Analysis of single-center Hemophilia A patients :demographics, clinical characteristics and treatment strategies

Analysis of single-center Hemophilia A patients :demographics, clinical characteristics and treatment strategies | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Analysis of single-center Hemophilia A patients :demographics, clinical characteristics and treatment strategies Lidong Zhao, Chunxia Dong, Jianmin Kang, Yanchun Ma, Xialin Zhang, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3068292/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Hemophilia A (HA) is an x-chromosome-related recessive disorder caused by a defect in the coagulation factor VIII gene, and timely and proper treatment can improve the quality of life of patients. Objectives Summarize the epidemiology, disease characteristics, and treatment of single-center HA patients in real-world China. Methods A retrospective analysis of 662 patients with HA in the Second Hospital of Shanxi Medical University was performed, and the basic information of the patients was summarized using descriptive statistics, and the differences between groups were compared using ANOVA, and the geographical distribution characteristics of patients with HA in Shanxi Province were introduced using heat maps. Results 662 patients with HA were registered at our center. Most patients had single status, low employment rates, and low educational levels. 85.3% had a moderate to severe HA, 13% had mild HA. Of these, 20.5% of the patients had an active inhibitor. The intron 22 inversion was the most common genetic mutation, accounting for 53.7% of severe HA patients. The joints and muscles were the most common bleeding sites, with 55.1% of the patients having target joints. The mean diagnostic delay time between mild and severe HA was statistically significant (p < 0.01). Regarding treatment, 43.5% of the patients were on prophylactic treatment, usually 2–3 times a week. Conclusions Based on the real data of a single center in China, this study shows the realistic situation of Chinese HA patients and has certain clinical significance, and better treatment measures to improve the quality of life of HA patients should be explored in the future. China Single center Hemophilia A Retrospective study Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Hemophilia A (HA) is a recessive genetic disorder linked to the X chromosome, caused by a mutation of the coagulation factor VIII gene (F8). According to the World Hemophilia Federation, the prevalence of this disorder worldwide is 17.1 cases per 100,000 men[1]. As China is a large population country, the number of HA patients is considerable and appropriate diagnosis and treatment are essential to reduce the burden of the disease. Clinically, HA is mainly characterized by recurrent spontaneous joint, muscle, and visceral bleeding, which can lead to life-long disability and even death in severe cases[2]. The severity of bleeding symptoms in HA patients usually correlates with the deficiency of the coagulation factor. Based on the factor VIII activity (FⅧ:C) levels in plasma, the HA phenotypes are classified as severe (< 1 IU/dL or < 1% of normal), moderate (1–5 IU/dL or 1%-5% of normal) and mild (5–40 IU/dL or 5–40% of normal)[3]. For those with severe HA, prompt diagnosis and treatment are essential to improve their quality of life. Currently, the primary approach to managing HA in China is the substitution therapy of exogenous coagulation factor VIII, which can reduce the number of bleeding episodes and improve quality of life. However, repeated infusions of FⅧ preparations can lead to the formation of neutralizing FⅧ antibodies, also known as FⅧ inhibitors. The prevalence of inhibitors among severe HA patients is as high as 30%, and moderate/mild HA patients have an incidence of 3–13%[4]. The production of inhibitors can impede the effectiveness of exogenous coagulation factor VIII replacement therapy and increase the financial burden on HA sufferers. This study was conducted to gain a comprehensive view of the situation of HA patients in our region. A retrospective analysis of the registered HA patients was performed to understand their demographics, clinical characteristics, and the treatment strategies used. Furthermore, the results of this study provide insight into the direction of future efforts in the Hemophilia Comprehensive Management Center of the National Rare Diseases Alliance at the Second Hospital of Shanxi Medical University, which has a large number of HA patients. Methods Patients The study was conducted ethically in accordance with the Helsinki Declaration of the World Medical Association, with the consent of the participants. The study population comprised patients with HA from the Second Hospital of Shanxi Medical University, excluding those with von Willebrand disease, acquired hemophilia, and other hemorrhagic diseases. Systematic data was collected to obtain basic information such as age, ethnicity, region, marital status, highest education level, occupation, health insurance type, family history, FVIII factor activity, inhibitors (low titer < 5 BU/ml, high titer ≥ 5 BU/ml), and type of gene mutations. Additionally, follow-up was conducted to collect data on patient bleeding manifestations, annual bleeding frequency, age at first bleeding, age at diagnosis, target joint, chronic haemartropathy, and treatment strategy (on demand, prophylaxis). Statistical analysis Patient demographics, clinical characteristics, and treatment strategies were summarized using descriptive statistics, including frequencies and percentages for categorical variables, as well as means, standard deviations, and medians for continuous variables. Comparisons between groups were made using ANOVA. Rates were compared using chi-square analysis. p < 0.05 indicated a statistically significant difference. The regional distribution of HA patients in Shanxi Province was illustrated using a heatmap. Delay in diagnosis was calculated as the difference between the age at first diagnosis and the age at first bleeding. Results Demographics A total of 662 patients with HA were registered at the Second Hospital of Shanxi Medical University as of August 2022. Of these, 647 (97.7%) were located in Shanxi Province (79 patients' Region information was incomplete and not shown in Fig. 1). The remaining patients were distributed in Inner Mongolia Autonomous Region, Hebei, Henan, Shandong, Shanxi, Sichuan, and Yunnan Provinces. Information on age was available for 386 patients. In addition to 661 male patients and one female patient, 407 cases were Han ethnic group, 96 (14.5%) were married, 87 (13.1%) had a college degree or higher, and 116 (16.6%) had a known family history of HA. Five (0.8%) patients died (Table 1 ). Table 1 Demographic characteristics of Chinese HA patients with single-center Haemophilia A(N = 662) N(%) Age < 18 120(18.1%) ≥ 18 266(40.2%) Unknown 276(41.7%) Sex Male 661(99.8%) Female 1(0.2%) Ethnic group Han 407(61.5%) Unknown 255(38.5%) Marriage status Married 96(14.5%) Single 243(35.7%) divorced 2(0.3%) Unknown 321(48.5%) Employment status Student 125(18.9%) Employed 137(20.7%) Unemployed 61(9.2%) Retired 12(1.8%) Unknown 327(49.4%) Education level College degree 87(13.1%) Junior high or high school 146(22.1%) Infant, primary school or below 92(13.9%) Unknown 337(50.9%) Insurance type Residents 395(59.7%) Employee 57(8.6%) Unknown 210(31.7%) Family history of haemophilia A Yes 116(17.5%) No 209(31.6%) Unknown 337(50.9%) Death No 657(99.2%) Yes 5(0.8%) Figure1 Heat map of the distribution of HA patients in Shanxi Province Clinical characteristics Among the HA patients registered in our center, 1.7% had missing FVIII: C results, while 651 patients had FVIII: C test results, of which 58.1% were classified as severe, 27.2% as moderate, and 13.0% as mild (Table 2 ). Inhibitor tests were conducted on 303 patients, 188 of whom had severe HA, 85 had moderate HA, and 30 had mild HA. The positive rate of inhibitor was highest among those with severe HA (Table 3 ). Patients with high titer of inhibitor were significantly more numerous than those with low titer (Inhibitor titers were unknown in two patients and were not shown in Fig. 2). Genetic test results of 221 patients revealed that the most common gene mutation type was intron 22 inversions (47%), followed by missense mutation, nonsense mutation, deletion, insertion, intron 1 inversion, splice site mutation, and other types (Fig. 3). Table 2 Disease severity in HA patients Classification N(%) Severe 385(58.1%) Moderate 180(27.2) Mild 86(13.0) Unknown 11(1.7%) Table 3 Detection of inhibitors in patients with HA Total,n Negative,n(%) Positive,n(%) Severe 188 143(76.1%) 45(23.9%) Moderate 85 70(82.4%) 15(17.6%) Mild 30 28(93.3%) 2(6.7%) Figure2 Inhibition titers in HA patients Figure 3 Summary of gene mutations in HA patients In a telephone follow-up of 305 HA patients, 4 had died and the cause of death was unknown, so only the clinical characteristics of the remaining 301 patients were summarized. Muscle was the most common site of the first bleeding, accounting for 28.9%. Other sites of the first bleeding included joints, head, and nasal passages. With age, the main bleeding sites shifted to joints, and some patients also experienced bleeding in muscles, viscera, and other parts(Table 4 ). Of the 163 patients who were diagnosed in a timely manner, most were diagnosed in infancy or early childhood, and 106 (65%) were classified as severe HA. The mean delay time for mild HA was 16.7 years, moderate HA 11.9 years, and severe HA 8.8 years, with a statistically significant difference between mild and severe HA (P < 0.01, Fig. 4). Of the 166 patients with target joints, most were large joints such as the knee, ankle, and elbow. Chronic haemartropathy was observed in 56.3% of severe HA patients (Table 5 ), and 8 patients had undergone arthroplasty. The total annual bleeding frequency of HA patients was mainly 0–5 times, with severe HA having a higher frequency than moderate and mild HA (Fig. 5). Table 4 Follow-up of bleeding sites in HA patients Haemophilia A with followed-up (N = 301) N(%) Site of first bleeding Epistaxis 30(10.0%) Draw blood from the vein 2(0.7%) Hemoptysis 1(0.3%) Joint 75(24.9%) Muscle 87(28.9%) Umbilical cord 6(2.0%) Oral 19(6.3%) Subcutaneous 4(1.3%) Surgery 18(6.0%) Head 30(10.0%) Trauma 7(2.3%) Digestive tract 5(1.7%) Gum 16(5.3%) No bleeding, developmental delay 1(0.3%) Currently major bleeding site Almost no bleeding 43(14.3%) Joint 147(48.9%) Joints and other areas* 38(12.6%) Epistaxis 6(2.0%) Muscle 38(12.6%) Oral 4(1.3%) Visceral 4(1.3%) Gum 11(3.7%) Surgery 1(0.3%) Intracranial bleeding 1(0.3%) Trauma 8(2.7%) *Recurrent joint bleeding, but also skin, gums, mouth, muscles, internal organs, trauma bleeding. Figure 4 Comparison of diagnostic delay time for each group Table 5 Delayed diagnosis and joint condition of HA patients Overall(n = 301) Severe (n = 176) Moderate (n = 87) Mild (n = 38) With diagnosis delay, n (%) 138(45.8%) 68(38.6%) 47(54.0%) 15(60.5%) Mean delay time in years (SD) 11.9 8.8 11.9 16.7 Median delay time in years (range) 10(0.08-59) 6.5(0.33-39) 10(0.08-39) 15(1–59) Target joints, n(%) 166(55.1%) 118(67%) 41(47.1%) 7(18.4%) Joint deformity, n(%) 134(44.5%) 99(56.3%) 29(33.3%) 6(15.8%) Figure 5 Annual bleeding frequency in HA patients Treatment strategies Exogenous coagulation factor FVIII was the most preferred treatment for patients with HA, with 301 patients in total. Of these, 132 (43.9%) were treated on demand, 131 (43.5%) received prophylactic treatment, and 38 (12.6%) did not receive any treatment regimen (Table 6 ). Of the 263 patients who varied in coagulation factor FVIII product selection, 96 (36.5%) used plasma-derived coagulation factor FVIII, 129 (49%) used recombinant coagulation factor FVIII, and 34 (12.9%) used both plasma-derived and recombinant coagulation factor FVIII. Additionally, two (0.8%) inhibitor-positive patients were treated with prothrombin complex, and two (0.8%) had an unclear coagulation factor FVIII product type (Fig. 6). The highest rate of prophylactic treatment was observed in severe HA patients, who were typically treated two to three times a week. Finally, comparing the incidence of inhibitors in terms of HA treated with plasma-derived and recombinant coagulation factor VIII, the results showed no statistically significant difference (P > 0.05). Table 6 Treatment strategies for HA patients Overall(n = 301) Severe(n = 176) Moderate(n = 87) Mild (n = 38) On-demand, n(%) 132(43.9%) 80(45.5%) 36(41.4%) 16(42.1%) prophylaxis, n(%) 131(43.5%) 89(50.5%) 34(39.1%) 8(21.1%) Unused, n(%) 38(12.6%) 7(4%) 17(19.5%) 14(36.8%) Figure 6 Type of exogenous coagulation factor FVIII in HA patients Discussion The World Federation of Hemophilia (WFH) has collaborated with Chinese medical centers to conduct various awareness and educational campaigns on World HA Day to enhance the knowledge of HA patients and their families, leading to a rise in the standardization of HA management and the advancement of regional diagnosis and treatment levels. This study provides a retrospective analysis of single-center HA patients in China, highlighting their demographics, clinical characteristics, and treatment approaches. This information is of great clinical value in terms of normalizing diagnosis, treatment, and management for HA patients in Shanxi Province. In our current study, 97.7% of the patients originated from Shanxi Province, and were distributed across different areas (Fig. 1). The heat map of the distribution characteristics reveals that, with Taiyuan, the provincial capital, as the boundary, the overall number of patients in the south is higher than that in the north (Jincheng being an exception), which may be attributed to the population and economic level. There was only one female patient with HA, whose coagulation factor VIII activity was 1.1%, indicative of moderate HA, with gum bleeding as the first manifestation and exogenous coagulation factor FVIII treatment being effective. No family history was present. The pathogenesis is most likely due to either homozygous gene mutation or heterozygous gene mutation with normal X chromosome non-random inactivation, the cause of which is still unclear[5, 6]. Our findings demonstrate the actual status of HA patients, including singleness, low employment and low educational attainment, as shown in Table 1 , and are more likely to be associated with financial burden and physical disability. However, a Danish study showed that by controlling for age differences, no significant differences were found in education and marital levels between PWH and the general population, and employment rates for PWH were significantly lower in 45–64 year olds than in their peers of the same age, but no differences were found in the younger (16–44 year old) group[7]. This may be because our analysis is for all age groups, and there is still a degree of wealth disparity in our large population. Therefore, we should enhance education and improve the economic level to reduce the burden of PWH disease and improve the quality of life. According to Table 2 , the majority of patients(58.1%) experienced severe HA, 27.2% had moderate HA and 13.0% had mild HA (as shown in Table 2 ). In comparison, Zhao et al. conducted a retrospective study of patients from 11 HA treatment centers in Shanxi Province and found that 50% had severe HA[8]. Additionally, in 2020, a single center in Tianjin, China, summarized and analyzed the clinical characteristics of 428 HA patients and reported that 52.9% of them had severe HA[9]. The higher proportion of severe HA observed in this study may be due to the fact that mild and moderate HA patients usually have mild bleeding symptoms and often do not seek medical attention, resulting in a low registration rate. With the gradual improvement of medical conditions in China, more and more HA patients are receiving exogenous coagulation factor VIII replacement treatment after diagnosis. The emergence of coagulation factor VIII inhibitors is one of the main challenges in HA treatment, and regular infusions of missing coagulation factor FVIII to induce immune tolerance is the first-line treatment option for the eradication of inhibitors. However, it is expensive and rarely used in the local population[10]. The positive rate of inhibitors in this center was 20.5%, 23.9% in severe HA, 17.6% in moderate HA, and 6.7% in mild HA (Table 3 ). Analysis of disease severity revealed that high-titers were the most common(Fig. 2). The generation of inhibitors may be linked to the type of F8 gene mutation, family history, ethnicity, and treatment strategy[4]. Studies have indicated that more than half of patients with HA have no family history of the condition due to new mutations in the F8 gene[11, 12]. Our genetic test results showed that intron 22 inversion was the most frequent type of gene mutation, followed by missense, nonsense, and deletion (Fig. 3). In patients with severe HA, the proportion of intron 22 inversion was as high as 53.7%, the ratio of intron 1 inversion was 2.4%, and the proportion of missense mutations in all patients tested was 20.8%, which is comparable to previous studies[13–15]. One patient had moderate HA due to synonymous mutations, which may be unrecognized and translated by the transport RNA, leading to pathogenicity. Through telephone follow-up, we discovered that muscle is the most frequent site of initial bleeding, usually caused by collision or extrusion in infants and young children. As age increases, the primary bleeding sites shift to the joints, such as the knee and ankle joints, which are related to daily activities and weight-bearing. Additionally, 12.6% of HA patients experienced multi-site bleeding, mainly in joints and other areas like the skin, gums, mouth, muscles, viscera, and trauma (Table 4 ). Despite the medical advances made in recent years, we still observed a diagnostic delay in 45.8% of the patients with HA, spanning almost 59 years. The diagnosis delay in mild HA was more severe, and the diagnosis delay time of mild HA was longer than in severe HA, which was statistically significant (P < 0.01, Fig. 4). This is likely due to the mild bleeding symptoms of mild HA and the lack of awareness of the disease. Therefore, it is essential to emphasize the dissemination of knowledge related to HA, particularly in remote and underdeveloped mountainous regions, to raise public awareness and ensure timely medical treatment. Patients with HA often experience joint bleeding, which can eventually lead to HA arthropathy in the target joint, resulting in decreased joint mobility, chronic pain, and a significant reduction in quality of life[16]. This study found that 166 (55.1%) patients had target joints, while 134 (44.5%) patients had pre-existing joint deformities, with most cases being severe HA (Table 5 ). Therefore, it is extremely important for the prevention treatment of severe HA, which can reduce joint bleeding, decrease the incidence of hemophilia arthropathy, and relieve the pain of patients. Eight of these patients underwent joint replacement surgery in the orthopedic department, with Hematology, Ultrasound, and Orthopedics being involved in assessing joint status and treatment. The Romanian Society of Hematology also recommends multidisciplinary team treatment, including hematologists, anesthesiologists, orthopedic surgeons, rehabilitation medicine specialists and physiotherapists[17]. This is what we need to work on in the future to effectively solve the problems of our patients. In the present study, due to the relatively high percentage of cases counted moderate/mild HA (40.2%) and 43.5% prophylaxis in all patients and the highest percentage of prophylaxis in severe HA (50.5%), resulting in an ABR of mainly 0–5(Fig. 5). An Indian study included 30 children with severe HA and the annual joint bleeding was reduced by 85.76% (14.5 to 2.2) before and after administration of low-dose recombinant FVIII prophylaxis, thus prophylaxis significantly reduced ABR[18]. Clinically, prophylaxis should be recommended for patients with severe HA whenever possible, which will again reduce bleeding to a great extent and improve quality of life. In recent years, our country has implemented a basic medical security system in order to reduce the financial burden of citizens, which includes medical insurance and secondary reimbursement for high treatment costs. Our center has achieved a follow-up prevention treatment rate of 43.5%, with the age range of 2 to 74 years old. Among them, 51.9% were ≤ 18 years old, and severe HA accounted for 50.5%. Compared with a retrospective study of patients with moderate to severe hemophilia A in China, the proportion of preventive treatment in this study is significantly higher, on the one hand, due to the increased awareness of patients and their families. On the other hand, it is closely related to national medical policies[19]. Despite this, there is still a considerable economic burden for patients and their families, particularly those living in poor mountainous areas who are unable to afford the cost of treatment. And for PWH in Nigeria most health care services need to be paid for out-of-pocket, and they will be more likely to feel the financial burden directly[20]. Our study found that 132 cases (43.9%) received on-demand treatment, which may be due to financial constraints. Additionally, 38 cases (12.6%) did not take any treatment measures, and 36.8% of the patients with mild HA opted out of treatment, mostly due to mild bleeding symptoms and the ability to stop bleeding without treatment (Table 6 ). In our study, nearly half of the patients utilized recombinant coagulation factor VIII, 36.5% used plasma-derived coagulation factor VIII, and 12.9% used both recombinant and plasma-derived coagulation factor VIII (Fig. 6). For those with positive inhibitors, due to the high price of non-factorial products and rFVIIa, only a small number of patients opted for the cheaper prothrombin complex treatment. In this study, only two patients used prothrombin complex and 30 patients still opted for coagulation factor VIII treatment when bleeding. Of the patients followed up, 32 were positive for inhibitors and 147 were negative for inhibitors. There was no statistically significant difference in the incidence of inhibitors and coagulation factor product type. A study of 574 patients with severe hemophilia also showed no statistically significant difference in the incidence of inhibitors between plasma-derived and rFⅧ preparations, whereas other studies have shown a higher incidence of inhibitors in patients using rFⅧ preparations than in patients using plasma-derived FⅧ preparations[21, 12, 22]. Because the number of cases followed up in this study was small, and the number of patients using plasma-derived coagulation factors was significantly less than those using recombinant coagulation factors, we need to expand the number of cases for further confirmation. Up to half of the patients in this study were treated with recombinant coagulation factor VIII, probably due to its greater safety profile by avoiding the transmission of blood disorders. In addition, there are various restrictions in the selection of coagulation factor products, as each region and hospital have limited access to these products. Some areas are unable to purchase recombinant coagulation factor VIII, thus patients and their families have to purchase plasma-derived coagulation factor VIII. This indicates that the entire process of HA treatment is influenced by the regional economic level. Conclusion This retrospective study, based on real data from a single center in China, examined the epidemiology, clinical characteristics, and treatment patterns of HA patients, providing insight into the situation of Chinese HA patients. Going forward, it is necessary to gain a comprehensive understanding of the economic status of HA patients, conduct further research into gene therapy for HA, seek out better treatment measures that can enhance the quality of life for HA patients, and improve the diagnosis and treatment level of HA through national policies, medical personnel, and social support. Declarations Ethics approval and consent to participate This study protocol was reviewed and approved by the Ethics Committee of the Second Hospital of Shanxi Medical University, approval number NO. 2022-YX-054. Consent for publication Not applicable. Availability of data and materials Authors may provide raw data to support their findings upon reasonable request. Competing interests No potential conflict of interest was reported by the author(s). Funding This study was supported by grants from the National Natural Science Foundation of China (No. 81970172, 8170011339), the Shanxi Provincial Key Research and Development Project (No. 201803D31123)and the Natural Science Foundation of Shanxi Province (No. 20210302123295). Author Contributions In this research, LD Z participated in the collection, collation, processing and writing of information. CX D, JM K, XL Z, J R gave guidance on data content and processing. YC M, LY W, LN L, S Fang, XC H, WK S helped collect and organize data. 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The Rodin (Research Of Determinants of INhibitor Development among PUPs with haemophilia) study: the clinical conundrum from the perspective of haemophilia treaters. Haemophilia. 2013;19(3):351-4. doi: 10.1111/hae.12149 . Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3068292","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":228062746,"identity":"14eb40fe-a9f0-4a39-ab0e-ca3bef4b6c40","order_by":0,"name":"Lidong Zhao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAw0lEQVRIiWNgGAWjYBACfobDBx98qLBh5mdvIFKLZOOxZMMZZ9LYJXsOEKnF4PAZM2HelkP8BjcSiNVy7IwZM2/DAWnJmY833mCosYkm7LAzx8oezt1xx5hfOq3YguFYWm4DIS18Nw5vN3h75lmy5OwcMwnGhsOEtTDcf2Amwdt2uH7DzTNEahE4cMRMEqiF2eAGD5FaJBsggcws2QP0SwIxfkGKysMbb3yosSHCL0jAQCKBFOUQLaTqGAWjYBSMgpEBAJgOSaFPlGKPAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-9181-7432","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":true,"prefix":"","firstName":"Lidong","middleName":"","lastName":"Zhao","suffix":""},{"id":228062747,"identity":"39319e5d-c59b-4cdd-9e70-f93ef505e8a7","order_by":1,"name":"Chunxia Dong","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chunxia","middleName":"","lastName":"Dong","suffix":""},{"id":228062748,"identity":"8e3fd0d7-9690-478c-a334-858a0d83c478","order_by":2,"name":"Jianmin Kang","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jianmin","middleName":"","lastName":"Kang","suffix":""},{"id":228062749,"identity":"8e902496-364d-4f2e-a9eb-ea37ea3a7e99","order_by":3,"name":"Yanchun Ma","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yanchun","middleName":"","lastName":"Ma","suffix":""},{"id":228062750,"identity":"03bf0587-36bb-44c2-9aff-fb5503be7afd","order_by":4,"name":"Xialin Zhang","email":"","orcid":"","institution":"Shanxi Bethune Hospital Department of Hematology","correspondingAuthor":false,"prefix":"","firstName":"Xialin","middleName":"","lastName":"Zhang","suffix":""},{"id":228062751,"identity":"1d9e97ac-5312-4145-8d1f-58367de7b6ac","order_by":5,"name":"Juan Ren","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Ren","suffix":""},{"id":228062752,"identity":"881b9eef-f867-4736-8ebe-d5d296a1c3d9","order_by":6,"name":"Lingyu Wang","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lingyu","middleName":"","lastName":"Wang","suffix":""},{"id":228062753,"identity":"a18b3078-3852-4dbd-bab6-ac002349e42b","order_by":7,"name":"Linna Lu","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Linna","middleName":"","lastName":"Lu","suffix":""},{"id":228062754,"identity":"42722f24-5abe-4b89-be06-dc8574f81979","order_by":8,"name":"Shuai Fang","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shuai","middleName":"","lastName":"Fang","suffix":""},{"id":228062755,"identity":"f9558831-e4bc-4803-8703-f8dabce6f69f","order_by":9,"name":"Xuchen Hu","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xuchen","middleName":"","lastName":"Hu","suffix":""},{"id":228062756,"identity":"6c2e25a5-2c2f-4208-9d56-bbc540a03754","order_by":10,"name":"Wukang Shen","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wukang","middleName":"","lastName":"Shen","suffix":""},{"id":228062757,"identity":"1d6129de-d05b-4976-9867-2544fbc498ef","order_by":11,"name":"Linhua Yang","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Linhua","middleName":"","lastName":"Yang","suffix":""},{"id":228062758,"identity":"219e975f-3366-4123-831e-de20ef133fab","order_by":12,"name":"Gang Wang","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Gang","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2023-06-15 14:19:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3068292/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3068292/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":42161864,"identity":"709eb578-bb0f-48f5-a0af-31b0c6c6103d","added_by":"auto","created_at":"2023-08-25 18:59:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":60138,"visible":true,"origin":"","legend":"\u003cp\u003eHeat map of the distribution of HA patients in Shanxi Province\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3068292/v1/dc848b9408993b293e57b1d4.png"},{"id":42161865,"identity":"bb3bdb7e-2d2d-4b87-a679-023469a6d51b","added_by":"auto","created_at":"2023-08-25 18:59:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":66248,"visible":true,"origin":"","legend":"\u003cp\u003eInhibition titers in HA patients\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3068292/v1/f43f71ec8aaf89d744e81bb9.png"},{"id":42161868,"identity":"a77c498a-3270-4edf-acba-98e258e33b08","added_by":"auto","created_at":"2023-08-25 18:59:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":34012,"visible":true,"origin":"","legend":"\u003cp\u003eSummary of gene mutations in HA patients\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3068292/v1/6e6479b6359241f208544ac2.png"},{"id":42161867,"identity":"cd8f60ef-f867-4072-96e6-ffe67f39d3f0","added_by":"auto","created_at":"2023-08-25 18:59:30","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":14437,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of diagnostic delay time for each group\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-3068292/v1/1627a32251ec9d2c34f7b79c.png"},{"id":42163067,"identity":"5e0c3fc4-f078-4791-8df0-ac57543a975f","added_by":"auto","created_at":"2023-08-25 19:07:30","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":66087,"visible":true,"origin":"","legend":"\u003cp\u003eAnnual bleeding frequency in HA patients\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-3068292/v1/3cd088ff0c5db82fd42b37ac.png"},{"id":42161869,"identity":"23705f34-3228-42e9-9c50-f4a168971de8","added_by":"auto","created_at":"2023-08-25 18:59:31","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":96884,"visible":true,"origin":"","legend":"\u003cp\u003eType of exogenous coagulation factor FVIII in HA patients\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-3068292/v1/c0b350eb588b5ef2458124ae.png"},{"id":43587347,"identity":"718e9981-68f0-497c-be64-47f1b6cd3036","added_by":"auto","created_at":"2023-09-24 10:44:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":818487,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3068292/v1/bbd06e0b-f4f2-4a37-b4af-f1a4e88370a6.pdf"}],"financialInterests":"","formattedTitle":"Analysis of single-center Hemophilia A patients :demographics, clinical characteristics and treatment strategies","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHemophilia A (HA) is a recessive genetic disorder linked to the X chromosome, caused by a mutation of the coagulation factor VIII gene (F8). According to the World Hemophilia Federation, the prevalence of this disorder worldwide is 17.1 cases per 100,000 men[1]. As China is a large population country, the number of HA patients is considerable and appropriate diagnosis and treatment are essential to reduce the burden of the disease. Clinically, HA is mainly characterized by recurrent spontaneous joint, muscle, and visceral bleeding, which can lead to life-long disability and even death in severe cases[2]. The severity of bleeding symptoms in HA patients usually correlates with the deficiency of the coagulation factor. Based on the factor VIII activity (FⅧ:C) levels in plasma, the HA phenotypes are classified as severe (\u0026lt;\u0026thinsp;1 IU/dL or \u0026lt;\u0026thinsp;1% of normal), moderate (1\u0026ndash;5 IU/dL or 1%-5% of normal) and mild (5\u0026ndash;40 IU/dL or 5\u0026ndash;40% of normal)[3]. For those with severe HA, prompt diagnosis and treatment are essential to improve their quality of life.\u003c/p\u003e \u003cp\u003eCurrently, the primary approach to managing HA in China is the substitution therapy of exogenous coagulation factor VIII, which can reduce the number of bleeding episodes and improve quality of life. However, repeated infusions of FⅧ preparations can lead to the formation of neutralizing FⅧ antibodies, also known as FⅧ inhibitors. The prevalence of inhibitors among severe HA patients is as high as 30%, and moderate/mild HA patients have an incidence of 3\u0026ndash;13%[4]. The production of inhibitors can impede the effectiveness of exogenous coagulation factor VIII replacement therapy and increase the financial burden on HA sufferers.\u003c/p\u003e \u003cp\u003eThis study was conducted to gain a comprehensive view of the situation of HA patients in our region. A retrospective analysis of the registered HA patients was performed to understand their demographics, clinical characteristics, and the treatment strategies used. Furthermore, the results of this study provide insight into the direction of future efforts in the Hemophilia Comprehensive Management Center of the National Rare Diseases Alliance at the Second Hospital of Shanxi Medical University, which has a large number of HA patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003e The study was conducted ethically in accordance with the Helsinki Declaration of the World Medical Association, with the consent of the participants. The study population comprised patients with HA from the Second Hospital of Shanxi Medical University, excluding those with von Willebrand disease, acquired hemophilia, and other hemorrhagic diseases. Systematic data was collected to obtain basic information such as age, ethnicity, region, marital status, highest education level, occupation, health insurance type, family history, FVIII factor activity, inhibitors (low titer\u0026thinsp;\u0026lt;\u0026thinsp;5 BU/ml, high titer\u0026thinsp;\u0026ge;\u0026thinsp;5 BU/ml), and type of gene mutations. Additionally, follow-up was conducted to collect data on patient bleeding manifestations, annual bleeding frequency, age at first bleeding, age at diagnosis, target joint, chronic haemartropathy, and treatment strategy (on demand, prophylaxis).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003ePatient demographics, clinical characteristics, and treatment strategies were summarized using descriptive statistics, including frequencies and percentages for categorical variables, as well as means, standard deviations, and medians for continuous variables. Comparisons between groups were made using ANOVA. Rates were compared using chi-square analysis. p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicated a statistically significant difference. The regional distribution of HA patients in Shanxi Province was illustrated using a heatmap. Delay in diagnosis was calculated as the difference between the age at first diagnosis and the age at first bleeding.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eDemographics\u003c/h2\u003e \u003cp\u003eA total of 662 patients with HA were registered at the Second Hospital of Shanxi Medical University as of August 2022. Of these, 647 (97.7%) were located in Shanxi Province (79 patients' Region information was incomplete and not shown in Fig.\u0026nbsp;1). The remaining patients were distributed in Inner Mongolia Autonomous Region, Hebei, Henan, Shandong, Shanxi, Sichuan, and Yunnan Provinces. Information on age was available for 386 patients. In addition to 661 male patients and one female patient, 407 cases were Han ethnic group, 96 (14.5%) were married, 87 (13.1%) had a college degree or higher, and 116 (16.6%) had a known family history of HA. Five (0.8%) patients died (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic characteristics of Chinese HA patients with single-center\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHaemophilia A(N\u0026thinsp;=\u0026thinsp;662)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN(%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e120(18.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e266(40.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e276(41.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e661(99.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(0.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eEthnic group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e407(61.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e255(38.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMarriage status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMarried\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e96(14.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e243(35.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003edivorced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(0.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e321(48.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eEmployment status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e125(18.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEmployed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e137(20.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnemployed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61(9.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetired\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12(1.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e327(49.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eEducation level\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCollege degree\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87(13.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJunior high or high school\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e146(22.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInfant, primary school or below\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e92(13.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e337(50.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eInsurance type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResidents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e395(59.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEmployee\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57(8.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e210(31.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eFamily history of haemophilia A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e116(17.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e209(31.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e337(50.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e657(99.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(0.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFigure1 Heat map of the distribution of HA patients in Shanxi Province\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eClinical characteristics\u003c/h2\u003e \u003cp\u003eAmong the HA patients registered in our center, 1.7% had missing FVIII: C results, while 651 patients had FVIII: C test results, of which 58.1% were classified as severe, 27.2% as moderate, and 13.0% as mild (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Inhibitor tests were conducted on 303 patients, 188 of whom had severe HA, 85 had moderate HA, and 30 had mild HA. The positive rate of inhibitor was highest among those with severe HA (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Patients with high titer of inhibitor were significantly more numerous than those with low titer (Inhibitor titers were unknown in two patients and were not shown in Fig.\u0026nbsp;2). Genetic test results of 221 patients revealed that the most common gene mutation type was intron 22 inversions (47%), followed by missense mutation, nonsense mutation, deletion, insertion, intron 1 inversion, splice site mutation, and other types (Fig.\u0026nbsp;3).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDisease severity in HA patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClassification\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN(%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e385(58.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e180(27.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e86(13.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11(1.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDetection of inhibitors in patients with HA\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal,n\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNegative,n(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePositive,n(%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e188\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e143(76.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e45(23.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e70(82.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15(17.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28(93.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2(6.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFigure2 Inhibition titers in HA patients\u003c/p\u003e \u003cp\u003eFigure 3 Summary of gene mutations in HA patients\u003c/p\u003e \u003cp\u003eIn a telephone follow-up of 305 HA patients, 4 had died and the cause of death was unknown, so only the clinical characteristics of the remaining 301 patients were summarized. Muscle was the most common site of the first bleeding, accounting for 28.9%. Other sites of the first bleeding included joints, head, and nasal passages. With age, the main bleeding sites shifted to joints, and some patients also experienced bleeding in muscles, viscera, and other parts(Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Of the 163 patients who were diagnosed in a timely manner, most were diagnosed in infancy or early childhood, and 106 (65%) were classified as severe HA. The mean delay time for mild HA was 16.7 years, moderate HA 11.9 years, and severe HA 8.8 years, with a statistically significant difference between mild and severe HA (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01, Fig.\u0026nbsp;4). Of the 166 patients with target joints, most were large joints such as the knee, ankle, and elbow. Chronic haemartropathy was observed in 56.3% of severe HA patients (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e), and 8 patients had undergone arthroplasty. The total annual bleeding frequency of HA patients was mainly 0\u0026ndash;5 times, with severe HA having a higher frequency than moderate and mild HA (Fig.\u0026nbsp;5).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFollow-up of bleeding sites in HA patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHaemophilia A with followed-up (N\u0026thinsp;=\u0026thinsp;301)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN(%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSite of first bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEpistaxis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30(10.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDraw blood from the vein\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(0.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHemoptysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(0.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJoint\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75(24.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMuscle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87(28.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUmbilical cord\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(2.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19(6.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSubcutaneous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(1.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18(6.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHead\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30(10.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTrauma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7(2.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDigestive tract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(1.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16(5.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo bleeding, developmental delay\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(0.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCurrently major bleeding site\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlmost no bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43(14.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJoint\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e147(48.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJoints and other areas*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38(12.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEpistaxis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(2.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMuscle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38(12.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(1.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVisceral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(1.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11(3.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(0.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntracranial bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(0.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTrauma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8(2.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e*Recurrent joint bleeding, but also skin, gums, mouth, muscles, internal organs, trauma bleeding.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFigure 4 Comparison of diagnostic delay time for each group\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDelayed diagnosis and joint condition of HA patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall(n\u0026thinsp;=\u0026thinsp;301)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSevere (n\u0026thinsp;=\u0026thinsp;176)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eModerate (n\u0026thinsp;=\u0026thinsp;87)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMild (n\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith diagnosis delay, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e138(45.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68(38.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e47(54.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15(60.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean delay time in years (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian delay time in years (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10(0.08-59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.5(0.33-39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10(0.08-39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15(1\u0026ndash;59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTarget joints, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e166(55.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e118(67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e41(47.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7(18.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJoint deformity, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e134(44.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e99(56.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29(33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6(15.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFigure 5 Annual bleeding frequency in HA patients\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eTreatment strategies\u003c/h2\u003e \u003cp\u003eExogenous coagulation factor FVIII was the most preferred treatment for patients with HA, with 301 patients in total. Of these, 132 (43.9%) were treated on demand, 131 (43.5%) received prophylactic treatment, and 38 (12.6%) did not receive any treatment regimen (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Of the 263 patients who varied in coagulation factor FVIII product selection, 96 (36.5%) used plasma-derived coagulation factor FVIII, 129 (49%) used recombinant coagulation factor FVIII, and 34 (12.9%) used both plasma-derived and recombinant coagulation factor FVIII. Additionally, two (0.8%) inhibitor-positive patients were treated with prothrombin complex, and two (0.8%) had an unclear coagulation factor FVIII product type (Fig.\u0026nbsp;6). The highest rate of prophylactic treatment was observed in severe HA patients, who were typically treated two to three times a week. Finally, comparing the incidence of inhibitors in terms of HA treated with plasma-derived and recombinant coagulation factor VIII, the results showed no statistically significant difference (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTreatment strategies for HA patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall(n\u0026thinsp;=\u0026thinsp;301)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSevere(n\u0026thinsp;=\u0026thinsp;176)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eModerate(n\u0026thinsp;=\u0026thinsp;87)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMild (n\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOn-demand, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e132(43.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80(45.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e36(41.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16(42.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eprophylaxis, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e131(43.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e89(50.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e34(39.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8(21.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnused, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e38(12.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7(4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e17(19.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e14(36.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFigure 6 Type of exogenous coagulation factor FVIII in HA patients\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe World Federation of Hemophilia (WFH) has collaborated with Chinese medical centers to conduct various awareness and educational campaigns on World HA Day to enhance the knowledge of HA patients and their families, leading to a rise in the standardization of HA management and the advancement of regional diagnosis and treatment levels. This study provides a retrospective analysis of single-center HA patients in China, highlighting their demographics, clinical characteristics, and treatment approaches. This information is of great clinical value in terms of normalizing diagnosis, treatment, and management for HA patients in Shanxi Province.\u003c/p\u003e \u003cp\u003eIn our current study, 97.7% of the patients originated from Shanxi Province, and were distributed across different areas (Fig.\u0026nbsp;1). The heat map of the distribution characteristics reveals that, with Taiyuan, the provincial capital, as the boundary, the overall number of patients in the south is higher than that in the north (Jincheng being an exception), which may be attributed to the population and economic level. There was only one female patient with HA, whose coagulation factor VIII activity was 1.1%, indicative of moderate HA, with gum bleeding as the first manifestation and exogenous coagulation factor FVIII treatment being effective. No family history was present. The pathogenesis is most likely due to either homozygous gene mutation or heterozygous gene mutation with normal X chromosome non-random inactivation, the cause of which is still unclear[5, 6]. Our findings demonstrate the actual status of HA patients, including singleness, low employment and low educational attainment, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, and are more likely to be associated with financial burden and physical disability. However, a Danish study showed that by controlling for age differences, no significant differences were found in education and marital levels between PWH and the general population, and employment rates for PWH were significantly lower in 45\u0026ndash;64 year olds than in their peers of the same age, but no differences were found in the younger (16\u0026ndash;44 year old) group[7]. This may be because our analysis is for all age groups, and there is still a degree of wealth disparity in our large population. Therefore, we should enhance education and improve the economic level to reduce the burden of PWH disease and improve the quality of life.\u003c/p\u003e \u003cp\u003eAccording to Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the majority of patients(58.1%) experienced severe HA, 27.2% had moderate HA and 13.0% had mild HA (as shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In comparison, Zhao et al. conducted a retrospective study of patients from 11 HA treatment centers in Shanxi Province and found that 50% had severe HA[8]. Additionally, in 2020, a single center in Tianjin, China, summarized and analyzed the clinical characteristics of 428 HA patients and reported that 52.9% of them had severe HA[9]. The higher proportion of severe HA observed in this study may be due to the fact that mild and moderate HA patients usually have mild bleeding symptoms and often do not seek medical attention, resulting in a low registration rate. With the gradual improvement of medical conditions in China, more and more HA patients are receiving exogenous coagulation factor VIII replacement treatment after diagnosis. The emergence of coagulation factor VIII inhibitors is one of the main challenges in HA treatment, and regular infusions of missing coagulation factor FVIII to induce immune tolerance is the first-line treatment option for the eradication of inhibitors. However, it is expensive and rarely used in the local population[10]. The positive rate of inhibitors in this center was 20.5%, 23.9% in severe HA, 17.6% in moderate HA, and 6.7% in mild HA (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Analysis of disease severity revealed that high-titers were the most common(Fig.\u0026nbsp;2). The generation of inhibitors may be linked to the type of F8 gene mutation, family history, ethnicity, and treatment strategy[4]. Studies have indicated that more than half of patients with HA have no family history of the condition due to new mutations in the F8 gene[11, 12]. Our genetic test results showed that intron 22 inversion was the most frequent type of gene mutation, followed by missense, nonsense, and deletion (Fig.\u0026nbsp;3). In patients with severe HA, the proportion of intron 22 inversion was as high as 53.7%, the ratio of intron 1 inversion was 2.4%, and the proportion of missense mutations in all patients tested was 20.8%, which is comparable to previous studies[13\u0026ndash;15]. One patient had moderate HA due to synonymous mutations, which may be unrecognized and translated by the transport RNA, leading to pathogenicity.\u003c/p\u003e \u003cp\u003eThrough telephone follow-up, we discovered that muscle is the most frequent site of initial bleeding, usually caused by collision or extrusion in infants and young children. As age increases, the primary bleeding sites shift to the joints, such as the knee and ankle joints, which are related to daily activities and weight-bearing. Additionally, 12.6% of HA patients experienced multi-site bleeding, mainly in joints and other areas like the skin, gums, mouth, muscles, viscera, and trauma (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Despite the medical advances made in recent years, we still observed a diagnostic delay in 45.8% of the patients with HA, spanning almost 59 years. The diagnosis delay in mild HA was more severe, and the diagnosis delay time of mild HA was longer than in severe HA, which was statistically significant (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01, Fig.\u0026nbsp;4). This is likely due to the mild bleeding symptoms of mild HA and the lack of awareness of the disease. Therefore, it is essential to emphasize the dissemination of knowledge related to HA, particularly in remote and underdeveloped mountainous regions, to raise public awareness and ensure timely medical treatment.\u003c/p\u003e \u003cp\u003ePatients with HA often experience joint bleeding, which can eventually lead to HA arthropathy in the target joint, resulting in decreased joint mobility, chronic pain, and a significant reduction in quality of life[16]. This study found that 166 (55.1%) patients had target joints, while 134 (44.5%) patients had pre-existing joint deformities, with most cases being severe HA (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Therefore, it is extremely important for the prevention treatment of severe HA, which can reduce joint bleeding, decrease the incidence of hemophilia arthropathy, and relieve the pain of patients. Eight of these patients underwent joint replacement surgery in the orthopedic department, with Hematology, Ultrasound, and Orthopedics being involved in assessing joint status and treatment. The Romanian Society of Hematology also recommends multidisciplinary team treatment, including hematologists, anesthesiologists, orthopedic surgeons, rehabilitation medicine specialists and physiotherapists[17]. This is what we need to work on in the future to effectively solve the problems of our patients.\u003c/p\u003e \u003cp\u003eIn the present study, due to the relatively high percentage of cases counted moderate/mild HA (40.2%) and 43.5% prophylaxis in all patients and the highest percentage of prophylaxis in severe HA (50.5%), resulting in an ABR of mainly 0\u0026ndash;5(Fig.\u0026nbsp;5). An Indian study included 30 children with severe HA and the annual joint bleeding was reduced by 85.76% (14.5 to 2.2) before and after administration of low-dose recombinant FVIII prophylaxis, thus prophylaxis significantly reduced ABR[18]. Clinically, prophylaxis should be recommended for patients with severe HA whenever possible, which will again reduce bleeding to a great extent and improve quality of life.\u003c/p\u003e \u003cp\u003eIn recent years, our country has implemented a basic medical security system in order to reduce the financial burden of citizens, which includes medical insurance and secondary reimbursement for high treatment costs. Our center has achieved a follow-up prevention treatment rate of 43.5%, with the age range of 2 to 74 years old. Among them, 51.9% were \u0026le;\u0026thinsp;18 years old, and severe HA accounted for 50.5%. Compared with a retrospective study of patients with moderate to severe hemophilia A in China, the proportion of preventive treatment in this study is significantly higher, on the one hand, due to the increased awareness of patients and their families. On the other hand, it is closely related to national medical policies[19]. Despite this, there is still a considerable economic burden for patients and their families, particularly those living in poor mountainous areas who are unable to afford the cost of treatment. And for PWH in Nigeria most health care services need to be paid for out-of-pocket, and they will be more likely to feel the financial burden directly[20]. Our study found that 132 cases (43.9%) received on-demand treatment, which may be due to financial constraints. Additionally, 38 cases (12.6%) did not take any treatment measures, and 36.8% of the patients with mild HA opted out of treatment, mostly due to mild bleeding symptoms and the ability to stop bleeding without treatment (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our study, nearly half of the patients utilized recombinant coagulation factor VIII, 36.5% used plasma-derived coagulation factor VIII, and 12.9% used both recombinant and plasma-derived coagulation factor VIII (Fig.\u0026nbsp;6). For those with positive inhibitors, due to the high price of non-factorial products and rFVIIa, only a small number of patients opted for the cheaper prothrombin complex treatment. In this study, only two patients used prothrombin complex and 30 patients still opted for coagulation factor VIII treatment when bleeding. Of the patients followed up, 32 were positive for inhibitors and 147 were negative for inhibitors. There was no statistically significant difference in the incidence of inhibitors and coagulation factor product type. A study of 574 patients with severe hemophilia also showed no statistically significant difference in the incidence of inhibitors between plasma-derived and rFⅧ preparations, whereas other studies have shown a higher incidence of inhibitors in patients using rFⅧ preparations than in patients using plasma-derived FⅧ preparations[21, 12, 22]. Because the number of cases followed up in this study was small, and the number of patients using plasma-derived coagulation factors was significantly less than those using recombinant coagulation factors, we need to expand the number of cases for further confirmation. Up to half of the patients in this study were treated with recombinant coagulation factor VIII, probably due to its greater safety profile by avoiding the transmission of blood disorders. In addition, there are various restrictions in the selection of coagulation factor products, as each region and hospital have limited access to these products. Some areas are unable to purchase recombinant coagulation factor VIII, thus patients and their families have to purchase plasma-derived coagulation factor VIII. This indicates that the entire process of HA treatment is influenced by the regional economic level.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis retrospective study, based on real data from a single center in China, examined the epidemiology, clinical characteristics, and treatment patterns of HA patients, providing insight into the situation of Chinese HA patients. Going forward, it is necessary to gain a comprehensive understanding of the economic status of HA patients, conduct further research into gene therapy for HA, seek out better treatment measures that can enhance the quality of life for HA patients, and improve the diagnosis and treatment level of HA through national policies, medical personnel, and social support.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study protocol was reviewed and approved by the Ethics Committee of the Second Hospital of Shanxi Medical University, approval number NO. 2022-YX-054.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors may provide raw data to support their findings upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo potential conflict of interest was reported by the author(s).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by grants from the National Natural Science Foundation of China (No. 81970172, 8170011339), the Shanxi Provincial Key Research and Development Project (No. 201803D31123)and the Natural Science Foundation of Shanxi Province (No. 20210302123295).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this research, LD Z participated in the collection, collation, processing and writing of information. CX D, JM K, XL Z, J R gave guidance on data content and processing. YC M, LY W, LN L, S Fang, XC H, WK S helped collect and organize data. LH Y, G W provided key guidance on the paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to express our gratitude to all those who helped with this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eIorio A, Stonebraker JS, Chambost H, Makris M, Coffin D, Herr C et al. Establishing the Prevalence and Prevalence at Birth of Hemophilia in Males: A Meta-analytic Approach Using National Registries. Ann Intern Med. 2019;171(8):540-6. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7326/M19-1208\u003c/span\u003e\u003c/span\u003e.\u003c/li\u003e\n \u003cli\u003eSoucie JM, Monahan PE, Kulkarni R, Konkle BA, Mazepa MA, Network USHTC. 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Eur J Haematol. 2010;85(3):264\u0026thinsp;\u0026minus;\u0026thinsp;72. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1600-0609.2010.01481.x\u003c/span\u003e\u003c/span\u003e.\u003c/li\u003e\n \u003cli\u003eLakich D, Kazazian HJ, Antonarakis SE, Gitschier J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nature genetics. 1993;5(3):236\u0026thinsp;\u0026minus;\u0026thinsp;41. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/ng1193-236\u003c/span\u003e\u003c/span\u003e.\u003c/li\u003e\n \u003cli\u003eBagnall RD, Waseem N, Green PM, Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. 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PLoS One. 2023;18(2):e0264600. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pone.0264600\u003c/span\u003e\u003c/span\u003e.\u003c/li\u003e\n \u003cli\u003ePeyvandi F, Mannucci PM, Garagiola I, El-Beshlawy A, Elalfy M, Ramanan V et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med. 2016;374(21):2054-64. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa1516437\u003c/span\u003e\u003c/span\u003e.\u003c/li\u003e\n \u003cli\u003eKessler CM, Iorio A. The Rodin (Research Of Determinants of INhibitor Development among PUPs with haemophilia) study: the clinical conundrum from the perspective of haemophilia treaters. Haemophilia. 2013;19(3):351-4. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/hae.12149\u003c/span\u003e\u003c/span\u003e.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"China, Single center, Hemophilia A, Retrospective study","lastPublishedDoi":"10.21203/rs.3.rs-3068292/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3068292/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eHemophilia A (HA) is an x-chromosome-related recessive disorder caused by a defect in the coagulation factor VIII gene, and timely and proper treatment can improve the quality of life of patients.\u003c/p\u003e\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eSummarize the epidemiology, disease characteristics, and treatment of single-center HA patients in real-world China.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA retrospective analysis of 662 patients with HA in the Second Hospital of Shanxi Medical University was performed, and the basic information of the patients was summarized using descriptive statistics, and the differences between groups were compared using ANOVA, and the geographical distribution characteristics of patients with HA in Shanxi Province were introduced using heat maps.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e662 patients with HA were registered at our center. Most patients had single status, low employment rates, and low educational levels. 85.3% had a moderate to severe HA, 13% had mild HA. Of these, 20.5% of the patients had an active inhibitor. The intron 22 inversion was the most common genetic mutation, accounting for 53.7% of severe HA patients. The joints and muscles were the most common bleeding sites, with 55.1% of the patients having target joints. The mean diagnostic delay time between mild and severe HA was statistically significant (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Regarding treatment, 43.5% of the patients were on prophylactic treatment, usually 2\u0026ndash;3 times a week.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eBased on the real data of a single center in China, this study shows the realistic situation of Chinese HA patients and has certain clinical significance, and better treatment measures to improve the quality of life of HA patients should be explored in the future.\u003c/p\u003e","manuscriptTitle":"Analysis of single-center Hemophilia A patients :demographics, clinical characteristics and treatment strategies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-08-25 18:59:26","doi":"10.21203/rs.3.rs-3068292/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f849b608-0a3a-4ff6-88ca-1e277225bb65","owner":[],"postedDate":"August 25th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-09-24T10:36:34+00:00","versionOfRecord":[],"versionCreatedAt":"2023-08-25 18:59:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3068292","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3068292","identity":"rs-3068292","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}