Received Mar 26, 2025
| Type | Name | Manufacturer | Dose | Lot | Route / Site |
|---|---|---|---|---|---|
| COVID19 | COVID19 (COVID19 (PFIZER-BIONTECH)) | PFIZER\BIONTECH | 1 | — | — |
Acquired FV inhibitor; Partial vitamin k deficiency; This is a literature report from the Regulatory Agency for the following literature source(s): Other Case identifier(s): PI450028-00060, PI450028-00089, PI450028-00317, US-MLMSERVICE-20250318-PI450028-00053-1. This case was detected in the medical literature by the Regulatory Agency. Acquired factor V inhibitor treated with rituximab. On 14 Mar 2025 This spontaneous case was reported in the medical literature by a physician and concerns a male patient in 50's (06 decades) who experienced serious adverse drug reaction of acquired FV inhibitor associated with tozinameran, ceftriaxone, azithromycin, ampicillin, tobramycin and partial vitamin k deficiency associated with ceftriaxone, azithromycin, ampicillin and tobramycin. The patient in his 50s presented to the hospital from a skilled nursing facility for behavioural and psychiatric issues. He had a complex medical history including chronic obstructive pulmonary disease, hypertension, type II diabetes mellitus, schizoaffective disorder and a severe COVID-19 infection 2 years prior resulting in tracheostomy and gastrostomy tube dependence. On admission, the patient had stable vital signs and appeared cachectic, with no signs of active bleeding or pallor on examination. His hospital course consisted of treatment for multiple multidrug-resistant urinary tract and pulmonary infections. On hospital day 16, the patient developed oozing at the peripheral IV and tracheostomy sites and was found to have markedly abnormal coagulation findings. He had an elevated activated partial thromboplastin time (aPTT) greater than 200s, an elevated prothrombin time (PT) of 58.0s, an elevated international normalised ratio of 6.7, haemoglobin of 90g/L, elevated fibrinogen at 595mg/dL, D-dimer 0.42 ug/mL and platelets 240x10^9 /L. The patient's previous coagulation studies approximately 1 year prior showed a normal aPTT of 30.1s and PT of 12.3s. Investigations: A 1:1 mixing study of the patient's plasma and normal pooled plasma did not correct the aPTT immediately, aPTT 59s, or after 60min of incubation, aPTT 63.7s, indicating the presence of a circulating fast-acting inhibitor. The thrombin time was normal 17.4s, indicating normal factor II function and excluding the presence of a thrombin inhibitor. Specific factor assays showed an FVII level of 39%, a factor X level of 51% and an FV level of < 1%. The FV inhibitor was present at an activity level of 184 Bethesda units/mL. Differential diagnosis: The results of liver studies, including ultrasonography and liver enzymes, were normal. HIV and viral hepatitis serologies were negative. There was no laboratory evidence of haemolysis as noted by haptoglobin, lactate dehydrogenase and total bilirubin within normal ranges along with the absence of schistocytes on peripheral smear. The iron panel was consistent with anaemia of chronic disease. The vitamin B12 and folate levels were within normal limits. Vitamin K was administered because of concerns regarding antibiotic-related deficiencies. Prophylactic low-molecular-weight heparin was discontinued. Despite these interventions, the patient continued to have prolonged aPTT and PT, with ongoing mucosal bleeding. Treatment: The patient was administered packed red blood cells, fresh frozen plasma (FFP) and platelets, along with immunosuppressive therapy initially with glucocorticoids (methylprednisolone 40mg daily) and intravenous immunoglobulin (IVIG) at 1g/kg/ day for 2days. Tranexamic acid was also administered intermittently over the next 3days to control acute mucosal bleeding episodes due to concerns regarding airway compromise. The patient's coagulopathy was still not corrected with these interventions. Author followed standard hospital protocol to discuss risk, benefits and alternatives with the patient and his family regarding rituximab use. Following this discussion and obtaining his consent, rituximab was started (375mg/m2 once weekly for 4weeks) and methylprednisolone was continued. His coagulapathy improved with the aPTT and PT trending down slowly. Outcome And Follow-Up : After 4weeks of treatment with rituximab and glucocorticoids, the author observed that the FV level increased from <1% to 15 % and the FV inhibitor level decreased from 184 BU/mL to 2.9 BU/mL The PT decreased from 58.0 s to 27.4 s and the aPTT decreased from >200.0s to 64.9s. By the end of his hospital course on day 65, there was a clear improvement in his overall labs. He was discharged with a prednisone taper, instructions to repeat future labs and close outpatient follow-up. Unfortunately, the patient did not show up to any of his future appointments and was ultimately lost to follow-up even after countless calls. Author stated that patient developed acquired factor V (FV) inhibitor during treatment with tozinameran for COVID-19 immunisation, ceftriaxone, azithromycin, ampicillin and tobramycin and partial vitamin k deficiency during treatment with ceftriaxone, azithromycin, ampicillin and tobramycin for enterococcus faecalis urinary tract infection and pseudomonas aeruginosa pulmonary infection. Additionally, he exhibited lack of efficacy during treatment with vitamin-k for partial vitamin k deficiency. Before admission, he had received 3 doses of tozinameran [pfizer-bioNTech-COVID-19-vaccine] for COVID-19 immunisation. Upon admission, he had stable vital signs and appeared cachectic. He was receiving ceftriaxone, azithromycin, ampicillin and tobramycin for enterococcus faecalis urinary tract infection and pseudomonas aeruginosa pulmonary infection. During hospitalization, he developed oozing at the peripheral and tracheostomy sites and had abnormal coagulation tests. His laboratory investigations revealed an elevated activated partial thromboplastin time (aPTT), an elevated prothrombin time (PT) of 58.0s, an elevated international normalised ratio of 6.7, haemoglobin of 90 g/L, elevated fibrinogen 595 mg/dL, fibrin D dimer 0.42 ug/mL and platelets 240x10^9 /L. Additionally, coagulation factor VII level was 39%, coagulation factor X level of 51% and coagulation factor V level of < 1%. He experienced anaemia of chronic disease. Thus, acquired FV inhibitor secondary to tozinameran, ceftriaxone, azithromycin, ampicillin and tobramycin and partial vitamin k deficiency secondary to ceftriaxone, azithromycin, ampicillin and tobramycin was confirmed. Subsequently, vitamin K was administered for partial vitamin k deficiency. His treatment with unspecified low-molecular-weight-heparins was discontinued. Despite treatment with vitamin K, he continued to had prolonged aPTT and PT, with ongoing mucosal bleeding (lack of efficacy). Thus, he required packed red blood cells, fresh frozen plasma and platelets. Additionally, methylprednisolone, immune-globulin and tranexamic-acid was administered for acquired FV inhibitor. However, he showed mild improvement and partial response. Thus, he started on off label use with rituximab 375 mg/m2 once weekly for 4 weeks and methylprednisolone was continued. His condition improved. After completion of treatment with rituximab and methylprednisolone, he had clear improvement. Subsequently, he was discharged with a prednisone. However, he lost to follow-up. The patient had a severe COVID-19 infection 1.5 years prior, which is unlikely to be causally related to the current presentation. However, he received three subsequent doses of Pfizer-BioNTech COVID-19 vaccines including the booster vaccine approximately 128 days before the diagnosis of his coagulopathy. Follow-up information has been requested. No follow-up attempts are possible.; Sender's Comments: Based on available information, the possible contributory role of suspect products cannot be excluded for the event acquired factor V deficiency. Conversely, it appears unlikely that the event Vitamin K deficiency was related to the BNT162b2 (COMIRNATY) therapy. Use of other co-suspect products may be a confounder. Case will be reassessed should additional information become available. 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.
Chronic obstructive pulmonary disease; Hypertension; Schizoaffective disorder; Type II diabetes mellitus
Medical History/Concurrent Conditions: COVID-19 (severe COVID-19 infection 1.5 years prior); COVID-19 (2 years prior resulting in tracheostomy and gastrostomy tube dependence.); Gastrostomy tube insertion (gastrostomy tube dependence); Tracheostomy tube insertion (tracheostomy tube dependence)
Azithromycin; Tobramycin; CEFTRIAXONE; AMPICILLIN
Test Name: Activated partial thromboplastin time; Result Unstructured Data: Test Result: Continued to have prolonged; Comments: Despite interventions; Test Name: Activated partial thromboplastin time; Result Unstructured Data: Test Result: trending down slowly; Comments: after rituximab and methylprednisolone; Test Name: Activated partial thromboplastin time; Result Unstructured Data: Test Result: more than 200 seconds; Comments: elevated; Test Name: Activated partial thromboplastin time; Test Result: 30.1s; Comments: normal 1 year prior; Test Name: Activated partial thromboplastin time; Test Result: 59s; Comments: A 1:1 mixing study of the patient's plasma and normal pooled plasma did not correct the aPTT immediately; Test Name: Activated partial thromboplastin time; Test Result: 63.7s; Comments: after 60min of incubation (presence of a circulating fast-acting inhibitor); Test Name: Activated partial thromboplastin time; Test Result: 64.9s; Comments: decreased; Test Name: total bilirubin; Result Unstructured Data: Test Result: within normal; Test Name: fibrinogen; Test Result: 595 mg/dl; Comments: elevated; Test Name: folate levels; Result Unstructured Data: Test Result: within normal limits; Test Name: iron panel; Result Unstructured Data: Test Result: consistent with anaemia of chronic disease; Test Name: lactate dehydrogenase; Result Unstructured Data: Test Result: within normal ranges; Test Name: FV inhibitor; Result Unstructured Data: Test Result:184; Comments: Units: [beth'U]/mL; Test Name: FV inhibitor; Result Unstructured Data: Test Result: 2.9; Comments: Units: [beth'U]/mL. After 4weeks of treatment decreased; Test Name: coagulation factor V level; Result Unstructured Data: Test Result: less than 1%; Test Name: FV level; Test Result: 15%; Comments: After 4weeks of treatment increased; Test Name: Coagulation factor VII level; Test Result: 39%; Test Name: coagulation factor X level; Test Result: 51%; Test Name: fibrin D dimer; Result Unstructured Data: Test Result:0.42 ug/ml; Test Name: haemoglobin; Result Unstructured Data: Test Result:90 g/l; Test Name: haptoglobin; Result Unstructured Data: Test Result: within normal ranges; Test Name: liver enzymes; Result Unstructured Data: Test Result: normal; Test Name: viral hepatitis serologies; Test Result: Negative; Test Name: HIV; Test Result: Negative; Test Name: international normalised ratio; Result Unstructured Data: Test Result: 6.7; Comments: Units:{INR} elevated; Test Name: platelets; Result Unstructured Data: Test Result:240 x10 9/l; Test Name: prothrombin time; Result Unstructured Data: Test Result: Continued to have prolonged; Comments: Despite interventions; Test Name: prothrombin time; Result Unstructured Data: Test Result: trending down slowly; Comments: after rituximab and methylprednisolone; Test Name: prothrombin time; Test Result: 58s; Comments: elevated; Test Name: prothrombin time; Test Result: 27.4s; Comments: decreased; Test Name: prothrombin time; Test Result: 12.3s; Comments: normal 1 year prior; Test Name: Peripheral smear; Result Unstructured Data: Test Result: absence of schistocytes; Test Name: thrombin time; Test Result: 17.4s; Comments: normal (indicating normal factor II function) and excluding the presence of a thrombin inhibitor; Test Name: ultrasonography; Result Unstructured Data: Test Result: normal; Test Name: Examination; Result Unstructured Data: Test Result: appeared cachectic, with no signs; Comments: of active bleeding or pallor; Test Name: vital signs; Result Unstructured Data: Test Result: stable and appeared cachectic; Comments: On admission; Test Name: vitamin B12; Result Unstructured Data: Test Result: within normal limits