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Prepublished online as a Blood First Edition Paper on April 17, 2002; DOI 10.1182/blood-2002-02-0344.
 Previous Article | Table of Contents | Next Article 
Blood, 15 July 2002, Vol. 100, No. 2, pp. 710-713
BRIEF REPORT
Von Willebrand factor-cleaving protease (ADAMTS13) in
thrombocytopenic disorders: a severely deficient activity is specific
for thrombotic thrombocytopenic purpura
Valentina Bianchi,
Rodolfo Robles,
Lorenzo Alberio,
Miha Furlan, and
Bernhard Lämmle
From the Central Hematology Laboratory, University
Hospital, Inselspital, Bern, Switzerland.
 |
Abstract |
A severe deficiency in von Willebrand factor-cleaving protease
(ADAMTS13) activity (< 5% that in normal plasma) has been observed in
most patients with a diagnosis of thrombotic thrombocytopenic purpura
(TTP) but not in those with a diagnosis of hemolytic uremic syndrome.
However, ADAMTS13 deficiency has been claimed not to be specific for
TTP, since it was observed in various thrombocytopenic and other
conditions. We studied 68 patients with thrombocytopenia due to severe
sepsis or septic shock (n = 17), heparin-induced thrombocytopenia (n = 16), idiopathic thrombocytopenic purpura (n = 10), or other hematologic (n = 15) or miscellaneous conditions (n = 10). Twelve of the 68 patients had subnormal levels of ADAMTS13 activity ( 30%), but none had less than 10%. Thus, the study showed
that ADAMTS13 activity is decreased in a substantial proportion of
patients with thrombocytopenia of various causes. A severe deficiency
of ADAMTS13 (< 5%), identified in more than 120 patients during 1996 to 2001 in our laboratory, is specific for a thrombotic microangiopathy
commonly labeled TTP.
(Blood. 2002;100:710-713)
© 2002 by The American Society of Hematology.
| |
Introduction |
In 1997, 4 patients with chronic relapsing
thrombotic thrombocytopenic purpura (TTP) were shown to completely lack
plasma activity of von Willebrand factor (VWF)-cleaving
protease,1 an enzyme identified in 19962,3 and
shown to cleave the peptide bond tyrosine 842-methionine 843 in
VWF.2 Two large retrospective studies of patients with
thrombotic microangiopathy showed severely deficient VWF-cleaving
protease activity in most patients with acute TTP,4,5 due
either to a constitutional deficiency4 or to abolishment of
the activity by autoantibodies.4,5 Patients given a
diagnosis of the clinically similar hemolytic uremic syndrome (HUS) had
normal VWF-cleaving protease activity.4 This finding seemed surprising because distinguishing between TTP and HUS is often
not possible because of the frequently overlapping clinical and
laboratory features of the 2 disorders.6 Still, a
prospective study by Veyradier et al7 essentially confirmed
these findings: all 25 patients with idiopathic TTP totally lacked
VWF-cleaving protease and all 17 patients with idiopathic HUS had
normal levels. Among the 69 patients with secondary thrombotic
microangiopathy, the distinction was somewhat less clear-cut; 7 of 41 patients with a diagnosis of secondary TTP had normal protease levels, whereas 6 of the 28 patients with a diagnosis of secondary HUS had
partial or complete protease deficiency.7
The reported N-terminal amino acid sequence8,9 and
complementary DNA10,11 of VWF-cleaving protease
characterize it as a new member of the ADAMTS family of
metalloproteinases (ADAMTS13). Genetic linkage studies in 4 pedigrees
with congenital TTP,12 sometimes referred to as
Upshaw-Schulman syndrome,13,14 led to identification of 12 different mutations in the gene for ADAMTS13 that accounted for 14 of
the 15 disease alleles studied.12 Clinically affected
patients with constitutional TTP were homozygous or doubly heterozygous
for ADAMTS13 mutations and had protease activity levels less than 10%
of normal values.12
Nevertheless, the specificity of ADAMTS13 deficiency for the thrombotic
microangiopathy commonly labeled TTP has been strongly challenged.15-17 Moore et al15 found deficient
protease activity in only 9 of 20 patients with TTP but also in 6 of 20 with idiopathic thrombocytopenic purpura (ITP), 6 of 10 with
disseminated intravascular coagulation (DIC), 5 of 10 with systemic
lupus erythematosus, 1 of 5 with leukemia, and even 2 of 20 healthy
controls. Furthermore, partial deficiency of ADAMTS13 (36% ± 24%)
was reported in 14 patients with DIC.16 Mannucci et
al17 found decreased ADAMTS13 activity in newborns; during
the second and third trimesters of pregnancy; in patients with liver
cirrhosis, uremia, or acute inflammatory disorders; and during the
postoperative period. They concluded that a low ADAMTS13 level was not
a specific beacon of TTP.
In this study, we investigated ADAMTS13 activity in patients with
thrombocytopenia due to different causes in order to clarify the
specificity of decreased ADAMTS13 activity for TTP.
| |
Study design |
Patients
We recruited 68 patients with thrombocytopenia (platelet count,
<140 × 109/L), including 17 patients from a previous
study18 with severe sepsis or septic shock with or without
DIC; 16 patients with heparin-induced thrombocytopenia type 2 (HIT)
studied between 1995 and 2001 (all with a high clinical
probability of HIT and the diagnosis confirmed by a high titer of
antiheparin-platelet factor 4 antibodies; L. Alberio, et al,
manuscript submitted); and 35 patients, prospectively enrolled from
July 2001 to December 2001, with thrombocytopenic states with the
following causes: ITP (n = 10), idiopathic osteomyelofibrosis (n = 3), myelodysplastic syndrome (MDS; n = 4), acute leukemia (n = 6), severe aplastic anemia (n = 2), and miscellaneous
(n = 10) (Table 1). In none of the 68 patients with thrombocytopenia had TTP or HUS been considered as an
alternative diagnostic possibility. Platelet count, hemoglobin level,
and leukocyte count were determined for each patient. VWF-cleaving
protease activity was measured in citrated plasma samples stored at
 20°C until assay. The study was approved by the responsible ethical
committee (Kantonale Ethische Kommission, Bern, Switzerland).
ADAMTS13 activity
We determined the activity of ADAMTS13 by using a previously
described immunoblotting test.1,2 Briefly, plasma samples diluted (1:20) in 0.01 M Tris and 0.15 M sodium chloride (pH
7.4) containing 1 mM Pefabloc SC (Boehringer Mannheim, Germany) were incubated with 10 mM barium chloride at 37°C for 5 minutes and then
added to purified protease-free VWF substrate. The reaction mixture was
dialyzed on the surface of a hydrophilic filter membrane for 16 to 20 hours at 37°C against a buffer containing 1.5 M urea and 5 mM Tris
(pH 8.0). The reaction was stopped by adding EDTA, and the extent of
VWF degradation was analyzed by multimer analysis on 1.4% sodium
dodecyl sulfate-agarose gels and immunoblotting using
peroxidase-conjugated rabbit antihuman VWF antibodies.1,2 Dilutions of a pool of normal human plasma (NHP) from 42 healthy male
donors were used for calibration of the protease assay in plasma
samples from patients. This technique allows accurate determination in
the range below 25% of normal activity, permitting discrimination of
activity levels of 3% of normal plasma from those below 1% (Figure
1). All plasma samples from patients were
tested at least twice, and samples with protease activity of 30% or
less were reassayed several times on different days. Each patient's
pattern of VWF degradation was compared with the standard curve
(Figure 1).
View larger version (44K):
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| Figure 1.
Activity of VWF-cleaving protease (ADAMTS13) in 68 patients with
thrombocytopenia.
Multimer analysis of VWF substrate digested by diluted (1:20) plasma
samples from patients. On each gel (A-H), a calibration curve using
dilutions of pooled plasma from healthy donors (1:20 dilution
corresponding to 100%) is included. Seventeen patients with severe
sepsis (gels A,B), 16 with HIT (gels C,D) and 35 with thrombocytopenia
due to various causes (gels E-H) were analyzed. Plasma samples were
applied on top of the gel. OMF indicates osteomyelofibrosis; AL, acute
leukemia; SAA, severe aplastic anemia; and MISC, miscellaneous.
|
|
| |
Results and discussion |
Among the 68 patients with thrombocytopenia, 12 (18%) had
ADAMTS13 activity of 30% or less, the lowest value being 10% (Figure 1, gel C, no. 1). Patients with thrombocytopenia associated with severe
sepsis or septic shock, often accompanied by DIC (Figure 1, gels A and
B), had a median ADAMTS13 activity level of 40% (range, 15%-80%) and
6 of 17 had levels between 15% and 30%. This is in agreement with
findings by Loof et al,16 who reported ADAMTS13 activity
of 36% ± 24% in 14 patients with DIC.
The 16 patients with confirmed HIT (Figure 1, gels C and D) had a
median ADAMTS13 activity level of 70% (range, 10%-100%). Among the
35 prospectively enrolled patients with thrombocytopenia due to various
hematologic or other conditions (Figure 1, gels E-H), one patient
with MDS had a 25% level of ADAMTS13 activity (Figure 1, gel H, no.
31), whereas all others had levels of 40% or higher (Table 1). All
plasma samples with an activity level of 30% or less were reanalyzed
at least once on different days; essentially concordant results were
obtained (Table 1), thus confirming reproducibility of the
immunoblotting assay.
The ADAMTS13 values in this series of patients with thrombocytopenia
contrast sharply with those obtained in our earlier multicenter study4 of patients with TTP or HUS: 20 of 24 patients with acute nonfamilial TTP had ADAMTS13 activity below 5% of normal levels,
due to a circulating inhibitor detected in 20 of the 24 patients.
All 6 patients with constitutional TTP had ADAMTS13 activity levels
below 5% as well, and no inhibitor was detected in their plasma.
By December 2001, we had identified more than 120 patients with
ADAMTS13 activity levels below 5% in our laboratory. According to the
(sometimes incomplete) clinical information available to us, all had
clinical and laboratory findings compatible with TTP except 2 apparently asymptomatic siblings of patients with hereditary TTP14 and one child with a diagnosis of Escherichia
coli-associated HUS who had a transient acquired severe
deficiency of ADAMTS13 activity.19
Therefore, because of the results of the current study in
thrombocytopenic patients all with ADAMTS13 levels of at least 10% that in NHPas well as the previous analyses of 120 healthy
subjects4 and 74 hospitalized or healthy
controls5all with ADAMTS13 levels of at least 45% of
NHPwe conclude that a severe ADAMTS13 deficiency (< 5% of the
activity in NHP) is a specific finding for a form of thrombotic
microangiopathy most often diagnosed as TTP. Our data
contradict the findings of Moore et al,15 who reported
severe ADAMTS13 deficiency not only in some patients with TTP but also
in several patients with thrombocytopenia due to other conditions.
Nevertheless, it is also evident from our study that slightly decreased
(25%-50%) or moderately decreased ADAMTS13 activity (10%-25%) is
rather common in thrombocytopenic patients with severe sepsis or HIT, a
finding that is compatible with the observation of mild ADAMTS13
deficiency in various inflammatory disease states17 and in
patients with metastasizing neoplasia20 or
neoplasia-associated thrombotic microangiopathy.21
Even though very low ADAMTS13 activity (< 5% of the activity in NHP)
is a specific feature of the clinical condition labeled TTP, the
sensitivity of this laboratory finding for the diagnosis of TTP remains
questionable. Although, in retrospective studies, Tsai and
Lian5 observed severe ADAMTS13 deficiency in 37 of 37 patients and Furlan et al4 in 26 of 30 patients with a
diagnosis of acute TTP, the prospective study by Veyradier et
al7 found a severe deficiency in only 47 of 66 patients
presenting with idiopathic or secondary TTP (sensitivity, 71%).
Therefore, besides severe acquired or hereditary ADAMTS13 deficiency,
other pathogenetically relevant factors may cause a thrombotic
microangiopathy clinically indistinguishable from TTP.
Further prospective studies are needed to delineate whether specific
clinical or laboratory features (including response to therapy) in
patients with thrombotic microangiopathy with severe ADAMTS13
deficiency are different from those in patients without such a
deficiency. If such differences are observed, a new classification scheme for thrombotic microangiopathies might be justified, with severe
acquired ADAMTS13 deficiency and severe constitutional ADAMTS13
deficiency categorized as 2 distinct
entities.14
Finally, it is important to distinguish ADAMTS13 activity levels of
10% or higher from those under 5%. Patients with chronic recurring
TTP caused by severe hereditary ADAMTS13 deficiency are kept in
remission by regular plasma infusions (every 2 to 3 weeks) that raise
ADAMTS13 activity to just above 10% to 15%, and 5% of activity may
be sufficient to degrade the unusually large VWF multimers and prevent
intravascular platelet clumping.14,22
| |
Acknowledgments |
We thank Drs W. A. Wuillemin, S. Zeerleder, and C. Caliezi for
providing plasma samples from patients with severe sepsis or septic shock.
| |
Footnotes |
Submitted February 4, 2002; accepted March 6, 2002.
Prepublished online
as Blood First Edition Paper, April 17, 2002; DOI
10.1182/blood-2002-02-0344.
Supported in part by a grant from the Fondazione per la ricerca sulla
trasfusione e sui trapianti, Lugano, Switzerland.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Bernhard Lämmle, Central Hematology
Laboratory, University Hospital, Inselspital, Freiburgstrasse, CH-3010,
Bern, Switzerland; e-mail: bernhard.laemmle{at}insel.ch.
| |
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Top
Abstract
Introduction