Sex: M
Vaccine: COVID19
Symptoms: Activated partial thromboplastin time prolonged, Anti factor IX antibody increased, Antiphospholipid antibodies, Computerised tomogram, Ecchymosis
Clinical narrative: Developed a large ecchymotic bruise around the deltoid injection site; haemophilic arthropathy; Tachycardia; Pale; A confluent large painful hematoma; Ecchymotic discoloration; This is a literature report for the following literature source(s): "Development of factor IX inhibitor in an adult with severe haemophilia B following COVID-19 vaccination: A case report", Haemophilia, 2022; pgs:1-3, DOI:DOI: 10.1111/hae.14542.  A 34 year-old male patient received bnt162b2 (COMIRNATY) (Batch/Lot number: unknown) as dose 1, single for covid-19 immunisation. Relevant medical history included: "severe factor IX deficiency (haemophilia B)" (unspecified if ongoing), notes: diagnosed from infancy (presented with intracerebral haemorrhage; baseline factor IX level < 1%); "symptomatic COVID-19" (unspecified if ongoing), notes: recovered uneventfully without hospitalization. The patient's concomitant medications were not reported. Past drug history included: Benefix, notes: 50 IU/kg three times weekly. The following information was reported: VACCINATION SITE HAEMORRHAGE (medically significant), outcome "recovered", described as "Developed a large ecchymotic bruise around the deltoid injection site"; HAEMOPHILIC ARTHROPATHY (medically significant), outcome "unknown", described as "haemophilic arthropathy"; TACHYCARDIA (non-serious), outcome "unknown", described as "Tachycardia"; PALLOR (non-serious), outcome "unknown", described as "Pale"; HAEMATOMA (non-serious), outcome "unknown", described as "A confluent large painful hematoma"; ECCHYMOSIS (non-serious), outcome "unknown", described as "Ecchymotic discoloration". The events "developed a large ecchymotic bruise around the deltoid injection site", "haemophilic arthropathy", "tachycardia", "pale", "a confluent large painful hematoma" and "ecchymotic discoloration" were evaluated at the emergency room visit. The patient underwent the following laboratory tests and procedures: activated partial thromboplastin time prolonged (23.4-36.2): 175.5 seconds; anti factor ix antibody increased: 6.7 bethesda units; 24 bethesda units/ml; antiphospholipid antibodies: negative; negative; computerised tomogram: large left flank and anterior abdominal wall hemat, notes: large left flank and anterior abdominal wall hematoma involving subcutaneous and muscular structures extending from the left lateral chest wall to the inguinal canal; no measurable hematoma; factor ix deficiency (78-184): <1 %; haemoglobin (12.5-16.5): 8.6 g/dl; heart rate: 110 bpm; physical examination: afebrile, tachycardic (heart rate of 110 bpm), notes: and pale. The remainder of the physical examination was unremarkable except for the evidence of chronic haemophilic arthropathy; platelet count (145-400): 282x109/l; prothrombin time (11.8-14.6): 14.5 seconds, notes: normal; white blood cell count (4.0-10.8): 8.3x 103/l. Therapeutic measures were taken as a result of vaccination site haemorrhage.  Additional information: A 34-year-old gentleman presented to the Emergency Department (ED) with multiple episodes of lightheadedness and syncope followed by a significant fall over the previous 5 days. He also noticed a large painful ecchymotic bruise and subcutaneous swelling that had been gradually expanding in size over the lower abdomen and left flank. His medical history included severe factor IX deficiency (haemophilia B) diagnosed from infancy (presented with intracerebral haemorrhage; baseline factor IX level < 1%), for which he had been compliant with his factor IX prophylaxis regimen (recombinant factor IX, BeneFIX, 50 IU/kg three times weekly). He had no prior or family history of an allo anti-FIX antibody or inhibitor. After he noted the onset of painful abdominal bruising, he had increased his factor IX replacement dosage to 10,000 units (100 IU/kg) daily for 5 days before seeking medical care in the ED. Six months prior to his ED encounter, the patient was diagnosed with symptomatic COVID-19 and recovered uneventfully without hospitalization. He subsequently received COVID-19 vaccine (BNT162b2 mRNA, Pfizer-BioNTech), the second dose of which was administered 2 weeks prior to his medical assessment. Within days after his first dose of vaccination, he developed a large ecchymotic bruise around the deltoid injection site that had gradually resolved with scheduled prophylactic infusion. Otherwise, he did not note any adverse reactions to vaccination. On physical examination, he was afebrile, tachycardic (heart rate of 110 bpm), and pale. A confluent large painful hematoma and ecchymotic discoloration were noted over his left flank and left lower abdominal wall with extension into the left groin. The remainder of the physical examination was unremarkable except for the evidence of chronic haemophilic arthropathy. His complete blood count revealed moderate normochromic normocytic anaemia (haemoglobin 8.6 g/dl, normal range 12.5-16.5 g/dl), white blood cells of 8.3 x 103/L (normal range 4.0-10.8 x 103/L), and platelets of 282 x 109/L (normal range 145-400 x 109/L). He had a normal prothrombin time at 14.5 s (normal range 11.8-14.6 s) and a markedly prolonged activated partial thromboplastin time (APTT) at 175.5 s (normal range = 23.4-36.2 s). Mixing studies with and without prolonged incubation showed no correction of APTT. Computed tomography of the abdomen and pelvis demonstrated a large left flank and anterior abdominal wall hematoma involving subcutaneous and muscular structures extending from the left lateral chest wall to the inguinal canal. His factor IX:C activity was < 1% (78-184%) and factor IX inhibitor was detected at 6.7 Bethesda Units. Assays for antiphospholipid antibodies and lupus anticoagulant were negative. F9 gene sequencing revealed amissensemutation (c.839-1G > A). A diagnosis of severe haemophilia B with factor IX inhibitor and intramuscular hematoma was made. His syncopal episodes were attributed to symptomatic anaemia resulting from acute blood loss. He was administered two units of packed red cells and intravenous recombinant FVIIa (Novoseven) 90 mcg/kg daily; his haemoglobin stabilized, and a subsequent repeat CT scan showed stabilization of the extensive hematoma. The inhibitor was treated with rituximab (375 mg/m2) during hospitalization along with prednisone 1mg/kg/day for 2 weeks and subsequent tapering over the following weeks. Three additional doses of weekly rituximab were initially planned, but were denied approval by the patient's health insurance. At the 4-week follow-up outpatient visit, the factor IX inhibitor had increased to 24 Bethesda Units/ml; however, the patients hematoma had continued to improve, and the patient did not develop any new bleeding episodes. CT scan of the abdomen and pelvis at that time indicated no measurable hematoma. The patient was continued on daily intravenous recombinant FVIIa.  DISCUSSION: Here, the authors report the first case of FIX inhibitor in haemophilia B developing in close temporal relationship with COVID-19 BNT162b2 mRNA vaccination. It remains speculative whether this association with the mRNA vaccine was causative or coincidental, or whether the vaccination hyper stimulated a pre-existing stoked immune response to a previous COVID-19 infection. In addition, the clinical bleeding manifestations in this patient, consisting of spontaneous onset of severe intramuscular hematomata and ecchymoses, resemble more the clinical pattern of autoantibody inhibitors to coagulation factors, such as acquired haemophilia A, than the joint centric bleeding associated with alloantibody inhibitors typically seen in severe haemophilia A and B. Furthermore, all antibody inhibitor development is a rare complication in haemophilia B, previously reported at 1.5-3% of severe haemophilia B patients, although a more recent study found a 10.2% cumulative incidence in an unselected prospective cohort. It was even more uncommon to observe such alloantibodies arise in an individual with greater than 150 exposure days to FIX replacement therapy. Development of neutralizing autoantibodies targeting factor IX is essentially anecdotal and has been reported predominantly in association in the elderly and those with underlying autoimmune diseases, cancer, or HIV infection. With the international roll-out of the various COVID-19 vaccination platforms, approximately 70% of Country name withheld population, and more than 50% worldwide, had received at least one dose of vaccine (as of Nov2021). It is not unreasonable to conjecture that such a rare coagulation complication such as a new onset of autoantibody formation could have simply been a coincidental epiphenomenon following vaccination and its specific attribution to them RNA COVID-19 vaccine cannot be definitive without other corroborative evidence. However, there are several reasons to support the possibility that the development of the neutralizing FIX antibody in this patient could have been related to autoimmunity rather than alloimmunity. Firstly, the patient was in his thirties and had been responding well to prophylactic FIX replacement since early childhood. Although rare cases in adults have been reported, FIX allo-antibody typically develop in young children (with a median age of 19.5 months and range of 7-156 months in one international registry) and shortly after early exposure to FIX replacement therapy (a median of 11 exposure days).1,3 Secondly, this patient presented with a large intramuscular hematoma and broad ecchymoses, which more resemble the presentation of acquired factor VIII type II inhibitors. This presentation was also distinct from the typical allergic/ anaphylactic reactions that present concurrently with FIX alloantibody inhibitors.4 Considered altogether, they believe that this patients novel de novo factor IX inhibitor could have been triggered secondarily as the consequence of an intense inflammatory reaction and activation of the immune system by the mRNA COVID-19 vaccine. It is appreciated that both allo- and auto-antibody inhibitors arise not infrequently in the context of physical and surgical trauma, inflammation, systemic infections, and dysregulation of the immune system such as connective tissue disorders, multiple sclerosis, and myasthenia gravis. Most FIX alloantibodies are strongly associated with large gene deletions or nonsense mutations with cross-reactive material negative (CRM-). This patient had a c.839-1G > A splice site mutation. In a F9 variant database, two out of seven cases were reported to develop inhibitors. Infection and vaccination have the potential to induce autoimmunity through molecular mimicry and bystander phenomenon. Since the COVID-19 pandemic, a number of autoimmune-mediated disorders have been described in the context of SARS-CoV-2 infection. Examples have included thrombotic thrombocytopenic purpura (TTP), immune thrombocytopenic purpura (ITP), cold agglutinin disease with autoimmune haemolytic anaemia, antiphospholipid antibodies, and Guillain- Barre syndrome. Interestingly, cases of acquired haemophilia A, both recurrent and de novo, have also been reported following SARS-CoV-2 infection.7,8 The clinical phenotype of those cases were indistinguishable from classic acquired haemophilia A. Shortly after the mRNA-based COVID-19 vaccines became available to the general population, rare cases of hematologic autoimmune disorders were reported and presumed to be secondary to the vaccination due to their temporal relationships. Of keen interest and pertinent to this case report were the several cases of acquired haemophilia. A developing after COVID-19 vaccination. These reports collectively included six elderly individuals (aged 67-85 years), who presented with mucocutaneous or intramuscular bleeding and detectable FVIII inhibitor 2 days to 3 weeks after receiving Pfizer-BioNTech or ModernaCOVID-19 vaccine. In our extensive literature search, we did not identify any reports of haemophilia patients developing factor IX inhibitors in close temporal relationship with COVID-19 vaccination. In this case, the patients factor IX inhibitor was detected 2 weeks after the second dose of vaccination. The causal relationship between the development of FIX inhibitor and COVID-19 vaccination could not be definitively confirmed. The potential mechanism through which vaccines could induce FIX inhibitors is also unknown. However, the observation serves to remind care providers of this condition as a possible cause of breakthrough bleeding in haemophilia patients following vaccination. With the rarity of adverse events, the risks of COVID-19 vaccines remain outweighed by the benefits of disease prevention. This case report should not hinder the decision to provide vaccination in haemophilia patients.; Sender's Comments: Patient is a diagnosed case of factor IX deficiency , the causal association of reported events haemophilic arthropathy and vaccination site haemorrhage is assessed as induced or put to higher probability brought about an existing blood clotting disorder.  The impact of this report on the benefit/risk profile of the Pfizer product is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review, as well as any appropriate action in response, will be promptly notified to regulatory authorities, Ethics Committees, and Investigators, as appropriate