Abstract
Background
The coronavirus disease 2019 (COVID-19)-associated mortality rate of hemophilia patients is similar to that of the general population, but the risk of hospitalization and bleeding is higher. However, the specific impact of this infection on hemophilia patients remains unknown. We aimed to investigate the impact of the pandemic on the infection susceptibility, symptoms, drug use, and social intercourse of patients with hemophilia.
Methods
A survey was distributed to 265 patients with hemophilia (185 adults and 80 children) in the Fujian hemophilia therapeutic center (Fuzhou City, China) during the COVID-19 pandemic, and data were collected between January 2022 and January 2023. The impacts of SARS-CoV-2 infection on hemophilia symptoms, drug use, and social intercourse of these patients were investigated, and the association between the recovery time and disease conditions was explored in infected patients.
Results
During the pandemic, compared with adult patients, pediatric patients had significantly reduced social intercourse and outdoor activities because of the fear of contracting COVID-19 (85.0% vs. 66.5%). Bleeding events were also significantly fewer in children than in adults (61.2% vs. 81.1%). The SARS-CoV-2 infection rate was significantly higher in patients living in urban areas than in those living in rural areas (74.3% vs. 53.6%). The duration of symptomatic recovery from COVID-19 was not significantly associated with hemorrhage, type and classification of hemophilia, presence of inhibitors, complications, and vaccination status.
Conclusion
Having COVID-19 infection did not significantly influence the symptoms and treatments in patients with hemophilia. Pediatric patients had significantly fewer bleeding events than adults.
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Background
Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was declared as a pandemic by the World Health Organization on March 11, 2020. On May 5, 2023, the World Health Organization officially announced that the COVID-19 pandemic was no longer a global health emergency [1, 2]. However, the infection of SARS-CoV-2 has resulted in millions of deaths worldwide and seriously threatened human health in the last 3 years. Studies have shown that COVID-19-related death is significantly associated with chronic diseases like diabetes, hypertension, cardiovascular disease, cerebrovascular disease, and chronic kidney disease [3]. Compared with patients without cancer, those with cancer, particularly those with hematologic malignancies, are at higher risks of SARS-CoV-2 infection and poorer prognoses [4, 5].
Notably, SARS-CoV-2 infection can result in immune dysregulation and can also affect hemostasis. Research findings suggest that the COVID-19-related mortality rate of patients with hemophilia is comparable to that of the general population; however, the former show higher risks of hospitalization and bleeding, particularly gastrointestinal bleeding [6]. Furthermore, patients with concurrent major bleeding also exhibit elevated levels of D-dimer, higher levels of fibrinogen degradation products, reduced levels of fibrinogen, and prolonged PT and APTT [7]. However, the impact of COVID-19 on the treatment and prognoses of patients with hemophilia have not been extensively investigated.
Hemophilia A and B are rare congenital recessive X-linked disorders which are caused by the deficiency of coagulation factor VIII (FVIII) or IX (FIX), and these diseases almost exclusively affect males. The major clinical manifestation is recurrent joint and muscle bleeding, and patients require long-term coagulation factor replacement therapy to reduce bleeding and prevent joint deformity [8]. In some rare cases, hemophilia can even induce intracranial or visceral hemorrhage, thus threatening the lives of patients [9].
The current prevalence of SARS-CoV-2 infection in patients with hemophilia and its impact on the symptoms, social intercourse, and treatment of these patients remain unknown [10]. The purpose of this study is to analyze the number of patients with hemophilia infected with SARS CoV-2 in our center during the COVID-19 pandemic from January 2022 to January 2023. In addition, the impact of this infection on symptoms, drug use, treatment and social intercourse of patients was investigated, and the association between the recovery time and disease conditions in these patients was explored. This study can provide suggestions for patients with hemophilia to cope with COVID-19 infection and reduce anxiety.
Methods
Participants and study design
The Haemophilia Diagnosis and Treatment Centre of Fujian Medical University Union Hospital (Fuzhou City, China) provided 24/7 (24 h a day, 7 days a week) online and offline services. An online interactive questionnaire survey was used to gather the data of hemophilia patients infected with COVID-19 for the aspects of their symptoms, drug use, treatment, and social intercourse every two months. The entire hemophilia patient population followed up in the center was invited to participate in the study. The inclusion criteria were as follows: (1) a diagnosis of hemophilia A or B and (2) FVIII or FIX activity < 40%. An electronic link to the questionnaire was disclosed through a social media platform, “WeChat,” and data were collected from February 01, 2023 to February 07, 2023.
Overall, 265 patients consented to participate in this study. The infected individuals tested positive for COVID-19 in a quantitative real-time PCR test. For children younger than 10 years, parents were asked to answer the questions on their behalf. Missing values were avoided by setting the required fields for every question in the online survey.
The self-reported data included age, sex, history of chronic diseases, and vaccination status. Meanwhile, we collected and analyzed the data on the following aspects of hemophilia patients: bleeding symptoms, COVID-19 infection, COVID-19 vaccination status, symptoms of COVID-19 infection, the use of various drugs from January 2022 to January 2023, and the impact of the COVID-19 pandemic on social activities. This research was approved by the Ethics Committee of Fujian Medical University Union Hospital (approval No. 2023KY107). The participants were informed that their participation was entirely voluntary and that they could withdraw without providing any justification or answering any survey questions at any time. Participants were guaranteed of the confidentiality of their information. Informed consent statement was provided on the home page of the online survey, which the participants had to read and agree to before starting the questionnaire, and thus, each completed questionnaire was considered to have the participant’s informed consent.
Statistical analysis
The data described the characteristics of the entire population, including adult and pediatric patients (< 10 years [parent responders] and ≥ 10 years [child responders]). The χ2 test or Fisher exact test was used to describe and compare the symptoms and social intercourses of patients with hemophilia. A P value of < 0.05 indicated a statistically significant difference. The categorical variables were described as frequencies and percentages. Continuous variables are represented as mean ± standard deviation or median (interquartile range). The categorical variables are represented by numbers (%). We used the Shapiro–Wilk test to evaluate the normal distribution of data. All P values were bilateral, and a P value of < 0.05 was considered significant. The difference in the duration of achieving symptomatic recovery from COVID-19 because of the effect of various general characteristics of patients with hemophilia was assessed using the independent-sample t test. All statistical analyses were performed using the SPSS software version 26.0 (IBM Corporation, Armonk, New York, USA).
Results
Baseline characteristics of patients
The social and clinical characteristics of the included participants are shown in Table 1. The mean age of the 185 adults was 31.83 ± 13.01 years and that of the 80 children was 7.75 ± 4.05 years. The parents answered the questions for children aged < 10 years (n = 42). A total of 236 patients (89.1%) had type A hemophilia (including 69 children), whereas 29 patients (10.9%) had type B hemophilia (including 11 children), and hemophilia was severe in 172 patients (65%), including 52 children. Regarding the permanent residence of patients, 140 patients (52.8%) lived in urban areas and 125 patients (47.2%) lived in rural areas. Seventeen patients (6.4%) received treatments with inhibitors; all of them were patients with hemophilia A. Only 80 patients (30.2%) could receive regular preventive treatment, whereas 121 patients (45.7%) were treated as needed, and 46 patients (17.3%) received intermittent prevention; only 1 child aged 3 years received the immune tolerance induction (ITI) treatment. Compared with adult patients, a significantly greater proportion of pediatric patients received regular preventive treatment (45% vs. 28.3%). Only one pediatric patient had comorbidities, which manifested as epilepsy. A total of 59 adult patients had comorbidities, predominantly manifesting as gastrointestinal diseases (10.9%) and hypertension (5.7%).
During the COVID-19 pandemic, 191 patients (72.1%) actively isolated themselves at home and reduced social intercourse because of the fear of infection. PCR was used to detect the SARS-CoV-2 nucleic acid in all patients, which showed positive results in 171 patients (64.5%). Only six patients were hospitalized for COVID-19, among whom four (accounting for 66.7% of all hospitalized patients) were unvaccinated (mean hospital stay, 11.25 ± 3.3 days) and two were vaccinated (mean hospital stay, 6 ± 1 days). None of the patients died during the course of the study.
Hemophilia symptoms, medication adherence, and social intercourse
Table 2 shows the differences in the aspects of bleeding symptoms, medication adherence, and social intercourse between adults and children during the COVID-19 pandemic. In patients with hemophilia A, the incidence rate of bleeding events was significantly higher in adults than in children [80.8% (n = 135) in adults vs. 59.4% (n = 41) in children, P = 0.001], and overall, hemarthrosis was the most predominant manifestation (84.4% in adults vs. 63.4% in children). In patients with hemophilia B, the incidence rate of bleeding events did not significantly differ between children and adults. hemarthrosis was the major manifestation in adults (93.3%), whereas only 37.5% of children had hemarthrosis. The frequency of bleeding in most patients (82.6% of children and 73.3% of adults) was stable or reduced during the COVID-19 pandemic.
In patients with hemophilia A, although the behavioral traits of reduction in social intercourse and active isolation at home to prevent COVID-19 were noted significantly more in children than in adults [85.5% (n = 59) in children vs. 68.9% (n = 115) in adults, P = 0.008], the percentage of patients with COVID-19 infection did not significantly differ between children and adults. The amounts of coagulation factors used during COVID-19 also did not significantly differ between adults and children (P = 0.483). Similar results were also found for patients with hemophilia B; however, owing to the small number of patients, analyses of statistical significance could not be performed.
In terms of disease severity, patients with hemophilia were categorized as having severe [anti-hemophilic factor (AHF), less than 1%, 172 patients], moderate (AHF, 1–5%, 83 patients), or mild hemophilia (AHF, more than 5% up to 40%, 10 patients). The bleeding symptoms, medication adherence, and social intercourse in different groups were compared (Table 3). The findings showed that the occurrence rate of bleeding events, bleeding frequency, amounts of coagulation factors used, and complications did not significantly differ between patients with hemophilia A and hemophilia B. In patients with hemophilia A, social intercourse and the rate of SARS-CoV-2 infection were not associated with the severity of hemophilia. However, in patients with hemophilia B, patients with mild or moderate hemophilia had a higher proportion of SARS-CoV-2 infection than those with severe hemophilia (36.4% vs. 77.8%, P = 0.048); this finding could be explained by patients with severe hemophilia reducing social intercourse and isolating themselves at home more actively than patients with mild or moderate hemophilia (72.7% vs. 50%) because of their more severe fear of COVID-19.
Hemophilia symptoms, medication adherence, and social intercourse by patients in urban and rural areas during the COVID-19 pandemic
About half of the patients lived in rural areas in Fujian Province, which did not have medical facilities or expertise of the level seen in urban areas. However, the findings of this study revealed no significant difference in bleeding events, bleeding frequency, and amounts of coagulation factors used between patients living in rural and urban areas (Table 4). Further, drugs are freely available for 87.9% of patients in urban areas and 83.2% of patients in rural areas in abundance. Even in the absence of significant differences in social intercourse, the proportion of patients with SARS-CoV-2 infection was still significantly lower in rural areas than in urban areas (53.6%, n = 67 vs. 74.3%, n = 104, P < 0.001), which could be attributed to the relatively smaller population and more effective social distancing in rural areas.
Effects of COVID-19 infection on the symptoms of patients with hemophilia
In this study, 171 patients (64.5%) contracted the SARS-CoV-2 infection. The effects of COVID-19 on patients with hemophilia are shown in Table 5. The results showed no significant difference in the severity of hemophilia and the amount of coagulation factor usage between patients who did and did not get COVID-19 infection. Bleeding events were significantly higher in noninfected patients than in infected patients (85.1% vs. 69.6%, P = 0.005). The symptoms of all patients improved, with an average symptomatic recovery period of 6.1 days. The analysis also showed that the lasting time of symptoms after SARS-CoV-2 infection was not significantly associated with bleeding, type and classification of hemophilia, inhibitors, comorbidities, and vaccination (Fig. 1).
The relationship between symptom duration and the condition of hemophilia patients after COVID-19 infection. The duration of COVID-19 symptoms in patients with different hemophilia types (A), disease severity (B), inhibitor status (C), comorbidities status (D), vaccination status (E), and bleeding status (F) were compared
Discussion
Over the last five decades, hemophilia treatment has advanced considerably. Patients with hemophilia can now have almost normal life expectancy and quality of life. However, the sudden pandemic of COVID-19 has posed a challenge to the management of patients with hemophilia [10]. In this study, we conducted an online interactive questionnaire survey administered to patients every two months (with a total of six follow-up visits) to ensure the accuracy of the data and minimize recall bias as much as possible. We performed follow-up observations in 265 patients with hemophilia during the COVID-19 pandemic, and the results showed that the frequency of bleeding events was stable and unchanged from the pre-pandemic levels. In patients with bleeding, the major manifestation was hemarthrosis, and the rate of bleeding events was significantly higher in adults than in children. Compared with 66.5% of adults, 85% of children reduced social intercourse and actively isolated themselves at home to prevent COVID-19 infection. At the same time, the proportion of individuals receiving preventive treatment was significantly higher in children than in adults. Nevertheless, no difference was found in the proportion of patients infected with SARS-CoV-2 between children and adults. In addition, the amount of coagulation factors used did not significantly differ between adults and children during the COVID-19 pandemic.
The initial treatment of patients with hemophilia involved blood-derived coagulation factors, such as purified factors (cryoprecipitate) [11]. This was followed by the development of recombinant coagulation factors, long-acting coagulation factors, and nonfactor preparations. Genetic therapy has been researched and has shown impressive results in reducing arthropathy and mortality rates in patients with hemophilia [9, 11, 12]. However, the evolution of treatments has been accompanied by the induction of inhibitors, which occurs more in patients with hemophilia A than in those with hemophilia B. Nonfactor treatments, such as ITI treatment [13, 14], bypass drug (recombinant activated coagulation factor VII and prothrombin complex) therapy [15], and emicizumab, are treatments for patients positive for inhibitors [16,17,18]. In addition, genetic therapies being studied in ongoing clinical trials are also very promising [19]. In this study, all 17 inhibitor-positive patients had hemophilia A [20, 21]. Currently, one patient is receiving ITI treatment in our center.
The lockdowns around the world during the COVID-19 pandemic inevitably impact patients with hemophilia. Most data show that lockdowns had little impact on hemophilia symptoms, medication adherence, and mental health of patients. Only one multicenter cross-sectional study performed in Germany investigated the mental health of patients with hereditary bleeding disorders and reported significant differences in the particular thoughts and concerns about COVID-19 in patients and their caregivers [22]. Thus far, no research has explored the impact of COVID-19 on the aspects of infection, bleeding symptoms, and medication adherence in patients with hemophilia. Our findings suggested that having COVID-19 did not significantly influence the symptoms and treatments in patients with hemophilia. Compared with adults, the pediatric patients had significantly fewer bleeding events.
In this study, about half of the patients lived in rural areas, which had poorer economic levels, medical levels, and transportation facilities than urban areas. During the COVID-19 pandemic, our center more actively used remote communication methods like WeChat, telephone, and online teleconferencing to maintain regular contact with patients, particularly those who need more attention and regular follow-ups. In addition, the three-level graded diagnosis and treatment that the Chinese government has been committed to has elevated the treatment level and supported drug allocation in village health centers. Consequently, the findings of this study showed no significant difference in bleeding events, bleeding frequency, and amounts of coagulation factors used between patients in rural and urban areas. In addition, 87.9% of patients in urban areas and 83.2% of patients in rural areas reported that they were capable of purchasing drugs without difficulties in accessibility of drugs. The only difference between patients in rural and urban areas was that the proportion of patients with SARS-CoV-2 infection was significantly lower in rural areas than in urban areas.
In this study, 171 patients (64.5%) contracted the SARS-CoV-2 infection. Similar to regular patients with SARS-CoV-2 infection, patients with hemophilia who contracted the SARS-CoV-2 infection also had symptoms of fever, cough, fatigue, sore throat, muscular or body aches, and headache [23, 24]. The presence of this infection did not significantly increase the bleeding volume in patients with hemophilia. However, the number of bleeding events was significantly higher in patients without the SARS-CoV-2 infection than in patients with it. This finding may be attributed to the decrease in physical activities of individuals infected with COVID-19 during the period of infection and convalescence. Moreover, this reduction is likely to be prolonged in the subsequent months because of the impact of COVID-19. Another possible reason is the hypercoagulable state of the body after infection with COVID-19 [25, 26] needs further verification using big data results. Six patients were hospitalized for pneumonia, including four unvaccinated and two vaccinated patients, with the former having had a significantly longer hospital stay. The average duration of symptoms after SARS-CoV-2 infection was approximately 6.1 days. However, this duration was not significantly associated with bleeding, type and classification of hemophilia, inhibitors, comorbidities, and vaccination status. These findings showed that SARS-CoV-2 infection did not significantly affect the symptoms and treatment of patients with hemophilia.
This study has some limitations. The social interactions of this report are mainly based on reports from patients and parents and cannot be independently verified. This may affect the rigor of the data to some extent. In addition, we only collected data from one hemophilia center, and COVID-19 is still mutating. In the future, we will further analyze the impact of COVID-19 infection on hemophilia patients by increasing the inclusion of data from multiple centers and incorporating detailed viral subtypes. Therefore, during the pandemic, patients with hemophilia should reduce social activities and take regular prophylaxis. Hemophilia diagnosis and treatment centers can help patients with hemophilia receive better support during disease epidemics using better communication measurements for management and preparation.
Conclusions
The findings of this study showed that the COVID-19 pandemic did not affect patients with mild or higher grades of hemophilia and had no significant effect on bleeding symptoms, factor therapy levels, and bleeding sites. However, compared with adult patients, pediatric patients had a significantly lower incidence of bleeding events, perhaps because of their reduced social intercourse and outdoor activities.
Data availability
No datasets were generated or analysed during the current study.
Abbreviations
- COVID-19:
-
Coronavirus disease 2019
- SARS-CoV-2:
-
Severe acute respiratory syndrome coronavirus 2
- AHF:
-
Anti-hemophilic factor
- SD:
-
Standard deviation
- ITI:
-
Immune tolerance induction
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Acknowledgements
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Funding
The Construction project of Fujian Medical Center of Hematology [Min201704]; and the National and Fujian Provincial Key Clinical Specialty Discipline Construction Program, P.R.C.
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MH and FY conceived and supervised the study; SZ and YL designed the experiments; CC, XL, SX and JC responsible for the management of haemophilia centers; BX and SY analyzed and interpreted the patient data. SZ was a major contributor in writing the manuscript. All authors read and approved the final manuscript.
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This research was approved by the Ethics Committee of Fujian Medical University Union Hospital (approval No. 2023KY107). The participants were informed that their participation was entirely voluntary and that they could withdraw without providing any justification or answering any survey questions at any time.
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Zhang, S., Xie, B., Lin, Y. et al. Impacts of the COVID-19 pandemic on pediatric and adult patients with hemophilia. Ann Hematol 104, 95–104 (2025). https://doi.org/10.1007/s00277-024-05992-6
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DOI: https://doi.org/10.1007/s00277-024-05992-6