Download PDF
Hamostaseologie 2019; 39(04): 326-338
DOI: 10.1055/s-0039-1692688
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Replacement Therapy in Patients with Von Willebrand Disease—Indications and Monitoring

Die Substitutionsbehandlung des von-Willebrand-Syndroms—Indikationen und Monitoring
Ulrike Nowak-Göttl
1   Department of Clinical Chemistry, Thrombosis and Hemostasis Unit, University Hospital of Kiel and Lübeck, Kiel, Germany
,
Wolfgang Miesbach
2   Medical Clinic II, Institute of Transfusion Medicine, Goethe University, Frankfurt, Germany
,
Jürgen Koscielny
3   Institute of Transfusion Medicine, Charité - University Medicine, Berlin, Germany
,
Carl-Erik Dempfle
4   Coagulation Center Mannheim, Mannheim, Germany
,
Marc Maegele
5   Department of Trauma and Orthopedic Surgery, Cologne-Merheim Medical Center, University of Witten/Herdecke, Cologne, Germany
,
Mario von Depka Prondzinski
6   Werlhof-Institute Hannover, Hannover, Germany
,
Dagmar Westrup
7   Arnold-Heller-Str. 3, buiding 17, 24105 Kiel, Bad Camberg, Germany
,
Michael Spannagl
8   Department of Hemostasis and Transfusion Medicine, Ludwig-Maximilians University, Munich, Germany
› Author Affiliations
Further Information

Publication History

30 October 2018

13 May 2019

Publication Date:
30 July 2019 (online)

Also available at
   Permissions and Reprints

Abstract

In patients with von Willebrand disease (VWD), replacement therapy may be indicated in the case of spontaneous bleeding, surgical interventions and injuries/trauma or as a prophylaxis of spontaneous bleeding episodes. The deficient von Willebrand factor (VWF) is replaced with or without factor VIII (FVIII). Dual VWF/FVIII concentrates can be beneficial in the case of low FVIII level, while repeated dosing may lead to very high FVIII levels, with a potential thrombogenic effect in individual VWD patients. An excessive FVIII:C increase can be limited by using a VWF product with a low level of FVIII, achieving a haemostatic adequate FVIII:C increase after 6 to 12 hours. Replacement therapy in patients with VWD shall be individualised considering VWD type, history and risk of bleeding and risk of thrombosis, as well as indication and the individually variable VWF and FVIII increase. Deviations from the dosages and minimum trough levels mentioned in guidelines or recommendations can be considered in justified cases. The objective of this review is to provide recommendations for specific constellations of replacement therapy based on the VWD-specific guidelines available in Europe, the available evidence, own experiences and the consensus of the interdisciplinary German author group.

Zusammenfassung

Bei Patienten mit von-Willebrand-Krankheit (VWD) kann eine Ersatztherapie bei spontanen Blutungen, chirurgischen Eingriffen und Verletzungen/Traumata oder zur Prophylaxe spontaner Blutungen angezeigt sein. Der mangelnde von Willebrand-Faktor (VWF) wird mit oder ohne Faktor VIII (FVIII) ersetzt. Duale VWF/FVIII-Konzentrate können bei niedrigem FVIII-Spiegel von Vorteil sein, während eine wiederholte Gabe zu sehr hohen FVIII-Spiegeln führen kann, die bei einzelnen VWD-Patienten einen potenziellen thrombogenen Effekt haben können. Ein übermäßiger Anstieg von FVIII:C kann durch die Verwendung eines VWF-Produkts mit einem niedrigen FVIII-Gehalt begrenzt werden, wodurch nach 6 bis 12 Stunden ein hämostatisch adäquater Anstieg von FVIII:C erreicht wird. Die Ersatztherapie bei Patienten mit VWD ist unter Berücksichtigung des VWD-Typs, der Vorgeschichte, des Blutungsrisikos und des Thromboserisikos sowie der Indikation und des individuell variablen Anstiegs von VWF und FVIII zu individualisieren. Abweichungen von den in Richtlinien oder Empfehlungen genannten Dosierungen und Mindest-Talspiegeln können in begründeten Fällen berücksichtigt werden. Ziel dieser Übersichtsarbeit ist es, Empfehlungen für spezifische Konstellationen der Ersatztherapie auf der Grundlage der in Europa verfügbaren VWD-spezifischen Leitlinien, der verfügbaren Evidenz, der eigenen Erfahrungen und des Konsenses der interdisziplinären deutschen Autorengruppe zu geben.

Keywords

von Willebrand disease - von Willebrand factor - factor VIII - replacement therapy - bleeding

Schlüsselwörter

von-Willebrand-Syndrom - von-Willebrand-Faktor - Faktor VIII - Substitutionstherapie - Blutung
 

  • References

  • 1 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
    CrossrefPubMedGoogle Scholar
  • 2 Haberichter SL, Shi Q, Montgomery RR. Regulated release of VWF and FVIII and the biologic implications. Pediatr Blood Cancer 2006; 46 (05) 547-553
    CrossrefPubMedGoogle Scholar
  • 3 Vlot AJ, Koppelman SJ, van den Berg MH, Bouma BN, Sixma JJ. The affinity and stoichiometry of binding of human factor VIII to von Willebrand factor. Blood 1995; 85 (11) 3150-3157
    CrossrefPubMedGoogle Scholar
  • 4 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 (03) 206-216
    CrossrefPubMedGoogle Scholar
  • 5 Federici AB. Clinical and laboratory diagnosis of VWD. Hematology (Am Soc Hematol Educ Program) 2014; 2014 (01) 524-530
    CrossrefPubMedGoogle Scholar
  • 6 Laffan MA, Lester W, O'Donnell JS. , et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards on Haematology. Br J Haematol 2014; 167 (04) 453-465
    CrossrefPubMedGoogle Scholar
  • 7 Flood VH, Christopherson PA, Gill JC. , et al. Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States. Blood 2016; 127 (20) 2481-2488
    CrossrefPubMedGoogle Scholar
  • 8 Federici AB, Bucciarelli P, Castaman G. , et al. The bleeding score predicts clinical outcomes and replacement therapy in adults with von Willebrand disease. Blood 2014; 123 (26) 4037-4044
    CrossrefPubMedGoogle Scholar
  • 9 Castaman G, Goodeve A, Eikenboom J. ; European Group on von Willebrand Disease. Principles of care for the diagnosis and treatment of von Willebrand disease. Haematologica 2013; 98 (05) 667-674
    CrossrefPubMedGoogle Scholar
  • 10 Franchini M, Mannucci PM. Von Willebrand factor (Vonvendi®): the first recombinant product licensed for the treatment of von Willebrand disease. Expert Rev Hematol 2016; 9 (09) 825-830
    CrossrefPubMedGoogle Scholar
  • 11 Mannucci PM. Venous thromboembolism in von Willebrand disease. Thromb Haemost 2002; 88 (03) 378-379
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 CSL Behring GmbH. Fachinformation Haemate® P 250/500/1000, effective January 2018. Available at: www.fachinfo.de . Accessed June 28, 2018
    PubMed
  • 13 CSL Behring GmbH. Fachinformation Voncento, effective April 2018. Available at: www.fachinfo.de . Accessed June 28, 2018
    PubMed
  • 14 Octapharma GmbH. Fachinformation Wilate 500/1000, effective June 2015. Available at: www.fachinfo.de . Accessed June 28, 2018
    PubMed
  • 15 Shire Deutschland GmbH. Fachinformation Immunate 500 I.E./1000 I. E., effective May 2018. Available at: www.fachinfo.de . Accessed June 28, 2018
    PubMed
  • 16 Baxalta Innovations GmbH. Fachinformation Veyvondi, effective August 2018. Available at: www.fachinfo.de . Accessed February 17, 2019
    PubMed
  • 17 Goudemand J, Scharrer I, Berntorp E. , et al. Pharmacokinetic studies on Wilfactin, a von Willebrand factor concentrate with a low factor VIII content treated with three virus-inactivation/removal methods. J Thromb Haemost 2005; 3 (10) 2219-2227
    CrossrefPubMedGoogle Scholar
  • 18 Gill JC, Castaman G, Windyga J. , et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood 2015; 126 (17) 2038-2046
    PubMedGoogle Scholar
  • 19 LFB Biomedicaments. Fachinformation Willfact, effective June 2015. www.fachinfo.de . Accessed June 28, 2018
    PubMed
  • 20 Saccullo G, Makris M. Prophylaxis in von Willebrand Disease: coming of age?. Semin Thromb Hemost 2016; 42 (05) 498-506
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Veyvondi: EPAR—Public assessment report 28 June 2018. Available at: https://www.ema.europa.eu/en/documents/assessment-report/veyvondi-epar-public-assessment-report_en.pdf . Accessed March 10, 2018
    PubMed
  • 22 Borel-Derlon A, Federici AB, Roussel-Robert V. , et al. Treatment of severe von Willebrand disease with a high-purity von Willebrand factor concentrate (Wilfactin): a prospective study of 50 patients. J Thromb Haemost 2007; 5 (06) 1115-1124
    CrossrefPubMedGoogle Scholar
  • 23 Lassila R, Holme PA, Landorph A, Petrini P, Onundarson PT, Hillarp A. Nordic Haemophilia Council's practical guidelines on diagnosis and management of von Willebrand disease. Semin Thromb Hemost 2011; 37 (05) 495-502
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Lissitchkov TJ, Buevich E, Kuliczkowski K. , et al. Pharmacokinetics, efficacy, and safety of a plasma-derived VWF/FVIII concentrate (VONCENTO) for on-demand and prophylactic treatment in patients with von Willebrand disease (SWIFT-VWD study). Blood Coagul Fibrinolysis 2017; 28 (02) 152-162
    CrossrefPubMedGoogle Scholar
  • 25 Kessler CM, Friedman K, Schwartz BA, Gill JC, Powell JS, Wilate PK. The pharmacokinetic diversity of two von Willebrand factor (VWF)/ factor VIII (FVIII) concentrates in subjects with congenital von Willebrand disease. Results from a prospective, randomizsd crossover study. Thromb Haemost 2011; 106: 279-288
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 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 (04) 323-330
    CrossrefPubMedGoogle Scholar
  • 27 Wissenschaftlicher Beirat der Bundesärztekammer. Querschnitts-Leitlinien zur Therapie mit Blutkomponenten und Plasmaderivaten – Herausgegeben von der Bundesärztekammer auf Empfehlung ihres Wissenschaftlichen Beirats; 4. überarbeitete Auflage; Deutscher Ärzte-Verlag, Köln, 2014
    PubMedGoogle Scholar
  • 28 Leebeek FWG, Eikenboom JCJ. Von Willebrand's disease. N Engl J Med 2016; 375 (21) 2067-2080
    CrossrefPubMedGoogle Scholar
  • 29 Mannucci PM, Franchini M. Von Willebrand's disease. N Engl J Med 2017; 376 (07) 701
    CrossrefPubMedGoogle Scholar
  • 30 Di Paola J, Lethagen S, Gill J. , et al. Presurgical pharmacokinetic analysis of a von Willebrand factor/factor VIII (VWF/FVIII) concentrate in patients with von Willebrand's disease (VWD) has limited value in dosing for surgery. Haemophilia 2011; 17 (05) 752-758
    PubMedGoogle Scholar
  • 31 Nowak-Göttl U, Limperger V, Kenet G. , et al. Developmental hemostasis: A lifespan from neonates and pregnancy to the young and elderly adult in a European white population. Blood Cells Mol Dis 2017; 67: 2-13
    CrossrefPubMedGoogle Scholar
  • 32 Mannucci PM, Franchini M, Castaman G, Federici AB. ; Italian Association of Hemophilia Centers. Evidence-based recommendations on the treatment of von Willebrand disease in Italy. Blood Transfus 2009; 7 (02) 117-126
    PubMedGoogle Scholar
  • 33 Abshire TC, Federici AB, Alvárez MT. , et al; VWD PN. Prophylaxis in severe forms of von Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN). Haemophilia 2013; 19 (01) 76-81
    CrossrefPubMedGoogle Scholar
  • 34 Berntorp E, Petrini P. Long-term prophylaxis in von Willebrand disease. Blood Coagul Fibrinolysis 2005; 16 (Suppl. 01) S23-S26
    CrossrefPubMedGoogle Scholar
  • 35 Halimeh S, Krümpel A, Rott H. , et al. Long-term secondary prophylaxis in children, adolescents and young adults with von Willebrand disease. Results of a cohort study. Thromb Haemost 2011; 105 (04) 597-604
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Batlle J, López-Fernández MF, Fraga EL, Trillo AR, Pérez-Rodríguez MA. Von Willebrand factor/factor VIII concentrates in the treatment of von Willebrand disease. Blood Coagul Fibrinolysis 2009; 20 (02) 89-100
    CrossrefPubMedGoogle Scholar
  • 37 Jenkins PV, Rawley O, Smith OP, O'Donnell JS. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol 2012; 157 (06) 653-663
    CrossrefPubMedGoogle Scholar
  • 38 Miesbach W, Berntorp E. Von Willebrand disease - the ‘dos’ and ‘don’ts' in surgery. Eur J Haematol 2017; 98 (02) 121-127
    CrossrefPubMedGoogle Scholar
  • 39 Coppola A, Franchini M, Makris M, Santagostino E, Di Minno G, Mannucci PM. Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies. Haemophilia 2012; 18 (03) e173-–e187
    CrossrefPubMedGoogle Scholar
  • 40 Girolami A, Tasinato V, Sambado L, Peroni E, Casonato A. Venous thrombosis in von Willebrand disease as observed in one centre and as reported in the literature. Blood Coagul Fibrinolysis 2015; 26 (01) 54-58
    CrossrefPubMedGoogle Scholar
  • 41 Gill JC, Mannucci PM. Thromboembolic incidence with transiently elevated levels of coagulation factors in patients with von Willebrand disease treated with VWF:FVIII concentrate during surgery. Haemophilia 2014; 20 (06) e404-e406
    CrossrefPubMedGoogle Scholar
  • 42 Franchini M, Veneri D, Poli G, Manzato F, Salvagno GL, Lippi G. High prevalence of inherited prothrombotic risk factors in 134 consecutive patients with von Willebrand disease. Am J Hematol 2006; 81 (06) 465-467
    CrossrefPubMedGoogle Scholar
  • 43 Makris M, Colvin B, Gupta V, Shields ML, Smith MP. Venous thrombosis following the use of intermediate purity FVIII concentrate to treat patients with von Willebrand's disease. Thromb Haemost 2002; 88 (03) 387-388
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Encke A, Haas S, Koop I. , et al. (2015) S3-Leitlinie Prophylaxe der venösen Thromboembolie (VTE). 2. Komplett überarbeitete Auflage, Stand: 15.10.2015. Available at: http://www.awmf.org/leitlinien/detail/ll/003-001.html . Accessed July 14, 2016
    PubMed
  • 45 Nichols WL, Hultin MB, James AH. , et al. 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 (02) 171-232
    CrossrefPubMedGoogle Scholar
  • 46 Makris M, Federici AB, Mannucci PM. , et al. The natural history of occult or angiodysplastic gastrointestinal bleeding in von Willebrand disease. Haemophilia 2015; 21 (03) 338-342
    CrossrefPubMedGoogle Scholar
  • 47 Ragni MV, Machin N, James AH. , et al. Feasibility of the Von Willebrand disease PREVENT trial. Thromb Res 2017; 156: 8-13
    CrossrefPubMedGoogle Scholar
  • 48 Federici AB, Castaman G, Franchini M. , et al. Clinical use of Haemate P in inherited von Willebrand's disease: a cohort study on 100 Italian patients. Haematologica 2007; 92 (07) 944-951
    CrossrefPubMedGoogle Scholar
  • 49 Berntorp E, Windyga J. ; European Wilate Study Group. Treatment and prevention of acute bleedings in von Willebrand disease–efficacy and safety of Wilate, a new generation von Willebrand factor/factor VIII concentrate. Haemophilia 2009; 15 (01) 122-130
    CrossrefPubMedGoogle Scholar
  • 50 Franchini M, Mannucci PM. Gastrointestinal angiodysplasia and bleeding in von Willebrand disease. Thromb Haemost 2014; 112 (03) 427-431
    Article in Thieme ConnectPubMedGoogle Scholar
  • 51 Mannuccio Mannucci P, Kyrle PA, Schulman S, Di Paola J, Schneppenheim R, Cox Gill J. Prophylactic efficacy and pharmacokinetically guided dosing of a von Willebrand factor/factor VIII concentrate in adults and children with von Willebrand's disease undergoing elective surgery: a pooled and comparative analysis of data from USA and European Union clinical trials. Blood Transfus 2013; 11 (04) 533-540
    PubMedGoogle Scholar
  • 52 van Galen KPM, Meijer K, Vogely HC. , et al; WiN study group. Joint surgery in von Willebrand disease: a multicentre cross-sectional study. Haemophilia 2016; 22 (02) 256-262
    CrossrefPubMedGoogle Scholar
  • 53 Federici AB. Prophylaxis in patients with von Willebrand disease: who, when, how?. J Thromb Haemost 2015; 13 (09) 1581-1584
    CrossrefPubMedGoogle Scholar
  • 54 Holm E, Carlsson KS, Lövdahl S, Lail AE, Abshire TC, Berntorp E. Bleeding-related hospitalization in patients with von Willebrand disease and the impact of prophylaxis: results from national registers in Sweden compared with normal controls and participants in the von Willebrand Disease Prophylaxis Network. Haemophilia 2018; 24 (04) 628-633
    CrossrefPubMedGoogle Scholar
  • 55 Lethagen S. Clinical experience of prophylactic treatment in von Willebrand disease. Thromb Res 2006; 118 (Suppl. 01) S9-S11
    CrossrefPubMedGoogle Scholar
  • 56 Tosetto A, Castaman G, Rodeghiero F. Assessing bleeding in von Willebrand disease with bleeding score. Blood Rev 2007; 21 (02) 89-97
    CrossrefPubMedGoogle Scholar
  • 57 Ragni MV, Machin N, Malec LM. , et al. Von Willebrand factor for menorrhagia: a survey and literature review. Haemophilia 2016; 22 (03) 397-402
    CrossrefPubMedGoogle Scholar
  • 58 Holm E, Abshire TC, Bowen J. , et al. Changes in bleeding patterns in von Willebrand disease after institution of long-term replacement therapy: results from the von Willebrand Disease Prophylaxis Network. Blood Coagul Fibrinolysis 2015; 26 (04) 383-388
    CrossrefPubMedGoogle Scholar
  • 59 Scholz U, Oppermann J, Siegemund A, Schobess R. Von Willebrand disease type 1 and pregnancy [in German]. Hamostaseologie 2011; 31 (Suppl. 01) S11-S13
    Article in Thieme ConnectPubMedGoogle Scholar
  • 60 James AH, Konkle BA, Kouides P. , et al. Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis. Haemophilia 2015; 21 (01) 81-87
    CrossrefPubMedGoogle Scholar
  • 61 Reynen E, James P. Von Willebrand disease and pregnancy: a review of evidence and expert opinion. Semin Thromb Hemost 2016; 42 (07) 717-723
    Article in Thieme ConnectPubMedGoogle Scholar
  • 62 Castaman G. Changes of von Willebrand factor during pregnancy in women with and without von Willebrand disease. Mediterr J Hematol Infect Dis 2013; 5 (01) e2013052
    CrossrefPubMedGoogle Scholar
  • 63 Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based register linkage study. BMJ 2000; 320 (7251): 1708-1712
    CrossrefPubMedGoogle Scholar
  • 64 Blohm F, Fridén B, Milsom I. A prospective longitudinal population-based study of clinical miscarriage in an urban Swedish population. BJOG 2008; 115 (02) 176-182 , discussion 183
    PubMedGoogle Scholar
  • 65 Skeith L, Rydz N, O'Beirne M, Goodyear D, Li H, Poon MC. Pregnancy loss in women with von Willebrand disease: a single-center pilot study. Blood Coagul Fibrinolysis 2017; 28 (05) 393-397
    CrossrefPubMedGoogle Scholar
  • 66 Su MT, Lin SH, Chen YC. Genetic association studies of angiogenesis- and vasoconstriction-related genes in women with recurrent pregnancy loss: a systematic review and meta-analysis. Hum Reprod Update 2011; 17 (06) 803-812
    CrossrefPubMedGoogle Scholar
  • 67 Starke RD, Ferraro F, Paschalaki KE. , et al. Endothelial von Willebrand factor regulates angiogenesis. Blood 2011; 117 (03) 1071-1080
    CrossrefPubMedGoogle Scholar
  • 68 Federici AB, Königs C, James AH. Contemporary issues in the management of von Willebrand disease. Thromb Haemost 2016; 116 (Suppl. 01) S18-S25
    Article in Thieme ConnectPubMedGoogle Scholar
  • 69 Mannucci PM, Federici AB. Management of inherited von Willebrand disease. Best Pract Res Clin Haematol 2001; 14 (02) 455-462
    CrossrefPubMedGoogle Scholar
  • 70 Fachinformation Minirin parenteral 2019
    PubMed
  • 71 James AH, Eikenboom J, Federici AB. State of the art: von Willebrand disease. Haemophilia 2016; 22 (Suppl. 05) 54-59
    PubMedGoogle Scholar
  • 72 Castaman G, Linari S. Human von Willebrand factor/factor VIII concentrates in the management of pediatric patients with von Willebrand disease/hemophilia A. Ther Clin Risk Manag 2016; 12: 1029-1037
    CrossrefPubMedGoogle Scholar
  • 73 Williams M, Patel J. Von Willebrand Disease: diagnosis and management. Paediatr Child Health 2015; 25 (08) 354-359
    CrossrefPubMedGoogle Scholar