regulators of the alternative complement pathway (factor H, factor I, or MCP) were identified in
74 of them.19 Thus, the clinical distinction between TTP
(mild renal insufficiency) and HUS (severe renal insufficiency) often correlates with distinct pathophysiologic
mechanisms. Because the features of idiopathic TTP and
atypical HUS can overlap, laboratory testing for
ADAMTS13 and complement function could be important,
because familial TTP caused by ADAMTS13 deficiency
responds to simple plasma infusion, whereas atypical HUS
responds poorly if at all to intensive plasma exchange and
has a much worse long term prognosis.19
III.B. Exceptional causes of autoimmune TTP
In general, secondary TTP (Table 1) is not associated with
severe ADAMTS13 deficiency and rarely responds to plasma
exchange, but there are a few interesting exceptions.
Autoimmune diseases of various kinds have been described in association with severe ADAMTS13 deficiency
and thrombotic microangiopathy that is indistinguishable
from idiopathic TTP.20-22 Conversely, patients with idio-

Hematology 2006

pathic TTP and severe ADAMTS13 deficiency (< 5%) often have manifestations of systemic lupus erythematosus
or other autoimmune diseases, such as antinuclear antibodies, polyarthritis, malar rash, extramembranous glomerulonephritis, discoid lupus, or autoimmune thyroiditis.23
Many autoimmune diseases can cause hemolytic anemia,
thrombocytopenia and organ dysfunction by several
mechanisms, and ADAMTS13 testing may facilitate the
recognition of idiopathic TTP in these complex cases.
Pregnancy-associated thrombotic microangiopathy
has many causes that can be difficult to diagnose correctly.
The features of preeclampsia or HELLP syndrome may overlap those of idiopathic TTP, but these patients do not have
ADAMTS13 deficiency.24 However, pregnancy can trigger
TTP in women who do have congenital or acquired
ADAMTS13 deficiency.25 ADAMTS13 testing may be useful for discriminating among the varieties of thrombotic
microangiopathy during pregnancy and postpartum.
Ticlopidine causes thrombotic microangiopathy with a
frequency of 1 case per 1600 to 5000 patients treated, usually
after 2 to 12 weeks of drug use, usually by inducing the formation of autoantibodies to ADAMTS13.26 The mechanism
of autoantibody induction is unknown. Ticlopidine-associated autoimmune TTP responds to plasma exchange, which
reduces the mortality from 60% without treatment to 14-20%
with treatment.27 TTP is much less common with clopidogrel,
a related thienopyridine antagonist of platelet ADP receptor
signaling,28 and in many cases has not been associated with
autoantibodies to ADAMTS13.
III.C. Prognostic significance
In three studies that included both idiopathic and secondary TTP (excluding D+HUS), patients with severe
ADAMTS13 deficiency had a good response rate to plasma
exchange (89-100%) and low mortality (8-19%), whereas
patients without ADAMTS13 deficiency had a lower response rate (54-82%) and higher mortality (18-56%).3-5
Unfortunately, knowledge of the ADAMTS13 level added
little because most of the differences in response rate and
mortality were captured by the clinical distinction between
idiopathic and secondary TTP.3,4
Focusing specifically on idiopathic TTP, however,
ADAMTS13 assays may provide useful prognostic information. In the Oklahoma TTP-HUS registry, 6 of 14 patients (43%) with severe ADAMTS13 deficiency later relapsed, compared to 2 of 25 patients (8%) without severe
ADAMTS13 deficiency.4 In studies of idiopathic TTP with
severe ADAMTS13 deficiency, patients with detectable
inhibitors had a delayed response to plasma exchange18,29
and an increased risk of relapse.3,17 Deaths occurred only in
patients with detectable inhibitors, for whom the death rate
was 17% to 25%.3,17,18 Although relatively few patients have
been studied to date, the results suggest that severe
ADAMTS13 deficiency with a significant inhibitor titer at
diagnosis confers an increased risk of early death and relapsing disease.
417

III.D. A biomarker of disease

For most patients, a complete response to plasma exchange
is accompanied by normalization of ADAMTS13 activity
and disappearance of ADAMTS13 inhibitors, if present.3,17
Interestingly, one-fourth to one-third of responders has persistent total ADAMTS13 deficiency, and many such patients also have unchanged or increased inhibitor titers during remission.3,17 Why does their disease remit in the first
place, and what is their risk of relapse?
The resolution of thrombotic microangiopathy without improvement in ADAMTS13 deficiency also occurs in
familial TTP caused by ADAMTS13 mutations. Some subjects with congenital ADAMTS13 deficiency require continuous prophylactic treatment with plasma to prevent
thrombotic microangiopathy, whereas others have long
disease-free intervals that may last years without treatment,
but develop acute thrombotic microangiopathy in association with infections, surgery, pregnancy, or other stress. A
very few adults with total ADAMTS13 deficiency have
never had thrombotic microangiopathy at all.30 Thus, inflammatory stress exacerbates TTP in congenital ADAMTS
deficiency, and the stress of surgery31 or pregnancy25 does
the same in acquired idiopathic TTP. In both familial and
acquired idiopathic TTP, the resolution of stress may restore a condition of compensated microvascular thrombosis that is insufficient to cause overt disease, thereby accounting for remissions with plasma therapy despite persistent ADAMTS13 deficiency, as well as relapses with later
episodes of inflammatory stress.
Nearly all patients with relapsing idiopathic TTP have
ADAMTS13 deficiency at the time of relapse,3,17 although
it is difficult to predict when or whether a relapse will occur. However, relapsing TTP is a catastrophic and sometimes fatal illness that strikes at least 30% of patients within
two years of surviving an acute episode of TTP. It is worth
considering whether the endpoint of treatment should remain the achievement of complete clinical response, or
whether the goal should include the eradication of autoantibody inhibitors and restoration of a normal ADAMTS13
level.
IV. Rituximab for Idiopathic TTP
The discovery that idiopathic TTP usually is an autoimmune disease has encouraged the routine use of immunosuppressive agents. For example, the efficacy of corticosteroids has not been demonstrated conclusively, but many
of us combine prednisone with plasma exchange, expecting that it may reduce autoantibody production. Even so,
many patients do not respond satisfactorily, and during the
past few years immunosuppression with rituximab has become popular as salvage therapy for refractory or relapsing
TTP. Rituximab is a humanized monoclonal antibody
against CD20, which is expressed on B cells, and it rapidly
clears B cells from the circulation. Most antibody-producing plasma cells live only a few days, and destruction of B
cells can prevent the replenishment of these pathological
418

plasma cells. Several case reports and small series suggest

that rituximab induces complete responses in the majority
of patients with TTP refractory to plasma exchange, corticosteroids, and other treatments such as vincristine or splenectomy. Responses to rituximab correlate with disappearance of ADAMTS13 inhibitors and a rise of the ADAMTS13
level into the normal range.32,33
Success with refractory disease suggests that rituximab
could be useful for newly diagnosed patients who achieve
remission but are at high risk of relapse.33 Assessing the
efficacy of rituximab in this setting may be difficult because the majority of patients do not experience relapses,
and the utility of ADAMTS13 data for predicting the risk
of relapse is still uncertain. These issues will be addressed
in a proposed randomized trial of plasma exchange, with or
without rituximab, as primary therapy for idiopathic TTP.34
V. Autoimmune ADAMTS13 Deficiency and
Thrombosis Without TTP
In principle, ADAMTS13 deficiency might cause devastating thrombosis in a critical organ such as the brain or heart,
without enough microvascular thrombosis to cause microangiopathic hemolysis and thrombocytopenia. In fact, 3
patients have been described who presented with acute
cerebrovascular events but normal platelet counts, normal
or trivially elevated LDH, and no schistocytes. Because
these patients had a prior history of TTP, ADAMTS13 activity was checked and found to be low, with a detectable inhibitor, and they responded to plasma exchange or
rituximab.35,36 Such cases raise the frightening possibility
that ADAMTS13 deficiency may cause stroke or other thrombosis in patients without any history of TTP. If this proves
to occur at a significant frequency, then ADAMTS13 testing would be appropriate for patients with acute thrombotic events who have no obvious risk factors, especially if
accompanied by thrombocytopenia.
VI. The Evolving Approach to Thrombotic
Microangiopathy
Recent discoveries have provided new insight into the
mechanism of idiopathic TTP but have had a relatively
modest impact on the clinical approach to diagnosing and
treating thrombotic microangiopathy. This may change as
the results of ongoing clinical research become available.
VI.A. Clinical strategy for today
Empiric plasma exchange for all idiopathic TTP. For now,
plasma exchange remains the primary treatment for idiopathic TTP, reducing the acute mortality from > 90% to
< 20%. Therefore, any patient who reasonably may have
idiopathic TTP should receive plasma exchange as soon as
possible, typically at 1.0 or 1.5 volumes of plasma per day.
Prednisone can be included at 1 or 2 mg/kg per day, in
divided doses. The criteria for selecting these patients include microangiopathic hemolytic anemia, thrombocytopenia, and the absence of an obvious alternative explanation
American Society of Hematology

such as cancer, sepsis, disseminated intravascular coagulation, tissue transplantation, certain drugs, and recent bloody
diarrhea. Significant renal insufficiency at presentation is
substantially more common in HUS but is not a sufficient
reason to withhold plasma exchange because it does occur
sometimes in idiopathic TTP that is caused by ADAMTS13
deficiency. However, a rapidly rising creatinine, especially
with oliguria, should prompt an aggressive search for secondary causes of TTP, for infection by Shiga toxinproducing organisms, and in some cases for complement regulatory defects.
ADAMTS13 testing and difficult decisions. If rapid
testing is available, a finding of severe ADAMTS13 deficiency can help to justify the continuation of plasma exchange when the clinical presentation is not typical of idiopathic TTP, especially when thrombotic microangiopathy
occurs in association with preexisting autoimmune disease
or during pregnancy. Also, patients with other potential
causes of secondary TTP do rarely acquire antibodies to
ADAMTS13. Appropriate testing can identify this minority with coincidental TTP caused by ADAMTS13 deficiency
that will, in fact, respond to plasma exchange.
ADAMTS13 as a biomarker in relapsing TTP. Relapsing idiopathic TTP almost always is caused by persistent
or recurrent autoimmune ADAMTS13 deficiency, and immunosuppression can prevent subsequent relapses by restoring normal ADAMTS13 activity. Therefore, testing can
identify refractory or relapsing patients with severe
ADAMTS13 deficiency, often with detectable inhibitors,
who may benefit from immunosuppression. ADAMTS activity and inhibitor titer also serve as biomarkers to monitor the response to treatment.
VI.B. Questions for tomorrow
Routine ADAMTS 13 assays. The possibility of using
ADAMTS13 data to manage thrombotic microangiopathy
obviously is premised on the widespread availability of
ADAMTS13 assays that are rapid, robust, and feasible for
most clinical laboratories. Several such assays are under
development. As one example, a potentially suitable
fluorogenic ADAMTS13 substrate has been described.37 Assays using this substrate can be adapted to measure
ADAMTS13 inhibitors, but more sensitive inhibitor assays
still are needed. Some pathogenic antibodies appear to promote the clearance of ADAMTS13 from blood without inhibiting its activity,38 and assays for these non-neutralizing antibodies and for ADAMTS13 antigen39 could be useful as well.
Primary versus secondary immunosuppression. The
successful treatment of relapsing TTP with rituximab suggests that combining rituximab with plasma exchange could
improve the long-term prognosis of newly diagnosed idiopathic TTP, especially if high-risk patients could be identified. Whether ADAMTS13 data will be useful for selecting
patients for immediate immunosuppressive treatment is unknown. Whether such treatment will actually reduce the

Hematology 2006

rate of future relapses also is unknown. A related issue is

whether asymptomatic patients with persistent ADAMTS13
deficiency should be treated while in remission to prevent
future relapses. These questions will need to be answered
by clinical trials.34
Idiopathic TTP without ADAMTS13 deficiency. The
ability to routinely measure ADAMTS13 level will enable
closer study of patients with idiopathic TTP despite having normal ADAMTS13 activity. Either their thrombotic
microangiopathy is caused by defective ADAMTS13 function that cannot be detected with our current in vitro assays, or it is caused by another mechanism that needs to be
characterized.
Thrombosis without idiopathic TTP. The clinical uses
of ADAMTS13 assays may prove to extend beyond the
evaluation of patients with idiopathic TTP. Patients with
severe autoimmune ADAMTS13 deficiency can present
with acute neurological deficits, in the absence of overt
thrombotic microangiopathy. This phenomenon could be
investigated as a potential cause of stroke in persons who
lack traditional risk factors and also have no history of
TTP. Finally, non-immune ADAMTS13 deficiency occurs
in some patients with liver failure or sepsis-induced DIC,
and has been proposed to contribute to microvascular
thrombosis and renal injury. If prospective studies confirm
a proposed relationship between ADAMTS13 deficiency
and tissue injury in these settings,13 then replacement
therapy to increase ADAMTS13 levels could be evaluated.
References
1. George JN. Clinical practice. Thrombotic thrombocytopenic
purpura. N Engl J Med. 2006;354:1927-1935.
2. Rock GA, Shumak KH, Buskard NA, et al. Comparison of
plasma exchange with plasma infusion in the treatment of
thrombotic thrombocytopenic purpura. Canadian Apheresis
Study Group. N Engl J Med. 1991;325:393-397.
3. Zheng XL, Kaufman RM, Goodnough LT, Sadler JE. Effect of
plasma exchange on plasma ADAMTS13 metalloprotease
activity, inhibitor level, and clinical outcome in patients with
idiopathic and nonidiopathic thrombotic thrombocytopenic
purpura. Blood. 2004;103:4043-4049.
4. Vesely SK, George JN, Lammle B, et al. ADAMTS13 activity
in thrombotic thrombocytopenic purpura-hemolytic uremic
syndrome: relation to presenting features and clinical
outcomes in a prospective cohort of 142 patients. Blood.
2003;102:60-68.
5. Raife T, Atkinson B, Montgomery R, Vesely S, Friedman K.
Severe deficiency of VWF-cleaving protease (ADAMTS13)
activity defines a distinct population of thrombotic
microangiopathy patients. Transfusion. 2004;44:146-150.
6. Tsai HM, Lian EC. Antibodies to von Willebrand factorcleaving protease in acute thrombotic thrombocytopenic
purpura. N Engl J Med. 1998;339:1585-1594.
7. Furlan M, Robles R, Galbusera M, et al. von Willebrand
factor-cleaving protease in thrombotic thrombocytopenic
purpura and the hemolytic-uremic syndrome. N Engl J Med.
1998;339:1578-1584.
8. Gerritsen HE, Robles R, Lammle B, Furlan M. Partial amino
acid sequence of purified von Willebrand factor-cleaving
protease. Blood. 2001;98:1654-1661.
9. Fujikawa K, Suzuki H, McMullen B, Chung D. Purification of
human von Willebrand factor-cleaving protease and its

419

identification as a new member of the metalloproteinase

family. Blood. 2001;98:1662-1666.
10. Levy GG, Nichols WC, Lian EC, et al. Mutations in a
member of the ADAMTS gene family cause thrombotic
thrombocytopenic purpura. Nature. 2001;413:488-494.
11. Soejima K, Mimura N, Hirashima M, et al. A novel human
metalloprotease synthesized in the liver and secreted into
the blood: possibly, the von Willebrand factor-cleaving
protease? J Biochem. 2001;130:475-480.
12. Zheng X, Chung D, Takayama TK, Majerus EM, Sadler JE,
Fujikawa K. Structure of von Willebrand factor-cleaving
protease (ADAMTS13), a metalloprotease involved in
thrombotic thrombocytopenic purpura. J Biol Chem.
2001;276:41059-41063.
13. Ono T, Mimuro J, Madoiwa S, et al. Severe secondary
deficiency of von Willebrand factor-cleaving protease
(ADAMTS13) in patients with sepsis-induced disseminated
intravascular coagulation: its correlation with development of
renal failure. Blood. 2006;107:528-534.
14. Kremer Hovinga JA, Studt JD, Alberio L, Lammle B. von
Willebrand factor-cleaving protease (ADAMTS-13) activity
determination in the diagnosis of thrombotic microangiopathies: the Swiss experience. Semin Hematol. 2004;41:7582.
15. Veyradier A, Obert B, Houllier A, Meyer D, Girma JP. Specific
von Willebrand factor-cleaving protease in thrombotic
microangiopathies: a study of 111 cases. Blood.
2001;98:1765-1772.
16. Matsumoto M, Yagi H, Ishizashi H, Wada H, Fujimura Y. The
Japanese experience with thrombotic thrombocytopenic
purpura-hemolytic uremic syndrome. Semin Hematol.
2004;41:68-74.
17. Bohm M, Betz C, Miesbach W, et al. The course of
ADAMTS-13 activity and inhibitor titre in the treatment of
thrombotic thrombocytopenic purpura with plasma exchange and vincristine. Br J Haematol. 2005;129:644-652.
18. Coppo P, Wolf M, Veyradier A, et al. Prognostic value of
inhibitory anti-ADAMTS13 antibodies in adult-acquired
thrombotic thrombocytopenic purpura. Br J Haematol.
2006;132:66-74.
19. Caprioli J, Noris M, Brioschi S, et al. Genetics of HUS: the
impact of MCP, CFH and IF mutations on clinical presentation, response to treatment, and outcome. Blood.
2006;103:1267-1279.
20. Ahmed S, Siddiqui AK, Chandrasekaran V. Correlation of
thrombotic thrombocytopenic purpura disease activity with
von Willibrand factor-cleaving protease level in ulcerative
colitis. Am J Med. 2004;116:786-787.
21. Rick ME, Austin H, Leitman SF, Krizek DM, Aronson DL.
Clinical usefulness of a functional assay for the von
Willebrand factor cleaving protease (ADAMTS 13) and its
inhibitor in a patient with thrombotic thrombocytopenic
purpura. Am J Hematol. 2004;75:96-100.
22. Fujisaki K, Masutani K, Yoshimitsu T, et al. Thrombotic
thrombocytopenic purpura associated with polyarteritis
nodosa. Clin Nephrol. 2005;64:305-310.
23. Coppo P, Bengoufa D, Veyradier A, et al. Severe ADAMTS13
deficiency in adult idiopathic thrombotic microangiopathies
defines a subset of patients characterized by various
autoimmune manifestations, lower platelet count, and mild
renal involvement. Medicine (Baltimore). 2004;83:233-244.
24. Lattuada A, Rossi E, Calzarossa C, Candolfi R, Mannucci
PM. Mild to moderate reduction of a von Willebrand factor
cleaving protease (ADAMTS-13) in pregnant women with
HELLP microangiopathic syndrome. Haematologica.
2003;88:1029-1034.

420

25. George JN. The association of pregnancy with thrombotic

thrombocytopenic purpura-hemolytic uremic syndrome.
Curr Opin Hematol. 2003;10:339-344.
26. Tsai HM, Rice L, Sarode R, Chow TW, Moake JL. Antibody
inhibitors to von Willebrand factor metalloproteinase and
increased binding of von Willebrand factor to platelets in
ticlopidine-associated thrombotic thrombocytopenic purpura.
Ann Intern Med. 2000;132:794-799.
27. Bennett CL, Davidson CJ, Raisch DW, Weinberg PD,
Bennett RH, Feldman MD. Thrombotic thrombocytopenic
purpura associated with ticlopidine in the setting of coronary
artery stents and stroke prevention. Arch Intern Med.
1999;159:2524-2528.
28. Bennett CL, Connors JM, Carwile JM, et al. Thrombotic
thrombocytopenic purpura associated with clopidogrel. N
Engl J Med. 2000;342:1773-1777.
29. Tsai HM, Li A, Rock G. Inhibitors of von Willebrand factorcleaving protease in thrombotic thrombocytopenic purpura.
Clin Lab. 2001;47:387-392.
30. Furlan M, Lmmle B. Aetiology and pathogenesis of
thrombotic thrombocytopenic purpura and haemolytic
uraemic syndrome: the role of von Willebrand factorcleaving protease. Best Pract Res Clin Haematol.
2001;14:437-454.
31. Anstadt MP, Carwile JM, Guill CK, et al. Relapse of thrombotic thrombocytopenic purpura associated with decreased
VWF cleaving activity. Am J Med Sci. 2002;323:281-284.
32. Yomtovian R, Niklinski W, Silver B, Sarode R, Tsai HM.
Rituximab for chronic recurring thrombotic thrombocytopenic purpura: a case report and review of the literature.
Br J Haematol. 2004;124:787-795.
33. Fakhouri F, Vernant JP, Veyradier A, et al. Efficiency of
curative and prophylactic treatment with rituximab in
ADAMTS13-deficient thrombotic thrombocytopenic purpura:
a study of 11 cases. Blood. 2005;106:1932-1937.
34. George JN, Woodson RD, Kiss JE, Kojouri K, Vesely SK.
Rituximab therapy for thrombotic thrombocytopenic purpura:
a proposed study of the Transfusion Medicine/Hemostasis
Clinical Trials Network with a systematic review of rituximab
therapy for immune-mediated disorders. J Clin Apher.
2006;21:49-56.
35. Tsai H-M, Shulman K. Rituximab induces remission of
cerebral ischemia caused by thrombotic thrombocytopenic
purpura. Eur J Haematol. 2003;70:183-185.
36. Downes KA, Yomtovian R, Tsai HM, Silver B, Rutherford C,
Sarode R. Relapsed thrombotic thrombocytopenic purpura
presenting as an acute cerebrovascular accident. J Clin
Apheresis. 2004;19:86-89.
37. Kokame K, Nobe Y, Kokubo Y, Okayama A, Miyata T.
FRETS-VWF73, a first fluorogenic substrate for ADAMTS13
assay. Br J Haematol. 2005;129:93-100.
38. Scheiflinger F, Knobl P, Trattner B, et al. Nonneutralizing IgM
and IgG antibodies to von Willebrand factor-cleaving
protease (ADAMTS-13) in a patient with thrombotic
thrombocytopenic purpura. Blood. 2003;102:3241-3243.
39. Feys HB, Liu F, Dong N, et al. ADAMTS-13 plasma level
determination uncovers antigen absence in acquired
thrombotic thrombocytopenic purpura and ethnic differences. J Thromb Haemost. 2006;4:955-962.

American Society of Hematology