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

Nevine Gamal Andrawes; Hossam Mousa Saker; Nouran Yousef Salah El-Din; Mervat Abd Elhakim Hussain

doi:10.1111/hae.14041

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

Haemophilia. 2020 Jul;26(4):607-614. doi: 10.1111/hae.14041. Epub 2020 May 23.

Authors

Nevine Gamal Andrawes¹, Hossam Mousa Saker², Nouran Yousef Salah El-Din¹, Mervat Abd Elhakim Hussain³

Affiliations

¹ Pediatric Department, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.
² Radiology Department, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.
³ Pediatric Department, Sheikh Zayed hospital, Cairo, Egypt.

PMID: 32445517
DOI: 10.1111/hae.14041

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.

Keywords: MRI joint score; arthropathy; inflammatory markers; severe haemophilia A.

MeSH terms

Biomarkers / blood*
Case-Control Studies
Child
Child, Preschool
Cross-Sectional Studies
Early Diagnosis
Factor VIII / therapeutic use*
Hemophilia A / blood
Hemophilia A / complications
Hemophilia A / drug therapy*
Humans
Joint Diseases / diagnostic imaging*
Joint Diseases / etiology
Joint Diseases / prevention & control
Magnetic Resonance Imaging / methods*
Male
Sensitivity and Specificity
Severity of Illness Index
Synovitis / diagnosis
Tissue Inhibitor of Metalloproteinase-1 / blood
Vascular Endothelial Growth Factor A / blood

Substances

Biomarkers
Tissue Inhibitor of Metalloproteinase-1
Vascular Endothelial Growth Factor A
Factor VIII