Abstract
Objective
Raising awareness of acquired hemophilia A (AHA) and early diagnosis is critical to reduce the associated mortality rate. We aimed to characterize acquired hemophilia in Chinese patients and evaluate the effectiveness of immunotherapy.
Methods
The clinical characteristics, laboratory test data, therapeutic approaches, and outcomes of 20 patients with AHA who were admitted to Xi’an Central Hospital between January 2012 and December 2020 were retrospectively studied.
Results
Nine of the patients (45%) were treated by single glucocorticoid administration; three (15%) with cyclophosphamide (CP) in combination with a glucocorticoid; four individuals (20%) received a combination therapy of rituximab with CP and glucocorticoid or rituximab with CP, vincristine, and a glucocorticoid; three (15%) by injection of human immunoglobulin in combination with a glucocorticoid; and one (5%) with CP alone. Six patients (30%) achieved total remission and 11 (55%) partial remission (PR), but three (15%) did not enter remission, indicating an objective response rate of 85%.
Conclusion
Combination therapy with rituximab or intravenous human immunoglobulin achieves superior results in some patients with AHA. Immunosuppression and the administration of coagulation factors can rapidly control the disease and are efficacious, but >50% of patients only achieved PR. These findings suggest that the complete elimination of inhibitors requires prolonged immunosuppression therapy.
Keywords
Introduction
Acquired hemophilia A (AHA) is an acquired clotting disorder that is not hereditary, and is commonly caused by the secretion of particular antibodies against coagulation factor VIII (FVIII), which is accompanied by spontaneous or surgical traumatic bleeding. The onset of AHA is acute and characterized by severe bleeding. The mortality rate increases when patients do not immediately undergo effective therapy. 1 AHA is commonly caused by autoimmune diseases, such as pemphigus, rheumatoid arthritis, Sjogren’s syndrome, and systemic lupus erythematosus; and malignant tumors, particularly lymphatic malignancies. The incidence of AHA is lower than that of hereditary hemophilia, and there are marked differences between hereditary and acquired hemophilia. Therefore, clinicians in China should develop their ability to identify and diagnose AHA at an early stage of the disease.
Materials and methods
Clinical information
In the present study, data for patients with AHA who had been admitted to a Xi’an City Center Hospital over the preceding 8 years were analyzed with respect to their clinical characteristics, their underlying diseases, and the efficacy and advantages of treatment with glucocorticoids, immunosuppressants, the intravenous injection of human immunoglobulin, and rituximab, to provide a reference for the diagnosis and treatment of AHA. The archived data and laboratory results of these patients, who were admitted to Xi’an Central Hospital, affiliated to Xi’an Jiaotong University, between January 2012 and December 2020, were retrieved and organized, and then retrospectively analyzed. All the patients underwent laboratory tests, including routine hematology, and the measurement of liver enzymes, indices of kidney function, coagulation, coagulation-related factors, factor (F)VIII inhibitor titration, autoantibodies, tumor markers, anti-cardiophospholipid antibodies, β glycoprotein 1, and lupus anticoagulants.
The diagnostic criteria for AHA were as follows: i. spontaneous or abnormal hemorrhage, caused by surgery, trauma, or an invasive procedure, with no previous history of hemorrhage or a family history of hereditary hemophilia; ii. normal plasma prothrombin time (PT), prolonged partial thromboplastin time (APTT), low factor VIII coagulation activity (FVIII:C); and iii. the APTT correction test after a 2-hour warm bath could not be completely corrected, and therefore the Bethesda method was used to detect FVIII inhibitors. 2 Patients with hereditary hemophilia A, with FVIII inhibitor syndrome, or antiphospholipid antibody syndrome were excluded.
Therapeutic regimen and criteria used to assess its efficacy
The treatment of patients with AHA involves the elimination of FVIII inhibitors and the supply of blood clotting factor to stop the hemorrhage. Immunosuppressive therapy, including with glucocorticoids, cyclophosphamide (CP) and vincristine, which can be combined with the intravenous injection of human immunoglobulin or rituximab, is commonly used to eliminate FVIII inhibitors. The type of hemostatic treatment used typically depends on the severity of the hemorrhage. In the present study, bypass hemostasis with prothrombin complex supplementation, in combination with the administration of human FVIII, fresh frozen plasma, cold precipitation, and antifibrotic drugs were used as the hemostatic treatment. For severe hemorrhage, activated recombinant human FVIIa could be also used. The criteria for evaluating the results were as follows: i. complete remission (CR), when symptoms of hemorrhage disappeared, the FVIII:C returned to normal, and FVIII inhibitors could not be detected; ii. partial remission (PR), when the FVIII:C increased by ≥20% and inhibitor concentrations decreased by 50%; and iii. no remission (NR), when the patient did not reach the diagnostic criteria for PR after treatment. 3
Ethics approval and consent to participate
The study was approved by the Ethics Committee of Xi’an Central Hospital, Affiliated to Xi’an Jiaotong University (approval no. LW-2022-020; Xi’an, China). The procedures involved were performed in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and the 2013 revision of the Declaration of Helsinki (1975). Consent for participation in the present study was not required by the committee, owing to the retrospective nature of the study. For the same reason, the requirement for registration in the Chinese Clinical Trial Registry was waived by the institutional review board.
Results
Patient characteristics
Twenty patients with AHA were studied, comprising six men and 14 women with a median age of 57.5 years (range, 19–82 years). Six patients (30%) had an autoimmune disease, five (25%) had a connective tissue disease, two (10%) had a malignant tumor, two (10%) had bullous dermatosis, two (10%) had viral hepatitis, and one (5%) was a postpartum woman. The median period of time between the onset of disease and diagnosis was 4.5 weeks (Table 1). The age and sex distribution of the patients are shown in Figure 1. The clinical manifestations of bleeding were skin ecchymosis in 10 patients (50%), gingival hemorrhage in five (25%), joint hematoma in four (20%), muscle hematoma in four (20%), abdominal hematoma in three (15%), hematuria in two (10%), epistaxis in two (10%), and digestive tract hemorrhage, vaginal hemorrhage, and luteal hemorrhage in one case (each 5%). The clinical manifestations of these types of hemorrhage could be present simultaneously in the same patient. The clinical symptoms of the patients are summarized in Figure 2. None of the patients had a history of anticoagulant drug use or the use of any other medication that could affect coagulation function prior to disease onset. Most of the patients presented with varying degrees of cutaneous bleeding. The most extensive ecchymoses involved the extremities, dorsal region, and buttocks, while milder cases exhibited a more limited area of skin ecchymosis. The patients who primarily presented with cutaneous hemorrhage experienced relatively mild bleeding. Conversely, those with muscular, articular, intra-abdominal, or gastrointestinal bleeding had more severe symptoms of hemorrhage. Three patients with intra-abdominal hemorrhage and one with gastrointestinal hemorrhage developed moderate-to-severe anemia.
Clinical characteristics of the patients.
Data are number (percentage), except where indicated. One case was complicated by both malignant tumor and autoimmune disease.
Age and sex distributions of the patients.
Prevalences of types of hemorrhage in the patients. The majority exhibited more than one type of hemorrhage.
Laboratory test results
The median APTT of the patients was 78.4 s (range, 51.3–120.2 s). The PT, von Willebrand factor-AC, fibrinogen, and thrombin levels were all normal. The median FVIII:C was 2.3% (range, 1%–31%), but the APTT could not be completely corrected. In addition, the qualitative or quantitative inhibitor levels were very high (Table 2). Furthermore, the antinuclear antibody (ANA) titers were high in six patients (30%). The levels of tumor markers were high in two patients (10%), but all of the patients were negative for anticardiolipin antibody, β-glycoprotein 1, and lupus anticoagulant.
Results of laboratory testing, treatment plan, and efficacy of therapy in each patient.
IVIG, intravenous human immunoglobulin; Pred, prednisone; CTX, cyclophosphamide; R, rituximab; DXM, dexamethasone; VCR, vincristine; M, methylprednisolone; NR, no remission; CR, complete remission; PR, partial remission; FFP, fresh-frozen plasma; APTT, activated partial thromboplastin time; FVIII, factor VIII; PCC, prothrombin complex concentrate; FVIII:C, factor VIII activity; BU, Bethesda units.
Treatment options and efficacy
Bypass hemostasis using prothrombin complex supplementation, along with human FVIII, fresh-frozen plasma, cryoprecipitate, and antifibrinolytic drugs, was used as the primary therapy for the patients. Those with severe hemorrhage were treated with activated recombinant human FVIIa (Table 2). Hemorrhage was well controlled in all 20 patients. However, only 55% of the patients achieved PR. Those who achieved CR demonstrated full control over their symptoms of hemorrhage, did not experience new manifestations of hemorrhage, and showed an improvement in disease remission. In patients who achieved PR, the symptoms of hemorrhage were also effectively managed, but some still experienced minor new hemorrhages, such as skin ecchymosis. Furthermore, immunosuppressive therapy was used to remove FVIII inhibitors. The patients underwent initial treatment by coagulation factor infusion and hemostasis, followed immediately by the initiation of immunosuppressive therapy upon disease diagnosis. Specifically, nine of the patients (45%) were treated by single glucocorticoid administration; three (15%) with CP in combination with a glucocorticoid; four individuals (20%) received a combination therapy of rituximab with CP and glucocorticoid or rituximab with CP, vincristine, and a glucocorticoid. In addition, three patients (15%) were treated by the intravenous injection of human immunoglobulin, in combination with glucocorticoids, and one (5%) underwent CP monotherapy. Rituximab was administered at a weekly dose of 375 mg/m2 for 4 weeks, and intravenous immunoglobulin was administered at 0.4 g/kg/day over 5 days. Glucocorticoid therapy consisted of prednisone at a daily dose of 1 mg/kg, which could be gradually tapered on the basis of disease progression or continued until the transition to an alternate regimen. Prednisone could be substituted by an equivalent dose of dexamethasone or methylprednisolone. Of the patients as a whole, 6 (30%) achieved CR, 11 (55%) achieved PR, and 3 (15%) achieved NR. As shown in Table 2, the objective response rate was 85%.
Discussion
AHA is an acquired autoimmune hemorrhagic disease that is characterized by the expression of FVIII autoantibodies in the peripheral circulation. The clinical symptoms of AHA typically include spontaneous or traumatic hemorrhage, hemorrhage of the skin mucosa, epistaxis, gingival hemorrhage, urogenital tract hemorrhage, muscle hematoma, and digestive tract hemorrhage. However, intracranial hemorrhage is rare. In addition, fatal bleeding in vital organs may occur. The mortality rate associated with AHA is high, implying that this condition seriously threatens patients’ lives. 1 A study performed at Cardiff University in the United Kingdom showed that the median age of AHA onset is 78 years and that its annual incidence is 0.148/100,000. 4 AHA is a rare hemorrhagic disease that has a high incidence in postnatal women and individuals of >60 years of age. It has been also reported that approximately 50% of patients with AHA have underlying diseases, such as autoimmune diseases and malignant tumors. 5 Among the autoimmune diseases that complicate AHA, connective tissue diseases are the most common, and these include rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome, and undifferentiated connective tissue disease. 6
International guidelines recommend that all patients with AHA who are being treated with immunosuppressive therapies, including glucocorticoids, CP, and rituximab, should undergo bypass hemostatic therapy to relieve the disease as soon as possible, to reduce the risk of a life-threatening hemorrhage. 7 Therefore, immunosuppressive therapy is an effective means of treating AHA. The most common approach to the treatment of AHA is the elimination of coagulation FVIII inhibitors and replacement therapy in the form of the administration of prothrombin complex or recombinant activated FVIIa anticoagulants to achieve bypass hemostasis. The principal means of immunosuppression that are used to eliminate FVIII inhibitors include the administration of glucocorticoids, CP, rituximab, or a combination of these. Previous studies have shown that the median remission time for AHA is 5 weeks. However, there was wide variation in the number of participants in these studies.5,6,8 For patients who do not respond to immunosuppressive therapy, the intravenous injection of human immunoglobulin, which has an efficacy of up to 30%, can also be used. In addition, immunoadsorption or plasma exchange therapy can be also used to remove inhibitors that are present at high concentrations. 9
In the present study, the median age of onset of AHA in the 20 patients was 57.5 years, which is lower than that reported in the study performed at Cardiff University. 4 The incidence of AHA was higher in older patients, which is consistent with the results of previous studies. 5 In 40% of the patients there was no clear cause of the AHA, in another 40% it was associated with autoimmune diseases or malignant tumors, 10% had viral hepatitis and skin disease, and 5% was a postpartum woman. These findings are consistent with those of previous studies,5,6 and suggesting that in the majority of cases, the development of AHA is associated with malignant tumors and autoimmune diseases, with connective tissue diseases being the most common potential underlying causes. The median period of time to diagnosis in the present group of patients was 4.5 weeks, but 25% spent long periods of time in other healthcare facilities, resulting in a time to diagnosis of >10 weeks, which is higher than that obtained during the EACH2 study. 10 These findings suggest that clinicians need to raise their level of awareness regarding AHA.
For older patients with hemorrhagic disease, but without an underlying genetic defect, the levels of FVIII and its inhibitors should be measured as soon as possible to facilitate an early diagnosis. To eliminate inhibitors, the present group of patients was treated with a glucocorticoid- and CP-based immunosuppressive therapeutic regimen, and in some cases with rituximab in combination with the intravenous injection of human immunoglobulin. This therapeutic approach achieved good results, with a total prevalence of efficacy of 85%. Therefore, it is recommended that once a diagnosis of AHA is confirmed, FVIII inhibitors should be immediately eliminated. However, immunosuppressive treatment led to PR in >50% of patients, which implies that the complete elimination of inhibitors might require multiple cycles of, or prolonged, immunosuppressive treatment. Currently, controversy exists regarding the use of rituximab for the treatment of AHA. The results of a previous study suggested that rituximab-mediated B cell eradication may increase the risk of lethal infection in patients with AHA. 11
Rituximab is a single anti-CD20 monoclonal antibody that is used to treat C20-positive B-cell lymphomas, such as follicular lymphoma and diffuse large B-cell lymphoma. It is also currently used to treat autoimmune diseases, such as autoimmune hemolytic anemia, immune thrombocytopenic purpura, and incurable rheumatoid arthritis.12–14 Rituximab can clear FVIII inhibitors by eliminating B cells, and it has been increasingly used as a first- or second-line therapy for patients with AHA, with great efficacy.15–17 The Each2 study showed that rituximab could be used as a first-line therapy for AHA, but its use was not associated with a higher prevalence of CR than that of a glucocorticoid and CP. However, when glucocorticoid or immunosuppressive therapy failed, rituximab was an effective second-line therapy. 18 In the present study, four patients were treated with rituximab in combination with immunosuppressants and glucocorticoids, of which two achieved CR and two achieved PR. All of these treatments had marked effects, which is consistent with the results of previous studies.12–14 Furthermore, no serious infections occurred, suggesting that rituximab could be used as a first-line therapy for AHA. It has been reported that rituximab has a synergistic effect with immunosuppressants and glucocorticoids and is safe.
The hemorrhage that characterizes AHA can be severe and originate simultaneously from multiple sites. The symptoms are heterogeneous, including skin and mucosal hemorrhage, muscle hematoma, intracranial hemorrhage, and gastrointestinal hemorrhage, although joint hemorrhage is relatively rare. 19 Consistent with the results of previous studies, in the present study the majority of patients experienced skin mucosal hemorrhage, gingival hemorrhage, and muscle hematoma. Multi-site, digestive tract, and abdominal hemorrhage accounted for 30% of all the recorded hemorrhages. 20 To achieve bypass hemostasis, treatment with activated prothrombin complex concentrate (PCC) or activated FVIIa is recommended as an alternative method of stopping hemorrhage. 1 However, the former is not available in China and the latter is too expensive for regular use. Therefore, clinicians tend to use the clotting enzyme PCC as the treatment in clinical practice. However, depending on the severity of hemorrhage, the administration of FVIII in combination with fresh-frozen plasma and cold precipitation may have a synergistic hemostatic effect. The treatment of the present patients by means of bypass hemorrhage therapy with PCC was effective, and no adverse events, such as thrombosis, were recorded. This implies that PCC has a particular hemostatic effect, perhaps because of the activation of coagulation factors during the production process. 21
In conclusion, AHA is a rare hemorrhagic disease that is closely associated with autoimmune diseases, malignancies, and viral hepatitis. The incidence of AHA is higher in older people, but can also be associated with pregnancy and parturition. In clinical practice, the onset of AHA is acute and is accompanied by severe hemorrhage. Therefore, the diagnosis of this disease as early as possible and the initiation of immunosuppressive treatment to remove FVIII inhibitors at an early stage are very important. In addition, the replenishment of the PCC-based clotting factor preparation is necessary to control the hemorrhage. When AHA is diagnosed and treated at an early stage, the prognosis is good for the majority of patients. Rituximab can be used in combination with immunosuppressants or glucocorticoids as a first-line therapy for AHA. In addition, when patients do not respond to this treatment strategy, rituximab can be recommended as a second-line therapy. However, in some patients, multiple cycles of, or prolonged, immunosuppressive therapy may be needed to completely eliminate FVIII inhibitors. However, because the present study was conducted at a single center, the number of patients was limited. Therefore, further, multi-center studies with larger sample sizes should be performed in the future to confirm the results of the present study.
Footnotes
Acknowledgements
The authors would like to thank Dr Changhu Dong (Center for Translational Medicine, The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China) and Dr Zhihui Zhou (Center for Translational Medicine, The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China) for providing suggestions regarding the writing of the Results section of the manuscript.
Author contributions
GL, CD, YS, BL, and MD conceived and designed the study. FG and ZL drafted the manuscript. FG, ZL, and MD performed the statistical analysis. All the authors critically reviewed the manuscript. GL and FG confirm the authenticity of all the raw data. All the authors read and approved the final version of the manuscript.
Declaration of conflicting interest
The authors declare that there is no conflict of interest.
Funding
The present study was supported by the National Natural Science Foundation of China (grant no. 81900134) and the Natural Science Foundation of Shaanxi Province (grant no. 2019JM-607).
