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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3798-3802
von Willebrand Factor Proteolysis Is Deficient in Classic, but not in
Bone Marrow Transplantation-Associated, Thrombotic Thrombocytopenic
Purpura
By
R. Martijn van der Plas,
Marion E. Schiphorst,
Eric G. Huizinga,
Ronald J. Hené,
Leo F. Verdonck,
Jan J. Sixma, and
Rob Fijnheer
From the Thrombosis and Haemostasis Laboratory, Department of
Haematology, Institute of Biomembranes, University Medical Centre
Utrecht, Utrecht, The Netherlands.
 |
ABSTRACT |
Thrombotic thrombocytopenic purpura (TTP) after bone marrow
transplantation (BMT) differs from classic TTP in its clinical course
and therapy. A characteristic of classic TTP is the inhibition of a
plasma protease that specifically cleaves von Willebrand factor (vWF),
thus reducing its multimeric size. We investigated whether this
protease was also inhibited in BMT-associated TTP. Plasma from patients
with classic or BMT-associated TTP was incubated with recombinant vWF
R834Q, a vWF mutant with enhanced sensitivity to the protease. The
proteolysis of vWF multimers was analyzed and quantified on Western
blot. Metalloprotease activity was strongly inhibited in the classic
TTP patient group. However, metalloprotease activity was normal in the
BMT-associated TTP patient group. The difference in activity between
the two patient groups was highly significant (P = .0016).
The results indicate that the etiologies of classic and BMT-associated
TTP are indeed different and provide an explanation for the lack of
success of plasma exchange in BMT-associated TTP.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
THROMBOTIC thrombocytopenic purpura (TTP)
is characterized by thrombocytopenia, microangiopathic hemolytic
anemia, fever, neurological symptoms, and renal impairment resulting
from the formation of platelet thrombi within the microvasculature. TTP
may develop spontaneously, but it can also occur as a dangerous complication after a bone marrow transplantation (BMT).1
It has been hypothesized that the presence of unusually high multimers
of von Willebrand factor (vWF) is the central cause of
TTP.2 vWF is a plasma glycoprotein that is involved in
platelet adhesion and aggregation.3 The vWF molecule is
present in plasma as a series of multimers, which may consist of up to
and over 80 monomers.4 It is generally believed that the
higher multimers are more active in hemostasis.
Multimeric vWF is specifically cleaved by a 300-kD plasma
metalloprotease between positions 842-843.5 In vitro, this
protease is not active towards native vWF, but it is active towards vWF that has been denatured by urea or towards vWF containing a von Willebrand disease type 2A mutation.6,7 Although the exact function of this protease is unknown, it is likely that it is necessary
for controlling the multimeric size of vWF and thereby its biological activity.
Furlan et al8 found that the activity of this
metalloprotease is decreased in patients with chronic relapsing classic
TTP. They hypothesized that inhibition of the metalloprotease causes diminished proteolysis of vWF multimers, resulting in the presence of
unusually high multimers of vWF in the circulation. These unusually high multimers of vWF then induce spontaneous platelet aggregation and
thrombus formation in the vasculature. Recently, inhibiting antibodies
against the metalloprotease have been found in patients with classic
TTP.9 Therapeutic plasma exchange is a very effective treatment of classic TTP. It is likely that plasma exchange removes the
inhibitors, the inhibited metalloprotease, and the unusual high
multimers of vWF, replacing them by active metalloprotease and vWF with
a normal multimeric pattern.
TTP may also develop as a complication after BMT.1
Recognition of this BMT-associated TTP has increased in recent
years.10 The reported incidence of TTP is 14% in allograft
and 7% in autograft recipients.1 Although the clinical
picture is the same as for classic TTP, plasma exchange as treatment is
generally unsuccessful.10-13 This suggests that
plasma-derived factors like vWF and the vWF degrading metalloprotease
are not important in the etiology of BMT-associated TTP. To investigate
whether this suggestion is true, we measured the activity of the vWF
degrading metalloprotease in TTP patients.
| |
MATERIALS AND METHODS |
Patients.
Thirteen patients with classic or BMT-associated TTP were studied. The
diagnosis of TTP was made if the patient had thrombocytopenia (defined
as a platelet count <100 × 109/L), microangiopathic
hemolytic anemia as indicated by red blood cell
fragmentation present in a peripheral blood smear and elevated lactate
dehydrogenase (LDH), without an identifiable cause for the
thrombocytopenia or microangiopathic hemolytic anemia (eg, sepsis,
disseminated intravascular coagulation, carcinoma, eclampsia).
The clinical data of all patients are shown in Table 1. Five patients
with classic TTP were studied. All patients with classic TTP were
successfully treated by plasma exchange. Patients received a minimum of
seven plasma exchanges over 9 days with assessment concerning further
treatment made at the end of this treatment cycle. One and a half
plasma volume of the patient was removed daily and replaced by the same
volume of fresh frozen plasma.
Eight patients with BMT-associated TTP were studied. The mean time
between the BMT and the development of TTP was 7 months (range, 3 to
13). In one patient, TTP developed after 18 months, when additional T
cells were infused because of relapse of acute lymphoblastic leukemia.
Progressive disease during plasma exchange was observed in two
autologous BMT patients (patients 8 and 9) and one allogeneic BMT
patient (patient 11) (further decline in renal function, no improvement
of hemoglobin, LDH, and platelet count). Subsequently, patients 8 and 9 received cyclosporin as alternative treatment. In another two
autologous BMT patients (patients 6 and 7), cyclosporin was given as a
first treatment. The TTP responded in all four patients.
All four patients with allogeneic BMT received oral cyclosporin and
suffered from graft-versus-host disease (GVHD) at the moment that TTP
developed. In three of these patients, cyclosporin was stopped followed
by a gradual improvement of the peripheral blood counts and
disappearance of TTP. However, all allogeneic BMT patients developed
lethal complications unrelated to TTP (pneumonia [two patients],
veno-occlusive disease of the liver, intracerebral hemorrhage).
Blood collection.
Unless otherwise indicated, samples were taken before treatment was
started. Blood was collected by vacutainer system in 3.1% citrate
(1:10). To obtain platelet-free plasma, the blood was centrifuged for
15 minutes at 4°C at 2,000g; the supernatant was removed
and centrifuged a second time. Samples were stored at  80°C.
Characterization of vWF and cellular fibronectin (FN) in plasma.
The following parameters were determined for each plasma sample: vWF
antigen concentration (vWF:Ag) and the vWF:ristocetin cofactor activity
(vWF RiCof).14 The multimeric structure of endogenous
patients' vWF was determined by agarose gel electrophoresis followed
by Western blotting as described by Lawrie et al.15 For
detection, horseradish peroxidase-labeled polyclonal antibodies to
human vWF were used (DAKOpatts, Glostrup, Denmark).
Cellular FN was determined as described previously.16
Preparation of recombinant vWF.
The construction, expression, and purification of recombinant human vWF
containing the mutation R834Q (vWF R834Q) was described previously.6
vWF proteolysis assay.
The activity of the vWF degrading metalloprotease was determined by a
modified version of the method described by Furlan et al.5,8 This method assays the activity of the protease in plasma. The plasma is diluted so far that endogenous vWF is not detectable, and purified vWF is then added as a substrate. Recombinant vWF R834Q, which has enhanced sensitivity to proteolysis by the metalloprotease, was used.
The experiments were performed as follows: citrate plasma (4 µL) was
mixed with 26 µL low ionic strength buffer (5 mmol/L Tris-HCl)
containing 1 mmol/L Pefabloc (Boehringer Mannheim, Almere, The
Netherlands). To activate the metalloprotease, 1 µL of 300 mmol/L
BaCl2 was added, and the mixture was incubated for 5 minutes at 37°C. Subsequently, 10 µL vWF R834Q was added (final
concentration approximately 14 µg/mL). The mixture was transferred
onto a hydrophilic filter membrane (VSWP, 25-µm diameter; Millipore,
Bedford, PA), floating on the surface of 50 mL dialysis buffer (1.5 mol/L urea and 5 mmol/L Tris-HCl, pH = 8.0) in a screw-cap plastic
tube. The tube was closed and the mixture was incubated overnight at 37°C. Samples were taken and mixed with 3 vol of sample buffer. The
multimeric structure of substrate vWF after incubation was determined
by agarose gel electrophoresis followed by Western blotting according
to Lawrie.15 Equal amounts of incubation mixture were
loaded on gel.
The extent of proteolysis of vWF by patient plasma was compared with
the proteolysis of vWF by normal plasma from a healthy volunteer. The
activity of the metalloprotease in control plasma was assessed without
EDTA (maximal proteolysis of vWF) or in the presence of EDTA (no
proteolysis of vWF). EDTA (1 mmol/L final concentration) was added to
both the incubation mixture and the dialysis buffer.
Data analysis.
To quantify the results, blots were scanned and analyzed with
ImageQuant software (Molecular Dynamics, Sunnyvale, CA). The integrated
pixel intensity was determined for the two lowest visible vWF multimer
bands ("LMW-vWF") and for all vWF visible in a lane ("total
vWF"). Values were corrected for background. The fraction LMW-vWF
was calculated by dividing the integrated pixel density of LMW-vWF
through the integrated pixel density of total vWF. The breakdown was
then calculated as the relative change in the fraction LMW-vWF,
expressed as a normalized ratio. The value for fraction LMW-vWF of the
control incubation with EDTA was taken as 0 and the value of the
control without EDTA was taken as 1 (note that this method may yield
values below 0 and above 1). For statistical analysis, the Mann-Whitney
test was used.
| |
RESULTS |
The vWF:Ag, vWF:RiCof, and cellular FN plasma
concentration of each patient are shown in
Table 1. The cellular FN concentrations in
plasma from patients with TTP were significantly higher compared with
control (2.9 µg/mL ± 1.1 in TTP; compared with 0.9 µg/mL ± 0.2 in plasma from 40 healthy controls; P < .001). The levels in BMT-associated TTP were not significantly different from those in
classic TTP. The concentration of vWF antigen was normal in patients
with classic TTP, but was increased in patients with BMT-associated TTP
(normal range, 70% to 130%). The multimeric distribution of
endogenous vWF of the patients was similar to the multimeric
distribution of vWF in normal pooled plasma (data not shown).
In Fig 1, the proteolysis of vWF by the
metalloprotease in plasma of patient 4 before and after plasma exchange
is shown. There is no active protease present in the plasma sample
taken before treatment, while after the start of plasma exchange, there is active protease present in the plasma; vWF R834Q was then
proteolysed by plasma from this patient to an extent comparable with
control plasma. This is in agreement with the results of Furlan et
al.9
View larger version (82K):
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[in a new window]
| Fig 1.
Western blot of the multimeric pattern of vWF R834Q after
incubation with plasma from patient 4 suffering from classic TTP before
(4A) and after (4B) plasma exchange. C1, plasma from a healthy donor
incubated with vWF R834Q. C2, plasma from a healthy donor incubated
with vWF R834Q in the presence of EDTA (1 mmol/L).
|
|
In Figs 2 and
3, the Western blots are shown from the
incubation of all patient plasmas with purified vWF R834Q. A
qualitative assessment of these Western blots shows that the multimer
size of vWF is not affected by incubation with plasma from patients with classic TTP, but is strongly reduced after incubation with plasma
from patients with BMT-associated TTP, indicating that there is a clear
difference in vWF breakdown between the patient groups.
View larger version (127K):
[in this window]
[in a new window]
| Fig 2.
Western blot of the multimeric pattern of vWF R834Q after
incubation with plasma from patients suffering from classic TTP. C1,
plasma from a healthy donor incubated with vWF R834Q. C2, plasma from a
healthy donor incubated with vWF R834Q in the presence of EDTA (1 mmol/L). Lanes 1 through 5, patient plasmas (numbers as in Table 1).
|
|
View larger version (100K):
[in this window]
[in a new window]
| Fig 3.
Western blot of the multimeric pattern of vWF R834Q after
incubation with plasma from patients suffering from BMT-associated TTP.
C1, plasma from a healthy donor incubated with vWF R834Q. C2, plasma
from a healthy donor incubated with vWF R834Q in the presence of EDTA
(1 mmol/L). Lanes 6 through 13, patient plasmas (numbers as in Table
1).
|
|
The results were quantified by scanning the Western blots and
expressing the extent of breakdown as a normalized ratio as is
described in Materials and Methods. A ratio of zero signifies that the
extent of breakdown is identical to the control in the presence of
EDTA, while a ratio of 1 signifies that the extent of breakdown is the
same as observed for normal plasma. The results of the quantitative
analysis are shown in Table 2. The mean
breakdown of vWF is 0.086 ± 0.094 for the classic TTP patient group
and 0.91 ± 0.092 for the BMT-associated TTP patient group. Each
patient group has one outlier with an intermediate normalized ratio.
One patient with classic TTP (patient 2) had a normalized ratio of 0.42 and one patient with BMT-associated TTP (patient 9) had a normalized
ratio of 0.48. The difference between the two patient groups, not
excluding both patients with an intermediate ratio, is highly
significant (Mann-Whitney test: P = .0016). The mean vWF
breakdown in the classic TTP group was not significantly different from
control with EDTA, which implies that this patient group has completely
inhibited metalloprotease activity. The mean vWF breakdown in the
BMT-associated TTP was not significantly different from control without
EDTA, which implies that this patient group has normal metalloprotease
activity.
| |
DISCUSSION |
Furlan et al8 have shown that the activity of a vWF
degrading plasma metalloprotease is decreased in patients with classic TTP. Inhibition of this protease was postulated as a general phenomenon in TTP. However, the observation that plasma exchange is ineffective in
patients with BMT-associated TTP10-13 suggests that this
plasma protease may not be involved in this form of TTP.
We assayed the activity of this metalloprotease in plasma from patients
with classic or BMT-associated TTP. Most (seven of eight) patients who
developed TTP after a BMT had a metalloprotease activity comparable to
normal control. The metalloprotease activity in one patient was
partially inhibited. In contrast, the metalloprotease activity was
virtually absent in plasmas from patients with classic TTP, again with
one exception of partial inhibition. The difference between these two
patient groups is statistically significant.
Plasma exchange is very effective in the treatment of classic TTP, and
we confirm in this report that plasma exchange results in restoration
of plasma metalloprotease activity.9 However, the patients
with BMT-associated TTP described in this and other reports10-13 did not improve after plasma exchange. This
difference is explained by the normal metalloprotease activity in
BMT-associated TTP. Apparently, plasma factors like the vWF degrading
metalloprotease are not involved in BMT-associated TTP.
The etiology of BMT-associated TTP remains unclear. In allografted BMT
patients, cyclosporin seems to be the most important risk factor for
the development of TTP. The underlying mechanism is not completely
understood, but cyclosporin is known to cause endothelial damage in
vivo17 and activation and tissue factor expression on
endothelial cells in vitro.18 It is possible that extensive
endothelial damage, microangiopathy, and other effects caused by
cyclosporin may finally lead to TTP.1,10 Discontinuing cyclosporin administration may thus result in disappearance of TTP.
However, GVHD may also be involved in the development of endothelial
damage and pathogenesis of TTP.
In autografted BMT patients, the TTP develops while patients are not
receiving cyclosporin and surprisingly, cyclosporin is an effective
treatment of TTP in these patients.11 There are two
possible explanations for this observation. First, cyclosporin stimulates production of nitric oxide by endothelial
cells,19 which may result in inhibition of platelet
activation and aggregation. Second, cyclosporin is an immunosuppressive
drug and may inhibit immune-mediated mechanisms in TTP.20
The balance between the opposing effects of cyclosporin, endothelial
damage versus inhibition of platelet activation, and antibody
production apparently differs between autologous and allogeneic BMT
patients. The immunosuppressive action of cyclosporin also explains the
observation that it can be beneficial in classic TTP.21
The plasma concentration of cellular FN, a marker for endothelial
damage, was elevated in both classic and BMT-associated TTP.
Endothelial cell damage is probably a common feature of all forms of
TTP. The increased vWF concentration in patients with BMT-associated
TTP may be a factor in the development of TTP. At least it is a marker
of the endothelial damage present. Surprisingly, the vWF concentration
is in the normal range in patients with classic TTP, while it is
expected to be increased because of the endothelial damage and the
reduced vWF proteolysis. Apparently, the consumption of unusually high
vWF multimers during the formation of platelet thrombi counteracts this effect.
We confirm that the metalloprotease that is involved in the proteolysis
of vWF multimers is inhibited in patients with classic TTP, and we show
that plasma exchange results in restoration of its activity. We
observed that this metalloprotease is normally active in all patients
with BMT-associated TTP. The present findings provide an explanation
why plasma exchange is not effective in patients with BMT-associated
TTP. It is, of course, of interest to study whether the vWF degrading
metalloprotease is inhibited in other forms of secondary TTP, like
pregnancy-, human immunodeficiency virus (HIV)-, cancer-, and
drug-induced TTP.
| |
FOOTNOTES |
Submitted August 26, 1998; accepted January 25, 1999.
Supported by Grant No. 902-26-193 from the Netherlands Organization for
Scientific Research (NWO) and by the University Medical Centre Utrecht.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to R. Martijn van der Plas, MSc,
Department of Haematology, Room No. G03.647, PO Box 85500, 3508 GA
Utrecht, The Netherlands; e-mail: j.vd.velde{at}digd.azu.nl.
| |
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TOP
ABSTRACT
INTRODUCTION