Acquired hemophilia A and deep vein thrombosis attributable to the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine-case report

Background: Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder that occurs in a sporadic, nonhereditary pattern. It is caused by circulating autoantibodies against clotting factor VIII that are triggered by several conditions. Moreover, AHA is clinically distinct from the inherited form of hemophilia A, with a different natural history and management approach, necessitating a high-index of suspicion in at-risk patients. Coronavirus disease 2019 (COVID-19) has emerged as a multisystemic disease whose manifestations are continuously being evaluated. There are few case reports of AHA associated with COVID-19 infection, while one case of AHA has been associated with COVID-19 vaccination. Similarly, deep venous thrombosis (DVT) frequently complicates COVID-19 infection, but two cases of DVT have been reported following COVID-19 vaccination. We report the occurrence of both AHA and DVT in a 63-year-old male patient within one week of receiving his first dose of the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine. Case Description: Patient is a 63-year-old male who presented with a 3-day history of left lower extremity (LLE) swelling and pain. He was hemodynamically stable, but examination showed exquisite tenderness, ecchymosis, and pitting edema at the calf of the LLE. He had normal platelet counts at presentation but had mild anemia (11.9 g/dL) and elevated activated partial thromboplastin time (APTT) of 68.0 seconds. Venous Doppler ultrasound showed acute DVT in the left popliteal vein, necessitating commencement on heparin drip. He developed progressively worsening hematomas, symptomatic anemia that required red cell transfusions, and persistently elevated APTT despite stopping the heparin drip. Work up for pulmonary embolism, malignancy, and disseminated intravascular coagulopathy (DIC) were negative. Antiphospholipid antibodies and lupus anticoagulant were also negative. He had low factor VIII levels, tested positive for factor VIII inhibitor, and PTT mixing studies were consistent with acquired factor inhibitor. Treatment involved administration of Factor Eight Inhibitor Bypassing Activity (FEIBA) as well as intravenous methylprednisolone and cyclophosphamide. Following resolution of active bleeding with evidence of stable hemoglobin concentration, he was discharged home on oral prednisone and cyclophosphamide. Conclusion(s): This case report highlights the possibility of AHA and DVT as rare, potentially life-threatening adverse events that could occur following COVID-19 vaccination, which is currently the most effective tool employed in controlling the COVID-19 pandemic.Copyright © Annals of Blood. All rights reserved.

Cases of acquired hemophilia A following COVID-19 vaccines: Cogent safety signal or possible reporting/detection bias? Preliminary evidence from Tuscany, Italy.

PURPOSE: Several case reports of acquired hemophilia A (AHA) following COVID-19 vaccines were recently published. A possible increased incidence of AHA during the COVID-19 vaccination campaign was also suggested. We aimed at generating evidence for the preliminary assessment of the association between AHA and COVID-19 vaccination through an ecological study in one Italian region, Tuscany. METHODS: An ecological study was performed using the population-based administrative data source of Tuscany. Per each year between 2017 and 2021, we included patients aged 5+ and active into the database as of January 1. Temporal patterns of annual incidence of possible AHA cases and AHA-tested patients were respectively observed. The rates of possible AHA cases per AHA-tested patients were calculated in 2021 and 2017-2019, respectively (calendar year 2020 was excluded because non-representative of the pre-pandemic era). Age-sex standardization was applied. Poisson's 95% confidence intervals (95% CI) were estimated. Statically significant differences were defined as absence of 95% CI overlap. RESULTS: In 2021, standardized incidence of both possible AHA cases (5.6/million subjects/year; 95% CI = 3.4-8.7) and AHA-tested patients (60.7/1000 subjects/year; 95% CI = 60.4-60.9) showed the lowest point estimates, though only the latter was statistically different compared to previous calendar years. The standardized rate of possible AHA cases per AHA-tested patients was 9.2/100000 (95% CI = 5.6-14.3) in 2021 and 12.5/100000 (95% CI = 8.2-18.1) during 2017-2019. CONCLUSIONS: These preliminary findings do not support the hypothesis of an increased incidence of AHA cases during the COVID-19 vaccination campaign. However, in 2021, the still ongoing healthcare access restrictions might have contributed to the low incidence of AHA and laboratory tests observed. Therefore, large-scale multi-database studies are warranted.

Acquired hemophilia A following COVID-19 vaccine: a case report.

BACKGROUND: In the literature, reported cases of Acquired hemophilia A (AHA) induced by COVID-19 vaccination occurred after Adenoviral Vector Deoxyribonucleic Acid (DNA)- and SARS-CoV-2 Messenger Ribonucleic acid (mRNA)-Based vaccines. Here, and to the best of our knowledge, we report the first case of AHA occurring after an inactivated Sinovac-coronavac COVID-19 vaccine. CASE PRESENTATION: A 69-year-old Tunisian male patient consulted for severe left leg pain limiting physical mobility due to a 5*6 cm large ecchymosis located at the left inner thigh, having spontaneously appeared 5 days prior consultation and without notion of trauma. The patient had no known personal medical history. He had received the second dose of CoronaVac-SinoVac vaccine 30 days prior to consultation. Further physical examination revealed the presence of two other ecchymoses: one at the inner face of the right forearm, starting at the wrist reaching the elbow and the other at the left flank of the abdomen. Diagnosis of AHA was based on clinical presentation and confirmed with prolonged a PTT, Factor VIII deficiency and the presence of an FVIII inhibitor. The patient was successfully treated with corticosteroids and low dose Rituximab. CONCLUSION: Clinicians should consider AHA in front of prolonged aPTT with or without spontaneous bleedings even after inactivated virus COVID-19.

[Acquired hemophilia A that developed after BNT162b2 mRNA COVID-19 vaccination and worsened following re-vaccination].

An 86-year-old Japanese male patient visited a nearby hospital with painful swelling in his left upper and lower limbs 35 days after the second dose of the BNT162b2 mRNA coronavirus disease-2019 (COVID-19) vaccine. He was referred to our hematological department due to a prolonged activated partial thromboplastin time and was urgently admitted. He was diagnosed with acquired hemophilia A (AHA) based on factor VIII (FVIII) activity of 1.7%, FVIII inhibitor of 152.3 BU/ml, and FVIII-binding antibodies detected by enzyme-linked immunosorbent assay. Immunosuppressive therapy with prednisolone (PSL) at 0.5 mg/kg/day was started owing to the risk of infection due to old age and poor activities of daily living. Hemostasis treatment with bypass hemostatic preparations (rFVIIa preparation, FVIIa/FX) was administered for each bleeding event, such as intramuscular and knee joint bleeding, resulting in good hemostatic effects. Coagulative complete remission was achieved on day 69 with PSL treatment; however, FVIII activity decreased with PSL tapering. AHA relapse with rectus abdominis muscle hematoma was observed after the third vaccination. This is the first Japanese report of AHA after COVID-19 vaccination and the world's first case, in which the presence of anti-FVIII-binding antibodies were observed.

Relapse of acquired hemophilia A following COVID-19.

Acquired hemophilia A (AHA) is a rare disease in which an autoantibody causes bleeding by interacting with and inhibiting the coagulation activity of endogenous factor VIII (FⅧ). Most cases of AHA are idiopathic, and other causes include autoimmune diseases, malignant tumors, pregnancy, drugs, and viral infections. An 86-year-old man was diagnosed with AHA based on the following results: activated partial thromboplastin time (aPTT) extension of 130.7 seconds, inhibitor pattern by mixing study, endogenous factor VIII (FⅧ) level at <1%, and FⅧ inhibitor titer at >5.1 Bethesda units (BU). The activity of von Willebrand factor (vWF) decreased (<10%), which was considered to be a complication of acquired von Willebrand syndrome (AVWS). The patient was started on prednisolone, and the inhibitor level eventually became negative. vWF values also became normal. However, 1 year later, he was hospitalized due to Coronavirus disease 2019 (COVID-19). His blood test showed an aPTT extension of 110.5 seconds, FⅧ level at 4%, and FⅧ inhibitor titer at 0.8 BU; thus, he was diagnosed with a relapse of AHA. After the administration of corticosteroid and remdesivir, he recovered from COVID-19 and AHA. The inhibitor level became negative on the 9th day of admission. Several articles have reported that COVID-19 infection and vaccination are implicated with AHA. We suggest that the aPTT should be measured when patients with AHA are infected with SARS-CoV2 to confirm AHA relapse.

Acquired hemophilia A (AHA) due to anti-SARS-CoV-2 vaccination: A systematic review.

Vaccination against SARS-CoV2 has been the largest vaccination campaign over the past two decades. The aim of this study is to qualitatively assess the reported cases of acquired hemophilia A (AHA) that developed after COVID-19 vaccination to further elaborate on incidence, presentation, treatment, and outcomes.We queried Medline (PubMed), Google Scholar, and Embase databases to find reported cases of AHA after COVID-19 vaccines. We found 14 studies (19 cases) for this descriptive analysis. Most patients were elderly (mean age 73 years) and males (n = 12) with multiple comorbidities. All cases developed after mRNA vaccines - BNT162b2 Pfizer-BioNTech (n = 13) and mRNA-1273 Moderna (n = 6). All except one patient were treated, with the most common therapy being a combination of steroids, immunosuppression, and rFVIII (n = 13). Two patients died due to acute respiratory distress, and gall bladder rupture with persistent bleeding, respectively. While evaluating a patient with bleeding diathesis after COVID-19 vaccination, AHA should be kept in the differential diagnosis. Given the low incidence, we believe that the benefit of vaccination still outweighs the risk of disease acquisition.

[Acquired hemophilia A following BNT162b2 mRNA COVID-19 vaccination].

Acquired hemophilia A (AHA) is a rare disease characteized by bleeding symptoms caused by decreased factor VIII activity due to the appearance of inhibitors to factor VIII triggered by malignancy or collagen disease. An 86-year-old woman developed purpura on her extremities after the first dose of the BNT162b2 mRNA COVID-19 vaccine. This symptom subsided after a few days. After the second dose of the BNT162b2 mRNA COVID-19 vaccine, purpura appeared again, and the patient was referred to our hospital Her APTT was remarkably prolonged to 110 seconds, and a cross-mixing test revealed an inhibitor pattern. Since FVIII activity was <1% and FVIII inhibitor was 51.6 BU, she was diagnosed with AHA. Prednisolone therapy was started, and coagulative complete remission was achieved. Because acquired hemophilia can develop after mRNA COVID-19 vaccination, as in this case, it is critical to monitor the appearance of bleeding symptom.

Acquired hemophilia A following COVID-19 vaccination - The importance of prompt diagnosis: A case report.

Acquired hemophilia A (AHA) is a rare coagulopathy characterized by hemorrhagic manifestations. It has been linked to various conditions, including autoimmune disorders, drugs, tumors, lymphoproliferative disorders, and infections. We present a case of AHA in a 71-year-old male patient with cutaneous hematoma occurring 8 days after vaccination for COVID-19. This report aims to highlight the risk of FVIII inhibitor development following an immune stimulus, thus improving our knowledge regarding possible vaccination-related adverse events. Furthermore, we underline how the potential risk of not recognizing disease manifestations promptly, together with specific coagulation alterations, could significantly affect the patient's outcome. Adequate management plans and the diffusion of shared guidelines are of fundamental importance in order to prevent the development of life-threatening complications and initiate appropriate treatment as soon as possible. DATA AVAILABILITY: All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Acquired Hemophilia A: An Update on the Etiopathogenesis, Diagnosis, and Treatment.

Acquired haemophilia A (AHA) is a rare bleeding disorder caused by inhibitory autoantibodies against coagulation factor VIII (FVIII). AHA is a disease that most commonly affects the elderly but has also been observed in children and in the postpartum period. AHA is idiopathic in 50% of cases and is associated with autoimmune diseases, malignancies, and infections in the remaining 50%. Recently, cases of association between AHA, COVID-19 vaccination, and infection have been reported in the literature. For diagnoses, determining FVIII levels is crucial to distinguish the different causes of aPTT prolongation. Treatment of AHA is based on bypassing agents (recombinant factor VIIa, activated prothrombin complex concentrate) and porcine FVIII to control the bleeding and immunosuppressive therapy (corticosteroids, rituximab, cyclophosphamide) to suppress autoantibody production. It is important to start a prophylactic regimen to prevent further bleeding episodes until the inhibitor is negative. Recently, the series of cases reported in the literature suggest that emicizumab may provide effective and safe haemorrhage prophylaxis in the outpatient setting.

Acute-type acquired hemophilia A after COVID-19 mRNA vaccine administration: A new disease entity?

Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder. Various autoimmune diseases, including AHA, have been reported to occur after the administration of mRNA COVID-19 vaccines. However, the characteristics of these AHA cases remain unclear. We report a case in which AHA arose in a young patient after the administration of an mRNA COVID-19 vaccine, but improved rapidly. The patient's factor VIII (FVIII) inhibitor titer spontaneously decreased to less than half of that seen at diagnosis. One week after the initial immunosuppressive therapy, the FVIII inhibitor had disappeared. Our case suggests that AHA that arises in young patients after COVID-19 vaccination may resolve spontaneously, and the levels of FVIII inhibitors may decrease more rapidly in such cases than in idiopathic AHA. Unlike for immune thrombocytopenic purpura (ITP), no acute type of AHA has been recognized. This case suggests that just as there is an acute type of ITP that develops in children/after vaccination, there may be an acute type of AHA that arises in young patients that receive mRNA COVID-19 vaccines.

Acquired hemophilia following COVID-19 vaccination: Case report and review of literature.

Background: Acquired hemophilia A (AHA) is a rare bleeding disorder that can lead to spontaneous hemorrhage or bleeding induced by invasive procedures or trauma. We describe a patient who presented with multiple hematomas and a relapse of bullous pemphigoid shortly after his first dose of Vaxzevria ChAdOx1-S COVID-19 vaccination. We reviewed literature for cases of AHA following COVID-19 vaccination. Key Clinical Question: Can COVID-19 vaccines induce (a recurrence of) AHA? Clinical Approach and Conclusions: The diagnosis of AHA with a relapse of bullous pemphigoid was made. The patient was treated with recombinant activated factor VII, emicizumab, rituximab, and methylprednisolone. There were no further bleeding events. However, the patient deteriorated because of sepsis and died on the fifteenth day of admission. Conclusion: Vaccines may trigger autoimmune events such as AHA. However, proof of causality is not possible and in this case the relapse of bullous pemphigoid before vaccination challenges this even more.

A case of acquired hemophilia A and bullous pemphigoid following SARS-CoV-2 mRNA vaccination.

Acquired hemophilia is a rare disease resulting from autoantibodies against endogenous factor VIII (FVIII), which associates with bleeding and a high mortality rate. The pathophysiology is still unclear. Recent studies suggest genetic and environmental factors trigger the breakdown of immune tolerance. We report a 77-year-old Taiwanese man presented with multiple ecchymoses and some hemorrhagic blisters three weeks after SARS-CoV-2 mRNA (Moderna) vaccination. Isolated activated partial thromboplastin time (aPTT) prolongation was found. Acquired hemophilia A (AHA) was confirmed by low factor VIII (FVIII) activity and high titer of FVIII inhibitor. The pathohistology of skin biopsy further supported the concomitant diagnosis of bullous pemphigoid. To date, 6 cases of acquired hemophilia A following SARS-CoV-2 mRNA vaccination were reported worldwide. We reviewed and summarized the characteristics of these cases. We also discussed the rare finding of concomitant acquired hemophilia A and bullous pemphigoid. Bullous pemphigoid results from autoantibody against epithelial basement membrane zone of skin. In this article, we proposed possibility of SARS-CoV-2 mRNA vaccine associated autoimmunity against FVIII and epithelial basement membrane zone.

Acquired hemophilia A after vaccination against SARS-CoV-2 with the mRNA-1273 (Moderna) vaccine.

Acquired hemophilia A is a rare bleeding diathesis most typically seen in systemic rheumatic disease, solid and hematologic malignancies, and pregnancy. We present a case of this condition that occurred immediately after vaccination against SARS-CoV-2 with the mRNA-1273 (Moderna) vaccine.

Acquired Hemophilia A After SARS-CoV-2 Infection: A Case Report.

Acquired hemophilia A is a rare autoimmune coagulation disorder associated to the development of neutralizing antibodies directed towards coagulation factor VIII, known as factor VIII inhibitors, in subjects with previous normal clotting system homeostasis and personal and family history negative for bleeding episodes. This condition, although variable in severity and clinical presentation, may lead to severe and life-threatening hemorrhages which can be either spontaneous or associated with traumatic events and invasive procedures. Here we report the case of a 53-year-old woman who was admitted to our Internal Medicine Unit "Cesare Frugoni", Policlinico di Bari, in July 2021, and diagnosed with acquired hemophilia A. We aim to raise awareness about this rare condition, its clinical presentation and therapeutic management options in order to obtain a quick diagnosis and an effective therapeutic intervention.

Acquired Hemophilia A Post-COVID-19 Vaccination: A Case Report and Review.

Acquired hemophilia A (AHA) is an inhibitory coagulopathy that represents a rare variant of hemorrhagic syndromes. We present a case of idiopathic AHA in a 75-year-old male patient with a cutaneous hematoma that could be attributed to a recent COVID-19 vaccination. The aim of this report is to raise awareness of a possible association between AHA and COVID-19 vaccination and to review similar reported cases and management plans to prevent the development of possible morbidity and debilitating complications. This case illustrates an exceptionally rare side effect of the COVID-19 vaccination. The advantages of obtaining the COVID-19 vaccine outweigh the risks.

Four cases of acquired hemophilia A following immunization with mRNA BNT162b2 SARS-CoV-2 vaccine.

Acquired hemophilia A (AHA) is a rare autoimmune disease caused by neutralizing autoantibodies against coagulation Factor VIII. Immunomodulatory effects of SARS-CoV-2 vaccination are still poorly understood, with reports of immune-mediated conditions developing after immunization. In the province of Reggio Emilia, Northern Italy, we observed four cases of AHA following SARS-CoV-2 immunization with mRNA BNT162b2 vaccine (produced by Pfizer-BioNTech) during the first eight months from the beginning of SARS-CoV-2 vaccination campaign. During this time frame, 235,597 people received at least one dose of BNT162b2 vaccine. The total population of Reggio Emilia province is 526,349. The unusual observation of four cases of AHA in our province could be of interest and could sensitize healthcare personnel toward a possible complication of SARS-Cov-2 immunization. Nonetheless, vaccination benefits exceed potential side effects and play a central role in individual and public health to effectively protect people from COVID-19 and to stop the pandemic.

Management of Acquired Factor VIII Inhibitors With NovoSeven and Obizur.

Acquired hemophilia A (AHA) is a rare hemorrhagic disorder caused by the production of autoantibodies against coagulation factor VIII (FVIII). AHA is associated with significant morbidity and mortality primarily as a result of bleeding. Although many disorders are associated with the development of these inhibitors, up to 50% of cases remain idiopathic. The approach to therapy involves an initial strategy often to control acute bleeding episodes followed by definitive treatment to eradicate the inhibitor with immunosuppressive agents. We present the case of a 63-year-old Caucasian male hospitalized for severe Covid-19 who developed bleeding due to an acquired FVIII inhibitor that had never been treated definitively. Our case presentation focuses on in-hospital management of this patient's acute bleeding episodes with by-passing agents and recombinant porcine factor VIII.

A Case of Acquired Hemophilia A Following SARS-CoV-2 Infection.

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by antibodies against coagulation factor VIII. The majority of AHA cases are reported in an elderly population with chronic co-morbidities but can also be associated with other conditions, drugs, infections, and pregnancy. AHA is likely under-diagnosed and often unrecognized due to limited data about incidence, diagnosis, and management. We report a patient with no significant medical history who developed spontaneous ecchymoses and hematomas after a recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection complicated by a pulmonary embolism. These skin manifestations were initially thought to be related to the use of the direct oral anticoagulant apixaban, but further investigation revealed the presence of factor VIII inhibitors confirming the diagnosis of AHA. The patient was treated with prednisone and cyclophosphamide to eradicate the inhibitors with excellent response. Literature review shows a few cases of AHA after coronavirus disease 2019 (COVID-19) vaccination, H1N1 vaccination, and two cases after COVID-19 infection.