A Three-Case Series of Thrombotic Deaths in Patients over 50 with Comorbidities Temporally after modRNA COVID-19 Vaccination

Abstract

Coronavirus disease 2019 (COVID-19) is the most dramatic pandemic of the new millennium; to counteract it, specific vaccines have been launched in record time under emergency use authorization or conditional marketing authorization by virtue of a favorable risk/benefit balance. Among the various technological platforms, there is that exploiting a nucleoside-modified messenger RNA (modRNA), such as Comirnaty®, and that which is adenoviral vector-based. In the ongoing pharmacovigilance, the product information of the latter has been updated about the risk of thrombotic thrombocytopenia, venous thromboembolism without thrombocytopenia and immune thrombocytopenia without thrombosis. However, from an in-depth literature review, the same adverse events can rarely occur with modRNA vaccines too. In support of this, we here report a three-case series of thrombotic deaths in patients over 50 with comorbidities temporally after Comirnaty®, investigated by means of post-mortem histopathology and immunohistochemistry. In two out of three cases, the cause of death is traced back to pulmonary microthromboses rich in activated platelets, quite similar morphologically to those described in patients who died from severe COVID-19. Even if remote in the face of millions of administered doses, clinicians should be aware of the possible thrombotic risk also after Comirnaty®, in order to avoid a misdiagnosis with potentially lethal consequences. Since COVID-19 vaccines are inoculated in subjects to be protected, maximum attention must be paid to their safety, and prophylactic measures to increase it are always welcome. In light of the evidence, the product information of modRNA COVID-19 vaccines should be updated about the thrombotic risk, as happened for adenoviral vector-based vaccines.

Safety Profiles of mRNA COVID-19 Vaccines Using World Health Organization Global Scale Database (VigiBase): A Latent Class Analysis

“…As a possible mechanism for thromboembolic events, massive platelet activation through platelet factor 4 has been proposed [ 30 ]. Prior studies have also reported thrombotic events after the onset of respiratory symptoms, which is consistent with cluster 3, which consisted primarily of patients ≥ 65 years (29.6% of cluster 3) [ 28 , 29 ]. Thus, physicians need to monitor patients who complain of respiratory symptoms for the possibility of further thrombotic events.…”

“…Therefore, we labeled cluster 3 as “respiratory/thrombotic AEs.” Moreover, cluster 3 showed a high proportion of vascular disorders, including pulmonary embolism, deep vein thrombosis, and thrombosis, along with respiratory disorders. Previous case reports have reported thrombotic death immediately after the onset of symptoms of dyspnea [ 28 ] and deep vein thrombosis [ 29 ] following administration of mRNA COVID-19 vaccines. As a possible mechanism for thromboembolic events, massive platelet activation through platelet factor 4 has been proposed [ 30 ].…”

A Real-World Nationwide Study on COVID-19 Trend in Italy during the Autumn–Winter Season of 2020 (before Mass Vaccination) and 2021 (after Mass Vaccination) Integrated with a Retrospective Analysis of the Mortality Burden per Year

“…Scientific proof of the possible complications, even fatal, in young people due to COVID-19 vaccination lies in vaccine-induced immune thrombotic thrombocytopenia (VITT), a new blood clotting syndrome initially described in association with adenovirus vector-based COVID-19 vaccines [ 22 , 23 , 24 ]. VITT is characterized by both arterial and venous thrombotic events in unusual sites, such as splanchnic veins and cerebral venous sinus, accompanied by low platelets count (<150 × 10 3 /mm 3 ), markedly elevated D-dimer (>4 times upper limit of normal), and positive Platelet Factor 4 (PF4) Heparin-Induced Thrombocytopenia (HIT) Enzyme-Linked Immuno-Sorbent Assay (ELISA), 4–42 days after vaccine administration; pulmonary embolism and disseminated intravascular coagulation may also occur [ 25 ]. Among the lab tests available today for the detection of pathological platelet-activating antibodies against PF4, that is to say, VITT triggers, HIT ELISA is the one with the greatest validity and reliability and with the most appropriate sensitivity, reaching around 95% [ 25 ].…”

“…VITT is characterized by both arterial and venous thrombotic events in unusual sites, such as splanchnic veins and cerebral venous sinus, accompanied by low platelets count (<150 × 10 3 /mm 3 ), markedly elevated D-dimer (>4 times upper limit of normal), and positive Platelet Factor 4 (PF4) Heparin-Induced Thrombocytopenia (HIT) Enzyme-Linked Immuno-Sorbent Assay (ELISA), 4–42 days after vaccine administration; pulmonary embolism and disseminated intravascular coagulation may also occur [ 25 ]. Among the lab tests available today for the detection of pathological platelet-activating antibodies against PF4, that is to say, VITT triggers, HIT ELISA is the one with the greatest validity and reliability and with the most appropriate sensitivity, reaching around 95% [ 25 ]. Although these adverse events are very rare, they exceeded what would be expected in the general population [ 26 ].…”

Histopathologically TMA-like distribution of multiple organ thromboses following the initial dose of the BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech): an autopsy case report

“…Among the few autopsy case reports that include histopathological analysis of HIT [30][31][32][33], the lung and gastrointestinal tract are reported as the main thrombosis sites in HIT. TTS/VITT, which is suspected to be associated with autoimmune HIT, develops 4 to 28 days after vaccination and causes thrombosis characteristically in atypical sites such as the cerebral venous sinus, hepatic vein, and splenic vein [34][35][36][37][38][39][40]. Although the thrombi in CAPS share an organ distribution similar to that of our case [41][42][43][44], thrombi in CAPS form regardless of the shear stress in arterioles and/or capillaries; thus, it might be difficult to explain our four characteristics findings.…”