von Willebrand disease (vWD) is the most common inherited disorder of hemostasis and comprises a spectrum of heterogeneous subtypes. Significant advances have been made in understanding von Willebrand factor (vWF) gene mutations, resultant physiologic deficits in the vWF peptide, and their correlation to clinical presentation. Diagnostic tests for this disorder are complex, and interpretation requires a thorough understanding of the underlying pathophysiology by the practicing physician. The objective of this review is to summarize our current understanding of pathophysiology, laboratory investigations, and evolving treatment paradigm of vWD with the availability of recombinant von Willebrand factor.
von WillebrandEA. Hereditary pseudohemophilia. Finska Lakarsallskapets Handl. 1926;67:7–112.
2.
PannekoekHVoorbergJ. Molecular cloning, expression and assembly of multimeric von Willebrand factor. Baillieres Clin Haematol. 1989;2(4):879-896.
3.
ZhouYFEngETZhuJLuCWalzTSpringerTA. Sequence and structure relationships within von Willebrand factor. Blood. 2012;120(2):449-458.
4.
KatsumiATuleyEABodóISadlerJE. Localization of disulfide bonds in the cystine knot domain of human von Willebrand factor. J Biol Chem. 2000;275(33):25585–25594.
5.
ZhouYFSpringerTA. Highly reinforced structure of a C-terminal dimerization domain in von Willebrand factor. Blood. 2014;123(12):1785–1793.
6.
HaberichterSLFahsSAMontgomeryRR. von Willebrand factor storage and multimerization: 2 independent intracellular processes. Blood. 2000;96(5):1808-1815.
7.
WagnerDDMayadasTMarderVJ. Initial glycosylation and acidic pH in the Golgi apparatus are required for multimerization of von Willebrand factor. J Cell Biol. 1986;102(4):1320-1324.
8.
SamorBMichalskiJCDebrayH. Primary structure of a new tetraantennary glycan of the N-acetyllactosaminic type isolated from human factor VIII/von Willebrand factor. Eur J Biochem. 1986;158(2):295–298.
9.
CanisKMcKinnonTANowakA. The plasma von Willebrand factor O-glycome comprises a surprising variety of structures including ABH antigens and disialosyl motifs. J Thromb Haemost. 2010;8(1):137–145.
10.
DongJFMoakeJLNolascoL. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood. 2002;100(12):4033–4039.
11.
FosterPAFulcherCAMartiTTitaniKZimmermanTS. 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):8443–8446.
12.
CruzMAYuanHLeeJRWiseRJHandinRI. 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):10822–10827.
13.
KoppelmanSJvan HoeijMVinkT. Requirements of von Willebrand factor to protect factor VIII from inactivation by activated protein C. Blood. 1996;87(6):2292–2300.
14.
JenkinsPVPasiKJPerkinsSJ. Molecular modeling of ligand and mutation sites of the type A domains of human von Willebrand factor and their relevance to von Willebrand’s disease. Blood. 1998;91(6)2032–2044.
15.
SugimotoMMohriHMcClintockRARuggeriZM. Identification of discontinuous von Willebrand factor sequences involved in complex formation with botrocetin. A model for the regulation of von Willebrand factor binding to platelet glycoprotein Ib. J Boil Chem. 1991;266(27):18172–18178.
16.
MiuraSLiCQCaoZWangHWardellMRSadlerJE. Interaction of von Willebrand factor domain A1 with platelet glycoprotein Ib alpha –(1-289). Slow intrinsic binding kinetics mediate rapid platelet adhesion. J Biol Chem. 2000;275(11):7539–7546.
17.
HaberichterSLMerricksEPFahsSAChristophersonPANicholsTCMontgomeryRR. Re-establishment of VWF-dependent Weibel-Palade bodies in VWD endothelial cells. Blood. 2005;105(1):145-152.
18.
ValentijnKMSadlerJEValentijnJAVoorbergJEikenboomJ. Functional architecture of Weibel-Palade bodies. Blood. 2011;117(19):5033-5043.
19.
GiblinJPHewlettLJHannahMJ. Basal secretion of von Willebrand factor from human endothelial cells. Blood. 2008;112(4):957–964.
20.
TsaiHMNagelRLHatcherVBSeatonACSussmanII. The high molecular weight form of endothelial cell von Willebrand factor is released by the regulated pathway. Br J Haematol. 1991;79(2):239–245.
21.
FerraroFKriston-ViziJMetcalfDJ. A two-tier Golgi-based control of organelle size underpins the functional plasticity of endothelial cells. Dev Cell. 2014;29(3):292–304.
22.
FiedlerUScharpfeneckerMKoidlS. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood. 2004;103(11):4150–4156.
23.
TorisuTTorisuKLeeIH. Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor. Nat Med. 2013;19(10):1281–1287.
24.
van SchootenCJShahbaziSGrootE. Macrophages contribute to the cellular uptake of von Willebrand factor and factor VIII in vivo. Blood. 2008;112(5):1704–1712.
25.
FavaloroEJLloydJRowellJ. Comparison of the pharmacokinetics of two von Willebrand factor concentrates [Biostate and AHF (high purity)] in people with von Willebrand disorder. A randomized cross-over, multi-centre study. Thromb Haemost. 2007;97(6):922–930.
26.
BrownSAEldridgeACollinsPWBowenDJ. Increased clearance of von Willebrand factor antigen post-DDAVP in Type 1 von Willebrand disease: Is it a potential pathogenic process?J Thromb Haemost. 2003;1(8):1714–1717.
27.
GallinaroLCattiniMGSztukowskaM. 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.
28.
GillJCEndres-BrooksJBauerPJMarksWJJrMontgomeryRR. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood. 1987;69(6):1691–1695.
29.
CastamanGTosettoARodeghieroF. Reduced von Willebrand factor survival in von Willebrand disease: pathophysiologic and clinical relevance. J Thromb Hemost. 2009;(7 supply 1):71–74.
30.
LongingPJChristopheODDenisCV. von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. Blood. 2015;125(13):2019–2028.
31.
FloodVHSchlauderaffACHaberichterSL; Zimmerman Program Investigators. Crucial role for the VWF A1 domain in binding to type IV collagen. Blood. 2015;125(14):2297–2304.
32.
LegendrePNavarreteAMRayesJ. Mutations in the A3 domain of von Willebrand factor inducing combined qualitative and quantitative defects in the protein. Blood. 2013;121(11):2135–2143.
33.
AndréPDenisCVWareJ. Platelets adhere to and translocate on von Willebrand factor presented by endothelium in stimulated veins. Blood. 2000;96(10):3322–3328.
34.
StoddartJHAndersenJLynchDC. Clearance of normal and type 2A von Willebrand factor in the rat. Blood. 1996;88(5):1692–1699.
35.
SavageBShattilSJRuggeriZM. Modulation of platelet function through adhesion receptors. A dual role for glycoprotein IIb-IIIa (integrin alpha IIb beta 3) mediated by fibrinogen and glycoprotein Ib-von Willebrand factor. J Biol Chem. 1992;267(16):11300–11306.
36.
FredricksonBJDongJFMcIntireLVLópezJA. Shear-dependent rolling on von Willebrand factor of mammalian cells expressing the platelet glycoprotein Ib-IX-V complex. Blood. 1998;92(10):3684–3693.
37.
FayPJCoumansJVWalkerFJ. von Willebrand factor mediates protection of factor VIII from activated protein C-catalyzed inactivation. J Biol Chem. 1991;266(4):2172–2177.
38.
SadlerJEMannucciPMBerntorpE. Impact, diagnosis and treatment of von Willebrand disease. Thromb Haemost. 2000;84(2):160–174.
39.
EikenboonJHilbertLRibbaAS. Expression of 14 von Willebrand factor mutations identified in patients with type 1 von Willebrand disease from the MCMDM-1VWD study. J Thromb Haemost. 2009;7(8):1304–1312.
40.
SandersYVFijnvandraatKBoenderJ; WiN Study Group. Bleeding spectrum in children with moderate or severe von Willebrand disease: Relevance of pediatric-specific bleeding. Am J Hematol. 2015;90(12):1142–1148.
41.
LyonsSEBruckMEBowieEJGinsburgD. Impaired intracellular transport produced by a subset of type IIA von Willebrand disease mutations. J Biol Chem. 1992;267(7):4424–4430.
42.
JamesPDNotleyCHegadornC. The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. Blood. 2007;109(1):145–154.
43.
SchneppenheimRMichielsJJObserT. A cluster of mutations in the D3 domain of von Willebrand factor correlates with a distinct subgroup of von Willebrand disease: type 2A/IIE. Blood. 2010;115(23):4894–4901.
44.
SchneppenheimRBrassardJKreyS. Defective dimerization of von Willebrand factor subunits due to a Cys-> Arg mutation in type IID von Willebrand disease. Proc Natl Acad Sci USA. 1996;93(8):3581–3586.
45.
HassenpflugWABuddeUObserT. Impact of mutations in the von Willebrand factor A2 domain on ADAMTS13-dependent proteolysis. Blood. 2006;107(6):2339–2345.
46.
HaberichterSLBuddeUObserTSchneppenheimSWermesCSchneppenheimR. The mutation N528 S in the von Willebrand factor (VWF) propeptide causes defective multimerization and storage of VWF. Blood. 2010;115(22):4580–4587.
47.
RuggeriZMParetiFIMannucciPMCiavarellaNZimmermanTS. Heightened interaction between platelets and factor VIII/von Willebrand factor in a new subtype of von Willebrand’s disease. N Engl J Med. 1980;302(19):1047–1051.
48.
CasonatoASartorelloFPontaraE. A novel von Willebrand factor mutation (I1372 S) associated with type 2B-like von Willebrand disease: an elusive phenotype and a difficult diagnosis. Thromb Haemost. 2007;98(6):1182–1187.
49.
JamesPDNotleyCHegadonC; Association of Hemophilia Clinic Directors of Canada. Challenges in defining type 2M von Willebrand disease: results from a Canadian cohort study. J Thromb Haemost. 2007;5(9):1914–1922.
50.
RiddellAFGomezKMillarCM. Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor. Blood. 2009;114(16):3489–3496.
51.
FavaloroEJMohammedS. Towards improved diagnosis of von Willebrand disease: comparative evaluations of several automated von Willebrand factor antigen and activity assays. Thromb Res. 2014;134(6):1292–1300.
52.
SadlerJEBuddeUEikenboomJC; 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;4:2103–2114.
53.
GoodeveAEikenboomJCastamanG. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood. 2007;109(1):112–121.
54.
ElbatamyMMollahSGrabellJ; Zimmerman Program Investigators. Normal range of bleeding scores of the ISTH-BAT: adult and pediatric data from the merging project. Hemophilia. 2014;20(6):831–835.
55.
MeyerDFressinaudEGaucherC. Gene defects in 150 unrelated French cases with type 2 von Willebrand disease: from the patient to the gene. INSERM Network on Molecular Abnormalities in von Willebrand disease. Thromb Haemost. 2007;7(1): 451–456.
56.
GoodeveAC. The genetic basis of von Willebrand disease. Blood Rev. 2010;24(3):123–134.
57.
BaroncianiLCozziGCancianiMT. Molecular defects in type 3 von Willebrand disease: updated results from 40 multiethnic patients. Blood cells Mol Dis. 2003;30(3):264–270.
58.
AllenSGoodeveAKPeakeIRDalyME. Endoplasmic reticulum retention and prolonged association of a von Willebrand’s disease-causing von Willebrand factor variant with ERp57 and calnexin. Biochem Biophys Res Commun. 2001;280(2):448–453.
59.
HaberichterSLBalistreriMChristophersonP. Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival. Blood. 2006;108(10):3344–3351.
60.
FedericiAB. Acquired von Willebrand Syndrome: an underdiagnosed and misdiagnosed bleeding complication in patients with lymphoproliferative and myeloproliferative disorders. Semin Hematol. 2006;43(1 suppl 1): S48–S58.
61.
CukerAConnorsJMKatzJTLevyBDLoscalzoJ. Clinical problem-solving. A bloody mystery. N Engl J Med. 2009;361(19):1887–1894.
62.
TiedeARandJHBuddeUGanserAFedericiAB. How I treat the acquired von Willebrand syndrome. Blood. 2011;117(25):6777–6785.
63.
CastamanGTosettoACappellettiA. Validation of a rapid test (WVF-LIA) for the quantitative determination of von Willebrand factor antigen in type 1 von Willebrand disease diagnosis within the European multicenter study MCMDM-1VWD. Thromb Res. 2010;126(3):227–231.
64.
NicholsWLHultinMBJamesAH. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008;14(2):171–232.
65.
Ledford-KraemerMR. Analysis of von Willebrand factor structure by multimer analysis. Am J Hematol. 2010;85(7):510–514.
66.
MillerJLKupinskiJMCastellaARuggeriZM. 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.
67.
NishinoMGirmaJPRothschildC. New variant of von Willebrand disease with defective binding to factor VIII. Blood. 1989;74(5):1591–1599.
68.
FavaloroEJ. Von Willebrand factor collagen-binding (activity) assay in the diagnosis of von Willebrand disease: a 15-year journey. Semi Thrombo Hemost. 2002;28(2):191–202.
69.
MichielsJJvan de VeldeAvan VlietHHvan der PlankenMSchroyensWBernemanZ. Response of von Willebrand factor parameters to desmopressin in patients with type 1 and type 2 congenital von Willebrand disease: diagnostic and therapeutic implications. Semin Thromb Hemost. 2002;28(2):111–132.
70.
FedericiABMazurierCBerntorpE. Biologic response to desmopressin in patients with severe type 1 and type 2 von Willebrand disease: results of a multicenter European study. Blood. 2004;103(6):2032–2038.
71.
JamesPLillicrapD. The role of molecular genetics in diagnosing von Willebrand disease. Semin Thromb Haemost. 2008;34(6):502–508.
72.
BellissimoDBChristophersonPAFloodVH. VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. Blood. 2012;119(9):2135–2140.
73.
OrtelTLCharlesLAKellerFG. Topical thrombin and acquired coagulation factor inhibitors: clinical spectrum and laboratory diagnosis. Am J Hematol. 1994;45(2):128–135.
74.
KouidesPAByamsVRPhilippCS. Multisite management study of menorrhagia with abnormal laboratory haemostasis: a prospective crossover study of intranasal desmopressin and oral tranexamic acid. Br J Haematol. 2009;145(2):212–220.
75.
HarrisonRLMcKeePA. Estrogen stimulates von Willebrand factor production by cultured endothelial cells. Blood. 1984;63(3):657–664.
76.
LillicrapDPoonMCWalkerIXieFSchwartzBA; Association of Hemophilia Clinic Directors of Canada. Efficacy and safety of the factor VIII/von Willebrand factor concentrate, haemate-P/humate-P: ristocetin cofactor unit dosing in patients with von Willebrand disease. Thromb Haemost. 2002;87(2):224–230.
77.
RivardGEAledortL; Alphanate Surgical Investigators. Efficacy of factor VIII/von Willebrand factor concentrate Alphanate in preventing excessive bleeding during surgery in subjects with von Willebrand disease. Haemophilia. 2008;14(2):271–275.
78.
WindygaJvon Depka-ProndzinskiM; European WilateStudy Group. Efficacy and safety of a new generation von Willebrand factor/factor VIII concentrate (Wilate) in the management of perioperative haemostasis in von Willebrand disease patients undergoing surgery. Thromb Haemost. 2011;105(6):1072–1079.
79.
GillJCCastamanGWindygaJ. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. 2015;126(17):2038–2046.
