Semin Thromb Hemost 2017; 43(01): 069-074
DOI: 10.1055/s-0036-1592166
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Blood Group O Protects against Inhibitor Development in Severe Hemophilia A Patients

Massimo Franchini
1   Department of Hematology and Transfusion Medicine, Carlo Poma Hospital, Mantova, Italy
,
Antonio Coppola
2   Regional Reference Center for Coagulation Disorders, Federico II University Hospital, Naples, Italy
,
Carlo Mengoli
3   University of Padua, Padua, Italy
,
Gianna Franca Rivolta
4   Regional Reference Centre for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy
,
Federica Riccardi
4   Regional Reference Centre for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy
,
Giovanni Di Minno
2   Regional Reference Center for Coagulation Disorders, Federico II University Hospital, Naples, Italy
,
Annarita Tagliaferri
4   Regional Reference Centre for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy
,
ad hoc Study Group
› Author Affiliations
Further Information

Publication History

Publication Date:
08 November 2016 (online)

Abstract

Increasing evidence supports the link between ABO(H) blood group determinants and hemostasis. In particular, the ABO-related different glycosylation patterns of von Willebrand factor strongly influence its clearance and functional levels, and this may contribute to the inter-individual variations in the half-life of infused Factor VIII (FVIII) in hemophilia A (HA) patients. We investigated the role of ABO blood groups in regulating FVIII immunogenicity by evaluating their distribution in patients with severe (FVIII < 1 IU/dL) HA according to inhibitor development and other known relevant factors. In a cohort of Italian severe HA patients (n = 209), the ABO blood group distribution was similar to that in the healthy general population. However, the distribution of inhibitors, developed in 56 patients overall (26.8%), was significantly different in the four ABO phenotypes (O, 18.2%; A, 31.9%; B, 39.1%, AB, 25%; p = 0.033); this difference seemed more pronounced when only high-titer inhibitors (overall, 21.1%) were considered (O, 11.4%; A, 27.7%; B, 34.8%; p = 0.011). Relative risks in O versus non-O blood group were 0.55 (95% CI: 0.33–0.92) and 0.40 (95% CI: 0.21–0.77) for any and high-titer inhibitors, respectively. In a multivariate logistic regression, O blood group was shown to lower (approximately twofold) inhibitor risk, similarly with plasma-derived FVIII, whereas high-risk F8 mutations were associated with increased risk. However, the estimated effect of O blood type on inhibitor development was free from any significant correlation to other covariates, including presence of high-risk F8 mutations and type of replacement FVIII used. In this retrospective cohort of severe hemophiliacs, blood group O appears to protect against inhibitor development, with independent effects from other covariates. Larger prospective studies are needed to confirm this finding and to delve deeper into its pathophysiologic mechanisms.

 
  • References

  • 1 Liumbruno GM, Franchini M. Beyond immunohaematology: the role of the ABO blood group in human diseases. Blood Transfus 2013; 11 (4) 491-499
  • 2 Wu O, Bayoumi N, Vickers MA, Clark P. ABO(H) blood groups and vascular disease: a systematic review and meta-analysis. J Thromb Haemost 2008; 6 (1) 62-69
  • 3 Jenkins PV, O'Donnell JS. ABO blood group determines plasma von Willebrand factor levels: a biologic function after all?. Transfusion 2006; 46 (10) 1836-1844
  • 4 Lenting PJ, Christophe OD, Denis CV. von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. Blood 2015; 125 (13) 2019-2028
  • 5 Gallinaro L, Cattini MG, Sztukowska M , et al. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood 2008; 111 (7) 3540-3545
  • 6 Vlot AJ, Mauser-Bunschoten EP, Zarkova AG , et al. 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 (1) 65-69
  • 7 Fijnvandraat K, Peters M, ten Cate JW. Inter-individual variation in half-life of infused recombinant factor VIII is related to pre-infusion von Willebrand factor antigen levels. Br J Haematol 1995; 91 (2) 474-476
  • 8 Fischer K, Pendu R, van Schooten CJ , et al. Models for prediction of factor VIII half-life in severe haemophiliacs: distinct approaches for blood group O and non-O patients. PLoS ONE 2009; 4 (8) e6745
  • 9 Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A ; Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12 (11) 1935-1939
  • 10 Gouw SC, van den Berg HM, Oldenburg J , et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood 2012; 119 (12) 2922-2934
  • 11 Tagliaferri A, Franchini M, Coppola A , et al. Effects of secondary prophylaxis started in adolescent and adult haemophiliacs. Haemophilia 2008; 14 (5) 945-951
  • 12 Rocino A, Coppola A, Franchini M , et al; Italian Association of Haemophilia Centres (AICE) Working Party. Principles of treatment and update of recommendations for the management of haemophilia and congenital bleeding disorders in Italy. Blood Transfus 2014; 12 (4) 575-598
  • 13 Franchini M, Crestani S, Frattini F, Sissa C, Bonfanti C. ABO blood group and von Willebrand factor: biological implications. Clin Chem Lab Med 2014; 52 (9) 1273-1276
  • 14 Dasgupta S, Repessé Y, Bayry J , et al. VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors. Blood 2007; 109 (2) 610-612
  • 15 Oldenburg J, Lacroix-Desmazes S, Lillicrap D. Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity. Haematologica 2015; 100 (2) 149-156
  • 16 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 9 (4) 418-435
  • 17 Iorio A, Halimeh S, Holzhauer S , et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010; 8 (6) 1256-1265
  • 18 Franchini M, Tagliaferri A, Mengoli C, Cruciani M. Cumulative inhibitor incidence in previously untreated patients with severe hemophilia A treated with plasma-derived versus recombinant factor VIII concentrates: a critical systematic review. Crit Rev Oncol Hematol 2012; 81 (1) 82-93
  • 19 Franchini M, Coppola A, Rocino A , et al; Italian Association of Hemophilia Centers (AICE) Working Group. Systematic review of the role of FVIII concentrates in inhibitor development in previously untreated patients with severe hemophilia a: a 2013 update. Semin Thromb Hemost 2013; 39 (7) 752-766
  • 20 Peyvandi F, Mannucci PM, Garagiola I , et al. A randomized trial of Factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med 2016; 374 (21) 2054-2064
  • 21 Gill JC, Stephany K, Newton-Nash D, Foster PA. Apparent IgG anti-factor VIII antibodies in normal individuals are specific for AB0 blood group substances. Thromb Haemost 1995; 86: 611 (abstract)
  • 22 Coppola A, Santoro C, Tagliaferri A, Franchini M, DI Minno G. Understanding inhibitor development in haemophilia A: towards clinical prediction and prevention strategies. Haemophilia 2010; 16 (Suppl. 01) 13-19
  • 23 Carpenter SL, Michael Soucie J, Sterner S, Presley R ; Hemophilia Treatment Center Network (HTCN) Investigators. Increased prevalence of inhibitors in Hispanic patients with severe haemophilia A enrolled in the Universal Data Collection database. Haemophilia 2012; 18 (3) e260-e265
  • 24 Miller CH, Benson J, Ellingsen D , et al; Hemophilia Inhibitor Research Study Investigators. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia 2012; 18 (3) 375-382
  • 25 Gouw SC, Fijnvandraat K. Identifying nongenetic risk factors for inhibitor development in severe hemophilia a. Semin Thromb Hemost 2013; 39 (7) 740-751