Download PDF
Semin Thromb Hemost 2022; 48(08): 911-925
DOI: 10.1055/s-0042-1749088
Review Article

A Review of Autoimmune Acquired von Willebrand Factor Deficiency in Japan

Akitada Ichinose
1   Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata, Japan
2   The Japanese Collaborative Research Group (JCRG) on Autoimmune Acquired Coagulation Factor Deficiencies supported by the Japanese Ministry of Health, Labor and Welfare (MHLW), Yamagata, Japan
,
Tsukasa Osaki
1   Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata, Japan
2   The Japanese Collaborative Research Group (JCRG) on Autoimmune Acquired Coagulation Factor Deficiencies supported by the Japanese Ministry of Health, Labor and Welfare (MHLW), Yamagata, Japan
3   Department of Public Health and Hygiene, Yamagata University Graduate School of Medical Science, Iida-Nishi, Yamagata, Japan
,
Masayoshi Souri
1   Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata, Japan
2   The Japanese Collaborative Research Group (JCRG) on Autoimmune Acquired Coagulation Factor Deficiencies supported by the Japanese Ministry of Health, Labor and Welfare (MHLW), Yamagata, Japan
3   Department of Public Health and Hygiene, Yamagata University Graduate School of Medical Science, Iida-Nishi, Yamagata, Japan
,
Emmanuel J. Favaloro 
4   Department of Haematology, Sydney Centres for Thrombosis and Haemostasis, Institute of Clinical Pathology and Medical Research (ICPMR), NSW Health Pathology, Westmead, New South Wales, Australia
5   Faculty of Science and Health, Charles Sturt University, Wagga Wagga, New South Wales, Australia
› Author Affiliations Funding This study was supported in part by research aids to A.I. from the Japanese Ministry of Health, Labor, and Welfare (21FC1008).
› Further Information
    Permissions and Reprints

Abstract

von Willebrand factor (VWF) forms high-molecular-weight multimers and plays an essential role in hemostasis, and thus its deficiency leads to bleeding symptoms. Acquired von Willebrand syndrome (AVWS) is rare, but potentially underdiagnosed, and develops in various underlying disorders. AVWS caused by anti-VWF autoantibodies is a rare subcategory of AVWS that can also be referred to as autoimmune VWF deficiency (AiVWFD). We performed a search of patients with autoimmune coagulation factor deficiencies in our nationwide survey in Japan. Among these, suspected cases of AiVWFD were extremely few, with only 11 case consultations in the last 10 years. Of these, three and five were respectively positive for anti-VWF autoantibodies (anti-VWF-Ab) and VWF inhibitor (VWF-inh). We also performed an extensive literature search of other cases from Japan, and in total, 40 cases were finally identified to have AiVWFD, with mean age of 55.0 years. Most underlying disorders were lympho- or myeloproliferative diseases, followed by autoimmune diseases. The major bleeding sites were subcutaneous and mucosal, the bleeding severity was moderate, and there were no hemorrhagic deaths. Bleeding time was prolonged; factor VIII activity, VWF antigen, and VWF activity were decreased, and high-molecular-weight VWF multimers were absent or decreased. These are similar to the common abnormal laboratory findings observed among general AVWS cases. Hemostatic therapy often involved VWF concentrates and vasopressin, and antibody eradication therapy often included corticosteroids and achieved remission. Notably, of all cases, 68% had anti-VWF-Abs, and 83% of anti-VWF-Ab-positive patients were also VWF-inh positive. To accumulate precise clinical information on AiVWFD, it is necessary to verify and improve the measurement methods for both anti-VWF-Ab and anti-VWF-inh. These findings from Japan should be confirmed in other geographic localities.

Keywords

von Willebrand factor - deficiency - inhibitor - autoantibody - neutralizing antibody - nonneutralizing antibody - lymphoproliferative disease

Authors' Contributions

A.I. initiated and designed the study, extracted data, wrote, edited, and proofread the manuscript. T.O. conducted experimental examinations, statistical analyses, and proofread the manuscript. M.S. performed experimental examinations, and proofread the manuscript. E.J.F. inspired the study, and critically edited the manuscript.


Supplementary Material



Publication History

Article published online:
08 July 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 1998; 67: 395-424
    CrossrefPubMedSearch in Google Scholar
  • 2 Stockschlaeder M, Schneppenheim R, Budde U. Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis. Blood Coagul Fibrinolysis 2014; 25 (03) 206-216
    CrossrefPubMedSearch in Google Scholar
  • 3 Lenting PJ, Christophe OD, Denis CV. von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. Blood 2015; 125 (13) 2019-2028
    CrossrefPubMedSearch in Google Scholar
  • 4 Michiels JJ, Budde U, van der Planken M, van Vliet HH, Schroyens W, Berneman Z. Acquired von Willebrand syndromes: clinical features, aetiology, pathophysiology, classification and management. Best Pract Res Clin Haematol 2001; 14 (02) 401-436
    CrossrefPubMedSearch in Google Scholar
  • 5 Tiede A, Rand JH, Budde U, Ganser A, Federici AB. How I treat the acquired von Willebrand syndrome. Blood 2011; 117 (25) 6777-6785
    CrossrefPubMedSearch in Google Scholar
  • 6 Federici AB. Acquired von Willebrand syndrome: is it an extremely rare disorder or do we see only the tip of the iceberg?. J Thromb Haemost 2008; 6 (04) 565-568
    CrossrefPubMedSearch in Google Scholar
  • 7 Federici AB, Budde U, Castaman G, Rand JH, Tiede A. Current diagnostic and therapeutic approaches to patients with acquired von Willebrand syndrome: a 2013 update. Semin Thromb Hemost 2013; 39 (02) 191-201
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Favaloro EJ. Von Willebrand disease: local diagnosis and management of a globally distributed bleeding disorder. Semin Thromb Hemost 2011; 37 (05) 440-455
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Colonne CK, Reardon B, Curnow J, Favaloro EJ. Why is misdiagnosis of von Willebrand disease still prevalent and how can we overcome it? A focus on clinical considerations and recommendations. J Blood Med 2021; 12: 755-768
    CrossrefPubMedSearch in Google Scholar
  • 10 Ichinose A. Diagnosis and treatment of acquired factor XIII/13 deficiencies: for all doctors treating the MHLW's designated intractable diseases [in Japanese]. Rinsho Ketsueki 2015; 56 (10) 2110-2122
    PubMedSearch in Google Scholar
  • 11 Ichinose A. The actual condition of autoimmune coagulation factor deficiency in Japan. J Jap Soc Intern Med. 2017;106 (Suppl.):183 [Abstract]
  • 12 Ichinose A. The present condition of and clinical guidance for autoimmune coagulation factor deficiencies in Japan. Jap J Thromb Hemost. 2018; 29: 251-261
    CrossrefPubMedSearch in Google Scholar
  • 13 Ihara A, Suzuki N, Matsushita T, Ichinose A. Acquired von Willebrand syndrome in a patient with immune thrombocytopenic purpura [in Japanese]. Rinsho Ketsueki 2015; 56 (07) 901-904
    PubMedSearch in Google Scholar
  • 14 Kobayashi N, Ogawa Y, Yanagisawa K. et al. Acquired immune-mediated von Willebrand syndrome accompanied by antiphospholipid syndrome. Rinsho Ketsueki 2017; 58 (06) 613-618
    PubMedSearch in Google Scholar
  • 15 Sakai M, Shima M, Izumi Y, Shirahata A. Acquired von Willebrand syndrome with autoimmune hemolytic anemia [in Japanese]. Rinsho Ketsueki 2004; 45 (03) 223-227
    PubMedSearch in Google Scholar
  • 16 Maeda T, Ando T, Nakamura Y. et al. A case of systemic lupus erythematosus associated with acquired von Willebrand's syndrome and circulating anticoagulant [in Japanese]. Nippon Naika Gakkai Zasshi 1984; 73 (05) 680-685
    CrossrefPubMedSearch in Google Scholar
  • 17 Ieko M, Yasukouchi T, Kohno M. et al. Study on the mechanism of bleeding in acquired von Willebrand syndrome. East Japan Dental Magazine 1997; 16 (02) 261-270
    PubMedSearch in Google Scholar
  • 18 Koyama T, Fujimoto K, Shima M. Acquired von Willebrand syndrome associated with Hashimoto's thyroiditis and subcutaneous mucosa-associated lymphoid tissue lymphoma. Intern Med 2013; 52 (23) 2661-2663
    CrossrefPubMedSearch in Google Scholar
  • 19 Aihara M, Narita K, Kimuta A, Chiba Y, Yoshda Y, Takamatsu H. A case of acquired von Willebrand's syndrome with gastrointestinal bleeding (author's transl) [in Japanese]. Rinsho Ketsueki 1978; 19 (12) 1672-1676
    PubMedSearch in Google Scholar
  • 20 Sawaki T, Okabe K, Ssakaguchi K, Sakakura H, Kaneko R, Hibi H. A case involving tooth extraction in a patient with acquired von Willebrand syndrome. Jap J Oral Maxillofacial Surg. 2021; 67 (07) 459-463
    CrossrefPubMedSearch in Google Scholar
  • 21 Igarashi N, Miura M, Kato E. et al. Acquired von Willebrand's syndrome with lupus-like serology. Am J Pediatr Hematol Oncol 1989; 11 (01) 32-35
    CrossrefPubMedSearch in Google Scholar
  • 22 Mohri H, Ohkubo T. Acquired von Willebrand's syndrome due to an inhibitor of IgG specific for von Willebrand's factor in polycythemia rubra vera. Acta Haematol 1987; 78 (04) 258-264
    CrossrefPubMedSearch in Google Scholar
  • 23 Mannucci PM, Kempton C, Millar C. et al; rVWF Ad Hoc Study Group. Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial. Blood 2013; 122 (05) 648-657
    CrossrefPubMedSearch in Google Scholar
  • 24 Tiede A, Priesack J, Werwitzke S. et al. Diagnostic workup of patients with acquired von Willebrand syndrome: a retrospective single-centre cohort study. J Thromb Haemost 2008; 6 (04) 569-576
    CrossrefPubMedSearch in Google Scholar
  • 25 Portuguese AJ, Sunga C, Kruse-Jarres R, Gernsheimer T, Abkowitz J. Autoimmune- and complement-mediated hematologic condition recrudescence following SARS-CoV-2 vaccination. Blood Adv 2021; 5 (13) 2794-2798
    CrossrefPubMedSearch in Google Scholar
  • 26 Leebeek FWG. New developments in diagnosis and management of acquired hemophilia and acquired von Willebrand syndrome. HemaSphere 2021; 5 (06) e586
    CrossrefPubMedSearch in Google Scholar
  • 27 Ichinose A, Osaki T, Souri M. A review of coagulation abnormalities of autoimmune acquired factor V deficiency with a focus on Japan. Semin Thromb Hemost 2022; 48 (02) 206-218
    Thieme ConnectPubMedSearch in Google Scholar
  • 28 Ichinose A, Osaki T, Souri M. Autoimmune coagulation factor X deficiency as a rare acquired hemorrhagic disorder: a literature review. Thromb Haemost 2022; 122 (03) 320-328
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 Collins PW, Hirsch S, Baglin TP. et al; UK Haemophilia Centre Doctors' Organisation. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation. Blood 2007; 109 (05) 1870-1877
    Search in Google Scholar
  • 30 Ichinose A. Japanese Collaborative Research Group on AH13. Autoimmune acquired factor XIII deficiency due to anti-factor XIII/13 antibodies: a summary of 93 patients. Blood Rev 2017; 31 (01) 37-45
    CrossrefPubMedSearch in Google Scholar
  • 31 Takai Y, Koya H, Himei S, Hayashi H. IgA RIPA inhibitor in a case of acquired von Willebrand syndrome [Japanese]. Rinsho Ketsueki 1989; 30 (12) 2183-2188
    PubMedSearch in Google Scholar
  • 32 Peyvandi F, Palla R, Menegatti M. et al; European Network of Rare Bleeding Disorders Group. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost 2012; 10 (04) 615-621
    CrossrefPubMedSearch in Google Scholar
  • 33 Fischer K, Pendu R, van Schooten CJ. et al. Models for prediction of factor VIII half-life in severe haemophiliacs: distinct approaches for blood group O and non-O patients. PLoS One 2009; 4 (08) e6745
    CrossrefPubMedSearch in Google Scholar
  • 34 Lancellotti S, Dragani A, Ranalli P. et al. Qualitative and quantitative modifications of von Willebrand factor in patients with essential thrombocythemia and controlled platelet count. J Thromb Haemost 2015; 13 (07) 1226-1237
    CrossrefPubMedSearch in Google Scholar
  • 35 Favaloro EJ, Soltani S, McDonald J, Grezchnik E, Easton L, Favaloro JW. Reassessment of ABO blood group, sex, and age on laboratory parameters used to diagnose von Willebrand disorder: potential influence on the diagnosis vs the potential association with risk of thrombosis. Am J Clin Pathol 2005; 124 (06) 910-917 Erratum in: Am J Clin Pathol. 2006;125(5):796
    CrossrefPubMedSearch in Google Scholar
  • 36 Raife TJ, Cao W, Atkinson BS. et al. Leukocyte proteases cleave von Willebrand factor at or near the ADAMTS13 cleavage site. Blood 2009; 114 (08) 1666-1674
    CrossrefPubMedSearch in Google Scholar
  • 37 Wohner N, Kovács A, Machovich R, Kolev K. Modulation of the von Willebrand factor-dependent platelet adhesion through alternative proteolytic pathways. Thromb Res 2012; 129 (04) e41-e46
    CrossrefPubMedSearch in Google Scholar
  • 38 Moake JL, Turner NA, Stathopoulos NA, Nolasco LH, Hellums JD. Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest 1986; 78 (06) 1456-1461
    CrossrefPubMedSearch in Google Scholar
  • 39 Budde U, Metzner HJ, Müller HG. Comparative analysis and classification of von Willebrand factor/factor VIII concentrates: impact on treatment of patients with von Willebrand disease. Semin Thromb Hemost 2006; 32 (06) 626-635
    Thieme ConnectPubMedSearch in Google Scholar
  • 40 Peyvandi F. Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery: Reply. J Thromb Haemost 2019; 17 (08) 1405-1406
    CrossrefPubMedSearch in Google Scholar
  • 41 Gill JC, Castaman G, Windyga J. et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood 2015; 126 (17) 2038-2046
    CrossrefPubMedSearch in Google Scholar
  • 42 James PD, Lillicrap D, Mannucci PM. Alloantibodies in von Willebrand disease. Blood 2013; 122 (05) 636-640
    CrossrefPubMedSearch in Google Scholar
  • 43 Federici AB, Stabile F, Castaman G, Canciani MT, Mannucci PM. Treatment of acquired von Willebrand syndrome in patients with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic approaches. Blood 1998; 92 (08) 2707-2711
    CrossrefPubMedSearch in Google Scholar
  • 44 Federici AB. Use of intravenous immunoglobulin in patients with acquired von Willebrand syndrome. Hum Immunol 2005; 66 (04) 422-430
    CrossrefPubMedSearch in Google Scholar
  • 45 Nakata R, Kushibki M, Ogasawara S. et al. A case of inhibitor-positive acquired von Willebrand syndrome that developed during treatment for cancer of esophagogastric junction. Jap J Med Technol 2018; 67 (03) 379-383
    PubMedSearch in Google Scholar
  • 46 Sugase T, Akimoto T, Kimura T, Yagisawa T, Kusano E, Nagata D. Acquired von Willebrand syndrome complicating nephrotic syndrome: a case of a patient with membranous nephropathy. Clin Med Insights Case Rep 2018; 11: 1179547618763371
    CrossrefPubMedSearch in Google Scholar
  • 47 James AH, Eikenboom J, Federici AB. State of the art: von Willebrand disease. Haemophilia 2016; 22 (Suppl. 05) 54-59
    CrossrefPubMedSearch in Google Scholar
  • 48 Mohri H, Motomura S, Kanamori H. et al. Clinical significance of inhibitors in acquired von Willebrand syndrome. Blood 1998; 91 (10) 3623-3629
    CrossrefPubMedSearch in Google Scholar
  • 49 Siaka C, Rugeri L, Caron C, Goudemand J. A new ELISA assay for diagnosis of acquired von Willebrand syndrome. Haemophilia 2003; 9 (03) 303-308
    CrossrefPubMedSearch in Google Scholar
  • 50 Franchi F, Biguzzi E, Stufano F, Siboni SM, Baronciani L, Peyvandi F. A two-step approach (Enzyme-linked immunosorbent assay and confirmation assay) to detect antibodies against von Willebrand factor in patients with Acquired von Willebrand Syndrome. Thromb Res 2014; 134 (06) 1316-1322
    CrossrefPubMedSearch in Google Scholar
  • 51 Dicke C, Holstein K, Schneppenheim S. et al. Acquired hemophilia A and von Willebrand syndrome in a patient with late-onset systemic lupus erythematosus. Exp Hematol Oncol 2014; 3: 21
    CrossrefPubMedSearch in Google Scholar
  • 52 Dicke C, Schneppenheim S, Holstein K. et al. Distinct mechanisms account for acquired von Willebrand syndrome in plasma cell dyscrasias. Ann Hematol 2016; 95 (06) 945-957
    CrossrefPubMedSearch in Google Scholar
  • 53 Budde U, Scheppenheim S, Dittmer R. Treatment of the acquired von Willebrand syndrome. Expert Rev Hematol 2015; 8 (06) 799-818
    CrossrefPubMedSearch in Google Scholar
  • 54 Federici AB, Rand JH, Bucciarelli P. et al; Subcommittee on von Willebrand Factor. Acquired von Willebrand syndrome: data from an international registry. Thromb Haemost 2000; 84 (02) 345-349 Erratum in: Thromb Haemost 2000;84(4):739. PMID: 10959711
    PubMedSearch in Google Scholar
  • 55 Nitu-Whalley IC, Lee CA. Acquired von Willebrand syndrome–report of 10 cases and review of the literature. Haemophilia 1999; 5 (05) 318-326
    CrossrefPubMedSearch in Google Scholar
  • 56 Voisin S, Hamidou M, Lefrançois A, Sigaud M, Mahé B, Trossaërt M. Acquired von Willebrand syndrome associated with monoclonal gammopathy: a single-center study of 36 patients. Medicine (Baltimore) 2011; 90 (06) 404-411
    CrossrefPubMedSearch in Google Scholar
  • 57 Kumar S, Pruthi RK, Nichols WL. Acquired von Willebrand's syndrome: a single institution experience. Am J Hematol 2003; 72 (04) 243-247
    CrossrefPubMedSearch in Google Scholar
  • 58 Budde U, Bergmann F, Michiels JJ. Acquired von Willebrand syndrome: experience from 2 years in a single laboratory compared with data from the literature and an international registry. Semin Thromb Hemost 2002; 28 (02) 227-238
    Thieme ConnectPubMedSearch in Google Scholar