Individualizing prophylaxis in hemophilia: a review

Abstract

Prophylaxis is considered optimal care for patients with severe hemophilia to prevent bleeding, including hemarthroses, which may cause arthropathy with chronic pain, occupational impairment and progressive loss of mobility. Questions remain regarding the optimal delivery of prophylaxis including how to individualize prophylaxis and optimize outcomes for each patient. Designing a prophylactic regimen for severe hemophilia must account for each patient’s unique disease course, bleeding pattern, presence/absence of joint damage, pharmacokinetic profile, level of physical activity and adherence to treatment. Standard weight-based prophylaxis regimens and regimens optimized by bleeding phenotype (i.e., patients are ‘allowed’ to bleed to dose optimization) fail to prevent complications in many patients. Pharmacokinetic-guided dosing enables precise adjustment of dosing level and frequency to maintain adequate hemostatic levels and prevent bleeding. Optimal outcomes, such as reducing or eliminating hemorrhages, preventing or minimizing joint damage, and improving quality of life, can be achieved through an individualized care approach.

Keywords:

• arthropathy
• hemarthroses
• hemophilia
• personalized medicine
• pharmacokinetics
• prophylaxis

Acknowledgements

Medical writing assistance was provided by SK Laden, MS (C4 MedSolutions, a CHC Group company; Yardley, PA, USA), and was funded by Baxter Healthcare, Westlake Village, CA, USA. All authors were involved in the collection, analysis, or interpretation of existing evidence and critically reviewed and approved the final version for submission.

Financial & competing interests disclosure

This study was funded by Baxter Healthcare, Westlake Village, CA, USA.

LA Valentino, A Gringeri, WM Re, and B Ewenstein are employees of Baxter. Rush University Medical Center (RUMC) received grant support on behalf of LA Valentino from Baxter Bioscience, Bayer Healthcare, Biogen, CSL Behring, GTC Biotherapeutics, Inspiration Bioscience, NovoNordisk, and Pfizer; and RUMC also received payments on behalf of LA Valentino for his participation in advisory boards and as a consultant for Baxter Bioscience, Bayer Healthcare, Biogen, CSL Behring, GTC Biotherapeutics, rEVO Biologics, Inspiration Bioscience, NovoNordisk, and Pfizer. Since the preparation of this manuscript, LA Valentino became an employee of Baxter Bioscience but continues in an academic capacity as a faculty member of RUMC.

P Petrini has received honoraria from Baxter Bioscience, Bayer Healthcare, Biogen Idec, NovoNordisk, Pfizer, Sobi, and Wyeth Pharmaceuticals.

Key issues

• Patients with severe hemophilia attributable to deficiencies in clotting factor VIII or factor IX are at risk of serious bleeding including hemarthroses and subsequent joint damage and of life-threatening hemorrhages.

• Prophylactic therapy with replacement clotting factor aimed at preventing bleeding and the resultant joint damage is considered optimal treatment for patients with severe hemophilia A or B.

• Prophylaxis regimens are best tailored to the individual patient by adjusting the dose and frequency of treatment based on the patient’s age, bleeding pattern, residual clotting factor levels, factor VIII or factor IX pharmacokinetic profile, physical activity and adherence to therapy.

• Joint damage revealed by radiographic or magnetic resonance imaging in patients with hemophilia may result from subclinical as well as clinically evident bleeding events; in the future, specific biomarkers for inflammation and joint remodeling associated with hemophilia may assist in individualization of prophylaxis regimens.

• Pharmacokinetic-guided prophylactic dosing aims to maintain adequate levels of the deficient hemostatic factor. In determining the optimal level and regimen for an individual patient, clinicians should consider the patient’s age, bleeding phenotype, pharmacokinetic profile, presence or absence of joint damage, physical activity, perceived risk of injury, and adherence to therapy.

• Adherence to prophylaxis therapy is high for children younger than 12 years, but the frequency of missed doses and the time during which hemostatic factor levels are <1 IU dL^–1 increase in older patients.

• For children with severe hemophilia, primary and secondary prophylaxis regimens are more effective than episodic treatment, especially when primary prophylaxis begun at a young age (<3 years old). Strategies for individualized prophylaxis in children and adolescents include tailoring dosing intensity based on the patient’s bleeding patterns, factor VIII/IX pharmacokinetics, and level of physical activity as well as addressing barriers to adherence to therapy.

• In adults with severe hemophilia, prophylactic replacement of the deficient hemostatic factor decreases bleeding rates and improves joint outcomes and quality of life. Prophylaxis individualized on the basis of pharmacokinetic response to replacement therapy, bleeding phenotype, and adherence motivators is a viable option for adults with severe hemophilia and existing joint damage. Because continuous prophylaxis declines throughout adulthood, understanding the impact of each bleeding event, the benefits of prophylaxis, the importance of adherence as well as establishing good relationships between patients and their healthcare professionals are key factors in optimizing adherence and ensuring optimal outcomes.

Notes