| Background:Hemophilia A/B (HA/B) is recessive X chromosome-linked hereditary bleeding disorders, respectively caused by a deficiency in blood coagulation factor (F) VIII and FIX. The clinical hallmarks of HA are joint and muscle hemorrhages. Three distinct phenotypes are typically recognized:Severe (<1%of normal clotting activity), moderate (1to5%of normal clotting activity), or mild (5to40%of normal clotting activity). Patients conventionally classified as having severe hemophilia have on an average15to35spontaneous joint bleeds and muscle bleeds per year without any treatment. However, within this group, there is considerable heterogeneity in clinical presentations. A subset of these patients (10to15%) with severe hemophilia has a clinically mild disease. Much work has done to define the factors in affecting the clinical phenotype, such as the level of various procoagulant and anticoagulant factors, the impact of inflammation, immune-regulatory and angiogenic factors (cytokines) on joints, and environmental factors. In this study, we have analyzed the clinical features and phenotypic heterogeneity of severe hemophilia, investigated factors that define clinical phenotypes of severe hemophilia patients.Objective:1. To analyze the clinical features and phenotypic heterogeneity of severe hemophilia.3. To investigate the factors those define clinical phenotypes of severe hemophilia patients.Methods:1. Clinical data and blood samples were collected from the hemophilia patients in Beijing, Hebei, Shanxi and Xinjiang.2. FⅧ/FⅨ Activity (FⅧ:C/FⅨ:C) were measured using one-stage coagulation assay; the antigen of von Willbrand Factor (vWF:Ag) determined by ELISA; FⅧ/FⅨ inhibitors (FⅧ:I/FⅨ:I) titred by the Bethesda assay; Antithrombin Ⅲ (ATⅢ) activity and Protein C (PC) activity detected by colorimetric assay; Protein S (PS) activity and Activated Protein C Resistance (APC-R) detected by clotting assay.3. Clinical and laboratory data was analyzed by SPSS17.0software, and P<0.05 was considered to indicate statistical significance.Results:1. Clinical features and phenotypic heterogeneity of severe hemophilia patients:143severe hemophilia patients were recruited. Age at first joint bleed was available for137patients, thier median age was1year (range:0-19). Age at first joint bleed was available for57patients, the median age was3year (range:0.03-16). The median of bleeding frequency was12bleeding per year, ranged from twice weekly to once yearly. The median of joint deformities was3(range:0-10),12.2%of131patients had no joint deformity.2. The deficiency of anticoagulant proteins (PC, AT-Ⅲ, PS) in hemophilia patients:11.1%and6.6%of244patients had PC and AT-Ⅲ deficiencies respectively.6.8%of279patients had PS deficiency. There were significant differences among hemophilia patients and normal population, P<0.005.3.The relationship between clinical phenotype heterogeneity of severe hemophilia and the deficiency of anticoagulant proteins (PC, AT-Ⅲ, PS):severe hemophilia patients (without inhibitors) were divided into clinical mild group (≤12bleeds per year and first bleed age>1year)) and clinical severe group (>12bleeds per year and first bleed age≤1year). The deficient rates of PC and PS had no significant difference between the two groups according to the Chi-Square test,but the deficient rate of AT-Ⅲ had significant difference (p=0.042), The mild group has a higher deficient rate of AT-Ⅲ.Conclusions:1. Severe hemophilia patients have apparent clinical phenotype heterogeneity in China. This heterogeneity reflects by variability in age at first bleed and first joint bleed, frequency of bleeding, joint deformities.2. The deficient rates of anticoagulant proteins PC, AT-Ⅲ, PS in hemophilia patients are significant higher than normal population, respectively.3. It seems that the clinical phenotype heterogeneity in severe hemophilia patients are related to the defect anticoagulant proteins AT-Ⅲ, The mild bleeding group has a higher deficient rate of AT-Ⅲ. |
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