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BackgroundArterial and venous thromboembolic events (TEEs) have been associated with intravenous Ig use, but the risk has been poorly quantified. We aimed to calculate the risk of TEEs associated with exposure to intravenous Ig.MethodsWe included participants from UK Biobank recruited over 3 years, data extracted September 2020.The study endpoints were incidence of myocardial infarction, other acute ischaemic heart disease, stroke, pulmonary embolism and other venous embolism and thrombosis.Predictors included known TEE risk factors: age, sex, hypertension, smoking status, type 2 diabetes mellitus, hypercholesterolaemia, cancer and past history of TEE. Intravenous Ig and six other predictors were added in the sensitivity analysis.Information from participants was collected prospectively, while data from linked resources, including death, cancer, hospital admissions and primary care records were collected retrospectively and prospectively.Findings14 794 of 502 492 individuals had an incident TEE during the study period. The rate of incident events was threefold higher in those with prior history of TEE (8 .7%) than those without previous history of TEE (3.0%).In the prior TEE category, intravenous Ig exposure was independently associated with increased risk of incident TEE (OR=3.69 (95% CI 1.15 to 11.92), p=0.03) on multivariate analysis. The number needed to harm by exposure to intravenous Ig in those with a history of TEE was 5.8 (95% CI 2.3 to 88.3).Intravenous Ig exposure did not increase risk of TEE in those with no previous history of TEE.InterpretationIntravenous Ig is associated with increased risk of further TEE in individuals with prior history of an event with one further TEE for every six people exposed. In practice, this will influence how clinicians consent for and manage overall TEE risk on intravenous Ig exposure.

The development of new drugs is often limited or even halted by their side effects on platelet number or function. This review introduces the signalling pathways and the role of various platelet receptors, such as GPIIb/IIIa, GPIb-IX-V, GPVI and P-selectin. The large scope of platelet function tests are described, including aggregometry, flow cytometry, VerifyNow, adhesion and in vivothrombosis and haemostasis assays. Several important examples of drugs that have off-target effects influencing platelet function are discussed, including GPIIb/IIIa inhibitors, oligonucleotides, BH3 mimetics and Bruton tyrosine kinase inhibitors. Finally, challenges for future drug development with regards to platelet function are outlined, including the conclusion that no single assay can fully predict drug effects and thus a combination of platelet function tests is often required to assess platelet function in the context of newly developed therapeutics.

Introduction:Pulmonary embolism (PE) requiring intensive care unit (ICU) admission is associated with high in-hospital mortality, however data on long-term survival outcomes and associated contributors remains limited. We sought to further investigate this using a large binational dataset.

Antiplatelet agents form a cornerstone of therapy for patients with acute coronary syndrome undergoing percutaneous coronary intervention, as well as in the secondary prevention of cardiovascular eventsCurrently available antiplatelet agents, including cyclooxygenase 1 inhibitors, P2Y purinoreceptor 12 (P2Y12) antagonists, protease-activated receptor 1 antagonists, and glycoprotein (GP) IIb/IIIa antagonists, inhibit processes important for both thrombosis and haemostasisBleeding remains a major limitation of current therapeutic approaches, with the most intensive antithrombotic regimens associated with an increased risk of bleedingThe adverse effects of bleeding on mortality and cardiovascular outcomes might offset the benefit of potent antiplatelet strategiesExperimental work has highlighted that thrombus formation in vivois a dynamic process; new regulators of thrombus formation and, therefore, therapeutic targets that do not impair haemostasis have been identifiedNew antiplatelet strategies, including inhibitors of phosphatidylinositol 3-kinase-β (PI3Kβ), protein disulfide-isomerase (PDI), activated GPIIb/IIIa, GPIIb/IIIa outside-in signalling, protease-activated receptors, and platelet GPVI-mediated adhesion pathways, are in preclinical and early-phase clinical trials

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare complication of adenovirus vector-based COVID-19 vaccines. VITT is associated with markedly raised levels of D-dimer; yet, how VITT modulates the fibrinolytic system is unknown.

Identifying the molecular mechanisms that promote optimal immune responses to coronavirus disease 2019 (COVID-19) vaccination is critical for future rational vaccine design. Here, we longitudinally profile innate and adaptive immune responses in 102 adults after the first, second, and third doses of mRNA or adenovirus-vectored COVID-19 vaccines. Using a multi-omics approach, we identify key differences in the immune responses induced by ChAdOx1-S and BNT162b2 that correlate with antigen-specific antibody and T cell responses or vaccine reactogenicity. Unexpectedly, we observe that vaccination with ChAdOx1-S, but not BNT162b2, induces an adenoviral vector-specific memory response after the first dose, which correlates with the expression of proteins with roles in thrombosis with potential implications for thrombosis with thrombocytopenia syndrome (TTS), a rare but serious adverse event linked to adenovirus-vectored vaccines. The COVID-19 Vaccine Immune Responses Study thus represents a major resource that can be used to understand the immunogenicity and reactogenicity of these COVID-19 vaccines.

Intracranial haemorrhage (ICH) is the most feared and lethal complication of oral anticoagulant (OAC) therapy. Resumption of OAC following ICH has long posed a challenge for clinicians, complicated by the expanding range of anticoagulant agents available in modern clinical practice, including the direct oral anticoagulants (DOACs) and more recently, the factor XI and XII inhibitors. A review of the current literature finds support for resuming OAC in the majority of patients post-ICH based on pooled retrospective data showing that resumption is associated a lower risk of mortality and thromboembolism without a significantly increased risk of recurrent haemorrhage. The optimal time to resume OAC is less clear, however the available evidence suggests the composite risk of both recurrent haemorrhage and thromboembolism is likely minimised somewhere between 4-6 weeks after ICH in most patients. Specific considerations to guide the optimal resumption time in the individual patient include ICH location, mechanism and anticoagulant class. Patients with mechanical heart valves and intracerebral malignancy represent high risk groups who require more nuanced decision-making. Here we appraise the literature with the aim of providing a practical guide for clinicians while also discussing priorities for future investigation.

Certain patients with antibody-mediated autoimmune disease exhibit poor responses to conventional immunosuppression, including B-cell depletion with rituximab. Proteasome inhibitors such as bortezomib demonstrate pleiotropic immunomodulatory effects, including direct toxicity to antibody-producing cells. Here, we report preliminary evidence for the efficacy of bortezomib as salvage therapy for refractory autoimmune hematological disease. Thirteen treatment episodes in 10 patients with autoimmune hematological phenomena (autoimmune hemolytic anemia [AIHA; n = 8], acquired hemophilia (n = 1), immune thrombocytopenia (n = 1), and thrombotic thrombocytopenic purpura [TTP; n = 3]) and a median of 5 (range, 3-12) prior lines of therapy demonstrated an overall response rate of 77% (10 of 13) including 38% (5 of 13) complete remissions. The majority of clinical improvements were rapid, correlated with biomarkers of autoantibody reduction, and were associated with an acceptable safety profile. Responses appeared durable following treatment of TTP and acquired hemophilia; AIHA responses were more limited with a pattern of relapse following bortezomib cessation. These data provide proof of concept for the utility of proteasome inhibition as antibody depletion therapy in autoimmune disease.

Certain patients with antibody-mediated autoimmune disease exhibit poor responses to conventional immunosuppression, including B-cell depletion with rituximab. Proteasome inhibitors such as bortezomib demonstrate pleiotropic immunomodulatory effects, including direct toxicity to antibody-producing cells. Here, we report preliminary evidence for the efficacy of bortezomib as salvage therapy for refractory autoimmune hematological disease. Thirteen treatment episodes in 10 patients with autoimmune hematological phenomena (autoimmune hemolytic anemia [AIHA; n = 8], acquired hemophilia (n = 1), immune thrombocytopenia (n = 1), and thrombotic thrombocytopenic purpura [TTP; n = 3]) and a median of 5 (range, 3-12) prior lines of therapy demonstrated an overall response rate of 77% (10 of 13) including 38% (5 of 13) complete remissions. The majority of clinical improvements were rapid, correlated with biomarkers of autoantibody reduction, and were associated with an acceptable safety profile. Responses appeared durable following treatment of TTP and acquired hemophilia; AIHA responses were more limited with a pattern of relapse following bortezomib cessation. These data provide proof of concept for the utility of proteasome inhibition as antibody depletion therapy in autoimmune disease.

Background: COVID-19 is associated with high rates of venous thromboembolism (VTE). The impact of common inherited thrombophilias on the development of COVID-19-associated VTE (COVID-19 VTE) is not well understood.

No relevant conflicts of interest to declare.

Neutrophil macroaggregates induce a distinct arterial-venous thrombotic response in the lung after gut ischemia.

Antiplatelet drugs might inhibit the nexus of platelet activation and amyloid-β aggregation in Alzheimer’s disease.

Off Label Use: The drug to be discussed is bortezomib and its use in managing refractory autoimmune haematological disorders (off label use). Catalano:Celgene, Roche, Gilead: Honoraria. Opat:Janssen Pharmaceuticals: Other: Provision of subsidized medications only. Shortt:Janssen Pharmaceuticals: Other: Provision of subsidized medications only.

Spencer: Celgene: Consultancy, Honoraria.

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