ABSTRACT
Introduction: Acquired haemophilia A (AHA) is a rare, haematological disorder characterized by the development of autoantibodies to Anti-Factor VIII (FVIII), which can cause spontaneous hemorrhage 1. During 2021, some authors reported an unusual and unexpected number of AHA diagnoses that were temporally related to COVID-19 vaccination2,3 Objective: To explore a possible signal of risk of AHA associated with COVID-19 immunization. Method(s): We performed a disproportionality analysis on the World Health Organization (WHO) database (VigiBase-) to investigate the presence of a signal of risk for AHA associated with COVID-19 vaccines. We calculated the information component (IC) for all the COVID-19 vaccines and for single COVID-19 vaccine product using the entire database as reference. Reports of AHA have been systematically reviewed all the selected cases to check for clinical plausibility Results: In Vigibase, we identified 150 cases of suspected AHA associated with COVID-19 vaccines (146 included the PT ''acquired haemophilia''). Only three vaccine products have been reported as suspected causative agents for AHA. The disproportionality analysis showed a significant IC for the Preferred term ''Acquired haemophilia'' associated with all COVID-19 vaccines (IC: 1.3;IC025: 1.1) and with the vaccine product BNT162b2 (IC: 1.9;IC025: 1.6). After the integration with data available on VAERS and on the medical literature, and after the elimination of duplicates, 96 unique cases of AHA following COVID-19 vaccines (mostly mRNA vaccines) have been reviewed. Overall, about 22% of cases occurred in patients B 65 and no case associated with pregnancy was reported. Patients with at least one pre-existing condition that can be considered a risk factor for AHA (history of AHA, cancer, autoimmune disorder) were 20 (21%). A pre-existing condition predisposing to AHA was excluded in 57 (59%) of cases and not reported in 19 (20%) cases. The outcome was death in 10 (11%) patients and complete resolution or recovering in 39 (41%) patients with a single resolution without specific AHA treatment. Median time from last vaccine dose to diagnosis was 18 days and 40% of cases documented the occurrence after the second dose. Conclusion(s): Our disproportionality analysis confirmed a reporting risk for AHA associated with COVID-19 vaccines. The case review analysis identified several good-quality reports of AHA for which no alternative causes other than COVID-19 immunization can be considered. Although detection bias should be considered to explain the unexpected frequency of AHA in the population, the signal identified is robust and deserves further investigation.
ABSTRACT
Introduction: Hypertension is a serious disease that occurs when blood pressure is persistently elevated over time1. During the COVID- 19 vaccination campaign, several reports of hypertension occurred in plausible temporal relationship with immunization have been reported. Objective(s): To explore a possible signal of risk of hypertension associated with COVID-19 immunization using VigiBase the World Health Organization (WHO) pharmacovigilance database and to review the evidence available from real world. Method(s): We performed a disproportionality analysis using data on spontaneous reports recorded in VigiBase-. Data have been extract on May 8th, 2022. We calculated reporting odds ratio (ROR) as a measure of disproportionality for hypertension defined by the Standardized Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ) narrow. ROR was estimated for all reports including the MedDRA preferred term (PT) ''hypertension'', ''blood pressure increased'' and ''hypertensive crisis'' (cases). All other reports have been defined as non-cases. All reports in which the suspected causative agent was a COVID-19 vaccine were used as index reports and all other reports as reference. A signal was defined by at least three reports of the PT of interest and ROR025>1. We reviewed the medical literature using MEDLINE from January 2021 to May 2022 using ''COVID-19 vaccines'' AND ''hypertension'' as a search terms to check for evidence from observational studies. Result(s): As of May 8th, 2022, VigiBase included 3,746,090 reports of adverse events following immunization for COVID-19 vaccines and 87,653 de-duplicated reports of hypertension define by the SMQ. We identified 34,955 reports of ''hypertension'' (ROR:1.3;ROR025:1.2), 47,733 reports of ''blood pressure increased'' (ROR:2.6;ROR025:2.6) and 3,741 reports of ''hypertensive crisis'' (ROR:4.0;ROR025:3.8) in which a COVID-19 vaccine was indicated as suspected causative agent. Most frequently co-reported symptoms (>9%) included headache (n = 16.817;19.2%), dizziness (n = 12,892;14.7%), fatigue (n = 8,406;9.6%). Overall, 75% of cases (n = 65,761) have been classified as not serious. A meta-analysis of observational studies that includes 357,387 individuals reported 13,444 events of blood pressure abnormal or increased2. These events have been often described as short periods of hypertensive response and often observed in patients with risk factors. Conclusion(s): Our results confirmed a signal of risk of events of elevated blood pressure following immunization with COVID-19 vaccines. However, there is no evidence that these episodes could result in serious complication typically associated with hypertension, such as stroke, aneurysms, heart failure, myocardial infarction and chronic kidney disease.
ABSTRACT
Introduction: During large-scale vaccination campaign against COVID-19, the Italian Medicines Agency (AIFA) in collaboration with the Regional Centres of Pharmacovigilance have carried out a closely monitoring of Individual Case Safety Reports (ICSRs) about Adverse Event Following Immunisation (AEFIs) related to COVID- 19 vaccines and have assured a constant communication through public monthly reports1. During the first months of the vaccination campaign, a signal of rare events of thrombosis associated with thrombocytopenia2, particularly in young women, was detected by health authorities associated with the viral vector vaccines ChAdOx1- S and Ad26.COV2-S. Objective(s): To present a comprehensive assessment of thrombotic and thromboembolic events associated with thrombocytopenia following COVID-19 immunisation with viral vector vaccines recorded in the Italian National Pharmacovigilance Network database Methods: We selected all ICSRs reported from 27 December 2020 to 26 December 2021 containing Preferred Terms (PT) related to platelet count reduction associated with PT related to thrombotic and thromboembolic events (clinical symptoms and/or diagnostic tests). All cases of thrombotic and thromboembolic events reporting thrombocytopenia in the narrative description of the report were also reviewed. The selected ICRSs were submitted to the independent evaluation of three pharmacovigilance experts who blindly classified into 5 levels of diagnostic certainty, according to the definition provided by the Brighton Collaboration Group (BCG)3. Disagreement were resolved by plenary discussion. Result(s): 12,166,236 doses of ChAdOx1-S and 1,500,746 of Ad26.COV2-S have been administered in Italy during the considered interval with overall 23,358/117,947 ICSRs related to ChAdOx1-S (19.8 %) and 1,580/117,947 related to Ad26.COV2-S (1.3 %). A total of 134 reports after vaccination with adenoviral vaccines were identified according to the inclusion criteria, of which 107 cases were defined as thrombotic thrombocytopenia (95 following ChAdOx1-S and 12 after Ad26.COV2-S). 27 reports were defined as ''not case'' (level 5, Brighton) on the basis of clinical examination or investigation, or because of the presence of heparin as a concomitant drug. Furthermore, 3 reports were excluded because of a hereditary thrombophilia or a previous history of other thrombotic episodes. Seventy-seven cases were classifiable as BCG levels 1, 2, and 3 (definite, probable and possible cases, respectively) with an overall reporting rate at about 1 case per approximately 200,000 doses administered. Women aged 30 to 49 years showed the highest reporting rates. Conclusion(s): In Italy, the rates of thrombotic thrombocytopenia following COVID-19 immunisation with viral vector vaccines are in line with those reported in other Countries.
ABSTRACT
Introduction: Acquired haemophilia A (AHA) is a rare, haematological disorder characterized by the development of autoantibodies to Anti-Factor VIII (FVIII), which can cause spontaneous hemorrhage 1. During 2021, some authors reported an unusual and unexpected number of AHA diagnoses that were temporally related to COVID-19 vaccination2,3 Objective: To explore a possible signal of risk of AHA associated with COVID-19 immunization. Methods: We performed a disproportionality analysis on the World Health Organization (WHO) database (VigiBase) to investigate the presence of a signal of risk for AHA associated with COVID-19 vaccines. We calculated the information component (IC) for all the COVID-19 vaccines and for single COVID-19 vaccine product using the entire database as reference. Reports of AHA have been systematically reviewed all the selected cases to check for clinical plausibility Results: In Vigibase, we identified 150 cases of suspected AHA associated with COVID-19 vaccines (146 included the PT "acquired haemophilia"). Only three vaccine products have been reported as suspected causative agents for AHA. The disproportionality analysis showed a significant IC for the Preferred term "Acquired haemophilia" associated with all COVID-19 vaccines (IC: 1.3;IC025: 1.1) and with the vaccine product BNT162b2 (IC: 1.9;IC025: 1.6). After the integration with data available on VAERS and on the medical literature, and after the elimination of duplicates, 96 unique cases of AHA following COVID-19 vaccines (mostly mRNA vaccines) have been reviewed. Overall, about 22% of cases occurred in patients B 65 and no case associated with pregnancy was reported. Patients with at least one pre-existing condition that can be considered a risk factor for AHA (history of AHA, cancer, autoimmune disorder) were 20 (21%). A pre-existing condition predisposing to AHA was excluded in 57 (59%) of cases and not reported in 19 (20%) cases. The outcome was death in 10 (11%) patients and complete resolution or recovering in 39 (41%) patients with a single resolution without specific AHA treatment. Median time from last vaccine dose to diagnosis was 18 days and 40% of cases documented the occurrence after the second dose. Conclusion: Our disproportionality analysis confirmed a reporting risk for AHA associated with COVID-19 vaccines. The case review analysis identified several good-quality reports of AHA for which no alternative causes other than COVID-19 immunization can be considered. Although detection bias should be considered to explain the unexpected frequency of AHA in the population, the signal identified is robust and deserves further investigation.
ABSTRACT
Introduction: Hypertension is a serious disease that occurs when blood pressure is persistently elevated over time1. During the COVID19 vaccination campaign, several reports of hypertension occurred in plausible temporal relationship with immunization have been reported. Objective: To explore a possible signal of risk of hypertension associated with COVID-19 immunization using VigiBase® the World Health Organization (WHO) pharmacovigilance database and to review the evidence available from real world. Methods: We performed a disproportionality analysis using data on spontaneous reports recorded in VigiBase®. Data have been extract on May 8th, 2022. We calculated reporting odds ratio (ROR) as a measure of disproportionality for hypertension defined by the Standardized Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ) narrow. ROR was estimated for all reports including the MedDRA preferred term (PT) "hypertension", "blood pressure increased" and "hypertensive crisis" (cases). All other reports have been defined as non-cases. All reports in which the suspected causative agent was a COVID-19 vaccine were used as index reports and all other reports as reference. A signal was defined by at least three reports of the PT of interest and ROR025 > 1. We reviewed the medical literature using MEDLINE from January 2021 to May 2022 using "COVID-19 vaccines" AND "hypertension" as a search terms to check for evidence from observational studies. Results: As of May 8th, 2022, VigiBase® included 3,746,090 reports of adverse events following immunization for COVID-19 vaccines and 87,653 de-duplicated reports of hypertension define by the SMQ. We identified 34,955 reports of "hypertension" (ROR:1.3;ROR025:1.2), 47,733 reports of "blood pressure increased" (ROR:2.6;ROR025:2.6) and 3,741 reports of "hypertensive crisis" (ROR:4.0;ROR025:3.8) in which a COVID-19 vaccine was indicated as suspected causative agent. Most frequently co-reported symptoms (> 9%) included headache (n = 16.817;19.2%), dizziness (n = 12,892;14.7%), fatigue (n = 8,406;9.6%). Overall, 75% of cases (n = 65,761) have been classified as not serious. A meta-analysis of observational studies that includes 357,387 individuals reported 13,444 events of blood pressure abnormal or increased2. These events have been often described as short periods of hypertensive response and often observed in patients with risk factors. Conclusion: Our results confirmed a signal of risk of events of elevated blood pressure following immunization with COVID-19 vaccines. However, there is no evidence that these episodes could result in serious complication typically associated with hypertension, such as stroke, aneurysms, heart failure, myocardial infarction and chronic kidney disease.
ABSTRACT
Introduction: During large-scale vaccination campaign against COVID-19, the Italian Medicines Agency (AIFA) in collaboration with the Regional Centres of Pharmacovigilance have carried out a closely monitoring of Individual Case Safety Reports (ICSRs) about Adverse Event Following Immunisation (AEFIs) related to COVID19 vaccines and have assured a constant communication through public monthly reports1. During the first months of the vaccination campaign, a signal of rare events of thrombosis associated with thrombocytopenia2, particularly in young women, was detected by health authorities associated with the viral vector vaccines ChAdOx1S S Ad26.COV2-S. Objective: To present a comprehensive assessment of thrombotic and thromboembolic events associated with thrombocytopenia following COVID-19 immunisation with viral vector vaccines recorded in the Italian National Pharmacovigilance Network database Methods: We selected all ICSRs reported from 27 December 2020 to 26 December 2021 containing Preferred Terms (PT) related to platelet count reduction associated with PT related to thrombotic and thromboembolic events (clinical symptoms and/or diagnostic tests). All cases of thrombotic and thromboembolic events reporting thrombocytopenia in the narrative description of the report were also reviewed. The selected ICRSs were submitted to the independent evaluation of three pharmacovigilance experts who blindly classified into 5 levels of diagnostic certainty, according to the definition provided by the Brighton Collaboration Group (BCG)3. Disagreement were resolved by plenary discussion. Results: 12,166,236 doses of ChAdOx1-S and 1,500,746 of Ad26.COV2-S have been administered in Italy during the considered interval with overall 23,358/117,947 ICSRs related to ChAdOx1-S (19.8 %) and 1,580/117,947 related to Ad26.COV2-S (1.3 %). A total of 134 reports after vaccination with adenoviral vaccines were identified according to the inclusion criteria, of which 107 cases were defined as thrombotic thrombocytopenia (95 following ChAdOx1-S and 12 after Ad26.COV2-S). 27 reports were defined as "not case" (level 5, Brighton) on the basis of clinical examination or investigation, or because of the presence of heparin as a concomitant drug. Furthermore, 3 reports were excluded because of a hereditary thrombophilia or a previous history of other thrombotic episodes. Seventy-seven cases were classifiable as BCG levels 1, 2, and 3 (definite, probable and possible cases, respectively) with an overall reporting rate at about 1 case per approximately 200,000 doses administered. Women aged 30 to 49 years showed the highest reporting rates. Conclusion: In Italy, the rates of thrombotic thrombocytopenia following COVID-19 immunisation with viral vector vaccines are in line with those reported in other Countries.
ABSTRACT
On late December 2019, an outbreak of a novel coronavirus (SARS-CoV-2) causing severe pneumonia (COVID-19) was reported in Wuhan, Hubei Province, China and then in all around the world. Data suggest that a lung-centric and systemic coagulopathy may play an important role. Elevated D-dimer levels which correlated inversely with overall survival were recently reported in Chinese studies. Critically however, severe COVID-19 infection is associated with a significant coagulopathy that correlates with disease severity and a 3-4-fold higher mortality risk. COVID-19 patients with acute respiratory failure present a severe hypercoagulability rather than consumptive coagulopathy. Fibrin formation and polymerization may predispose to thrombosis and correlate with a worse outcome. However, increasing the prophylaxis towards high prophylactic doses to the patients admitted to the ICU, going from enoxaparin 40 mg OD to 40 mg BID, prevents major vascular complications and reduces mortality rate.