Highlights
- •Persons with hemophilia enjoy nowadays a normal life expectancy.
- •This goal was achieved through the availability of safe and efficacious therapies.
- •Gene replacement therapy is promising to offer a cure to this scourge.
- •Multimorbidity and related polypharmacy are a forthcoming in older patients.
- •Thus, hemophilia management requires also the holistic approach of internists and geriatricians.
Abstract
The management of inherited coagulation disorders such as hemophilia A and B has witnessed
dramatic progresses since the last few decades of the last century. Accordingly, persons
with hemophilia (PWH) now enjoy a life expectancy at birth not different from that
of males in the general population, at least in high income countries. Nowadays, a
substantial proportion of PWH are aging, like their peers in the general population.
This outstanding progress is accompanied by problems that are in part similar to those
of any old person (multiple concomitant diseases and the resulting intake of multiple
drugs other than those specific for hemophilia treatment). In addition, older PWH
suffer from the consequences of the comorbidities that developed when their treatment
was at the same time poorly available and unsafe. Typical hemophilia comorbidities
affect the musculoskeletal system following joint and muscle bleeds, but also the
liver and kidney are often impaired due to previous bloodborne infections such as
viral hepatitis and HIV. Thus, the comorbidities of hemophilia superimposed on the
multimorbidity and polypharmacy associated with aging create peculiar problems in
the current management of these patients, that demand the coordinated holistic intervention
of internists, geriatricians and clinical pharmacologists in addition to the care
traditionally provided by pediatricians and hematologists.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of Internal MedicineAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The hemophilias – from royal genes to gene therapy.N Engl J Med. 2001; 344: 1773-1779
- Modern haemophilia care.Lancet. 2012; 379: 1447-1456
- Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis.Thromb Haemost. 2001; 85: 560
- A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs.J Intern Med. 1994; 236: 391-399
- The phenotypic heterogeneity of severe hemophilia.Semin Thromb Hemost. 2008; 34: 128-142
- Definitions in hemophilia: communication from the SSC of the ISTH.J Thromb Haemost. 2014; 12: 1935-1939
- Is VIII worse than IX?.Blood. 2009; 114: 750-751
- Is haemophilia B less severe than haemophilia A?.Haemophilia. 2013; 19: 499-502
- Clinical, instrumental, serological and histological findings suggest that hemophilia B may be less severe than hemophilia A.Haematologica. 2016; 101: 219-225
- Prevention and treatment of musculoskeletal disease in the haemophilia population: role of prophylaxis and synovectomy.Haemophilia. 2006; 12: 159-168
- The overall effectiveness of prophylaxis in severe haemophilia.Haemophilia. 2003; 9: 272-278
- Highpotency antihaemophilic factor concentrate prepared from cryoglobulin precipitate.Nature. 1964; 203: 312
- Production of high-potency concentrates of antihaemophilic globulin in a closedbag system.N Engl J Med. 1965; 273: 1443-1447
- Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B.J Intern Med. 1992; 232: 25-32
- Expression of active human factor VIII from recombinant DNA clones.Nature. 1984; 312: 330-337
- Use of recombinant antihemophilic factor in the treatment of two patients with classic hemophilia.N Engl J Med. 1989; 320: 166-170
- Virus safety of solvent/detergent-treated antihaemophilic factor concentrate.Lancet. 1988; 2: 186-189
- The epidemiology of virus transmission by plasma derivatives: clinical studies verifying the lack of transmission of hepatitis B and C viruses and HIV type 1.Transfusion. 1999; 39: 1160-1168
- Recombinant clotting factors.Thromb Haemost. 2008; 99: 840-850
- Massive factor-VIII infusion in haemophiliac with factor-VIII inhibitor, high responder.Lancet. Oct 29 1977; 2: 933
- Immune tolerance for the treatment of factor VIII inhibitors—twenty years' ‘bonn protocol’.Vox Sang. 1996; 70: 30-35
- The principal results of the International Immune Tolerance Study: a randomized dose comparison.Blood. 2012; 119: 1335-1344
- Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS study group.Blood. 2003; 102: 2358-2363
- The use of enhanced half-life coagulation factor concentrates in routine clinical practice: guidance from UKHCDO.Haemophilia. 2016; 22: 487-498
- Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A.J Thromb Haemost. 2014; 12: 488-496
- Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A.Blood. 2014; 123: 317-325
- Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A.Blood. Aug 27 2015; 126: 1078-1085
- Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A.J Thromb Haemost. 2013; 11: 670-678
- Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B.N Engl J Med. 2013; 369: 2313-2323
- Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial.Blood. 2014; 124: 3880-3886
- Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial.Blood. 2016; 127: 1761-1769
- Mortality and causes of death in patients with hemophilia, 1992–2001: a prospective cohort study.J Thromb Haemost. 2006; 4: 510-516
- Present and future challenges in the treatment of haemophilia: a clinician's perspective.Blood Transfus. 2013; 11: s77-s81
- Rationale for individualizing hemophilia care.Blood Coagul Fibrinolysis. 2015; 26: 849-857
- Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART) [published correction appears in J Thromb Haemost. 2014;12:119–122.].J Thromb Haemost. 2013; 11: 1119-1127
- Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.N Engl J Med. 2007; 357: 535-544
- A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT study).J Thromb Haemost. 2011; 9: 700-710
- On-demand vs. prophylactic treatment for severe haemophilia in Norway and Sweden: differences in treatment characteristics and outcome.Haemophilia. 2003; 9: 555-566
- Epidemiological survey of the orthopedic status of severe haemophilia A and B patients in France.Haemophilia. 2000; 6: 23-32
- 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: 689-697
- Prophylactic treatment for severe haemophilia: comparison of an intermediate dose to a high-dose regimen.Haemophilia. 2002; 8: 753-760
- The past and future of haemophilia: diagnosis, treatments, and its complications.Lancet. 2016; 388: 187-197
- Limited blood sampling for pharmacokinetic dose tailoring of FVIII in the prophylactic treatment of haemophilia A.Haemophilia. 2010; 16: 597-605
- Tailored prophylaxis in severe hemophilia A: interim results from the first 5 years of the Canadian Hemophilia Primary Prophylaxis Study.J Thromb Haemost. 2006; 4: 1228-1236
- Musculoskeletal health of subjects with hemophilia A treated with tailored prophylaxis: Canadian Hemophilia Primary Prophylaxis (CHPS) Study.J Thromb Haemost. 2013; 11: 460-466
- Prophylactic dosing of factor VIII and factor IX from a clinical pharmacokinetic perspective.Haemophilia. 2003; 9 ([discussion 9-10]): 101-108
- Comparative pharmacokinetics of plasma and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age related differences and implications for dose tailoring.J Thromb Haemost. 2010; 8: 730-736
- Considerations in individualizing prophylaxis in patients with hemophilia A.Haemophilia. 2014; 20: 607-615
- 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: 359-367
- Participants, on behalf of the EUHASS. Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project.Thromb Haemost. 2015; 113: 968-975
- Inhibitor development in previously treated hemophilia A patients: a systematic review, meta-analysis, and meta-regression.J Thromb Haemost. 2013; 11: 1655-1662
- 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: 1256-1265
- Haemophilia A: mutation type determines risk of inhibitor formation.Thromb Haemost. 1995; 74: 1402-1406
- Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study.Blood. 2007; 109: 4648-4654
- Inhibitors occur more frequently in African-American and Latino haemophiliacs.Haemophilia. 1998; 4: 68
- The epidemiology of inhibitors in haemophilia A: a systematic review.Haemophilia. 2003; 9: 418-435
- Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A.Blood. 2006; 107: 46-51
- Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A.Haemophilia. 2007; 13: 149-155
- Plasma-derived factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A: report of the FranceCoag Network.J Thromb Haemost. 2015; 13: 148
- A randomized trial of factor VIII and neutralizing antibodies in hemophilia A.N Engl J Med. 2016; 374: 2054-2064
- How I treat age-related morbidities in elderly persons with hemophilia.Blood. 2009; 114: 5256-5263
- Factors influencing the long-term outcome of primary total knee replacement in haemophiliacs: a review of 116 procedures at a single institution.Br J Haematol. 2009; 145: 227-234
- Bone mineral density in men and children with haemophilia A and B: a systematic review and metaanalysis.Osteoporos Int. 2014; 25: 2399-2407
- Management of cardiovascular disease in aging persons with haemophilia.Hamostaseologie. 2017; 37 ([Epub ahead of print])
- Understanding cardiovascular risk in hemophilia: a step towards prevention and management.Thromb Res. 2016; 140: 14-21
- Atrial fibrillation in patients with haemophilia: a cross-sectional evaluation in Europe.Haemophilia. 2014; 20: 682-686
- European AIDS Clinical Society (EACS) guidelines on the prevention and management of metabolic diseases in HIV.HIV Med. 2008; 9: 72-81
- Renal disease among males with haemophilia.Haemophilia. 2003; 9: 703-710
- Minimizing risks of NSAIDs: cardiovascular, gastrointestinal and renal.Expert Rev Neurother. 2006; 6: 1643-1655
- Self-reported prevalence, description and management of pain in adults with haemophilia: methods, demographics and results from the Pain, Functional Impairment, and Quality of life (P-FiQ) study.Haemophilia. 2017; https://doi.org/10.1111/hae.13214
- Managing chronic pain in adults with haemophilia: current status and call to action.Haemophilia. 2015; 21: 41-51
- Clinical consequences of polypharmacy in elderly.Expert Opin Drug Saf. 2014; 13: 57-65
- Measurement, correlates, and health outcomes of medication adherence among seniors.Ann Pharmacother. 2004; 38: 303-312
- Prevalence of unplanned hospitalizations caused by adverse drug reactions in older veterans.J Am Geriatr Soc. 2012; 60: 34-41
- A pharmacoepidemiologic study of community-dwelling, disabled older women: factors associated with medication use.Am J Geriatr Pharmacother. 2010; 8: 215-224
- Association between Potentially Inappropriate Medication (PIM) use and risk of hospitalization in older adults: an observational study based on routine data comparing PIM use with use of PIM alternatives.PLoS One. 2016; 11e0146811
- The challenge of managing drug interactions in elderly people.Lancet. 2007; 370: 185-191
- Clinically important drug-disease interactions and their prevalence in older adults.Clin Ther. 2006; 28: 1133-1143
- Association of polypharmacy with nutritional status, functional ability and cognitive capacity over a three-year period in an elderly population.Pharmacoepidemiol Drug Saf. 2010; 20: 514-522
- Adenovirus-associated virus vector-mediated gene transfer in hemophilia B.N Engl J Med. 2011; 365: 2357-2365
- Long-term safety and efficacy of factor IX gene therapy in hemophilia B.N Engl J Med. 2014; 371: 1994-2004
- Current status of haemophilia gene therapy.Haemophilia. 2014; 20: 43-49
- Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant.Blood. 2013; 121: 3335-3344
- Efficient production of dual recombinant adeno-associated viral vectors for factor VIII delivery.Hum Gene Ther Methods. 2014; 25: 261-268
- A microRNA-regulated and GP64-pseudotyped lentiviral vector mediates stable expression of FVIII in a murine model of hemophilia A.Mol Ther. 2011; 19: 723-730
Article info
Publication history
Published online: May 20, 2017
Accepted:
May 11,
2017
Received in revised form:
May 10,
2017
Received:
March 2,
2017
Identification
Copyright
© 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
