ABSTRACT
In Mexico, 15% of haemophilia A (HA) patients develop inhibitory alloantibodies in response to replacement therapy with factor VIII (FVIII), requiring bypass therapy such as activated prothrombin complex concentrate (APCC). Because bypass therapy has not been broadly available in Mexico even in recent years, this study aimed to evaluate the thrombin generation assay (TGA) in assessing the response to FVIII or APCC treatment in patients with severe HA positive to inhibitors. We studied 189 patients with severe HA. Clinical severity was verified by one-stage APTT-based clotting assay. Inhibitors to FVIII were investigated by the Nijmegen-Bethesda (N-B) method, and type of inhibition was assessed through serial plasma dilutions. Thrombin generation was measured with the calibrated automated thrombogram in inhibitor-positive plasmas previously spiked and incubated with FVIII or APCC. Data were analysed using anova, Student or Fisher's exact tests. We detected 47 (24.9%) subjects with high-titre (5-1700 N-B U mL(-1)) and 25 (13.2%) subjects with low-titre inhibitor antibodies (0.6-4.7 N-B U mL(-1)). We found an association between kinetic behaviour and clinical response to FVIII (P = 0.0049) or vs. FVIII response evaluated with TGA (P = 0.0007). Global concordance between clinical and in vitro response was 70%. By evaluating the capacity of thrombin formation in a plasma sample, TGA predicts the response to FVIII or APCC therapy and allows individual optimization of resources in patients with severe HA and high-titre inhibitors. The inhibition pattern of the antibodies to FVIII:C correlated with the TGA parameters and showed an association with the clinical response to FVIII.
Subject(s)
Factor VIII/immunology , Hemophilia A/blood , Hemophilia A/immunology , Isoantibodies/immunology , Thrombin/metabolism , Adolescent , Adult , Blood Coagulation , Blood Coagulation Tests , Child , Child, Preschool , Factor VIII/metabolism , Factor VIII/therapeutic use , Hemophilia A/drug therapy , Humans , Infant , Isoantibodies/blood , Male , Middle Aged , Prognosis , Treatment Outcome , Young AdultABSTRACT
During childhood growth, bone undergoes modelling involving separate osteoblastic and osteoclastic processes. Markers of bone turnover circulate at high concentrations, parallel the childhood growth curve and correlate with height velocity. The aim of this study was to compare serum markers of bone turnover in children with haemophilia and normal bone mineral density (BMD) vs. those with low BMD. In a cross-sectional study, 69 children with haemophilia were evaluated, 45 children with normal spine BMD vs. 24 with low BMD. Lumbar spine BMD was determined using dual X-ray absorptiometry and Z-scores were calculated. Serum samples of markers of bone turnover, osteocalcin (bone formation) and C-telopeptide of type I collagen (bone resorption) were measured using ELISA. The mean BMD (g cm(-2) ) in the normal group was 0.656 ± 0.15 vs. 0.558 ± 0.12 in those with low BMD (P = 0.007), osteocalcin levels in children with normal BMD were 9.29 ± 4.97 vs. 7.06 ± 2.17 ng µL(-1) in the low BMD group (P = 0.012). C-telopeptide levels in the normal group were 1.06 ± 1.4 vs. 0.74 ± 0.3 ng mL(-1) in the low BMD group (P = 0.169). Our results showed that low osteocalcin levels predominated in the group with low BMD, which indicates a diminished osteoblastic bone formation activity while there were no differences with regard to bone resorption markers. Moreover, osteocalcin levels explain 10% of the variation of lumbar spine Z-score.
