scientific and standardization committee communication
TRANSCRIPT
Scientific and Standardization Committee Communication Scientific Report of the Registry on Acquired von Willebrand
Syndrome: Recommendations for Diagnosis and Management
On behalf of the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis
Augusto B. Federici (1)*, Jacob H. Rand (2), Paolo Bucciarelli (1), Ulrich Budde (3), Perry J.J. van Genderen (4), Hiroshi Mohri (5), Dominique Meyer (6), Francesco Rode-ghiero (7) and J. Evan Sadler (8)
From the (1)Angelo Bianchi Bonomi Hemophilia Thrombosis Center, Department of Internal Medicine, IRCCS Maggiore Hospital and University of Milan ; Hematology Division Mount Sinai School of Medicine, New York, USA (2); Coagulation Laboratory, Hamburg, Germany (3); Department of Hematology, University Hospital, Rotterdam, The Netherlands (4); Yokohama City University, 1st Dept of Internal Medicine, Yokohama, Japan (5); Hopital de Bicetre, Paris, France (6); Hemophilia and Thrombosis Center, Department of Hematology, Vicenza, Italy (7); Howard Hughes Medical Institutions, Washington University, St. Louis , USA (8).
Summary
The acquired von Willebrand Syndrome (AVWS) is a rare bleeding disorder with laboratory find-ings similar to those of congenital von Willebrand disease (VWD). Despite the numerous cases reported in the literature until 1999 (n = 266), large studies on AVWS are not available. Moreover, diagnosis of AVWS has been difficult and treatment empirical. These considerations prompted us to organize an international registry. A questionnaire, devised to collect specific information on AVWS, was sent to all the members of the International Society on Thrombosis and Haemostasis (ISTH). Each member was invited to respond if they had diagnosed AVWS cases. 156 members answered the questionnaire and 54 of them sent information on 211 AVWS patients from 50 cen-ters. Data were compared with those already published in the literature and 25 cases already described or not correctly diagnosed were excluded. The 186 AVWS cases that qualified for the registry were associated with lymphoproliferative (48 %) and myeloproliferative disorders (15 %), neoplasia (5 %), immunological (2 %) and cardiovascular disorders (21 %), miscella-neous (9 %). Ristocetin cofactor activity (VWF:RCo) or collagen binding assay (VWF:CB) were usually low in AVWS (median values 20 U/dL, range 3-150), while factor VIII coagulant activity was sometimes normal (median 25 U/dL, range 3-191). Anti-FVIII/VWF inhibiting activities were present in only a minority of cases (7 %). Bleeding episodes in AVWS were mostly mucocu-taneous (68 %) and were managed by DDAVP (20 %), FVIII/VWF concentrates (23 %), intrave-nous immunoglobulin (11 %), plasmapheresis (2 %), corticosteroids (5 %) and immunosuppressive or chemotherapic agents (13 %). Based upon the data of this international registry, it appears that AVWS is specially frequent in lympho- or myeloproliferative and cardio-vascular diseases. Therefore, AVWS should be suspected and searched with the appropriate labo-ratory tests especially when excessive bleeding occurs in patients with these disorders. On the basis of the information provided by this registry we have also attempted to prepare guidelines for the diagnosis and management of the AVWS.
*.Correspondence to: Augusto B. Federici, MD, Hemophilia and Thrombosis Center, Via Pace 9, 20122, 20122 MILANO, Italy, tel +39 2 5503 5356, fax +39 2 5503 5347, email: [email protected].
Introduction
The acquired von Willebrand Syndrome (AVWS) is a rare bleeding disorder similar to congeni-tal von Willebrand disease (VWD) in terms of laboratory findings, being characterized by a pro-longed bleeding time (BT) and low plasma levels of factor VIII-von Willebrand factor (FVIII/VWF) measurements. AVWS usually occurs in individuals without a personal or family history of bleeding. Since the original description in 1968 of a patient with systemic lupus erythematosus (1), 266 cases of AVWS have been described until 1999, and a list of references in order of publi-cation date is reported (1-183). Several review articles have been also published (45, 110, 112, 113, 156, 161, 163, 175, 182) but no studies on a large series of patients are available until now. These observations prompted us to organize, on behalf of the Subcommittee on VWF of the Sci-entific and Standardization Committee of the International Society of Thrombosis and Haemosta-sis (ISTH), an international registry on AVWS. It was thought that a retrospective analysis of the data obtained from patients actually followed by expert physicians such as members of ISTH might improve our understanding on the pathogenesis, diagnosis and management of AVWS. In this report, we have summarized the results of the registry on AVWS and compared them with the data available from the literature. On the basis of such a large number of actual observations, we have also attempted to prepare guidelines for the diagnosis and management of AVWS.
Patients and methods
Questionnaires were prepared by the co-ordinators of the registry. They were devised to collect data on clinical history, type of underlying disorder, laboratory measurements and type of therapy used to prevent or treat bleeding. Physicians had to indicate whether or not therapy was effective to stop bleeding (Appendix A). Through the Executive Office of the ISTH, questionnaires were distributed to all the ISTH members in February 1998. 156 ISTH members answered the ques-tionnaires and 55/156 sent data about one or more patients with AVWS diagnosed and followed by them. On the whole, information on 211 patients from 50 Centers world-wide was provided and analyzed by the co-ordinators. The cases of the questionnaires were compared with those reported in the literature and cases already reported were excluded. The following minimal requirements for diagnosis of AVWS were considered: a) description of the acquired bleeding his-tory with exclusion of congenital VWD; b) indication of the underlying disorders; c) abnormal values of VWF:RCo or VWF:CB; d) values of VWF:RCo/Ag and VWF:CB/Ag ratios less than 0.7 in case of border-line or normal values of the VWF:RCo and VWF:CB, but only in the pres-ence of severe bleeding history. All the information was recorded in a database and analyzed. Fre-quencies were expressed as percentages and laboratory measurements as median and range.
Results and discussion
Literature review Our search of the literature from 1968 to 1999 identified 183 references related to AVWS (see reference list). 123 are case reports describing a total of 266 patients with AVWS characterized by demonstrated reduced plasma levels of VWF (1-5, 9-15, 17-32, 35, 37-39, 42-46, 48-54, 56-58, 60-62, 64, 66-75, 77, 78, 80, 82-85, 87, 88, 90-97, 99-107, 109, 111, 114, 116, 117, 121-125, 127-130, 132-134, 136-140, 142, 143, 145, 146, 148, 149, 151, 153, 154, 159, 160, 164, 170-174, 178, 183); 25 are review articles, letters or commentaries on AVWS (36, 40,
45, 55, 59, 63, 110, 112, 113, 126, 131, 135, 144, 156-158, 161, 163, 166, 175, 180); 23 are origi-nal articles describing conditions characterized by the demonstration of abnormal structure/func-tion of VWF in the presence of normal levels of plasma VWF (16, 33, 34, 41, 65, 76, 79, 81, 86, 89, 98, 108, 115, 118-120, 141, 150, 155, 165, 167, 169, 180); 12 are reports describing methods useful for AVWS diagnosis (6-8, 47, 147, 162, 168, 172, 176-179). According to the available lit-erature, the 266 AVWS cases reported are mainly associated with the following six categories of disorders: lymphoproliferative disorders, myeloproliferative disorders, neoplasia, immune dis-eases, cardiovascular diseases and other miscellaneous conditions including drugs, infectious dis-eases, hypothyroidism, diabetes, uremia, hemoglobinopathies, telangiectasia and also idiopathic forms (Table 1). These six categories have also been used to include the additional 186 AVWS cases from the registry and the corresponding percentage are shown for comparison in Table 1. In the published reports diagnosis of AVWS is usually based on the laboratory parameters typical for VWD in the absence of a family history of bleeding. A list of tests useful for diagnosis and char-acterization of AVWS, with their references is shown in Table 2. As far as pathophisiology of AVWS, data from the literature demonstrated that VWF is normally synthesized in most patients, except for those with hypothyrodisms who are characterized by decreased VWF synthesis or release (38, 71, 72, 91, 96, 129, 134, 139). When VWF is normally synthesized, its decrease is due to accelerated removal from plasma through six possible pathogenetic mechanisms (Table 3). However none of the proposed mechanisms appears to be disease-specific: the same mechanism can be responsible for AVWS in different underlying disorders known to be associated with AVWS. At variance with acquired hemophilia A which is due to anti-FVIII inhibitors, anti FVIII/VWF inhibitors in AVWS have been reported in 38/226 cases only (14 %) (1, 5, 6, 8, 10, 14, 18, 19, 21, 22, 28, 42, 47, 48, 51, 60, 66, 75, 95, 102, 124, 125, 137, 143, 145, 160, 173, 174, 181). In the absence of a consistent pathogenetic mechanism, management of AVWS has usually been empirical. The goals of treatments are threefold: a) to control actual bleeding episodes; b) to pre-vent bleeding when an invasive procedure is necessary; c) to treat, when possible, the underlying disease. In several disorders associated with AVWS, surgery (24, 35, 46, 53, 81, 103, 107, 149), chemotherapy (26, 32, 50, 114, 157), radiotherapy (15) hormone replacement (62) and discontin-uation of the responsible drugs (104, 141) can sometimes control the underlying disease, with res-olution of the bleeding diathesis and normalization of the laboratory abnormalities. Unfortunately, in few cases of AVWS, the underlying disorders can not be identified (159) and cases should be defined idiopathic. In others, such as AVWS associated with a monoclonal gammopathy of uncer-tain significance, the underlying disease is usually not treated. Hence the best approach to stop bleeding episodes and/or to prevent bleeding during surgery must be searched (171). A variety of therapeutic approaches have been used in AVWS, including desmopressin (41, 44, 58, 84, 158, 170, 177), factor VIII/VWF concentrates (23, 43, 50, 148, 170), high-dose I.V. immunoglobulin (73, 77, 100, 111, 128, 136, 138, 148, 170, 173), plasmapheresis (70, 88), cortocosteroids and immusuppressive drugs (95).
TA
BL
E 1
: M
AIN
DIS
EA
SE
S A
SS
OC
IAT
ED
WIT
H A
VW
S [
case
s n
um
ber
(%)]
DIS
EA
SE
ST
OT
AL
CA
SE
SR
EG
IST
RY
(n=
186)
LIT
ER
AT
UR
E(n
=26
6)R
EF
ER
EN
CE
S(c
itat
ion
nu
mb
er)
LY
MP
HO
PR
OL
IFE
RA
TIV
E89
(4
8)79
(30
)M
onoc
lona
l Gam
mop
athy
of
unde
term
ined
sig
nifi
canc
e43
(2
3)37
(14
)(2
); (
3); (
5); (
21);
(23
); (
28);
(37
); (
42);
(44
); (
47);
(48
); (
56);
(73
); (
75);
(77
);(8
4); (
95);
(10
0); (
106)
; (11
1); (
124)
; (12
8); (
136)
; (17
1); (
180)
;M
ulti
ple
mye
lom
a16
(9
)19
(7
)(1
7); (
42);
(44
); (
51);
(58
); (
66);
(85
); (
94);
(13
6); (
145)
; (17
3); (
174)
; (18
2);
Wal
dens
tröm
mac
rogl
obul
inem
ia16
(9
)5
(2)
(19)
; (30
); (
44);
(70
); (
182)
;N
on-H
odgk
in’s
lym
phom
a8
(4)
10 (
4)(8
); (
15);
(18
); (
26);
(60
); (
78);
(13
8); (
164)
; (17
3); (
182)
;C
hron
ic ly
mph
ocyt
ic le
ukem
ia5
(
3)7
(3)
(11)
; (44
); (
75);
(88
); (
173)
;H
airy
-cel
l leu
kem
ia0
1(3
1);
Acu
te ly
mph
ocyt
ic le
ukem
ia1
0
MY
EL
OP
RO
LIF
ER
AT
IVE
29
(15)
48
(18)
Ess
enti
al T
hrom
bocy
tem
ia21
(1
1)17
(6)
(43)
; (68
); (
99);
(11
4); (
135)
; (17
3);
Pol
ycyt
hem
ia v
era
19
(3)
(43)
; (67
); (
173)
;C
hron
ic g
ranu
locy
tic
leuk
emia
5 (
3)22
(8
)(3
2); (
43);
(80
); (
152)
; (17
3);
Mye
lofi
bros
is2
(1)
0
NE
OP
LA
SIA
9
(5)
15
(6)
Wil
m’s
tum
or (
neph
robl
asto
ma)
011
(4
)(2
4); (
35);
(61
); (
103)
; (15
1);
Car
cino
mas
and
sol
id tu
mor
s9
(5
)3
(1
)(2
9); (
50);
(10
7);
Per
iphe
ral n
euro
ecto
derm
al tu
mou
r0
1(1
46);
IMM
UN
E4
(2
)15
(
6)S
yste
mic
lupu
s er
ythe
mat
osus
06
(2)
(1);
(2)
; (12
4); (
183)
;A
utoi
mm
une
dise
ase
4 (
2)6
(2
)(5
); (
25);
(13
2); (
140)
; (14
3); (
159)
;M
ixed
con
nect
ive
tiss
ue d
isea
se0
1(8
3);
Gra
ft-V
ersu
s-H
ost d
isea
se0
1(1
33);
Ehl
ers
Dan
los
synd
rom
e0
1(2
0);
TA
BL
E 1
(con
tin
ued
): M
AIN
DIS
EA
SE
S A
SS
OC
IAT
ED
WIT
H A
VW
S [
case
s n
um
ber
(%)]
CA
RD
IOV
AS
CU
LA
R39
(21
)31
(12
)C
onge
nita
l and
acq
uire
d ca
rdia
cde
fect
s:(2
0);
Mul
tipl
e or
not
def
ined
24 (
13)
0V
entr
icul
ar s
epta
l def
ect
010
(4)
(54)
; (59
);A
tria
l sep
tal d
efec
t2
(1
)1
(54)
;A
orti
c st
enos
is7
(4
)5
(2)
(54)
; (14
9);
Mit
ral v
alve
pro
laps
e2
(1
)10
(4)
(34)
; (74
);O
ther
s:A
ngio
dysp
lasi
a4
(2
)5
(2)
(9);
(27
); (
39);
(82
); (
127)
;M
ISC
EL
LA
NE
OU
S16
(9
)78
(
28)
Dru
gs :
Cip
rofl
oxac
in0
2 (
1)(1
30);
Gri
seof
ulvi
n0
1(1
02);
Val
proï
c ac
id1
19
(7)
(92)
;H
ydro
xyet
hyl s
tarc
h0
11
(4)
(49)
; (69
); (
104)
; (15
3); (
154)
;In
fect
ious
dis
ease
s:H
ydat
ic c
yst
01
(46)
;E
pste
in B
arr
Vir
us in
fect
ion
11
(97)
;In
fect
ive
Col
itis
10
Sar
coid
osis
10
Oth
er s
yste
mic
dis
ease
s:H
ypot
hyro
idis
m3
(2)
21 (
8)(3
8) ;
(62)
; (64
); (
71);
(72
); (
91);
(96
); (
122)
; (12
9); (
134)
; (13
9); (
182)
;D
iabe
tes
07
(3)
(10)
; (93
);U
rem
ia6
(3
)3
(1)
(41)
;H
emog
lobi
nopa
thie
s2
10 (
4)(1
3); (
90);
Tel
angi
ecta
sia
01
(22)
;Id
iopa
thic
11
(182
);
Data of the registry Twenty five of 211 were excluded from the registry because they did not meet the minimal criteria of AVWS diagnosis or because already published. Therefore, data were analyzed in AVWS 186 patients.
TABLE 2--LIST OF LABORATORY TESTS USEFUL FOR THE DIAGNOSIS OF AVWS
(*) Specific references in case of new additional tests are indicated
Type of test References (*)
Bleeding time (min)
Closure time by PFA-100 (sec) (172, 178)
APTT (sec)
FVIII:C (U/dL)
VWF:RCo (U/dL)
VWF:CB (U/dL) (135, 177, 179)
Ristocetin induced platelet Agglutination (RIPA, mg/ml)
(6-8, 10)
Plasma VWF multimers (15, 23, 43, 54, 60, 80, 107, 116)
Platelet VWF (45, 76, 85, 116, 119, 141, 142, 144)
VWF Subunit (52, 101, 108, 120, 142, 150, 169)
VWF propeptide (U/dL) (147, 176)
FVIII/VWF activities after mixing test with normal plasma:
anti-FVIII:C; anti-VWF:RCo; anti-CB; anti-VWF:Ag
(45)
Binding of Immunoglobulins to immobilized VWF from concentrates or plasma
Test for inhibitors by using solid-phase systems
(6-8, 18, 47, 137, 173, 174)
Clinical features of AVWS according to the underlying disorder AVWS was associated with lymphoproliferative (48 %) or myeloproliferative (15 %) disorders, neoplasia (5 %), immuno-logic diseases (2 %), cardiovascular diseases (21 %) and miscellaneous conditions (9 %), as reported in Table 1. The frequency of the underlying disorders is substantially similar to that obtained from the analysis of the literature but lymphoproliferative and cardiovascular diseases seem to be more represented in the registry (Table 1). The main clinical features of AVWS according to the groups of underlying disorders are shown in Table 4. Sex distribution is similar in AVWS (males 53 %). Even though AVWS has been reported also in children, the disease is typ-ical of adulthood, with a median age at onset of 62 years. Many patients enrolled in the registry were still alive at the time of completion of the questionnaire (53 %), suggesting that AVWS is mainly a chronic disease with relatively good prognosis. AVWS was usually accompanied by bleeding symptoms in 72 % of the cases but was also diagnosed by abnormalities found during routine screening tests for hemostasis (28 % of cases). Mucocutaneous bleeding is a frequent symptom (68 %) in all underlying disorders, as one might expect in a bleeding diathesis due to VWF defects.
Laboratory diagnosis of AVWS Table 4 shows that in average the bleeding time (BT) was prolonged, with median values of 15 min and wide ranges (3-35 min): no data on BT were avail-able in patients with cardiovascular diseases. APTT values, expressed as ratios, were slightly pro-longed consistently with the slightly reduced levels of FVIII:C. However both APTT and FVIII:C were normal in some AVWS groups such as cardiovascular diseases (Table 4). In aver-age, VWF antigen was reduced with median values of 33 U/dL but a wide range of values was observed (4-404). "Functional" assays of VWF, measured either as ristocetin cofactor activity (VWF:RCo) or as collagen binding assay (VWF:CB), appeared to be the most sensitive to test the VWF defect of AVWS, with median values of both functional assays of 20 U/dL (range 3-150). The ratio between VWF:RCo or VWF:CB and VWF:Ag were calculated by the co-ordinators and were always lower than 0.7. Two reports emphasized the role of VWF:Ag2 in diagnosis of AVWS (147-176). In our registry there were only 5/186 (3 %) patients tested for VWF:Ag2, measured
TABLE 3 - PATHOGENETIC MECHANISMS OF AVWS ______________________________________________________________________
a) specific auto-antibodies to FVIII/VWF;
b) nonspecific antibodies that form circulating immune-complexes and favor VWF clear-
ance by Fc-bearing cells;
c) absorption of VWF onto malignant cell clones;
d) increased proteolytic degradation of VWF;
e) loss of high VWF multimers by high shear stress conditions.
f) Reduced VWF synthesis or release
______________________________________________________________________
only in patients with lymphoproliferative disorders: levels were always normal (median 75 and range 60-121) in the presence of reduced VWF:Ag. Plasma VWF multimers were analyzed in approximately two third of the patients and large molecular forms were missing in the majority of cases tested (83 %). This finding suggests that the mechanisms responsible for AVWS induce a selective removal from plasma of the higher molecular weight multimers. VWF were tested in platelets only in 12/186 cases (6 %) and was normal. The methods most often used to search for inhibitory activity against FVIII/VWF were based upon the measurement of the FVIII/VWF properties in plasma after mixing patients plasma with normal plasma (mixing-tests). This was carried out in 170/186 (93 %) cases reported but an inhibitory activity was found only in a minor-ity of cases, 13/186 (7 %), as shown in Table 4. The prevalence of anti-FVIII/VWF activities found in the registry is significantly lower than that reported in the literature where inhibitors were found in 38/226 (14 %). This strongly suggests that the techniques currently used to measure anti-FVIII/VWF activities are not sensitive enough or that in the AVWS the reduction of factor VIII/VWF occurs through other mechanisms (e.g. reduced synthesis/release or increased clear-ance due to non-immunologic mechanisms)
Management of AVWS According to the results of the registry, more than one therapeutic approach was used in all AVWS cases (Table 5). Desmopressin (DDAVP) was used in 121/186cases (65 %) and stopped bleeding in 37 (20 %) of them by restoring normal levels of FVIII/VWF in plasma. DDAVP is relatively inexpensive and carries no risk of blood borne infections. The main problems with the use of DDAVP in AVWS are generally related to the short half-life of endogenous FVIII/VWF released by the compound. Due to the heterogeneity of the mechanisms inducing AVWS, it is not surprising that the response to DDAVP is variable from patient to patient, even in those with the same underlying disorders. Hence a DDAVP infusion test, with BT and FVIII/VWF measured pre- and post-infusion, is advisable for every new diagnosis of AVWS (45, 171). FVIII/VWF concentrates were also used in 119/186 patients with AVWS (64 %) and they were clinically effective in 43 cases (23 %). Compared to DDAVP, plasma FVIII/VWF con-centrates are more expensive and may carry some risks, albeit remote, of transmitting bloodborne infections. The half-life of FVIII/VWF is shortened by one of the mechanisms causing AVWS and therefore concentrate efficacy should be evaluated each time by serial measurement of FVIII/VWF following their administration (171). Dosage and number of infusions used to stop bleeding were not part of the questionnaire and therefore these data are not available. High dose i.v. Immu-noglobulin (IV:Ig) were tried in 63/186 patients (34 %) and were effective only in 21 cases (11 %), mainly in immune diseases (22%), lymphoproliferative disorders (20 %) and neoplasia (11%). It has been proposed that IV:Ig are more effective in AVWS cases characterized by the presence of anti-FVIII/VWF inhibitor. At the moment, prospective data are not available, but data of the registry show that 13/21 (62 %) AVWS patients responsive to IV:Ig had these anti-FVIII/VWF inhibitors. Due to the high cost of this treatment, IV:Ig should be reserved for AVWS patients proven to be unresponsive to DDAVP and FVIII/VWF concentrates and for cases with anti-FVIII/VWF inhibitors (174). However, DDAVP and/or FVIII/VWF concentrates should also be used together with IV:Ig during acute bleeding because FVIII/VWF activities are not immedi-ately improved by IV:Ig administration (171). Few cases were treated with plasmapheresis or extracorporeal immunoadsorption (overall, 2 %) and corticosteroids (overall, 5 %). There was one failure and one success following plasmapheresis. Nine cases with autoimmune diseases and chronic lymphocytic leukemia were treated by corticosteroids and AVWS disappeared in only two immune disorders.
TA
BL
E 4
–MA
IN C
LIN
ICA
L A
ND
LA
BO
RA
TO
RY
FIN
DIN
GS
(%
or
med
ian
and
rang
e) I
N 1
86 C
AS
ES
OF
AvW
S
Ass
ocia
ted
diso
rder
s:C
ase
nu
mb
er (
%):
Lym
phop
roli
fera
tive
89 (
48)
Mye
lopr
olif
erat
ive
29 (
15)
Neo
plas
ia9
(5)
Imm
un
olog
ic4
(2)
Car
diov
ascu
lar
39 (
21)
Mis
cell
aneo
us
16 (
9)T
OT
AL
186
(10
0)S
ex (
% o
f m
ale)
6335
4520
5736
53
Age
at o
nset
(ye
ars)
64(2
8-96
)45
(27-
72)
62(2
6-93
)52
(40-
58)
68(2
-85)
44(6
-75)
62(2
-96)
Sti
ll a
live
(%
)55
2467
8057
7353
Ble
eder
s (%
)87
4875
6077
5772
Ble
edin
g ti
me
(min
)15
(3->
30)
11(3
-22)
20(5
-20)
5(3
-8)
14(5
->30
)20
(10-
>30
)15
(3->
30)
AP
TT
(pa
tien
t /no
rmal
rat
io)
1.4
(1-2
.5)
1.0
(1-1
.37)
1.0
(0.9
-1.7
)1.
20(0
.86-
1.89
)1.
37(1
.2-1
.7)
1.2
(1.2
-1.7
)1.
30(0
.9-2
.5)
FV
III:
C (
U/d
L,m
ean)
20(4
-92)
45(1
6-75
)23
(12-
83)
112
(33-
191)
28(3
-185
)33
(3-1
91)
25(3
-191
)
VW
F:A
g (U
/dL
,)17
(4-8
0)70
(20-
404)
20(5
-59)
39(1
4-91
)11
3(8
-300
)94
(10-
221)
33(4
-404
)
VW
F:R
Co
or
VW
F:C
B (
U/d
L)
8(3
-45)
39(3
-130
)10
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0.53
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0.47
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57)
0.58
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0.50
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VW
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t.n.
t.n.
t.n.
t.n.
c.
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7686
9680
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not
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ON
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BR
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(num
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of p
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who
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Ass
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(%):
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16 (
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186
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)
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/ 59
3 / 1
43
/ 41
/ 33
/ 30
2 / 9
38 /
119
(32
%)
FV
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ncen
trat
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/ 56
2 / 1
46
/ 6--
-4
/ 30
2 / 9
42 /
115
(37
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I.V
. Im
mun
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n18
/ 48
---
2 / 2
1 / 2
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00
/ 121
/ 63
(33
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Pla
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sis
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0--
---
---
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--6
/ 32
(19
%)
Cor
tico
ster
oids
10 /
31--
-0
/ 1--
-2
/ 25
0 / 6
12 /
63(1
9 %
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mun
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ts o
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py
17 /
475
/ 14
1 / 2
---
---
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23 /
66(3
5 %
)
*mor
e th
an o
ne a
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ach
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sed
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ent
Recommendations for diagnosis and management of AVWS Figure 1: Diagnostic flow chart of patients with underlying disorders known to be associated with AVWS should include the following steps. In case of excessive bleeding or before surgery AVWS should be suspected (1). VWF:RCo or VWF:CB with VWF:RCo/Ag or VWF:RCo/Ag (a) and FVIII:C (b) should be performed (2). In case of reduced values of these assays (a and b), the diagnosis of AVWS is possible (3). To make definite diagnosis of AVWS the following criteria should be used: 4) the congenital VWD in the family (c) exclude; 5) VWF:Ag2 (d) measured; 6) the anti-FVIII/VWF inhibitors (e) searched for; 7) plasma multimers (f) and 8) platelet VWF (g) tested. A definite AVWS (9) is characterized by negative family history, normal VWF:Ag2, positive anti-FVIII/VWF inhibitors ( < 15 % only), abnormal ( > 80 %) multimers in plasma and normal platelet VWF. See the text for further detail.
Diagnosis Once a patient with one of the underlying disorders usually associated with AVWS develops excessive bleeding, AVWS should be suspected (Figure 1). The BT and APTT are not very useful for diagnostic purpose because they can be normal. Since VWF:Ag and FVIII:C can be also normal in AVWS (Table 4), a functional assay for VWF, either VWF:RCo or VWF:CB, is recommended to determine the degree of the VWF defect and to establish a diagnosis of AVWS. Reduced VWF:RCo/Ag or VWF:CB/Ag ratios suggest the presence of an abnormal VWF (Figure 1, a). FVIII:C levels are also reduced in about 60 % of the cases (Figure 1, b). Diagnosis of con-genital VWD should then be excluded by evaluating family members and by a careful analysis of the previous bleeding history of the patient (Figure 1, c): the search for response to previous hemostatic challenges is always critical to determine whether or not the patient is devoid of a per-sonal history of bleeding. The measurement of VWF:Ag2 can be also used to diagnose AVWS, since VWF:Ag2 is always normal or increased in AVWS when VWF:Ag is reduced (Figure 1 d). Only then, the search for anti-FVIII/VWF activities and multimeric analysis of plasma and platelet VWF should be performed. Methods for searching anti-FVIII/VWF activities in patients should be also useful, because AVWS with anti-FVIII/VWF might particularly benefit from IV:Ig therapy (Figure 1, e). These methods are not well standardized and are not available in all routine laboratories. A diagnostic approach is proposed in Table 6. The first step includes the search for
anti-FVIII/VWF inhibitors according to a modified Bethesda method by measuring the residual FVIII/VWF activities after incubation of patient’ plasma with normal plasma (Mixing tests): since inhibitors might be directed against different sites of the VWF molecule, all the assays available to characterize VWF must be evaluated (VWF:RCo, VWF:CB, VWF:Ag, FVIII:C). This first approach should be recommended to all the physicians who can suspect a case with AVWS: the additional steps should be reserved to laboratories specialized in VWF characteriza-tion (Table 6). Additional tests to characterize patients are the plasma multimeric structure which is usually (> 80 %) abnormal (Figure 1, f) and the platelet VWF content which is usually normal (Figure 1, g).
Management DDAVP should be the first choice because it is transiently effective in at least one third of AVWS patients (Table 5) and is less expensive than FVIII/VWF concentrates. A test infusion with BT, FVIII:C and VWF:RCo or VWF:CB measured before and 1, 2, 4 hours follow-ing DDAVP is recommended for each new case of AVWS to evaluate the actual response to this agent (45, 171). When repeated DDAVP doses are given, FVIII/VWF activities should be mea-sured before and after infusion to be sure that tachyphylaxis has not occurred and that the com-pound continues to be effective. Only in case of DDAVP failures should other options be considered. Plasma-derived FVIII/VWF concentrates are the second choice, because they are effective in more than one third of AVWS patients (Table 5). Considering the relatively high cost and the possible risk of blood borne infections, their use is only recommended in DDAVP-unre-sponsive cases. Post-treatment FVIII/VWF measurements are required to adjust dosage and time of infusions (171). When they are used in case of major surgery, a pre-surgical infusion trial is recommended to establish the half-life of VWF in the patient and to select in advance the appro-
Table 6 - Methods to search for Anti-FVIII/VWF activities in patients with AVWS
_____________________________________________________________________
First Step (available in all laboratories):
Searching for inhibitors according to a modified Bethesda Method by measuring
the residual FVIII/VWF activities after incubation:
a) Mixing tests of VWF:RCo, VWF:CB, VWF:Ag, FVIII:C
Second Step (available only in laboratories specialized on VWF characterization):
Measurement of binding of Immunoglobulin to immobilized VWF from concentrates (b)
or plasma (c):
b) direct binding of a concentrate to microtiter plates
c) binding of plasma VWF to immobilized anti-VWF
Preparation of a solid phase system:
a) Protein-A Sepharose
______________________________________________________________________
priate dosage. High-dose IV:Ig are the third choice. IV:Ig were effective in one third of AVWS patients who tried this approach. However, compared to the FVIII/VWF concentrates, IV:Ig are even more expensive and have a delayed effect (2-3 days) in raising FVIII/VWF. Therefore, IV:Ig should be used only in cases unresponsive to DDAVP and FVIII/VWF concentrates or in patients with anti-FVIII/VWF inhibitors. In case of bleeding, IV:Ig should be given together with DDAVP or FVIII/VWF concentrate, because the latter cover the time interval of 2-3 days before IV:Ig are effective in raising FVIII/VWF. Measurements should be performed daily for 7-15 days following infusions to demonstrate efficacy. It has been shown that two daily IV:Ig infusions induce a prompt and sustained increase of FVIII/VWF activities and shortening of the BT for at least 15 days in patients with IgG-MGUS but not in those with IgM-MGUS (171). Plasmapheresis and extracorporeal Immunoadsorption should be considered alternative therapeutic approaches.
Conclusions
The results of this first retrospective analysis on diagnosis and therapy of AVWS, based on the voluntary response to questionnaires confirm that the AVWS occurs in association with a variety of underlying disorders, being particularly frequent in lymphoproliferative disorders, cardiovas-cular disease and myeloproliferative disorders. AVWS is extremely heterogeneous and its basic mechanisms remain undefined in many cases. Functional assays of VWF in patients’ plasma are essential for making a firm diagnosis of AVWS. Assays for anti-FVIII/VWF activities should be performed to identify patients with inhibitors, however, these often yield negative results. Man-agement of bleeding episodes in AVWS rely mainly on DDAVP, FVIII/VWF concentrates and high-dose IV:Ig: but no single drug is effective for all AVWS cases. As bleeding episodes are sometimes life-threatening and require prolonged hospitalization with the infusion of large doses of blood products, the organization of large prospective studies should be encouraged.
Acknowledgements
This registry was established under the auspices of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (SSC-ISTH). Data of the registry were presented during the meetings of the Sub-Committee on VWF of 1998 and 1999 and recom-mendations were finally discussed and approved by the ISTH members during the meeting in Washington, August 1999. We thank Dr. Harold R. Roberts and the ISTH-Executive Office for their help in the distribution of the questionnaire and all the ISTH members who sent information to the coordinators (see below). This article is based upon the report of the registry presented by A.B. Federici and J.H. Rand in Washington on August 15, 1999 and by the fruitful discussion among the members of the Working Group on AVWS: J.H.Rand had the original idea of a registry on AVWS and acted as coordinator together with A.B. Federici; P. Bucciarelli performed the entire retrospective analysis of the data from the registry and matched these results with those from the literature; U. Budde and P.J.J. van Genderen contributed to the preparation of the diag-nostic flow-chart ; H. Mohri and D. Meyer contributed to the preparation of the therapeutic flow chart; F. Rodeghiero and J. E. Sadler, the present and the past Chairmen of the Sub Committee on VWF, revised the results and the manuscript. The authors express their gratitude to Professor Mannucci for his suggestions and his critical reading of the manuscript. The help of Miss Marina Ferrario during the preparation of the manuscript is also acknowledged.
List of contributors to the international registry: J.F. Abgrall, Brest, France; Y.S. Arkel, Summit, New Jersey, USA; G. Baele, Ghent, Belgium; D. Blinder, St. Louis, Missouri, USA; Z. Boda, Debrecen, Hungary; C. Boyer-Neumann, Clamart, France; F. Brohee, Chu A Vesale, Belgium; U. Budde, Hamburg, Germany; N. de Bosch, Caracas, Venezuela; G. Castaman, Vicenza, Italy; W. Egbring, Marburg/L., Germany; J.C.J. Eikenboom, Leiden, The Netherlands;D.I. Feinstein, Los Angeles, California, USA; N. Franck, Aachen, Germany; E. Fressinaud, Nantes, France; W.A. Fricke, Rochester, New York, USA; H. Geisen, Würzburg, Germany; P. Giraud, Poitiers, France; M. Goualt-Heilmann, Créteil, France; J. Goudemand, Lille, France; D.Green, Chicago, Illinois, USA; W.T. Hanna, Knoxville, Tennessee, USA; K.A. High, Philadelphia, Pennsylvania, USA;M.W. Hilgartner, New York, New York, USA; J.E. Humphries, Charlottesville, Virginia, USA; A. Inbal, Tel-Hashomer, Israel; P.M. Juhan-Vague, Marseille, France; D.M. Keeling, Oxford, United Kingdom; T. Kinoshita, Higashi-Osaka, Japan;J.W. Koopman, Amsterdam, The Netherlands; R. Leithäuser, Hamburg, Germany; S. Lethagen, Malmoe, Sweden; C.A. Ludlam, Edinburgh, United Kingdom;R. Mesters, Muenster, Germany; D. Meyer, Le Kremlin Bicetre, Paris, France;H. Mohri, Yokohama, Japan; D.A. Nelson, Valhalla, New York, USA; W. Nichols, Rochester, Minnesota, USA; P.A: Ockelford, Auckland, New Zealand; K.A: Rickard, Sidney, Australia; E. Rocha, Pamplona, Spain; F. Ruiz-Laez, Caracas, Venezuela; M. Sadd, Le Mans, France; M. W. ,Schambeck, Würzburg, Germany; I. Scharrer, Frankfurt am Main, Germany; G. Scholz, Hamburg, Germany; P. Sié, Toulouse, France; Y. Sultan, Poitiers, France; H. Takahashi, Niigata, Japan; J. Vermylen, Leuven, Belgium; M. Verpoort, Hamburg, Germany; J.L. Wautier, Paris, France; G.C. White, Chapel Hill, North Carolina, USA; K. Williams, Wisconsin, USA; R.E. Wolf, Hamburg, Germany
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Appendix A – Questionnaire of the International Registry on AVWS
PART A :
DATE OF SUBMISSION: _____/ _____/ _____
PATIENT NAME (Initials) _____ Sex (M/F) ______ Birth date __/___/___
Medical Center __________________________ MD referral ________________________
MD address _____________________ ph _______________________ fax _____________
A) FAMILY HISTORY FOR BLEEDING : negative _____ not tested ________
B) PERSONAL HISTORY Age at presentation with bleeding _____
Previous hemostatic challenge without excessive bleeding: _____________________________
Nature of acquired bleeding diathesis : ____________________________________________
PATIENT CURRENTLY: Alive _____ In follow-up _______ Unknown _____
Died: bleeding ______HIV ______ Liver failure ______ Other ______________
C) ASSOCIATED DISEASE WITH AVWS : MGUS ______ Lymphomas ______
Myeloma __ Chronic Lymphocytic Leukemia __ Chronic Myelogenous Lekemia ___
Polycythemia Vera __ Essential Thrombocythemia __Systemic Lupus Erythem.____
Other autoimmune condition (Define type) _______________________________
Neoplasia (type of ) _________________ Drugs (type of) ____________________
Other diseases: _______________________________________________________
______________________________________________________________________
______________________________________________________________________
PART B :
D) LABORATORY DATA :
Bleeding time (min) : _____ PT ratio ______ PTT ratio _____
F VIII C (U/dL) _____ plasma VWF:Ag (U/dL) ____ plasma VWF:RCo or CBA _____
plasma multimers (normal/abnormal) _______ platelet VWF tested (y/n) ________
platelet multimers (normal) _________
Mixing experiments to test anti-FVIII/VWF activities:
anti-FVIII:C _______ anti-VWF:Ag _______ anti-collagen binding ______
Other positive tests for inhibitory activities: ___________________________
Serum IEP/ Immunofixation _______ Levels of IgG ____ IgA _____ IgM _____
Urine Bence Jones (pos/neg) ______ Urine IEP/Immunofixation _______________
Lymphocyte markers : _________________________________________________
b2-micocroglobulin ______ Other tests __________________________________
______________________________________________________________________ E) THERAPEUTIC APPROACHES (yes/no):
Tested : effective : always --- sometimes ---- never
_____ Desmopressin : _____ _____ _____
_____ Cryoprecipitate : ______ _____ _____
______ FVIII/VWF concentrate: _____ ______ _____ which concentrates : ________________________________
_____ High-dose Immunoglobulin: ____ _____ ______
_____ Plasmapheresis : _____ _____ _____
_____ Steroids _____ _____ ____
_____ Immunosuppressive drugs: _____ ______ ______