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Semin Thromb Hemost 2015; 41(08): 860-863
DOI: 10.1055/s-0035-1552562
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Targeting Factor Replacement Therapy in Severe Hemophilia: Which Level Is Important?

Kathelijn Fischer
1   Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands
2   Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
,
Erik Berntorp
3   Department of Clinical Sciences, Malmö, Lund University, Skåne University Hospital, Malmö, Sweden
4   Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Malmö, Sweden
› Author Affiliations
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Publication History

Publication Date:
09 October 2015 (online)

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Abstract

The original aim of prophylactic replacement therapy was to convert the bleeding pattern of severe hemophilia to that of moderate hemophilia through regular infusions of clotting factor concentrates. However, targeting prophylaxis on minimum trough levels does not prevent all bleeding. At the group level, there is a clear association of factor levels with bleeding and outcome. But bleeding phenotype in individual patients shows large variation, independent of trough levels maintained. The association of peak levels with bleeding on prophylaxis is not established. Experience with surgery suggests that certain peak levels need to be achieved during other hemostatic challenges, such as playing sports. Individualization of prophylaxis should include timing of infusion according to special activities. The clinical relevance of factor levels is even more urgent since the recent introduction of long-acting clotting factor concentrates with their different pharmacokinetic profiles and the prospect of gene therapy resulting in constant factor levels. It should be considered that the success of any prophylactic regimen is also dependent on other factors, such as the age at initiation of prophylaxis, adherence, lifestyle, cartilage susceptibility, and the other components of the clotting system. Factor levels are thus an important but quite small piece in the total picture of treating hemophilia and we currently cannot identify a specific trough or peak level to use for monitoring. At the same time, knowledge of a patients' level during the infusion intervals may help to individualize and adjust treatment according to the clinical symptoms.

Keywords

prophylaxis - pharmacokinetics - trough level - peak level
 

  • References

  • 1 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; 77 (suppl): 77 , 3–132
    PubMedSearch in Google Scholar
  • 2 Nilsson IM, Hedner U, Ahlberg A. Haemophilia prophylaxis in Sweden. Acta Paediatr Scand 1976; 65 (2) 129-135
    CrossrefPubMedSearch in Google Scholar
  • 3 Van Creveld S. Prophylaxis of joint hemorrhages in hemophilia. Acta Haematol 1969; 41 (4) 206-214
    CrossrefPubMedSearch in Google Scholar
  • 4 Berntorp E. History of prophylaxis. Haemophilia 2013; 19 (2) 163-165
    CrossrefPubMedSearch in Google Scholar
  • 5 Berntorp E, Astermark J, Björkman S , et al. Consensus perspectives on prophylactic therapy for haemophilia: summary statement. Haemophilia 2003; 9 (Suppl. 01) 1-4
    PubMedSearch in Google Scholar
  • 6 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
    CrossrefPubMedSearch in Google Scholar
  • 7 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
    CrossrefPubMedSearch in Google Scholar
  • 8 Valentino LA, Mamonov V, Hellmann A , et al; Prophylaxis Study Group. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost 2012; 10 (3) 359-367
    CrossrefPubMedSearch in Google Scholar
  • 9 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
    PubMedSearch in Google Scholar
  • 10 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
    CrossrefPubMedSearch in Google Scholar
  • 11 Den Uijl IE, De Schepper AM, Camerlinck M, Grobbee DE, Fischer K. Magnetic resonance imaging in teenagers and young adults with limited haemophilic arthropathy: baseline results from a prospective study. Haemophilia 2011; 17 (6) 926-930
    CrossrefPubMedSearch in Google Scholar
  • 12 Björkman S. Limited blood sampling for pharmacokinetic dose tailoring of FVIII in the prophylactic treatment of haemophilia A. Haemophilia 2010; 16 (4) 597-605
    PubMedSearch in Google Scholar
  • 13 Björkman S. Population pharmacokinetics of recombinant factor IX: implications for dose tailoring. Haemophilia 2013; 19 (5) 753-757
    CrossrefPubMedSearch in Google Scholar
  • 14 Carlsson M, Berntorp E, Björkman S, Lindvall K. Pharmacokinetic dosing in prophylactic treatment of hemophilia A. Eur J Haematol 1993; 51 (4) 247-252
    PubMedSearch in Google Scholar
  • 15 Carlsson M, Berntorp E, Bjorkman S, Lethagen S, Ljung RCR. Improved cost-effectiveness by pharmacokinetic dosing of factor VIII in prophylactic treatment of haemophilia A. Haemophilia 1997; 3 (2) 96-101
    CrossrefPubMedSearch in Google Scholar
  • 16 Carlsson M, Björkman S, Berntorp E. Multidose pharmacokinetics of factor IX: implications for dosing in prophylaxis. Haemophilia 1998; 4 (2) 83-88
    CrossrefPubMedSearch in Google Scholar
  • 17 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
    CrossrefPubMedSearch in Google Scholar
  • 18 Biggs R, MacFarlane RG. Haemophilia and related conditions: a survey of 187 cases. Br J Haematol 1958; 4 (1) 1-27
    CrossrefPubMedSearch in Google Scholar
  • 19 Den Uijl IE, Mauser Bunschoten EP, Roosendaal G , et al. Clinical severity of haemophilia A: does the classification of the 1950s still stand?. Haemophilia 2011; 17 (6) 849-853
    CrossrefPubMedSearch in Google Scholar
  • 20 van Dijk K, Fischer K, van der Bom JG, Grobbee DE, van den Berg HM. Variability in clinical phenotype of severe haemophilia: the role of the first joint bleed. Haemophilia 2005; 11 (5) 438-443
    CrossrefPubMedSearch in Google Scholar
  • 21 Ahnström J, Berntorp E, Lindvall K, Björkman S. A 6-year follow-up of dosing, coagulation factor levels and bleedings in relation to joint status in the prophylactic treatment of haemophilia. Haemophilia 2004; 10 (6) 689-697
    CrossrefPubMedSearch in Google Scholar
  • 22 Collins PW, Blanchette VS, Fischer K , et al; rAHF-PFM Study Group. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J Thromb Haemost 2009; 7 (3) 413-420
    CrossrefPubMedSearch in Google Scholar
  • 23 Collins PW, Fischer K, Morfini M, Blanchette VS, Björkman S ; International Prophylaxis Study Group Pharmacokinetics Expert Working Group. Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia. Haemophilia 2011; 17 (1) 2-10
    CrossrefPubMedSearch in Google Scholar
  • 24 Astermark J, Petrini P, Tengborn L, Schulman S, Ljung R, Berntorp E. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. Br J Haematol 1999; 105 (4) 1109-1113
    CrossrefPubMedSearch in Google Scholar
  • 25 Fischer K, van der Bom JG, Mauser-Bunschoten EP , et al. The effects of postponing prophylactic treatment on long-term outcome in patients with severe hemophilia. Blood 2002; 99 (7) 2337-2341
    CrossrefPubMedSearch in Google Scholar
  • 26 den Uijl I, Biesma D, Grobbee D, Fischer K. Outcome in moderate haemophilia. Blood Transfus 2014; 12 (Suppl. 01) s330-s336
    PubMedSearch in Google Scholar
  • 27 Lindvall K, Astermark J, Björkman S , et al. Daily dosing prophylaxis for haemophilia: a randomized crossover pilot study evaluating feasibility and efficacy. Haemophilia 2012; 18 (6) 855-859
    CrossrefPubMedSearch in Google Scholar
  • 28 Oldenburg J, Albert T. Novel products for haemostasis - current status. Haemophilia 2014; 20 (Suppl. 04) 23-28
    CrossrefPubMedSearch in Google Scholar
  • 29 Nathwani AC, Reiss UM, Tuddenham EG , et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 2014; 371 (21) 1994-2004
    CrossrefPubMedSearch in Google Scholar
  • 30 Broderick CR, Herbert RD, Latimer J , et al. Association between physical activity and risk of bleeding in children with hemophilia. JAMA 2012; 308 (14) 1452-1459
    CrossrefPubMedSearch in Google Scholar