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CC BY 4.0 · Thromb Haemost 2020; 120(05): 728-736
DOI: 10.1055/s-0040-1709519
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Modeling to Predict Factor VIII Levels Associated with Zero Bleeds in Patients with Severe Hemophilia A Initiated on Tertiary Prophylaxis

Pratima Chowdary
1   Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London, United Kingdom
,
Kathelijn Fischer
2   Van Creveldkliniek, Department of Hematology, University Medical Center, Utrecht, The Netherlands
,
Peter W. Collins
3   School of Medicine, Cardiff University, Cardiff, United Kingdom
,
Amy Cotterill
4   Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria
,
Barbara A. Konkle
5   Bloodworks Northwest, Seattle, Washington, United States
6   Department of Medicine, University of Washington, Seattle, Washington, United States
,
Victor Blanchette
7   Department of Paediatrics, Division of Haematology/Oncology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
,
Steven W. Pipe
8   Department of Pediatrics and Pathology, University of Michigan, Ann Arbor, Michigan, United States
,
Erik Berntorp
9   Department of Translational Medicine and Centre for Thrombosis and Haemostasis, Lund University, Malmö, Sweden
,
Martin Wolfsegger
4   Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria
,
Werner Engl
4   Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria
,
Gerald Spotts
10   Baxalta US Inc, a member of the Takeda group of companies, Lexington, Massachusetts, United States
› Institutsangaben Funding This study was funded by Baxalta US Inc, a member of the Takeda group of companies, Lexington, Massachusetts, United States.
Weitere Informationen

Publikationsverlauf

22. November 2019

20. Februar 2020

Publikationsdatum:
05. Mai 2020 (online)

   Lizenzen und Reprints

Abstract

Background Factor VIII (FVIII) trough levels > 1 IU/dL in patients with severe hemophilia A receiving regular prophylaxis may optimize bleed protection.

Objectives In this post hoc analysis of patients receiving tertiary prophylaxis for approximately 1 year, the relationship between estimated FVIII levels and reported bleeds was investigated to predict the potential for zero bleeds.

Methods Sixty-three patients (median [range] age, 28 [7–59] years) with severe hemophilia A (229 bleeds) were included. FVIII levels at time of each bleed were estimated from single-dose individual pharmacokinetics. The highest estimated FVIII level at which patients experienced a bleed was considered the “potentially effective trough level” for that bleed type. Kaplan–Meier estimates of proportions of patients with no bleeds above certain estimated FVIII levels were determined. Those not experiencing a bleed in the trial were assumed to have a bleed at 0 IU/dL (pragmatic approach) or at their median trough level (conservative approach).

Results Kaplan–Meier estimates based on pragmatic approach predicted zero all bleeds, joint bleeds, and spontaneous joint bleeds in 1 year in 40, 43, and 63% of patients, respectively, when the potentially effective trough FVIII level was set at 1 IU/dL. Between 1 and 10 IU/dL, every 1 IU/dL rise in estimated FVIII level was associated with an additional 2% of patients having zero all bleeds.

Conclusion This post hoc analysis confirms benefits with trough levels of approximately 1 to 3 IU/dL in most patients starting tertiary prophylaxis; prophylaxis with higher trough levels may help patients to achieve zero bleeds.

Keywords

coagulation factors - hemophilia A/B - factor VIII - pharmacodynamics

Authors' Contributions

P.C., K.F., P.W.C., and G.S. jointly designed the analysis, interpreted the results, and wrote the first draft of the manuscript. A.C. performed the statistical analysis and discussed and interpreted the results. B.A.K., V.B., and S.W.P. discussed and interpreted the results. E.B. participated in designing the study and discussed and interpreted the results. M.W. performed the PK analysis and discussed and interpreted the results. W.E. revised the graphical representation of results and discussed and interpreted the results. All authors reviewed the manuscript drafts and approved the final version.


 

  • 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; ;(Suppl 77): 3-132
    PubMedGoogle Scholar
  • 2 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 (04) 391-399
    CrossrefPubMedGoogle Scholar
  • 3 Fischer K, Collins PW, Ozelo MC, Srivastava A, Young G, Blanchette VS. When and how to start prophylaxis in boys with severe hemophilia without inhibitors: communication from the SSC of the ISTH. J Thromb Haemost 2016; 14 (05) 1105-1109
    CrossrefPubMedGoogle Scholar
  • 4 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 (04) 498-507
    CrossrefPubMedGoogle Scholar
  • 5 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 (06) 535-544
    CrossrefPubMedGoogle Scholar
  • 6 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 (04) 700-710
    CrossrefPubMedGoogle Scholar
  • 7 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 (01) 25-32
    CrossrefPubMedGoogle Scholar
  • 8 Mazepa MA, Monahan PE, Baker JR, Riske BK, Soucie JM. ; US Hemophilia Treatment Center Network. Men with severe hemophilia in the United States: birth cohort analysis of a large national database. Blood 2016; 127 (24) 3073-3081
    CrossrefPubMedGoogle Scholar
  • 9 Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood 2015; 125 (13) 2038-2044
    CrossrefPubMedGoogle Scholar
  • 10 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 (03) 413-420
    CrossrefPubMedGoogle Scholar
  • 11 Valentino LA, Pipe SW, Collins PW. , et al. Association of peak factor VIII levels and area under the curve with bleeding in patients with haemophilia A on every third day pharmacokinetic-guided prophylaxis. Haemophilia 2016; 22 (04) 514-520
    CrossrefPubMedGoogle Scholar
  • 12 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 (06) 849-853
    CrossrefPubMedGoogle Scholar
  • 13 Gringeri A, Lambert T, Street A, Aledort L. ; Adolescent/Adult Prophylaxis Expert Working Group of the International Prophylaxis Study Group. Tertiary prophylaxis in adults: is there a rationale?. Haemophilia 2012; 18 (05) 722-728
    CrossrefPubMedGoogle Scholar
  • 14 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 (03) 359-367
    CrossrefPubMedGoogle Scholar
  • 15 Srivastava A, Brewer AK, Mauser-Bunschoten EP. , et al; Treatment Guidelines Working Group on Behalf of The World Federation of Hemophilia. Guidelines for the management of hemophilia. Haemophilia 2013; 19 (01) e1-e47
    CrossrefPubMedGoogle Scholar
  • 16 Björkman S, Oh M, Spotts G. , et al. Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight. Blood 2012; 119 (02) 612-618
    CrossrefPubMedGoogle Scholar
  • 17 Ahlberg A, Nilsson IM, Bauer GC. Use of antihemophilic factor (plasma fraction I-O) during correction of knee-joint deformities in hemophilia A. Report of three cases including one osteotomy. J Bone Joint Surg Am 1965; 47: 323-332
    CrossrefPubMedGoogle Scholar
  • 18 McCarthy A, Moore A, Redhead L, McLaughlin P, Iorio A, Chowdary P. Development of haemophilic arthropathy of the ankle: results of a Delphi consensus survey on potential contributory factors. Haemophilia 2015; 21 (01) 116-123
    CrossrefPubMedGoogle Scholar
  • 19 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
    CrossrefPubMedGoogle Scholar
  • 20 Anderson A, Forsyth A. . Playing it safe: bleeding disorders, sports and exercise: National Haemophilia Foundation; 2017 Available at: https://www.hemophilia.org/sites/default/files/document/files/Playing-It-Safe.pdf . Accessed July 1, 2019
    PubMed
  • 21 Liesner RJ, Khair K, Hann IM. The impact of prophylactic treatment on children with severe haemophilia. Br J Haematol 1996; 92 (04) 973-978
    CrossrefPubMedGoogle Scholar
  • 22 Lusher JM, Shapiro SS, Palascak JE, Rao AV, Levine PH, Blatt PM. Efficacy of prothrombin-complex concentrates in hemophiliacs with antibodies to factor VIII: a multicenter therapeutic trial. N Engl J Med 1980; 303 (08) 421-425
    CrossrefPubMedGoogle Scholar
  • 23 Ceponis A, Wong-Sefidan I, Glass CS, von Drygalski A. Rapid musculoskeletal ultrasound for painful episodes in adult haemophilia patients. Haemophilia 2013; 19 (05) 790-798
    CrossrefPubMedGoogle Scholar
  • 24 Collins PW. Personalized prophylaxis. Haemophilia 2012; 18 (Suppl. 04) 131-135
    CrossrefPubMedGoogle Scholar
  • 25 Valentino LA. Considerations in individualizing prophylaxis in patients with haemophilia A. Haemophilia 2014; 20 (05) 607-615
    CrossrefPubMedGoogle Scholar
  • 26 Collins PW, Björkman S, Fischer K. , et al. Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe hemophilia A: influences of variance in pharmacokinetics and treatment regimens. J Thromb Haemost 2010; 8 (02) 269-275
    CrossrefPubMedGoogle Scholar
  • 27 Björkman S, Collins P. ; Project on Factor VIII/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 (01) 180-182
    PubMedGoogle Scholar
  • 28 Stass H. Determination of minimal sampling time points for reliable pharmacokinetic evaluation of recombinant factor VIII – an exploratory population pharmacokinetic analysis in paediatric patients suffering from severe haemophilia. Haemophilia 2006; 12 (Suppl. 04) 50-55
    CrossrefPubMedGoogle Scholar
  • 29 Björkman S. Limited blood sampling for pharmacokinetic dose tailoring of FVIII in the prophylactic treatment of haemophilia A. Haemophilia 2010; 16 (04) 597-605
    PubMedGoogle Scholar
  • 30 Iorio A, Keepanasseril A, Foster G. , et al; WAPPS-Hemo co-investigator network. Development of a Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo): study protocol. JMIR Res Protoc 2016; 5 (04) e239
    CrossrefPubMedGoogle Scholar
  • 31 Klamroth R, Windyga J, Radulescu V. , et al. PK-guided rurioctocog alfa pegol prophylaxis in patients with severe hemophilia A targeting two FVIII trough levels: results from the phase 3 PROPEL study. Res Pract Thromb Haemost 2019; 3 (Suppl. 01) 106-107
    PubMedGoogle Scholar