From www.bloodjournal.org by guest on September 8, 2019. For personal use only.

ASH 50th anniversary review

Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura

J. Evan Sadler1
1Department of Medicine, Department of Biochemistry and Molecular Biophysics, and Howard Hughes Medical Institute, Washington University School of

Medicine, St Louis, MO

Discoveries during the past decade have sue infarction. Although approximately should determine whether adjuvant rit-
revolutionized our understanding of id- 80% of patients respond to plasma ex- uximab with plasma exchange also is
iopathic thrombotic thrombocytopenic change, which removes autoantibody beneficial at first diagnosis. A major
purpura (TTP). Most cases in adults are and replenishes ADAMTS13, one third unanswered question is whether plasma
caused by acquired autoantibodies that to one half of survivors develop refrac- exchange is effective for the subset of
inhibit ADAMTS13, a metalloprotease tory or relapsing disease. Intensive im- patients with idiopathic TTP who do not
that cleaves von Willebrand factor within munosuppressive therapy with ritux- have severe ADAMTS13 deficiency.
nascent platelet-rich thrombi to prevent imab appears to be effective as salvage (Blood. 2008;112:11-18)
hemolysis, thrombocytopenia, and tis- therapy, and ongoing clinical trials

Clinical features of idiopathic TTP

In January of 19241 and apparently for a second time in February,2 transfusion therapy for TTP were published during the next
Moschcowitz presented a case before the New York Pathological 50 years, and only one of them described a favorable outcome.6
Society of “a hitherto undescribed disease (ref. 1 at 21)” that he felt was The situation changed dramatically in 1976, when Bukowski et al
“remarkable, clinically and anatomically (ref. 2 at 89).” A healthy published their experience with whole blood exchange transfusion.
16-year-old girl suddenly developed weakness in her arms, pain on Amazingly, 8 of 14 patients with TTP responded quickly and had
moving her wrists and elbows, pallor, and fever (38°C-39°C). Her remissions lasting from several months to more than 13 years. The
symptoms worsened and on the tenth day of illness she was admitted to effects of exchange transfusion often were dramatic: in 4 cases,
the hospital with anemia, leukocytosis, a few petechiae on one arm, and profound neurologic deficits—coma, delirium, and hemiparesis—
occult blood in gastric contents and stool. The serum creatinine was resolved in less than 24 hours, sometimes during the exchange
normal. Four days later she developed mild left hemiparesis and facial transfusion procedure.7 Very quickly, the active principle in blood was
paralysis. The next day she became comatose and died. A limited shown to be in the plasma fraction.8 One particularly elegant case report
autopsy showed hyaline thrombi in terminal arterioles and capillaries of showed that replacement with either plasma or cryosupernatant was
the heart, kidney, spleen, and liver; the lungs were spared. Moschcowitz effective, whereas albumin was not, and simple plasma infusions could
did not obtain a platelet count and did not report schistocytes in the induce prolonged remissions in some patients.9
blood film, so we do not have a complete description from him of The value of plasma therapy was demonstrated conclusively in a
thrombocytopenia or microangiopathic hemolytic anemia. But based on randomized, prospective comparison of plasma infusion and plasma
the pathology at autopsy, we recognize this patient as the first published exchange for the treatment of adults with TTP. Survival at 6 months was
example of idiopathic thrombotic thrombocytopenic purpura (TTP). 78% with plasma exchange and 63% with plasma infusion, a significant
During the next 50 years, the clinical features of TTP became difference in favor of plasma exchange (P ⫽ .036).10 Because of this
progressively better defined. Most patients were females between the trial, standard treatment for TTP today includes plasma exchange at
ages of 10 and 39, and they usually exhibited a pentad of signs without 40 to 60 mL/kg daily until the patient has a normal platelet count and a
obvious alternative causes: microangiopathic hemolytic anemia, throm- normal LDH, and any nonfocal neurologic deficits have resolved. If
bocytopenia, neurologic findings, renal damage, and fever. Unfortu- plasma exchange cannot be performed for some reason, patients may be
nately, the prognosis remained grim: mortality exceeded 90%, the treated instead with plasma infusion at up to 30 mL/kg daily, provided
average hospital stay was 14 days before death, and 80% of patients died they can tolerate the fluid load.
within 3 months after the onset of symptoms.3

Upshaw-Schulman syndrome, a congenital

Plasma therapy form of TTP
Moschcowitz also reported that one of his colleagues, Lederer, had In retrospect, the potential value of plasma therapy had been
seen 4 patients resembling his own case, and all recovered demonstrated by 1960, when Schulman reported the case of an
promptly after a single blood transfusion.2 Lederer published his 8-year-old girl who suffered from infancy with repeated episodes
observations4,5 but none of the patients had significant thrombocy- of thrombocytopenia and hemolytic anemia.11 The child responded
topenia, which cast doubt on their diagnosis, and ultimately his consistently to plasma with normalization of the platelet count and
papers had no impact. Fewer than a half dozen other reports on hemolysis within a few days, and she was maintained in remission

Submitted February 10, 2008; accepted February 26, 2008; DOI 10.1182/blood-2008- © 2008 by The American Society of Hematology
02-078170.

BLOOD, 1 JULY 2008 䡠 VOLUME 112, NUMBER 1 11

 From www.bloodjournal.org by guest on September 8, 2019. For personal use only.

12 SADLER BLOOD, 1 JULY 2008 䡠 VOLUME 112, NUMBER 1

by prophylactic plasma infusions every 1 or 2 weeks. Unfortu-

nately, this report did not describe schistocytes as a feature of
disease and the thrombocytopenia was attributed to “thrombopoi- Figure 1. Structure of ADAMTS13. The primary translation product consists of 1427
etin” deficiency, which must have delayed the recognition of amino acid residues. Motifs include a signal peptide (S), propeptide (P), metallopro-
tease (M), disintegrin (D), Cys-rich, spacer, CUB, and thrombospondin (TSP1)
similarities between this patient’s congenital illness and acquired
domains (1-8).
idiopathic TTP.
This connection was made by Upshaw, who saw a 16-year-
old girl with a history of relapsing hemolytic anemia and
thrombocytopenia since infancy. The patient had always re- tease with thrombospondin repeats” family of metalloproteases
sponded dramatically to blood transfusions, becoming clinically (Figure 1).24 Furthermore, mutations in the ADAMTS13 gene were
well within 48 hours.12 During the next 11 years, Upshaw shown to cause congenital TTP.23 Almost 80 years after Moschcow-
successfully treated 32 episodes of thrombocytopenia and itz published the first case report, we finally had a molecular
microangiopathic hemolysis with plasma infusions. Acute epi- mechanism for both congenital and acquired idiopathic TTP
sodes almost always were precipitated by some factor such as a (Figure 2).
minor infection, surgical procedure, pregnancy, fecal impaction, The last 5 years have seen more progress in understanding how
or pancreatitis. Asymptomatic intervals could last from 3 weeks ADAMTS13 regulates the biologic function of VWF, but how to
to 20 months, during which the patient had a normal platelet use this knowledge clinically remains uncertain. The major ques-
count and a compensated hemolytic state, but shortened intravas- tions revolve around how to use ADAMTS13 test results and how
cular platelet and red cell survival. These abnormalities were to use intensive immunosuppressive therapy.
normalized after the infusion of 2 units of plasma.
Upshaw proposed that his patient had a congenital TTP-like
disorder identical to that described earlier by Schulman. In a
prescient final paragraph, he also suggested that the efficacy of
Diagnosis and differential diagnosis of
plasma therapy for idiopathic TTP in adults and for congenital TTP idiopathic TTP
could be explained if it replaced a single plasma factor that was
The landmark clinical trial that established plasma exchange as the
deficient in both conditions.12
standard of care for idiopathic TTP10 also gave us a case definition
that is still generally accepted: microangiopathic hemolytic anemia
and thrombocytopenia, without an alternative cause such as
VWF and ADAMTS13 in the pathophysiology autoimmune hemolysis, disseminated intravascular coagulation,
of TTP cancer, eclampsia, drug toxicity (eg, treatment with calcineurin
inhibitors), hematopoietic stem cell transplantation, or malignant
The deficient plasma factor would not be characterized for hypertension. Patients with certain of these predisposing condi-
another 20 years, but a clue to its function was recognized much tions, particularly treatment with calcineurin inhibitors or stem cell
earlier by Moake, who published an influential paper in 1982 transplants, are considered to have “secondary” TTP rather than
that linked von Willebrand factor (VWF) to the pathogenesis of idiopathic TTP. Notably, the 3 other features of the classic
TTP.13 He found that patients with relapsing acquired or pentad—renal involvement, neurologic symptoms, and fever—are
congenital TTP had circulating “unusually large” or “ultralarge” not necessary. These signs of end organ damage are considered to
VWF multimers when they were in remission, and ultralarge
VWF was absent from the plasma of healthy persons. Moake
proposed that his patients lacked a VWF depolymerase, possibly
a protease, that normally cleaved ultralarge VWF to prevent it
from causing the intravascular platelet aggregation and thrombo-
sis that characterize TTP. Plasma therapy might replace this
depolymerase or remove an inciting cofactor.13 Interestingly,
2 of Moake’s 4 subjects were the same patients with congenital
TTP who were studied as children by Schulman11 and Upshaw.12
Years later, they became central to deciphering and linking the
pathophysiologic mechanisms of both congenital TTP and
acquired idiopathic TTP in adults.
In 1996, a candidate VWF-cleaving protease finally was
identified in human plasma by Tsai14 and independently by
Furlan.15 The protease did not cleave VWF unless the substrate was
subjected to fluid shear stress or treated with low concentrations of
protein denaturants such as urea or guanidine hydrochloride. The
next year, VWF-cleaving protease was shown to be missing from
the plasma of patients with congenital TTP.16 Soon after, adults
with acquired idiopathic TTP were reported to have severe
VWF-cleaving protease deficiency caused by IgG autoantibodies Figure 2. Pathogenesis of idiopathic TTP caused by ADAMTS13 deficiency.
that inhibit the enzyme.17,18 Multimeric VWF adheres to endothelial cells or to connective tissue exposed in the
vessel wall. Platelets adhere to VWF through platelet membrane GPIb. In flowing
During the next few years, the VWF-cleaving protease was
blood, VWF in the platelet-rich thrombus is stretched and cleaved by ADAMTS13,
purified,19,20 cloned,21-23 and named ADAMTS13 because it be- limiting thrombus growth. If ADAMTS13 is absent, VWF-dependent platelet accumu-
longed to the recently discovered “a disintegrin-like and metallopro- lation continues, eventually causing microvascular thrombosis and TTP.
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BLOOD, 1 JULY 2008 䡠 VOLUME 112, NUMBER 1 VWF, ADAMTS13, AND TTP 13

be relatively late events that should be avoided if possible by at the relationship between ADAMTS13 levels at diagnosis and the
prompt diagnosis and treatment. response to plasma exchange, the frequency of relapse, and
These diagnostic criteria are not specific for idiopathic TTP survival.25,27,37,38 Interestingly, patients with and without severe
caused by ADAMTS13 deficiency. Among patients with appar- ADAMTS13 deficiency have had similar response rates and
ent idiopathic TTP, the fraction with severe ADAMTS13 short-term survival (each ⬃80%-90%). In contrast, patients with
deficiency (ADAMTS13 activity ⬍ 5%) has varied from 33% to severe ADAMTS13 deficiency have a significantly increased risk
100% across several studies, with 75% as a rough aver- of relapsing TTP (⬃30% across all studies), whereas patients
age.17,18,25-30 The cause of this variation is not known. It may without severe ADAMTS13 deficiency rarely relapse (⬃9% across
reflect differences in ADAMTS13 assay methods or case all studies).25,27,37,38
definitions, variable attention to secondary causes of thrombotic These comparisons may underestimate the predictive power of
microangiopathy, or the application of additional selection severe ADAMTS13 deficiency because the likelihood of relapse
criteria. For example, exclusion of subjects with serum creati- increases with time, but many study patients had been followed for
nine level higher than 310 ␮M (3.5 mg/dL) reportedly increases only a few months. Our experience at Washington University
the frequency of ADAMTS13 deficiency in patients with illustrates this effect. In 2004, we reported that 6 (38%) of
idiopathic thrombotic microangiopathy to at least 90%.30,31 16 patients with idiopathic TTP and severe ADAMTS13 deficiency
Conversely, patients with secondary TTP almost never have had relapsed by the time of publication, with a follow-up of 8 to
severe ADAMTS13 deficiency. In addition, ADAMTS13 defi- 33 months.27 Three years later, 11 (69%) of these 16 patients have
ciency rarely if ever occurs in diarrhea-associated hemolytic had at least one relapse after disease-free intervals of 8 months to
uremic syndrome (D ⫹ HUS) caused by Shiga toxin–producing 5 years, and 5 of them (31%) have died.
Escherichia coli, which is characterized by abdominal pain, bloody Assays for autoantibodies to ADAMTS13 provide additional
diarrhea, thrombotic microangiopathy, thrombocytopenia, and acute prognostic information. In several studies, the presence of detect-
oliguric renal failure. For example, in the Oklahoma TTP-HUS able inhibitors at diagnosis has correlated with a higher risk of
registry, none of 92 patients with secondary TTP or D ⫹ HUS had relapsing disease.25,27,30,39 High-titer antibodies also have been
severe ADAMTS13 deficiency.25 HUS without antecedent diarrhea associated with a delayed response to plasma exchange, refractory
is referred to as “atypical HUS.” Patients with atypical HUS disease, and early death.39-42 However, these conclusions are based
seldom have ADAMTS13 deficiency and frequently turn out to on relatively few patients and some studies have not observed a
have abnormalities in the regulation of the alternate complement relationship between anti-ADAMTS13 antibody titer and short-
pathway due to mutations in complement factor H, factor I, factor term outcomes.43
B, or membrane cofactor protein.32
Thus, severe ADAMTS13 deficiency identifies a large subset of
patients with idiopathic TTP who suffer from VWF-dependent
microvascular thrombosis. Congenital ADAMTS13 deficiency
ADAMTS13 testing during remission
does not always present during childhood and may be difficult to Because ADAMTS13 activity and autoantibody levels can vary
distinguish from acquired idiopathic TTP in adult patients who do rapidly during the course of idiopathic TTP, it is a pleasant
not have a history of prolonged responses to simple plasma surprise that a single test at diagnosis can predict the risk of
infusions. In such cases, the detection of autoantibodies against subsequent relapse. As one might expect, though, measurements
ADAMTS13 supports a diagnosis of acquired idiopathic TTP. The during remission improve the correlation between ADAMTS13
cause of disease is not known for most patients with idiopathic TTP levels and clinical outcomes. Several reports have described
who do not have severe ADAMTS13 deficiency, and clinical patients with idiopathic TTP who responded completely to
criteria do not reliably identify them. As a practical matter, very plasma exchange despite persistent severe ADAMTS13 defi-
few laboratories can perform ADAMTS13 assays rapidly enough, ciency,27,28,43,44 but most such patients with ongoing autoim-
and the clinician must make a diagnosis and initiate therapy mune responses against ADAMTS13 do relapse eventually. In a
without this information. recent study of 109 patients achieving a complete response to
plasma exchange, approximately one-third of them still had
severe ADAMTS13 deficiency at some time during remission.
ADAMTS13 testing at presentation Relapses occurred in 60% of patients with persistent severe
ADAMTS13 deficiency compared with only 19% of patients
In general, patients with idiopathic TTP usually respond to plasma without ADAMTS13 deficiency at the time of testing.44
exchange and those with secondary TTP do not. Because Concentrating on only those patients known to have
ADAMTS13 deficiency is extremely rare in secondary TTP, ADAMTS13 deficiency before treatment further strengthens the
ADAMTS13 deficiency correlates with a good response to plasma relationship. Pooling the results of 2 relevant studies, the
exchange when all patients with idiopathic or secondary TTP are incidence of relapse was 44% for 16 patients presenting with
lumped together.25,27 However, ADAMTS13 testing is not particu- ADAMTS13 deficiency that persisted during remission, com-
larly useful for most patients with secondary TTP because they can pared with 7% for 27 patients without continuing ADAMTS13
be identified without it. For example, severe ADAMTS13 defi- deficiency. ADAMTS13 inhibitors exhibited a similar pattern:
ciency does not occur in secondary TTP associated with bone relapses occurred in 57% of 14 patients with a detectable
marrow transplantation or cyclosporine A, and these disorders also inhibitor during remission, compared with 4% of 28 patients
do not respond well to plasma exchange.33-36 without inhibitors.27,43
For idiopathic TTP, the value of distinguishing patients with and Furthermore, essentially all patients with a prior history of severe
without ADAMTS13 deficiency has been uncertain, but as more ADAMTS13 deficiency will have it again when they relapse with TTP,
data have become available it seems clear that ADAMTS13 assays whether they had normal ADAMTS13 levels at some other time during
provide useful prognostic information. Several studies have looked remission.30,43 An update of our earlier study27 is consistent with this
 From www.bloodjournal.org by guest on September 8, 2019. For personal use only.

14 SADLER BLOOD, 1 JULY 2008 䡠 VOLUME 112, NUMBER 1

conclusion: patients 1, 7, and 8 responded completely to plasma ence with congenital TTP also suggests that ADAMTS13 levels
exchange and subsequently had normal ADAMTS13 activity, but have of approximately 5% to 10% are sufficient to prevent thrombotic
relapsed with TTP and severe ADAMTS13 deficiency between 4 and microangiopathy.60-63 The same appears to be true for idiopathic
5 years after their first episode. TTP,30,43 so that monitoring ADAMTS13 levels during treatment
It seems clear that idiopathic TTP caused by ADAMTS13 could be useful to determine whether plasma exchange should
deficiency tends to relapse, and relapses are associated with be intensified, decreased, or discontinued. In addition, monitor-
persistent or recurrent severe ADAMTS13 deficiency. Regular ing during remission could identify patients with persistent or
laboratory monitoring after treatment with plasma exchange might recurrent ADAMTS13 deficiency and a high risk of relapse,
identify patients with ADAMTS13 deficiency and a high risk of which might be forestalled by additional immunosuppressive
imminent relapse. Of course, monitoring would presuppose the therapy.64
ready availability of rapid assays for ADAMTS13 activity and Of course, these hypothetical applications would require the
autoantibodies. ready availability of rapid assays for ADAMTS13 activity and
autoantibodies. Several such assays have been devised65-67 but are
available now only in a few specialized laboratories. We need more
clinical data concerning the utility of ADAMTS13 levels to
Clinical research questions determine whether rapid ADAMTS13 assays are useful. If so, they
should be deployed more widely.
Our recent progress in understanding the pathophysiology of TTP
has focused attention on several urgent clinical questions for which
the answers seem just out of reach. I will discuss 3 of them that When should we use immunosuppressive therapy for
seem particularly ripe for study. idiopathic TTP?

Plasma exchange helps most patients with idiopathic TTP survive

Do we need real-time ADAMTS13 assays? their acute episode of thrombotic microangiopathy, but does
nothing specific to reduce the production of pathogenic anti-
One can argue—and I have supported this position—that rapid ADAMTS13 autoantibodies. Many physicians routinely use corti-
ADAMTS13 assays are unnecessary because all patients with costeroids for this purpose, and reserve more aggressive immuno-
idiopathic TTP should be treated with plasma exchange until they suppressive therapy for refractory or relapsing disease.
achieve a remission, regardless of ADAMTS13 level.45-47 How- In this setting, rituximab appears to be effective at normalizing
ever, this point deserves reexamination. ADAMTS13 levels and inducing durable remissions. Published
Severe ADAMTS13 deficiency identifies a specific mechanism small series and case reports have described approximately
of idiopathic TTP that usually responds well to plasma exchange 100 patients with refractory or relapsing idiopathic TTP treated
but tends to relapse,25,27,37,38 and high titer antibodies to with rituximab, usually at doses of 375 mg/m2 weekly for an
ADAMTS13 correlate with refractory disease and mortality.39-42 average of 4 doses.64,68,69 Approximately 95% of reported patients
Therefore, rapid ADAMTS13 assays are likely to provide useful have had a complete clinical and laboratory responses within 1 to
prognostic information at diagnosis. 3 weeks of starting treatment, including a normal ADAMTS13
More prosaically, rapid ADAMTS13 testing could speed the level and disappearance of anti-ADAMTS13 antibodies. Mild
institution of plasma exchange therapy for the occasional patient acute reactions to ritixumab infusions were controlled by premedi-
with ADAMTS13 deficiency who presents with neurologic cation with steroids, antihistamines, and analgesics. More serious
deficits or other signs of tissue ischemia before developing overt complications have been relatively uncommon. One patient had
thrombotic microangiopathy.48,49 In addition, idiopathic TTP transient cardiogenic shock70 and another had symptomatic gastro-
can be misdiagnosed because of symptoms suggesting gastroen- intestinal infection with Strongyloides.64 Relapses have been
teritis, sepsis, or transient cerebral ischemia,45 and rapid infrequent, occurring in approximately 10% of patients after
ADAMTS13 testing could prevent these errors. Testing can intervals of 9 months to 4 years; all but one of these patients
identify patients with severe ADAMTS13 deficiency who are had a second prolonged complete remission upon retreatment
unlucky enough to also have another potential cause of throm- with rituximab.64,69,71-74
botic microangiopathy, such as a stem cell50 or solid organ These reports have all the limitations and potential biases of
transplant.51-53 Patients with autoimmune diseases such as case series, and they should be interpreted cautiously. In particular,
systemic lupus erythematosis can develop thrombocytopenia judging the efficacy of rituximab is difficult because patients
and neurologic dysfunction as a result of vasculitis, but they also usually receive multiple different treatments. Nevertheless, ritux-
can have autoimmune ADAMTS13 deficiency.37,54-56 Throm- imab seems to rescue most patients with refractory or relapsing
botic microangiopathy during pregnancy may be caused by idiopathic TTP. Moreover, by abolishing autoantibody production,
preeclampsia or HELLP (hemolysis, elevated liver function, and adjuvant rituximab at first diagnosis (combined with plasma
low platelets) syndrome, which are not associated with exchange) might further improve outcomes by shortening the
ADAMTS13 deficiency.57 However, pregnancy can also induce duration of plasma exchange, reducing early mortality, and prevent-
acute TTP in women with congenital or acquired ADAMTS13 ing relapses. Therefore, the major questions about rituximab can be
deficiency,58 and ADAMTS13 assays may be useful to identify reduced to just one: should intensive immunosuppression with
patients who could benefit from prophylactic plasma exchange rituximab be used as adjuvant or salvage therapy for autoimmune
therapy during pregnancy.59 Thus, ADAMTS13 testing may help idiopathic TTP?
to distinguish the different mechanisms of thrombotic microan- Consider some of the tradeoffs between adjuvant versus
giopathy in complex clinical situations. salvage therapy. Using Medicare/Medicaid reimbursement as a
For patients with idiopathic TTP, ADAMTS13 deficiency is a standard for comparisons, a typical course of rituximab (⬃700 mg
biomarker for a high risk of relapsing disease.25,27,30,39 Experi- ⫻ 4 doses, ⬃$491/100 mg) is reimbursed at approximately
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BLOOD, 1 JULY 2008 䡠 VOLUME 112, NUMBER 1 VWF, ADAMTS13, AND TTP 15

$14 000.75 A typical 10-day course of plasma exchange is at We have the tools to do so now, although some issues
least as costly, amounting to approximately $20 000 for the concerning ADAMTS13 assays need attention. First of all, most
plasma exchange procedures alone (⬃$780 plus ⬃4200 mL ADAMTS13 assay methods require substantial dilution of
plasma at ⬃$74/250 mL, or ⬃$2023/exchange).75 Approxi- plasma samples, which also dilutes any autoantibody inhibitors
mately 30% of patients achieving a complete remission with and can lead to overestimation of ADAMTS13 activity and
plasma exchange relapse within 5 years, often several times, and misclassification of patients. This circumstance appears to be
any relapse may cause disability or death. Therefore, if adjuvant uncommon, and different assay methods usually show good
rituximab prevented all relapses, with no offsetting toxicity, the agreement,65-67 but improved assays would be welcome. Second,
number needed to treat (NNT) to prevent one relapse would be autoantibodies to distal ADAMTS13 domains might theoreti-
less than approximately 3. The NNT would increase if rituximab cally block VWF cleavage in vivo without affecting clinical
were less successful, preventing or delaying only some relapses, ADAMTS13 assays that use smaller substrates in vitro,79
or merely reducing the duration of plasma exchange needed to leading to misclassification of patients. However, the available
achieve a complete response. Even so, whatever your metric— data on inhibitor epitope specificity80-82 suggest this problem
NNT to prevent disability or death, cost per quality-adjusted will be rare, and affected patients should be identifiable with
life-year (QALY), or something else—the cost effectiveness of appropriate assays to detect their autoantibodies.
adjuvant rituximab might prove comparable with that of ac-
cepted interventions such as hypertension medication or choles-
terol management ($10 000-$60 000 per QALY).76 The relative
The future
merits of adjuvant versus salvage immunosuppressive therapy
can best be determined through an appropriately designed I have outlined several questions that I believe are feasible to
clinical trial. address through clinical trials, and the answers could signifi-
cantly improve patient outcomes. The major obstacle is that
How should we treat idiopathic TTP without ADAMTS13 patients with idiopathic TTP are rare. The annual incidence of
deficiency? idiopathic TTP is approximately 4 per million,83 so that a large
hospital like Barnes-Jewish Hospital in St Louis, Missouri, may
The clinical trial that proved the efficacy of plasma exchange10 see only approximately 10 new patients a year. This number is
was conducted before the discovery of ADAMTS13, and it is too low to sustain an adequately powered study to compare
impossible to know which participants may have had normal treatments directly. However, several promising multicenter
ADAMTS13 levels. Until we learn better, plasma exchange trials are in progress or will open soon. A prospective observa-
should plausibly remain the standard therapy for idiopathic TTP, tional study in France is enrolling adult and pediatric patients
regardless of ADAMTS13 levels. As a practical matter, most of with TTP for longitudinal measurements of ADAMTS13
us cannot get ADAMTS13 assays performed rapidly enough, activity, antigen, and autoantibodies, and ADAMTS13 gene
so we must start plasma exchange without benefit of these sequencing (NCT00426686). A single-arm phase 2 study across
results. In addition, the limited data published on this question Canada will evaluate rituximab plus plasma exchange for
suggest that the response rates to plasma exchange are similar relapsed or refractory TTP, and enrollment should begin soon
for idiopathic TTP with or without severe ADAMTS13 (NCT00531089). The French and Canadian trials should yield
deficiency.25,27,37,38,77 important insight into the utility of ADAMTS13 testing and the
But despite the equivalent early outcomes, the groups differ efficacy of rituximab as salvage therapy, respectively.
profoundly in the likelihood of relapse. Approximately one-half The Transfusion Medicine/Hemostasis Network in the United
of patients with severe ADAMTS13 deficiency suffer at least States is about to open a phase 3 randomized comparison of
one relapse within 2 years, whereas patients without severe plasma exchange with or without rituximab for idiopathic TTP.84
ADAMTS13 deficiency almost never relapse.25,27,37,38 This dif- Patients on the plasma exchange arm who fail with refractory or
ference strongly suggests that distinct pathophysiologic mecha- relapsing disease can receive rituximab later. Therefore, this
nisms are responsible for idiopathic TTP with severe trial will address whether rituximab is best used as adjuvant or
ADAMTS13 deficiency versus idiopathic TTP without severe salvage therapy. Because severe ADAMTS13 deficiency will not
ADAMTS13 deficiency. In particular, the rarity of relapses be required for participation, this trial will include some patients
among patients without severe ADAMTS13 deficiency suggests with idiopathic TTP who do not have severe ADAMTS13
that their disease is not caused by an autoimmune response. If deficiency, and the results should indicate whether such patients
there are no autoantibodies (or autoreactive cells) to remove, differ fundamentally from those with severe ADAMTS13 defi-
and therefore no autoimmune target to replenish, then it is ciency in their response to plasma exchange, incidence of
difficult to understand how plasma exchange could be relapse, and response to rituximab. Samples for ADAMTS13
beneficial. Perhaps patients with normal ADAMTS13 activity assays will be obtained throughout the course of disease and will
have a self-limited illness that improves independent of be analyzed after the trial is completed. The results should
plasma exchange. clearly demonstrate whether rapid ADAMTS13 assays could be
My point is that we lack convincing data for or against the useful for diagnosis or to guide therapy.
use of plasma exchange to treat patients with idiopathic TTP In short, within a few years we should have answers for the
who do not have severely decreased plasma ADAMTS13 clinical research questions that I have posed here. We will know
activity. We prescribe plasma exchange just the same, but with which patients benefit from plasma exchange or intensive
the nagging doubt that the treatment may be irrelevant. Given immunosuppressive therapy, and whether ADAMTS13 assays
the high cost,75 inconvenience, invasiveness, and risks78 of can identify them. Furthermore, ADAMTS13 deficiency is not
plasma exchange, we should learn whether it helps or harms responsible for all cases of TTP, and we can look forward to
these patients. recognizing and characterizing other causes. The results of
 From www.bloodjournal.org by guest on September 8, 2019. For personal use only.

16 SADLER BLOOD, 1 JULY 2008 䡠 VOLUME 112, NUMBER 1

ongoing basic and clinical research will place our treatment of

idiopathic TTP on an even stronger empiric foundation, with the
benefit of understanding the underlying pathophysiologic
Authorship
mechanisms. Contribution: J.E.S. wrote the paper.
Conflict-of-interest disclosure: J.E.S. is a consultant and mem-
ber of clinical advisory boards for Baxter BioSciences.
Acknowledgment Correspondence: J. Evan Sadler, Howard Hughes Medical
Institute, Washington University School of Medicine, 660 S Euclid
This work was supported in part by National Institutes of Health Ave, Box 8022, St Louis, MO 63110; e-mail: esadler@
grants HL72917 and HL89746. im.wustl.edu.

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21-24. factor-cleaving protease in acute thrombotic of ADAMTS-13 activity and inhibitor titre in the
2. Moschcowitz E. An acute febrile pleiochromic thrombocytopenic purpura. N Engl J Med. 1998; treatment of thrombotic thrombocytopenic pur-
anemia with hyaline thrombosis of the terminal 339:1585-1594. pura with plasma exchange and vincristine. Br J
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BLOOD, 1 JULY 2008 䡠 VOLUME 112, NUMBER 1 VWF, ADAMTS13, AND TTP 17

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 From www.bloodjournal.org by guest on September 8, 2019. For personal use only.

18 SADLER BLOOD, 1 JULY 2008 䡠 VOLUME 112, NUMBER 1

I became seriously interested in research as a chemistry major, studying organometallic com-

pounds with Jeffrey Schwartz at Princeton. Although determined to become a doctor, I had no real
idea how to pursue both research and medicine. While leafing through a stack of medical school
application forms, I came across an insert describing the MD/PhD program at Duke University. Not
knowing anything about such programs, I filled it out. Duke eventually accepted me and provided
a perfect environment to learn how to make a career that combined chemistry and medicine. He-
matology was a natural fit. My clinical experiences as a student impressed me with the importance
and variety of hematologic diseases. It seemed clear to me that pioneering advances in our under-
standing of many biologic processes—from hemostasis to carcinogenesis—would be made by
hematologists, and this impression has certainly proved correct. As a graduate student in Robert
Hill’s laboratory, I absorbed the lesson that enzymology and protein chemistry were fundamental
to learning how molecules worked. Later I pursued hematology training at the University of Wash-
ington, where I joined Earl Davie’s laboratory and watched recombinant DNA technology trans-
form his approach to research. Finally, I was lucky to be recruited to Washington University in
St Louis, an institution that understands and nurtures the careers of new scientists with abundant
protected time and supportive colleagues. Looking back at the changes in hematology and bio-
medical research 24 years later, several observations stand out. First, terrible diseases eventually
can be understood, treated, and sometimes cured. When I started my training, TTP was a mysteri-
ous, fatal disease. In time, we learned to treat it with plasma exchange and discovered at least one
J. Evan Sadler
causative molecular mechanism, and we may soon be able to treat it with recombinant
ADAMTS13. Other diseases have had similar trajectories and more will follow, which sustains
hope. Second, success in science depends critically on serendipity, mentorship, and continuous self-teaching. The importance of luck and mentors
needs little emphasis. However, the importance of “learning how to learn”—a trite saying that happens to be true—cannot be overstated. It is amazing to
me how much of my essential daily working knowledge simply did not exist when I was in school, but had to be acquired later on the fly. Listing a few ex-
amples will date me, but they include the discovery of tyrosine kinases, RNA interference, apoptosis, restriction endonucleases, microRNAs, prions, on-
cogenes, and ribozymes; and the invention of monoclonal antibodies, PCR, DNA cloning and sequencing, transgenic and knockout mice, MRI, and bone
marrow transplantation. Witnessing and contributing to this steady progression in basic and clinical knowledge is immensely satisfying. I could not have
asked for a better way to spend my life.
 From www.bloodjournal.org by guest on September 8, 2019. For personal use only.

2008 112: 11-18

doi:10.1182/blood-2008-02-078170

Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic

purpura
J. Evan Sadler

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