Roles Of Inflammatory Cytokines And Vascular Endothelial Growth Factorin Patients With Severe Hemophilia Afollowing Intra-articular Bleeding

Background and objective:Intra-articular bleeding is the clinical hallmark of severe hemophilia A(SHA),which is often diagnosed by imaging examination.Unfortunately,there were no well-established prognostic indicators for early intra-articular bleeding.In animal models of hemophiliac arthropathy,intra-articular bleeding leads to sustained inflammation in which inflammatory cytokines including leukocytes and C-reactive protein(CRP)play an important part.CRP has been shown to be dramatically increased after tissue injury and acute inflammation and exhibits a predictive valuein the development of many diseases.Expression of vascular endothelial growth factor(VEGF)is associated with microvessel density(MVD)and numbers of new blood vessels when angiogenesis occurs in early hemophiliac arthropathy.Furthermore,expression of VEGF might reflect disease severity and occurrence of complications.In the present study,we determined expression levels of inflammatory cytokines and VEGF in patients with SHA following intra-articular bleeding and further to evaluate their predictive performance.Methods:A total of 48 male patients with SHA from Shandong Blood Center between May 2015 and November 2017 were enrolled in the study and split into a bleeding group(n=22)and non-bleeding group(n=26).A control group consisted of 30 healthy male volunteers.Patient height,body weight and body mass index(BMI)were recorded.Numbers of white blood cells,monocytes and platelets were calculated.Levels of hemoglobin,CRP,ferritin,lactic acid,VEGF and ES were measured.Data were analyzed by using SPSS 21.0 and a difference of two-sided p<0.05 was considered statistically significant.Results:Compared with the control group,the bleeding group and non-bleeding group showed more white blood cells and increased levels of CRP and ferritin(p<0.05).More white blood cells and higher levels of CRP and ferritin were found in the bleeding group in contrast to the non-bleeding group.The levels of CRP were(16.88+3.27)mg/L,(6.79± 1.23)mg/L and(2.56+0.67)mg/L in the bleeding group,non-bleeding group and control group.The level of VEGF was higher in the bleeding group with(113.26± 15.49)pg/ml than in the non-bleeding group with(70.63 ± 11.24)pg/ml,both of which were higher than that in the control group with(54.38±9.67)pg/ml.However,no significant difference was found among the three groups concerning BMI,numbers of platelets,levels of hemoglobin,lactic acid and ES(p>0.05).The results of univariate analysis showed that CRP(OR=6.363),VEGF(OR=4.515)and ferritin(OR=3.768)were correlated with the occurrence of intra-articular bleeding in patients with SHA.Multivariate analysis demonstrated CRP(OR=2.234)and VEGF(OR=2.826)as independent risk factors of intra-articular bleeding in patients with SHA(p<0.05).Analysis of receiver operating characteristic(ROC)curve suggested predictive values of CRP and VEGF for SHA with intra-articular bleeding.CRP yielded area under the curve(AUC)of 0.729(p<0.05),sensitivity of 86.36%and specificity of 65.38%.VEGF produced AUC of 0.678(p<0.05),sensitivity of 77.27%and specificity of 53.85%.Conclusion:Numbers of white blood cells,levels of ferritin,CRP and VEGF were increased in patients with SHA,and increases became more significant after intra-articular bleeding.The CRP and VEGF were shown to be an independent risk factor of intra-articular bleeding in patients with SHA,presenting a predictive value.