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Best Practice & Research Clinical Haematology Vol. 14, No. 2, pp. 401±436, 2001

doi:10.1053/beha.2001.0141, available online at http://www.idealibrary.com on

11 Acquired von Willebrand syndromes: clinical features, aetiology, pathophysiology, classi®cation and management Jan Jacques Michiels

MD, PhD

Internist/Hematologist Haemostasis Thrombosis Research, Department of Haematology, University Hospital Antwerp, Belgium Goodheart Institute, International Haemostasis Thrombosis Science Center, Rotterdam, The Netherlands

Ulrich Budde

Dr Med

Clinical Chemist Coagulation Laboratory, Hamburg, Germany

Marc van der Planken

MD

Laboratory Hematologist Haematology Laboratory, Department of Clinical Biology, University Hospital Antwerp, Belgium

Huub H. D. M. van Vliet

PhD

Biochemist Haemostasis and Thrombosis Laboratory, Department of Haematology, University Hospital Rotterdam, The Netherlands

Wilfried Schroyens MD, PhD Internist/Hematologist Haemostasis Thrombosis Research, Department of Haematology, University Hospital Antwerp, Belgium

Zwi Berneman

MD, PhD

Internist/Hematologist Haemostasis Thrombosis Research, Department of Haematology, University Hospital Antwerp, Belgium

Acquired von Willebrand syndrome (AVWS) associated with hypothyroidism is of type 1, results from a decreased synthesis of factor VIII and von Willebrand factor (VWF), responds to desmopressin with normal half-life times for factor VIII and VWF parameters, and disappears after treatment with l-thyroxine. AVWS type I or III, which occurs in a minority of patients with Wilms' tumour in the complete absence of an inhibitor against VWF and no absorption of factor VIII or VWF onto nephroblastoma cells, responds to chemotherapy and/or tumour resection. Hyaluronic acid produced by nephroblastoma cells may be the causative factor in atypical AVWS in Wilms' tumour. AVWS associated with thrombocythaemia of various myeloproliferative disorders is characterized by normal factor VIII and von Willebrand factor antigen (VWF:Ag) levels and a selective de®ciency of functional ristocetin co-factor activity (VWF:RCo) and collagen-binding activity (VWF:CBA). AVWS type II in thrombocythaemia is caused by a platelet-dependent proteolysis of large VWF multimers, given the inverse 1521±6926/01/020401‡36 $35.00/00

c 2001 Harcourt Publishers Ltd. *

402 J. J. Michiels et al

relationship between platelet count and large VWF multimers in plasma and speci®c increases in the number of proteolytic VWF fragments in plasma. The laboratory ®ndings of AVWS associated with systemic lupus erythematosus or IgG benign monoclonal gammopathy are characterized by a prolonged bleeding time and activated partial thromboplastin time, decreased or absent ristocetin-induced platelet activity, low to very low levels of factor VIII coagulant activity (mean 15%), VWF:Ag (mean 10.7%) and VWF:RCo (mean 6.2%), and a type II multimeric pattern of VWF. Neutralizing and nonneutralizing anti-VWF autoantibodies, usually IgG, have been detected in patient plasma either free or tightly bound to the intermediate and high molecular weight VWF factor VIII particles. The bound auto antibody±antigen complex is rapidly cleared from the circulation, resulting in low levels of factor VIII, VWF parameters as documented by a poor response to desmopressin and VWF factor VIII concentrate. High-dose intravenous immunoglobulin transiently corrects the factor VIII coagulant and VWF levels, lasting for a few weeks in AVWS type II associated with systemic lupus erythematosus or IgG benign monoclonal gammopathy. Prednisolone is e€ective in AVWS associated with autoimmune disorder. Prednisolone and chemotherapy will not a€ect AVWS associated with IgG benign monoclonal gammopathy because the monoclonal IgG protein remains to act as an anti-VWF autoantibody. An absorption of VWF to malignant cells has been documented in a few patients with various lymphoproliferative disorders or adrenal carcinoma and suggested to result in a depletion of VWF. The clinical picture of AVWS associated with early-stage IgG multiple myeloma, chronic lymphocytic leukaemia or non-Hodgkin's lymphoma without a paraprotein or no detectable underlying disorder is similar to that of AVWS type II in IgG benign monoclonal gammopathy but poorly documented with regard to the underlying immune mechanism of AVWS. The mechanical destruction of large VWF multimers may be of relevance in conditions in which the shear rate of ¯owing blood is increased, as may occur in cases of aortic stenosis, other heart valve defects or stenosed vessels. Drug-induced AVWS has been described in association with the use of pesticides valproic acid, cipro¯oxacin, griseofulvin, tetracycline, thrombolytic agents and hydroxyethyl starch. Key words: acquired von Willebrand syndrome; von Willebrand factor; monoclonal gammopathy; multiple myeloma; macroglobulinaemia; lymphoproliferative disorders; nonHodgkin's lymphoma; chronic lymphocytic leukaemia; thrombocythaemia; myeloproliferative disorders.

The key to acquired von Willebrand syndrome (AVWS) is its late onset of bleeding diathesis with a negative family history and no prior history of prolonged bleeding after previous haemostatic challenges.1 Bleeding manifestations in AVWS most closely parallel the mild-to-moderate bleeding severity of congenital von Willebrand disease (VWD) types 1 and 2.2±4 AVWS has been reported in patients with various underlying diseases, including benign monoclonal gammopathy, lymphoproliferative disorders, myeloproliferative syndromes, thrombocytosis, autoimmune diseases, drugs, congenital heart valve defects, solid tumours, hypothyroidism and infectious diseases, as well as the absence of any detectable underlying disorder.1,5±12 The type, natural history and severity of bleeding manifestations in patients with AVWS depend largely on the mechanism and degree of the VWF de®ciency associated with or caused by the nature of the underlying disorder. In this chapter, we critically analyse the aetiology, pathophysiology, laboratory features, clinical manifestations and outcome of treatment in the reported cases of AVWS in view of each of the underlying disorders or use of drugs. Based on this detailed analysis, a more clear and concise ¯owchart related to the aetiology, pathophysiology, classi®cation and treatment recommendations for AVWS is presented for clinicians to treat their patients appropriately.

Acquired von Willebrand syndromes 403

METHODS The severity of bleeding manifestations in AVWS was graded according to the classi®cation of bleeding symptoms in VWD by Eikenboom et al.13 The diagnostic tools to characterize the VWF defect in the reported cases of AVWS include: . an assessment of platelet function: Ivy or Simplate bleeding time, platelet count, and platelet aggregation induced by collagen, ADP, epinephrine and ristocetine; . coagulation and factor VIII/VWF parameters, including prothrombin time and activated partial thromboplastin time (APTT), factor VIII coagulant activity (FVIIIC), VWF antigen (VWF:Ag) level, VWF ristocetin co-factor activity (VWF:RCo), VWF collagen-binding activity (VWF:CBA) and VWF multimers (VWF:MM); acquired haemophilia A was ruled out by the absence of factor VIII, autoantibodies in the Bethesda assay; . the response of the AVWS to intravenous desmopressin (DDAVP) and factor VIIIc/ VWF concentrate; . the response to intravenous gamma globulin in immune-mediated AVWS; . an analysis of the underlying mechanism causing AVWS in view of the underlying disorder; . the correction of AVWS in response to the treatment of the underlying mechanism or disorder.

RESULTS AVWS and hypothyroidism AVWS and hypothyroidism have been reported to occur together in 19 cases, 18 women and one man, at a mean age of 31 years, ranging from 13 to 82 years (Table 1).10,14±23 Six of these were asymptomatic, and 11 presented with mild-tomoderate bleeding symptoms including easy bruising, menorrhagia and non-severe bleeding after dental extraction. The routine bleeding time was normal in ®ve and prolonged in 11 patients, normal platelet counts being seen in all. Ristocetin-induced platelet activity (RIPA) was not tested in 13, was normal in case 17 and was indicated to be decreased in case ®ve. The APTT was normal in six, ®ve of whom had an F-VIIIc level in excess of 60%. The APTT was prolonged in 11, eight of whom had an F-VIIIc level of between 18% and 45%, three being in excess of 50% (Table 1). AVWS type I was documented by crossimmunoelectrophoresis in three and by a multimeric analysis of VWF in the plasma in six cases (Table 1). AVWS type I was highly likely in all cases because of a normal VWF:RCo to VWF:Ag ratio. A typical DDAVP response with an eight-fold increase in FVIIIC/VWF parameters was observed in one case tested, which is consistent with the absence of an inhibitor against VWF21 (Table 1). Fifteen patients with AVWS and hypothyroidism were symptomatic and presented with mild bleeding symptoms. The lowest values of VWF:Ag and VWF:RCo lay in the range of 17% to 46% of normal. In the prospective study by Levesque et al20, four out of 11 patients with hypothyroidism had asymptomatic AVWS type 1 with a mild de®ciency of VWF parameters of between 26% and 49%. A de®ciency of other coagulation factors, including factors VII, V, IX and X, caused by a generalized decreased protein synthesis in hypothyroidism, may have contributed to the prolongation of the APTT.24

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15b 16 17 18 19

18 F 1M

17 F 53 F 29 F 34 F 29 F 13 F 34 F 17 F 15 F 32 F 43 M 82 F 40 F 13 F 13 F 29 F 30 F 22 F 34 F

Age M/F

48%

67 18 45 31 36 62 38 36 70 62 80 82 40 41 33 38 42 58 36

FVIIIc (%)

33%

45 17 34 17 30 27 25 36 32 41 46 49 26 39 37 30 38 42 24

VWF:Ag (%)

37%

27 17 55 19 ± ± 50 31 44 48 46 44 30 30 36 30 39 55 27

VWF:RCof (%)

Cure 18 VWD 1

Type 1a Type 1a Type 1a Type 1 Type 1 Type 1 Type 1 Type 1 Type 1 Type 1a Type 1a Type 1a Type 1a Type 1 Type 1 Type 1 Type 1 Type 1a Type 1a

AVWS (MM)a Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes

Cure

For abbreviations, see text.

DDAVP responseb in case 15: FVIIIc VWF:AG before 33% 37% after 240% 320%

VWF:RCof 36% 278%

(MM)a ˆ type 1 AVWS documented by von Willebrand factor crossed immunoelectrophoresis or multimeric analysis. N ˆ normal; . ˆ no data.

Total

Mean

Bruggers (twin sisters) (1994)21 Tjan-Heijnen et al (1994)22 Aylesworth et al (1995)23 Nitu-Whalley and Lee (1999)10

MacCallum et al (1987)17 Blesing et al (1990)18 Coccia and Barnes (1991)19 Levesque et al (1993)20

Takahashi et al (1987)15 Smith and Auger (1987)16

Dalton et al (1987)14

Case

Before thyroxine

100%

122 85 126 103 100 169 59 120 79 115 93 97 70 71 90 70 N . .

FVIIc

After thyroxine

90%

144 74 93 69 86 147 80 79 105 112 80 85 35 51 . 56 N . .

VWF-Ag

Table 1. Acquired von Willebrand syndrome (AVWS) type I in hypothyroidism in 19 reported cases: reversal after treatment with thyroxine.

101%

120 68 139 60 ± 450 . 71 144 86 140 102 38 160 110 75 N . .

VWF:RCo

404 J. J. Michiels et al

Acquired von Willebrand syndromes 405

The treatment of hypothyroidism with thyroxine was associated with the correction of bleeding times, APTT and FVIIIC/VWF parameters to normal. The decreased mean values of FVIIIC, VWF:Ag and VWF:RCo before treatment with thyroxine increased to normal after treatment, this being accompanied by the complete relief of bleeding in all cases except one (Table 1). In the latter case, congenital VWD is likely. The observed changes in the FVIIIC/VWF complex before and after treatment re¯ect the non-speci®c action of thyroxine on protein synthesis through a stimulation of mRNA synthesis by tri-iodothyroxine.25 The complete relief of AVWS in hypothyroidism by treatment with thyroxine is the ®nal proof of this association and causal relationship. AVWS and Wilms' tumour AVWS associated with Wilms' tumour (nephroblastoma) has been reported in 10 children26±31, four boys, four girls and two of unknown sex and age, at a mean age of 3.3 years (range 0.33±9.0 years; Table 2). Three cases presented with mild or moderate bleeding symptoms, and seven cases were asymptomatic at time of diagnosis of AVWS. In the prospective study by Coppes et al30, only four out of 50 (8%) consecutive patients with the diagnosis of Wilms' tumour were found to have asymptomatic AVWS (Table 2, cases 5±8). The bleeding time was prolonged in six and normal in four. RIPA was decreased in a case with severe VWF:Ag de®ciency and not tested in the other nine cases. The APPT was prolonged in seven patients, who had an FVIIIC level of between 5% and 27%. The APPT was normal in one case with an FVIIIC level of 37%. The values for FVIIIC lay between 5% and 37%, with a mean of 15% (Table 2). AVWS was characterized by a very low VWF:Ag level of between less than 1% and 6% (mean 3%) and a signi®cantly higher level of VWF:RCo of between 5% and 54% (mean 24%) in seven cases. The high ratios for VIIIc to VWF:Ag (5.8) and for VWF:RCo to VWF:Ag (8.3) are unexplained. A multimeric analysis of the VWF revealed type I AVWS in three cases and type III AVWS in two (Table 2). AVWS is questionable in case 8. Experiments incubating patient plasma and normal plasma failed to show any inhibition of FVIIIC, VWF:Ag and VWF:RCo in the ®ve patients evaluated (Table 2). Case 3 was associated with hyperviscosity caused by an elevated serum hyaluronic acid level and showed undetectable factor VIII/VWF-related antigen levels in a Laurell rocket immunoelectrophoretic assay as well as a much less pronounced de®ciency of FVIIIC and VWF:RCo consistent with spurious VWF:Ag de®ciency (Table 2). Mixing studies of hyaluronic acid and normal pooled plasma showed an 80±90% inhibition of FVIIIC activity and a complete inhibition of factor VIII/VWF:Ag to undetectable levels in Laurell rocket immunoelectrophoresis. These in vitro data may explain the ex vivo ®ndings of undetectable or very low VWF:Ag and the much less pronounced functional de®ciency of FVIIIC and VWF:RCo, which result in an inversed and abnormally increased VWF:RCo to VWF:Ag ratio. The same inverse and abnormally increased VWF:RCo to VWF:Ag ratio of 20.1:3 (ˆ 6.7) could be demonstrated in seven cases, which is consistent with a highly atypical variant of AVWS (cases 1±7, Table 2). The response to DDAVP was not tested in these seven cases and was very good in case 8, with atypical AVWS. Indirect immuno¯uorescence of Wilms' tumour specimens in cases 2 and 4 (Table 2) using monospeci®c rabbit anti-VIII showed no absorption of factor VIII/VWF onto the nephroblastoma cells and a normal expression of factor VIII in vessel wall endothelial cells. Chemotherapy in seven children with a Wilms' tumour (cases 3 and 5±10, Table 2) was successful in reducing the tumour burden, which was accompanied by the disappearance of the AVWS. Subsequent surgical resection of the residual tumour mass

Scott et al (1981)27

Noronha et al (1979)26

7.5 months M Mild

Case Reference

Age Sex M/F Bleeding

NT

Yes Cure 120 170 179

NT

No ÿ

Yes Cure

61/78 59/72 92/34

No

Chemotherapy Outcome of AVWS

Surgery Outcome of AVWS Postoperative: FVIIIc VWF:Ag VWF:RCo

Recurrence of AVWS

No

n n n

Yes ÿ

Yes Cure

NT

n/‡ NT 37 51 16 ÿ NT

3.8 years F Moderate

Bracey et al (1987)28

3

No

107 98 80

Yes Cure

No ÿ

Type I

n Decreased 6 4 18 ÿ No

4 months M ÿ

Han et al (1987)29

4

No

n n n

Yes ÿ

Yes Cure

Type III

‡ NT 10 4 8 NT Nt

4.5 years M ÿ

5

ÿ ˆ absent; ‡ ˆ prolonged; n ˆ normal; NT ˆ not tested; MM ˆ multimeric pattern von Willebrand factor. For abbreviations, see text.

No

No ÿ

‡ NT 18 56 28 ÿ No

‡ NT 5 52 NT ÿ NT

Bleeding time Platelets FVIIIc(%) VWF:Ag VWF:RCo VWF inhibitor Absorption of VWF onto tumour cells AVWS MM*

9 years F Mild

2

1

No

n n n

Yes ÿ

Yes Cure

Type III/I

‡ NT 10 51 5 NT NT

7

No

n n n

Yes ÿ

Yes Cure

Type I

‡ NT 27 4 46 NT NT

4.5 years F ÿ

Coppes et al (1992)30 2 years M ÿ

6

Table 2. Acquired von Willebrand syndrome (AVWS) in 10 cases of Wilms' tumour.

No

n n n

Yes ÿ

Yes Cure

Type I

n NT 27 76 54 NT NT

1.5 years F ÿ

8

No/no

n/n n/n n/n

Yes ÿ/ÿ

Yes Cure

NT

n/n n/n 13/27 25/12 12/27 NT NT

?/? ?/? ÿ/ÿ

Jonge et al (1996)31

9/10

406 J. J. Michiels et al

Acquired von Willebrand syndromes 407

by nephrectomy without the need for factor VIII/VWF substitution was uneventful. Surgery as the primary treatment modality under the cover of substitution therapy including cryoprecipitate or factor VIII/VWF concentrate was uneventful in cases 1 and 4, and complicated by serious bleeding in case 2, for which additional therapy including factor VIII concentrate, fresh frozen plasma, platelets and whole blood were required. The surgical removal of the Wilms' tumour in these three children was followed by the recovery of FVIIIC, VWF:Ag and VWF:RCo levels to normal (Table 2). AVWS and systemic lupus erythematosus AVWS associated with systemic lupus erythematosus (SLE) has been reported in 12 cases, four men and eight women, with a mean age of 37 years (range 13±72 years).32± 41 Two patients (cases 9 and 12) were asymptomatic. Ten patients presented with recently acquired bleeding symptoms, of mild severity in eight and moderate severity in two cases (Table 3). A prolonged bleeding time and APTT, a normal platelet count with decreased or absent RIPA, a normal prothrombin time and very low levels of FVIIIC, VWF:Ag and VWF:RCo, and an absent or decreased RIPA were consistent with overt AVWS in nine cases (Table 3). Two patients with no or minor bleeding symptoms (cases 9 and 10) had FVIIIC and VWF parameters of between 20% and 42%, and a normal RIPA, consistent with the clinical and laboratory features of very mild AVWS (Table 3). In case 12, a selective VWF:RCo de®ciency, normal values for FVIIIC and VWF:Ag and near-normal RIPA are probably related to the associated increased platelet count of 960  109/1.8,42±44 A multimeric analysis of the VWF in the ®ve cases evaluated showed a type II pattern in four AVWS cases and a type I pattern in one (Table 3). The response to DDAVP was poor in one case with type II AVWS and in the case with type I AVWS, showing a decreased recovery and a shortened half-life for factor VIII and VWF parameters. The response to DDAVP was not tested in the other cases of AVWS in SLE (Table 3). The response to FVIIIC/VWF concentrate was poor in four cases evaluated with AVWS type II and one case of AVWS type I showing a low recovery and very short half-life for FVIIIC and VWF parameters, indicating a rapid clearance of the FVIIIC/VWF autoantibody complex from the circulation. The response to high-dose intravenous IgG in two cases with AVWS type II showed a transient correction of FVIIIC and VWF parameters lasting for a few weeks, thus con®rming the immune-mediated aetiology of AVWS in systemic lupus erythematosus. Experiments mixing patients' plasma with normal plasma demonstrated an inhibitory e€ect on VWF:RCo in cases 9±12 (Table 3). The detection and quantitation of anti-VWF antibodies in the plasma of case 8 was performed by an enzymelinked immunosorbent assay (ELISA) technique using surface-bound puri®ed VWF and labelled anti-human IgG, IgA and IgM. Anti-VWF binding activities in the plasma samples of case 8 were observed in the immunoglobulin class IgG and also, albeit much less so, with IgA and IgM. The plasma of a patient with severe type III VWD known to have a high titre of inhibitor to VWF yielded a much higher and very strong positive signal in the anti-VWF ELISA with the anti-IgG conjugate but no signi®cant signal with anti-IgA and anti-IgM conjugates. The plasma of two VWD patients and one patient with AVWS associated with a Wilms' tumour yielded no activity for IgG, IgA and IgM above the background activity of control plasma. Therapy with prednisolone (30±40 mg or 1±2 mg/kg daily) was uniformly e€ective in eight symptomatic cases of AVWS together, also relieving the signs and symptoms of systemic lupus erythematosus. Prednisolone 60 mg daily for 1 month in case 11 with

30 mg Cure

NT NT NT

NT NT ÿ NT NT

‡ n ‡ NT 10

‡

54 M

Poole-Wilson and Jones (1972)34

3

2 mg/kg Cure

NT Poor NT

55 53 ÿ ‡‡‡ NT

‡ n ‡ Zero 8

‡

16 F

Gazengel et al (1978)35

4

xx Cure

NT Poor NT

NT 47 ÿ NT NT

‡ n ‡ Decreased 6

‡

29 F

Pizzuto et al (1979)36

5

10 mg Cure

Good Poor NT

510 1.6 ÿ NT I

‡ n ‡ Zero 11

‡

12 M

Yoshida et al (1988)37

6

30 mg Cure

NT NT NT

510 18 ÿ NT NT

‡ n ‡ Zero 21

‡

53 F

Igarashi et al (1989)38

7

40 mg Cure

NT Poor NT

510 51 ÿ ‡‡‡ II

‡ n ‡ Zero 10

‡

17 F

So€ and Green (1993)39

8

NT NT NT

23 20 ÿ ‡‡‡ II

? n ‡ n 42

‡

48 F

NT NT no minor symptoms

NT NT Good

39 23 NT NT II

n n ‡ n 16

ÿ

47 F

Hanley et al (1994)40

9

Poor Poor Good

4 51 ÿ ‡‡‡ II

‡ n ‡ Decreased 8

‡

72 F

Viallard et al (1999)41

11

60 mg Plus 700 mg m2/iv Cure

10

NT NT Noa

94a 13a ÿ ‡ II*

‡ n ‡/ÿ n 76a

ÿ

48 F

1 mg/kg Outcome See text

12

a

‡ ˆ present or prolonged; ÿ ˆ absent; n ˆ normal; NT ˆ not tested or not treated. xx ˆ unknown. von Willebrand factor parameters and type II AVWS associated with reactive thrombocytosis (platelets 960  109/l with no response to high-dose intravenous immunoglobulin). For abbreviations, see text.

1 mg/kg Cure

30 mg Cure

NT NT ÿ NT NT

NT Poor NT

NT NT ÿ NT NT

VWF:Ag (%) VWF:RCo (%) Inhibitor FVIIIc IG inhibitor VWF AVWD type MM

‡ n ‡ NT 10

‡

NT NT NT

‡ n ‡ NT 4

Laboratory data Bleeding time Prothrombin time APTT RIPA FVIIIc (%)

Response to DDAVP FVIII concentrate Intravenous immunoglobulin Prednisone Dose per day Outcome Cyclophosphamide

‡

Bleeding

55 M

Ingram et al (1971)33

Simone et al (1968)32

13 M

2

1

Age M/F

Reference

Case

Table 3. Laboratory features and response to treatment in 12 reported cases of acquired von Willebrand syndrome (AVWS) associated with systemic lupus erythematosus.

408 J. J. Michiels et al

Acquired von Willebrand syndromes 409

severe FVIIIC and VWF de®ciencies induced increases in FVIIIC and VWF to 28% and 24% respectively. Adjuvant treatment with one intravenous dose of cyclophosphamide 700 mg/m2 was followed by a complete correction of both FVIIIC and VWF levels to normal (Table 3). Case 12, with thrombocytosis, did not respond to intravenous immunoglobulin, treatment of the systemic lupus erythematosus with prednisolone 1 mg/kg daily resulting in a correction of the platelet count and VWF:RCo together with the relief of the signs and symptoms of systemic lupus erythematosus (Table 3). AVWS in monoclonal gammopathies and lymphoproliferative disorders The underlying lymphoproliferative disorders in 83 reported cases of AVWS (51 men, 31 women and 1 of unknown gender) are summarised in Tables 4 and 5.33,45±102 AVWS is most frequently observed in IgG benign monoclonal gammopathy (n ˆ 44) and occasionally reported in multiple myeloma (n ˆ 14), IgM monoclonal gammopathies (n ˆ 9), chronic lymphocytic leukaemia (n ˆ 8), non-Hodgkins lymphoma (n ˆ 6) and hairy cell leukaemia (n ˆ 1) without a paraprotein (Tables 4 and 5). The main clinical manifestations include frequent and recurrent epistaxis, easy bruising, menorrhagia and recurrent blood loss from the gastrointestinal tract combined with a negative family history of a congenital bleeding disorder and no history of excessive bleeding after previous haemostatic challenge. The bleeding severity of AVWS associated with lymphoproliferative disorders is mild to moderate. The age at which AVWS occurred in association with a lymphoproliferative disorder ranged from 30 to 85 years (Tables 4 and 5). AVWS and IgG benign monoclonal gammopathy The laboratory ®ndings in 44 cases of AVWS associated with IgG benign monoclonal gammopathy (IgG kappa 25, IgG lambda 14, IgG 4 and free lambda 1) show a prolonged bleeding time and APTT, a normal prothrombin time and platelet count, decreased or absent RIPA and low to very low levels of FVIIIC (mean 15%), VWF:Ag (mean 5 10.7%) and VWF:RCo (mean 5 6.2%), consistent with AVWS (Table 4). On multimeric analysis of the AVWS, a type II pattern with an absence of large VWF multimers was documented in 13 cases evaluated. Type I AVWS was reported in a few cases. Mixing the patient's plasma and normal plasma showed an inhibition of RIPA in ®ve and no inhibition of RIPA in 10 cases tested, as well as an inhibition of VWF:RCo in ®ve and no inhibition of VWF:RCo in 15 cases of AVWS tested. In a case of AVWS associated with IgG monoclonal gammopathy, Gouault-Heilman et al 49 found the presence of an inhibitor against VWF activity (ristocetin-induced agglutination cofactor). Fractions from the patient's serum containing pure IgG (including monoclonal IgG) did not inhibit VWF activity, but puri®ed IgM had an inhibitor activity against RIPA but not against FVIIIC and VIII:Ag. Mixing experiments using VWF:RCo failed to detect an inhibitor in our three cases of AVWS associated with IgG benign monoclonal gammopathy, whereas using VWF:CBA clearly showed a neutralizing anti-VWF inhibitor in only one of these three.70,71,73 Subsequent immunoprecipitation experiments using recombinant fragments of VWF showed that not an IgG but an IgM antibody reacted with the collagenbinding sites (A1 and A3 domains) of VWF.70 The response to factor VIII/VWF concentrate infusion is poor, as has been documented since 1973 by a decreased recovery and rapid clearance within a few hours of all factor VIII and VWF in at least 21 representative cases of AVWS associated

Fricke et al (1985)57 Macik et al (1988)58 Lopez-Fernandez et al (1987)59 Kinsey et al (1987)60 Delannoy and Sailler (1988)61 Goudemand et al (1988)62 Castaman et al (1989)63 Rhamani et al (1990)64 Stewart and Glynn (1990)65 Castaman et al (1992)66 Delmer et al (1992)67 Scrobohaci et al (1993)68 White and Chisholm et al (1993)69 Van Genderen et al (1994)70,71 (1994)72 (1995)73 Sailler et al (1996)74

Mannucci et al (1984)56

Horellou et al (1983)55

IgG benign monoclonal gammopathy Ingram et al (1971)33 Mant et al (1973)45 Meyer et al (1974)46 Rosborough and Swai (1978)47 Meyer et al (1979)48 Gouault-Heilman et al (1979)49 Zetterval and Nilsson (1979)50 Gan et al (1980)51 Sitbon et al (1981)52 Wood and Losowsky (1982)53 Sampson et al (1983)54

‡/‡ ‡/‡ ‡/. ‡/‡ ‡/‡ ‡/‡ ‡/‡ ‡/‡ n/‡ ‡/n ‡/‡ ‡/‡ ‡/‡ ‡/‡ ‡/‡ ‡/. ‡/. ‡/. n/‡

‡/‡ ‡/‡ ‡/. ‡/‡ ‡/‡ n/‡ n/n ‡ /‡ ‡/‡ ‡/‡ ‡/‡ ‡ /‡ ‡ /‡ ‡ /‡ n/‡

60/M 42/M 68/. 80/M 58/M 72/M 67/M 58/M 85/F 54/M 70/F 64/M 85/F 47/F 40/M 45/F 39/M 57/F 73/M

60/F 81/M 42/F 77/M 56/M 63/M 62/F 66/M 47/M 74/M 72/M 72/M 30/F 31/F 72/M

Age/ sex

Bleeding time/ APTT

Decr Zero Zero . . Zero . Decr . . Decr Zero Decr Zero .

. . . . Zero Decr . Decr Zero Decr Zero Zero Decr Zero Decr . . . Zero

RIPA

18 12 37 28 29 25 . 13 12 24 29 2 12 6 40

20 6 10 9 9 17 36 8 14 40 8 20 14 8 7 3 6 1 13

FVIII (%)

16 8 7 22 8 11 . 8 510 18 16 8 10 55 33

. 4 55 53 6 510 25 0 . 32 5 55 25 510 15 6 6 6 3

VWF:Ag (%)

53 55 6 510 58 510 55 5

6 58 0 24 17 6

. . 55 . 53 . 26 0 0 20 55 55 0 510 0 6 6 6 0

WVF:RCof (%)

II II II II

II I II II II I

II

I I I II

II

. II

VWS type

. . . ÿ . . . . . ÿ . ÿ ÿ ÿ ‡

. . . . ÿ ‡ . ÿ ‡ . . . . . . . . . ‡

RIPA

ÿ ÿ ÿ ÿ ÿ . ÿ .

ÿ ‡ . ‡ ÿ ÿ

. . ‡ ‡ . . . ÿ ÿ ÿ .

ÿ

. . . . .

RCof

Inhibitor VWF

ÿ . . . IgM . IgG .

ÿ IgG . IgG . .

. . . . ÿ IgM IgG IgG IgG . IgG IgG . . . . . . IgG

Ig

Poor Poor Poor NT Poor Poor Poor NT

Poor NT NT Poor Decr Poor

NT NT . NT NT NT NT NT NT NT NT NT NT NT NT Poor Poor Poor Poor

DDAVP

Good Good NT NT Good Good Good Good

NT NT Good NT NT NT

NT NT . NT NT NT NT NT NT NT NT NT NT NT NT NT NT NT Good

Intravenous immunoglobulin

Response AVWS to

Poor NT NT Poor Poor Poor Poor Poor

NT Poor NT Poor NT Poor

NT Poor . Poor Poor Poor Poor NT Poor Poor Poor Poor Poor Poor Poor NT NT NT Poor

FVIII/ VWF

Table 4. Acquired von Willebrand syndrome (AVWS) in IgG benign monoclonal gammopathy, multiple myeloma, IgM benign monoclonal gammopathy, IgM WaldenstroÈm's disease, chronic lymphocytic leukaemia/non-Hodgkin's lymphoma without a paraprotein and rare cases with no underlying disorder.

410 J. J. Michiels et al

60/M 65/F 64/F 62/F 56/M 43/M 49/M 62/M 50/F 48/F 72/F 43/M 67/M

n/‡ ‡/‡ ‡/‡ ‡/‡ ‡/‡ ‡/. ./. ‡/. n/. n/. ‡ /n ‡ /n ‡/‡

Decr Zero Zero Decr . Decr Decr Decr . . Zero Zero Increased

30 14 14 30 15 6 10 8 31 19 165 120 8

5 9±36

18 22 13 26 10 28 7 32 27 12 370 121 5

0 3±16

9 510 3 53 2 5 4 9 34 6 150 127 10

0 56

‡/‡ ‡/‡

‡/. ‡/. ‡/‡ ./. ‡/‡ ‡/. n/. ‡/.

‡/‡ ‡/n ‡/‡

66/M 58/M

Chronic lymphocytic leukaemia (no paraprotein) Wautier et al (1976)86 68/F 72/M Mannucci et al (1984)56 67/F Goudemand et al (1988)62 50/M Uelinger et al (1991)87 88 75/M Brownlee and Shockley (1991) 64/F Mohri et al (1998)9 85/F 52/F

Non-Hodgkin's lymphoma (no paraprotein) 62/M Handin et al (1976)89 53/M Joist et al (1978)90 91 63/M Tran-Thangh et al (1985)

IgM WaldenstroÈm's disease Mazurier et al (1980)84 Silberstein et al (1987)85

Zero Zero Zero

Decr . . Zero . Decr Decr Decr

Decr .

14 45 20

52 13 45 8.5 26 15 24 9

27 13

10 55 52

15 51 30 0 80 36 22 22

10 51

13 55 6

8 54 12 . 0 12 9 7

53 54

66/M ‡/‡ Zero 25 21 . 60/M ‡/. . 15 17 6 69/M ‡ /‡ 69 150 520 69/F ‡ /. . 20 26 56 43/M ‡ /. . 30 37 56 Underlying mechanism primary ®brinolysys and proteolysis of von Willebrand factor, response to tranexamic acid

IgM benign monoclonal gammopathy Cass et al (1980)82 Mannucci et al (1984)56 Eikenboom et al (1992)83 Federici et al (1998)76

Mannucci et al (1984)56 Bovill et al (1986)79 Mohri et al (1987)80 Drouin et al (1989)81

IgG Multiple myeloma Horellou et al (1983)55 Sampson et al (1983)54 Takahashi et al (1986)77 Gross et al (1992)78 Mohri et al (1998)9

Van de Bosch et al (1998)75 76/M n/‡ . 8 cases ‡/. . Federici et al (1998)76 (8 cases: age/sex 43/F, 28/F, 57/F, 36/F, 66/M, 72/M, 56/M, 78/M)

.

. . .

. .

. ‡ ‡ ÿ ÿ

. .

II II

‡ ÿ .

. . II ÿ . (atypical AVWS)

II I II II II

IIB

II II II II II II I I I

I

. ÿ ‡

. ÿ ‡ . . ‡ ‡ ÿ

‡ ÿ

. ÿ . ÿ ÿ

. ‡ . . ÿ ‡ ‡ ‡ ÿ ÿ

. ÿ

Poor Poor

Good Good

IgG . .

IgA . Ig . .

IgG ÿ

ÿ ÿ

ÿ

NT NT NT

NT NT Poor NT ? ? NT NT

NT NT

NT Poor Poor Poor Poor

Poor Poor Poor

NT NT Poor Poor ? NT NT NT

NT NT

NT NT Poor Poor Poor

NT

Poor NT NT NT Poor NT NT NT NT NT

Poor Poor

Table continued over page

NT NT NT

NT NT NT NT Poor NT NT NT

Poor NT

NT NT No response No response No response

NT NT NT NT Poor NT Poor NT NT Good NT NT NT NT NT NT Poor NT Poor NT ‡ Acquired Bernard Soulier syndrome ‡ Acquired Bernard Soulier syndrome Good NT

. . . . .

. ÿ

Acquired von Willebrand syndromes 411

45/M

Typical AVWS Inbal et al (1997)98

‡/‡

125 ‡/n

‡/‡

Decr

68 Decr

.

12

66 200

6

39 8

1

12 16 29

FVIII (%)

90

54

41

4

50

54

31 55

5

55 11 17

VWF:Ag (%)

50

36

2

28

54

55 55

5

55 51 510

WVF:RCo (%)

II

II II II

VWS type

ÿ

.

.

. ‡

.

ÿ .

RIPA

25

10

7

II

ÿ

NT NT

NT

Poor NT

DDAVP

NT NT

NT

Good NT

Intravenous immunoglobulin

ÿ

IgG

Ig

NT

NT

NT

NT

NT

NT

Good

NT

ÿ

Poor

NT

Inhibitor against FVIIIc and VWF:RCof

‡ ˆ prolonged; ÿ ˆ negative; . ˆ unknown; decr ˆ decreased; n ˆ normal; NT ˆ not tested; BU ˆ Bethesda Unit. For abbreviations, see text.

Epstein±Barr virus infection 6/F ‡/. Decr Kinoshita et al (1991)102 Transient AVWS with spontaneous remission within 2 months

ÿ

‡

ÿ

. .

.

ÿ IgG

Ig

Response AVWS to

Precipitating antibodies against FVIII:Ag NT NT

`No antibody'

‡ ÿ

.

. ÿ

RCo

Inhibitor VWF

Graft versus host disease after bone marrow transplantation for acute myeloid leukaemia 41/M ‡/‡ . 51 56 2 III Lazarchik and Green (1994)101 Combined treatment with intravenous immunoglobulin prednisone followed by apheresis and FVIII/VWF concentrate was e€ective

12/M ‡/n . Nowak-GoÈttl et al (1995)100 Atypical AVWS: malignant peripheral neurectodermal tumour

Atypical AVWS 31/F ‡/‡ Decr 39 Richard et al (1984)99 Atypical AVWS: factor VIII inhibitor 3 BU and inhibitor against VWF:RCof Benign hydatid disease of the spleen, disappearance of AVWS after splenectomy

73/M

62/M

Woodlock et al (1988)97

Transient AVWS: follow-up

McGrath et al (1979)96

No underlying disorder, no paraprotein Typical AVWS

‡/‡ ‡/‡

Zero Zero

. . .

Zero

‡/. ‡/‡ n/‡

RIPA

Adenocarcinoma stomach, no paraprotein 76/M Holland et al (1980)95 74/M Sampson et al (1983)54

64/F 76/M 58/M

Bleeding time/ APTT

AVWS in disorders in which the association is coincidental Ehlers-Danlos syndrome, no paraprotein 72/M ‡/‡ Clough et al (1979)94

Ball et al (1987)92 Macik et al (1988)58 Rao et al (1988)93

Age/ sex

Table 4. Continued.

NT

Good

NT

Poor

Good

Poor

NT Poor

Poor

NT Poor

FVIII/ VWF

412 J. J. Michiels et al

Acquired von Willebrand syndromes 413 Table 5. Acquired von Willebrand syndrome and absorption of von Willebrand factor (VWF) on tumour cells in ®ve cases of lymphoproliferative disorder and one case of adrenocortical carcinoma. Brody et al (1979)104

Roussi et al (1980)105

Richard et al (1990)106

Facon et al (1992)107

Scrobohaci et al (1993)68

32 M

31 M

67 F

26 F

74 M

WaldenstroÈm disease

Hairy cell leukaemia

Multiple myeloma

Adrenal carcinoma

IgMlambda 57 g/l

?

IgA 15 g/l

no

Monoclonal Gammapathyof Undetermined Signi®cance (MGUS) IgGkappa 11 g/l

IgMkappa/lambda 9 g/l

Bleeding time Platelets RIPA Prothrombin time APTT

‡ ND NT ND ND

‡ 80 NT N ‡

n n Decreased N ‡

‡ 48 Decreased ND ‡

‡ n NT n ‡

ND ND NT ND ND

FVIIIc (%) VWF:Ag (%) VWF:RCof (%) AVWS MM VWF:RCof inhibitor Ig anti-WF Response to DDAVP FVIII/VWF Intravenous immunoglobulin Absorption of FVIII/ VWF on:

5 10 NT NT NT . NT NT NT

27 32 NT Type II Absent . NT Decreased NT

31 40 39 Type I Absent . Good* NT NT

31 36 32 Type II Absent . Poor NT NT

24 18 6 Type II Absent . Poor NT NT

28 56 512 Type II Absent . Poor Good* No response

Lymphocytes from blood and spleen

NT

Plasma cells

Adrenal tumour cells

Plasma cells

ÿ

ÿ

ÿ

ÿ

Splenectomy

Splenectomy

Cure

Cure

Melphalan/ prednisone Cure

Surgical resection Cure

Age M/F Underlying disorder

Paraprotein

Pathophysiology Treatment for malignancy Outcome of AVWS

Te€eri et al (1997)108 69 F Non-Hodgkin's lymphoma

Non-Hodgkin's lymphoma cells from blood and spleen Expression of glycoprotein on: Plasma cells Non-Hodgkin's lymphoma cells ND CHOP chemotherapy ND Cure

‡ ˆ increased or prolonged; n ˆ normal; ÿ ˆ ?????/; NT ˆ not tested; ND ˆ no data; . ˆ unknown; MGUS ˆ Monoclonal Gammapathy of Undetermined Signi®cance. * Response good but shortened half-lives of FVIII/VWF parameters. For abbreviations, see text.

with benign IgG monoclonal gammopathy (see Table 4 above). The response to intravenous DDAVP is also poor, reports as far back as 1984 showing similar ®ndings in at least 15 representative cases of AVWS associated with benign monoclonal gammopathy (see Table 4 above). A typical poor response to DDAVP in our case of AVWS and IgG benign monoclonal gammopathy is shown in Figure 1. Studies of the binding of an autoantibody to the factor VIII/VWF complex in AVWS associated with benign monoclonal gammopathy are scarce. In 1978, Zetterval and Nilsson50 studied a case of AVWS and IgG benign monoclonal gammopathy, with a poor response to factor VIII/VWF concentrate (KABI) and no inhibitory activity in vitro of the patient's plasma or puri®ed IgG against FVIIIC, VIII:Ag and VIIIVWF:RCo. In 1980, Gan et al51 studied a case of AVWS type II associated with IgG benign monoclonal gammopathy, a poor response to factor VIII/VWF concentrate and no inhibition of VWF:RCo in experiments mixing an equal volume of the patient's plasma and normal plasma. Zetterval and Nilsson50 and Gan et al51 demonstrated that the

414 J. J. Michiels et al

0.50 0.45 0.40

FVIII/VWF complex related activities after infusion of DDAVP (0.4 µg/kg b.w.) Ivy bleeding time >12´



>12´

>12´ FVIII:C

Activity (U/ml)

0.35

VWF:Ag

0.30 0.25

VWF:RCo

0.20

VWF:CBA

0.15 0.10 0.05 0.00

Before

15´

60´

120´

Time after infusion (minutes) Figure 1. E€ect of intravenous desmopressin (DDAVP) 0.3 mg/kg body weight on Ivy bleeding times and factor VIII/von Willebrand factor parameters in a case of acquired von Willebrand syndrome type II associated with IgG benign monoclonal gammopathy. For abbreviations, see text.

incubation of factor VIII/VWF concentrate with puri®ed IgG from patient plasma followed by protein A sepharose treatment resulted in the removal of FVIIIC, VWF:Ag, VWF:RCo and IgG, whereas the incubation of factor VIII/VWF concentrate with IgG from normal plasma following protein A sepharose treatment resulted in the removal of only IgG and not of the factor VIII and VWF species. Immune complexes were demonstrated in the mixture of patient IgG and factor VIII/VWF concentrate before treatment with protein A sepharose, these being absent after treatment with protein A sepharose. These experiments indicate that the patient's IgG binds tightly to factor VIII/VWF and that IgG bound to the factor VIII/VWF complex does not inhibit VWF:RCo. Zetterval and Nilsson50 and Gan et al51 postulated that monoclonal IgG and factor VIII/ VWF:Ag form complexes in vivo and that these are rapidly removed by the reticuloendothelial system. Gan et al51 also suggested that the larger immune complexes (IgG autoantibody±FVIII/VWF complexes) were preferentially cleared, leading to an abnormal factor VIII:Ag on two-dimensional crossed immunoelectrophoresis, indicating the loss of large VWF multimers (AVWS type II). In 1985, Fricke et al57 studied a typical case of AVWS and IgG benign monoclonal gammopathy with an inhibitor against VWF:RCo in mixing experiments. Their case showed a poor response to intravenous factor VIII/VWF concentrate and DDAVP.58 The treatment of patient plasma with protein A removed the VWF:RCo neutralizing activity, suggesting that a protein A±IgG antibody complex had been formed. The antibody-binding site lay in the VWF compound of the factor VIII/VWF complex. The antibody of the AVWS patient had a high-titre VWF-binding capacity and a weak inhibitory activity on VWF:RCo but no e€ect on VWF botrocetin or FVIIIC. Michiels and coworkers studied a typical case of AVWS type II and IgG benign monoclonal gammopathy with a poor response to DDAVP and factor VIII/VWF

Acquired von Willebrand syndromes 415

IgG

IgM VWF MM

2.6

VWF MM

HMW

IMW

Relative binding

2.0

LMW

HMW

Controls

1.0

LMW

0.2 0

0.05

0.1

Plasma dilution

0.2

0

0.05

0.1

0.2

Plasma dilution

Figure 2. Preferential binding of IgG immunoglobulin from patient plasma to immobilized high (HMW) and intermediate (IMW) molecular weight von Willebrand factor (VWF) multimers (MM) and no binding of IgM immunoglobulin to high and low (LMW) molecular weight VWF multimers compared with control plasma in a case of acquired von Willebrand syndrome type II associated with IgG benign monoclonal gammopathy. VWF multimers were isolated by sepharose 4B gel ®ltration of Haemate P and covalently linked to the wells of a microplate (Covalink, Nunc A/S, Roskilde, Denmark) according to the manufacturer's instructions. The binding of IgG and IgM immunoglobulins, after incubation with dilutions of patient and normal pooled plasma on immobilized VWF, was measured by Electro Immuno Assay (EIA), using horseradish peroxidase conjugate rabbit anti-human IgG and IgM immunoglobulins (Dako A/S, Roskilde, Denmark) respectively.

concentrate, and no inhibitory activity against VWF:RCo and VWF:CBA.73 The binding of IgG and IgM was measured by ELISA after the incubation of patient plasma and normal plasma on immobilized puri®ed large VWF multimers and the use of horseradish peroxidase conjugate rabbit anti-human IgG and IgM immunoglobulins. A non-neutralizing IgG anti-VWF antibody was demonstrated by preferential IgG binding and a lack of binding of IgM from the patient's plasma to puri®ed large VWF multimers.73 In a subsequent experiment, in which large, intermediate and small VWF multimers were separated and covalently linked to the wells of a microtitre plate, van Vliet demonstrated a preferential binding of the IgG antibody to large and intermediate VWF multimers (Figure 2). The successful use of high-dose intravenous immunoglobulin (1 g/kg body weight for 2 days or 0.4 g/kg for 5 days) in patients with AVWS and IgG benign monoclonal gammopathy has been well documented in several cases since 1988.58,66,73,103 In the ®rst patient with AVWS type II, IgG benign monoclonal gammopathy and a weak inhibitor against VWF:RCo, Fricke et al57 found a circulating IgG anti-VWF antibody bound to the factor VIII/VWF complex. This case responded poorly to DDAVP and factor VIII/ VWF concentrate, but an intravenous immunoglobulin infusion was followed by a

416 J. J. Michiels et al

correction of all factor VIII and VWF parameters for about 21 days, allowing multiple dental extractions to be safely carried out.58 Delannoy and Sailler61 reported a patient with AVWS and IgG benign monoclonal gammopathy in whom three courses of chemotherapy (cyclophosphamide, vincristine and prednisolone) were ine€ective but intravenous immunoglobulin (0.4 g/kg for 5 days) e€ectively corrected the factor VIII and VWF levels for about 20 days. One month later, a 1-day infusion of 0.4 g/kg immunoglobulin was without bene®cial e€ect. Seven courses of chemotherapy including melphalan, vincristine, cyclophosphamide and prednisolone over a 6 month period were ine€ective in a case of AVWS type II, IgG monoclonal gammopathy and a poor response to DDAVP and factor VII/VWF concentrate.64 Sailler et al74 documented that high-dose intravenous immunoglobulin (1 g/kg for 2 days) every 3 weeks in a case of AVWS type II and IgG benign monoclonal gammopathy resulted in the correction of the AVWS with peak levels of factor VIII/VWF above 100% and the lowest levels at 10±20%, whereas previous chemotherapy with four courses of melphalan and prednisolone was ine€ective. Castaman et al66 clearly documented a patient with AVWS type II, IgG benign monoclonal gammopathy, an inhibitor against VWF:RCo and a poor response to DDAVP and factor VIII/VWF concentrate (see Table 4 above). After intravenous immunoglobulin (1 g/kg body weight for 2 days), the factor VIII and VWF parameters were completely corrected, with a return to pre-infusion values after 15 days (Figure 3). A multimeric analysis of VWF showed a reappearance of all multimers 24 hours after immunoglobulin infusion and a progressive disappearance of the high and intermediate weight VWF multimers in the following 15±21 days. Twenty-four repeated courses with a single infusion of intravenous immunoglobulin (1 g/kg for 1 day) every 3±4 weeks proved similarly e€ective in improving the factor VIII and VWF levels, and the long-term relief of bleeding complications (Figure 4). Federici et al76 con®rmed that repeated doses of intravenous immunoglobulin 1 g/kg every 3 weeks are e€ective and that lower doses of 0.75 g/kg or 0.5 g/kg every 3 weeks are not e€ective in correcting the factor VIII and VWF parameters. It takes about 48 hours after the start of immunoglobulin infusion to reach normal levels of factor VIII and VWF because the rapid clearance of factor VIII/VWF is delayed and normalized immediately after high-dose immunoglobulin infusion.71±73,75,103 This o€ers the opportunity to treat severe or life-threatening bleeding by high-dose intravenous immunoglobulin (1 g/kg) followed by factor VIII/VWF substitution to obtain levels of factor VIII and VWF within a few hours sucient to control bleeding.75,103 AVWS and multiple myeloma Various variants of AVWS have been reported in multiple myeloma: AVWS type II in six cases9,54,55,77,78, type two in three cases9,56 and type IIB in 1 case81 (see Tables 4 and 5 above). Mixing patients' plasma with normal plasma demonstrated an inhibition of RIPA in two and no inhibition of RIPA in another two cases tested. Similar experiments showed an inhibition of VWF:RCo in four and no inhibition of VWF:RCo in three cases tested (see Table 4 above). A search for immunoglobulin binding to factor VIII/VWF complexes was not performed. The response to DDAVP was poor in four cases tested (see Table 4 above). The response to intravenous immunoglobulin was poor in one case and not tested in the other cases of AVWS associated with multiple myeloma. Normal values for APTT, factor VIII and VWF parameters, prolonged bleeding time, absence of RIPA and inhibition of RIPA in

Acquired von Willebrand syndromes 417

IG 1g/Kg/day 170

VWF:Ag

VIII/VWF Measurements (IU/dL)

VIII:C 120

RCo Bleeding time

100 80 60 40 20 0

17´

13´ 5´

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Days

Figure 3. E€ect of high-dose intravenous immunoglobulin (Ig; 1 g/kg body weight for 2 days) on Simplate bleeding times and factor VIII/von Willebrand factor parameters in a case of acquired von Willebrand syndrome type II associated with benign IgG monoclonal gammopathy, as described by Castaman et al. (Reproduced from Castaman et al 1992 American Journal of Hematology 41: 132±136) with permission. For abbreviations see text.

mixing experiments in two cases of multiple myeloma are consistent with an acquired Bernard Soulier syndrome.79.80 The two patients with acquired Bernard Soulier syndrome and the patient with AVWS type IIB responded to chemotherapy (see Table 4 above). AVWS and absorption of VWF on tumour cells AVWS resulting from an absorption onto tumour cells has been reported in six patients (see Table 5 above) with various lymphoproliferative disorders, including IgA multiple myeloma106, IgG kappa MGUS68, advanced WaldenstroÈm's macroglobulinaemia104, non-Hodgkins lymphoma with biclonal IgM kappa and lambda paraproteinaemia105, hairy cell leukaemia 105 and one case of adrenocortical carcinoma.107 These patients were all symptomatic and presented with a prolonged bleeding time and APTT, a decreased RIPA and mild-to-pronounced AVWS type II in four, type I in one and unspeci®ed in another patient (see Table 5 above). Inhibitor screening for VWF:Ag and VWF:RCo by incubating patient plasma or puri®ed paraprotein with pooled normal plasma was negative in ®ve patients and not tested in one (see Table 5 above). A search for immunoglobulin binding to factor VIII/VWF complex (nonneutralizing antibody) was not performed. Using speci®c immunohistochemical staining techniques, the presence of VWF on or inside the malignant cells was demonstrated in ®ve patients. Evidence for a selective

418 J. J. Michiels et al

IG(1g/Kg/day)IG

IG

IG

IG

VIII/VWF measurements (IU/dL)

100

VWF:Ag VIII:C RCo

80

60

40

20

0

0 First infusion

20

40

60 Days

80

0 20 24th infusion

Figure 4. Consistent response of repeated courses of high-dose intravenous immunoglobulin (Ig; 1 g/kg body weight for 1 day) on factor VIII/von Willebrand factor (VWF) parameters in a case of acquired von Willebrand syndrome type II associated with IgG benign monoclonal gammopathy, as described by Castaman et al. Courses of intravenous immunoglobulin 0.75 g/kg or less failed to correct factor VIII/VWF parameters.61,76 (Reproduced from Castaman et al 1992 American Journal of Hematology 41: 132±136) with permission. For abbreviations see text.

mechanism of VWF adsorption onto tumour cells was provided by an aberrant expression of glycoprotein Ib, a major platelet VWF receptor, on bone marrow plasma cells in one case68 with MGUS and on non-Hodgkins lymphoma cells from peripheral blood and spleen in another case108 (see Table 5 above). The response to DDAVP and high-dose intravenous immunoglobulin was poor in this case of AVWS and IgM nonHodgkin's lymphoma. The treatment of the underlying disorder, either by splenectomy, tumour resection or chemotherapy, uniformly resulted in the cure of AVWS in ®ve cases (see Table 5 above). AVWS and IgM monoclonal gammopathies AVWS associated with benign IgM monoclonal gammopathy has been reported in one occasional report82 and in three well-documented cases56,76,83 (see Table 4 above). High-dose intravenous immunoglobulin (1 g/kg for 2 days) failed to correct the factor VIII and VWF de®ciency in two cases of AVWS type II associated with IgM kappa benign monoclonal gammopathy with a poor response to DDAVP and factor VIII/VWF concentrate.76 Eikenboom et al83 described an unique case of AVWS type II and IgM monoclonal gammopathy with a poor response to DDAVP and factor VIII/VWF and no response to intravenous gammaglobulin. This patient displayed signs of increased primary ®brinolysis de®ned by the consumption of ®brinogen, plasminogen and alpha2-antiplasmin, and the presence of ®brinogen degradation products but no increase of

Acquired von Willebrand syndromes 419

®brin degradation products and a normal anti-thrombin level. Treatment with tranexamic acid resulted in the disappearance of the primary hyper®brinolysis and the AVWS type II. There are only three reports describing AVWS and WaldenstroÈm's macroglobulinaemia.84,85,104 The case reported by Brody et al104 (see Table 5 above) underwent plasmapheresis with an increase in his factor VIIIc level. Splenectomy was followed by a normalization of FVIIIC lasting for 7 months after surgery, after which the level slowly declined. In this case, there was a monomeric IgM expressed on the surface of the lymphocytes. Indirect immuno¯uorescence of the peripheral blood and splenic lymphocytes was positive after treatment with factor VIII antibody and ¯uoresceincoupled antibody to gammaglobulin. An inhibitor against VWF:RCo was found in Mazurier et al's case with AVWS type II and macroglobulinaemia.84 Serum fractionation showed that the inhibitor against VWF:RCo was independent of IgM, subsequent puri®cation demonstrating that the inhibitor was an IgG (see Table 4 above). Silberstein et al described a case with severe AVWS and macroglobulinaemia who did not respond to CHOP chemotherapy85 (see Table 4 above). AVWS in lymphoproliferative disorders without a paraprotein AVWS type II associated with lymphoproliferative disorders, and no paraprotein has been reported in seven cases with chronic lymphocytic leukaemia9,56,86±88 and six cases with non-Hodgkin's lymphoma89±93 (see Table 4 above). Combining the patient's plasma and normal plasma showed an inhibition of RIPA in one and no inhibition of RIPA in three cases tested, and an inhibition of VWF:RCo in four and no inhibition of VWF:RCo in four cases (see Table 4 above). In two cases, the antibody activity was located in the immunoglobulin and IgG fraction respectively (see Table 4 above). One patient with chronic lymphocytic leukaemia had an IgA antibody.86 The puri®ed IgA but not IgG or IgM was inhibitory in that the patient's plasma mixed with normal plasma inhibited platelet aggregation by ristocetin. However, the causal relationship between the IgA and AVWS remains elusive in this patient with chronic lymphocytic leukaemia. The response to DDAVP was documented as poor in one case and was not tested in seven. The response to factor VIII/VWF was documented as poor in ®ve cases and not tested in three. Data on the response to intravenous immunoglobulin are lacking in seven case reports on chronic lymphocytic leukaemia and non-Hodgkin's lymphoma with AVWS and no paraprotein, and documented only in two cases (see Table 4 above). AVWS of undetermined aetiology Ehlers±Danlos syndrome94 and adenocarcinoma of the stomach54,95 can be regarded as disorders in which the association with AVWS is coincidental (see Table 4 above). AVWS of unknown aetiology has been reported in seven cases96±102 (see Table 4 above). An inhibitor against RIPA or VWF:RCo may be absent or present in mixing studies, and an Ig antibody activity against VWF has been detected in a few cases (see Table 4 above). The response to DDAVP and intravenous immunoglobulin has not been tested in seven cases of AVWS of unknown aetiology except in one case described by Inbal et al.98 This patient, with typical AVWS and the presence of an antiVWF-binding IgG, responded poorly to factor VII/VWF and well to high-dose intravenous immunoglobulin for 55±60 days after each immunoglobulin infusion (see Table 4 above).

420 J. J. Michiels et al

AVWS and shear stress of ¯owing blood Recent studies have shown that a high shear rate of ¯owing blood may promote the proteolysis of large VWF multimers in plasma.109 The mechanical destruction of these multimers may be of relevance in conditions in which the shear rate of ¯owing blood is increased. This may occur in cases of aortic stenosis and other heart valve defects or stenosed vessels.110±114 Benson et al115 described the occurrence of AVWS in six young anaemic patients aged 14±21 with haemoglobin E-beta0-thalassaemia. Four patients were asymptomatic, and epistaxis was present in two. The abnormal feature in all patients was a qualitative loss of high molecular weight VWF multimers on crossed immuno-electrophoresis. The bleeding time was prolonged and the VWF parameters slightly decreased in three cases. The bleeding time and VWF parameters were normal in the other three patients. The authors speculate that there may be a proteolysis of VWF through high cardiac output shear stress in these anaemic patients. In diabetes mellitus with inadequate glycaemic control, VWF abnormalities have been reported116, probably as a consequence of vascular endothelial cell damage and the aberrant glycosylation of VWF, which may result in an increased susceptibility to the proteolytic degradation of VWF in the plasma.117 Acquired functional VWF de®ciency with increasing platelet count in myeloproliferative thrombocythaemia and reactive thrombocytosis The values of the functional VWF:RCo are decreased and inversely related to increased platelet counts in patients with essential thrombocythaemia, polycythaemia vera and reactive thrombocytosis (Table 6). The absolute values of VWF:Ag level usually, however, remain normal, which results in a decreased ratio of VWF:RCo to VWF:Ag (Table 6). In chronic myeloid leukaemia with slight thrombocytosis, the VWF values were signi®cantly higher in one study122 but much lower in another study9 compared with the VWF values in thrombocythaemia arising from various myeloproliferative disorders (Table 6). The selective decrease of VWF:RCo in thrombocythaemia related to myeloproliferative disorders is caused by loss of large VWF multimers in essential thrombocythaemia, polycythaemia vera and reactive thrombocytosis.8,42±44,121,127,128 The relative content of large VWF multimers in essential thrombocythaemia was positively related to the VWF:RCo to VWF:Ag ratio and inversely related to the platelet count.8,42,44 Intravenous DDAVP induced a signi®cant increase in VWF:RCo level with a reappearance of large VWF multimers, followed by a rapid clearance of the largest VWF multimers with shortened half-lives for VWF:RCo and VWF:CBA128,129 (Figure 5). Using high-resolution gels, a transient increase in the number of satellite bands for each multimer was noted a few hours after DDAVP, indicating a proteolysis of VWF comparable to that seen in VWD types IIa and IIb.119,120,128 The proteolysis of VWF in thrombocythaemia patients was demonstrated by the presence of the 176 kDa and 140 kDa degradation products in increased proportions compared with the intact 225 kDa VWF bands in the gel electrophoresis of reduced VWF.128,129 As shown in Figure 6 thrombotic manifestations in thrombocythaemia already occur at platelet counts in excess of 400  109/l (see references 131±134). Microcirculatory thrombotic complications in thrombocythaemia are relieved by the reduction of the platelet count to normal (5350  109/l) or the control of platelet function with low-dose aspirin.43,131±136 Thrombocythaemia with a platelet count in excess of

Acquired von Willebrand syndromes 421

U/ml 4.00

VWF parameters T ½ hours (hrs)

3.00 VWF:Ag 12.5 hrs 2.00

VWF:RCo 7.3 hrs

1.00

0.50

VWF:CBA 3.0 hrs

0

1

2

3

4

5

6

hours after DDAVP i.v.

Figure 5. Response to intravenous desmopressin (DDAVP) 0.3 mg/kg on von Willebrand factor (VWF) parameters showing a pronounced shortened half-life time for VWF:CBA, a shortened half-life for VWF:RCo) and a normal half-life time for VWF:Ag in a case of haemorrhagic thrombocythaemia at the time of a very high platelet count of 3850  109/l.

1000  109/l is frequently associated with the paradoxical occurrence of thrombosis and bleeding.43,132,133,137 Mucocutaneous bleeding occurs spontaneously with an increasing platelet count far in excess of 1000  109/l and usually disappears or improves after the reduction of the platelet count to below 1000  109/l (see references 137, 138). Haemorrhagic thrombocythaemia is de®ned as a clinical syndrome of recurrent bleeding from the mucous membranes of the gums, nose and digestive tract, bruises and secondary haemorrhages associated with a very high platelet count.137,138 The haemorrhagic manifestations reported in these studies included gastrointestinal bleeding as the major bleeding diathesis, followed by mucocutaneous haemorrhage and excessive bleeding during and following surgery. Gastrointestinal bleeding usually occurred as melaena and/or haematemesis. Severe bleeding was usually seen after tooth extraction or surgery. Nose-bleeds were usually profuse and frequently relapsed. Skin bleeding was recorded as easy bruisability, subcutaneous haemorrhage,

HT cases Leupin et al (1983)123 Case 1 Budde et al (1984)124 Case 2 Before splenectomy

Mohri et al (1998)9

Van Genderen et al (1996)43

Castaman et al (1995)122

Mohri (1987)119 Lopez-Fernandez et al (1987)120 Tatewaki et al (1988)121

Fabris et al (1987)118

Bleeding time (minutes) 415 5 6

47/F

27/M

10 13 10 8 15 12 10 11 8 36 26 3 3 8

Number of patients

Age/Sex

PV ET PV ET/PV PV ET PV ET CML ET RT ET PV CML

Diagnosis

498 716

1924

1111 + 990 1296 + 626 472 (181±780) 1542 (600±2760) 738 + 607 1143 + 551 568 + 299 997 + 114 334 + 108 750 (401±3110) 746 (401±2329) 1243 (1205±1301) 694 (607±780) 496 (219±847)

Platelets (109/l)

110 130

60

97 + 25 108 + 32 114 + 30 165 (79±240) 118 + 28 170 + 87 167 + 74 138 + 31 248 + 27 110 (67±326) 219 (57±486) 66 96 (60±121) 47 (27±68)

VWF:Ag (%)

95 57

2.5

68 + 19 60 + 39 56 + 25 110 (56±259) 100 + 30 117 + 48 103 + 47 85 + 27 157 + 17 92 (10±161) 188 (38±386) 38 27 (20±40) 25 (22±40)

VWF:RCof (%)

0.86 0.44

0.04

0.70 0.56 0.49 0.68 0.84 0.66 0.66 0.61 0.64 0.75 0.85 0.58 0.28 0.53

Ratio VWF:RCof to VWF:Ag

ÿ ÿ

‡‡

Bleeding symptoms

Table 6. von Willebrand disease (VWF) parameters in the thrombocythaemia of various myeloproliferative disorders ± essential thrombocythaemia (ET), polycythaemia vera (PV), chronic myeloid leukaemia (CML) ± and in nine cases of haemorrhagic thrombocythaemia (HT).

422 J. J. Michiels et al

40 F

42 F

Murakawa et al (1992)126 Case 8

Van Genderen et al (1994)127 Case 9

‡‡ ˆ present; ÿ ˆ absent at time of investigation. For abbreviations, see text.

33 F 45 F

62/M

22/F

Raman et al (1987)125 Case 6 Case 7

Case 5

Fabris et al (1987)118 Case 4 After chemotherapy

After busulphan

Case 3 Post-splenectomy

After busulphan

After splenectomy

415

9

3700

1926

1285 1548

3500 1300 300 2900

2571 2260 507

415

10

5860 5000 1005 1057

415 415 2.30

146

92

77 ÿ

110 120 120 86

76 105 190

90 110 140 80

46

37

9 8

37 50 118 24

10 33 133

9 14 86 49

0.35

0.40

0.12

0.34 0.42 0.98 0.28

0.13 0.31 0.70

0.10 0.13 0.61 0.61

±

‡‡

ÿ

‡‡ ‡‡

‡‡ ÿ ÿ ‡‡

‡‡ ‡‡ ÿ

‡‡ ‡‡ ÿ ÿ

Acquired von Willebrand syndromes 423

424 J. J. Michiels et al

ETT

Platelet

ETT + HT

counts × 109/l: 0

HT 350 500 400

1000

1500

2000

3000

ETT HT ASPIRIN Hydroxyurea ~ Anagrelide ~ Interferon a2b

ETT: Erythromelalgic Thrombotic Thrombocythaemia HT: Haemorrhagic Thrombocythaemia Figure 6. The Rotterdam concept of clinical and laboratory ®ndings in erythromelalgic thrombotic thrombocythaemia (ETT) and haemorrhagic thrombocythaemia (HT). High shear stress-induced endarterial microvascular circulation disturbances and thrombotic events in thrombocythaemia, including erythromelalgia, atypical and typical cerebral and ocular transient ischaemic attacks and acute coronary syndromes (ETT), already occur at platelet counts in excess of 400  109/l and usually respond to low-dose aspirin. Lowdose aspirin is highly e€ective and safe in the cure and prevention of thrombotic and ischaemic events and does not elicit bleeding at a platelet count of below 1000  109/l (ETT). Spontaneous haemorrhage usually occurs at very high platelet counts far in excess of 1500  109/l (HT). At platelet counts of between 1000 and 2000  109/l, thrombosis and bleeding (ETT and HT) frequently occur in sequence or paradoxically, and lowdose aspirin prevents thrombotic complications but aggravates or may elicit bleeding symptoms. The reduction of the platelet count in HT patients to below 1000  109/l by platelet-lowering agents usually results in the disappearance of the bleeding tendency, but the thrombotic tendency persists as long as the platelet count is above the upper limit of normal of 350  109/l.

ecchymosis and bleeding under the conjunctiva. Petechiae were never reported. This spectrum of bleeding symptoms closely resembles the haemorrhagic manifestations of von Willebrand disease. Iron de®ciency anaemia and splenomegaly were frequently present. The mean platelet counts in the 100 patients from the literature with haemorrhagic thrombocythaemia were 2050 + 1107  109/1 (see reference 137). The laboratory ®ndings of AVWS with spontaneous bleeding symptoms at the time of investigation in nine reported cases of haemorrhagic thrombocythaemia (see Table 6 above) are characterized by a very high platelet count, usually in excess of 1500± 2000  109/l, a prolonged bleeding time, normal values for prothrombin time, APTT, FVIIIC and VWF:Ag, and a selective de®ciency of VWF:RCo. Multimeric analysis of VWF multimers reveals the absence of large and intermediate VWF multimers, simulating a type II von Willebrand disease.118,127,128 The response to DDAVP is good,

Acquired von Willebrand syndromes 425

2.0

Activity (U/ml)

VWF:RCo VWF:Coll

1.0

0.6

0

0

1000

2000

3000

4000

Platelets × 109/l Figure 7. Intrapatient relationship between platelet count and the functional VWF parameters of ristocetin co-factor activity (VWF:RCo) and VWF collagen-binding activity (VWF:Coll) in a case of haemorrhagic thrombocythaemia described by Van Genderen et al.127 The reduction of platelet count with hydroxyurea resulted in a normalization of the platelet count and VWF parameters together with the disappearance of the bleeding tendency. Subsequent discontinuation of the hydroxyurea treatment resulted in a progressive increase in platelet count, a decrease in the functional VWF parameters and a reappearance of bleeding symptoms at platelet counts in excess of 2000  109/l.

with a normal half-life for VWF:Ag and a shortened half-life for VWF:RCo and VWF:CBA, because of the proteolysis of VWF (see Figure 6 above). The severity of functional VWF de®ciency is causally related to the increasing platelet count. In our case, we prospectively studied plasma VWF parameters in relation to platelet count. A reduction of platelet count with hydroxyurea resulted in the disappearance of the bleeding symptoms. After discontinuation of the hydroxyurea, bleeding became apparent at a platelet count in excess of 2000  109/l, and the platelet count rose again to values of between 3500 and 4000  109/l. The intrapatient relationships between platelet count and either VWF:RCo or VWF:CBA are shown in Figure 7). The cytoreduction of the platelet count to about 1000  109/l was associated with a disappearance of bleeding symptoms, an improvement of VWF:RCo to low-normal levels (see Table 6 above) and a reappearance of the intermediate and some of the large VWF multimers.118,127,128 The correction of the platelet count to normal is associated with a complete correction of the VWF multimeric pattern and a correction of all VWF-parameters to normal values.127±129

Drug-induced AVWS In 1970, Veltkamp et al139 observed a case of acquired bleeding disorder 5 days after the suicidal intake of a pesticide (lindane, pyretrum, acetone, kerosine) that showed a prolonged bleeding time, a FVIIIC level of 3% and a poor response to factor VIII concentrate very suggestive for AVWS.

426 J. J. Michiels et al

Kreuz et al140 observed an acquired history of mild mucocutaneous bleeding in 23 out of 85 children who were receiving continuous anti-convulsant treatment with valproic acid 20±30 mg/kg. The AVWS was characterized by mild FVIIIC, VWF:Ag and VWF:RCo de®ciency and type 1 AVWS on the multimeric analysis of VWF. In no case of bleeding did the anti-convulsant treatment with valproic acid have to be interrupted. Patients on continuous valproic acid should be tested for AVWS in case surgery is required or bleeding is present. Kreuz et al observed one instance of convulsion during DDAVP treatment, which should, therefore, be avoided. Conrad and Latour141 reported AVWS in a 51-year-old man who developed bleeding while receiving griseofulvin therapy for skin dermatitis for 2 months. AVWS was featured by prolonged bleeding and APTT times as a result of a severe FVIIIC (10%) and VWF:Ag (8%) de®ciency, no inhibitor against FVIIIC or VWF, no paraprotein and normal thyroid function. The AVWS abated within a few days after discontinuation of the griseofulvin therapy. Castaman et al142 analysed two cases of transient AVWS associated with the use of cipro¯oxacin in the absence of an inhibitor against factor VIII or VWF and no evidence of an underlying disorder. The AVWS demonstrated a prolonged bleeding time and APTT, FVIIIC and VWF de®ciency with a decreased ratio of VWF:RCo to VWF:Ag, to less than 0.4, and type II AVWS on multimeric analysis of the VWF. The subunit composition of the plasma VWF showed a marked reduction in the native 225 kDa VWF subunit and an increase in the 189, 176 and 140 kDa fragments, consistent with enhanced proteolysis of the VWF. The AVWS disappeared spontaneously, without any speci®c therapy, over a 5 month period after discontinuing the cipro¯oxacin. The aetiology underlying AVWS after the repeated administration of hydroxyethyl starch is a precipitation of the factor VIII/VWF complex.143±148 Hydroxyethyl starch, with a large in vivo molecular weight and a prolonged volume-expanding e€ect, has the disadvantage of causing bleeding as a result of severe factor VIII/VWF de®ciency if large volumes need to be administered for a prolonged period of time.148 To prevent bleeding complications, a starch solution with a low in vivo molecular weight should be used to prevent factor VIII/VWF de®ciency.148 RECOMMENDATIONS FOR THE DIAGNOSIS, CLASSIFICATION AND TREATMENT OF AVWS The classi®cation, diagnosis and pathophysiology of AVWS, and its treatment options in view of its association with the various underlying disorders reported in this chapter, are shown in Table 7. When a patient with one of the underlying disorders develops mucocutaneous bleeding, AVWS should be suspected. The bleeding time and APTT are very useful for diagnostic screening purposes to detect clinically relevant and overt cases of AVWS. Multimer analysis of the VWF by an expert haemostasis and thrombosis research laboratory is recommended to distinguish clearly between type I and type II AVWS. A prolonged classical bleeding time or in vitro platelet function analysis test and a normal platelet count but decreased or absent RIPA in combination with a prolonged APPT and normal prothrombin time suggest a combined defect of primary haemostasis and intrinsic coagulation. The combined de®ciency of both factor VIII and VWF parameters is indicative of AVWS associated with the various underlying disorders, except thrombocythaemia.43,103. AVWS associated with thrombocythaemia in various myeloproliferative disorders or reactive thrombocytosis is featured by a

Acquired von Willebrand syndromes 427

prolonged bleeding time, a normal APTT, normal values for factor VIII and VWF:Ag, and decreased levels of the functional VWF parameters VWF:RCo and VWF:CBA.103,127,129 AVWS type 1 associated with hypothyroidism is usually mild, responds to DDAVP with a normal half-life for factor VIII and VWF parameters and disappears after treatment with 1-thyroxine without the need to search for an inhibitor against the VWF. AVWS type I or III occurs in a minority of patients with Wilms' tumour in the complete absence of an inhibitor against VWF:Ag or VWF:RCo and no absorption of factor VIII or VWF onto the nephroblastoma cells. Paediatricians should be aware that the nephroblastoma cells of the Wilms' tumour may produce hyaluronic acid, which may be a causative factor in atypical AVWS characterized by a very low or undetectable VWF:Ag level and somewhat higher but still de®cient levels of factor VIII and VWF:RCo. In AVWS type II associated with thrombocythaemia in various myeloproliferative disorders, the proteolysis of large VWF multimers appears to be a platelet-dependent event given the inverse relationship between platelet count and large VWF multimers in plasma and speci®c increases in proteolytic VWF fragments in the plasma.8 A cytoreduction of the increased platelet count to normal results in an abatement of proteolysis, a complete restoration of the VWF multimeric pattern and a correction of all VWF parameters to normal.43,127 AVWS associated with systemic lupus erythematosus or IgG benign monoclonal gammopathy is usually type II, which is consistent with the laboratory ®ndings characterized by a prolonged bleeding time and APTT, decreased or absent RIPA and low to very low levels of FVIIIC (mean 15%), VWF:Ag (mean 5 10.7%) and VWF:RCo (mean 5 6.2%), consistent with AVWS. The poor response to DDAVP is caused by a rapid immune-mediated clearance of the factor VIII/VWF complex and therefore predicts a poor response to and clinical inecacy of factor VIII/VWF substitution for the prevention and treatment of bleeding.58,66,70,71,103 A search for anti-VWF antibodies is recommended when AVWS is associated with autoimmune disease (especially systemic lupus erythematosus), benign monoclonal gammopathies, lymphoproliferative disorders and rare cases with a solid tumour or no detectable underlying disorder. The presence or absence of neutralizing antibodies can easily be ascertained by measuring the inhibition of VWF:RCo or RIPA in mixing experiments of patient plasma and normal plasma. Such experiments have several drawbacks.1 First, they usually fail to detect low-titre anti-VWF antibodies whereas these antibodies may still be of clinical relevance to VWF function in vivo. Second, mixing experiments identify only those inhibitors which lead to an inactivation of the functional domains of VWF (neutralizing antibodies) but fail to detect non-neutralizing antibodies. Third, neutralizing anti-VWF antibodies can not explain the rapid clearance of the factor VIII/VWF complex. We therefore recommend an ELISA technique that measures the binding of IgG and IgM anti-VWF antibodies from patient plasma to surface-bound puri®ed VWF73,103 (see Figure 2 above). Anti-VWF autoantibodies, usually IgG, are present in patient plasma either free or tightly bound to the intermediate and high molecular weight factor VIII/VWF particles and this IgG-autoantibody±FVIII/VWF-antigen complex is rapidly cleared from the circulation, resulting in low levels of factor VIII and VWF. As the IgG monoclonal protein acts as an anti-VWF autoantibody, the clinical picture, laboratory features, aetiology and response to treatment of AVWS in systemic lupus erythematosus and IgG benign monoclonal gammopathy are identical. These data can readily explain the poor response to DDAVP and factor VIII/VWF concentrate and the e€ectiveness of

N

19

10

9

11

44

8

4

1

1 1 1

AVWS/disorder

Hypothyroidism

Wilms' tumour

Thrombocythaemia in myeloproliferative disorders

Systemic lupus erythematosus

IgG BMG

IgG myeloma

IgM BMG

IgM BMG

Absorption FVIII/VWF on tumour cells IgM non-Hodgkin's lymphoma MGUS MM

II II I

II

II

II

II

II

II

I/III

I

AVWS type

28 24 31

69

22

20.6 (14±30)

15.3 (1±40)

13.2 (4±42)

Normal

18 (5±37)

48 (18±80)b

a

FVIIIc (%)

56 18 40

150

27

17.8 (10±26)

510.7 (0±25)

14.4 (4±39)

104 (60±146)

6.5 (1±25)

33 (17±49)

VWF:Ag (%)

512 6 39

20

6

5 5.4 (2± 5 10)

5 6.2 (0±24)

14.3 (1±23)

20 ( 3±46)

24 (5±46)

37 (17±55)

VWF:RCo (%)

Glycoprotein Ib expression Glycoprotein Ib expression NT

Proteolysis of VWF Primary ®brinolysis

Mechanism? Clearance? or proteolysis of VWF?

Autoantibody clearance VWF/FVIII complex

Autoantibody clearance VWF/FVIII complex

Autoantibody clearance VWF/FVIII complex

VWF proteolysis due to increased platelet count

Hyaluronic acid VWF absorption?

Decreased synthesis

Mechanism

Poor Poor NT

Poor

Poor

Poor

Poor

Poor

Good

NT

Good

Poor NT NT

Poor

Poor

Good

Good

Good

No

NT (no?)

No

Response to: DDAVP/intravenous immunoglobulin

Chemotherapy ? Chemotherapy

Tranexamic acid

Untreatable

Intravenous immunoglobulin e€ective/chemotherapy?

Intravenous immunoglobulin e€ective/chemotherapy ine€ective

Prednisone/intravenous immunoglobulin e€ective

Platelet reduction

Chemotherapy/tumour resection

Thyroxine

Treatment 1st/2nd option

Table 7. Classi®cation, diagnosis and pathophysiology of acquired von Willebrand syndrome (AVWS) and treatment options in view of its association with various underlying disorders.

428 J. J. Michiels et al

2

II?

ABSS

2 20

8 29 (19±31) Normal

13.2 (1±39)

25.9 (9±52)

22

brange.

5

5 26 (12±14) Normal

9.8 (4±31)

11 (0±15)

27

3,5

10 26 (6±39) Normal

5 4.2 (2±5)

58 (0±13)

18

Various mechanisms

Platelet glycoprotein Ib inhibition? NT

NT NT

NT Anti-VWF antibody? Absorption of VWF? Autoantibody?

NT

NT

Poor

Good NT

Poor?

NT

Poor

NT

NT

NT NT

Good?

NT

NT

Discontinuation of drug

Chemotherapy

Chemotherapy

Chemotherapy Chemotherapy

Intravenous immunoglobulin e€ective in 1, NT in 4

Intravenous immunoglobulin chemotherapy

Chemotherapy Splenectomy Tumour resection

value; ABSS ˆ acquired Bernard Soulier syndrome; NT ˆ not tested; BMG ˆ Benign Monoclonal Gammapathy; HCL ˆ Hairy Cell Leukemia; MGUS ˆ Monoclonal Gammapathy of Undetermined Signi®cance; MM ˆ Multiple Myeloma; Myelome ˆ Myeloma; WD ˆ WaldenstroÈm Disease.

aMean

Drug-induced AVWS: valproic acid, cipro¯oxacin, hydroxyethyl starch, etc.

IgM WD

IIB I

1 3

II

6

Atypical AVWS Myeloma

II

13

Chronic lymphocytic leukaemia/ non-Hodgkin's lymphoma no paraprotein No underlying disorder

II

4

WaldenstroÈm's disease, HCL, multiple myeloma and adrenocortical carcinoma

Acquired von Willebrand syndromes 429

430 J. J. Michiels et al

high-dose intravenous immunoglobulin in AVWS associated with systemic lupus erythematosus and IgG benign monoclonal gammopathy. High-dose intravenous immunoglobulin is thought to exert its action by blocking the Fc-receptors on the reticuloendothelial system, thereby preventing the clearance of autoantibody±VWF/FVIII complexes from the circulation. Others believe that highdose intravenous immunoglobulin contains anti-idioptypic antibodies because of its polyspeci®city. As is the case in other autoimmune disorders, prednisolone has proved to be e€ective in AVWS associated with systemic lupus erythematosus. Prednisolone and chemotherapy will not a€ect AVWS associated with IgG benign monoclonal gammopathy because the monoclonal IgG protein persists to act as an anti-VWF autoantibody. In contrast to IgG autoimmune haemolytic anaemia, IgM autoantibodies in cold agglutinin syndrome associated with IgM benign monoclonal gammopathy employ a complement-mediated mechanism to lyse red cells and therefore do not respond to prednisolone and intravenous immunoglobulin. In this respect, the observation that primary ®brinolysis and VWF proteolysis in a case of IgM monoclonal gammopathy responded to tranexamic acid but not to intravenous immunoglobulin is a unique observation in nature83 and may be of great importance when considering the possible explanation for the observed non-responsiveness to intravenous immunoglobulin in two cases of IgM benign gammopathy.76 The absorption of VWF onto malignant cells has been suggested as another mechanism, which is assumed to result in a depletion of VWF in a few patients with various lymphoproliferative disorders or adrenal carcinoma (see Table 5 above). An additional autoimmune mechanism may, however, be operative in these patients. Therefore, a search for an anti-VWF antibody by an ELISA technique is recommended. Evidence for a highly selective mechanism of VWF absorption has been provided by the demonstration of an aberrant expression of glycoprotein Ib, a major platelet VWF receptor, on tumour cells (see Table 5 above). The clinical picture and laboratory features of AVWS, mainly type II, associated with early-stage IgG multiple myeloma, chronic lymphocytic leukaemia or non-Hodgkin's lymphoma without a paraprotein and with no detectable underlying disorder are similar to those of AVWS type II associated with IgG benign monoclonal gammopathy. Prospective co-operative studies and proper documentation using relevant techniques are needed to elucidate the true nature of its autoimmune aetiology. Atypical variants of AVWS have been reported in association with advanced multiple myeloma and WaldenstroÈm's disease (see Tables 4 and 5 above), chronic lymphocytic leukaemia, malignant peripheral neurectodermal tumour and some cases with no underlying disorder (see Table 4 above). Transient AVWS type II has been observed in a case of Epstein±Barr virus infection and a case with no underlying disorder (see Table 4 above). The mechanical destruction of large VWF multimers may be of relevance in conditions in which the shear rate of ¯owing blood is increased, as may occur in cases of aortic stenosis, other heart valve defects and stenosed vessels. Drug-induced AVWS has been described in association with the use of pesticides, valproic acid, cipro¯oxacin, griseofulvin, tetracycline, thrombolytic agents and hydroxyethyl starch.

Acknowledgements The technical assistance of Hans van Daele and Jack van Geel during so many years of clinical research in the University Blood Coagulation Laboratory of Rotterdam is highly appreciated.

Acquired von Willebrand syndromes 431

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* *

* *

*

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