Semin Thromb Hemost 2012; 38(01): 55-63
DOI: 10.1055/s-0031-1300952
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

New Insights into von Willebrand Disease and Platelet Function

Tímea Szántó
1   Coagulation Disorders Unit, Departments of Hematology and Clinical Chemistry (HUSLAB Laboratory Services), Helsinki University Central Hospital, Helsinki, Finland
,
Lotta Joutsi-Korhonen
1   Coagulation Disorders Unit, Departments of Hematology and Clinical Chemistry (HUSLAB Laboratory Services), Helsinki University Central Hospital, Helsinki, Finland
,
Hans Deckmyn
2   Laboratory for Thrombosis Research, IRC, KU Leuven Campus Kortrijk, Kortrijk, Belgium
,
Riitta Lassila
1   Coagulation Disorders Unit, Departments of Hematology and Clinical Chemistry (HUSLAB Laboratory Services), Helsinki University Central Hospital, Helsinki, Finland
› Author Affiliations
Further Information

Publication History

Publication Date:
07 February 2012 (online)

Abstract

Regulation of binding between von Willebrand factor (VWF) and the platelet receptor glycoprotein (GP) Ibα is one of the key steps in controlling hemostasis and thrombosis. On vascular injury at sites of high shear rates, the GPIbα interaction with subendothelial-bound VWF will initiate the tethering of circulating platelets to the vessel wall. Tethered platelets subsequently roll on the damaged vessel wall, a process that is amplified by the activation of the platelet integrin αΙΙbβ3 (GPIIb/IIIa). The initial tethering to VWF is rapidly followed by platelet binding to collagen through specific receptors (GPVI and α2β1), leading to firm adhesion, activation, and additional stable bonds mediated by αΙΙbβ3. The above described interactions can result in two distinct processes: physiological hemostasis and pathological thrombosis. Furthermore, VWF carries coagulation factor VIII, which is involved in thrombin formation that in addition to activating platelets, mediates fibrin formation and has several other actions. The importance of VWF in hemostasis is well known in patients suffering from von Willebrand disease (VWD) who present with a defect in both platelet plug and fibrin formation. Type 2B VWD is of special interest as it may provide further insight into the mechanism by which VWF promotes the adhesion of platelets to a thrombogenic surface under conditions of high shear stress. The variant phenotypic manifestations in patients affected with type 2B VWD, however, have raised the question of locus heterogeneity in VWD as a consequence of, for example, additional defects in receptor or signaling proteins mediating platelet adhesion and aggregation. Indeed, quite a few polymorphisms of platelet receptors have been associated with increased bleeding in VWD. However, many aspects of the disease remain to be elucidated. For instance, thrombin and platelet procoagulant activity may be important counterplayers to determine the severity of the bleeding complications associated with VWD.

 
  • References

  • 1 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 8 (11) 1227-1234
  • 2 Sixma JJ, van Zanten GH, Huizinga EG , et al. Platelet adhesion to collagen: an update. Thromb Haemost 1997; 78 (1) 434-438
  • 3 Moroi M, Jung SM, Nomura S, Sekiguchi S, Ordinas A, Diaz-Ricart M. Analysis of the involvement of the von Willebrand factor-glycoprotein Ib interaction in platelet adhesion to a collagen-coated surface under flow conditions. Blood 1997; 90 (11) 4413-4424
  • 4 Savage B, Almus-Jacobs F, Ruggeri ZM. Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell 1998; 94 (5) 657-666
  • 5 Christophe O, Obert B, Meyer D, Girma JP. The binding domain of von Willebrand factor to sulfatides is distinct from those interacting with glycoprotein Ib, heparin, and collagen and resides between amino acid residues Leu 512 and Lys 673. Blood 1991; 78 (9) 2310-2317
  • 6 Mazurier C, Ribba AS, Gaucher C, Meyer D. Molecular genetics of von Willebrand disease. Ann Genet 1998; 41 (1) 34-43
  • 7 Emsley J, Cruz M, Handin R, Liddington R. Crystal structure of the von Willebrand Factor A1 domain and implications for the binding of platelet glycoprotein Ib. J Biol Chem 1998; 273 (17) 10396-10401
  • 8 Bienkowska J, Cruz M, Atiemo A, Handin R, Liddington R. The von willebrand factor A3 domain does not contain a metal ion-dependent adhesion site motif. J Biol Chem 1997; 272 (40) 25162-25167
  • 9 Lankhof H, van Hoeij M, Schiphorst ME , et al. A3 domain is essential for interaction of von Willebrand factor with collagen type III. Thromb Haemost 1996; 75 (6) 950-958
  • 10 Siedlecki CA, Lestini BJ, Kottke-Marchant KK, Eppell SJ, Wilson DL, Marchant RE. Shear-dependent changes in the three-dimensional structure of human von Willebrand factor. Blood 1996; 88 (8) 2939-2950
  • 11 Novák L, Deckmyn H, Damjanovich S, Hársfalvi J. Shear-dependent morphology of von Willebrand factor bound to immobilized collagen. Blood 2002; 99 (6) 2070-2076
  • 12 Ulrichts H, Udvardy M, Lenting PJ , et al. Shielding of the A1 domain by the D’D3 domains of von Willebrand factor modulates its interaction with platelet glycoprotein Ib-IX-V. J Biol Chem 2006; 281 (8) 4699-4707
  • 13 Doggett TA, Girdhar G, Lawshé A , et al. Selectin-like kinetics and biomechanics promote rapid platelet adhesion in flow: the GPIb(alpha)-vWF tether bond. Biophys J 2002; 83 (1) 194-205
  • 14 Zhang X, Halvorsen K, Zhang CZ, Wong WP, Springer TA. Mechanoenzymatic cleavage of the ultralarge vascular protein von Willebrand factor. Science 2009; 329: 1330-1334
  • 15 Tsai HM. Mechanisms of microvascular thrombosis in thrombotic thrombocytopenic purpura. Kidney Int Suppl 2009; 112 (112) S11-S14
  • 16 Ruggeri ZM, Zimmerman TS. Variant von Willebrand’s disease: characterization of two subtypes by analysis of multimeric composition of factor VIII/von Willebrand factor in plasma and platelets. J Clin Invest 1980; 65 (6) 1318-1325
  • 17 Miller JL, Kupinski JM, Castella A, Ruggeri ZM. von Willebrand factor binds to platelets and induces aggregation in platelet-type but not type IIB von Willebrand disease. J Clin Invest 1983; 72 (5) 1532-1542
  • 18 Casonato A, Gallinaro L, Cattini MG , et al. Reduced survival of type 2B von Willebrand factor, irrespective of large multimer representation or thrombocytopenia. Haematologica 2010; 95 (8) 1366-1372
  • 19 Dong JF, Berndt MC, Schade A, McIntire LV, Andrews RK, López JA. Ristocetin-dependent, but not botrocetin-dependent, binding of von Willebrand factor to the platelet glycoprotein Ib-IX-V complex correlates with shear-dependent interactions. Blood 2001; 97 (1) 162-168
  • 20 Kasirer-Friede A, Cozzi MR, Mazzucato M, De Marco L, Ruggeri ZM, Shattil SJ. Signaling through GP Ib-IX-V activates alpha IIb beta 3 independently of other receptors. Blood 2004; 103 (9) 3403-3411
  • 21 Reséndiz JC, Kroll MH, Lassila R. Protease-activated receptor-induced Akt activation—regulation and possible function. J Thromb Haemost 2007; 5 (12) 2484-2493
  • 22 Reininger AJ, Heijnen HF, Schumann H, Specht HM, Schramm W, Ruggeri ZM. Mechanism of platelet adhesion to von Willebrand factor and microparticle formation under high shear stress. Blood 2006; 107 (9) 3537-3545
  • 23 Emsley J, Knight CG, Farndale RW, Barnes MJ, Liddington RC. Structural basis of collagen recognition by integrin alpha2beta1. Cell 2000; 101 (1) 47-56
  • 24 Siljander PR, Munnix IC, Smethurst PA , et al. Platelet receptor interplay regulates collagen-induced thrombus formation in flowing human blood. Blood 2004; 103 (4) 1333-1341
  • 25 Schoolmeester A, Vanhoorelbeke K, Katsutani S , et al. Monoclonal antibody IAC-1 is specific for activated alpha2beta1 and binds to amino acids 199 to 201 of the integrin alpha2 I-domain. Blood 2004; 104 (2) 390-396
  • 26 Van de Walle GR, Schoolmeester A, Iserbyt BF , et al. Activation of alphaIIbbeta3 is a sufficient but also an imperative prerequisite for activation of alpha2beta1 on platelets. Blood 2007; 109 (2) 595-602
  • 27 Inoue O, Suzuki-Inoue K, Ozaki Y. Redundant mechanism of platelet adhesion to laminin and collagen under flow: involvement of von Willebrand factor and glycoprotein Ib-IX-V. J Biol Chem 2008; 283 (24) 16279-16282
  • 28 Kulkarni S, Dopheide SM, Yap CL , et al. A revised model of platelet aggregation. J Clin Invest 2000; 105 (6) 783-791
  • 29 Jackson SP, Nesbitt WS, Kulkarni S. Signaling events underlying thrombus formation. J Thromb Haemost 2003; 1 (7) 1602-1612
  • 30 Ni H, Yuen PS, Papalia JM , et al. Plasma fibronectin promotes thrombus growth and stability in injured arterioles. Proc Natl Acad Sci U S A 2003; 100 (5) 2415-2419
  • 31 André P, Prasad KS, Denis CV , et al. CD40L stabilizes arterial thrombi by a beta3 integrin—dependent mechanism. Nat Med 2002; 8 (3) 247-252
  • 32 Cosemans JM, Schols SE, Stefanini L , et al. Key role of glycoprotein Ib/V/IX and von Willebrand factor in platelet activation-dependent fibrin formation at low shear flow. Blood 2011; 117 (2) 651-660
  • 33 Whincup PH, Danesh J, Walker M , et al. von Willebrand factor and coronary heart disease: prospective study and meta-analysis. Eur Heart J 2002; 23 (22) 1764-1770
  • 34 Smith NL, Rice KM, Bovill EG , et al. Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis. Blood 2011; 117 (22) 6007-6011
  • 35 Wu D, Vanhoorelbeke K, Cauwenberghs N , et al. Inhibition of the von Willebrand (VWF)-collagen interaction by an antihuman VWF monoclonal antibody results in abolition of in vivo arterial platelet thrombus formation in baboons. Blood 2002; 99 (10) 3623-3628
  • 36 Szanto T, Vanhoorelbeke K, Toth G , et al. Identification of a VWF peptide antagonist that blocks platelet adhesion under high shear conditions by selectively inhibiting the VWF-collagen interaction. J Thromb Haemost 2009; 7 (10) 1680-1687
  • 37 Kleinschnitz C, De Meyer SF, Schwarz T , et al. Deficiency of von Willebrand factor protects mice from ischemic stroke. Blood 2009; 113 (15) 3600-3603
  • 38 Sadler JE, Budde U, Eikenboom JC , et al; Working Party on von Willebrand Disease Classification. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006; 4 (10) 2103-2114
  • 39 van Schooten CJ, Shahbazi S, Groot E , et al. Macrophages contribute to the cellular uptake of von Willebrand factor and factor VIII in vivo. Blood 2008; 112 (5) 1704-1712
  • 40 Hoylaerts MF, Nuyts K, Peerlinck K, Deckmyn H, Vermylen J. Promotion of binding of von Willebrand factor to platelet glycoprotein Ib by dimers of ristocetin. Biochem J 1995; 306 (Pt 2) 453-463
  • 41 Flood VH, Gill JC, Morateck PA , et al. Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor. Blood 2010; 116 (2) 280-286
  • 42 Flood VH, Friedman KD, Gill JC , et al. Limitations of the ristocetin cofactor assay in measurement of von Willebrand factor function. J Thromb Haemost 2009; 7 (11) 1832-1839
  • 43 National Institutes of Health Staff. NIH-NHLBI. Clinical guidelines: the diagnosis, evaluation and management of von Willebrand disease. Available at http://www.nhlbi.nih.gov/guidelines/vwd/1_frontmatter.htm . 2007. U.S. Department of Health and Human Services
  • 44 Favaloro EJ, Bonar R, Marsden K. Lower limit of assay sensitivity: an under-recognised and significant problem in von Willebrand disease identification and classification. Clin Lab Sci 2008; 21 (3) 178-183
  • 45 Hillarp A, Stadler M, Haderer C, Weinberger J, Kessler CM, Römisch J. Improved performance characteristics of the von Willebrand factor ristocetin cofactor activity assay using a novel automated assay protocol. J Thromb Haemost 2010; 8 (10) 2216-2223
  • 46 Vanhoorelbeke K, Cauwenberghs N, Vauterin S, Schlammadinger A, Mazurier C, Deckmyn H. A reliable and reproducible ELISA method to measure ristocetin cofactor activity of von Willebrand factor. Thromb Haemost 2000; 83 (1) 107-113
  • 47 Flood VH, Gill JC, Morateck PA , et al. Gain-of-function GPIb ELISA assay for VWF activity in the Zimmerman Program for the Molecular and Clinical Biology of VWD. Blood 2011; 117 (6) e67-e74
  • 48 Bonnefoy A, Romijn RA, Vandervoort PA, VAN Rompaey I, Vermylen J, Hoylaerts MF. von Willebrand factor A1 domain can adequately substitute for A3 domain in recruitment of flowing platelets to collagen. J Thromb Haemost 2006; 4 (10) 2151-2161
  • 49 Flood VH, Lederman CA, Wren JS , et al. Absent collagen binding in a VWF A3 domain mutant: utility of the VWF:CB in diagnosis of VWD. J Thromb Haemost 2010; 8 (6) 1431-1433
  • 50 Favaloro EJ. Collagen binding assay for von Willebrand factor (VWF:CBA): detection of von Willebrands Disease (VWD), and discrimination of VWD subtypes, depends on collagen source. Thromb Haemost 2000; 83 (1) 127-135
  • 51 Siljander P, Lassila R. Studies of adhesion-dependent platelet activation: distinct roles for different participating receptors can be dissociated by proteolysis of collagen. Arterioscler Thromb Vasc Biol 1999; 19 (12) 3033-3043
  • 52 Lisman T, Raynal N, Groeneveld D , et al. A single high-affinity binding site for von Willebrand factor in collagen III, identified using synthetic triple-helical peptides. Blood 2006; 108 (12) 3753-3756
  • 53 Sztukowska M, Gallinaro L, Cattini MG , et al. 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 2008; 143 (1) 107-114
  • 54 Ruggeri ZM. Type IIB von Willebrand disease: a paradox explains how von Willebrand factor works. J Thromb Haemost 2004; 2 (1) 2-6
  • 55 Rayes J, Hommais A, Legendre P , et al. Effect of von Willebrand disease type 2B and type 2M mutations on the susceptibility of von Willebrand factor to ADAMTS-13. J Thromb Haemost 2007; 5 (2) 321-328
  • 56 Szántó T, Schlammadinger A, Salles I , et al. Type 2B von Willebrand disease in seven individuals from three different families: phenotypic and genotypic characterization. Thromb Haemost 2007; 98 (1) 251-254
  • 57 Virchow RLK. Thrombose und Embolie. Gefässentzündung und septische Infektion. Gesammelte Abhandlungen zur wissenschaftlichen Medicin 1856. Frankfurt am Main: : Von Meidinger & Sohn;; 219-732
  • 58 Zabaneh D, Gaunt TR, Kumari M , et al. Genetic variants associated with Von Willebrand factor levels in healthy men and women identified using the HumanCVD BeadChip. Ann Hum Genet 2011; 75 (4) 456-467
  • 59 Smith NL, Chen MH, Dehghan A , et al; Wellcome Trust Case Control Consortium. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation 2010; 121 (12) 1382-1392
  • 60 Szántó T, Schlammadinger A, Staelens S , et al. The A/T1381 polymorphism in the A1-domain of von Willebrand factor influences the affinity of von Willebrand factor for platelet glycoprotein Ibalpha. Thromb Haemost 2007; 98 (1) 178-185
  • 61 James PD, Paterson AD, Notley C , et al; Association of Hemophilia Clinic Directors of Canada. Genetic linkage and association analysis in type 1 von Willebrand disease: results from the Canadian type 1 VWD study. J Thromb Haemost 2006; 4 (4) 783-792
  • 62 Davies JA, Collins PW, Hathaway LS, Bowen DJ. Effect of von Willebrand factor Y/C1584 on in vivo protein level and function and interaction with ABO blood group. Blood 2007; 109 (7) 2840-2846
  • 63 Mohlke KL, Purkayastha AA, Westrick RJ , et al. Mvwf, a dominant modifier of murine von Willebrand factor, results from altered lineage-specific expression of a glycosyltransferase. Cell 1999; 96 (1) 111-120
  • 64 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 (6) 910-917
  • 65 Gallinaro L, Cattini MG, Sztukowska M , et al. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood 2008; 111 (7) 3540-3545
  • 66 Kunicki TJ, Baronciani L, Canciani MT , et al. An association of candidate gene haplotypes and bleeding severity in von Willebrand disease type 2A, 2B, and 2M pedigrees. J Thromb Haemost 2006; 4 (1) 137-147
  • 67 Kunicki TJ, Federici AB, Salomon DR , et al. An association of candidate gene haplotypes and bleeding severity in von Willebrand disease (VWD) type 1 pedigrees. Blood 2004; 104 (8) 2359-2367
  • 68 Bauduer F, Ducout L. Is the assessment of von Willebrand disease prevalence an achievable challenge? The example of the French Basque Country where blood group O and factor XI deficiency are highly prevalent. J Thromb Haemost 2004; 2 (10) 1724-1726
  • 69 Santos KF, Battisti V, Corrêa MdeC , et al. Enzymes that hydrolyze adenine nucleotides in platelets and polymorphisms in the alpha2 gene of integrin alpha2beta1 in patients with von Willebrand disease. Mol Cell Biochem 2010; 340 (1-2) 249-256
  • 70 Rugeri L, Beguin S, Hemker C , et al. Thrombin-generating capacity in patients with von Willebrand’s disease. Haematologica 2007; 92 (12) 1639-1646
  • 71 Béguin S, Kumar R, Keularts I, Seligsohn U, Coller BS, Hemker HC. Fibrin-dependent platelet procoagulant activity requires GPIb receptors and von Willebrand factor. Blood 1999; 93 (2) 564-570
  • 72 Forestier M, Reséndiz JC, Pontiggia L, Lassila R, Beer JH. Platelet microparticle suppressing antibody against GP Ibalpha acts independently of the filamin cleavage and increases protein tyrosine phosphorylation. Blood Coagul Fibrinolysis 2008; 19 (8) 801-806
  • 73 Magwenzi SG, Ajjan RA, Standeven KF, Parapia LA, Naseem KM. Factor XIII supports platelet activation and enhances thrombus formation by matrix proteins under flow conditions. J Thromb Haemost 2011; 9 (4) 820-833
  • 74 Jurk K, Clemetson KJ, de Groot PG , et al. Thrombospondin-1 mediates platelet adhesion at high shear via glycoprotein Ib (GPIb): an alternative/backup mechanism to von Willebrand factor. FASEB J 2003; 17 (11) 1490-1492
  • 75 Rayes J, Hollestelle MJ, Legendre P , et al. Mutation and ADAMTS13-dependent modulation of disease severity in a mouse model for von Willebrand disease type 2B. Blood 2010; 115 (23) 4870-4877
  • 76 Pruss CM, Golder M, Bryant A , et al. Pathologic mechanisms of type 1 VWD mutations R1205H and Y1584C through in vitro and in vivo mouse models. Blood 2011; 117 (16) 4358-4366