COMMENTARY

To bleed or not to bleed – is that a question?

L . M. ALEDORTMount Sinai School of Medicine, New York, NY, USA

To cite this article: Aledort LM. To bleed or not to bleed – is that a question? J Thromb Haemost 2010; 8: 81–2.

See also Collins P, Faradji A, Morfini M, Enriquez MM, Schwartz L. Efficacy and safety of secondary prophylactic vs. on-demand sucroseformulated

recombinant factor VIII treatment in adults with severe hemophilia A: results from a 13-month crossover study. This issue, pp 83–9.

Bleeding is the major complication of patients with hemophilia.

Other than life-threatening bleeds, joint bleeds have been the

major cause of morbidity, with long-term joint damage, and

restriction in activity, as well as limitation of vocational choices.

The introduction of self-infusion or family infusion of available

concentrates made surgical correction and reduction in joint

pathology possible. The early [1] introduction of prophylaxis

initiated a therapeutic intervention that has markedly altered

outcomes.

These initial observations have led to a large body of

literature that has included anecdotes and clinical trials.

Various regimens for prophylaxis have been studied in

prospective fashion, varying from initiating prophylaxis once

a week in children to treatment every other day.

Recently, a prospective, randomized, longitudinal study

comparing prophylaxis with on-demand treatment in children

clearly showed that prophylaxis markedly reduced bleeding

episodes and led to less joint damage when a highly sensitive

magnetic resonance imaging technique was used [2].

Few prospective studies have evaluated clinical practice in

adults with assessment of outcomes as they related to on-

demand treatment vs. prophylaxis. One large study [3] dem-

onstrated that prophylaxis gave better orthopedic outcomes,

involved the use of substantially more factor than on-demand

treatment, and would slow progression of arthropathy in those

with previous joint disease. Patients who have been on

prophylaxis from childhood not infrequently stop in adult-

hood, only to resume if bleeding becomes an issue.

In this journal issue, an article by Collins et al. [4], entitled

�Secondary prophylaxis versus on-demand treatment with

sucrose-formulated recombinant factor VIII: a 13-month

crossover study of adults with severe hemophilia A�, deals

with a recombinant factor VIII product in a prospective study

of 19 adult patients, whose mean age was 36.4 years and who

had 16 target joints among them. This was an open label study

in severe hemophilia A patients with FVIII < 1%. The

patients were followed for 6 months on demand, and then

switched to 7 months of prophylaxis with 20–40 IU kg)1 three

times a week. The change in the major outcome of bleeds was

very dramatic, with the median number of joint bleeds on

demand being 15 (11–26), and dropping to 0 (0–3)

(P < 0.001). The decrease in all bleeds went from 20.5 (14–

37) to 0 (0–3) (P < 0.001). Treatment was well tolerated.

Although this article describes a small study, recruiting

patients for clinical trials has become a significant challenge.

These observations confirm those of the orthopedic outcome

study [3], in that bleeding episodes and changes in orthopedic

measurements improve on prophylaxis. Using theGilbert score

[5] to measure joint function, there was also significant

improvement solely based on bleeding. In the long-term study

[3], the Gilbert score changed even more dramatically.

In this article, the quality of life and health economy

measurements were not significant, but would not be expected

to be over such a short period of time. Pediatric, early

primary or secondary prophylaxis has now been clearly

shown to be practical, with growing numbers of patients being

treated in this fashion, and with continuing investigations

regarding optimal regimens. More emphasis is now being put

on tailoring treatment to meet the bleeding patterns of

patients.

On the other hand, prophylaxis in adolescents and adults has

seriously lagged behind, both from an investigative standpoint

and in terms of being put into clinical practice [6]. The

economic impact of prophylaxis has been described, and it is

more costly, even when one corrects it for improvements in

health-related parameters [7]. However, in the orthopedic

outcome study (OOS) programs, using equivalently high

doses of factor, the on-demand group fared worse than those

on prophylaxis in both bleeding and orthopedic outcome

measures.

This article underscores the marked benefit of instituting a

prophylaxis program in patients who have already demon-

strated joint pathology. Younger adults who have never been

on prophylaxis, but, because of early intervention demand

therapy, have good joints, may well benefit from prophylaxis in

the long term to prevent joint damage. Problems of compli-

ance, as more frequent treatment is required, and finances may

become key determinants in making therapeutic decisions in

Correspondence: Louis M. Aledort, The Mary Weinfeld Professor of

Clinical Research in Hemophilia, Mount Sinai School of Medicine,

NY, USA.

E-mail: louis.aledort@mssm.edu

Journal of Thrombosis and Haemostasis, 8: 81–82 DOI: 10.1111/j.1538-7836.2009.03668.x

� 2009 International Society on Thrombosis and Haemostasis

the USA. The USA has pluralistic reimbursement programs,

and with many uninsured, this can be rate-limiting in making

this therapeutic modality available.

This interesting study needs to be reproduced with larger,

randomized designs. It is clearly better not to bleed than to

bleed.

Disclosure of Conflict of Interests

The author states that he has no conflict of interest.

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Haemost 2009; 8: 83–9.

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82 L. M. Aledort

� 2009 International Society on Thrombosis and Haemostasis