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

• Published in: Haemophilia : the official journal of the World Federation of Hemophilia Vol. 26; no. 4; pp. 607 - 614
• Main Authors: Andrawes, Nevine Gamal, Saker, Hossam Mousa, Salah El‐Din, Nouran Yousef, Abd Elhakim Hussain, Mervat
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.07.2020
• Subjects: arthropathy; Biomarkers - blood; Case-Control Studies; Child; Child, Preschool; Coagulation factors; Cross-Sectional Studies; Early Diagnosis; Factor VIII - therapeutic use; Factor VIII deficiency; Hemophilia; Hemophilia A - blood; Hemophilia A - complications; Hemophilia A - drug therapy; Humans; inflammatory markers; Joint Diseases - diagnostic imaging; Joint Diseases - etiology; Joint Diseases - prevention & control; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Male; Metalloproteinase; MRI joint score; Population studies; Prophylaxis; Sensitivity and Specificity; severe haemophilia A; Severity of Illness Index; Synovitis; Synovitis - diagnosis; Tissue Inhibitor of Metalloproteinase-1 - blood; Tissue inhibitor of metalloproteinases; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - blood; inflammatory markers; MRI joint score; severe haemophilia A; arthropathy
• ISSN: 1351-8216; 1365-2516
• DOI: 10.1111/hae.14041

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.