In December 2019 a global health crisis arose due to the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first starting in Wuhan and declared a worldwide pandemic on March 11th, 2020. Within the following years the coronavirus disease 2019 (COVID-19) has been responsible for immense morbidity and mortality resulting in over 6 million deaths around the globe. To date, there is no effective drug for treating COVID-19 despite many trials. ¹ This situation resulted in an unprecedented race by pharmaceutical companies attempting to develop effective vaccines and as of November 2020, nine vaccines were already in phase III trials. ² Subsequently a number of effective vaccines were given global authorization and were effective in reducing morbidity and mortality. ³ However, in order to facilitate and promptly reduce the impact of the pandemic on healthcare systems and global economy, a number of these vaccines were issued emergency use authorization. Shortly after initiation of COVID-19 vaccination a number of side-effects were reported, the most common being fatigue, muscle pain, headache and chills. ^{4 , 5} Over time, there have been several cases of more serious vaccine-related diseases such as myocarditis, ⁶ vaccine-induced immune thrombotic thrombocytopenia, ⁷ thrombotic thrombocytopenic purpura ⁸ and acquired hemophilia A (AHA). ⁹

Several cases of AHA following COVID-19 vaccines have been described in the literature. ^{9 – 14} Described as early as in the 18th century, ¹⁵ Hemophilia A is a rare bleeding disorder caused by a partial or total deficiency of coagulation factor VIII (FVIII). The concept of a lack of a plasma clotting factor dates back to 1840 ¹⁶ and since then many extremely effective treatments have been developed. ¹⁷ As opposed to congenital hemophilia, AHA is a rare autoimmune disease due to the production of IgG autoantibodies to coagulation FVIII that burdens high morbidity and mortality. ¹⁸ The exact pathophysiology behind AHA remains uncertain, with a probable genetic predisposition and an association to certain underlying diseases (autoimmune disorders, respiratory diseases, allergic reactions). ^{18 , 19}

We report a case of AHA occurring after an inactivated sinovac-coronavac COVID-19 vaccine. The patient was successfully treated with corticosteroids and low-dose rituximab in the acute phase. To the best of our knowledge, this is the first report of AHA after inactivated virus COVID-19 vaccine treated with low-dose rituximab in the acute phase.

A 69-year-old Tunisian retired man consulted the emergency department (ED) in June, 2022 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 to consultation with no recollection of trauma.

The patient had no known personal medical history, a family history of gastric cancer (father) and no psycho-social relevant history. He had received the second dose of CoronaVac-SinoVac vaccine 60 days prior to consultation. The patient reported a small ecchymosis appearing and disappearing spontaneously 3 weeks after the vaccination.

Further physical examination at the ED revealed the presence of two other ecchymoses: one at the inner face of the right forearm, starting at the wrist reaching the elbow, measuring 15 * 5 cm and the other at the left flank of the abdomen reaching the left iliac crest, measuring 40 * 12 cm ( Figure 1).

Both of these were secondarily reported by the patient as having spontaneously started 5 days ago, with no context of trauma. Soft tissue ultrasound performed in regard of the initial ecchymosis at the left inner thigh because of a 5cm-asymmetry between the two thigh sizes eliminated the presence of a hematoma, revealing a hyperechoic infiltration of soft tissue located at the left inner tight.

Laboratory findings performed at the ED were as follows: at the complete blood count, marcrocytic normochromic anemia with a hemoglobin at 8.4 g/dl; mean corpuscular volume, 103fl; mean corpuscular hemoglobin, 32 pg/cell; a normal platelet count, 475 109/L; the determination of Prothrombin Time (PT), prolonged activated partial thromboplastin time (aPTT) and coagulation factors were performed by coagulometric technique on ACL TOP. In our patient’s case, the hemostasis exploration showed an isolated and prolonged aPTT (100 sec/30 s; ratio = 3.33), that has not been corrected on the mixing test, with a normal Prothrombin Time PT = 75%.

In front of the presumptive diagnosis of acquired hemophilia A (AHA), treatment by systemic corticotherapy of 80mg/day of prednisolone IV was immediately initiated as of the first day along with 3g/day of tranexamic acid IV for four weeks for the bleeding and transfusion of two packed red blood cells for the anemia. Bypass therapy was not considered if front of the absence of life-threatening bleeding. The patient was then transferred to the hematology department.

Considering the patient’s age, the absence of history of bleeding or heparin-based treatment and the spontaneous occurrence of hematomas and ecchymoses along with the isolated aPTT prolongation, a deficiency of coagulation factors was suspected. Specific determination of coagulation factors was conducted, available 13 days later, revealing an isolated decrease of factor VIII (FVIII) activity (FVIIIc equal to 1%). Factor VIII deficiency was confirmed on two separate samples. The presence of an FVIII inhibitor was confirmed and titrated by the modified-Bethesada assay (BA) =121 Bethesada units/ml, affirming the diagnosis of AHA.

The diagnosis of AHA was confirmed. After 17 days of corticosteroid treatment, a worsening of the ecchymosis was noted along with the non-improvement of the aTTP. The decision was then made to add low-dose rituximab (100mg/week) IV to the treatment plan. Which was administrated for a duration of 4 weeks.

As for the etiology of the AHA, a panel of immunological testing (antinuclear antibodies, rheumatoid factor, anti-citrullinated protein antibodies) was negative. Hepatitis B, hepatitis C and human immunodeficiency virus serologic tests were negative and a malignant underlying disease was eliminated by a full-body computed tomography scan and negative tumoral markers (alpha fetoprotein, carcinoembryonic antigen, carbohydrate antigen 19-9). There was also no history of illicit drug intake or recent medication.

The patient was later discharged after the first dose of rituximab and followed-up weekly at the out-patient clinic. Follow-up showed a significant clinical (healing of the ecchymoses and no reoccurrence of further signs of bleeding) and biological improvement, aPTT was normalized as of 18 days of treatment with corticosteroids along with rituximab. The detailed therapeutic schedule along with the biological improvement trends over 63 days are displayed in Figure 2. There were no treatment-related adverse effects.

Acquired hemophilia A is a rare autoimmune disorder resulting from the production of autoantibodies against FVIII affecting mainly the elderly with an incidence of around 1.4 cases per 1.000.000 ²⁰ and carrying high morbidity and mortality especially if untreated. AHA should be suspected in front of an isolated prolonged aPTT with or without bleeding and confirmed by detecting a FVIII inhibitor. ¹⁹ Mostly with no identifiably trigger (43.6%-51.9% of cases), ¹⁹ AHA has been described to be associated with genetic predispositions, certain underlying diseases such as autoimmune disorders, respiratory diseases and malignancies or to a triggering factor such as infections or pregnancies. ^{18 , 19}

Among the most noticeable global response to the COVID-19 pandemic was the celerity in developing vaccines with 92 COVID-19 vaccines under development and 21 authorized for use within only 15 months after the first official infection. ²¹ In the literature, there have been several cases of AHA occurring after COVID-19 vaccination. ^{10 – 14} There is not enough evidence about the causality of COVID-19 vaccines on the occurrence of particular auto-immune phenomena thus causing autoimmune diseases, so this remains unclear and debated. ²²

The strength of this study is that, to the best of our knowledge, it reports the first occurrence of AHA after an inactivated COVID-19 vaccination (Sinovac-CoronaVac). In this case, it occurred 3 weeks after the second dose of the Sinovac-CoronaVac vaccine. All vaccine-related information was verified by consulting the patients’ vaccination certificate within the national register of vaccination (Government’s EVAX website).

This study has some limitations. First, it reports the case of only one patient. Second, we do not have evidence that the AHA was caused by the vaccine.

Currently, no post-vaccination surveillance programs recommend screening for clinical or biological signs of AHA, nor any other rare autoimmune disorders. Attention needs to be paid in the post-vaccine period mainly based on auto-surveillance. Apart from presentations with spontaneous or uncontrolled bleeding, clinicians must consider the diagnosis of AHA when faced with isolated prolonged aPTT. Treatment is focused on symptomatically treating any bleeding along with etiological treatment.

In urgent situations such as uncontrolled bleeding, the administration of recombinant FVII activated or the activated prothrombin complex can help control bleeding. ¹⁹

The main treatment of AHA focuses on inhibitor eradication relying on immunosuppressive agents such as corticosteroids, rituximab and cyclophosphamide. ^{23 , 24}

In the current case, low dose Rituximab (100 mg/week) was used along with corticosteroids rather than the standard dose (375mg/m2) to limit occurrence of side effects, mainly neutropenia, potentially dangerous to the elderly who have increased sensibility to infections. ²⁵

This article highlights potential safety concerns regarding COVID-19 vaccination. Although benefits acquired from vaccination highly outweighs the risks, post-vaccine surveillance is important to detect potential uncommon side-effects. Clinicians should consider AHA in front of prolonged aPTT with or without spontaneous bleedings, which, without prompt treatment, could be a life –threatening disease. Lower RTX doses may lead to shorter infusion duration, lower risk of adverse events and lower costs.

Written informed consent for publication of their clinical details and clinical images was obtained from the patient.

This study received approval from the Institutional Research and Ethics Committee of the University Hospital Farhat Hached, Sousse.