614 Blood. Vol 64, No 3 (September), 1984: pp 614-62 1

Studies of the Pathophysiology of Acquired von Willebrand’s Diseasein Seven Patients With Lymphoproliferative Disorders or Benign

Monoclonal Gammopathies

By P.M. Mannucci, R. Lombardi, R. Bader, M.H. Horellou, G. Finazzi, C. Besana, J. Conard, and M. Samama

In seven patients with acquired von Willebrand’s disease

(AvWD) associated with lymphoproliferative disorders or

benign monoclonal gammopathies. the platelet contents of

von Willebrand factor antigen and ristocetin cofactor

(vWF:Ag and vWF:RiCof, respectively) were normal. All

the multimers of vWF:Ag could be seen in the 1.6%

SDS-agarose gel electrophoresis patterns of plasma and

platelet lysates. Infusion of 1 -deamino-8-D-arginine vaso-

pressin (DDAVP) augmented plasma levels of vWF:Ag and

vWF:RiCof of all patients and corrected prolonged bleeding

times (BT). However. compared with patients with congen-

ital vWD type I and comparable degrees of baseline abnor-

A SYN DROM E RESEM BLING the congenital

bleeding disorder, von Willebrand’s disease

(vWD), sometimes occurs in patients without family

history or previous symptoms of abnormal bleeding.

The syndrome, usually called acquired von Wille-

brand’s disease (AvWD), is strikingly similar to the

congenital disease in terms of laboratory findings,

being characterized by a prolonged bleeding time (BT)

and low plasma levels of factor VIII-von Willebrand

factor (FVIII-vWF) measurements.’ FVIII-vWF is a

macromolecular complex of two related, but nonidenti-

cal, proteins: factor VIII, which can be measured as

coagulant activity ( FV I I I :C) or antigen ( FVI I I:CAg),and von Willebrand factor, measured either immuno-

logically (vWF:Ag) or as ristocetin cofactor activity

(vWF:RiCof).’Our review of 36 cases reported in full in the

literature indicates that AvWD occurs most often in

association with autoimmune or lymphoproliferative

disorders, with or without associated monoclonal gam-

mopathies. Even though this association strongly mdi-

cates that AvWD has an immunologic basis, there are

cases in which the underlying disease (solid tumors,

angiodysplasias, etc) has no obvious relationship to any

From the Angelo Bianchi Bonomi Hemophilia and Thrombosis

Centre and Third Institute ofClinical Medicine, Maggiore Hospital

and University of Milano. Italy: the Central Hematology Labora-

tory, Hotel Dieu Hospital. Paris; and the Institute of Medical

Pathology, San Raffaele Hospital and University of Milano.

Supported in part by a grant from Consiglio Nazionale delle

Ricerche, Progetto Finalizzato ‘Ingegneria Genetica, “ Sottopro-

getto Basi Molecolari delle Malattie Genetiche (No. 83.0/0.11.5/).

Submitted Oct 5, 1983; accepted March 29, 1984.

Address reprint requests to Dr P.M. Mannucci, Via Pace 9.

Milano. Italy.(C) /984 by Grune & Stratton. Inc.

0006-497l/84/6403-0005$03.00/0

malities treated in the same way. vWF:Ag and vWF:RiCof

were increased less and cleared more rapidly from plasma

and the BT remained normal for a shorter period of time.

These studies provide evidence that these AvWD patients

have qualitatively normal vWF in plasma. but at lower

concentrations. that vWF in platelets is normal both quali-

tatively and quantitatively. and that cellular vWF can be

rapidly released into plasma by DDAVP to correct the

hemostatic abnormalities. However. vWF is removed rap-

idly from plasma. making the correction more transient

than in congenital vWD type I.

abnormality of the immune system. Three general

mechanisms to explain the pathogenesis of AvWD

have been proposed. The first implies that antibodies

either inactivate the biologic activities of FVIII-

vWF,2 � bind to the complex without affecting theactive sites, or induce rapid clearance of the complex

from the circulation through the formation of immuno-

complexes.’2”3 The second proposes that AvWD is the

result of the selective absorption of FVIII-vWF to

abnormal lymphocytic clones or malignant cells, lead-

ing to low plasma levels.’�’9 Finally, the third states

that there is defective synthesis of FVIII-vWF in

cellular compartments (megakaryocytes, endothelial

cells) and/or there is defective release into plasma. We

decided to apply three new approaches to investigating

the problem of the pathogenesis of AvWD in seven

patients with AvWD associated with lymphoprolifera-

tive disorders or benign monoclonal gammopathies.

The first was the measurement of vWF (as vWF:Agand vWF:RiCof) in platelets, which are easily accessi-

ble cells of megakaryocytic origin from which the vWF

content of cellular compartments can be evaluated.20’2’

The second was the assessment of the plasma release

and clearance of FVIII-vWF by monitoring the changes

of vWF:Ag, vWF:RiCof, and FVIII:C after infusion of

I-deamino-8-D-arginine vasopressin (DDAVP), a drug

that probably releases FVIII-vWF from cellular com-

partments.22 The third was the electrophoretic analysis

of the structure of FVIII-vWF, which consists of a

multimeric series of oligomers of a protomer composed

of a variable number of identical subunits,2325 in plasma

and platelets.

MATERIALS AND METHODS

Patients

The clinical details for the patients are listed in Table 1 . The most

typical features were the onset of mildly to moderately severe

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ACQUIRED VON WILLEBRAND’S DISEASE 615

Table 1 . Clinical Details of Se yen Patients W ith Acquired von Willebrand’s Disease

Age’ Previous Hemostatic Challenge Nature of Acquired

Patient No. (yr) Sex Underlying Disease Family History Without Excessive Bleeding Bleeding Diathesis

1 45 F Monoclonal gammopathy,

lgG kappa

None Tonsillectomy; multiple tooth

extractions

Recurrent epistaxis requiring

transfusion; posttraumatic he-

matomas

2 39 M Monoclonal gammopathy,

lgG lambda

None Multiple tooth extractions Posttraumatic hematomas and

hemarthroses; massive gas-

trointestinal bleeding; bleeding

after hernia repair

3 57 F Monoclonal gammopathy,

lgG lambda

None Hysterectomy Easy bruising; spontaneous and

posttraumatic hematomas;

epistaxis; menorrhagia

4 50 F Myeloma, lgG kappa None None None (fortuitous finding of ab-

normal hemostasis tests)

5 48 F Myeloma. IgA kappa None Appendectomy Easy bruising; gum bleeding; pro-

longed bleeding after tooth ex-

traction

6 60 M Primary macroglobuli-

nemia

None Orthopedic surgery Easy bruising; excessive bleeding

from superficial cuts

7 72 M Chronic lymphocytic leu-

kemia

None Multiple tooth extractions Epistaxis

Age at pr esentatio n with bleeding.

mucosal and postoperative bleeding in patients who had no previous

history of excessive spontaneous or postoperative bleeding until their

underlying diseases became manifest. None of the patients had any

pertinent family history.

Five French patients were jointly examined by the two teams in

Paris, and samples of plasma obtained before and after DDAVP and

platelet hysates were transported in dry ice to Milan for further

analysis. Plasma obtained before and after DDAVP and platelet

lysates were obtained in Milan from two Italian patients.

Methods

The methods for collection of blood and plasma preparation have

been published.26 Platelets were washed free of plasma constituents

and then lysed according to previously published procedures.2#{176}

Assay methods and standards. FVIII:C was assayed by a

one-stage clotting technique,26 and FVIII:CAg was assayed by a

two-site immunoradiometric assay,27 using a homologous nonhemo-

phihic antibody kindly provided by Dr L. Holmberg (Malm#{246}, Swe-

den). Concentrations of FVIII:C and FVIII:CAg were expressed in

U/dL and referred to a pooled normal plasma that was calibrated

against the First International Reference Preparation for Factor

VIII-Related Activities in Plasma (National Institute for Biological

Standards and Controls, London). vWF:Ag was measured by dcc-

troimmunoassay (EIA) and immunoradiometric assay (IRMA).26

vWF:RiCof activity was assayed with formahin-fixed platelets.26

These measurements were expressed in U/dL with reference to the

International Reference Preparation.

Inhibitor screening. Inhibitors of FVIII:C were sought by the

Bethesda method, after heating those plasmas that contained mea-

surable FVIII:C at 56 #{176}Cfor ten minutes. Inhibitors ofvWF:Ag and

vWF:RiCof were sought by incubating 2 vol of patient plasma with I

vol of pooled normal plasma. Controls were mixtures of nine

different normal plasmas (1 vol) with phosphate-buffered saline

containing 3% albumin (2 vol). The first incubation was at 37 #{176}Cfor

one hour, then at 4 #{176}Cfor an additional I 2 hours. Patient and normal

phasmas were also incubated, without mixing, under the same

conditions. The samples were then centrifuged at 2,500 g for 20

minutes, and ahiquots of the supernatants were assayed for vWF:Ag

(IRMA) and vWF:RiCof against pooled normal plasma incubated

under the same conditions (observed values). Expected values,

assuming no inhibitor in the mixtures, were calculated from the

values for patient plasma and normal plasma incubated and assayed

separately and from their proportions in the mixture. Percentage

differences between expected and observed values were also calcu-

hated, and the significance of these differences from zero was

determined. Percentage differences between patients and controls

were also compared.

Multimeric analysis. The multimeric composition of FVIII-

vWF was analyzed by SDS thin-layer agarose gel ehectrophoresis,

using the discontinuous buffer system of Ruggeri and Zimmerman,25

and differed from their procedure in that electrophoresis was for I 8

hours at a constant current of 6 mA/gel (instead of five to six hours

and 10 to 12.5 mA/gel) and multimers were identified by exposing

the gels to ‘25I-labeled affinity-purified rabbit (instead of emu)

antibodies, prepared as described elsewhere.26 Agarose gel concen-

trations were I .6%.

DDA VP infusion. I -Deamino-8-D-arginine vasopressin

(DDAVP) was infused IV into patients at a dose of 0.4 zg/kg, with

blood samples and bleeding times (BT) (Simplate II, General

Diagnostics, Milano, Italy) obtained before and after the infusion

according to a published protocol.22 All subjects were aware of the

experimental nature of the studies and gave their informed consent,

and all experiments were performed in accord with the Declaration

of Helsinki.

Analysis of results. To eliminate the large between-patient

differences in baseline FVlll-vWF measurements, responses after

DDAVP were expressed not only as absolute concentrations in

U/dL, but also as relative changes over baseline values, taken as I.Values were transformed logarithmically before testing the signifi-

cance of differences between groups; they were then evaluated by

means of two-way analysis of variance and the Student’s t test for

paired data. The rate of return of FVIII-vWF measurement to

resting values after their maximal DDAVP-induced rise was deter-

mined by using the best curve fitted by the method of least squares

on the posttreatment values, expressed as percentage of the peak

value reached after DDAVP. Half-disappearance times and the

corresponding slopes were then calculated for each FVIII-vWF

measurement, assuming first-order kinetics.28 Good agreement with

a one-compartment model of distribution of the FVIII-vWF mea-

For personal use only.on October 3, 2017. by guest www.bloodjournal.orgFrom

surements was observed. This was also checked by testing the

regression curves for linearity. Half-disappearance times were com-

pared by the Wilcoxon matched-pair signed ranks test.

RESULTS

Table 3. Inhibitory Activity Against vWF:Ag and vWF:RiCof in Plasmas of Seven Patients With Acquired von Willebrand’s Disease

Mixtures of

1 part + 2 parts of

vWF:Ag vWF:RiCof

Expected Observed Percent Difference Expected Observed Percent Difference

Normal + buffer (controls) 33 34 1 33 32 -2

(30-37) (-8-+10) (28-37) (-15-+11)

Normal + patient 1 plasma 35 29 - 1 7 33 30 -9

Normal + patient 2 plasma 35 30 - 14 33 44 +25

Normal + patient 3 plasma 34 30 - 1 1 33 29 - 12

Normal + patient 4 plasma 55 57 + 3 55 56 + 2

Normal + patient 5 plasma 43 5 1 + 1 5 37 39 +5

Normal + patient 6 plasma 42 38 -9 37 34 -8

Normal + patient 7 plasma 4 1 45 + 9 43 49 + 12

39t

(35-45)

40

(32-48)

-3

(- 12-+6)

39

(32-45)

40

(33-47)

2

(-8-+ 12)

Observed values are expressed as percentages of pooled normal plasma incubated under the same conditions as the mixtures, set arbitrarily at 100%

(medians of three different experiments). Expected values were calculated from the values of normal and patient plasmas incubated and assayed

separately. Percentage differences between observed and expected values were also calculated.

Means and 95% confidence limits (between parentheses) for nine normal subjects. Percentage differences were not significantly different from those

for patients.

tMeans and 95% confidence limits (between parentheses) for seven AvWD patients. Percentage differences were not significantly different from zeronor from the control values.

616 MANNUCCI ET AL

Table 2. Baseline Labors tory Findings of Seven Patients With Acquired von Willebr and’s Disease

Patient No.

Plasma Factor VIII-von Willebrand Factor-Related Measurements (U/dL)

Bleeding Time

(mm)FVlll:C

vWF:Ag vWF:Ag

FVIII:CAg (Laurell) (IRMA) vWF:RiCof

1

2

3

4

5

6

7

3

6

1

31

19

15

13

12 <6 3

6 <6 3

2 <6 2

32 27 33

- 12 16

7 17 14

- 12 12

<6

<6

<6

34

6

6

16

10

11

14

5

5

6

8

Normallaboratoryrange 50-165 47-151 55-168 53-180 58-170 3-7

Plasma FVIII-vWF Measurements

Baseline values for these measurements and the BT

are given in Table 2. Patients 1 , 2, and 3 were the most

severely affected patients, with plasma vWF:Ag (EIA

method) and vWF:RiCof below the lower limits ofdetection of the methods (6 U/dL). Very low concen-

trations of vWF:Ag, however, could be measured by

the IRMA method, which gave dose-response curves

parallel to those of normal plasma and maximal anti-

body-binding capacity like that of normal plasma. The

BT was prolonged, but less than would have beenexpected from the severity of the plasma FVIII-vWFdeficits. In the remaining four patients (No. 4 to 7), all

the plasma FVIII-vWF measurements were less low

than in the first three patients. The BT of patients 4 to

6 were normal.

Inhibitors of FVIIJ-vWF

In AvWD plasma heated to destroy FVIII:C, therewas no evidence of inhibitory activity against FVIII:C

(data not shown). After prolonged incubation of nor-

mal and AvWD plasmas, observed values of residual

vWF:Ag and vWF:RiCof did not significantly differfrom the values expected from the values of plasmas

incubated separately (nor from the values of the con-

trol plasmas), indicating that no significant inactiva-

tion of vWF:Ag and vWF:RiCof was induced in nor-

mal plasma by incubation with AvWD plasma (Table3).

Platelet FVJII-vWF Measurements

Platelet vWF:Ag and vWF:RiCof concentrations

were normal in all patients except No. 5, who had low

borderline values (Fig 1). This patient has myeloma

and was anemic, and hence, it was difficult to avoid

contamination with red cells in washed platelets and

lysates. Such contamination is likely to have led to a

higher protein content and thus to underestimation of

platelet vWF:Ag and vWF:RiCof.

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�- #{149}A �VWD� 0.3

! 02 #{149} : : �

�o1 � ::�,�j

�o 2 ANORMALS VWD

Fig 1 . Platelet von Willebrand factor antigen (vWF:Ag) mea-

sured with IRMA (squares) and ristocetin cofactor (vWF:RiCof)(triangles) in nine healthy subjects (normals). seven patients withcongenital von Willebrand’s disease (CvWD. closed symbols). andseven patients with acquired von Willebrand’s disease (AvWD,open symbols). No significant difference between groups for eachmeasurement was found with a one-way analysis of variance.

vWF:Ag IRMA (#{149}).vWF: RiCof (A).

A

ACQUIRED VON WILLEBRAND’S DISEASE 617

FVIII-vWF Multimeric Pattern

All the multimers present in normal plasma could be

seen in all patients (Fig 2), with the pattern similar to

that for normal plasma and plasma from patients with

the “classical” form of congenital vWD (type I). The

relative intensities of the bands were decreased in

rough proportion to the plasma concentrations of

FVIII-vWF measurements. Larger multimers than

Fig 2. Autoradiograph pattern of factor VIll-von Wille-brand factor (FVlll-vWF) electrophoresed in 1 .6% agarose inthe presence of sodium dodecyl sulfate and detected byreaction with ‘2�l-labeled affinity-purified antibody. Thearrow indicates the origin of the running gel. and the anode isat the botton of the gel. (A) From left to right: normal plasma;plasmas from AvWD patients 4. 5. 6. 2, and 3; platelet lysatesfrom a normal subject and AvWD patient 3. (B) From left toright: plasmas from patient 1 . normal control. and patient 7.

4

were present in plasma were seen in the platelet lysates

of all the patients tested. A representative example

(patient 3) is shown in Fig 2.

DDA VP Studies

In order to evaluate the magnitude and time courseof FVIII:C, vWF:Ag, and vWF:RiCof changes in

AvWD patients after DDAVP, we have chosen to use

as a control group seven patients with congenital vWD

(CvWD) type I treated with DDAVP in the same

manner (Table 4). The rationale for this choice was

that these patients had the following features in com-

mon with the AvWD patients: low plasma levels of

FVIII:C, vWF:Ag, and vWF:RiCof (Table 4); normalplatelet vWF:Ag and vWF:RiCof (Fig 1); and intact

multimeric structure in plasma and platelets. Bleeding

times, however, were prolonged in all patients. Figure

3 compares the extent and time course of plasma

changes in these measurements after DDAVP in the

two groups. In both, there was a marked increase of

FVIII:C, vWF:Ag, and vWF:RiCof over baseline val-

ues. The mean increase of vWF:Ag and vWF:RiCof

for AvWD patients, however, was slightly less

(P < .05) than for CvWD immediately after infusion.

In AvWD, there was also a more rapid return of

vWF:Ag and vWF:RiCof to the baseline after the end

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time (Ii)

Table 5. Half-Disappearance Times of Factor VIII Coagulant

Activity (FVlll:C). von Willebrand Factor Antigen (vWF:Ag). and

Ristocetin Cofactor (vWF:RiCof) in Patients With Congenital and

Acquired von Willebrand’s Disease

Fig 3. Quantitative changes of FVlll-vWF factor (measured asFVlll:C, vWF:RiCof. and vWF:Ag) at various time intervals (hours)after DDAVP infusion in seven patients with CvWD (solid lines)and seven patients with AvWD (dotted lines). Results areexpressed as mean changes ( ± SD) over baseline values taken as 1..-. CvWD, #{149}---#{149}AvWD.

Acquired vWD (N - 7)

Congenital vWD (N - 7)

‘Means ± SEM.

tP < .05 v CvWD patients.�P < .01 vCvWD patients.

618 MANNUCCI ET AL

Table 4. Baseline Lab oratory Findi ngs for Seven “Control” Patients With Congenital von Will ebrand’s Dise ase Type I

Patient No.

Plasma Factor Vlll-von Willebrand Factor-Related Measurements (U/dL)

Bleeding Time

(mm)FVlll:C

vWF:Ag vWF:Ag

FVlll:CAg (Laurell) (IRMA) vWF:RiCof

8

9

10

11

12

13

14

1

4

1

15

15

11

17

5 <6 4

6 <6 7

5 < 6 4

15 19 20

- 10 11

15 10 15

- 17 -

<6

<6

< 6

16

13

11

6

19

12

13

11

12

13

14

Normallaboratoryrange 50-165 47-151 55-168 53-180 58-170 3-7

of the DDAVP infusion, as shown by their mean

half-disappearance times reported in Table 5.

After DDAVP, electrophoretic analysis of vWF:Agmultimers showed the same patterns in patients with

AvWD and CvWD. There was an increase in plasmaconcentration of all multimers and an early postinfu-

sion appearance of larger multimers than were present

in plasma before DDAVP (Fig 4). However, the stain-

ing intensity of all the multimers became weaker

earlier in AvWD than in CvWD patients (Fig 4).

Bleeding time became much shorter or returned tonormal 30 minutes after DDAVP infusion in the

CvWD and AvWD patients in whom it had beenprolonged before DDAVP (Table 6). However, in

AvWD, the BT tended to be longer again four hours

after DDAVP, unlike that in patients with CvWD,

despite their longer baseline BT.

DISCUSSION

Nine patients with AvWD were previously shown to

have qualitative abnormalities of plasma FVIII-vWF,which did not show the more slowly moving forms on

crossed immunoelectrophoresis 11 3.I4.I6I8.29

Only two of the 1 1 AvWD patients studied by thistechnique had shown a normal pattern (both hadmonoclonal gammopathies).6”2 Three of the nine

patients with abnormal CIE had lymphoproliferative

disorders,8”4”7 three had benign monoclonal gammop-

�.0

U..-Xe --a-

athies,’#{176}”3’6 and the remaining three had carcinoma of

the stomach,” chronic myeloid leukemia,’8 and secon-

dary amyloidosis.29 In one patient,’6 abnormalities

were also detected by IRMA, indicating that in this

assay, dysfunctional FVIII-vWF does not react with

the same antigen-antibody reaction kinetics as normalplasma. The observed abnormalities have usually been

attributed to the deficiency of larger FVIII-vWF mul-

timers, selectively removed from plasma by increased

catabolism or specific absorption to abnormal cell

lines. We have reassessed this problem in seven

patients with AvWD associated with lymphoprolifera-

tive disorders or benign monoclonal gammopathies by

using IRMA and SDS agarose gel electrophoresis,

which illustrate more directly than CIE the multimeric

structure of FVIII-vWF. In AvWD plasma, the mul-

timeric structure was intact. Moreover, the IRMA of

vWF:Ag gave dose-response curves parallel with thoseof normal plasma and maximal antibody-binding

capacities similar to those of normal plasma.

In AvWD platelets, vWF:Ag and vWF:RiCof were

normal, as in CvWD platelets, and the multimeric

structure was intact, indicating that the synthesis of

FVIII-vWF in megakaryocytes is quantitatively andqualitatively normal. However, our studies certainly do

not rule out the possibilities that FVIII-vWF abnor-

malities might occur in some patients with AvWD,

because our patients constitute only a small group of

those with the syndrome.

Two other possible pathogenetic mechanisms of

HaIf-Di

Patient Category FVIII:C

sappearance Tim es (mm)

vWF:Ag vWF:RiCof

76 ± 7 34 ± 19t 23 ± 14�76±8 63±13 60±12

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ACQUIRED VON WILLEBRAND’S DISEASE 61�

Fig 4. (A) Autoradiograph pattern of plasma FVlll-vWF mul-timers of CvWD patient 3 before (time 0) and at various timesafter DDAVP infusion. N shows a normal plasma pattern. (B)Autoradiograph pattern of plasma FVlll-vWF multimers of AvWDpatient 3 before (time 0) and after DDAVP. N shows a normalplasma pattern.

4

4

A

N

N

VWD TYPE I0’ 15’ 30’ 60’ 2h

AVWD

0’ 15’ 30’ 60’ 2h

4h

4h

AvWD-defective release of FVIII-vWF from cellular

compartments or increased plasma clearance-were

evaluated by comparing the effects of DDAVP in

AvWD and CvWD patients, on the assumption thatthis agent should amplify the physiologic mechanisms

for releasing FVIII-vWF from cellular compartments

and clearing it from plasma. In AvWD, FVIII:C,

vWF:Ag, and vWF:RiCof markedly increased soon

after the infusion, and larger multimers, possibly

released from cellular compartments,22 appeared tran-

siently in the circulation. This behavior was similar to

that of patients with CvWD type I, but differed in that

the increase was of lesser magnitude and more short-

lived, at least for vWF:Ag and vWF:RiCof. A more

rapid plasma clearance of FVIII-vWF could probably

explain both the lower peak values and the shorter

half-disappearance times of vWF:Ag and vWF:RiCof,

even though an additional role of defective release

from cells cannot be excluded by our data. Rapid

plasma clearance might be due to at least three causes:

(1) specific autoantibodies that inactivate FVIII-vWF;

(2) specific autoantibodies that bind FVIII-vWF but

are not directed against the so-called FVII1-vWF

active sites; and (3) nonspecific antibodies that form

circulating immunocomplexes with FVIII-vWF and

favor its clearance by Fc-bearing cells of the reticu-

loendothelial system.’2”3 Unlike some previous stud-

ies,2�”3#{176}but in agreement with many others,’2�9’29’3133

our patients’ plasmas did not inactivate FVIII:C,vWF:Ag, and vWF:RiCof in normal plasma in vitro,

Table 6. Bleeding Times Before and After DDAVP in Patients

With Congenital and Acquired von Willebrand’s Disease

PatientNo. Diagnosis

Bleeding Times (mm)

Baseline

30 mm

Postinfusion

4 h

Postinfusion

1

2

3

4

5

6

7

8

9

10

11

12

13

14

AvWD

AvWD

AvWD

AvWD

AvWD

AvWD

AvWD

CvWD

CvWD

CvWD

CvWD

CvWD

CvWD

CvWD

10

11

14

5

5

6

8

19

12

13

11

12

13

14

4

6

7

ND

ND

ND

ND

10

6

4

5

6

7

8

11

10

13

ND

ND

ND

ND

8

7

5

4

7

5

5

ND, not done because baseline bleeding times were normal or

borderline.

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620 MANNUCCI ET AL

ruling out the presence of inactivating antibodies.

Although we have not directly tested the other two

possibilities, our findings would be compatible with

either of them.

The results of this investigation might also have

therapeutic implications. DDAVP transiently normal-

ized the bleeding time in all AvWD patients and

increased plasma concentrations of FVIII:C, vWF:Ag,

and vWF:RiCof. Even though the correction did not

last as long as in patients with CvWD, DDAVP might

be useful for treating bleeding episodes or securing

hemostasis for surgical procedures without resorting to

cryoprecipitate, with its inherent risk of hepatitis.

NOTE ADDED IN PROOF

Schneider et al8 have previously reported a case of

AvWD associated with a malignant lymphoma and

characterized by the absence of the more slowly mov-

ing forms of plasma FVIII-vWF on CIE. We have now

studied the FVIII-vWF multimeric structure in the

plasma of this patient and found a defect of large and

intermediate-sized multimers reverting to normal after

clinical remission of the lymphoma.

ACKNOWLEDGMENT

We are indebted to Drs Baumelou, Rugarhi, Shumberger, and

Zittoun who referred their patients to us for investigation. Dr Betty

Rubin revised the manuscript.

REFERENCES

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3. Stabheforth P, Tamagnini GL, Dormandy KM: Acquired von

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activity and ristocetin-induced platelet aggregation. Br J Haematol

33:565, 1970

4. Wautier iL, Levy-Toledano 5, Caen JP: Acquired von Wille-

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phocytic leukemia. Scand i Haematol 16:128, 1976

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1984 64: 614-621  

PM Mannucci, R Lombardi, R Bader, MH Horellou, G Finazzi, C Besana, J Conard and M Samama gammopathiesseven patients with lymphoproliferative disorders or benign monoclonal Studies of the pathophysiology of acquired von Willebrand's disease in 

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