Tissue-inhibitors of metalloproteinase-1 and vascular-endothelial growth-factor in severe haemophilia A children on low dose prophylactic recombinant factor VIII: Relation to subclinical arthropathy

Abstract

Background: Subclinical synovitis occur long before clinical haemophilic arthropathy (HA). New biomarkers are needed for early detection of HA. Aim: To compare the levels of tissue inhibitors of metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF)in severe haemophilia A boys on prophylaxis and on-demand therapy to healthy boys and correlate them with the haemophilia joint health score (HJHS) & the Denver magnetic resonance imaging (MRI) scale; hence, determine their values in early detection of HA. Methods: Haemophilia joint health score, serum TIMP-1, VEGF and Denver MRI score were assessed in 50 boys with severe haemophilia A (31 on prophylactic factor VIII therapy (62%) with a dose of 15 IU/kg/twice weekly) and 50 age-matched healthy boys. Results: Boys with severe haemophilia A had significantly higher TIMP-1 240 ng/mL, SD200-350 (P <.001) and VEGF 600 pg/mL, SD400-1100 (P <.001). Their mean HJHS was 4.5 ± 3.0 (0-11) and their mean Denver MRI score was 5.55 ± 1.6 (2.00-8.00). A significant positive correlation was found between TIMP-1 and VEGF (P <.001), BMI Z-score (P =.029), HJHS (P =.041)and total MRI score (<.001). Significant correlations were found between VEGF and age (P <.001), HJHS (P =.003) and total MRI score (P <.001). Boys with severe haemophilia A on prophylaxis therapy had significantly lower HJHS (P =.021), VEGF (P <.001), TIMP-1 (P =.002) and total MRI score (P =.021) than those on on-demand therapy. Receiver operating characteristic curve, defined a cut-off value of 160 ng/mL for TIMP-1 with a sensitivity of 90% and specificity of 60% and that of 350 pg/mL for VEGF with a sensitivity of 78% and specificity of 88% for discrimination between severe haemophilia A and healthy boys. Conclusion: Vascular endothelial growth factor and TIMP-1 can be used for early detection of HA. Further prospective studies should include larger study populations. In addition, studies should address the role of various anti-VEGFs as potential therapy for HA and their impact on prevention and treatment of HA.