Skip to main content

Advertisement

SpringerLink
Log in

Acquired Von Willebrand Syndrome (AVWS) in cardiovascular disease: a state of the art review for clinicians

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

Von Willebrand Factor (vWF) is a large glycoprotein with a broad range of physiological and pathological functions in health and disease. While vWF is critical for normal hemostasis, vascular integrity and repair, quantitative and qualitative abnormalities in the molecule can predispose to serious bleeding and thrombosis. The heritable form of von Willebrand Disease was first described nearly a century ago, but more recently, recognition of an acquired condition known as acquired von Willebrand Syndrome (AVWF) has emerged in persons with hematological, endocrine and cardiovascular diseases, disorders and conditions. An in-depth understanding of the causes, diagnostic approach and management of AVWS is important for practicing clinicians.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Lassila R, Lindberg O (2013) Erik von Willebrand. Haemophilia 19(5):643–647

    Article  CAS  PubMed  Google Scholar 

  2. Ruggeri ZM (2000) Role of von Willebrand factor in platelet thrombus formation. Ann Med 32(Suppl 1):2–9

    CAS  PubMed  Google Scholar 

  3. Huisman B et al (2017) Modeling the cleavage of von Willebrand factor by ADAMTS13 protease in shear flow. Med Eng Phys 48:14–22

    Article  PubMed  Google Scholar 

  4. Sadler JE (1998) Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 67:395–424

    Article  CAS  PubMed  Google Scholar 

  5. Valentijn KM et al (2011) Functional architecture of Weibel–Palade bodies. Blood 117(19):5033–5043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Favaloro EJ, Pasalic L, Curnow J (2016) Type 2 M and Type 2A von Willebrand disease: similar but Different. Semin Thromb Hemost 42(5):483–497

    Article  CAS  PubMed  Google Scholar 

  7. Xu ER, Blythe EE (2017) Structural analyses of von Willebrand factor C domains of collagen 2A and CCN3 reveal an alternative mode of binding to bone morphogenetic protein-2. J Biol Chem 292(30):12516–12527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Casa LDC, Ku DN (2017) Thrombus formation at high shear rates. Annu Rev Biomed Eng 19:415–433

    Article  CAS  PubMed  Google Scholar 

  9. Lynch CJ, Lane DA, Luken BM (2014) Control of VWF A2 domain stability and ADAMTS13 access to the scissile bond of full-length VWF. Blood 123(16):2585–2592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang X et al (2009) Mechanoenzymatic cleavage of the ultralarge vascular protein von Willebrand factor. Science 324(5932):1330–1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bharati KP, Prashanth UR (2011) Von Willebrand disease: an overview. Indian J Pharm Sci 73(1):7–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dayananda KM et al (2010) von Willebrand factor self-association on platelet GpIbalpha under hydrodynamic shear: effect on shear-induced platelet activation. Blood 116(19):3990–3998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rack K, Huck V (2017) Margination and stretching of von Willebrand factor in the blood stream enable adhesion. 7(1):14278

    Google Scholar 

  14. Coenen DM, Mastenbroek TG (2017) Cosemans, J, Platelet interaction with activated endothelium: mechanistic insights from microfluidics. Blood. 130(26):2819–2828

    Article  CAS  PubMed  Google Scholar 

  15. Meyer D et al (2001) Type 2 von Willebrand disease causing defective von Willebrand factor-dependent platelet function. Best Pract Res Clin Haematol 14(2):349–364

    Article  CAS  PubMed  Google Scholar 

  16. Sutherland JJ et al (2004) Molecular modeling of the von Willebrand factor A2 Domain and the effects of associated type 2A von Willebrand disease mutations. J Mol Model 10(4):259–270

    Article  CAS  PubMed  Google Scholar 

  17. Dong JF et al (2003) ADAMTS-13 metalloprotease interacts with the endothelial cell-derived ultra-large von Willebrand factor. J Biol Chem 278(32):29633–29639

    Article  CAS  PubMed  Google Scholar 

  18. Brown SA et al (2003) Increased clearance of von Willebrand factor antigen post-DDAVP in Type 1 von Willebrand disease: is it a potential pathogenic process? J Thromb Haemost 1(8):1714–1717

    Article  CAS  PubMed  Google Scholar 

  19. Sztukowska M et al (2008) Von Willebrand factor propeptide makes it easy to identify the shorter Von Willebrand factor survival in patients with type 1 and type Vicenza von Willebrand disease. Br J Haematol 143(1):107–114

    Article  CAS  PubMed  Google Scholar 

  20. Gallinaro L et al (2008) A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood 111(7):3540–3545

    Article  CAS  PubMed  Google Scholar 

  21. Gill JC et al (1987) The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 69(6):1691–1695

    CAS  PubMed  Google Scholar 

  22. van Schooten CJ et al (2008) Macrophages contribute to the cellular uptake of von Willebrand factor and factor VIII in vivo. Blood 112(5):1704–1712

    Article  PubMed  CAS  Google Scholar 

  23. Casari C et al (2013) Accelerated uptake of VWF/platelet complexes in macrophages contributes to VWD type 2B-associated thrombocytopenia. Blood 122(16):2893–2902

    Article  CAS  PubMed  Google Scholar 

  24. Grewal PK et al (2008) The Ashwell receptor mitigates the lethal coagulopathy of sepsis. Nat Med 14(6):648–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pegon JN et al (2012) Factor VIII and von Willebrand factor are ligands for the carbohydrate-receptor Siglec-5. Haematologica 97(12):1855–1863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Christodoulides N et al (2001) Glycoprotein Ib/IX/V binding to the membrane skeleton maintains shear-induced platelet aggregation. Thromb Res 102(2):133–142

    Article  CAS  PubMed  Google Scholar 

  27. Jy W et al (2005) Endothelial microparticles induce formation of platelet aggregates via a von Willebrand factor/ristocetin dependent pathway, rendering them resistant to dissociation. J Thromb Haemost 3(6):1301–1308

    Article  CAS  PubMed  Google Scholar 

  28. Yuan, Y., et al., Calpain regulation of cytoskeletal signaling complexes in von Willebrand factor-stimulated platelets. Distinct roles for glycoprotein Ib-V-IX and glycoprotein IIb-IIIa (integrin alphaIIbbeta3) in von Willebrand factor-induced signal transduction. J Biol Chem, 1997. 272(35): p. 21847-54

  29. Randi AM, Smith KE, Castaman G (2018) von Willebrand factor regulation of blood vessel formation. Blood 132(2):132–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zimmerman TS, Ratnoff OD, Powell AE (1971) Immunologic differentiation of classic hemophilia (factor 8 deficiency) and von Willebrand’s dissase, with observations on combined deficiencies of antihemophilic factor and proaccelerin (factor V) and on an acquired circulating anticoagulant against antihemophilic factor. J Clin Invest 50(1):244–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Boender, J., et al., Clinically relevant differences between assays for von Willebrand factor activity. J Thromb Haemost, 2018

  32. Just S (2017) Laboratory Testing for von Willebrand Disease: the Past, Present, and Future State of Play for von Willebrand Factor Assays that Measure Platelet Binding Activity, with or without Ristocetin. Semin Thromb Hemost 43(1):75–91

    CAS  PubMed  Google Scholar 

  33. Nichols WL et al (2008) von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 14(2):171–232

    Article  CAS  PubMed  Google Scholar 

  34. Chapin J (2018) Von Willebrand disease in the elderly: clinical perspectives. Clin Interv Aging 13:1531–1541

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Favaloro EJ et al (2018) Differential sensitivity of von Willebrand factor activity assays to reduced VWF molecular weight forms: a large international cross-laboratory study. Thromb Res 166:96–105

    Article  CAS  PubMed  Google Scholar 

  36. Tiede A et al (2011) How I treat the acquired von Willebrand syndrome. Blood 117(25):6777–6785

    Article  CAS  PubMed  Google Scholar 

  37. Deconinck S et al (2018) Differences in von Willebrand factor function in type 2A von Willebrand disease and left ventricular assist device-induced acquired von Willebrand syndrome. Res Pract Thromb Haemost 2(4):762–766

    Article  PubMed  PubMed Central  Google Scholar 

  38. Waldow HC et al (2014) Acquired von Willebrand syndrome in adult patients with congenital heart disease. Int J Cardiol 176(3):739–745

    Article  PubMed  Google Scholar 

  39. Binnetoglu FK et al (2016) Acquired von Willebrand syndrome in children with aortic and pulmonary stenosis. Cardiovasc J Afr 27(4):222–227

    Article  PubMed  PubMed Central  Google Scholar 

  40. Massyn, M.W. and S.A. Khan, Heyde syndrome: a common diagnosis in older patients with severe aortic stenosis. Age Ageing, 2009. 38(3): p. 267-70; discussion 251

  41. Warkentin TE, Moore JC (2010) Heyde’s syndrome: from controversy to mainstream. Thromb Haemost 103(2):251–253

    Article  CAS  PubMed  Google Scholar 

  42. Vincentelli A et al (2003) Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med 349(4):343–349

    Article  PubMed  Google Scholar 

  43. Ibrahim H, Rondina MT, Kleiman NS (2018) Von Willebrand factor and the aortic valve: concepts that are important in the transcatheter aortic valve replacement era. Thromb Res 170:20–27

    Article  CAS  PubMed  Google Scholar 

  44. Van Belle E et al (2016) Von Willebrand Factor Multimers during Transcatheter Aortic-Valve Replacement. N Engl J Med 375(4):335–344

    Article  PubMed  CAS  Google Scholar 

  45. Froom P et al (1988) Von Willebrand factor and mitral valve prolapse. Thromb Haemost 60(2):230–231

    Article  CAS  PubMed  Google Scholar 

  46. Blackshear JL et al (2011) Hypertrophic obstructive cardiomyopathy, bleeding history, and acquired von Willebrand syndrome: response to septal myectomy. Mayo Clin Proc 86(3):219–224

    Article  PubMed  PubMed Central  Google Scholar 

  47. Onimoe G et al (2011) Acquired von Willebrand Syndrome in congenital heart disease: does it promote an increased bleeding risk? Br J Haematol 155(5):622–624

    Article  PubMed  Google Scholar 

  48. Federici AB et al (2013) Current diagnostic and therapeutic approaches to patients with acquired von Willebrand syndrome: a 2013 update. Semin Thromb Hemost 39(2):191–201

    Article  CAS  PubMed  Google Scholar 

  49. Bongers TN et al (2006) High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability. Stroke 37(11):2672–2677

    Article  CAS  PubMed  Google Scholar 

  50. Pedrazzini G et al (2016) Acquired intracoronary ADAMTS13 deficiency and VWF retention at sites of critical coronary stenosis in patients with STEMI. Blood 127(23):2934–2936

    Article  CAS  PubMed  Google Scholar 

  51. Jacquemin M, Peerlinck K (2015) Free hemoglobin: a boost to platelet thrombi. Blood 126(20):2262–2263

    Article  PubMed  Google Scholar 

  52. Muslem R, Caliskan K, Leebeek FWG (2018) Acquired coagulopathy in patients with left ventricular assist devices. J Thromb Haemost 16(3):429–440

    Article  CAS  PubMed  Google Scholar 

  53. Da Q et al (2014) Platelet adhesion involves a novel interaction between vimentin and von Willebrand factor under high shear stress. Blood 123(17):2715–2721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Selvam SN et al (2017) Abnormal angiogenesis in blood outgrowth endothelial cells derived from von Willebrand disease patients. Blood Coagul Fibrinolysis 28(7):521–533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bartoli CR et al (2018) Clinical and In Vitro Evidence That Left Ventricular Assist Device-Induced von Willebrand Factor Degradation Alters Angiogenesis. Circ Heart Fail 11(9):e004638

    Article  CAS  PubMed  Google Scholar 

  56. Starling RC et al (2014) Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J Med 370(1):33–40

    Article  CAS  PubMed  Google Scholar 

  57. Zhou Z et al (2009) Haemoglobin blocks von Willebrand factor proteolysis by ADAMTS-13: a mechanism associated with sickle cell disease. Thromb Haemost 101(6):1070–1077

    Article  CAS  PubMed  Google Scholar 

  58. Arkebauer MR et al (2011) Carbon monoxide and nitric oxide modulate alpha(2)-antiplasmin and plasmin activity: role of heme. Blood Coagul Fibrinolysis 22(8):712–719

    Article  CAS  PubMed  Google Scholar 

  59. Meyer AL et al (2014) Acquired von Willebrand syndrome in patients with a centrifugal or axial continuous flow left ventricular assist device. JACC Heart Fail 2(2):141–145

    Article  PubMed  Google Scholar 

  60. Shankaran H, Neelamegham S (2004) Hydrodynamic forces applied on intercellular bonds, soluble molecules, and cell-surface receptors. Biophys J 86(1 Pt 1):576–588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Shim K et al (2008) Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress. Blood 111(2):651–657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Letsou GV et al (2005) Gastrointestinal bleeding from arteriovenous malformations in patients supported by the Jarvik 2000 axial-flow left ventricular assist device. J Heart Lung Transplant 24(1):105–109

    Article  PubMed  Google Scholar 

  63. Uriel N et al (2014) Device thrombosis in HeartMate II continuous-flow left ventricular assist devices: a multifactorial phenomenon. J Heart Lung Transplant 33(1):51–59

    Article  PubMed  Google Scholar 

  64. Vincent F et al (2018) Arterial Pulsatility and Circulating von Willebrand Factor in Patients on Mechanical Circulatory Support. J Am Coll Cardiol 71(19):2106–2118

    Article  CAS  PubMed  Google Scholar 

  65. Brehm MA et al (2014) von Willebrand disease type 2A phenotypes IIC, IID and IIE: a day in the life of shear-stressed mutant von Willebrand factor. Thromb Haemost 112(1):96–108

    CAS  PubMed  Google Scholar 

  66. Keesler DA, Flood VH (2018) Current issues in diagnosis and treatment of von Willebrand disease. Research and Practice in Thrombosis and Haemostasis 2(1):34–41

    Article  PubMed  Google Scholar 

  67. Draper K et al (2015) Thalidomide for treatment of gastrointestinal angiodysplasia in patients with left ventricular assist devices: case series and treatment protocol. J Heart Lung Transplant 34(1):132–134

    Article  PubMed  Google Scholar 

  68. Borel-Derlon A et al (2007) Treatment of severe von Willebrand disease with a high-purity von Willebrand factor concentrate (Wilfactin): a prospective study of 50 patients. J Thromb Haemost 5(6):1115–1124

    Article  CAS  PubMed  Google Scholar 

  69. Grosman-Rimon L et al (2018) The Physiological Rationale for Incorporating Pulsatility in Continuous-Flow Left Ventricular Assist Devices. Cardiol Rev 26(6):294–301

    PubMed  Google Scholar 

  70. Edwards AL et al (2018) Association of Pulsatility with Gastrointestinal Bleeding in a Cohort of HeartMate II Recipients. ASAIO J 64(4):472–479

    Article  PubMed  Google Scholar 

  71. Halder LC et al (2017) Time in Therapeutic Range for Left Ventricular Assist Device Patients Anticoagulated With Warfarin: a Correlation to Clinical Outcomes. ASAIO J 63(1):37–40

    Article  CAS  PubMed  Google Scholar 

  72. Molina TL et al (2018) Gastrointestinal Bleeding in Left Ventricular Assist Device: octreotide and Other Treatment Modalities. ASAIO J 64(4):433–439

    Article  PubMed  Google Scholar 

  73. Hollis IB et al (2017) Inhaled Desmopressin for Refractory Gastrointestinal Bleeding in a Patient With a HeartMate II Left Ventricular Assist Device. ASAIO J 63(4):e47–e49

    Article  CAS  PubMed  Google Scholar 

  74. Goudemand J et al (2005) Pharmacokinetic studies on Wilfactin, a von Willebrand factor concentrate with a low factor VIII content treated with three virus-inactivation/removal methods. J Thromb Haemost 3(10):2219–2227

    Article  CAS  PubMed  Google Scholar 

  75. Tsai HM et al (1997) Proteolytic cleavage of recombinant type 2A von Willebrand factor mutants R834 W and R834Q: inhibition by doxycycline and by monoclonal antibody VP-1. Blood 89(6):1954–1962

    CAS  PubMed  Google Scholar 

  76. Rauch A et al (2014) Antibody-based prevention of von Willebrand factor degradation mediated by circulatory assist devices. Thromb Haemost 112(5):1014–1023

    Article  PubMed  Google Scholar 

  77. Lenting PJ, Christophe OD, Denis CV (2015) von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. Blood 25(13):2019–2028

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Radha Mehta, Muhammad Athar, Sameh Girgis & Atif Hassan

  2. Stonehill Professor of Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, CVC 4th Floor, Room 4936, Cincinnati, 45267, OH, USA

    Richard C. Becker

Authors
  1. Radha Mehta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Muhammad Athar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sameh Girgis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Atif Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Richard C. Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard C. Becker.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mehta, R., Athar, M., Girgis, S. et al. Acquired Von Willebrand Syndrome (AVWS) in cardiovascular disease: a state of the art review for clinicians. J Thromb Thrombolysis 48, 14–26 (2019). https://doi.org/10.1007/s11239-019-01849-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-019-01849-2

Keywords

Search

Navigation