Reversal agents are used in patients taking direct oral anticoagulants (DOACs) to manage bleeding, but evidence for their effectiveness remains limited.

From the beginning of the millennium and the development of genome-wide analyses, the technical advances and remarkable increase in research sample sizes have led to an escalating number of discoveries revealing genetic determinants of levels of the main factors regulating hemostasis and thrombosis, and demonstrating a clear polygenic complex regulation of most coagulation factors. These discoveries have been useful to understand the biology underlying hemostasis regulation, and to understand risk of associated thrombotic disease, such as venous thromboembolism, coronary artery disease, and ischemic stroke. In this historical review, we outline the main discoveries in genetic studies of coagulation factors (fibrinogen and its alternatively spliced γ' isoform, D-dimer, factor V, factor VII, factor VIII, von Willebrand factor, and factor XI), the main natural anticoagulants (protein C, protein S, antithrombin), components of fibrinolysis (tissue plasminogen activator [tPA, plasminogen activator inhibitor-1 [PAI-1]), and global coagulation tests (prothrombin time [PT], activated partial thromboplastin time [aPTT]). We explore the clinical implications of these discoveries and suggest new avenues for future investigation.

Endothelial injury is the core factor of venous thrombosis. m6A plays a critical role in metabolism and cellular processes. Moreover, the balance of mitochondrial dynamics is essential in regulating cellular growth, apoptosis, and mobility. Now, The roles of m6A modification and mitochondrial dynamics in regulating venous endothelial cells remains elusive.

One-third of patients undergoing transcatheter aortic valve implantation (TAVI) have a concomitant indication for oral anticoagulation (OAC). Previous studies suggested that periprocedural continuation of OAC could reduce transient hypercoagulation after TAVI.

Acute pulmonary embolism (PE) includes clinical presentations with a wide spectrum of severities, making risk stratification essential to guide the decision-making process in daily practice. However, international guidelines differ in definition of risk classes and consequent treatment recommendations.

Failure rates of clinical decision rules (CDRs) combined with D-dimer to exclude pulmonary embolism (PE) are higher in patients with cancer compared to non-cancer patients, raising concerns about their use in this patient group.

Adherence to oral anticoagulants (OACs) for atrial fibrillation (AF) stroke prevention is traditionally defined as taking 80% of doses as prescribed, but this threshold has not been clinically validated.

Diagnosing inherited thrombophilia as the cause of venous thromboembolism is important for patient management. Deficiencies in antithrombin, protein C, and protein S are usually diagnosed by plasma-based assays. Genetic testing can confirm the congenital nature of these deficiencies. Factor V Leiden can be detected using activated protein C resistance assays, followed by or replaced by molecular confirmation, whereas prothrombin G20210A can only be detected genetically. During the last decade, molecular techniques have evolved from single-gene sequencing to multigene sequencing panels. To understand current thrombophilia testing practices, a questionnaire was designed focusing on thrombophilia testing in coagulation laboratories and how genetic testing is placed in the diagnostic workflow. All International Society on Thrombosis and Haemostasis members and participants in external quality control schemes on thrombophilia testing were invited to complete the survey. Eighty-two unique responses were received. This international survey showed that laboratories perform plasma-based thrombophilia testing, but 42% restrict it to requests from thrombosis/hemostasis specialists, patients without anticoagulant treatment, or those with a strong personal of familial history of venous thrombosis. However, phenotypic testing is not always performed according to published guidelines. More specifically, the transference of reference intervals from manufacturers or literature is often suboptimal. For results interpretation, anticoagulant use and acquired causes were considered the most. Genetic testing is not systematically included in the diagnostic work-up algorithms and is mostly restricted to single-variant testing. Multigene panel testing is only performed by a minority of laboratories. Our results highlight the necessity for recommendations on how and when to perform this kind of testing.

Activated protein C (APC) is a serine protease known for its anticoagulant, anti-inflammatory, and cytoprotective properties. Although clinical evidence links protein C (PC) deficiency to various retinal pathologies, the physiological role of APC in the retina remains unexplored.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening thrombotic microangiopathy. More and more studies have clearly shown a high prevalence of several adverse long-term health issues following recovery in these patients. Therefore, nowadays, the paradigm of iTTP as an acute episodical disease is quickly changing, and it should be considered a chronic disorder. The present review focuses on the two main long-term complications occurring during clinical remission in these patients (i.e. cardiovascular and neurological complications). Our goal is to provide an updated overview on this topic, explaining the main related pathogenic mechanisms and highlighting how iTTP is emerging as a model not only of acute but also of chronic systemic microvascular dysfunction. The most accredited hypothesis supporting the chronicity of the disease is that after recovery from an acute iTTP episode a state of cumulative microvascular damage could persist and progress over time. However, the trajectory remains rather unpredictable and there is still a poor evidence on preclinical biomarkers able to identify those patients at higher risk of long-term cardiovascular and neurological complications, as well as drugs able to prevent chronic cardiac or brain organ damages. To date, there are no clear guidelines in this field and the clinical practice is quite heterogeneous between reference centers. A task force within the scientific community would be important for the standardization of the most appropriate monitoring tools as well as preventive approaches for long-term complications in iTTP patients.