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Intern Med J ; 52(5): 717-723, 2022 05.
Article in English | MEDLINE | ID: covidwho-1816561


Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare, but serious, syndrome characterised by thrombocytopenia, thrombosis, a markedly raised D-dimer and the presence of anti-platelet factor-4 (PF4) antibodies following COVID-19 adenovirus vector vaccination. VITT occurs at a rate of approximately 2 per 100 000 first-dose vaccinations and appears exceedingly rare following second doses. Our current understanding of VITT pathogenesis is based on the observations that patients with VITT have antibodies that bind to PF4 and have the ability to form immune complexes that induce potent platelet activation. However, the precise mechanisms that lead to pathogenic VITT antibody development remain a source of active investigation. Thrombosis in VITT can manifest in any vascular bed and affect multiple sites simultaneously. While there is a predilection for splanchnic and cerebral venous sinus thrombosis, VITT also commonly presents with deep vein thrombosis and pulmonary embolism. Pillars of management include anticoagulation with a non-heparin anticoagulant, intravenous immunoglobulin and 'rescue' therapies, such as plasma exchange for severe cases. VITT can be associated with a high mortality rate and significant morbidity, but awareness and optimal therapy have significantly improved outcomes in Australia. A number of questions remain unanswered, including why VITT is so rare, reasons for the predilection for thrombosis in unusual sites, how long pathological antibodies persist, and the optimal duration of anticoagulation. This review will provide an overview of the presentation, diagnostic workup and management strategies for patients with VITT.

COVID-19 , Thrombocytopenia , Thrombosis , Vaccines , Anticoagulants/adverse effects , COVID-19 Vaccines/adverse effects , Humans , Platelet Factor 4/adverse effects , SARS-CoV-2 , Thrombocytopenia/chemically induced , Thrombosis/chemically induced , Thrombosis/complications , Vaccines/adverse effects
Circ Res ; 130(8): 1187-1203, 2022 04 15.
Article in English | MEDLINE | ID: covidwho-1789065


The risk of stroke and cerebrovascular disease complicating infection with SARS-CoV-2 has been extensively reported since the onset of the pandemic. The striking efforts of many scientists in cooperation with regulators and governments worldwide have rapidly brought the development of a large landscape of vaccines against SARS-CoV-2. The novel DNA and mRNA vaccines have offered great flexibility in terms of antigen production and led to an unprecedented rapidity in effective and safe vaccine production. However, as mass vaccination has progressed, rare but catastrophic cases of thrombosis have occurred in association with thrombocytopenia and antibodies against PF4 (platelet factor 4). This catastrophic syndrome has been named vaccine-induced immune thrombotic thrombocytopenia. Rarely, ischemic stroke can be the symptom onset of vaccine-induced immune thrombotic thrombocytopenia or can complicate the course of the disease. In this review, we provide an overview of stroke and cerebrovascular disease as a complication of the SARS-CoV-2 infection and outline the main clinical and radiological characteristics of cerebrovascular complications of vaccinations, with a focus on vaccine-induced immune thrombotic thrombocytopenia. Based on the available data from the literature and from our experience, we propose a therapeutic protocol to manage this challenging condition. Finally, we highlight the overlapping pathophysiologic mechanisms of SARS-CoV-2 infection and vaccination leading to thrombosis.

COVID-19 , Stroke , Thrombocytopenia , Thrombosis , Vaccines , COVID-19/complications , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Platelet Factor 4/adverse effects , SARS-CoV-2 , Stroke/epidemiology , Stroke/etiology , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis , Thrombosis/etiology , Vaccination/adverse effects , Vaccines/adverse effects
Semin Hematol ; 59(2): 108-114, 2022 04.
Article in English | MEDLINE | ID: covidwho-1778659


In hundreds of patients worldwide, vaccination against COVID-19 with adenovirus vector vaccines (ChAdOx1 nCoV-19; Ad26.COV2.S) triggered platelet-activating anti-platelet factor 4 (PF4) antibodies inducing vaccine-induced immune thrombotic thrombocytopenia (VITT). In most VITT patients, platelet-activating anti-PF4-antibodies are transient and the disorder is discrete and non-recurring. However, in some patients platelet-activating antibodies persist, associated with recurrent thrombocytopenia and sometimes with relapse of thrombosis despite therapeutic-dose anticoagulation. Anti-PF4 IgG antibodies measured by enzyme-immunoassay (EIA) are usually detectable for longer than platelet-activating antibodies in functional assays, but duration of detectability is highly assay-dependent. As more than 1 vaccination dose against COVID-19 is required to achieve sufficient protection, at least 69 VITT patients have undergone subsequent vaccination with an mRNA vaccine, with no relevant subsequent increase in anti-PF4 antibody titers, thrombocytopenia, or thrombotic complications. Also, re-exposure to adenoviral vector-based vaccines in 5 VITT patients was not associated with adverse reactions. Although data are limited, vaccination against influenza also appears to be safe. SARS-CoV-2 infection reported in 1 patient with preceding VITT did not influence anti-PF4 antibody levels. We discuss how these temporal characteristics of VITT provide insights into pathogenesis.

COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombosis , Ad26COVS1/adverse effects , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , ChAdOx1 nCoV-19/adverse effects , Humans , Platelet Factor 4/adverse effects , Purpura, Thrombocytopenic, Idiopathic/chemically induced , SARS-CoV-2 , Thrombosis/chemically induced , Thrombosis/complications