Skip to main content

Advertisement

Log in

Von Willebrand Factor and Platelet Aggregation: from Bench to Clinical Practice

  • Blood Management (KA Tanaka, Section Editor)
  • Published:
Current Anesthesiology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This review describes von Willebrand factor (VWF)-mediated platelet function in inherited and acquired bleeding disorders, and current and novel approaches from bench to clinical practice used to perform research, diagnose, and treat bleeding disorders.

Recent Findings

Patients can present with either qualitative or quantitative defects in VWF and/or platelets, which can be inherited or acquired. Understanding the structure–function relationships of VWF and platelets has led to clinically useful classification and treatment of coagulopathy. However, current bench and clinical assays can be time-consuming and have limitations that preclude assessment of important mechanistic drivers, including physiologically relevant flow conditions pertinent to VWF-mediated platelet function.

Summary

The purpose of this review is to discuss current and traditional laboratory-based assessment of VWF-mediated platelet function and the translation to clinical practice with specific focus on patient bleeding risks and the tools available for their management.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Jaffe EA, Hoyer LW, Nachman RL. Synthesis of von Willebrand factor by cultured human endothelial cells. Proc Natl Acad Sci U S A. 1974;71(5):1906–9. https://doi.org/10.1073/pnas.71.5.1906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sporn LA, Chavin SI, Marder VJ, Wagner DD. Biosynthesis of von Willebrand protein by human megakaryocytes. J Clin Invest. 1985;76(3):1102–6. https://doi.org/10.1172/JCI112064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pannekoek H, Voorberg J. Molecular cloning, expression and assembly of multimeric von Willebrand factor. Baillieres Clin Haematol. 1989;2(4):879–96. https://doi.org/10.1016/s0950-3536(89)80050-2.

    Article  CAS  PubMed  Google Scholar 

  4. Peyvandi F, Garagiola I, Baronciani L. Role of von Willebrand factor in the haemostasis. Blood Transfus. 2011;9(Sippl 2):s3–8. https://doi.org/10.2450/2011.002S.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Reininger AJ. Function of von Willebrand factor in haemostasis and thrombosis. Haemophilia. 2008;14(Suppl 5):11–26. https://doi.org/10.1111/j.1365-2516.2008.01848.x.

    Article  CAS  PubMed  Google Scholar 

  6. Sobel M, McNeill PM, Carlson PL, Kermode JC, Adelman B, Conroy R, et al. Heparin inhibition of von Willebrand factor-dependent platelet function in vitro and in vivo. J Clin Investig. 1991;87(5):1787–93. https://doi.org/10.1172/JCI115198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Foster PA, Fulcher CA, Marti T, Titani K, Zimmerman TS. A major factor VIII binding domain resides within the amino-terminal 272 amino acid residues of von Willebrand factor. J Biol Chem. 1987;262(18):8443–6.

    Article  CAS  Google Scholar 

  8. Endenburg SC, Hantgan RR, Lindeboom-Blokzijl L, Lankhof H, Jerome WG, Lewis JC, et al. On the role of von Willebrand factor in promoting platelet adhesion to fibrin in flowing blood. Blood. 1995;86(11):4158–65.

    Article  CAS  Google Scholar 

  9. Loscalzo J, Inbal A, Handin RI. von Willebrand protein facilitates platelet incorporation in polymerizing fibrin. J Clin Invest. 1986;78(4):1112–9. https://doi.org/10.1172/jci112668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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(3):206–16. https://doi.org/10.1097/mbc.0000000000000065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lenting PJ, Christophe OD, Denis CV. von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. Blood. 2015;125(13):2019–28. https://doi.org/10.1182/blood-2014-06-528406.

    Article  CAS  PubMed  Google Scholar 

  12. Nightingale T, Cutler D. The secretion of von Willebrand factor from endothelial cells; an increasingly complicated story. J Thromb Haemost. 2013;11(s1):192–201. https://doi.org/10.1111/jth.12225.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Giblin JP, Hewlett LJ, Hannah MJ. Basal secretion of von Willebrand factor from human endothelial cells. Blood. 2008;112(4):957–64. https://doi.org/10.1182/blood-2007-12-130740.

    Article  CAS  PubMed  Google Scholar 

  14. Hassan MI, Saxena A, Ahmad F. Structure and function of von Willebrand factor. Blood Coagul Fibrinolysis. 2012;23(1):11–22. https://doi.org/10.1097/MBC.0b013e32834cb35d.

    Article  CAS  PubMed  Google Scholar 

  15. Zeineddin A, Dong JF, Wu F, Terse P, Kozar RA. Role of Von Willebrand factor after injury: it may do more than we think. Shock. 2021;55(6):717–22. https://doi.org/10.1097/shk.0000000000001690.

    Article  PubMed  Google Scholar 

  16. da Silva ML, von Cutler DF. Willebrand factor multimerization and the polarity of secretory pathways in endothelial cells. Blood. 2016;128(2):277–85.

    Article  Google Scholar 

  17. Sporn LA, Marder VJ, Wagner DD. Inducible secretion of large, biologically potent von Willebrand factor multimers. Cell. 1986;46(2):185–90. https://doi.org/10.1016/0092-8674(86)90735-x.

    Article  CAS  PubMed  Google Scholar 

  18. Luo GP, Ni B, Yang X, Wu YZ. von Willebrand factor: more than a regulator of hemostasis and thrombosis. Acta Haematol. 2012;128(3):158–69. https://doi.org/10.1159/000339426.

    Article  CAS  PubMed  Google Scholar 

  19. Gardiner EE, Andrews RK. Platelets in Thrombotic and Non-Thrombotic Disorders. Cham, Switzerland: Springer; 2017.

    Google Scholar 

  20. Cruz MA, Yuan H, Lee JR, Wise RJ, Handin RI. Interaction of the von Willebrand Factor (vWF) with Collagen: LOCALIZATION OF THE PRIMARY COLLAGEN-BINDING SITE BY ANALYSIS OF RECOMBINANT vWF A DOMAIN POLYPEPTIDES *. J Biol Chem. 1995;270(18):10822–7. https://doi.org/10.1074/jbc.270.18.10822.

    Article  CAS  PubMed  Google Scholar 

  21. Lankhof H, van Hoeij M, Schiphorst ME, Bracke M, Wu YP, Ijsseldijk MJ, et al. A3 domain is essential for interaction of von Willebrand factor with collagen type III. Thromb Haemost. 1996;75(6):950–8.

    Article  CAS  Google Scholar 

  22. Auton M, Sowa KE, Behymer M, Cruz MA. N-terminal flanking region of A1 domain in von Willebrand factor stabilizes structure of A1A2A3 complex and modulates platelet activation under shear stress. J Biol Chem. 2012;287(18):14579–85. https://doi.org/10.1074/jbc.M112.348573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. De Meyer SF, Deckmyn H, Vanhoorelbeke K. von Willebrand factor to the rescue. Blood. 2009;113(21):5049–57. https://doi.org/10.1182/blood-2008-10-165621.

    Article  CAS  PubMed  Google Scholar 

  24. Miura S, Li CQ, Cao Z, Wang H, Wardell MR, Sadler JE. Interaction of von Willebrand factor domain A1 with platelet glycoprotein Ibalpha-(1–289). Slow intrinsic binding kinetics mediate rapid platelet adhesion. J Biol Chem. 2000;275(11):7539–46. https://doi.org/10.1074/jbc.275.11.7539.

    Article  CAS  PubMed  Google Scholar 

  25. Chen J, Zhou H, Diacovo A, Zheng XL, Emsley J, Diacovo TG. Exploiting the kinetic interplay between GPIbα–VWF binding interfaces to regulate hemostasis and thrombosis. Blood. 2014;124(25):3799–807. https://doi.org/10.1182/blood-2014-04-569392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ruggeri ZM. The role of von Willebrand factor in thrombus formation. Thromb Res. 2007;120(Suppl 1):S5-9. https://doi.org/10.1016/j.thromres.2007.03.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hathcock JJ. Flow effects on coagulation and thrombosis. Arterioscler Thromb Vasc Biol. 2006;26(8):1729–37. https://doi.org/10.1161/01.ATV.0000229658.76797.30.

    Article  CAS  PubMed  Google Scholar 

  28. Ruggeri ZM. von Willebrand factor. J Clin Investig. 1997;99(4):559–64. https://doi.org/10.1172/JCI119195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sakariassen KS, Orning L, Turitto VT. The impact of blood shear rate on arterial thrombus formation. Future Sci OA. 2015;1(4):30. https://doi.org/10.4155/fso.15.28.

    Article  CAS  Google Scholar 

  30. Shetty S, Kasatkar P, Ghosh K. Pathophysiology of acquired von Willebrand disease: a concise review. Eur J Haematol. 2011;87(2):99–106. https://doi.org/10.1111/j.1600-0609.2011.01636.x.

    Article  CAS  PubMed  Google Scholar 

  31. Gogia S, Neelamegham S. Role of fluid shear stress in regulating VWF structure, function and related blood disorders. Biorheology. 2015;52(5–6):319–35. https://doi.org/10.3233/bir-15061.

    Article  CAS  PubMed  Google Scholar 

  32. Ruggeri ZM, Orje JN, Habermann R, Federici AB, Reininger AJ. Activation-independent platelet adhesion and aggregation under elevated shear stress. Blood. 2006;108(6):1903–10. https://doi.org/10.1182/blood-2006-04-011551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Denis CV, Lenting PJ. von Willebrand factor: at the crossroads of bleeding and thrombosis. Int J Hematol. 2012;95(4):353–61. https://doi.org/10.1007/s12185-012-1041-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schneider SW, Nuschele S, Wixforth A, Gorzelanny C, Alexander-Katz A, Netz RR, et al. Shear-induced unfolding triggers adhesion of von Willebrand factor fibers. Proc Natl Acad Sci U S A. 2007;104(19):7899–903. https://doi.org/10.1073/pnas.0608422104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shattil SJ, Hoxie JA, Cunningham M, Brass LF. Changes in the platelet membrane glycoprotein IIb.IIIa complex during platelet activation. J Biol Chem. 1985;260(20):11107–14. https://doi.org/10.1016/S0021-9258(17)39154-8.

    Article  CAS  PubMed  Google Scholar 

  36. Savage B, Saldívar E, Ruggeri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell. 1996;84(2):289–97. https://doi.org/10.1016/s0092-8674(00)80983-6.

    Article  CAS  PubMed  Google Scholar 

  37. Dong JF, Moake JL, Nolasco L, Bernardo A, Arceneaux W, Shrimpton CN, et al. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood. 2002;100(12):4033–9. https://doi.org/10.1182/blood-2002-05-1401.

    Article  CAS  PubMed  Google Scholar 

  38. Zheng X, Chung D, Takayama TK, Majerus EM, Sadler JE, Fujikawa K. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem. 2001;276(44):41059–63. https://doi.org/10.1074/jbc.C100515200.

    Article  CAS  PubMed  Google Scholar 

  39. Pimanda J, Hogg P. Control of von Willebrand factor multimer size and implications for disease. Blood Rev. 2002;16(3):185–92. https://doi.org/10.1016/s0268-960x(02)00017-6.

    Article  PubMed  Google Scholar 

  40. Martin SE, Marder VJ, Francis CW, Barlow GH. Structural studies of the functional heterogeneity of von Willebrand protein polymers. Blood. 1981;57(2):313–23.

    Article  CAS  Google Scholar 

  41. Sadler JE. A new name in thrombosis, ADAMTS13. Proc Natl Acad Sci. 2002;99(18):11552–4. https://doi.org/10.1073/pnas.192448999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Moore JC, Hayward CPM, Warkentin TE, Kelton JG. Decreased von Willebrand factor protease activity associated with thrombocytopenic disorders. Blood. 2001;98(6):1842–6. https://doi.org/10.1182/blood.V98.6.1842.

    Article  CAS  PubMed  Google Scholar 

  43. Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998;339(22):1578–84. https://doi.org/10.1056/nejm199811263392202.

    Article  CAS  PubMed  Google Scholar 

  44. Thomas MR, de Groot R, Scully MA, Crawley JT. Pathogenicity of anti-ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura. EBioMedicine. 2015;2(8):942–52. https://doi.org/10.1016/j.ebiom.2015.06.007.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Chow TW, Turner NA, Chintagumpala M, McPherson PD, Nolasco LH, Rice L, et al. Increased von Willebrand factor binding to platelets in single episode and recurrent types of thrombotic thrombocytopenic purpura. Am J Hematol. 1998;57(4):293–302. https://doi.org/10.1002/(sici)1096-8652(199804)57:4%3c293::aid-ajh5%3e3.0.co;2-p.

    Article  CAS  PubMed  Google Scholar 

  46. Tsai HM. Pathophysiology of thrombotic thrombocytopenic purpura. Int J Hematol. 2010;91(1):1–19. https://doi.org/10.1007/s12185-009-0476-1.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Mazurier C, Ribba AS, Gaucher C, Meyer D. Molecular genetics of von Willebrand disease. Ann Genet. 1998;41(1):34–43.

    CAS  PubMed  Google Scholar 

  48. Schneppenheim R, Budde U. Phenotypic and genotypic diagnosis of von Willebrand disease: A 2004 update. Semin Hematol. 2005;42(1):15–28. https://doi.org/10.1053/j.seminhematol.2004.10.002.

    Article  CAS  PubMed  Google Scholar 

  49. Federici AB 2003 The factor VIII/von Willebrand factor complex: basic and clinical issues. Haematologica. 88(6):EREP02-EREP. https://doi.org/10.3324//x

  50. Tiede A, Rand JH, Budde U, Ganser A, Federici AB. How I treat the acquired von Willebrand syndrome. Blood. 2011;117(25):6777–85. https://doi.org/10.1182/blood-2010-11-297580.

    Article  CAS  PubMed  Google Scholar 

  51. Tiede A. Diagnosis and treatment of acquired von Willebrand syndrome. Thromb Res. 2012;130:S2–6. https://doi.org/10.1016/S0049-3848(13)70003-3.

    Article  CAS  PubMed  Google Scholar 

  52. Kellermair J, Ott HW, Baumgartner H, Kiblboeck D, Blessberger H, Kammler J, et al. High-molecular-weight von Willebrand factor multimer ratio: a novel biomarker for low-flow, low-gradient aortic stenosis subclassification. J Am Coll Cardiol. 2018;72(16):1982–4. https://doi.org/10.1016/j.jacc.2018.05.080.

    Article  PubMed  Google Scholar 

  53. Pareti FI, Lattuada A, Bressi C, Zanobini M, Sala A, Steffan A, et al. Proteolysis of von Willebrand factor and shear stress-induced platelet aggregation in patients with aortic valve stenosis. Circulation. 2000;102(11):1290–5. https://doi.org/10.1161/01.cir.102.11.1290.

    Article  CAS  PubMed  Google Scholar 

  54. Slaughter MS. Hematologic effects of continuous flow left ventricular assist devices. J Cardiovasc Transl Res. 2010;3(6):618–24. https://doi.org/10.1007/s12265-010-9222-6.

    Article  PubMed  Google Scholar 

  55. Vincentelli A, Susen S, Le Tourneau T, Six I, Fabre O, Juthier F, et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med. 2003;349(4):343–9. https://doi.org/10.1056/NEJMoa022831.

    Article  PubMed  Google Scholar 

  56. D’Andrea G, Chetta M, Margaglione M. Inherited platelet disorders: thrombocytopenias and thrombocytopathies. Blood Transfus. 2009;7(4):278–92. https://doi.org/10.2450/2009.0078-08.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Konkle BA. Acquired Disorders of Platelet Function. Hematology. 2011;2011(1):391–6. https://doi.org/10.1182/asheducation-2011.1.391.

    Article  PubMed  Google Scholar 

  58. Dispenzieri A, Kyle RA. Multiple myeloma: clinical features and indications for therapy. Best Pract Res Clin Haematol. 2005;18(4):553–68. https://doi.org/10.1016/j.beha.2005.01.008.

    Article  CAS  PubMed  Google Scholar 

  59. Papadakis E, Hoffman R, Brenner B. Thrombohemorrhagic complications of myeloproliferative disorders. Blood Rev. 2010;24(6):227–32. https://doi.org/10.1016/j.blre.2010.08.002.

    Article  PubMed  Google Scholar 

  60. Zainal A, Salama A, Alweis R. Immune thrombocytopenic purpura. J Community Hosp Intern Med Perspect. 2019;9(1):59–61. https://doi.org/10.1080/20009666.2019.1565884.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Elena L, Carolyn O. Familial myelodysplastic syndromes: a review of the literature. Haematologica. 2011;96(10):1536–42. https://doi.org/10.3324/haematol.2011.043422.

    Article  Google Scholar 

  62. Scharf RE. Drugs that Affect Platelet Function. Semin Thromb Hemost. 2012;38(08):865–83.

    Article  CAS  Google Scholar 

  63. Handin RI. Inherited Platelet Disorders. Hematology. 2005;2005(1):396–402. https://doi.org/10.1182/asheducation-2005.1.396.

    Article  Google Scholar 

  64. Nurden AT. Glanzmann thrombasthenia. Orphanet J Rare Dis. 2006;1:10. https://doi.org/10.1186/1750-1172-1-10.

    Article  PubMed  PubMed Central  Google Scholar 

  65. López JA, Andrews RK, Afshar-Kharghan V, Berndt MC. Bernard-Soulier Syndrome. Blood. 1998;91(12):4397–418. https://doi.org/10.1182/blood.V91.12.4397.

    Article  PubMed  Google Scholar 

  66. Miller JL, Castella A. Platelet-Type von Willebrand’s Disease: Characterization of a New Bleeding Disorder. Blood. 1982;60(3):790–4. https://doi.org/10.1182/blood.V60.3.790.790.

    Article  CAS  PubMed  Google Scholar 

  67. Hayward CPM. Inherited disorders of platelet alpha-granules. Platelets. 1997;8(4):197–210. https://doi.org/10.1080/09537109777249.

    Article  CAS  PubMed  Google Scholar 

  68. White JG, Weiss HJ. Platelet granule disorders. Crit Rev Oncol Hematol. 1986;4(4):337–77. https://doi.org/10.1016/S1040-8428(86)80027-0.

    Article  CAS  PubMed  Google Scholar 

  69. Michiels JJ, Berneman ZN, van der Planken M, Schroyens W, Budde U, van Vliet HH. Bleeding prophylaxis for major surgery in patients with type 2 von Willebrand disease with an intermediate purity factor VIII-von Willebrand factor concentrate (Haemate-P). Blood Coagul Fibrinolysis. 2004;15(4):323–30. https://doi.org/10.1097/00001721-200406000-00006.

    Article  PubMed  Google Scholar 

  70. Thompson AR, Gill JC, Ewenstein BM, Mueller-Velten G, Schwartz BA, Humate PSG. Successful treatment for patients with von Willebrand disease undergoing urgent surgery using factor VIII/VWF concentrate (Humate-P). Haemophilia. 2004;10(1):42–51. https://doi.org/10.1046/j.1351-8216.2003.00809.x.

    Article  CAS  PubMed  Google Scholar 

  71. Gill JC, Shapiro A, Valentino LA, Bernstein J, Friedman C, Nichols WL, et al. von Willebrand factor/factor VIII concentrate (Humate-P) for management of elective surgery in adults and children with von Willebrand disease. Haemophilia. 2011;17(6):895–905. https://doi.org/10.1111/j.1365-2516.2011.02534.x.

    Article  CAS  PubMed  Google Scholar 

  72. Slusarz MJ, Slusarz R, Ciarkowski J. Investigation of mechanism of desmopressin binding in vasopressin V2 receptor versus vasopressin V1a and oxytocin receptors: molecular dynamics simulation of the agonist-bound state in the membrane-aqueous system. Biopolymers. 2006;81(5):321–38. https://doi.org/10.1002/bip.20420.

    Article  CAS  PubMed  Google Scholar 

  73. Miesbach W, Berntorp E. Von Willebrand disease - the “Dos” and “Don’ts” in surgery. Eur J Haematol. 2017;98(2):121–7. https://doi.org/10.1111/ejh.12809.

    Article  PubMed  Google Scholar 

  74. Orsini S, Noris P, Bury L, Heller PG, Santoro C, Kadir RA, et al. Bleeding risk of surgery and its prevention in patients with inherited platelet disorders. Haematologica. 2017;102(7):1192–203. https://doi.org/10.3324/haematol.2016.160754.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Mannucci PM, Meyer D, Ruggeri ZM, Koutts J, Ciavarella N, Lavergne JM. Precipitating antibodies in von Willebrand’s disease. Nature. 1976;262(5564):141–2. https://doi.org/10.1038/262141a0.

    Article  CAS  PubMed  Google Scholar 

  76. James PD, Lillicrap D, Mannucci PM. Alloantibodies in von Willebrand disease. Blood. 2013;122(5):636–40. https://doi.org/10.1182/blood-2012-10-462085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Garcia D, Erkan D. Diagnosis and Management of the Antiphospholipid Syndrome. N Engl J Med. 2018;378(21):2010–21. https://doi.org/10.1056/NEJMra1705454.

    Article  CAS  PubMed  Google Scholar 

  78. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295–306. https://doi.org/10.1111/j.1538-7836.2006.01753.x.

    Article  CAS  PubMed  Google Scholar 

  79. Cohn CS. Platelet transfusion refractoriness: how do I diagnose and manage? Hematology Am Soc Hematol Educ Program. 2020;2020(1):527–32. https://doi.org/10.1182/hematology.2020000137.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Forest SK, Hod EA. Management of the Platelet Refractory Patient. Hematol Oncol Clin North Am. 2016;30(3):665–77. https://doi.org/10.1016/j.hoc.2016.01.008.

    Article  PubMed  Google Scholar 

  81. Chassot PG, Marcucci C, Delabays A, Spahn DR. Perioperative antiplatelet therapy. Am Fam Physician. 2010;82(12):1484–9.

    PubMed  Google Scholar 

  82. Arepally GM. Heparin-induced thrombocytopenia. Blood. 2017;129(21):2864–72. https://doi.org/10.1182/blood-2016-11-709873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ranger A, Gaspar M, Elkhatteb A, Jackson T, Fox S, Aw TC, et al. The heparin-von Willebrand factor interaction and conventional tests of haemostasis - the challenges in predicting bleeding in cardiopulmonary bypass. Br J Haematol. 2021;192(6):1073–81. https://doi.org/10.1111/bjh.17263.

    Article  CAS  PubMed  Google Scholar 

  84. Hirakata H, Ushikubi F, Toda H, Nakamura K, Sai S, Urabe N, et al. Sevoflurane inhibits human platelet aggregation and thromboxane A2 formation, possibly by suppression of cyclooxygenase activity. Anesthesiology. 1996;85(6):1447–53. https://doi.org/10.1097/00000542-199612000-00027.

    Article  CAS  PubMed  Google Scholar 

  85. Kozek-Langenecker SA. The effects of drugs used in anaesthesia on platelet membrane receptors and on platelet function. Curr Drug Targets. 2002;3(3):247–58. https://doi.org/10.2174/1389450023347759.

    Article  CAS  PubMed  Google Scholar 

  86. Bozdogan N, Madenoglu H, Dogru K, Yildiz K, Kotanoglu MS, Cetin M, et al. Effects of isoflurane, sevoflurane, and desflurane on platelet function: a prospective, randomized, single-blind, in vivo study. Curr Ther Res Clin Exp. 2005;66(4):375–84. https://doi.org/10.1016/j.curtheres.2005.08.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wu Y, Zhang M, Hauch KD, Horbett TA. Effect of adsorbed von Willebrand factor and fibrinogen on platelet interactions with synthetic materials under flow conditions. J Biomed Mater Res A. 2008;85(3):829–39. https://doi.org/10.1002/jbm.a.31505.

    Article  CAS  PubMed  Google Scholar 

  88. Callaghan S, Cai T, McCafferty C, Van Den Helm S, Horton S, MacLaren G et al 2020 Adsorption of blood components to extracorporeal membrane oxygenation (ECMO) surfaces in humans: a systematic review. J Clin Med. 9(10). https://doi.org/10.3390/jcm9103272.

  89. Kalbhenn J, Schmidt R, Nakamura L, Schelling J, Rosenfelder S, Zieger B. Early diagnosis of acquired von Willebrand Syndrome (AVWS) is elementary for clinical practice in patients treated with ECMO therapy. J Atheroscler Thromb. 2015;22(3):265–71. https://doi.org/10.5551/jat.27268.

    Article  CAS  PubMed  Google Scholar 

  90. Solomon C, Budde U, Schneppenheim S, Czaja E, Hagl C, Schoechl H, et al. Acquired type 2A von Willebrand syndrome caused by aortic valve disease corrects during valve surgery. Br J Anaesth. 2011;106(4):494–500. https://doi.org/10.1093/bja/aeq413.

    Article  CAS  PubMed  Google Scholar 

  91. Yoshida K, Tobe S, Kawata M, Yamaguchi M. Acquired and reversible von Willebrand disease with high shear stress aortic valve stenosis. Ann Thorac Surg. 2006;81(2):490–4. https://doi.org/10.1016/j.athoracsur.2005.07.074.

    Article  PubMed  Google Scholar 

  92. Rauch A, Susen S, Zieger B. Acquired von Willebrand syndrome in patients with ventricular assist device. Front Med (Lausanne). 2019;6:7. https://doi.org/10.3389/fmed.2019.00007.

    Article  Google Scholar 

  93. Heilmann C, Geisen U, Beyersdorf F, Nakamura L, Benk C, Trummer G, et al. Acquired von Willebrand syndrome in patients with extracorporeal life support (ECLS). Intensive Care Med. 2012;38(1):62–8. https://doi.org/10.1007/s00134-011-2370-6.

    Article  PubMed  Google Scholar 

  94. Mazzeffi M, Bathula A, Tabatabai A, Menaker J, Kaczorowski D, Madathil R, et al. Von Willebrand factor concentrate administration for acquired Von Willebrand syndrome- related bleeding during adult extracorporeal membrane oxygenation. J Cardiothorac Vasc Anesth. 2021;35(3):882–7. https://doi.org/10.1053/j.jvca.2020.06.083.

    Article  CAS  PubMed  Google Scholar 

  95. Dane KE, Lindsley JP, Kickler T, Streiff MB, Moliterno A, Yui J, et al. Continuous-infusion von Willebrand factor concentrate is effective for the management of acquired von Willebrand disease. Blood Adv. 2021;5(14):2813–6. https://doi.org/10.1182/bloodadvances.2021004843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Steinlechner B, Dworschak M, Birkenberg B, Duris M, Zeidler P, Fischer H, et al. Platelet dysfunction in outpatients with left ventricular assist devices. Ann Thorac Surg. 2009;87(1):131–7. https://doi.org/10.1016/j.athoracsur.2008.10.027.

    Article  PubMed  Google Scholar 

  97. Morici N, Varrenti M, Brunelli D, Perna E, Cipriani M, Ammirati E, et al. Antithrombotic therapy in ventricular assist device (VAD) management: from ancient beliefs to updated evidence. A narrative review. Int J Cardiol Heart Vasc. 2018;20:20–6. https://doi.org/10.1016/j.ijcha.2018.06.005.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Bollinger D, Tanaka KA 2017 Coagulation management strategies in cardiac surgery. Curr Anesthesiol Rep. 265–72. https://doi.org/10.1007/s40140-017-0220-y.

  99. Weinstein M, Ware JA, Troll J, Salzman E. Changes in von Willebrand factor during cardiac surgery: effect of desmopressin acetate. Blood. 1988;71(6):1648–55.

    Article  CAS  Google Scholar 

  100. Rinder CS, Bohnert J, Rinder HM, Mitchell J, Ault K, Hillman R. Platelet activation and aggregation during cardiopulmonary bypass. Anesthesiology. 1991;75(3):388–93. https://doi.org/10.1097/00000542-199109000-00002.

    Article  CAS  PubMed  Google Scholar 

  101. Kondo C, Tanaka K, Takagi K, Shimono T, Shinpo H, Yada I, et al. Platelet dysfunction during cardiopulmonary bypass surgery. With special reference to platelet membrane glycoproteins. ASAIO J. 1993;39(3):M550-3.

    CAS  PubMed  Google Scholar 

  102. Maquelin KN, Berckmans RJ, Nieuwland R, Schaap MC, ten Have K, Eijsman L, et al. Disappearance of glycoprotein Ib from the platelet surface in pericardial blood during cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1998;115(5):1160–5. https://doi.org/10.1016/s0022-5223(98)70416-7.

    Article  CAS  PubMed  Google Scholar 

  103. Holada K, Simak J, Kucera V, Roznova L, Eckschlager T. Platelet membrane receptors during short cardiopulmonary bypass–a flow cytometric study. Perfusion. 1996;11(5):401–6. https://doi.org/10.1177/026765919601100508.

    Article  CAS  PubMed  Google Scholar 

  104. Perrin EJ, Ray MJ, Hawson GA. The role of von Willebrand factor in haemostasis and blood loss during and after cardiopulmonary bypass surgery. Blood Coagul Fibrinolysis. 1995;6(7):650–8. https://doi.org/10.1097/00001721-199510000-00005.

    Article  CAS  PubMed  Google Scholar 

  105. Panagiotopoulos I, Palatianos G, Michalopoulos A, Chatzigeorgiou A, Prapas S, Kamper EF. Alterations in biomarkers of endothelial function following on-pump coronary artery revascularization. J Clin Lab Anal. 2010;24(6):389–98. https://doi.org/10.1002/jcla.20416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kutcher ME, Redick BJ, McCreery RC, Crane IM, Greenberg MD, Cachola LM, et al. Characterization of platelet dysfunction after trauma. The journal of trauma and acute care surgery. 2012;73(1):13–9. https://doi.org/10.1097/TA.0b013e318256deab.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Jacoby RC, Owings JT, Holmes J, Battistella FD, Gosselin RC, Paglieroni TG. Platelet activation and function after trauma. J Trauma. 2001;51(4):639–47. https://doi.org/10.1097/00005373-200110000-00003.

    Article  CAS  PubMed  Google Scholar 

  108. Verni CC, Davila A Jr, Balian S, Sims CA, Diamond SL. Platelet dysfunction during trauma involves diverse signaling pathways and an inhibitory activity in patient-derived plasma. The journal of trauma and acute care surgery. 2019;86(2):250–9. https://doi.org/10.1097/TA.0000000000002140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Vulliamy P, Montague SJ, Gillespie S, Chan MV, Coupland LA, Andrews RK, et al. Loss of GPVI and GPIbalpha contributes to trauma-induced platelet dysfunction in severely injured patients. Blood Adv. 2020;4(12):2623–30. https://doi.org/10.1182/bloodadvances.2020001776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Dyer MR, Plautz WE, Ragni MV, Alexander W, Haldeman S, Sperry JL, et al. Traumatic injury results in prolonged circulation of ultralarge von Willebrand factor and a reduction in ADAMTS13 activity. Transfusion. 2020;60(6):1308–18. https://doi.org/10.1111/trf.15856. Dyer et al. found that VWF levels increase and ADATMS13 activity concurrently decreases in trauma patients at admission and 24 hours post-admission, and ultralarge VWF were elevated at the same timepoints. ADAMTS13 activity also predicted coagulopathy in these patients.

    Article  CAS  PubMed  Google Scholar 

  111. Insititute CLS 2008 H21-A5 collection, transport, and processing of blood specimens for testing plasma-based coagulation assays and molecular hemostasis assays, 5th Edition. Fifth ed., 48.

  112. Goodeve A. Diagnosing von Willebrand disease: genetic analysis. Hematology Am Soc Hematol Educ Program. 2016;2016(1):678–82. https://doi.org/10.1182/asheducation-2016.1.678.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Smith JW, Steinhubl SR, Lincoff AM, Coleman JC, Lee TT, Hillman RS, et al. Rapid platelet-function assay: an automated and quantitative cartridge-based method. Circulation. 1999;99(5):620–5. https://doi.org/10.1161/01.cir.99.5.620.

    Article  CAS  PubMed  Google Scholar 

  114. van Asten I, Schutgens REG, Baaij M, Zandstra J, Roest M, Pasterkamp G, et al. Validation of flow cytometric analysis of platelet function in patients with a suspected platelet function defect. J Thromb Haemost. 2018;16(4):689–98. https://doi.org/10.1111/jth.13952.

    Article  PubMed  Google Scholar 

  115. Favaloro EJ, Mohammed S. Laboratory testing for von Willebrand factor collagen binding (VWF:CB). Methods Mol Biol. 2017;1646:417–33. https://doi.org/10.1007/978-1-4939-7196-1_31.

    Article  CAS  PubMed  Google Scholar 

  116. Tantry US, Bonello L, Aradi D, Price MJ, Jeong YH, Angiolillo DJ, et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol. 2013;62(24):2261–73. https://doi.org/10.1016/j.jacc.2013.07.101.

    Article  CAS  PubMed  Google Scholar 

  117. Karkouti K, Callum J, Wijeysundera DN, Rao V, Crowther M, Grocott HP, et al. Point-of-care hemostatic testing in cardiac surgery: a stepped-wedge clustered randomized controlled trial. Circulation. 2016;134(16):1152–62. https://doi.org/10.1161/CIRCULATIONAHA.116.023956. Karkouti et al. performed an RCT to compare 4-factor prothrombin complex concentrate (PCC) to frozen plasma use in cardiac surgery. Patients that received PCC had lower blood loss and fewer transfusions.

    Article  PubMed  Google Scholar 

  118. Chatterton S, Dignan R, Luu Q, Aty W, Chandrasiri S, French JK. Platelet activity measured by VerifyNow® aspirin sensitivity test identifies coronary artery bypass surgery patients at increased risk for postoperative bleeding and transfusion. Heart Lung Circ. 2020;29(3):460–8. https://doi.org/10.1016/j.hlc.2019.03.016.

    Article  PubMed  Google Scholar 

  119. Strony J, Beaudoin A, Brands D, Adelman B. Analysis of shear stress and hemodynamic factors in a model of coronary artery stenosis and thrombosis. Am J Physiol. 1993;265(5 Pt 2):H1787–96. https://doi.org/10.1152/ajpheart.1993.265.5.H1787.

    Article  CAS  PubMed  Google Scholar 

  120. Anaya R, Rodriguez M, Gil JM, Vilalta N, Merchan-Galvis A, Moral V et al 2021 Correlation between PlateletWorks((R)) and PFA-100((R)) for measuring platelet function before urgent surgery in patients with chronic antiplatelet therapy. J Clin Med. 10(2). https://doi.org/10.3390/jcm10020255.

  121. Al Ghaithi R, Drake S, Watson SP, Morgan NV, Harrison P. Comparison of multiple electrode aggregometry with lumi-aggregometry for the diagnosis of patients with mild bleeding disorders. J Thromb Haemost. 2017;15(10):2045–52. https://doi.org/10.1111/jth.13784.

    Article  CAS  PubMed  Google Scholar 

  122. Matkovic M, Novakovic T, Bilbija I, Lazovic JM, Tutus V, Cubrilo M, et al. The routine use of platelet function tests in elective coronary artery bypass grafting: a prospective observational trial. J Card Surg. 2021;36(2):629–36. https://doi.org/10.1111/jocs.15284.

    Article  PubMed  Google Scholar 

  123. Kong R, Trimmings A, Hutchinson N, Gill R, Agarwal S, Davidson S, et al. Consensus recommendations for using the Multiplate(®) for platelet function monitoring before cardiac surgery. Int J Lab Hematol. 2015;37(2):143–7. https://doi.org/10.1111/ijlh.12279.

    Article  CAS  PubMed  Google Scholar 

  124. Cattaneo M. Light transmission aggregometry and ATP release for the diagnostic assessment of platelet function. Semin Thromb Hemost. 2009;35(2):158–67. https://doi.org/10.1055/s-0029-1220324.

    Article  CAS  PubMed  Google Scholar 

  125. Girma JP, Takahashi Y, Yoshioka A, Diaz J, Meyer D. Ristocetin and botrocetin involve two distinct domains of von Willebrand factor for binding to platelet membrane glycoprotein Ib. Thromb Haemost. 1990;64(2):326–32.

    Article  CAS  Google Scholar 

  126. Hanke AA, Roberg K, Monaca E, Sellmann T, Weber CF, Rahe-Meyer N, et al. Impact of platelet count on results obtained from multiple electrode platelet aggregometry (Multiplate). Eur J Med Res. 2010;15(5):214–9. https://doi.org/10.1186/2047-783x-15-5-214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Nakajima Y, Nogami K, Yada K, Ogiwara K, Furukawa S, Shimonishi N, et al. Whole blood ristocetin-induced platelet impedance aggregometry does not reflect clinical severity in patients with type 1 von Willebrand disease. Haemophilia. 2019;25(3):e174–9. https://doi.org/10.1111/hae.13725.

    Article  CAS  PubMed  Google Scholar 

  128. Haas T, Cushing MM, Varga S, Gilloz S, Schmugge M. Usefulness of multiple electrode aggregometry as a screening tool for bleeding disorders in a pediatric hospital. Platelets. 2019;30(4):498–505. https://doi.org/10.1080/09537104.2018.1475631.

    Article  CAS  PubMed  Google Scholar 

  129. Lansink-Hartgring AO, Hoffmann R, van den Bergh W, de Vries A 2020 Changes in red blood cell properties and platelet function during extracorporeal membrane oxygenation. J Clin Med. 9(4). https://doi.org/10.3390/jcm9041168.

  130. Gallandat Huet RC, de Vries AJ, Cernak V, Lisman T. Platelet function in stored heparinised autologous blood is not superior to in patient platelet function during routine cardiopulmonary bypass. PLoS ONE. 2012;7(3):e33686. https://doi.org/10.1371/journal.pone.0033686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Oran I, Cinar C, Bozkaya H, Parildar M, Duman S. Reduced activity of von Willebrand factor after flow-diverting stent implantation for intracranial aneurysms: a link to acquired von willebrand disease? AJNR Am J Neuroradiol. 2020;41(1):140–6. https://doi.org/10.3174/ajnr.A6343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kornblith LZ, Robles AJ, Conroy AS, Hendrickson CM, Calfee CS, Fields AT, et al. Perhaps it’s not the platelet: Ristocetin uncovers the potential role of von Willebrand factor in impaired platelet aggregation following traumatic brain injury. The journal of trauma and acute care surgery. 2018;85(5):873–80. https://doi.org/10.1097/ta.0000000000002025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. O’Donnell JS, Lavin M. Perioperative management of patients with von Willebrand disease. Hematology Am Soc Hematol Educ Program. 2019;2019(1):604–9. https://doi.org/10.1182/hematology.2019000065.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Higgins RA, Goodwin AJ. Automated assays for von Willebrand factor activity. Am J Hematol. 2019;94(4):496–503. https://doi.org/10.1002/ajh.25393.

    Article  CAS  PubMed  Google Scholar 

  135. Favaloro EJ. Clinical utility of closure times using the platelet function analyzer-100/200. Am J Hematol. 2017;92(4):398–404. https://doi.org/10.1002/ajh.24620.

    Article  CAS  PubMed  Google Scholar 

  136. Corredor C, Wasowicz M, Karkouti K, Sharma V. The role of point-of-care platelet function testing in predicting postoperative bleeding following cardiac surgery: a systematic review and meta-analysis. Anaesthesia. 2015;70(6):715–31. https://doi.org/10.1111/anae.13083.

    Article  CAS  PubMed  Google Scholar 

  137. Al Ghaithi R, Mori J, Nagy Z, Maclachlan A, Hardy L, Philippou H, et al. Evaluation of the Total Thrombus-Formation System (T-TAS): application to human and mouse blood analysis. Platelets. 2019;30(7):893–900. https://doi.org/10.1080/09537104.2018.1535704.

    Article  CAS  PubMed  Google Scholar 

  138. Sikora J, Karczmarska-Wodzka A, Bugieda J, Sobczak P 2021 The use of total thrombus formation analysis system as a tool to assess platelet function in bleeding and thrombosis risk-a systematic review. Int J Mol Sci. 22(16). https://doi.org/10.3390/ijms22168605.

  139. Ting LH, Feghhi S, Taparia N, Smith AO, Karchin A, Lim E, et al. Contractile forces in platelet aggregates under microfluidic shear gradients reflect platelet inhibition and bleeding risk. Nat Commun. 2019;10(1):1204. https://doi.org/10.1038/s41467-019-09150-9. Ting et al. test a microfluidic device that induces platelet aggregation onto arrays of block-post constructs, which was commercialized as the Stasys device. This study shows differences in force generation over time due to platelet inhibition as well as in a cardiology patient.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Clavería V, Yang PJ, Griffin MT, Ku DN. Global thrombosis test: occlusion by coagulation or SIPA? TH Open. 2021;5(3):e400–10. https://doi.org/10.1055/s-0041-1732341.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Otsui K, Gorog DA, Yamamoto J, Yoshioka T, Iwata S, Suzuki A, et al. Global Thrombosis Test - a possible monitoring system for the effects and safety of dabigatran. Thromb J. 2015;13:39. https://doi.org/10.1186/s12959-015-0069-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Nalla BP, Freedman J, Hare GM, Mazer CD. Update on blood conservation for cardiac surgery. J Cardiothorac Vasc Anesth. 2012;26(1):117–33. https://doi.org/10.1053/j.jvca.2011.07.024.

    Article  PubMed  Google Scholar 

  143. Thomas KA, Shea SM, Yazer MH, Spinella PC. Effect of leukoreduction and pathogen reduction on the hemostatic function of whole blood. Transfusion. 2019;59(S2):1539–48. https://doi.org/10.1111/trf.15175.

    Article  PubMed  Google Scholar 

  144. Fitzpatrick GM, Cliff R, Tandon N. Thrombosomes: a platelet-derived hemostatic agent for control of noncompressible hemorrhage. Transfusion. 2013;53(Suppl 1):100S-S106. https://doi.org/10.1111/trf.12043.

    Article  PubMed  Google Scholar 

  145. Hickman DA, Pawlowski CL, Shevitz A, Luc NF, Kim A, Girish A, et al. Intravenous synthetic platelet (SynthoPlate) nanoconstructs reduce bleeding and improve “golden hour” survival in a porcine model of traumatic arterial hemorrhage. Sci Rep. 2018;8(1):3118. https://doi.org/10.1038/s41598-018-21384-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Mangin PH, Neeves KB, Lam WA, Cosemans J, Korin N, Kerrigan SW, et al. In vitro flow-based assay: from simple toward more sophisticated models for mimicking hemostasis and thrombosis. J Thromb Haemost. 2021;19(2):582–7. https://doi.org/10.1111/jth.15143.

    Article  PubMed  Google Scholar 

  147. Hardy ET, Sakurai Y, Lam WA. Miniaturized vascularized bleeding model of hemostasis. Methods Mol Biol. 2022;2373:159–75. https://doi.org/10.1007/978-1-0716-1693-2_10.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Susan M. Shea.

Ethics declarations

Conflict of Interest

The authors do not have any potential conflicts of interest to disclose.

Additional information

Publisher's Note

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

This article is part of the Topical Collection on Blood Management

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ashworth, K.J., Thomas, K.A. & Shea, S.M. Von Willebrand Factor and Platelet Aggregation: from Bench to Clinical Practice. Curr Anesthesiol Rep 12, 329–341 (2022). https://doi.org/10.1007/s40140-022-00521-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40140-022-00521-5

Keywords

Navigation