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Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and d-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.In this Consensus Statement, the authors delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess thrombotic risk in these patients. Consensus recommendations are made about the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombosis and in-hospital mortality.

Despite increasing improvement in extracorporeal membrane oxygenation (ECMO) technology and knowledge, thrombocytopenia and impaired platelet function are usual findings in ECMO patients and the underlying mechanisms are only partially elucidated. The purpose of this meta-analysis and systematic review was to thoroughly summarize and discuss the existing knowledge of platelet profile in adult ECMO population. All studies meeting the inclusion criteria (detailed data about platelet count and function) were selected, after screening literature from July 1975 to August 2019. Twenty-one studies from 1.742 abstracts were selected. The pooled prevalence of thrombocytopenia in ECMO patients was 21% (95% CI 12.9–29.0; 14 studies). Thrombocytopenia prevalence was 25.4% (95% CI 10.6–61.4; 4 studies) in veno-venous ECMO, whereas it was 23.2% (95% CI 11.8–34.5; 6 studies) in veno-arterial ECMO. Heparin-induced thrombocytopenia prevalence was 3.7% (95% CI 1.8–5.5; 12 studies). Meta-regression revealed no significant association between ECMO duration and thrombocytopenia. Platelet function impairment was described in 7 studies. Impaired aggregation was shown in 5 studies, whereas loss of platelet receptors was found in one trial, and platelet activation was described in 2 studies. Platelet transfusions were needed in up to 50% of the patients. Red blood cell transfusions were administered from 46 to 100% of the ECMO patients. Bleeding events varied from 16.6 to 50.7%, although the cause and type of haemorrhage was not consistently reported. Thrombocytopenia and platelet dysfunction are common in ECMO patients, regardless the type of ECMO mode. The underlying mechanisms are multifactorial, and understanding and management are still limited. Further research to design appropriate strategies and protocols for its monitoring, management, or prevention should be matter of thorough investigations.

Experimental data suggest that the hemostatic system can accelerate plaque vulnerability to thrombosis in vivo. However, clinical support for these findings remains weak. This comprehensive summary reviews the evidence. Cardiovascular disease is one of the leading causes of death and complications worldwide. The classic concept of atherosclerosis assigns a pivotal role to inflammation in the onset and progression of this disease. 1 , 2 Various inflammatory cell types (e.g., macrophages, neutrophils, and lymphocytes) play crucial roles in the destabilization and subsequent rupture or erosion of an atherosclerotic plaque, ultimately resulting in atherothrombosis. 3 Inflammation is closely linked to coagulation in several pathologic conditions. 4 Intriguingly, extensive bidirectional cross-talk between the two systems has been established in many complex diseases, 5 , 6 including atherosclerosis. Although there is no clinical evidence of a role for the . . .

Patients who are admitted to the hospital with coronavirus disease 2019 (Covid-19) are at high risk for thrombosis, particularly venous thromboembolism (VTE). In a meta-analysis of 66 studies, the overall prevalence of VTE among patients with Covid-19 was 14.1%, with the highest incidence (22.7%) among those admitted to intensive care units (ICUs). 1 Systemic hypercoagulability is a feature of Covid-19, and early studies have shown an association between plasma d -dimer levels and survival. 2 These data have prompted a search for better thrombosis prevention, considering that the high frequencies of VTE occurred in patients who were already receiving standard thromboprophylaxis, mostly with . . .

Anticoagulant-related nephropathy (ARN) is a rare but important disease and often misdiagnosed. The hallmark of the diagnosis is acute kidney injury (AKI) superimposed on preexisting kidney disease due to anticoagulation-induced glomerular hemorrhage with histologic features of widespread tubular obstruction by red blood cells and red cell casts. As ARN is a diagnosis of exclusion only proven by renal biopsy, the diagnosis is often unlikely to be confirmed histologically because of fear of biopsy-related bleeding during anticoagulant therapy. Given the large differential diagnosis in AKI, diagnosing ARN remains a challenge for clinicians. A case report and the pitfalls related to diagnosis and management will be discussed in this paper.

Autoimmune disorders are often associated with low platelet count or thrombocytopenia. In immune-induced thrombocytopenia (IIT), a common mechanism is increased platelet activity, which can have an increased risk of thrombosis. In addition, or alternatively, auto-antibodies suppress platelet formation or augment platelet clearance. Effects of the auto-antibodies are linked to the unique structural and functional characteristics of platelets. Conversely, prior platelet activation may contribute to the innate and adaptive immune responses. Extensive interplay between platelets, coagulation and complement activation processes may aggravate the pathology. Here, we present an overview of the reported molecular causes and consequences of IIT in the most common forms of autoimmune disorders. These include idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), drug-induced thrombocytopenia (DITP), heparin-induced thrombocytopenia (HIT), COVID-19 vaccine-induced thrombosis with thrombocytopenia (VITT), thrombotic thrombocytopenia purpura (TTP), and hemolysis, the elevated liver enzymes and low platelet (HELLP) syndrome. We focus on the platelet receptors that bind auto-antibodies, the immune complexes, damage-associated molecular patterns (DAMPs) and complement factors. In addition, we review how circulating platelets serve as a reservoir of immunomodulatory molecules. By this update on the molecular mechanisms and the roles of platelets in the pathogenesis of autoimmune diseases, we highlight platelet-based pathways that can predispose for thrombocytopenia and are linked thrombotic or bleeding events.

Direct oral anticoagulants (DOACs) have demonstrated a favorable benefit-risk profile in several thromboembolic disorders and are increasingly used in routine clinical practice. A number of real-world studies on DOACs are ongoing, and data published so far have shown broadly similar outcomes to those demonstrated in the respective phase III trials. Despite their beneficial attributes, bleeding risk (as with any other anticoagulants) is often a concern for physicians when prescribing DOACs, particularly in elderly patients, those with significant comorbidities, and other high-risk patient populations. Although the absence of routine coagulation monitoring is an advantage of the DOACs, measuring their anticoagulant effect and/or plasma drug levels may be helpful in certain clinical scenarios to help patient management and improve outcomes. In this paper, practical guidance and recommendations are provided for clinical situations in which the test results may aid clinical decision-making, including patients with life-threatening bleeding events, patients without bleeding but with test results indicating a risk of bleeding, for those patients with a suspected thromboembolism while receiving a DOAC, or prior to patients undergoing elective or urgent surgical procedures. Finally, appropriate monitoring of the DOACs could be of substantial benefit to patients, and there is a high potential for development in this area in the future.

Only 10% of plasma TFPIα (TFPI) exists in the full length form, the rest circulates as a C-terminally truncated form. However, blood platelets exclusively contain full length TFPI, which is released at the site of injury upon platelet activation, and which could play an important local regulatory role in thrombin generation and prevention of thrombosis. The anticoagulant activities of full length and truncated TFPI were investigated using thrombin generation assays. Blood samples were obtained from 30 healthy volunteers (10 male subjects, 10 female subjects, and 10 females using oral contraceptives). Platelet TFPI was released in platelet rich plasma and in platelet isolates using convulxin or thrombin, and measured by free TFPI ELISA and thrombin generation assays. Full length TFPI and platelet TFPI were much more potent inhibitors of thrombin generation than truncated TFPI, which was virtually inactive. Although mean plasma TFPI antigen levels decreased from men (0.30 nM) to women (0.20 nM) to women using oral contraceptives (0.11 nM), no relevant differences were found in platelet TFPI among those subgroups. Platelets release similar amounts of TFPI regardless of plasma TFPI concentrations and is unaffected by sex or oral contraceptive use. We speculate that platelet TFPI is important to prevent systemic coagulation and thrombosis and restrict thrombus formation to the site of the growing platelet plug. The stable contribution of platelet TFPI to the anticoagulant potential in plasma is likely to become particularly relevant under conditions of low plasma TFPI levels in combination of oral contraceptives use.

To evaluate the cost-saving of a specialized, eHealth-based management service (CS) in comparison to regular medical care (RMC) for the management of patients receiving oral anticoagulation (OAC) therapy. Costs of hospitalization were derived via diagnosis-related groups which comprise diagnoses (ICD-10) and operation and procedure classification system (OPS), which resulted in OAC-related (i.e. bleeding/ thromboembolic events) and non-OAC-related costs for both cohorts. Cost for anticoagulation management comprised INR-testing, personnel, and technical support. In total, 705 patients were managed by CS and 1490 patients received RMC. The number of hospital stays was significantly lower in the CS cohort compared to RMC (CS: 23.4/100 py; RMC: 68.7/100 py); with the most pronounced difference in OAC-related admissions (CS: 2.8/100 py; RMC: 13.3/100 py). Total costs for anticoagulation management amounted to 101 EUR/py in RMC and 311 EUR/py in CS, whereas hospitalization costs were 3261 [IQR 2857–3689] EUR/py in RMC and 683 [504–874] EUR/py in CS. This resulted in an overall cost saving 2368 EUR/py favoring the CS. The lower frequency of adverse events in anticoagulated patients managed by the telemedicine-based CS compared to RMC translated into a substantial cost-saving, despite higher costs for the specialized management of patients. Trial registration: ClinicalTrials.gov, unique identifier NCT01809015, March 8, 2013.

Atherosclerosis is a progressive inflammatory vascular disorder, complicated by plaque rupture and subsequently atherothrombosis. In vitro studies indicate that key clotting proteases, such as factor Xa (FXa), can promote atherosclerosis, presumably mediated through protease activated receptors (PARs). Although experimental studies showed reduced onset of atherosclerosis upon FXa inhibition, the effect on pre-existing plaques has never been studied. Therefore, we investigated effects of FXa inhibition by rivaroxaban on both newly-formed and pre-existing atherosclerotic plaques in apolipoprotein-e deficient (ApoE −/− ) mice. Female ApoE −/− mice (age: 8–9 weeks, n = 10/group) received western type diet (WTD) or WTD supplemented with rivaroxaban (1.2 mg/g) for 14 weeks. In a second arm, mice received a WTD for 14 weeks, followed by continuation with either WTD or WTD supplemented with rivaroxaban (1.2 mg/g) for 6 weeks (total 20 weeks). Atherosclerotic burden in aortic arch was assessed by haematoxilin & eosin immunohistochemistry (IHC); plaque vulnerability was examined by IHC against macrophages, collagen, vascular smooth muscle cells (VSMC) and matrix metalloproteinases (MMPs). In addition, PAR1 and -2 expressions and their main activators thrombin and FXa in the plaque were determined in the plaque. Administration of rivaroxaban at human therapeutic concentrations reduced the onset of atherosclerosis (−46%, p  <  0.05) , and promoted a regression of pre-existing plaques in the carotids (−24%, p  <  0.001 ). In addition, the vulnerability of pre-existing plaques was reduced by FXa inhibition as reflected by reduced macrophages (−39.03%, p  <  0.05 ), enhanced collagen deposition (+38.47%, p  <  0.05 ) and diminished necrotic core (−31.39%, p  <  0.05 ). These findings were accompanied with elevated vascular smooth muscle cells and reduced MMPs. Furthermore, expression of PARs and their activators, thrombin and FXa was diminished after rivaroxaban treatment. Pharmacological inhibition of FXa promotes regression of advanced atherosclerotic plaques and enhances plaque stability. These data suggest that inhibition of FXa may be beneficial in prevention and regression of atherosclerosis, possibly mediated through reduced activation of PARs.