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Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3623-3629
Clinical Significance of Inhibitors in Acquired von Willebrand
Syndrome
By
Hiroshi Mohri,
Shigeki Motomura,
Heiwa Kanamori,
Michio Matsuzaki,
Shin-ichiro Watanabe,
Atsuo Maruta,
Fumio Kodama, and
Takao Okubo
From the First Department of Internal Medicine, Division of Blood
Transfusion and Laboratory Medicine, Yokohama City University,
Yokohama, Japan and the Department of Hematology/Chemotherapy, Kanagawa
Cancer Center, Yokohama, Japan.
 |
ABSTRACT |
Of 260 patients enrolled, 25 patients (9.6%) were associated with
acquired von Willebrand syndrome (AvWS). We studied 25 patients with
AvWS, retrospectively. AvWS was diagnosed by reduced levels of von
Willebrand factor (vWF) (decrease of von Willebrand factor antigen
[vWF:Ag] and von Willebrand ristocetin cofactor
[vWF:RCoF]), a decrease of ristocetin-induced platelet
agglutination (RIPA), sometimes decreased high-molecular-weight
multimers, and prolonged bleeding time with neither prior nor family
histories of bleeding problems and the evidence of normal vWF:RCoF in
their families. The inhibitor of vWF was determined by mixing patient
plasma with pooled normal plasma. Eight patients in this study had the
inhibitors to vWF that were of the IgG class; the subclasses were
IgG1 (7 cases) and IgG2 (1 case). Multimeric
analysis of vWF showed selective loss of large multimers in most
patients with AvWS similar to that of congenital type-2 von Willebrand
disease (vWD). All inhibitors blocked ristocetin-mediated vWF binding
to platelets. Five out of 6 IgGs evaluated here recognized the 39/34-kD
fragment (residues 480/481-718) and Fragment III (residues 1-1365) that
implied binding domain of glycoprotein Ib (GPIb), whereas 1 recognized
Fragment I (residues 911-1365). A close relationship was found
between the presence of the inhibitor and bleeding tendency. Of the 7 patients with inhibitors, 6 patients (86%) had a bleeding tendency, as
well as 1 of the 15 patients without inhibitors (6%). The efficacy of
treatment of underlying diseases and/or therapy with deamino D-arginine vasopressin (DDAVP) for the treatment of AvWS
also depends on the presence of an inhibitor. Four of 8 patients with inhibitors (50%) had poor response to treatment of the underlying disease and/or therapy with DDAVP, as well as 1 of the 16 patients without inhibitors (6%). These results indicate that
patients with AvWS developing inhibitors to vWF are likely to have
bleeding problems and might be resistant to treatment of underlying
diseases and/or therapy with DDAVP for bleeding to AvWS. We
also showed evidence that intravenous immunoglobulin therapy (0.3 g/kg,
3 days) was effective to correct a hemostatic defect and manage severe
bleeding in a patient with AvWS developing inhibitors. We might
consider an additional treatment including expensive high-dose
immunoglobulin therapy when uncontrollable bleeding is continued after
the treatment of the underlying diseases and/or therapy with
DDAVP.
| |
INTRODUCTION |
VON WILLEBRAND FACTOR (vWF) is a
multimeric plasma glycoprotein that is involved in adhesion and
aggregation of platelets at the site of vascular injury.1
Its key functions include binding to the platelet membrane receptors,
glycoprotein (GP) Ib and IIb/IIIa.2 Acquired von Willebrand
syndrome (AvWS) results from quantitative and/or qualitative
defects in vWF mimicking the clinical and laboratory features of
hereditary von Willebrand disease (vWD). The incidence of AvWS in
various diseases has not been clearly known. A recent prospective study
unexpectedly found AvWS in 8% of Wilms tumor patients.3
Laboratory examination shows that bleeding time is normal or prolonged
and ristocetin cofactor activity (vWF:RCoF) is characteristically low
or nearly absent, whereas von Willebrand factor antigen (vWF:Ag) is low or normal. Furthermore, multimeric analysis of vWF most commonly shows
a pattern similar to type-2 congenital vWD, with selective loss of high
molecular weight multimers.4
AvWS is reported in association with monoclonal gammaglobulins,
lymphoproliferative disorders such as lymphomas, myelomas, Wilms'
tumors and autoimmune disorders, suggesting that deficiency of vWF has
an immunological etiology. Two mechanisms have been proposed to explain
the pathogenesis of the acquired deficiency of vWF in these cases: (1)
the presence of circulating antibodies that inactivate functional
domains of vWF or form a complex with vWF by binding to its functional
sites, the bound vWF is rapidly cleared from the
circulation5-8 (however, antibodies to vWF are shown in
vitro in only a minority of the cases); and (2) selective absorption of
large and intermediate multimers of vWF by malignant cells9
(however, in the majority of patients the mechanism of the vWF
deficiency has not been clearly delineated).
Treatment of AvWS depends on the underlying disease process and the
mechanisms responsible for development of the syndrome. The treatment
of underlying diseases is crucial for treatment of AvWS. However, it is
not possible to predict which patients will have a good response to the
treatment of underlying diseases and/or therapy with deamino
D-arginine vasopressin (DDAVP). We hypothesized that the presence of
the inhibitor predicts the response to the treatment of AvWS.
In this paper we described a series of 25 patients with AvWS to
evaluate the laboratory features, possible pathogenetic mechanisms for
AvWS, and therapeutic strategies for the treatment of AvWS. We found
that the presence of inhibitors was a sensitive and specific predictor
of both the response to treatment of the underlying diseases
and/or therapy with DDAVP, and bleeding tendency.
| |
PATIENTS AND METHODS |
Patients.
From January 1985 to December 1996 at Yokohama City University School
of Medicine, Yokohama, Japan, we have studied 260 patients with various
disorders; 125 patients with chronic myeloproliferative disorders
(chronic myelocytic leukemia [CML], 57 patients; polycythemia rubra
vera [PV], 37 patients; essential thrombocythemia [ET], 31 patients), 51 patients with non-Hodgkin's lymphoma (NHL), 42 patients
with multiple myeloma (MM), 28 patients with acute leukemia (acute
myelocytic leukemia [AML], 15 patients; acute myelomonocytic leukemia
[AMMoL], 7 patients; acute lymphocytic leukemia [ALL], 6 patients),
and 14 patients with chronic lymphocytic leukemia (CLL) (stage II, 4 patients; stage III, 5 patients; stage IV, 5 patients). The diagnosis
of CML was confirmed by the cytogenetic finding of the Ph1
chromosome. All patients with CML were in chronic phase. PV was
diagnosed by the criteria described elsewhere.10 The
criteria of ET were based on abnormal proliferation of the megakaryocytes and platelet count more than
106/mm3 with splenomegaly.11 The
diagnosis of lymphoma was confirmed by lymph node biopsy and lymphomas
were classified as non-Hodgkin's lymphoma or Hodgkin's disease
according to the Rye classification.12 The diagnosis of MM
was established according to the criteria of the Southwest Oncology
Group.13 Acute leukemia was classified according to the
French-American-British classification.14 Subclasses of AML
were based on morphological and cytochemical criteria. The diagnosis of
CLL was based on clinical, morphological, and immunophenotypic criteria
as described elsewhere.15
Study design.
The criteria for diagnosis of AvWS were reduced levels of vWF (decrease
of vWF:Ag and vWF:RCoF), a decrease of ristocetin-induced platelet
agglutination (RIPA), sometimes decreased high-molecular-weight multimers and prolonged bleeding time with no prior history of bleeding
problems and a family history negative for a bleeding tendency, whereas
that of inherited vWD (except for type 2B and platelet type) were those
with family history.16 In patients with type-2B and
platelet-type vWD, RIPA showed increased sensitivity. To exclude
inherited vWD, blood samples from some family members were tested for
vWF:Ag, vWF:RCoF, and RIPA. ABO blood type was also evaluated.
All patients were evaluated before treatment. Blood samples were
obtained from all patients and tested for platelet count, vWF:Ag,
vWF:RCoF, and RIPA. The tests were performed by laboratory staff
without knowledge of the patients' clinical presentations. Inhibitors
of vWF were also determined by a mixing study that was performed by
incubation of patient plasma with pooled normal plasma.
Laboratory studies.
The bleeding time was measured by the modified method of
Ivy17 using an automatic template device (Simplate; General
Diagnostic, Morris Plains, NJ). The normal laboratory range for
bleeding time is 4 to 8 minutes. vWF antigen (vWF:Ag) was evaluated by
the Laurel technique of quantitative
immunoelectrophoresis.18 The normal range for
both factors in our laboratory is 50% to 150%. vWF:RCoF was assayed
with formalin-fixed platelets as described elsewhere.19 The
normal range is 60% to 150%. The multimeric composition of vWF was
analyzed by sodium dodecyl sulfate (SDS) 0.9% agarose gel
electrophoresis according to the method described
elsewhere.20
Platelet aggregation was performed in siliconized cuvettes at 37°C
and stirred at 1,000 rpm as described previously.21
Ristocetin (1.2 mg/mL) was added to platelet-rich plasma. Aggregation
was recorded as the increase in the light transmission through the mixture.
Assay of an inhibitor against FVIII:C was performed as described
elsewhere.22 Inhibitors of vWF were sought by incubating 1 volume of patient plasma with 1 volume of pooled normal plasma for 1 hour at 37° as described elsewhere.5,23 Controls were determined by mixture of normal plasma (1 volume) with
phosphate-buffered saline (PBS) (1 volume). Patient and normal plasmas
were also incubated independently under the same conditions. The
expected values were calculated from the values for patient plasma and normal plasma incubated and assayed separately.
The Ig class of the inhibitors was identified as previously
described.5,23 In brief, serum from the patients was added in increasing concentration to the wells coated with vWF for 1 hour at
22°. After washing with PBS, 0.05% Tween 20, horseradish peroxidase (HRP)-conjugated goat Igs to either human IgG (Zymed Inc,
South San Francisco, CA), IgM, or IgA (Bioscience, Copenhagen, Denmark) was added to each well. Then the peroxidase
substrate (o-phenylenediamine; Zymed) was added and the reaction was
blocked with 2 mol/L H2SO4.
Human vWF was produced from cryoprecipitate (a kind gift from Dr
Zaverio M. Ruggeri; Scripps Research Institute, La Jolla, CA) and was
also purchased from Bio Pur AG (Bubendorf, Switzerland). Human plasma
fibronectin was purchased from Bachen Chemical Co, Ltd (Torrance, CA).
A monomeric 39/34-kD fragment of human vWF (residues 480/481-718) was
obtained by dispase digestion of purified vWF and purified by a
heparin-Sepharose affinity chromatography as described
elsewhere.24 This fragment is crucial for the binding to
GPIb. Fragment I (residues 911-1365), Fragment II (residues 1366-2050),
and Fragment III (residues 1-1365) were generated by digestion of vWF
with Staphylococcus aureus V8 protease (SV8) and were
characterized as described previously.25
To evaluate the effect of the inhibitor on the ristocetin-mediated
vWF-GPIb interaction, 125I-vWF (2 µg/mL) was incubated
with formalin-fixed platelets (1 × 108/mL),
ristocetin (1 mg/mL), and Hepes buffer or the inhibitor at various
concentrations for 30 minutes at 22°C. Bound ligand was separated
from free ligand by centrifugation. And then platelet-associated radioactivity was determined as described elsewhere.2 vWF
was iodinated with 125I (Amersham, Arlington Heights,
IL) using Iodo-Gen (Pierce Chemical Co, Rockford, IL)
according to a method described elsewhere.26
Recognition site(s) of inhibitors were identified in enzyme-linked
immunosorbent assay (ELISA) as described elsewhere.23 In
brief, polystyrene microtiter plates were coated with a solution of
purified vWF or proteolytic fragments of vWF. Purified IgGs were added
to the wells coated with vWF or proteolytic fragments of vWF. Then
HRP-conjugated goat Igs to either human IgG were added to each well.
After incubation, the peroxidase substrate (o-phenylenediamine) was
added. The reaction was blocked with 2 mol/L
H2SO4.
DDAVP (desmopressin, Minirin, Ferring-Malmo, Sweden) at a dose of 0.3 µg/kg body weight was administered intravenously over 30 minutes.
Blood samples were obtained before the infusion and after various time
intervals (60, 120, 240, and 480 minutes).
Statistical analysis.
We calculated the specificity, sensitivity, and positive and negative
predictive values of inhibitors as a predictor of bleeding.
| |
RESULTS |
Of 260 patients enrolled, AvWS was diagnosed in 25 patients (13 women
and 12 men; 9.6 %) with a mean age of 54 years (range, 30 to 85 years). Of these 25 patients, 14 had chronic myeloproliferative disorders (CMPD; [CML, 8 patients; PV, 3 patients; ET, 3 patients]), 4 had acute leukemia (AML, 2 patients; AMMoL, one patient; ALL, one
patient), 3 had MM, 3 had CLL, and 1 had NHL
(Table 1).
Clinical manifestation of AvWS included purpura (in 28% of the
patients), petechiae (in 12%), and gastrointestinal bleeding (in 4%).
In patients with CMPD, only two patients (14%) had a bleeding
complication when AvWS was diagnosed. In contrast, in other groups, 5 out of 11 patients (46%) had bleeding episodes (Table 2).
In patients with CMPD and NHL, the laboratory features were mostly
characterized by a prolonged bleeding time, normal vWF:Ag, and a mild
or moderate decrease of RIPA and/or vWF:RCoF. In other groups
of patients, RIPA and/or vWF:RCoF were moderately or severely impaired, and bleeding time was prolonged in 16 out of 20 patients (80%) (Table 2). The patients' plasmas contained no inhibitory activity against FVIII:C. In some family members of these patients evaluated, vWF:Ag, vWF:RcoF, and RIPA were all normal (data not shown).
ABO blood type in these patients was also evaluated because of its
major genetic determinant of plasma vWF antigen levels. The normal
range for persons with type O is reported 20% to 30% lower than that
of other ABO blood types.27,28 In patients with type O in
this study, vWF:Ag levels were 7%, 27%, and 32%, suggesting that low
levels of vWF:Ag in these patients did not depend on ABO blood types
(Table 2).
Multimeric analysis of vWF was done in 6 patients with inhibitor and 6 patients without inhibitor (Table 3). It
showed selective loss of large multimers in 11 patients out of 12 patients. This pattern was similar to that of congenital type-2 vWD.
Normal multimeric pattern with decrease of vWF:Ag was found only in one
patient. Furthermore, 10 out of 13 patients without multimeric analysis showed a relative reduced ratio of vWF:RCoF as compared with vWF:Ag (Table 2).
Mixing studies were evaluated in 24 out of 25 patients (Case 23 was not
done). In 8 patients out of 24 patients (33%), the significant
reduction of vWF:RCoF activity was observed in the mixture of one
volume of normal pool plasma with one volume of patient plasma diluted
by eight volumes of saline buffer (vWF:RCoF activity; 10% to 26%) as
compared with controls (vWF:RCoF activity; 58%). These results
suggested the presence of inhibitor to vWF in these 8 patients (all 3 patients tested with MM, 2 patients with CLL, 1 patient with AML, 1 with CML, and 1 with PV) (Table 2).The inhibitors were of the IgG class
and subclasses were IgG1 (7 cases) and IgG2 (1 case). The IgGs from
these patients also inhibited the binding of 125I-vWF to
platelets in the presence of ristocetin. The recognition site(s) of
these inhibitors were then evaluated (Table
4). All 6 IgGs evaluated here reacted with native vWF, 5 recognized the 39/34-kD fragment and Fragment III, and 1 recognized Fragment I.
We evaluated the relationship between the presence of inhibitors to vWF
and bleeding tendency. There was a close relationship between the
presence of inhibitors to vWF and bleeding tendency (Fig 1A). Of the 8 patients with
inhibitors, 6 patients (75%) had a bleeding tendency, as did 1 of the
16 patients without inhibitors (6%). The sensitivity of
the presence of the inhibitor as a predictor of bleeding was 86%, and
the specificity was 88%, with a positive predictive value of 75% and
a negative predictive value of 93%.
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| Fig 1.
(A) Relationship between the presence of inhibitors and
the clinical manifestation of bleeding tendency. There was a close relationship between the presence of inhibitor to vWF and bleeding tendency. Six patients out of the 8 patients with inhibitors (75 %)
had bleeding tendency, as well as one of the 15 patients without inhibitors (6%). The sensitivity of the presence of the inhibitor as a
predictor of bleeding was 86%, and the specificity was 88%, with a
positive predictive value of 75% and a negative predictive value of
93%. (B) Relationship between the absence of inhibitors and the
efficacy of the treatment of underlying diseases and/or DDAVP
therapy. Four patients of the 8 patients with inhibitors (50%) had
poor response to treatment of the underlying disease and/or
DDAVP therapy, as well as one of the 16 patients without inhibitors
(6%) . The sensitivity of the absence of inhibitor as a predictor of
response to these therapy was 79%, and the specificity was 80%, with
positive predictive value of 94% and a negative predictive value of
50%.
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Furthermore, we studied the presence of inhibitors as a possible
predictor of the response to treatment of the underlying disease
and/or therapy with DDAVP for bleeding. There was a close relationship between the absence of inhibitor to vWF and efficacy of
these therapies (Fig 1B). In 20 out of 25 patients (80%), laboratory features of AvWS returned to normal after the treatment of the underlying diseases and/or therapy with DDAVP. Then we studied quantitative changes of vWF:Ag and vWF:RCoF at various periods after
DDAVP infusion in 4 patients with AvWS (Case No 2, 8-10), and in 3 patients with inherited type-1 vWD. Although therapy with DDAVP rapidly
increased vWF:Ag, vWF:RCoF, and FVIII:C, there was a rapid return of
vWF:RCoF to baseline in the patients with AvWS compared with that with
inherited vWD, as shown by their half-disappearance time
(Fig 2). These results suggested that therapy of DDAVP was transient and that normal return of laboratory features of AvWS mainly depends on the treatment of the underlying diseases. Four patients of the 8 patients with inhibitors (50%) had
poor response to the treatment of the underlying disease and/or therapy with DDAVP, as well as one of the 16 patients without inhibitors (6%). The sensitivity of the absence of inhibitor as a
predictor of response to this therapy was 79%, and the specificity was
80%, with positive predictive value of 94% and a negative predictive
value of 50%.
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| Fig 2.
Quantitative changes of vWF:Ag, vWF:RCoF, and Factor VIII
after DDAVP infusion and half disappearance time of these parameters. Results are shown as mean values (±SD) over baseline values taken as
1.
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In one case (Case No 19), intravenous immunoglobulins were used to
correct hemostatic defects because a patient had severe gastrointestinal bleeding. Bleeding time was 15.5 minutes, VWF:Ag, vWF:RCoF, and FVIII:C activity were 28%, 5%, and 6%, respectively. Therapy with DDAVP was not effective to improve hemostatic defects. After the infusion of intravenous immunoglobulins (Venilon, Teijin Co
Ltd, Tokyo, Japan) at a dose of 0.3 g/kg for 3 days, levels of VWF:Ag,
vWF:RcoF, and FVIII:C activity rapidly increased, reaching normal
values by the fourth day. Active bleeding resolved rapidly after
immunoglobulin therapy. VWF:Ag, vWF:RCoF, and FVIII:C activity increased up to 150%, 64%, and 58%, respectively. Then these
activities gradually decreased, with a return of pretreatment values
within 7 days after the last immunoglobulin infusion.
| |
DISCUSSION |
AvWS is an uncommon bleeding disorder that has remained difficult to
characterize pathophysiologically and challenging to treat
successfully. Although the mechanism of AvWS is unclear, several
mechanisms may lead to plasma deficiency of vWF. The mechanism involves
a decrease in synthesis or a defective release of vWF. However, it
seems unlikely that such mechanisms are operative in AvWS because vWF
levels increase after DDAVP infusion. The second mechanism involves all
kinds of conditions basically affecting the survival of vWF in the
circulation. Two general mechanisms were proposed to explain the
pathogenesis of AvWS. First, autoantibodies inactivate the biological
activities of vWF and induce rapid clearance of vWF from the
circulation.5-8 Second, there is a selective absorption of
vWF on clonal lymphoid cells in patients with associated lymphoid
malignancies.9 With respect to underlying disorders, AvWS
is most commonly associated with lymphoproliferative diseases and
monoclonal gammopathy, and less often with specific malignancies including chronic myeloproliferative disorders, Wilms' tumor, and
adrenal adenocarcinoma.29 AvWS has been infrequently
reported in association with autoimmune diseases such as systemic lupus erythematosus.
The sensitivity and specificity of the current standard diagnostic
tests such as vWF:Ag, vWF:RCoF, FVIII:C, and bleeding times may be as
low as 60%.30 Additional variety is contributed by blood
group.27,28 Mean vWF:Ag levels can vary from 70% to 80% for blood type-O individuals to 123% for type AB, when compared with
the standard donor plasma pool. As a result, the diagnosis of AvWS may
be more readily established in patients of blood type O. In our study,
vWF:Ag levels were significantly low in our patients with blood type O,
suggesting these patients could be definitely diagnosed as AvWS.
Type-2 congenital vWD is an example of selective loss of large
multimers.31 In the majority of the patients with AvWS, the multimeric analysis of plasma vWF showed a type-2 deficiency that is
most accurately reflected in vitro by a relative reduced ratio of
vWF:RCoF as compared with vWF:Ag in agreement with previous reports.29,32 Our results also showed that 11 out of 12 patients had loss of large molecular weight multimers. In patients with AvWS, vWF is rapidly cleared from the circulation by the evidence of a
rapid return of vWF:RCoF to baseline after DDAVP infusion. These results support that one of the mechanisms responsible for development of the syndrome is a rapid clearance of vWF from the circulation independent of the presence of inhibitors
Acquired bleeding disorders are in general often associated with
development of an inhibitor, typically an antibody to the functional
domain of a coagulation factor. Our study indicated that 8 out of 25 patients (32%) had inhibitors to vWF. All inhibitors tested here were
IgGs that reacted with native vWF subunits. Five recognized the
39/34-kD fragment and Fragment III of vWF, which are well-known to
retain the binding domain to GPIb.24,25 These results were
consistent with the hypothesis that these inhibitors recognized the
crucial vWF binding domain(s) to GPIb. Furthermore, it should be noted
that there was a close relationship between the inhibitors and bleeding
tendency.
Treatment of AvWS depends on the underlying disease process and on the
mechanisms responsible for development of the syndrome. Our results
also support that treatment in AvWS should, of course, start with
treatment of the underlying diseases. Similar to treatment for
congenital vWD, patients with AvWS were treated with high doses of
cryoprecipitate and this approach was reported to be useful in some
patients with AvWS associated with myeloproliferative syndromes.33 However, bleeding was usually controlled in
the short term.34 Furthermore, we should consider that
factor replacement would be costly and expose the patient to the risk
of transfusion-transmitted diseases. DDAVP has been used with some
success in AvWS associated with lymphoproliferative and autoimmune
disorders, in which the presence of circulating inhibitor to vWF has
been shown.35 DDAVP often augments the plasma level of
vWF:Ag and vWF:RCoF and corrects the prolonged bleeding time. However,
in comparison to patients with congenital vWD, these increased levels
and activities are less, vWF cleared more rapidly from the plasma, and
the bleeding times were corrected for a short time6 in
agreement with our results. On the basis of these results DDAVP may be
effective, but not enough for treatment of bleeding episodes in AvWS.
Clinical bleeding tendency was sometimes uncontrollable even when
therapy with DDAVP and/or the treatment of the underlying diseases was done in most patients with the inhibitors to vWF. We
believe that these patients should immediately receive additional treatment for AvWS. The usefulness of high-dose intravenous
immunoglobulins has been shown in patients with antibodies to
FVIII:C.36 Recently, possible use for intravenous
immunoglobulins in AvWS was shown by in vitro
experiments.37 There have been many reports of successful intravenous immunoglobulin infusions for AvWS associated with monoclonal gammopathies of uncertain significance resulting in a rapid
and sustained response.38-41 Epistaxis, gastrointestinal hemorrhage, and other active bleeding usually resolve rapidly after
intravenous immunoglobulin infusions. In our patient with an inhibitor,
severe gastrointestinal bleeding was successively under control by use
of immunoglobulin therapy. The mechanism is unknown but might be
related to an effect of intravenous immunoglobulin on the clearance of
vWF-antibody complex in AvWS.42 It is true that therapy
with DDAVP and/or the treatment of the underlying diseases
would be the first choice of treatment for bleeding problems in AvWS.
The high cost of intravenous immunoglobulin preparation precludes their
systematic use in all patients with AvWS. However, they should be
reserved for patients with severe bleeding not responding to therapy
with DDAVP or for the management of major surgery.
Figure 3 shows one current view of therapy
strategy for AvWS. There is no doubt that the treatment of underlying
diseases and/or therapy of DDAVP are the first step for
treatment of AvWS. When uncontrollable bleeding occurs in cases with
inhibitors, intravenous immunoglobulin infusions might be reserved to
correct vWF levels.
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| Fig 3.
Strategy of therapy for AvWS. The treatment of underlying
diseases and/or DDAVP administration would be the first step
for treatment of AvWS. When severe bleeding occurs in AvWS with
inhibitors, expensive intravenous immunoglobulin infusions might be
considered to correct vWF levels.
|
|
| |
FOOTNOTES |
Submitted September 22, 1997;
accepted January 2, 1998.
Address reprint requests to Hiroshi Mohri, MD, PhD,
Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236, Japan.
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.
| |
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Abstract
Introduction
Abstract