Semin Thromb Hemost 2002; 28(2): 173-190
DOI: 10.1055/s-2002-27820
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Laboratory Diagnosis of Congenital von Willebrand Disease

Ulrich Budde1 , Elke Drewke1 , Kerstin Mainusch1 , Reinhard Schneppenheim2
  • 1Coagulation Laboratory, Laboratory Association Prof. Arndt and Partners, Hamburg
  • 2Department of Hematology, Children's Hospital, University Clinic, Hamburg, Germany
Further Information

Publication History

Publication Date:
03 May 2002 (online)

ABSTRACT

Von Willebrand disease (vWD) is caused by quantitative or qualitative defects, or both, of the von Willebrand factor (vWF), a multimeric high-molecular glycoprotein (GP). Typically, it affects the primary hemostatic system, which is reflected by a mucocutaneous bleeding tendency simulating a platelet function defect. The vWF promotes its function in two ways: (1) by supporting platelet adhesion to the injured vessel wall under conditions of high shear forces and (2) by its carrier function for factor VIIIc (FVIIIc) in plasma. Because of the complexity of the disease, diagnosis of vWD is one of the most challenging of any coagulation disorder. The stepwise diagnosis of vWD includes patients and family history, screening procedures (bleeding time [BT], filter tests, platelet counts, activated partial thromboplastin time [aPTT]), confirmatory tests (vWF antigen [vWF:Ag], vWF ristocetin cofactor activity [vWF:RCo], vWF collagen-binding [vWF:CB] assay, ristocetin-induced platelet aggregation [RIPA], FVIIIc) and tests for final classification (multimeric analysis, FVIII binding capacity of vWF [vWF:FVIIIB], platelet vWF). In 1999, we classified 303 patients with congenital vWD as type 1 (n = 122), type 2 (n = 171), and type 3 (n = 10). Type 2 was further subdivided into type 2A (n = 126), type 2B (n = 17), type 2M (n = 22), and type 2N (n = 6). Type 2A showed a remarkable heterogeneity, with only 27.8% (n = 36) of the ``classic'' IIA pattern. The other high-frequency patterns were type IB (25.4% n = 32) and type IIE/F/H-like structural abnormalities (28.6% n = 36). The spectrum was completed with samples from patients with types 2D, 2C, 2C Miami, smeary structures, and other rare subtypes (together 18.9% n = 23).

REFERENCES

  • 1 Sadler J E, Mannucci P M, Berntorp E. Impact, diagnosis and treatment of von Willebrand disease.  Thromb Haemost . 2000;  84 160-174
  • 2 Ruggeri Z M. Structure and function of von Willebrand factor.  Thromb Haemost . 1999;  82 576-584
  • 3 Schneppenheim R, Thomas K B, Sutor A H. Von Willebrand disease in childhood.  Semin Thromb Haemost . 1995;  21 261-275
  • 4 von Willebrand A E. Hereditär pseudohemofili.  Finska Läk Sällsk Handl . 1926;  68 87-112
  • 5 Nilsson I M. Von Willebrand's disease from 1926-1983.  Scand J Haematol . 1984;  33(Suppl 40) 21-43
  • 6 Mancuso D J, Tuley E A, Westfield L A. Structure of the gene for human von Willebrand factor.  J Biol Chem . 1989;  264 19514-19527
  • 7 Furlan M, Robles R, Solenthaler M, Lämmle B. Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura.  Blood . 1997;  91 3097-3103
  • 8 Ruggeri Z M, Zimmerman T S. Von Willebrand factor and von Willebrand disease.  Blood . 1987;  70 895-904
  • 9 Sadler E J. A revised classification of von Willebrand disease.  Thromb Haemost . 1994;  71 520-525
  • 10 Sadler E J, Gralnick H R. Commentary: A new classification for von Willebrand disease.  Blood . 1994;  84 676-679
  • 11 Nishino M, Girma J P, Rothschild C, Fressinaud E, Meyer D. New variant of von Willebrand disease with defective binding to factor VIII.  Blood . 1989;  74 1591-1599
  • 12 Mazurier C. Von Willebrand disease masquerading as haemophilia A.  Thromb Haemost . 1992;  67 391-396
  • 13 Schneppenheim R, Budde U, Ruggeri Z M. A molecular approach to the classification of von Willebrand disease.  Baillieres Clin Haematol . 2001;  14 281-298
  • 14 Rodeghiero F, Castaman G C, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease.  Blood . 1987;  69 454-459
  • 15 Miller C H, Lenzi R, Breen C. Prevalence of von Willebrand's disease among US adults.  Blood . 1987;  70 377-383
  • 16 Werner E J, Emmett H, Tucker E. Prevalence of von Willebrand disease in children. A multiethnic study.  J Pediatr . 1993;  123 893-898
  • 17 Holmberg L, Nilsson I M. Von Willebrand's disease.  Clin Hematol . 1985;  14 461-488
  • 18 Vlot A J, Mauser Bunschoten P E, Zarkova A G. The half-life of infused factor VIII is shorter in hemophiliac patients with blood group O than in those with blood group A.  Thromb Haemost . 2000;  83 65-69
  • 19 Oerstavik K H, Kornstad L, Reisner H, Berg K. Possible effect of secretor locus on plasma concentration of factor VIII and von Willebrand factor.  Blood . 1989;  73 990-993
  • 20 Gill J C, Endres-Brooks J, Bauer P J, Marks W J, Montgomery R R. The effect of ABO blood group on the diagnosis of von Willebrand disease.  Blood . 1987;  69 1691-1695
  • 21 Pottinger B E, Read R C, Paleolog E M, Higgins P C, Pearson J D. Von Willebrand factor is an acute phase reactant in man.  Thromb Res . 1989;  53 387-395
  • 22 Sixma J J, de Groot G P. Von Willebrand factor and the blood vessel wall.  Mayo Clin Proc . 1991;  66 623-628
  • 23 Rodeghiero F, Castaman G, Ruggeri M, Tosetto A. The bleeding time in normal subjects is mainly determined by platelet von Willebrand factor and is independent from blood group.  Thromb Res . 1992;  65 605-615
  • 24 DiPaola J, Federici A B, Mannucci P M. Low platelet alpha(2)beta(1) levels in type 1 von Willebrand disease correlate with impaired platelet function in a high shear stress system.  Blood . 1999;  93 3578-3582
  • 25 Lind S E. The bleeding time does not predict surgical bleeding.  Blood . 1991;  77 2547-2552
  • 26 Duke W W. The relation of blood platelets to hemorrhagic disease.  JAMA . 1910;  55 1185-1192
  • 27 Ivy A C, Shapiro P F, Melnick P. The bleeding tendency in jaundice.  Surg Gynecol Obstet . 1935;  60 781-784
  • 28 Mielke C H. Influence of aspirin on platelets and the bleeding time.  Am J Med . 1983;  74 72-78
  • 29 Sramek R, Sramek A, Koster T, Briet E, Rosendaal F R. A randomized and blinded comparison of 3 bleeding time techniques-The Ivy method, and the Simplate-II method in 2 directions.  Thromb Haemost . 1992;  67 514-518
  • 30 Kratzer M AA, Born G VR. Simulation of primary hemostasis in vitro.  Haemostasis . 1985;  15 357-362
  • 31 Weippert-Kretschmer M, Witte M, Budde U. The Thrombostat 4000. A sensitive screening test for von Willebrand's disease.  Semin Thromb Haemost . 1995;  21(Suppl 2) 44-51
  • 32 Fressinaud E, Veyradier A, Truchaud F. Screening for von Willebrand disease with a new analyzer using high shear stress: A study of 60 cases.  Blood . 1998;  91 1232-1231
  • 33 O'Brien J R, Salmon G P. Shear stress activation of platelet glycoprotein IIb/IIIa plus von Willebrand factor causes aggregation: filter blockage and the long term bleeding time in von Willebrand's disease.  Blood . 1987;  70 1354-1361
  • 34 Schlammadinger A, Kerenyi A, Muszbek L, Boda Z. Comparison of the O'Brien filter test and the PFA-100 platelet analyzer in the laboratory diagnosis of von Willebrand's disease.  Thromb Haemost . 2000;  84 88-92
  • 35 Dean J A, Blanchette V S, Carcao M D. von Willebrand disease in a pediatric based population-Comparison of type 1 diagnostic criteria and use of the PFA-100 and a von Willebrand factor/collagen-binding assay.  Thromb Haemost . 2000;  84 401-409
  • 36 Cramer A D, Melaragne A J, Phifer S J, Hougie C. Von Willebrand disease San Diego, a new variant.  Lancet . 1976;  ii 122
  • 37 Bux-Gewehr I, Morgenschweis K, Zotz R B, Budde U, Scharf R. Combined von Willebrand factor deficiency and factor XII deficiency.  Thromb Haemost . 2000;  83 514-516
  • 38 Baumgartner H R, Tschopp T B, Meyer D. Shear rate dependent inhibition of platelet adhesion and aggregation on collagenous surfaces by antibodies to human factor VIII/von Willebrand factor.  Br J Haematol . 1980;  44 127-139
  • 39 Sakariassen K S, Nieuwenhuis K, Sixma J J. Differentiation of patients with subtype IIb-like von Willebrand's disease by means of perfusion experiments with reconstituted blood.  Br J Haematol . 1985;  59 459-470
  • 40 Varon D, Lashevski I, Brenner B. Cone and plate(let) analyzer: monitoring glycoprotein IIb/IIIa antagonists and von Willebrand disease replacement therapy by testing platelet deposition under flow conditions.  Am Heart J . 1998;  135(Suppl) S187-S193
  • 41 Hellem A J. Platelet adhesiveness in von Willebrand's disease. A study with a new modification of the glass bead filter method.  Scand J Haematol . 1970;  7 374-382
  • 42 Salzman E W. Measurement of platelet adhesiveness. A simple in vitro technique demonstrating an abnormality in von Willebrand's disease.  J Lab Clin Med . 1983;  62 724-735
  • 43 Hubbard A R, Rigsby P, Barrowcliffe T W. Standardisation of factor VIII and von Willebrand factor in plasma: Calibration of the 4th International Standard (97/586).  Thromb Haemost . 2001;  85 634-638
  • 44 Nitu-Whalley H IC, Lee C A, Griffioen A, Jenkins P V, Pasi K J. Type 1 von Willebrand disease-a clinical retrospective study of the diagnosis, the influence of the ABO blood group and the role of the bleeding history.  Br J Haematol . 2000;  108 259-264
  • 45 Gralnick H R, Rick M E, McKeown L P. Platelet von Willebrand factor: an important determinant of the bleeding time in type I von Willebrand's disease.  Blood . 1986;  68 58-61
  • 46 Rodeghiero F, Castaman G C, Tosetto A, Lattuada A, Mannucci P M. Platelet von Willebrand factor assay-results using 2 methods for platelet lysis.  Thromb Res . 1990;  59 259-267
  • 47 Zimmerman T S, Hoyer L W, Dickinson, Edgington T S. Determination of the von Willebrand's disease antigen (factor VIII-related antigen) in plasma by immunoelectrophoresis.  J Lab Clin Med . 1975;  86 152-159
  • 48 Cejka J. Enzyme immunoassay for factor VIII-related antigen.  Clin Chem . 1992;  28 1356-1358
  • 49 Veyradier A, Fressinaud E, Sigaud M, Wolf M, Meyer D. A new automated method for von Willebrand factor antigen measurement using latex particles.  Thromb Haemost . 1999;  81 320-321
  • 50 Weiss H J, Hoyer L W, Rickles F, Varma A, Rogers J. Quantitative assay of a plasma factor in von Willebrand's disease that is necessary for platelet aggregation.  J Clin Invest . 1973;  52 2701-2716
  • 51 Macfarlane D E, Stibbe J, Kirby E P. A method for assaying von Willebrand factor (ristocetin cofactor).  Thrombosis et Diathesis Haemorrhagica . 1975;  34 306-308
  • 52 Brinkhous K M, Graham J E, Cooper H A, Allain J P, Wagner R H. Assay of von Willebrand factor in von Willebrand's disease and hemophilia: use of a macroscopic platelet aggregation test.  Thromb Res . 1975;  6 267-272
  • 53 Brinkhous K M, Read M S. Preservation of platelet receptors for platelet aggregation factor/von Willebrand factor by air drying, freezing or lyophilization: new stable platelet preparations for von Willebrand factor assays.  Thromb Res . 1987;  13 591-595
  • 54 Favaloro E J, Smith J, Petinos P, Hertzberg H, Koutts J. on behalf of the RCPA Quality Assurance Program (QAP) in Haematology Haemostasis Advisory Panel. Laboratory testing for von Willebrand disease: an assessment of current diagnostic practice and efficacy by means of a multi-laboratory survey.  Thromb Haemost . 1999;  82 1276-1282
  • 55 Vanhoorelbeke K, Cauwenbergs N, Vauterin S. A reliable and reproducible ELISA method to measure ristocetin cofactor activity of von Willebrand factor.  Thromb Haemost . 2000;  83 107-113
  • 56 Murdock P J, Woodhams B J, Matthews K B, Pasi J, Goodall A H. Von Willebrand factor activity detected in a monoclonal antibody-based ELISA: an alternative to the ristocetin platelet agglutination assay for diagnostic use.  Thromb Haemost . 1997;  78 1272-1277
  • 57 Preston F E. Assays for von Willebrand factor functional activity: a UK NEQAS survey.  Thromb Haemost (Letter) . 1998;  80 866
  • 58 Favaloro E. 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;  83 127-135
  • 59 Nitu-Whalley I C, Ridell A, Lee C A. Identifications of type 2 von Willebrand disease in previously diagnosed type 1 patients: a reappraisal using phenotypes, genotypes and molecular modelling.  Thromb Haemost . 2000;  84 998-1004
  • 60 Favaloro E J. Detection of von Willebrand disorder and identification of qualitative von Willebrand factor defects. Direct comparison of commercial ELISA-based von Willebrand factor activity options.  Am J Clin Pathol . 2000;  114 608-618
  • 61 Howard M A, Perkin J, Salem H H, Firkin B G. The agglutination of human platelets by bothrocetin: evidence that bothrocetin and ristocetin act at different sites on the factor VIII molecule and platelet membrane.  Br J Haematol . 1984;  57 25-35
  • 62 Fujimura Y, Miyata S, Nishida S. The interaction of bothrocetin with normal or variant von Willebrand factor (type-IIA and type-IIB) and its inhibition by monoclonal antibodies that block receptor binding.  Thromb Haemost . 1992;  68 464-469
  • 63 Brown J E, Bosak J O. An ELISA test for the binding of von Willebrand factor antigen to collagen.Thromb Res .  1986;  43 303-311
  • 64 Thomas K B, Sutor A H, Zieger B. A simple test for the determination of the von Willebrand factor function: the collagen binding activity.  Hämostaseologie . 1994;  14 133-139
  • 65 Pietu G, Fressinaud E, Girma J P. Binding of human von Willebrand factor to collagen and to collagen-stimulated platelets.  J Lab Clin Med . 1987;  109 637-646
  • 66 Budde U, Schneppenheim R, Zieger B. CBA/vWF:Ag ratio for diagnosis of von Willebrand disease (vWD): incorrect classification in more than 10% of patients with vWD type 2.  Thromb Haemost (Abst) . 1999;  100 (Suppl)
  • 67 Favaloro E J, Dean M, Grispo L, Exner T, Koutts J. von Willebrand's disease: use of collagen binding assay provides potential improvement to laboratory monitoring of desmopressin (DDAVP) therapy.  Am J Hematol . 1994;  45 205-211
  • 68 Kempfer A C, Silaf M R, Farias C E. Binding of von Willebrand factor to collagen by flow cytometry.  Am J Clin Pathol . 1999;  111 418-423
  • 69 Howard M A, Firkin B G. Ristocetin-a new tool in the investigation of platelet aggregation.  Thrombosis et Diathesis Haemorrhagica . 1971;  26 362-369
  • 70 Ruggeri Z M, Pareti F I, Mannucci P M, Ciavarella N, Zimmerman T S. Hightened interaction between platelets and factor VIII/von Willebrand factor in a new subtype of von Willebrand's disease.  N Engl J Med . 1980;  302 1047-1051
  • 71 Weiss H J, Meyer D, Rabinowitz R. Pseudo-von Willebrand's disease: an intrinsic platelet defect with aggregation by unmodified human factor VIII/von Willebrand factor and enhanced adsorption of its high-molecular-weight multimers.  N Engl J Med . 1982;  307 326-333
  • 72 Hilbert L, Jenkins P V, Gaucher C. Type 2M vWD resulting from a lysine deletion within a four lysine residue repeat in the A1 loop of von Willebrand factor.  Thromb Haemost . 2000;  84 188-194
  • 73 De Marco L, Mazzuccato M, Del Ben G M. Type IIB von Willebrand factor with normal sialic acid content induces platelet aggregation in the absence of ristocetin.  J Clin Invest . 1987;  80 475-482
  • 74 van Genderen J J P, Leenknegt H. Normal binding of plasma von Willebrand factor to platelets in essential thrombocythemia.  Am J Hematol . 1999;  61 153-154
  • 75 de Romeuf C, Mazurier C. Interest of a simple and fast method for platelet von Willebrand factor characterization.  Thromb Res . 1996;  15 287-298
  • 76 Vischer U M, Ingerslev J, Wollheim C B. Acute von Willebrand factor secretion from the endothelium in vivo: assessment through plasma propeptide (vWf:AgII) levels.  Thromb Haemost . 1997;  77 387-393
  • 77 de Romeuf C, Mazurier C. Comparison between von Willebrand factor (vWF) and vWF antigen II in normal individuals and patients with von Willebrand disease.  Thromb Haemost . 1998;  80 37-41
  • 78 van Genderen J J P, Boertjes R C, van Mourik A J. Quantitative analysis of von Willebrand factor and its propeptide in plasma in acquired von Willebrand syndrome.  Thromb Haemost . 1998;  80 495-498
  • 79 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
  • 80 Ruggeri Z M, Zimmerman T S. 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 1318-1325
  • 81 Hoyer L W, Shainoff J R. Factor VIII-related protein circulates in normal human plasma as high molecular weight multimers.  Blood . 1998;  55 1056-1059
  • 82 Dent J A, Galbusera M, Ruggeri Z M. Heterogeneity of plasma von Willebrand factor multimers resulting from proteolysis of the constituent subunit.  J Clin Invest . 1991;  88 774-782
  • 83 Budde U, Schneppenheim R, Plendl H. Luminographic detection of von Willebrand factor multimers in agarose gels and on nitrocellulose membranes.  Thromb Haemost . 1990;  63 312-315
  • 84 Enayat M S. Multimeric analysis of von Willebrand factor. In: Hemostasis and Thrombosis Protocols (Methods in Molecular Medicine Series) 1999 31: 187-200
  • 85 Aihara M, Sawada Y, Ueno K. Visualization of von Willebrand factor multimers by immunoenzymatic stain using avidin-biotin peroxidase complex.  Thromb Haemost . 1986;  55 263-267
  • 86 Bukh A, Ingerslev J, Stenbjerg S, Hundahl Möller P N. The multimeric structure of plasma FVIII:RAg studied by electroelution and immunoperoxidase detection.  Thromb Res . 1986;  43 579-584
  • 87 Baillod P, Affolter B, Kurt G H, Pflugshaupt R. Multimeric analysis of von Willebrand factor by vertical sodium dodecyl sulphate agarose gel electrophoresis, vacuum blotting technology and sensitive visualization by alkaline phosphatase anti-alkaline phosphatase complex.  Thromb Res . 1992;  66 745-755
  • 88 Schneppenheim R, Plendl H, Budde U. Luminography-an alternative assay for detection of von Willebrand factor multimers.  Thromb Haemost . 1988;  60 133-136
  • 89 Zimmerman T S, Dent J A, Ruggeri Z M, Nannini L H. Subunit composition of plasma von Willebrand factor. Cleavage is present in normal individuals, increased in IIA and IIB von Willebrand disease, but minimal in variants with aberrant structure of individual oligomers (types IIC, IID and IIE).  J Clin Invest . 1986;  77 947-951
  • 90 Budde U, Scharf R, Hartmann-Budde K, Dent J, Ruggeri Z M. Elevated platelet count as a cause of abnormal von Willebrand factor multimer distribution in plasma.  Blood . 1993;  82 1749-1757
  • 91 Mannucci P M, Moia M, Rebulla P. Correction of the bleeding time in treated patients with von Willebrand disease is not solely dependent on the normal multimeric structure of plasma von Willebrand factor.  Am J Hematol . 1987;  25 55-65
  • 92 Mazurier C, Samor B, Goudemand M. Improved characterization of plasma von Willebrand factor heterogeneity when using 2.5% agarose gel electrophoresis.  Thromb Haemost . 1986;  55 61-69
  • 93 Jorieux S, Gaucher C, Goudemand J, Mazurier C. A novel mutation in the D3 domain of von Willebrand factor markedly decreases its abiliy to bind factor VIII and affects its multimerization.  Blood . 1998;  92 4463-4670
  • 94 Budde U, Dent J A, Berkowitz S D, Ruggeri Z M, Zimmerman T S. Subunit composition of plasma von Willebrand factor in patients with the myeloproliferative syndrome.  Blood . 1986;  68 1213-1217
  • 95 Pareti F I, Lattuada A, Bressi C. Proteolysis of von Willebrand factor and shear stress-induced platelet aggregation in patients with aortic valve stenosis.  Circulation . 2000;  102 1290-1295
  • 96 Lopez Fernandez F M, Blanco Lopez J M, Castineira M P, Batlle J. Further evidence for recessive inheritance of von Willebrand disease with abnormal binding of von Willebrand factor to factor VIII.  Am J Hematol . 1992;  40 20-27
  • 97 Schneppenheim R, Budde U, Krey S. Results of a screening for von Willebrand disease type 2N patients with suspected haemophilia A or von Willebrand disease type 1.  Thromb Haemost . 1996;  76 598-602
  • 98 Mazurier C, Meyer D. Factor VIII binding assay of von Willebrand factor and the diagnosis of type 2N von Willebrand disease-results of an international survey.  Thromb Haemost . 1996;  76 270-274
  • 99 Mazurier C, Goudemand J, Hilbert L. Type 2N von Willebrand disease: clinical manifestations, pathophysiology, laboratory diagnosis and molecular biology.  Baillieres Clin Haematol . 2001;  14 337-347
  • 100 Allen S, Abuzenadah A M, Blagg J L. A novel type 2N von Willebrand disease-causing mutation that results in defective factor VIII binding, multimerization, and secretion of von Willebrand factor.  Blood . 2000;  95 2000-2007
  • 101 Jorieux S, Fressinaud E, Goudemand J. Conformational changes in the D′ domain of von Willebrand factor induced by CYS25 and CYS95 mutations lead to factor VIII binding defect and multimeric impairment.  Blood . 2000;  95 3139-3145
  • 102 Schneppenheim R, Obser T, Lenk H. Characterization of a combined defect of FVIII binding and multimerization in a patient with von Willebrand disease type 2N.  Blood (Abst) . 2000;  96 566a
  • 103 Schneppenheim R, Budde U, Obser T. Expression and characterization of von Willebrand dimerization defects in different types of von Willebrand disease.  Blood . 2001;  97 2059-2066
  • 104 Gaucher C, Dieval J, Mazurier C. Characterization of von Willebrand factor gene defects in two unrelated patients with type IIC von Willebrand disease.  Blood . 1994;  84 1024-1030
  • 105 Schneppenheim R, Obser T, Schneppenheim S. Von Willebrand disease type 2A with aberrant structure of individual oligomers is caused by mutations clustering in the von Willebrand factor D3 domain.  Blood (Abst) . 2000;  96 566a
  • 106 Hilbert L, Jenkins P V, Gaucher C, Meriane E, Pasi J K, Mazurier C. Type 2M vWD resulting from a lysine deletion within a four lysine residue repeat in the A1 loop of von Willebrand factor.  Thromb Haemost . 2000;  84 188-194
  • 107 Casonato A, Pontara E, Sartorello F. Type 2M von Willebrand disease variant characterized by abnormal multimerization.  J Lab Clin Med . 2001;  137 70-76
  • 108 Mannucci P M, Lombardi R, Bader R. Heterogeneity of type I von Willebrand disease: evidence for a subgroup with an abnormal von Willebrand factor.  Blood . 1985;  66 796-802
  • 109 Hoyer L W, Rizza C R, Tuddenham E G. von Willebrand factor multimer patterns in von Willebrand's disease.  Br J Haematol . 1983;  55 493-507
  • 110 Weiss H J, Pietu G, Rabinowitz R. Heterogeneous abnormalities in the multimeric structure, antigenic properties, and plasma-platelet content of factor VIII/von Willebrand factor in subtypes of classic (type I) and variant (type IIA) von Willebrand's disease.  J Lab Clin Med . 1983;  10 411-425
  • 111 Ruggeri Z M, Nilsson I M, Lombardi R, Holmberg L, Zimmerman T S. Aberrant multimeric structure of von Willebrand factor in a new variant of von Willebrand's disease (type IIC).  J Clin Invest . 1982;  70 1124-1127
  • 112 Kinoshita S, Harrison J, Lazerson J, Abildgaard C F. A new variant of dominant type II von Willebrand's disease with aberrant multimeric pattern of factor VIII-related antigen (type IID).  Blood . 1984;  63 1369-1371
  • 113 Hill F G, Enayat M S, George A J. Investigation of a kindred with a new autosomal dominantly inherited variant type von Willebrand's disease (possible type IID).  J Clin Pathol . 1985;  38 665-670
  • 114 Mannucci P M, Lombardi R, Federici A B. A new variant of type II von Willebrand disease with aberrant multimeric structure of plasma but not platelet von Willebrand factor (type IIF).  Blood . 1986;  68 269-274
  • 115 Gralnick H R, Williams S B, McKeown L P. A variant of type II von Willebrand disease with an abnormal triplet structure and discordant effects of protease inhibitors on plasma and platelet von Willebrand factor structure.  Am J Hematol . 1987;  24 259-266
  • 116 Federici A B, Mannucci P M, Lombardi R. Type II H von Willebrand disease: new structural abnormality of plasma and platelet von Willebrand factor in a patient with prolonged bleeding time and borderline levels of ristocetin cofactor activity.  Am J Hematol . 1989;  32 287-293
  • 117 Castaman G, Rodeghiero F, Lattuada A, Mannucci P M. A new variant of von Willebrand disease (type II I) with a normal degree of proteolytic cleavage of von Willebrand factor.  Thromb Res . 1992;  65 343-351
  • 118 Weiss H J, Sussman I I. A new von Willebrand variant (type I, New York): increased ristocetin-induced platelet aggregation and plasma von Willebrand factor containing the full range of multimers.  Blood . 1986;  68 149-156
  • 119 Holmberg L, Berntorp E, Donner M, Nilsson I M. von Willebrand's disease characterized by increased ristocetin sensitivity and the presence of all von Willebrand factor multimers in plasma.  Blood . 1986;  68 668-672
  • 120 Firkin B, Firkin F, Stott L. von Willebrand's disease type B: a newly defined bleeding diathesis.  Aust N Z J Med . 1973;  33 225-229
  • 121 Mannucci P M, Lombardi R, Castaman G. von Willebrand disease ``Vicenza'' with larger-than-normal (supranormal) von Willebrand factor multimers.  Blood . 1988;  71 65-70
  • 122 Ciavarella G, Ciavarella N, Antoncecchi S. High-resolution analysis of von Willebrand factor multimeric composition defines a new variant of type I von Willebrand disease with aberrant structure but presence of all size multimers (type IC).  Blood . 1985;  66 1423-1429
  • 123 Lopez-Fernandez M F, Gonzalez-Boullosa R, Blanco-Lopez M J, Perez M, Batlle J. Abnormal proteolytic degradation of von Willebrand factor after desmopressin infusion in a new subtype of von Willebrand disease (ID).  Am J Hematol . 1991;  36 163-170
  • 124 Zimmerman T S, Ruggeri Z M. von Willebrand's disease.  Prog Hemost Thromb . 1982;  6 203-236
    >