Correlation between oxidative stress and biomarkers of joint damage in patients with severe haemophilia treated by different prophylaxis regimens

Abstract

Background: Haemophilic arthropathy is the main cause of morbidity in indi- viduals with severe haemophilia and prevention of joint disease is the primary goal of treatment. Recurrent bleeding into joints causes damage to all joint structures, but the precise mechanism by which this induces haemophilic arthropathy is still unclear. Recently, it was shown that one effect of blood in the joint is degradation of cartilage. Biomarkers of cartilage turnover can be meas- ured in physiological fluids, such as plasma and urine. Aims: The aims of this study were to detect correlation between a marker of oxidative stress -advanced oxidation protein products (AOPP) and serum/urine concentrations of biomarkers of joint cartilage degradation, as well as to esti- mate the influence of different prophylaxis regimens for severe haemophilia on this process. Methods: The study included 20 adult patients with severe haemophilia, man- ifested by plasma factor (F)VIII/IX <1% of normal, without inhibitor. Five patients with haemophilia A received prophylaxis with FVIII concentrate in the standard dose of 20 IU/kg three times per week, while another five patients with haemophilia A were given an intermediate dose of FVIII concentrate as prophy- laxis, 10-15 IU/kg thrice weekly. Seven patients with haemophilia A and three with haemophilia B, received FVIII/IX concentrate only on-demand. The follow- ing were measured: a) AOPP - a serum marker of oxidative stress and b) bio- markers of joint cartilage degradation - serum cartilage oligomeric matrix pro- tein (COMP) and urinary C-terminal telopeptide of type II collagen (CTX-II). Blood and urine samples were collected initially, before the start of treatment (labelled AOPP-1, COMP-1 and CTX-II-1) and after 3 months follow-up (labelled AOPP-2, COMP-2 and CTX-II-2). Results: The mean age of the patients was 32 years (range 19-55). In the group of patients given standard dose prophylaxis, the mean values of AOPP- 2 (p=0.018), COMP-2 (p=0.043) and CTX-II-2 (p=0.014) were significantly low- er than those for AOPP-1, COMP-1 and CTX-II-2. Likewise, the mean values for AOPP-2 (p=0.047) and CTX-II-2 (p=0.028) in the five patients receiving intermediate dose prophylaxis were also decreased when compared to initial values, but COPM level was not significantly changed. In patients treated on demand the mean values for AOPP, COMP and CTX-II did not alter significant- ly. The results showed marked positive correlations between AOPP and both COMP and CTX-II. Namely, lower values of AOPP were significantly associat- ed with decreased levels of both biomarkers of cartilage degradation: COMP (p=0.008) and CTX-II (p=0.014). Summary and Conclusions: The precise mechanism of joint disease in patients with severe haemophilia remains unknown but probably involves blood- induced increase of oxidative stress, which leads to higher joint cartilage turnover. The most important clinical strategy for management of these patients and prevention of severe arthropathy is treatment by continuous prophylaxis with intravenously applied FVIII/IX.