Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3611-3613
CORRESPONDENCE
von Willebrand Factor Proteolysis in Thrombotic Thrombocytopenic
Purpura
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LETTER |
To the Editor:
von Willebrand factor (vWF)-cleaving protease has been shown to be
deficient in patients with thrombotic thrombocytopenic purpura
(TTP).1,2 The recent article by van der Plas et
al3 confirms the observation that vWF-cleaving protease is
severely decreased or missing in plasma of patients with classic TTP,
whereas normal protease activities were found in patients with bone
marrow transplantation (BMT)-associated TTP. The investigators found no
significant difference between the 2 groups regarding the levels of
cellular fibronectin. However, as shown in Table 1 of their report,
there was a very significant difference in vWF:Ag and vWF:Rcof between
classic TTP and BMT-associated TTP, even though the number of patients
in each group was quite limited (5 and 8 patients, respectively). Thus,
the median values of vWF:Ag were 88% in classic TTP and 292% in
BMT-associated TTP. The respective median values of vWF:Rcof were 67%
and 161%. The Mann-Whitney rank sum test resulted in P values
of .010 (vWF:Ag) and .011 (vWF:Rcof) for the difference between classic
and BMT group. These results suggest that, in contrast to the classic
group, there was massive release of vWF from the endothelial cells in
the BMT group, possibly due to graft-versus-host disease and/or
cyclosporin treatment.4,5 It is conceivable that the
excessive mobilization of abnormally adhesive very large multimeric
forms in the BMT patients leads to aggregation of the circulating
platelets and to thrombotic microangiopathy, even in the presence of
vWF-cleaving protease.6
Thrombotic microangiopathy (TMA), which is associated with BMT, is
sometimes labeled as TTP and sometimes as hemolytic-uremic syndrome
(HUS). Hematologists seem to favor the diagnosis of TTP, whereas
nephrologists tend to call it HUS. There is no distinct boundary
between TTP and HUS: diagnosis of TTP is preferred for cases with
neurologic disturbances, whereas cases involving predominantly renal
impairment are classified as HUS. No information is given in the study
of van der Plas3 regarding the clinical symptoms and
criteria, according to which the TMA in their patients had been
classified as TTP. It is obvious (Table 1) that the creatinine level
was normal in patients with classic TTP (median value, 76 µmol/L),
but significantly increased (P = .019) in patients with BMT-associated TTP (median value, 178 µmol/L). Therefore, the TMA in
the BMT group should be classified as HUS rather than as TTP.
In our study on vWF-cleaving protease in patients with TTP and
HUS,1 we observed deficient or strongly decreased protease activity in patients with familial and nonfamilial TTP, but normal protease activity in patients classified as having HUS. It should be
added that 2 patients were included into the latter study who presented
with symptoms of TMA after BMT: the patient no. 24A, classified as
having TTP, had 25% protease activity, whereas the symptoms in the
patient no. 35A were compatible with the diagnosis of HUS and the
patient had normal activity of vWF-cleaving protease. Although there
were no neurological symptoms observed in patient no. 24A, his
diagnosis was apparently misclassified as TTP by the participating
investigator, because the creatinine levels had been only moderately increased.
It appears that the discrepancy between conclusions of our
report1 and the report of van der Plas et al3
only arises from the differential diagnosis of the TMA in BMT patients.
If the BMT cases had been classified by van der Plas et al3
as HUS, which may be appropriate regarding the laboratory data, their report would perfectly confirm our observation that the vWF-cleaving protease is deficient in patients with TTP but present in patients with HUS.
| |
ACKNOWLEDGMENT |
Our studies were supported by grants from the Swiss National Science
Foundation (Grant No. 32-47033.96); from the Central Laboratory, Blood
Transfusion Service, Swiss Red Cross; from Immuno (Vienna, Austria);
and from the Malcolm Hewitt Wiener Foundation (New York, NY).
Miha Furlan
Central Hematology Laboratory
University
Hospital
Inselspital
Bern, Switzerland
| |
REFERENCES |
1.
Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B, Krause M, Scharrer I, Aumann V, Mittler U, Solenthaler M, Lämmle B:
von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.
N Engl J Med
339:1578, 1998[Abstract/Free Full Text]
2.
Tsai H-M, Lian EC-Y:
Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.
N Engl J Med
339:1585, 1998[Abstract/Free Full Text]
3.
van der Plas RM, Schiphorst ME, Huizinga EG, Hené RJ, Verdonck LF, Sixma JJ, Fijnheer R:
von Willebrand factor proteolysis is deficient in classic, but not in bone marrow transplantation-associated, thrombotic thrombocytopenic purpura.
Blood
93:3798, 1999[Abstract/Free Full Text]
4.
Paquette RL, Tran L, Landaw EM:
Thrombotic microangiopathy following allogeneic bone marrow transplantation is associated with intensive graft-versus-host disease prophylaxis.
Bone Marrow Transplant
22:351, 1998[Medline]
[Order article via Infotrieve]
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Thrombotic microangiopathic syndromes after bone marrow transplantation.
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Endothelial cell activation.
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Response
The level of vWF in the BMT-associated TTP was indeed higher
compared with the level in patients with classic TTP. Furlan states
that the massive release of vWF from the endothelium in the BMT group
could play a role in the development of the TTP. Endothelial activation
with an increase in vWF is known to occur in patients using cyclosporin
as well as in patients receiving a BMT.1,2 Not all of these
patients develop TTP. Moreover, a lot of other circumstances, eg,
sepsis and exercise, are also known to induce a massive increase in vWF
without development of TTP.3 So, an increase of vWF is not
enough to induce TTP, and other mechanisms are probably involved.
TMA is a clinical diagnosis that includes HUS and TTP. Both
are characterized by microangiopathic hemolytic anemia,
thrombocytopenia, microvascular thrombosis, and multiorgan
failure.4 Typical verotoxin-associated HUS, mostly due to
Escherichia coli 0157:H7 infection, is associated with
prodromal diarrhea followed by acute renal failure and is considered a
disease with a good outcome. Atypic HUS covers 2 clinical
conditions. The first form is characterized by severe gastrointestinal
prodromes, acute onset anuria, and neurological involvement. The second
form is without diarrhea prodromes but with progressive renal function
deterioration and neurological involvement that resembles TTP. Hence,
TTP and HUS appear to be closely related and part of a
disease continuum. Renal function was only slightly impaired in our
patients.5 A rapid renal insufficiency with diarrhea was
not observed. No spontaneous improvement occurred, and patients with
an autologous BMT-associated TMA were successfully treated
with cyclosporin. Our patients did not respond to plasmapheresis. This
makes the BMT-associated TMA a specific subgroup. The normal
vWF-cleavage protease activity in what is defined HUS and deficiency of
the protease in TTP provides insight in a different pathophysiologic mechanism.6 Patients with BMT-associated TTP had normal vWF proteolysis, and this confirms the observation that TMA occurs with a
normal vWF cleaving activity. It is of interest to study whether the
ineffectiveness of plasmapheresis in our BMT-TTP patients can also be
observed in the other TMAs with normal vWF protease activity. A clear
clinical and pathophysiologic distinction between vWF-cleaving protease
present and deficient TMA's could define a better classification system.
Rob Fijnheer
Martijn van der Plas
Eric Huizinga
Ronald Hené
Jan Sixma
Leo Verdonck
Department of Haematology and Nephrology
University Medical
Center Utrecht
Utrecht, The Netherlands
| |
REFERENCES |
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Richard S, Seigneur M, Blann A, Adams R, Renard M, Puntous M, Boiron JM, Amiral J, Reiffers J, Boisseau M:
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2.
Tiemann C, Prohaska W, Korfer R, Korner M, Brinkmann T, Kleesiek K:
Effect of cyclosporin A on the release of tissue factor pathway inhibitor from endothelial cells in heart transplant patients and cell culture.
Eur J Clin Chem Clin Biochem
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3.
van Mourik JA, Boertjes R, Huisveld IA, Fijnvandraat K, Pajkrt D, van Genderen PJ, Fijnheer R:
von Willebrand factor propeptide in vascular disorders: A tool to distinguish between acute and chronic endothelial cell perturbation.
Blood
94:179, 1999[Abstract/Free Full Text]
4.
Thompson CE, Damon LE, Ries CA, Linker CA:
Thrombotic microangiopathies in the 1980s: Clinical features, response to treatment, and the impact of the human immunodeficiency virus epidemic.
Blood
80:1890, 1992[Abstract/Free Full Text]
5.
van der Plas RM, Schiphorst ME, Huizinga EG, Hené RJ, Verdonck LF, Sixma JJ, Fijnheer R:
von Willebrand factor proteolysis is deficient in classic, but not in bone marrow transplantation-associated, thrombotic thrombocytopenic purpura.
Blood
93:3798, 1999
6.
Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B, Krause M, Scharrer I, Aumann V, Mittler U, Solenthaler M, Lammle B:
von Willebrand factor-cleaving protease in thrombotic throbocytopenic purpura and the hemolytic-uremic syndrome.
N Engl J Med
339:1578, 1998
