High Prevalence of Anti-PF4 Antibodies Following ChAdOx1 nCov-19 (AZD1222) Vaccination Even in the Absence of Thrombotic Events

Abstract

It is unclear whether the ChAdOx1 nCov-19 vaccine can induce the development of anti-PF4 antibodies in vaccinated individuals who have not developed thrombosis. The aim of this prospective study was to evaluate the presence of antibodies against heparin/PF4 in adults who received a first dose of the ChAdOx1 nCov-19 vaccine, and correlate them with clinical data and antibody responses to the vaccine. We detected non-platelet activating anti-PF4 antibodies in 67% (29/43) of the vaccinated individuals on day 22 following the first dose of the ChAdOx1 nCov-19 vaccine, though these were detected in low titers. Furthermore, there was no correlation between the presence of anti-PF4 IgG antibodies and the baseline clinical characteristics of the patients. Our findings suggest that the ChAdOx1 nCov-19 vaccine can elicit anti-PF4 antibody production even in recipients without a clinical manifestation of thrombosis. The presence of anti-PF4 antibodies was not sufficient to provoke clinically evident thrombosis. Our results offer an important insight into the ongoing investigations regarding the underlying multifactorial pathophysiology of thrombotic events induced by the ChAdOx1 nCov-19 vaccine.

COVID‐19 coagulopathies: Human blood proteins mimic SARS‐CoV‐2 virus, vaccine proteins and bacterial co‐infections inducing autoimmunity

“…Transient but significant titers of anti‐PF4 antibodies were found in 5.6% of BNT162β (the Pfizer‐Biontech mRNA vaccine) and around 8.0% of ChAdOx1 nCoV‐19 (the AstraZeneca adenovirus 5‐based vaccine) in several studies [ 107 , 108 , 109 ] and low‐titer antibodies in 67% of vaccinees in another AstraZeneca vaccine study. [ 110 ] No one in these studies developed clinically overt coagulopathies, again emphasizing the point that molecular mimicry may induce autoantibodies without inducing autoimmune disease and making antibody positivity studies of limited value in predicting complications. [ 107 , 108 , 109 , 110 , 111 ] However, these transient anti‐PF4 antibodies could result in sub‐clinical interference with blood clotting by blocking PF4's antagonism of heparin, thereby resulting in some SARS‐CoV‐2 vaccinees experiencing longer blood‐clotting times, developing blood blisters or bruises more easily, and causing some women to experience unusually heavy and early menstrual periods.…”

“…[ 110 ] No one in these studies developed clinically overt coagulopathies, again emphasizing the point that molecular mimicry may induce autoantibodies without inducing autoimmune disease and making antibody positivity studies of limited value in predicting complications. [ 107 , 108 , 109 , 110 , 111 ] However, these transient anti‐PF4 antibodies could result in sub‐clinical interference with blood clotting by blocking PF4's antagonism of heparin, thereby resulting in some SARS‐CoV‐2 vaccinees experiencing longer blood‐clotting times, developing blood blisters or bruises more easily, and causing some women to experience unusually heavy and early menstrual periods. [ 112 ] Clinically evident coagulopathy following vaccination does involve PF4 antibodies producing a heparin‐induced thrombocytopenia (HIT)‐like syndrome characterized by activation of platelet aggregation but in the absence of previous exposure to heparin.…”

An Appraisal of the Current Scenario in Vaccine Research for COVID-19

“…Recently, a vaccine efficacy result for AZD1222 with 11,636 participants was reported with an overall vaccine efficacy of 90.0% (67.4%-97%) for those who received two standard doses and 70.4% for those who received one standard dose [120]. Notably, several patients were reported with prothrombotic immune thrombocytopenia after receiving AZD1222 [121][122][123][124]. Patients involved are presented with a thrombotic disorder, including cerebral venous sinus thrombosis, splanchnic vein thrombosis, arterial cerebral thromboembolism, or thrombotic microangiopathy [121][122][123][124].…”

“…Notably, several patients were reported with prothrombotic immune thrombocytopenia after receiving AZD1222 [121][122][123][124]. Patients involved are presented with a thrombotic disorder, including cerebral venous sinus thrombosis, splanchnic vein thrombosis, arterial cerebral thromboembolism, or thrombotic microangiopathy [121][122][123][124]. Furthermore, the hematologic analysis found the presence of anti-platelet factor 4 autoantibodies in patients' sera, which targets healthy donor platelet in an AZD1222 dependent manner, despite no previous history of heparin-induced thrombocytopenia [121][122][123][124].…”

“…Furthermore, the hematologic analysis found the presence of anti-platelet factor 4 autoantibodies in patients' sera, which targets healthy donor platelet in an AZD1222 dependent manner, despite no previous history of heparin-induced thrombocytopenia [121][122][123][124]. Importantly, such aggregation can be resolved and suppressed by heparin [121][122][123][124]. Collectively, AZD1222 demonstrated vaccine efficacy against COVID-19, but its application is associated with severe autoimmune prothrombotic disorders.…”