Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Activation of the coagulation cascade is a critical, evolutionarily conserved mechanism that maintains hemostasis by rapidly forming blood clots in response to blood-borne infections and damaged blood vessels. Coagulation is a key component of innate immunity since it prevents bacterial dissemination and can provoke inflammation. The term immunothrombosis describes the process by which the innate immune response drives aberrant coagulation, which can result in a lethal condition termed disseminated intravascular coagulation, often seen in sepsis. In this review, we describe the recently uncovered molecular mechanisms underlying inflammasome-and STING-driven immunothrombosis induced by bacterial and viral infections, culminating in tissue factor (TF) activation and release. Current anticoagulant therapeutics, while effective, are associated with a lifethreatening bleeding risk, requiring the urgent development of new treatments. Targeting immunothrombosis may provide a safer option. Thus, we highlight preclinical tools which target TF and/or block canonical (NLRP3) or noncanonical (caspase-11) inflammasome activation as well as STING-driven TF release and discuss clinically approved drugs which block key immunothrombotic processes and, therefore, may be redeployed as safer anticoagulants.

The interplay between innate immunity and coagulation after infection or injury, termed immunothrombosis, is the primary cause of disseminated intravascular coagulation (DIC), a condition that occurs in sepsis. Thrombosis associated with DIC is the leading cause of death worldwide. Interest in immunothrombosis has grown because of COVID-19, the respiratory disease caused by SARS-CoV-2, which has been termed a syndrome of dysregulated immunothrombosis. As the relatively new field of immunothrombosis expands at a rapid pace, the focus of academic and pharmacological research has shifted from generating treatments targeted at the traditional ‘waterfall’ model of coagulation to therapies better directed towards immune components that drive coagulopathies. Immunothrombosis can be initiated in macrophages by cleavage of the non-canonical inflammasome which contains caspase-11. This leads to release of tissue factor (TF), a membrane glycoprotein receptor that forms a high-affinity complex with coagulation factor VII/VIIa to proteolytically activate factors IX to IXa and X to Xa, generating thrombin and leading to fibrin formation and platelet activation. The mechanism involves the post-translational activation of TF, termed decryption, and release of decrypted TF via caspase-11-mediated pyroptosis. During aberrant immunothrombosis, decryption of TF leads to thromboinflammation, sepsis, and DIC. Therefore, developing therapies to target pyroptosis have emerged as an attractive concept to counteract dysregulated immunothrombosis. In this review, we detail the three mechanisms of TF control: concurrent induction of TF, caspase-11, and NLRP3 (signal 1); TF decryption, which increases its procoagulant activity (signal 2); and accelerated release of TF into the intravascular space via pyroptosis (signal 3). In this way, decryption of TF is analogous to the two signals of NLRP3 inflammasome activation, whereby induction of pro-IL-1β and NLRP3 (signal 1) is followed by activation of NLRP3 (signal 2). We describe in detail TF decryption, which involves pathogen-induced alterations in the composition of the plasma membrane and modification of key cysteines on TF, particularly at the location of the critical, allosterically regulated disulfide bond of TF in its 219-residue extracellular domain. In addition, we speculate towards the importance of identifying new therapeutics to block immunothrombotic triggering of TF, which can involve inhibition of pyroptosis to limit TF release, or the direct targeting of TF decryption using cysteine-modifying therapeutics.

Type I interferons (IFNs) are central mediators of anti-viral and anti-bacterial host defence. Detection of microbes by innate immune cells via pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and cGAS-STING, induces the expression of type I IFN-stimulated genes. Primarily comprising the cytokines IFN-α and IFN-β, type I IFNs act via the type I IFN receptor in an autocrine or exocrine manner to orchestrate rapid and diverse innate immune responses. Growing evidence pinpoints type I IFN signalling as a fulcrum that not only induces blood coagulation as a core feature of the inflammatory response but is also activated by components of the coagulation cascade. In this review, we describe in detail recent studies identifying the type I IFN pathway as a modulator of vascular function and thrombosis. In addition, we profile discoveries showing that thrombin signalling via protease-activated receptors (PARs), which can synergize with TLRs, regulates the host response to infection via induction of type I IFN signalling. Thus, type I IFNs can have both protective (via maintenance of haemostasis) and pathological (facilitating thrombosis) effects on inflammation and coagulation signalling. These can manifest as an increased risk of thrombotic complications in infection and in type I interferonopathies such as systemic lupus erythematosus (SLE) and STING-associated vasculopathy with onset in infancy (SAVI). We also consider the effects on coagulation of recombinant type I IFN therapies in the clinic and discuss pharmacological regulation of type I IFN signalling as a potential mechanism by which aberrant coagulation and thrombosis may be treated therapeutically.

Background Medicines Reconciliation (MR) involves obtaining a Best-Possible Medication History (BPMH) and is essential for reducing medication errors and adverse events. Recommendations on how best to undertake MR range from utilising the patient alone to using ≥2 sources (in addition to the patient). Few studies evaluate the use of >1 source as a measure of MR quality. Methods This observational study was undertaken in a major teaching hospital that provides a dedicated pharmacist-led MR service. Eligible patients (aged ≥65 years, admitted through the Emergency Department) were randomly recruited. MRs were compiled using 2 sources and compared to individual 1-source MRs (both in addition to patient/carer interview). Additional Medication Discrepancies (AMDs), or differences between 1-source and 2-source MR, were assessed and potential predictors analysed. Results A total of 114 patients were included. Community pharmacy was the most frequently used and most accurate source (full agreement in 97.4% of BPMHs). Two-thirds of MRs would not differ if either of the two sources were used in isolation, alongside patient/carer interview. The remaining MRs identified a total of 85 AMDs (1–6 per MR). The majority were drug omissions (49.4%). Most were deemed “low” potential clinical significance (59%). Higher patient/carer reliability was associated with lower incidence (p=0.001) and fewer AMDs (p=0.001). Conclusion Contrary to some international guidelines, using >1 source (in addition to patient/carer interview) does not add value to the BPMH in the majority of cases.