PF4 Immunoassays in Vaccine-Induced Thrombotic Thrombocytopenia.
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ABSTRACT:
SUBMITTER: Vayne C
PROVIDER: S-EPMC8174029 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Life-threatening thrombotic events at unusual sites have been reported after vector-based vaccinations against severe acute respiratory syndrome coronavirus 2. This phenomenon is now termed vaccine-induced immune thrombotic thrombocytopenia (VITT). The pathophysiology of VITT is similar to that of heparin-induced thrombocytopenia (HIT) and is associated with platelet-activating antibodies (Abs) against platelet factor 4 (PF4). Therefore, current guidelines suggest nonheparin anticoagulants to treat VITT patients. In this study, we investigated the interactions of heparin, danaparoid, fondaparinux, and argatroban with VITT-Ab/PF4 complexes using an ex vivo model for thrombus formation as well as in vitro assays to analyze Ab binding and platelet activation. We found that immunoglobulin Gs (IgGs) from VITT patients induce increased adherent platelets/thrombus formation in comparison with IgGs from healthy controls. In this ex vivo flow-based model, the procoagulant activity of VITT IgGs was effectively inhibited with danaparoid and argatroban but also by heparin. Interestingly, heparin and danaparoid not only inhibited IgG binding to PF4 but were also able to effectively dissociate the preformed PF4/IgG complexes. Fondaparinux reduced the in vitro generation of procoagulant platelets and thrombus formation; however, it did not affect platelet aggregation. In contrast, argatroban showed no effect on procoagulant platelets and aggregation but significantly inhibited VITT-mediated thrombus formation. Taken together, our data indicate that negatively charged anticoagulants can disrupt VITT-Ab/PF4 interactions, which might serve as an approach to reduce Ab-mediated complications in VITT. Our results should be confirmed, however, in a clinical setting before a recommendation regarding the selection of anticoagulants in VITT patients could be made.
| S-EPMC8949646 | biostudies-literature
Project description:In response to the COVID-19 pandemic, vaccines for SARS-CoV-2 were developed, tested, and introduced at a remarkable speed. Although the vaccine introduction had a major impact on the evolution of COVID-19, some potential rare side-effects of the vaccines were observed. Within a short period, three scientific groups from Norway, Germany, and the UK reported cerebral venous sinus thrombosis with thrombocytopenia and anti-platelet factor 4 (anti-PF4) antibodies in individuals following AstraZeneca-Oxford vaccination and named this new syndrome vaccine-induced immune thrombotic thrombocytopenia (VITT). This syndrome was subsequently reported in individuals who received Johnson & Johnson vaccination. In this Viewpoint, we discuss the epidemiology, pathophysiology, and optimal diagnostic and therapeutic management of VITT. Presentation of an individual with possible VITT should raise prompt testing for anti-PF4 antibodies and initiation of treatment targeting autoimmune processes with intravenous immunoglobulin and prothrombotic processes with non-heparin anticoagulation.
| S-EPMC8585488 | biostudies-literature
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| S-EPMC8063912 | biostudies-literature
Project description:The novel coronavirus pandemic has taken a toll on the global healthcare systems and economy. Safety precautions, along with vaccination, are the most effective preventive measures. The global vaccination program against COVID-19 has dramatically reduced the number of deaths and cases. However, the incidence of thrombotic events and thrombocytopenia post-COVID-19 vaccination known as vaccine-induced thrombotic thrombocytopenia has raised safety concerns. This has led to an element of vaccine hesitancy. The exact mechanism for vaccine-induced thrombotic thrombocytopenia is unknown. Although the incidence of thrombosis associated with COVID-19 vaccination is low, it still requires attention, especially in older people, smokers, and people with preexisting comorbidities. This study aims to review the pathophysiology, diagnosis, and management of vaccine-induced thrombotic thrombocytopenia, to provide a concise and comprehensive update.
| S-EPMC8556865 | biostudies-literature
Project description: Not available
| S-EPMC8279091 | biostudies-literature
Project description:The use of high-dose intravenous immune globulin (IVIG) plus anticoagulation is recommended for the treatment of vaccine-induced immune thrombotic thrombocytopenia (VITT), a rare side effect of adenoviral vector vaccines against coronavirus disease 2019 (Covid-19). We describe the response to IVIG therapy in three of the first patients in whom VITT was identified in Canada after the receipt of the ChAdOx1 nCoV-19 vaccine. The patients were between the ages of 63 and 72 years; one was female. At the time of this report, Canada had restricted the use of the ChAdOx1 nCoV-19 vaccine to persons who were 55 years of age or older on the basis of reports that VITT had occurred primarily in younger persons. Two of the patients in our study presented with limb-artery thrombosis; the third had cerebral venous and arterial thrombosis. Variable patterns of serum-induced platelet activation were observed in response to heparin and platelet factor 4 (PF4), indicating the heterogeneity of the manifestations of VITT in serum. After the initiation of IVIG, reduced antibody-induced platelet activation in serum was seen in all three patients. (Funded by the Canadian Institutes of Health Research.).
| S-EPMC8362588 | biostudies-literature
Project description:In the spring of 2021, reports of rare and unusual venous thrombosis in association with the ChAdOx1 and Ad26.COV2.S adenovirus-based coronavirus vaccines led to a brief suspension of their use by several countries. Thromboses in the cerebral and splanchnic veins among patients vaccinated in the preceding 4 weeks were described in 17 patients out of 7.98 million recipients of the Ad26.COV2.S vaccine (with 3 fatalities related to cerebral vein thrombosis) and 169 cases of cerebral vein thrombosis among 35 million ChAdOx1 recipients. Events were associated with thrombocytopenia and anti-PF4 (antibodies directed against platelet factor 4), leading to the designation vaccine-induced immune thrombotic thrombocytopenia. Unlike the related heparin-induced thrombotic thrombocytopenia, with an estimated incidence of <1:1000 patients treated with heparin, and a mortality rate of 25%, vaccine-induced immune thrombotic thrombocytopenia has been reported in 1:150 000 ChAdOx1 recipients and 1:470 000 Ad26.COV.2 recipients, with a reported mortality rate of 20% to 30%. Early recognition of this complication should prompt testing for anti-PF4 antibodies and acute treatment targeting the autoimmune and prothrombotic processes. Intravenous immunoglobulin (1 g/kg for 2 days), consideration of plasma exchange, and nonheparin anticoagulation (argatroban, fondaparinux) are recommended. In cases of cerebral vein thrombosis, one should monitor for and treat the known complications of venous congestion as they would in patients without vaccine-induced immune thrombotic thrombocytopenia. Now that the Ad26.COV2.S has been reapproved for use in several countries, it remains a critical component of our pharmacological armamentarium in stopping the spread of the human coronavirus and should be strongly recommended to patients. At this time, the patient and community-level benefits of these two adenoviral vaccines vastly outweigh the rare but serious risks of vaccination. Due to the relatively low risk of severe coronavirus disease 2019 (COVID-19) in young women (<50 years), it is reasonable to recommend an alternative vaccine if one is available. Ongoing postmarketing observational studies are important for tracking new vaccine-induced immune thrombotic thrombocytopenia cases and other rare side effects of these emergent interventions.
| S-EPMC8378439 | biostudies-literature
Project description:Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare yet serious adverse effect of the adenoviral vector vaccines ChAdOx1 nCoV-19 (AstraZeneca) and Ad26.COV2.S (Janssen) against COVID-19. The mechanisms involved in clot formation and thrombocytopenia in VITT are yet to be fully determined. Here we show neutrophils undergoing NETosis and confirm expression markers of NETs in VITT patients. VITT antibodies directly stimulate neutrophils to release NETs and induce thrombus formation containing abundant platelets, neutrophils, fibrin, extracellular DNA and citrullinated histone H3 in a flow microfluidics system and in vivo. Inhibition of NETosis prevents VITT-induced thrombosis in mice but not thrombocytopenia. In contrast, in vivo blockage of FcγRIIa abrogates both thrombosis and thrombocytopenia suggesting these are distinct processes. Our findings indicate that anti-PF4 antibodies activate blood cells via FcγRIIa and are responsible for thrombosis and thrombocytopenia in VITT. Future development of NETosis and FcγRIIa inhibitors are needed to treat VITT and similar immune thrombotic thrombocytopenia conditions more effectively, leading to better patient outcomes.
| S-EPMC9441824 | biostudies-literature
Project description:BackgroundVaccine-induced thrombotic thrombocytopenia (VITT) is a rare but devastating adverse event following adenoviral vector-based vaccinations for COVID-19, resulting in thrombosis, especially of the cerebral and splanchnic vasculature. Despite the progress in laboratory techniques for early diagnosis, VITT remains a clinical diagnosis supplemented by coagulation studies. We report on VITT for the first time from India.CaseWe describe cortical venous sinus thrombosis and intracerebral bleed associated with severe thrombocytopenia in two young men who had no other contributory cause besides a recent ChAdOx1 nCoV-19 vaccination. The diagnosis was supported with PF-4 antibodies in one patient. The second patient's test could not be processed to technical limitations. Both patients were treated with IVIG at 1 g/kg for 2 days and anticoagulation (Apixaban). One patient fully recovered with no residual deficits, and the other is under treatment and recovering.ConclusionVITT can cause devastating fatality and morbidity in otherwise healthy patients via potential immune-mediated effects. Clinicians should have a high suspicion index and treat VITT in the appropriate setting even if the PF-4 antibody testing by ELISA is unavailable or delayed. Though counterintuitive, clinicians must not delay the administration of non-heparin anticoagulation, IVIG and restrict platelet transfusion even in the presence of intracerebral haemorrhage.
| S-EPMC8894558 | biostudies-literature
Project description:Vaccines to combat SARS-CoV-2 infection and the COVID-19 pandemic were quickly developed due to significant and combined efforts by the scientific community, government agencies, and private sector pharmaceutical and biotechnology companies. Following vaccine development, which took less than a year to accomplish, randomized placebo controlled clinical trials enrolled almost 100,000 people, demonstrating efficacy and no major safety signals. Vaccination programs were started, but shortly thereafter a small number of patients with a constellation of findings including thrombosis in unusual locations, thrombocytopenia, elevated D-dimer and often low fibrinogen led another intense and concentrated scientific effort to understand this syndrome. It was recognized that this occurred within a short time following administration of adenoviral vector SARS-CoV-2 vaccines. Critical to the rapid understanding of this syndrome was prompt communication among clinicians and scientists and exchange of knowledge. Now known as vaccine-induced immune thrombotic thrombocytopenia syndrome (VITT), progress has been made in understanding the pathophysiology of the syndrome, with the development of diagnostic criteria, and most importantly therapeutic strategies needed to effectively treat this rare complication of adenoviral vector vaccination. This review will focus on the current understanding of the pathophysiology of VITT, the findings that affected patients present with, and the rational for therapies, including for patients with cancer, as prompt recognition, diagnosis, and treatment of this syndrome has resulted in a dramatic decrease in associated mortality.
| S-EPMC9133965 | biostudies-literature