Download PDF
Semin Thromb Hemost 2016; 42(05): 498-506
DOI: 10.1055/s-0036-1581106
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Prophylaxis in von Willebrand Disease: Coming of Age?

Giorgia Saccullo
1   Centro di Riferimento Regionale per le Coagulopatie Congenite del bambino e dell'adulto, U.O. Ematologia con TMO, Policlinico Paolo Giaccone, Palermo, Italia
,
Mike Makris
2   Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
02 June 2016 (online)

    Permissions and Reprints

Abstract

Although in most cases von Willebrand disease (VWD) is a mild disorder, a subgroup of patients experience frequent bleeding. In contrast to severe hemophilia in which prophylaxis is the accepted standard of care, this is less frequently used in VWD. Most type 1 VWD patients can be adequately managed with episodic desmopressin and tranexamic acid. In patients with more severe disease, especially those with type 3 VWD, joint bleeds, epistaxis, menorrhagia, and gastrointestinal bleeding are problematic and usually require treatment with von Willebrand factor/factor VIII (VWF/FVIII) concentrate. While in the past these patients were managed with on-demand VWF/FVIII concentrate, several recent reports have demonstrated the value of prophylactic treatment. Despite some uncertainties about the economic impact of treatment of severe VWD, prophylaxis with VWF concentrate should now be considered as the standard of care for the more severe end of the spectrum of affected individuals. The recent introduction of recombinant VWF concentrate is likely to improve the acceptability of prophylaxis in VWD.

Keywords

von Willebrand disease - hemophilia - prophylaxis - von Willebrand factor concentrate
 

  • References

  • 1 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease. Blood 1987; 69 (2) 454-459
    PubMedGoogle Scholar
  • 2 Castaman G, Federici AB, Rodeghiero F, Mannucci PM. Von Willebrand's disease in the year 2003: towards the complete identification of gene defects for correct diagnosis and treatment. Haematologica 2003; 88 (1) 94-108
    PubMedGoogle Scholar
  • 3 Ramgren O. Haemophilia in Sweden. III. Symptomatology, with special reference to differences between haemophilia A and B. Acta Med Scand 1962; 171: 237-242
    PubMedGoogle Scholar
  • 4 Ahlberg A. Haemophilia in Sweden. VII. Incidence, treatment and prophylaxis of arthropathy and other musculo-skeletal manifestations of haemophilia A and B. Acta Orthop Scand Suppl 1965; (Suppl. 77) 77 , 3–132
    PubMedGoogle Scholar
  • 5 Nilsson IM, Berntorp E, Löfqvist T, Pettersson H. Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992; 232 (1) 25-32
    CrossrefPubMedGoogle Scholar
  • 6 Berntorp E, Boulyjenkov V, Brettler D , et al. Modern treatment of haemophilia. Bull World Health Organ 1995; 73 (5) 691-701
    PubMedGoogle Scholar
  • 7 Aledort LM, Haschmeyer RH, Pettersson H ; The Orthopaedic Outcome Study Group. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. J Intern Med 1994; 236 (4) 391-399
    CrossrefPubMedGoogle Scholar
  • 8 Kreuz W, Escuriola-Ettingshausen C, Funk M, Schmidt H, Kornhuber B. When should prophylactic treatment in patients with haemophilia A and B start?—The German experience. Haemophilia 1998; 4 (4) 413-417
    CrossrefPubMedGoogle Scholar
  • 9 van den Berg HM, Fischer K, Mauser-Bunschoten EP , et al. Long-term outcome of individualized prophylactic treatment of children with severe haemophilia. Br J Haematol 2001; 112 (3) 561-565
    CrossrefPubMedGoogle Scholar
  • 10 Gilbert MS. Prophylaxis: musculoskeletal evaluation. Semin Hematol 1993; 30 (3) (Suppl. 02) 3-6
    PubMedGoogle Scholar
  • 11 Pettersson H, Ahlberg A, Nilsson IM. A radiologic classification of hemophilic arthropathy. Clin Orthop Relat Res 1980; (149) 153-159
    PubMedGoogle Scholar
  • 12 Iorio A, Marchesini E, Marcucci M, Stobart K, Chan AK. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Cochrane Database Syst Rev 2011; (9) CD003429
    PubMedGoogle Scholar
  • 13 Manco-Johnson MJ, Abshire TC, Shapiro AD , et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357 (6) 535-544
    CrossrefPubMedGoogle Scholar
  • 14 Gringeri A, Lundin B, von Mackensen S, Mantovani L, Mannucci PM ; ESPRIT Study Group. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 2011; 9 (4) 700-710
    CrossrefPubMedGoogle Scholar
  • 15 Meunier S, Trossaërt M, Berger C , et al; Groupe Prophylaxie CoMETH [French guidelines. Long-term prophylaxis for severe haemophilia A and B children to prevent haemophiliac arthropathy]. Arch Pediatr 2009; 16 (12) 1571-1578
    CrossrefPubMedGoogle Scholar
  • 16 Richards M, Williams M, Chalmers E , et al; Paediatric Working Party of the United Kingdom Haemophilia Doctors' Organisation. A United Kingdom Haemophilia Centre Doctors' Organization guideline approved by the British Committee for Standards in Haematology: guideline on the use of prophylactic factor VIII concentrate in children and adults with severe haemophilia A. Br J Haematol 2010; 149 (4) 498-507
    CrossrefPubMedGoogle Scholar
  • 17 Fischer K, Steen Carlsson K, Petrini P , et al. Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s. Blood 2013; 122 (7) 1129-1136
    CrossrefPubMedGoogle Scholar
  • 18 Santoro C, Baldacci E, Mercanti C, Mazzucconi MG. Tailored versus standard dose prophylaxis in children with hemophilia A. Semin Thromb Hemost 2013; 39 (7) 711-722
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Fernandes S, Carvalho M, Lopes M, Araújo F. Impact of an individualized prophylaxis approach on young adults with severe hemophilia. Semin Thromb Hemost 2014; 40 (7) 785-789
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Collins PW. Personalized prophylaxis. Haemophilia 2012; 18 (Suppl. 04) 131-135
    CrossrefPubMedGoogle Scholar
  • 21 Björkman S, Collins P ; Project on Factor VI I I/Factor IX Pharmacokinetics of the Factor VIII/Factor IX Scientific and Standardization Committee of The Isth. Measurement of factor VIII pharmacokinetics in routine clinical practice. J Thromb Haemost 2013; 11 (1) 180-182
    PubMedGoogle Scholar
  • 22 Oldenburg J, Albert T. Novel products for haemostasis—current status. Haemophilia 2014; 20 (Suppl. 04) 23-28
    CrossrefPubMedGoogle Scholar
  • 23 Petrini P. What factors should influence the dosage and interval of prophylactic treatment in patients with severe haemophilia A and B?. Haemophilia 2001; 7 (1) 99-102
    CrossrefPubMedGoogle Scholar
  • 24 Kurnik K, Bidlingmaier C, Engl W, Chehadeh H, Reipert B, Auerswald G. New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development. Haemophilia 2010; 16 (2) 256-262
    CrossrefPubMedGoogle Scholar
  • 25 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
  • 26 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
  • 27 Mannucci PM. Treatment of von Willebrand's disease. N Engl J Med 2004; 351 (7) 683-694
    CrossrefPubMedGoogle Scholar
  • 28 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 (2) 117-126
    PubMedGoogle Scholar
  • 29 Favaloro EJ, Franchini M, Lippi G. Biological therapies for von Willebrand disease. Expert Opin Biol Ther 2012; 12 (5) 551-564
    CrossrefPubMedGoogle Scholar
  • 30 Mannucci PM. Hemostatic drugs. N Engl J Med 1998; 339 (4) 245-253
    CrossrefPubMedGoogle Scholar
  • 31 Castaman G, Lethagen S, Federici AB , et al. Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD. Blood 2008; 111 (7) 3531-3539
    CrossrefPubMedGoogle Scholar
  • 32 Federici AB, Mazurier C, Berntorp E , et al. 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
    CrossrefPubMedGoogle Scholar
  • 33 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 in Haematology. Br J Haematol 2014; 167 (4) 453-465
    CrossrefPubMedGoogle Scholar
  • 34 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 (2) 171-232
    CrossrefPubMedGoogle Scholar
  • 35 Mazurier C, Goudemand J, Hilbert L, Caron C, Fressinaud E, Meyer D. Type 2N von Willebrand disease: clinical manifestations, pathophysiology, laboratory diagnosis and molecular biology. Best Pract Res Clin Haematol 2001; 14 (2) 337-347
    CrossrefPubMedGoogle Scholar
  • 36 Riddell AF, Gomez K, Millar CM , et al. 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
    CrossrefPubMedGoogle Scholar
  • 37 Smith TJ, Gill JC, Ambruso DR, Hathaway WE. Hyponatremia and seizures in young children given DDAVP. Am J Hematol 1989; 31 (3) 199-202
    CrossrefPubMedGoogle Scholar
  • 38 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 (5) 667-674
    CrossrefPubMedGoogle Scholar
  • 39 Bond L, Bevan D. Myocardial infarction in a patient with hemophilia treated with DDAVP. N Engl J Med 1988; 318 (2) 121
    PubMedGoogle Scholar
  • 40 Federici AB, Baudo F, Caracciolo C , et al. Clinical efficacy of highly purified, doubly virus-inactivated factor VIII/von Willebrand factor concentrate (Fanhdi) in the treatment of von Willebrand disease: a retrospective clinical study. Haemophilia 2002; 8 (6) 761-767
    CrossrefPubMedGoogle Scholar
  • 41 Mannucci PM, Chediak J, Hanna W , et al; Alphanate Study Group. Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study. Blood 2002; 99 (2) 450-456
    CrossrefPubMedGoogle Scholar
  • 42 Lillicrap D, Poon MC, Walker I, Xie F, Schwartz BA ; 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
    PubMedGoogle Scholar
  • 43 Franchini M, Rossetti G, Tagliaferri A , et al. Efficacy and safety of factor VIII/von Willebrand's factor concentrate (Haemate-P) in preventing bleeding during surgery or invasive procedures in patients with von Willebrand disease. Haematologica 2003; 88 (11) 1279-1283
    PubMedGoogle Scholar
  • 44 Thompson AR, Gill JC, Ewenstein BM, Mueller-Velten G, Schwartz BA ; Humate-P Study Group. Successful treatment for patients with von Willebrand disease undergoing urgent surgery using factor VIII/VWF concentrate (Humate-P). Haemophilia 2004; 10 (1) 42-51
    CrossrefPubMedGoogle Scholar
  • 45 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 (7) 944-951
    CrossrefPubMedGoogle Scholar
  • 46 Lethagen S, Kyrle PA, Castaman G, Haertel S, Mannucci PM ; HAEMATE P Surgical Study Group. von Willebrand factor/factor VIII concentrate (Haemate P) dosing based on pharmacokinetics: a prospective multicenter trial in elective surgery. J Thromb Haemost 2007; 5 (7) 1420-1430
    CrossrefPubMedGoogle Scholar
  • 47 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 (6) 1115-1124
    CrossrefPubMedGoogle Scholar
  • 48 Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345 (8943) 152-155
    CrossrefPubMedGoogle Scholar
  • 49 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 (5) 752-758
    PubMedGoogle Scholar
  • 50 Mannucci PM, Kempton C, Millar C , et al; rVWF Ad Hoc Study Group. Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial. Blood 2013; 122 (5) 648-657
    CrossrefPubMedGoogle Scholar
  • 51 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 (3) 387-388
    PubMedGoogle Scholar
  • 52 de Wee EM, Fijnvandraat K, de Goede-Bolder A , et al; WiN Study Group. Impact of von Willebrand disease on health-related quality of life in a pediatric population. J Thromb Haemost 2011; 9 (3) 502-509
    CrossrefPubMedGoogle Scholar
  • 53 James P, Lillicrap D. Genetic testing for von Willebrand disease: the Canadian experience. Semin Thromb Hemost 2006; 32 (5) 546-552
    Article in Thieme ConnectPubMedGoogle Scholar
  • 54 Kadir RA, Chi C. Women and von Willebrand disease: controversies in diagnosis and management. Semin Thromb Hemost 2006; 32 (6) 605-615
    Article in Thieme ConnectPubMedGoogle Scholar
  • 55 Tosetto A, Rodeghiero F, Castaman G , et al. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD). J Thromb Haemost 2006; 4 (4) 766-773
    CrossrefPubMedGoogle Scholar
  • 56 Halimeh S. Menorrhagia and postpartum haemorrhage in women with rare bleeding disorder. Thromb Res 2015; 135 (Suppl. 01) S34-S37
    CrossrefPubMedGoogle Scholar
  • 57 Franchini M, Mannucci PM. Von Willebrand disease-associated angiodysplasia: a few answers, still many questions. Br J Haematol 2013; 161 (2) 177-182
    CrossrefPubMedGoogle Scholar
  • 58 Warkentin TE, Moore JC, Anand SS, Lonn EM, Morgan DG. Gastrointestinal bleeding, angiodysplasia, cardiovascular disease, and acquired von Willebrand syndrome. Transfus Med Rev 2003; 17 (4) 272-286
    CrossrefPubMedGoogle Scholar
  • 59 Makris M, Federici AB, Mannucci PM , et al. The natural history of occult or angiodysplastic gastrointestinal bleeding in von Willebrand disease. Haemophilia 2015; 21 (3) 338-342
    CrossrefPubMedGoogle Scholar
  • 60 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 (1) 76-81
    CrossrefPubMedGoogle Scholar
  • 61 Makris M. Gastrointestinal bleeding in von Willebrand disease. Thromb Res 2006; 118 (Suppl. 01) S13-S17
    CrossrefPubMedGoogle Scholar
  • 62 Hirri HM, Green PJ, Lindsay J. Von Willebrand's disease and angiodysplasia treated with thalidomide. Haemophilia 2006; 12 (3) 285-286
    CrossrefPubMedGoogle Scholar
  • 63 Nomikou E, Tsevrenis V, Gafou A, Bellia M, Theodossiades G. Type IIb von Willebrand disease with angiodysplasias and refractory gastrointestinal bleeding successfully treated with thalidomide. Haemophilia 2009; 15 (6) 1340-1342
    CrossrefPubMedGoogle Scholar
  • 64 Alikhan R, Keeling D. Von Willebrand disease, angiodysplasia and atorvastatin. Br J Haematol 2010; 149 (1) 159-160
    CrossrefPubMedGoogle Scholar
  • 65 Sohal M, Laffan M. Von Willebrand disease and angiodysplasia responding to atorvastatin. Br J Haematol 2008; 142 (2) 308-309
    CrossrefPubMedGoogle Scholar
  • 66 Metjian AD, Wang C, Sood SL , et al; HTCN Study Investigators. Bleeding symptoms and laboratory correlation in patients with severe von Willebrand disease. Haemophilia 2009; 15 (4) 918-925
    CrossrefPubMedGoogle Scholar
  • 67 Nilsson IM, Blomback M, Jorpes E, Blomback B, Johansson SA. Von Willebrand's disease and its correction with human plasma fraction 1-0. Acta Med Scand 1957; 159 (3) 179-188
    PubMedGoogle Scholar
  • 68 Berntorp E, Petrini P. Long-term prophylaxis in von Willebrand disease. Blood Coagul Fibrinolysis 2005; 16 (Suppl. 01) S23-S26
    CrossrefPubMedGoogle Scholar
  • 69 Federici AB. Highly purified VWF/FVIII concentrates in the treatment and prophylaxis of von Willebrand disease: the PRO. WILL Study. Haemophilia 2007; 13 (Suppl. 05) 15-24
    CrossrefPubMedGoogle Scholar
  • 70 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 (4) 597-604
    Article in Thieme ConnectPubMedGoogle Scholar
  • 71 Berntorp E, Abshire T ; von Willebrand Disease Prophylaxis Network Steering Committee. The von Willebrand disease prophylaxis network: exploring a treatment concept. J Thromb Haemost 2006; 4 (11) 2511-2512
    CrossrefPubMedGoogle Scholar
  • 72 Abshire T, Cox-Gill J, Kempton CL , et al. Prophylaxis escalation in severe von Willebrand disease: a prospective study from the von Willebrand Disease Prophylaxis Network. J Thromb Haemost 2015; 13 (9) 1585-1589
    CrossrefPubMedGoogle Scholar
  • 73 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 (4) 383-388
    CrossrefPubMedGoogle Scholar
  • 74 Rodeghiero F, Tosetto A, Abshire T , et al; ISTH/SSC joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 8 (9) 2063-2065
    CrossrefPubMedGoogle Scholar
  • 75 Federici AB, Mannucci PM, Castaman G , et al. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. Blood 2009; 113 (3) 526-534
    CrossrefPubMedGoogle Scholar
  • 76 Castaman G, Tosetto A, Federici AB, Rodeghiero F. Bleeding tendency and efficacy of anti-haemorrhagic treatments in patients with type 1 von Willebrand disease and increased von Willebrand factor clearance. Thromb Haemost 2011; 105 (4) 647-654
    Article in Thieme ConnectPubMedGoogle Scholar
  • 77 Castaman G, Federici AB, Tosetto A , et al. Different bleeding risk in type 2A and 2M von Willebrand disease: a 2-year prospective study in 107 patients. J Thromb Haemost 2012; 10 (4) 632-638
    CrossrefPubMedGoogle Scholar
  • 78 Schinco P, Cultrera D, Valeri F , et al. Cost-consequence analysis of long-term prophylaxis in the treatment of von Willebrand disease in the Italian context. Clinicoecon Outcomes Res 2015; 7: 17-25
    PubMedGoogle Scholar
  • 79 Miesbach W, Krekeler S, Wolf Z, Seifried E. Clinical use of Haemate® P in von Willebrand disease: a 25-year retrospective observational study. Thromb Res 2015; 135 (3) 479-484
    CrossrefPubMedGoogle Scholar
  • 80 Khair K, Batty P, Riat R , et al. Wilate use in 47 children with von Willebrand disease: the North London paediatric haemophilia network experience. Haemophilia 2015; 21 (1) e44-e50
    CrossrefPubMedGoogle Scholar
  • 81 Batty P, Chen YH, Bowles L, Hart DP, Platton S, Pasi KJ. Safety and efficacy of a von Willebrand factor/factor VIII concentrate (Wilate®): a single centre experience. Haemophilia 2014; 20 (6) 846-853
    CrossrefPubMedGoogle Scholar
  • 82 Nowak-Göttl U, Krümpel A, Russo A, Jansen M. Efficacy and safety of Wilate in paediatric VWD patients under 6 years of age—results of a prospective multicentre clinical study including recovery information. Haemophilia 2013; 19 (6) 887-892
    CrossrefPubMedGoogle Scholar
  • 83 Castaman G, Coppola A, Zanon E , et al. Efficacy and safety during formulation switch of a pasteurized VWF/FVIII concentrate: results from an Italian prospective observational study in patients with von Willebrand disease. Haemophilia 2013; 19 (1) 82-88
    CrossrefPubMedGoogle Scholar
  • 84 Howman R, Barnes C, Curtin J , et al. The clinical efficacy and safety of the FVIII/VWF concentrate, BIOSTATE®, in children with von Willebrand disorder: a multi-centre retrospective review. Haemophilia 2011; 17 (3) 463-469
    CrossrefPubMedGoogle Scholar