A Short History of Diagnostic Tests for von Willebrand Disease: In Memory of Barry Firkin (1930 to 2001) and Ted Zimmerman (1937 to 1988)

ABSTRACT

By the end of the 1960s, von Willebrand disease (vWD) was accepted as a combined deficiency of factor (F) VIII coagulation and a plasma factor responsible for normal platelet adhesion. Just how these two functions related to each other was unclear, and the diagnostic tests available at the time were poorly reproducible, cumbersome, and unreliable. As a consequence, the condition was poorly delineated from other coagulation and platelet disorders. In the early 1970s, ristocetin-induced platelet aggregation was described and formed the basis of the first consistent and reliable test that quantified the platelet adhesive function missing in vWD. Immunoprecipitating techniques specific for the molecule missing in vWD were defined. The application of these technologies allowed a clearer understanding of the heterogeneity of vWD and continues to form a basis for the diagnosis of this condition. Concurrently, exploration of the structure and function of von Willebrand factor (vWF) has contributed greatly to the understanding of platelet physiology, ligand receptor interaction, and pathways of cellular interaction and activation. Despite all of the progress during the last 35 years, including extensive developments in the field of molecular biology and genetics of vWD, the diagnosis of this condition in many, if not most cases, remains controversial. The final plasma level of vWF is influenced substantially by epigenetic and environmental factors. This natural heterogeneity is further compounded by significant imprecision of existing tests. As a consequence, defining vWD on the basis of a variation from the normal range alone is more than likely to be incorrect. The high frequency of a positive bleeding disorder in the normal population does not assist discrimination. It has been suggested that the diagnosis of mild type 1 vWD be discarded because it does not exhibit consistent linkage to the VWF gene and does not predict bleeding.

KEYWORDS

von Willebrand disease (vWD) - diagnosis - history

REFERENCES

• 1 von Willebrand A E. Hereditar pseudohemofili.  Finska Laekaresaellsk Handl. 1926;  67 87-112
• 2 Duke W W. The pathogenesis of purpura hemorrhagica with special reference to the part played by blood platelets.  Arch Intern Med. 1912;  10 445-469
• 3 Ivy A C, Nelson D, Bucher G. The standardization of certain factors in the cutaneous “venostasis bleeding time technique”.  J Lab Clin Med. 1941;  26 1812-1822
• 4 Borchgrevink C F. The haemostatic effect of normal platelets in haemophilia and factor V deficiency.  Acta Med Scand. 1961;  170 378-383
• 5 Salzman E W. Measurement of platelet adhesiveness: a simple in vitro technique demonstrating an abnormality in von Willebrand's disease.  J Lab Clin Med. 1963;  62 724-735
• 6 Bowie E JM, Owen Jr C A, Thompson Jr J H et al.. Platelet adhesiveness in von Willebrand's disease.  Am J Clin Pathol. 1969;  52 69-77
• 7 Larrieu M J, Caen J P, Meyer D O et al.. Congenital bleeding disorders with long bleeding time and normal platelet count. II. Von Willebrand's disease (report of thirty seven patients).  Am J Med. 1968;  45 354-372
• 8 Rodgers R PC, Levin J. A critical reappraisal of the bleeding time.  Semin Thromb Hemost. 1990;  16 1-20
• 9 Lind S E. The bleeding time does not predict surgical bleeding.  Blood. 1991;  77 2547-2552
• 10 Howard M A, Firkin B G. Ristocetin: a new tool in the investigation of platelet aggregation.  Thromb Diath Haemorrh. 1971;  26 362-369
• 11 Howard M A, Sawers R J, Firkin B G. Ristocetin: a means of differentiating von Willebrand's disease into two groups.  Blood. 1973;  41 687-690
• 12 Weiss H J, Hoyer L W, Rickles F R et al.. Quantitative assay of a plasma factor, deficient in von Willebrand's disease, that is necessary for platelet aggregation. Relationship to factor VIII pro-coagulant activity and antigen content.  J Clin Invest. 1973;  52 2708-2716
• 13 Jenkins C S, Meyer D, Dreyfus M D et al.. Von Willebrand factor and ristocetin. 1. Mechanism of ristocetin induced platelet aggregation.  Br J Haematol. 1974;  28 561-578
• 14 Olson J D, Brockway W I, Fass D N. Evaluation of ristocetin-Willebrand factor assay and ristocetin induced platelet aggregation.  Am J Clin Pathol. 1975;  63 210-218
• 15 Zimmerman T S, Ratnoff O D, Powell A E. Immunological differentiation of classical hemophilia (factor VIII deficiency) and von Willebrand's disease with observations on combined deficiencies of antihemophilic factor and proaccelerin (factor V) and an acquired anticoagulant against antihemophilic factor.  J Clin Invest. 1971;  50 244-254
• 16 Zimmerman T S, Hoyer L W, Dickinson L, Edgington T S. Determination of the von Willebrand's disease antigen (factor VIII related antigen) in plasma by quantitative immunoelectrophoresis.  J Lab Clin Med. 1975;  86 152-159
• 17 Peake I R, Bloom A L. The use of an immunoradiometric assay for FVIII related antigen in the study of atypical von Willebrand's disease.  Thromb Res. 1977;  10 27-32
• 18 Sixma J J, Wester J. The hemostatic plug.  Semin Hematol. 1977;  14 265-299
• 19 Koutts J, Howard M A, Firkin B G. Factor VIII physiology and pathology in man. In: Brown E Progress in Hematology. XI. New York; Grune and Stratton 1979: 115-145
• 20 Zimmerman T S. Factor VIII/von Willebrand factor. Structure and function.  Ann NY Acad Sci. 1987;  509 53-59
• 21 Vehar G A, Keyt B, Eaton D et al.. Structure of human factor VIII.  Nature. 1984;  312 337-342
• 22 Ruggeri Z M, Zimmerman T S. Variant von Willebrand 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 1318-1325
• 23 Siedlecki C A, Lestini J, Kottke-Marchant K K et al.. Shear dependent changes in the three dimensional structure of human von Willebrand factor.  Blood. 1996;  88 2939-2950
• 24 Ruggeri Z M. Von Willebrand factor.  J Clin Invest. 1997;  99 559-564
• 25 Ginsburg D, Handin R I, Bonthron D T. Human von Willebrand factor (VWF): isolation of complementary DNA (cDNA) clones and chromosomal localisation.  Science. 1985;  228 1401-1406
• 26 Sadler J E, Shelton-Inloes B B, Sorace J M et al.. Cloning and characterization of two cDNAs coding for human von Willebrand factor.  Proc Natl Acad Sci USA. 1985;  82 6394-6398
• 27 Von Willebrand factor mutation database .http://Available at: http://www.vwf.group.shef.ac.uk/ Accessed on October 7, 2005
• 28 Ruggeri Z M. Von Willebrand factor, platelets and endothelial cell interactions.  J Thromb Haemost. 2003;  1 1335-1342
• 29 Ozaki Y, Asazuma N, Suzuki I et al.. Platelet GP-IX-V dependent signalling.  J Thromb Haemost. 2005;  3 1745-1751
• 30 Watson S P, Auger J M, McCarty O JT et al.. GPVI and integrin alphaIIbeta3 signaling in platelets.  J Thromb Haemost. 2005;  3 1752-1762
• 31 Coller B S. Platelet GPIIb/IIIa antagonists: the first anti-integrin receptor therapeutics.  J Clin Invest. 1997;  99 1467-1471
• 32 Ruggeri Z M. Old concepts and new developments in the study of platelet aggregation.  J Clin Invest. 2000;  105 699-701
• 33 Nilsson I M. von Willebrand's disease from 1926-1983.  Scand J Haematol. 1984;  33(suppl 40) 21-43
• 34 Minot G. A familial hemorrhagic condition associated with a prolongation of the bleeding time.  Am J Med Sci. 1928;  175 301-306
• 35 Biggs R, Eveling J, Richards G. The assay of antihaemophilic-globulin activity.  Br J Haematol. 1955;  1 20-24
• 36 Hardisty R M, Macpherson J C. A one stage factor VIII (antihaemophilic globulin) assay and its use on venous and capillary plasma.  Thromb Death Haemorrh. 1962;  7 215-228
• 37 Alexander B, Goldstein R. Dual hemostatic defect in pseudohemophilia.  J Clin Invest. 1953;  32 551 (abst)
• 38 Nilsson I M, Blombäck M, von Fränckel I. On an inherited autosomal haemorrhagic diathesis with antihaemophilic globulin (AHG) deficiency and prolonged bleeding time.  Acta Med Scand. 1957;  159 35-37
• 39 Shulman J, Smith C H, Erlandson M et al.. Vascular hemophilia. A familial hemorrhagic disease in males and females characterized by combined antihemophilic globulin deficiency and vascular abnormalities.  Pediatrics. 1956;  18 347-361
• 40 Blackburn E K, Macfie J M, Monaghan J H, Page A P. Antihaemorphilic factor deficiency: capillary defects of von Willebrand type, and idiopathic thrombocytopenia occurring in one family.  J Clin Path. 1961;  14 540-542
• 41 Nilsson I M, Blombäck M, von Blombäck B. Willebrand's disease in Sweden. Its pathogenesis and treatment.  Acta Med Scand. 1959;  164 263-278
• 42 Cornu P, Larrieu M J, Caen J et al.. Transfusion studies in von Willebrand's disease: effect on bleeding time and factor VIII.  Br J Haematol. 1963;  9 189-202
• 43 Miller C H, Graham J B, Goldin L R et al.. Genetics of classic von Willebrand's disease. 1. Phenotypic variations within families.  Blood. 1979;  54 117-136
• 44 Abildgaard C F, Suzuki Z, Harrison J et al.. Serial studies in von Willebrand's disease: variability versus “variants”.  Blood. 1980;  56 712-716
• 45 Born G VR. Aggregation of blood platelets by adenosine diphosphate and its reversal.  Nature. 1982;  194 827-829
• 46 Grundy W E, Sinclair A C, Theriault R J et al.. Ristocetin, antimicrobial properties.  Antibiotics Ann. 1956-7;  1 687-698
• 47 Gangarosa E J. Complications of ristocetin therapy.  Lancet. 1958;  1 1179-1180
• 48 Herting R J, Lees B, Zimmerman A J et al.. Ristocetin-a statistical review of 333 cases.  JAMA. 1959;  170 176-178
• 49 Clancy R L, Jenkins E, Firkin B. Qualitative platelet abnormalities in idiopathic thrombocytopaenic purpure.  N Engl J Med. 1972;  286 622-626
• 50 Clancy R, Jenkins E, Firkin B. Platelet defects in infectious mononucleosis.  BMJ. 1971;  4 646-648
• 51 Van der Weyden M B, Clancy R L, Howard M A et al.. Qualitative platelet defects with reduced life span in acute leukaemia.  Aust N Z J Med. 1972;  4 339-345
• 52 Howard M A, Hutton R A, Hardisty R M. Hereditary giant platelet syndrome: a disorder of a new aspect of platelet function.  Br Med J. 1973;  2 586-588
• 53 Sadler J E. for the Subcommittee on von Willebrand Factor of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. A revised classification of von Willebrand disease.  Thromb Haemost. 1994;  71 520-525
• 54 Italian Working Group . Spectrum of von Willebrand's disease. A study of 100 cases.  Br J Haematol. 1977;  35 101-112
• 55 Ruggeri Z M, Pareti F I, Mannucci P M et al.. Heightened interaction between platelets and factorVIII/von Willebrand factor in a new subtype of von Willebrand's disease.  N Engl J Med. 1980;  302 1047-1051
• 56 Ware J, Dent J A, Azuma H et al.. Identification of a point mutation in type IIb von Willebrand disease illustrating the regulation of von Willebrand factor affinity for the platelet membrane glycoprotein Ib-IX receptor.  Proc Natl Acad Sci USA. 1991;  88 2946-2950
• 57 Randi A M, Rabinowitz I, Mancuso D J et al.. Molecular basis of von Willebrand disease type IIB.  J Clin Invest. 1991;  87 1220-1226
• 58 Cooney K A, Nichols W C, Bruck M E et al.. The molecular defect in type IIB von Willebrand disease. Identification of four potential missense mutations within the putative GpIb binding sequence.  J Clin Invest. 1991;  87 1227-1233
• 59 Takahashi H. Studies in the pathophysiology and treatment of von Willebrand's disease. IV. Mechanisms of increased ristocetin induced platelet aggregation in von Willebrand's disease.  Thromb Res. 1980;  19 857-867
• 60 Miller J I, Castella A. Platelet type von Willebrand's disease: characterization of a new bleeding disorder.  Blood. 1982;  60 790-794
• 61 Weiss H J, Meyer D, Rabinowitz R et al.. Pseudo-von Willebrand's disease. An intrinsic platelet defect with aggregation by unmodified human factorVIII/von Willebrand factor and enhanced absorbtion of its high molecular weight multimers.  N Engl J Med. 1982;  306 326-333
• 62 Miller C H, Cunningham D, Lyle V A et al.. Mutation in the gene encoding the alpha chain of platelet glycoprotein Ib in platelet type von Willebrand's disease.  Proc Natl Acad Sci USA. 1991;  88 4761-4765
• 63 Russell S D, Roth G J. Pseudo-von Willebrand's disease: a mutation in the platelet glycoprotein Ib alpha gene associated with a hyperactive platelet receptor.  Blood. 1993;  81 1787-1791
• 64 Phillips D R, Jennings L K, Edwards H H. Identification of membrane proteins mediating the interaction of human platelets.  J Cell Biol. 1980;  86 77-86
• 65 Coller B S, Peerschke E I, Scudder L E et al.. Studies with a murine monoclonal antibody that abolishes ristocetin induced binding of von Willebrand factor to platelets: additional evidence in support of GPIb as a platelet receptor for von Willebrand factor.  Blood. 1983;  61 99-110
• 66 Nurden A J, Caen J P. Specific roles for platelet surface glycoproteins in platelet function.  Nature. 1975;  255 720-722
• 67 Clementson K J, McGregor J L, James E et al.. Characterization of the platelet membrane glycoprotein abnormalities in Bernard Soulier syndrome and comparison with normal with by surface labelling techniques and high resolution two dimensional gel electrophoresis.  J Clin Invest. 1982;  70 304-311
• 68 Fujimura Y, Titani K, Holland L Z et al.. von Willebrand factor: a reduced and alkylated 52/48 kDa fragment beginning at amino acid residue 449 contains the domain interacting with platelet glycoprotein Ib.  J Biol Chem. 1986;  261 381-385
• 69 Read M S, Shermer R W, Brinkhous K. Venom coagglutin: an activator of platelet aggregation dependent on von Willebrand factor.  Proc Natl Acad Sci USA. 1978;  75 4514-4518
• 70 Kirby E P. The agglutination of human platelets by bovine factor VIII.  J Lab Clin Med. 1982;  100 963-976
• 71 Moake J L, Turner N A, Stathopoulos N A et al.. Involvement of large plasma von Willebrand factor (VWF) multimers and unusually large VWF forms derived from endothelial cells in shear stress induced platelet aggregation.  J Clin Invest. 1986;  78 1456-1461
• 72 Ikeda Y, Handa M, Kawano K et al.. The role of von Willebrand factor and fibrinogen in platelet aggregation under shear stress.  J Clin Invest. 1991;  87 1234-1240
• 73 Pasi K J, Collins P W, Keeling D M et al.. von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organisation.  Haemophilia. 2004;  10 218-231
• 74 Favaloro E J, Koutts J. Laboratory assays for von Willebrand factor: relative contribution to the diagnosis of von Willebrand's disease.  Pathology. 1997;  29 385-391
• 75 Favaloro E J, Smith J, Petinos P et al.. On behalf of the RCPA quality assurance program (QAP) in haematology-haemostasis scientific advisory panel. Laboratory testing for von Willebrand's disease: an assessment of current diagnostic practice and efficacy by means of a multi-laboratory survey.  Thromb Haemost. 1999;  82 1276-1282
• 76 Budde U, Drewke E, Mainusch K et al.. Laboratory diagnosis of congenital von Willebrand's disease.  Semin Thromb Hemost. 2002;  28 173-190
• 77 Van Hoorelbeke K, Cauwenberghs N, Vandercasteele G et al.. A reliable von Willebrand factor: ristocetin co-factor enzyme linked immunoabsorbent assay to differentiate between type 1 and type 2 von Willebrand's disease.  Semin Thromb Hemost. 2002;  28 161-166
• 78 Murdock P J, Woodhams B J, Mathews K B et al.. Von Willebrand factor activity detected in a monoclonal antibody based ELISA: an alternative to the ristocetin cofactor platelet agglutination assay for diagnostic use.  Thromb Haemost. 1997;  78 1272-1277
• 79 Favaloro E J, Grispo L, Exner T et al.. Development of a simple collagen based ELISA assay aids in the diagnosis of, and permits sensitive discrimination between type I and type II von Willebrand's disease.  Blood Coagul Fibrinolysis. 1991;  2 285-291
• 80 van Mourik J A, Mochtar I A. Purification of human antihaemophilic factor (factor VIII) by gel chromatography.  Biochim Biophys Acta. 1970;  221 677-679
• 81 Hoyer I W, Shainoff J R. Factor VIII related protein circulates in human plasma as high molecular weight multimers.  Blood. 1980;  55 1056-1059
• 82 Counts R B, Paskell S L, Elgee S. Disulfide bonds and the quaternary structure of factor VIII/von Willebrand factor.  J Clin Invest. 1978;  62 702-709
• 83 Over J, Bouma B M, van Mourik J A et al.. Heterogeneity of human Factor VIII. I. Characterisation of factor VIII present in the supernatant of cryoprecipitate.  J Lab Clin Med. 1978;  91 32-46
• 84 Sixma J J, Over J, Bouma B N et al.. Predominance of normal low molecular weight forms of factor VIII in “variant” von Willebrand's disease.  Thromb Res. 1978;  12 929-935
• 85 Gralnick H R, Williams S B, Morisato D K. Effect of multimeric structure of factor VIII/von Willebrand factor protein on binding to platelets.  Blood. 1981;  58 387-397
• 86 Koutts J, Stott L, Sawers R J. Variant pattern of von Willebrand's disease.  Thomb Research. 1974;  5 557-564
• 87 Ruggeri Z M, Zimmerman T S. Von Willebrand factor and von Willebrand disease.  Blood. 1987;  70 895-904
• 88 Holmberg L, Nilsson I M. Genetic variants of von Willebrand's disease.  BMJ. 1972;  3 317-320
• 89 Firkin B, Firkin F, Stott L. von Willebrand's disease type B: a newly defined bleeding diathesis.  Aust NZ J Med. 1973;  3 225-229
• 90 Meyer D, Jenkins C SP, Dreyfus M D et al.. Willebrand factor and ristocetin. II. Relationship between Willebrand factor, Willebrand antigen and factor VIII activity.  Br J Haematol. 1974;  28 579-599
• 91 Peake I R, Bloom A L, Giddings J C. Inherited variants of factor VIII related protein in von Willebrand's disease.  N Engl J Med. 1974;  291 113-117
• 92 Peake I R, Liddel M B, Moodie P et al.. Severe type III von Willebrand's disease caused by deletions of exon42 of the von Willebrand factor gene: family studies that identify carriers of the condition and compound heterozygous individuals.  Blood. 1990;  75 654-661
• 93 Schneppenheim R, Kreey S, Bergmann F et al.. Genetic heterogeneity of severe von Willebrand disease type III in the German population.  Hum Genet. 1994;  94 640-652
• 94 Zhang Z P, Lindsedt M, Falk G et al.. Nonsense mutations of the von Willebrand gene in patients with von Willebrand disease type III and type I.  Am J Hum Genet. 1992;  51 850-858
• 95 Mannucci P M, Meyer D, Ruggeri Z M et al.. Precipitating antibodies in von Willebrand's disease.  Nature. 1976;  262 141-142
• 96 Sadler J E, Gralnick H R. Commentary: a new classification for von Willebrand's disease.  Blood. 1994;  84 676-679
• 97 Howard M A, Salem H H, Thomas K B et al.. Variant von Willebrand's disease type B revisited.  Blood. 1982;  60 1420-1428
• 98 Mannucci P M, Lombardi R, Castaman C et al.. Von Willebrand disease “Vicenza” with larger than normal (supra-normal) von Willebrand factor multimers.  Blood. 1988;  71 65-70
• 99 Ciavarella G, Ciavarella N, Antoncecchi S et al.. High resolution analysis of von Willebrand factor multimeric composition defines a new variant of type 1 von Willebrand's disease with aberrant structure, but presence of all size multimers (type 1C).  Blood. 1985;  66 1423-1429
• 100 Lyons S E, Bruck M E, Bowie E J et al.. Impaired intracellular transport produced by a subset of Type IIA von Willebrand disease mutations.  J Biol Chem. 1992;  267 4424-4430
• 101 Dent J A, Berkowitz S D, Ware J et al.. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in Type IIA von Willebrand factor.  Proc Natl Acad Sci USA. 1990;  87 6306-6310
• 102 Schneppenheim R, Brassard J, Kray S et al.. 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 3581-3586
• 103 Ginsburg D, Wagner D D. In: Hoffmann R, Benz EJ, Shattil SJ, et al Hematology: Basic Principles and Practice. 4th ed. Philadelphia, PA; Churchill Livingstone 2005: 2111-2114
• 104 Weiss H J, Kochwa S. Molecular forms of antihemophilic globulins in plasma, cryoprecipitate and after thrombin activation.  Br J Haematol. 1970;  18 89-100
• 105 Weiss H J, Hoyer L W. Von Willebrand factor: dissociation from antihemophilic factor procoagulant activity.  Science. 1973;  182 1149-1151
• 106 Owen W G, Wagner R H. Antihemophilic factor separation of an active fragment following dissociation by salts and detergents.  Thromb Diath Haemorrh. 1972;  27 502-515
• 107 Zimmerman T S, Edgington T S. Factor VIII coagulant activity and factor VIII like antigen: independent molecular entities.  J Exp Med. 1973;  138 1015-1020
• 108 Koutts J, Gude N, Firkin B G. The dynamic interrelationship between factor VIII and von Willebrand factor.  Thromb Res. 1976;  8 533-541
• 109 Koutts J, Lavergne J M, Meyer D. Immunological evidence that human factor VIII is composed of two moieties.  Br J Haematol. 1977;  37 415-427
• 110 Foster P A, Fulcher C A, Marti T et al.. A major factor VIII binding domain resides within the amino terminal 272 amino acid residues of von Willebrand factor.  J Biol Chem. 1987;  262 8443-8446
• 111 Weiss H J, Sussman I I, Hoyer L W. Stabilization of factor VIII in plasma by the von Willebrand factor.  J Clin Invest. 1977;  60 390-404
• 112 Nishino M, Girma J-P, Rothschild C et al.. New variant of von Willebrand's disease with defective binding to factor VIII.  Blood. 1989;  74 1591-1599
• 113 Sadler J E. Von Willebrand disease type: a diagnosis in search of a disease.  Blood. 2003;  101 2089-2093
• 114 Rodeghiero F. Willebrand disease: still an intriguing disorder in the era of molecular medicine.  Haemophilia. 2002;  8 292-300
• 115 Alperin J B. Estrogen and surgery in women with von Willebrand's disease.  Am J Med. 1982;  73 367-371
• 116 Hoyer L W. The factor VIII complex: structure and function.  Blood. 1981;  58 1-13
• 117 Gill J C, Endres-Brooks J, Bauer P J et al.. The effect of ABO blood group on the diagnosis of von Willebrand disease.  Blood. 1987;  69 1691-1695
• 118 Mannucci P M, Lattuada A, Castaman G et al.. Heterogeneous phenotypes of platelet and plasma von Willebrand factor in obligatory heterozygotes for severe von Willebrand disease.  Blood. 1989;  74 2433-2436
• 119 Mohlke K L, Ginsbrg D. Von Willebrand disease and quantitative variation in von Willebrand factor.  J Lab Clin Med. 1997;  130 252-261
• 120 Werner E J, Broxson E H, Tucker E L et al.. Prevalence of von Willebrand disease in children: a multicentre study.  J Pediatr. 1993;  123 893-898
• 121 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease.  Blood. 1987;  69 454-459
• 122 Castaman G, Eikenboom J CL, Bertina R M et al.. Inconsistency of association between type 1 von Willebrand disease phenotype and genotype in families identified in an epidemiological investigation.  Thromb Haemost. 1999;  82 1065-1070
• 123 Sadler J E, Mannucci P M, Berntrop E et al.. Impact, diagnosis and treatment of von Willebrand disease.  Thromb Haemost. 2000;  84 160-174
• 124 Kouides P A. Females with von Willebrand's disease: 72 years as the silent majority.  Haemophilia. 1998;  4 665-676
• 125 Kouides P A. Menorrhagia from a haematologist's point of view. Part 1: initial evaluation.  Haemophilia. 2002;  8 330-338
• 126 Foster P A. The reproductive health of women with von Willebrand disease unresponsive to DDAVP-results of an international survey.  Thromb Haemost. 1995;  74 784-790
• 127 Biron C, Mahieu B, Rochette P et al.. Preoperative screening for von Willebrand disease type 1: low yield and limited ability to predict bleeding.  J Lab Clin Med. 1999;  134 605-609
• 128 Coller B S, Schneiderham P I. In: Hoffman R, Benz EJ, Shattil SJ, et al Haematology: Basic Principles and Practice. 4th ed. Philadelphia, PA; Churchill Livingstone 2005: 1976-1982