The Study On The Phenotypic Heterogeneity In Chineses Severe Hemophilia A And Its Influencing Factors

BackgroundHemophilia A(HA) is an X chromosome linked hereditary bleeding disorder, pathological mechanism is that the qualitative or quantitative defects in FVIII production because of mutations in the FVIII gene (FVIII). The main clinical manifestations are spontaneous joint and tissue bleeding, and deformities caused by bleeding. Three distinct phenotypes are typically recognized Sever, moderate or mild. However, the severity and frequency of bleeding may be different in hemophiliacs sharing the same factor activity, a mild bleeding tendency being reported in10-15%of severe hemophiliacs.The phenotypic heterogeneity of sever haemophilia indicates that maybe there are some other factors that impact on the clinical manifestations besides the plasma coagulation factor levels.It is increasingly obvious that the phenotype of even a monogenic disease is not determined by an abnormality of a single parameter. Many environmental and genetic differences between patients could account for the differences in clinical phenotype observed.Many researches were done about the factors that define clinical phenotypesof sever HA patients,such as genotype, pharmacokinetics of administered clotting factor concentrates, coagulation proteins, fibrinolytic system, platelet function and environmental factors.Until the1970s, it was common practice to discourage persons with hemophilia from any kind of sports because of the risk of bleeds. Until now, many hemophiliacs and non-hemophliac doctors still believe that more physically active person will be at higher risk for traumatic bleeds so the patients should be away from physical activity. Although the view that physical activity is beneficial to patients with severe hemophilia A because of restoration and protection of muscal and joint function have been recognized, the relationship between physical activity and bleeding frequency is controversial. There is no report in factor limited people of developing cuntries as China.The clotting system is balance under the maintaince of various coagulation factors and fibriolysis factors. The bleeding manifestations in hemophilia can be considered to be a function of the altered thrombo-hemorrhagic balance of the dichotomy of the hemostastic system. Until now, most of studies focused on the relationship between anticoagulant protein and phenotypic heterogeneity, but fewer study have suggested an association of the fibrinolytic activity and the bleeding phenotype in hemophilia patients.In our study we described variation in phenotypes of sever heamophilia A,and investigate the clinical factors influenced the phenotypic heterogeneity in severe hemophilia A by analyzeing the physical activities of patients,and detecting the plasma levels of fibrinolytic markers.MethodsVariations in the clinical profile of severe haemophilia and the predict clinical factors.1. Case Information:We define the severe HA of FⅧ:C≤2%according to Bethil TC program.274cases from Hemophilia Information Management Center of Guangdong Province (ie, Nanfang Hospital), which were registered a complete medical history data, with long-term follow-up conditions for hemophilia A patients (mostly from southern China) were screened.33patients with factor Ⅷ inhibitors and18patients with prophylaxis were excluded. Of the223patients met the inclusion, the median age was15years ranging between10months and70years (interquartile range:6-26).2. Clinical Information Collection:Participations or their parents filled out the Chinese Haemophilia Cooperative Group Registration Form. The main information included:name, age, height, weight, age at first bleed, age at first joint bleed,bleeding frequency, arthropaty number. Body mass index (BMI) was calculated from weight/height2.3. The blood samples were collected to detect the plasma of FⅧ:C by one assay and FⅧ inhibitor by Bethesda method.The physical actibity paticipation and bleeding characteristics in Chinese people with sever hemophilia A1. Case:The study’s inclusion criteria were:severe HA patients; aged16-69yeats; volunteered to paticipate in this study and fill out the questionnaire; able to walk or other physical actibities independently. Excluded were patients with factor Ⅷ inhibitors; patients with continuoued prophylaxis treatment over3moths within the last year; patients with other clotting disorders and disease which may affect their physical activities (including liver and kidney dysfunction, heart failure,HIV-positive patient). From september to november, of the47questionaires completed,45questionaires were valid.2. Qustionnaire:International Physical Activity Questionnaire-Long (Chines version).3. We filled in the questionnair after asking the physical activities of the last7 days in patients by face-to-face an telephone interview. The information regarding bleeding frequencu within the nearly1months and the cause of these bleedings also were collected. IPAQ scores were calculated according to the consumption of metabolic equivalents.The realationship between fibrinolytic markers and phenotypic heterogeneity of severe hemophilia A1. Case:All patients with sever hemophilia,with no history of inhibitors and treating on prophylaxis more than3months within the last year and infection of HBV/HCV/HIV were considerd to be eligible. Patients were defined as cases or controls on the basis of their bleeding frequency and hemophilic arthropathy number. Cases (mild bleeders) were patients with an extremely mild bleeding tendency, defined by an annual frequency of six or fewer bleeding episodes and with deformity joints fewer than one. Controls were patients with an annual bleeding frequency of more than24episodes and/or deformity joints more than one.2. With in formed patient consent, venous blood was collected. D-dimer and fibrin degradation products were measured by immunonephelometry. Fibrinogen was measured by clouse. Alpha2-antiplasmin and plasminogen were measured by chromogenic assays.Results1. Clinical feature and phenotypic heterogeneity of sever hemophilia A patients: The median age at first bleed was1year [range:0-19, interquartile range (IQR):0.5-2]. The patients whose first bleeding age <1year,≥2years and≥6years were94/212(44.3%),73/212(34.4%) and23/212(10.8%), respectively. The median age at first joint bleed was2.25years (range:1-5, IQR:1-5). The patients whose first bleeding age≤1year,≥2years and≥6years were24/94(25.5%),54/94(57.4%) and17/107 (18.1%), respectively. The patients who has not occurred joint bleeding were7/94(7.4%), whose median age was4years (2-29). The median of annual bleed frequency was24bleeding per year (range:1-180, IQR:12-48), The proportion of patients whose annual bleed episodes less than6times was12.9%. For patients treated on-demand, the median of joints deformities was2(range:0-10, IQR:0.75-4).24.7%patients didn’t have any joints deformities. In0-14years old and more than15years old patients,53.8%and90.7%patients have joints deformities. There is a significant positive correlation between the number of joints deformities and age.2. The age of first bleeding and first joint bleeding of ’clinically milder’ were older than ’clinically severe’. A discriminant funcion was established with the indepents of the age of first bleeding and first joint bleeding to predict the bleeding frequency.85.6%of original grouped cases correctly classified.3. In patients over the age of15, the age at first bleed and first joint bleed also have significant differences between the patients have or don’t have joint deformities. In the0-14-year-old patients, negative associations of the first bleeding age and the first joint bleeding were found between the patients have or don’t have joint deformities. A discriminant funcion was established with the indepents of the age of first bleeding and first joint bleeding to predict the joint deformity.97.7%of original grouped cases correctly classified.4. BMI of’clinically milder’ was significantly lower than ’clinically severe’. The BMI of the patients who don’t have joints deformities may lower than the patients who have joints deformities (P=0.058). The significant positve correlation between BMI and bleeding frequency was found (P<0.05).5. There were no significant differences in bleeding frequency and proportion of bleeds due to traumatic reasons among the patients with three levels of physical activity. No differences in physical activity levels were noted among the patients with the bledding frequency≤1、2-4and>4(P=0.334)6. The relationship between clinical phenotype heterogeneity of sever HA and fibrinolytic markers:There were no significant differences in plasma level of D-dimer, alpha2-antiplasmin and fibrin degradation products between the two groups. The plasminogen activity of sever clinical phenotype group was signicantly higher than mild clinical phenotype group [(99.13±5.94)%vs(85.41±7.98)%, P=0.003].Conclusion1. Severe haemophilia A patients have appearant clinical pheotype heterogeneity in China. This heterogeneity was reflected by variability in age at first bleed and first joint bleed, frequency of bleeding and joint deformities.2. The age of first bleeding and first joint bleeding may predict the clinical severity in the early stage.3. BMI can reflect the clinical feature of sever HA. Greater the BMI, more bleeding.4. The physical activity was not related with total bleeding frequency and traumatic bleeding.5. It seems that the clinical phenotype heterogeneity in severe HA patients is related to the activity of plasminogen.