Joint Bleeds in Adults: Not All Pharmacokinetics
Commentary by David Stephensen (PhD), Physiotherapist, Kent Haemophilia & Thrombosis Centre, Canterbury, and the Haemophilia Centre, Royal London Hospital, London, UK
Prophylaxis at a dose that maintains factor levels above target reduces the frequency of joint bleeds in people with haemophilia – but often it does not prevent them completely. Perhaps the target factor level should be higher or perhaps, as a study from the United States suggests, the fundamental problem lies with the damaged joint (Clinical and Applied Thrombosis/Hemostasis 2019;25:1-10).
Twenty-six patients with haemophilia (21 A, 5 B) of any severity (severe 18, moderate 4, mild 4) and at least one joint with arthropathy were followed up for 30 months. During this time, they underwent joint health assessments every 6 – 12 months and when experiencing acute painful joints. Pain was assessed by visual analogue scale and joint health by Pettersson score and Haemophilia Joint Health Score (HJHS); a joint bleed was confirmed by ultrasound; and joint vascularity was assessed by power Doppler.
Patients’ median age was 38 (interquartile range [IQR] 29 – 54); 21 (81%) were using prophylaxis and the remainder used on demand treatment. At baseline median HSHS was 10 (IQR 5 – 29) and median total Pettersson score was 23 (10 – 47). In all, nine patients had no bleeds during the observation period. There were 18 painful episodes with bleeds (knee 4, elbow 9, ankle 5) (‘bleed/pain’) and 11 without (4,1,6) (’no bleed/pain’). Of six patients on prophylaxis with an extended half-life factor VIII, one had joint pain (it is not clear whether that person had a bleed).
“About a third of painful joint episodes in patients with arthropathy are not associated with bleeds but are in fact an exacerbation of arthropathy. This raises a number of challenges – what is the best way of diagnosing bleed or non-bleed episodes? How accurate are annual bleed rates in reported studies. And should the number of joint bleeds be the primary end-point in studies of new treatments?”
Looking at factor pharmacokinetics, half-life and volume of distribution were greater in the nine patients with no bleeds compared with the bleed/pain and no bleed/pain groups. However, consumption of factor and ‘concentration hours’ (a measure of the total factor administered) were greatest in the bleed/pain group. This is contrary to expectations and suggests that low factor use did not account for the bleeds. An alternative explanation, the authors suggest, is that ‘over the lifetime of bleeders their treatment dose was progressively increased in response to a suboptimal control of bleeding’. Further more, there was no difference between the groups in time spent below target factor level and, as well as finding no differences between patients, the study found no variation over time within individuals that could account for the occurrence of bleeds and pain.
“It would be interesting to look at patients’ individual joint health and function – do those with greater joint health impairment experience more or less bleeding or painful episodes? There is a lack of research into individually tailoring prophylaxis or treatment choice on an individual’s physical health.”
What it did show was that joints affected by bleeds were associated with high HJHS and Pettersson scores and older age, and painful joint bleeds were associated with higher ultrasound/Doppler scores than joint pain without a bleed. This suggests that arthropathy and age-related vascular fragility were possible factors in provoking bleeds.
“Pain is an individual perception and is not related to degree of joint damage – more research is needed to improve understanding of joint pain.”
The authors conclude: ‘Bleed propensity in arthropathic joints of hemophilic patients was not explained by pharmacokinetic parameters alone, but associated with pronounced vascular remodelling suggesting synovitis flares, possibly initiating or perpetuating bleeds’. The data suggest there is a trend to lower risk of bleeds with longer half-life (note the low frequency in patients using an extended half-life product) but that is far from the whole story. It is now clear that management of joint health is as important as optimising factor replacement therapy in preventing joint bleeds and, by inference, long term complications.
“The results of this study show that the choice of treatment should be tailored by considering the both the individual’s pharmacokinetic profile and their physical health profile.”