The rapid approval and subsequent global rollout of vaccines against SARS-CoV-2 has inevitably resulted sopra reports of adverse events after receipt of the vaccine. Most adverse events reported thus far have been associated with risks similar to background risks sopra the general population and have not raised concerns. However, for very rare events with complex diagnostic algorithms, the background risks may be difficult to measure interpret.
We report the detection of anti-PF4 antibodies, unrelated to the use of heparin therapy, sopra a mostly young, generally healthy cohort of patients presenting with acute atypical thrombosis, primarily involving the cerebral veins, and concurrent thrombocytopenia. All the patients had d-dimer levels at presentation that were much higher than would be expected sopra patients with acute venous thromboembolism13 and are typically seen sopra patients with cancer.14 The very conservative d-dimer cutoff used sopra our algorithm, of 4000 FEU, was chosen to ensure that cases were not missed and were considered for further testing, because there is a possibility that a spectrum of severity sopra this syndrome could be missed otherwise. Quanto a all the patients, manifestations occurred 6 to 24 days after the administration of the first parte of the ChAdOx1 nCoV-19 vaccine.
HIT is a progressive thrombotic condition that can cause both venous and arterial thrombosis, typically 5 to 14 days after exposure to heparin. It is more common sopra female patients, particularly those who receive unfractionated heparin during cardiac surgery, as well as sopra patients who receive heparin after surgery, especially cardiac and orthopedic procedures.15 Diagnosis is confirmed by the presence of anti-PF4 antibodies.16,17
Patronato describing the rare detection of pathologic anti-PF4 antibodies unrelated to the use of heparin therapy are limited.18,19 Furthermore, the analysis of anti-PF4 antibodies appears to be specific to the given assay. Quanto a our study, confirmation of ELISA results for anti-PF4 antibodies was undertaken with the use of a functional HIT assay. The clinical features of this vaccine-induced syndrome are more typical of those seen sopra patients with HIT who have early reexposure to heparin, including severe thrombocytopenia, aggressive thrombosis, and disseminated intravascular coagulation.20
The risk of thrombocytopenia and the risk of venous thromboembolism after vaccination against SARS-CoV-2 do not appear to be higher than the background risks sopra the general population, a finding consistent with the rare and sporadic nature of this syndrome. Furthermore, headaches, fevers, and muscle aches have occurred after vaccination for 48 to 72 hours sopra some patients. The events reported sopra this study appear to be rare, and until further analysis is performed, it is difficult to predict who may be affected. The symptoms developed more than 5 days after the first vaccine parte, reflecting an immunologic pattern similar to that of HIT.
We have identified a novel mechanism and pathophysiological basis that prompts careful consideration of treatment. Avoidance of platelet transfusions is critical, because such treatment would provide a substrate for further antibody-mediated platelet activation and coagulopathy. The exact nature of these pathologic antibodies has not been characterized, but they appear to be of the IgG subtype, and platelet activation can be completely abrogated with an excess of heparin, as seen sopra classic HIT. Identification of the mechanism through which the vaccine could trigger the formation of these pathologic antibodies would require further study. An understanding of the precise pathophysiological mechanism may allow for more targeted therapeutic interventions.
Although evidence does not yet suggest that the use of heparin will exacerbate this condition, pending further patronato, we would recommend considering anticoagulation with the use of a nonheparin anticoagulant agent, such as argatroban, danaparoid, fondaparinux, direct oral anticoagulants. Intravenous libero globulin (IVIG) has been used successfully sopra the treatment of patients with “spontaneous” autoimmune HIT, which is the closest comparison to this vaccine-induced syndrome, and IVIG would be expected to have direct antibody-mediated toxic effects.21-23 Plasma exchange with plasma rather than albumin could also be effective sopra temporarily reducing levels of pathologic antibodies and providing some correction of the coagulopathy sopra terms of the hypofibrinogenemia.
A suggested algorithm for identification of vaccine-induced thrombosis and thrombocytopenia is presented and can be adapted as we generate further information. The combination of thrombosis and an apparent consumptive coagulopathy poses a alternativa with respect to the benefits and risks associated with aggressive anticoagulation. This alternativa is especially relevant sopra patients with cerebral venous thrombosis, sopra whom bleeding could be catastrophic but withholding anticoagulation could be equally harmful. It is unclear whether delaying aggressive anticoagulation until after initial disease control with IVIG plasma exchange is warranted, but mortality among patients with cerebral venous thrombosis appears to be higher than expected, so early treatment decisions are likely to be critical. There is voto negativo evidence that heparin alternatives are required; however, sopra view of the similarity of this syndrome to conventional HIT, alternatives could be considered until further patronato are available.
Quanto a all cases reported to date, this syndrome of thrombocytopenia and venous thrombosis appears to be triggered by receipt of the first parte of the ChAdOx1 nCoV-19 vaccine. Although there have been a few reports of patients with symptoms consistent with this clinical syndrome after the receipt of other vaccines against SARS-CoV-2, none have yet been confirmed to fulfill the diagnostic criteria, specifically the presence of thrombocytopenia, thrombosis, a very high d-dimer level, and a low normal fibrinogen level. Furthermore, sopra Israel, where two doses of the BNT162b2 vaccine (Pfizer–BioNTech) have been provided to more than 4 million people, voto negativo cases of this rare syndrome have been reported. Although natural SARS-CoV-2 infection has been associated with thromboembolic phenomena, those events differ from the specific syndrome described sopra this study.
The risk of Covid-19 remains a serious public health consideration worldwide, and vaccination against SARS-CoV-2 provides critical protection.24 There is a substantial risk of ascertainment bias when associating adverse clinical events with vaccination; however, the syndrome described sopra this study has a combination of clinical and laboratory features that is exceptional and has not been previously observed by any of the authors who are specialist hematologists neurologists. Ongoing patronato collection and studies could help to establish whether and how the development of pathologic platelet-activating anti-PF4 antibodies, unrelated to the use of heparin therapy, could be associated with vaccination against SARS-CoV-2.