Human and mouse platelet transcriptomes and proteomes for phenotyping 3474 genes with hemostatic and platelet traits.

The hemostatic process relies on platelet and coagulation activation, with additional roles of red blood cells and the vessel wall. By systematic screening of databases for gene-linked information on hemostasis, we collected phenotypic profiles of 3474 orthologous human and mouse genes regarding bleeding, arterial thrombosis, thrombophilia, platelet traits, coagulation, and erythrocytes. Comparisons showed that defects in 252 mouse genes led to increased bleeding combined with platelet dysfunction or thrombocytopenia, in addition to 150 human orthologs that are registered for familial bleeding disorders, based on panel sequencing.

Plasminogen activation and plasmin activity are not required to prevent venous thrombosis/thromboembolism.

Suppression of plasminogen activation and/or plasmin activity (PA) reduces blood loss and decreases hemorrhage-related death. However, whether the endogenous PA system is a biological mechanism to prevent intravascular thrombus formation is debated, and the potential that reduced PA may increase venous thrombosis/thromboembolism (VTE) risk cautions against the use of antifibrinolytic agents. We aimed to determine the contribution of PA to VTE.

Elevated levels of (active) von Willebrand factor during anticoagulation are associated with early recurrence of venous thromboembolism.

Background: Venous thromboembolism (VTE) can recur shortly after stopping anticoagulation, highlighting the need for reliable biomarkers to identify high-risk patients during treatment.

Objectives: To determine whether platelet and endothelial markers predict VTE recurrence.

Methods: We used data and samples from the randomized controlled VISTA trial (2011-2015), which included patients with unprovoked VTE who were treated with vitamin K antagonists for 6 months.

Length of ischemia duration is associated with fibrin film coverage of acute myocardial infarction thrombi.

Background: Coronary artery disease plaque rupture leads to occlusive thrombosis, causing acute myocardial infarction requiring immediate life-saving treatment. The blood clot is supported by a mesh of fibrin fibers that are generated through the polymerization of fibrin. We recently showed that fibrin also produces a film on the surface of blood clots.

Enhancing hemostasis potency in hemophilia with a small interfering ribonucleic acid targeting protein S.

Background: One hemophilia treatment concept focuses on rebalancing coagulation and anticoagulation to restore normal blood clotting. Targeting the coagulation regulator, protein S (PS), in hemophilia shows promise to increase the generation of thrombin, a critical enzyme in the clotting process.

Objectives: This study aimed to: (1) assess whether inhibiting PS increases thrombin generation (TG) in plasma from individuals with hemophilia A (HA) and B (HB); and (2) develop a hepatocyte-targeted PS small interfering RNA (siRNA) therapy using N-acetylgalactosamine conjugation to restore hemostasis in hemophilia without increasing thromboembolic risks.

Role of inflammation and haemostasis on aetiology and prognosis in young patients with ischaemic stroke: study protocol of the Observational Dutch Young Symptomatic StrokE study-EXTended (ODYSSEY-nEXT) - a multicentre prospective cohort study.

Introduction: The cause of ischaemic stroke at a young age remains unknown in 30% of cases, highlighting the need to identify hidden causes and risk factors in young patients. Transient and chronic risk factors may interact with the inflammatory and haemostatic systems, potentially driving key mechanisms in the pathogenesis. The 'Observational Dutch Young StrokE study-Extended' (ODYSSEY-nEXT) aims to enhance our understanding of these complex interactions through detailed phenotyping of the immune and haemostatic system and explore their relationship with long-term prognosis.

Age- and sex-dependency of thrombin generation parameters in the general Italian population: the Moli-sani study.

Background: Recent developments have made the thrombin generation (TG) test accessible to the clinical laboratory. Therefore, the clinical interpretation of TG parameters has become of increasing interest, and reference values are required. Age and sex have been shown to affect TG parameters, but no consensus has been reached on the subject.

Patients with cirrhosis have a disbalance between coagulation and fibrinolysis resulting in a prothrombotic phenotype.

Background: Patients with cirrhosis develop multiple hemostatic alterations. Although fibrinolysis is also affected by liver disease, studies have produced conflicting results, highlighting the need for a reliable fibrinolysis assay. Assessing the kinetics of plasmin generation (PG) is a new method to study the fibrinolytic state of cirrhosis patients.

High Prevalence of Acquired Platelet Secretion Defects in Multiple Myeloma.

Thrombocytopenia at admission predicts mortality in multiple myeloma (MM) and might link to disease progression. Although thrombocytopenia is known to be associated with MM, a possible thrombopathy is clinically less known. We conducted a case-control study comparing platelet responses of MM patients to controls via flow cytometry, integrin αIIbβ3 activation and P-selectin exposure, and a bioluminescent assay, ATP release.

Interpreting high levels of unfolded Von Willebrand Factor in patients with the antiphospholipid syndrome.

Introduction: Unfolded Von Willebrand Factor (VWF) is increased in thrombotic pathologies such as myocardial infarction. Unfolded VWF mediates the binding of platelets without the need for collagen. β-glycoprotein I (β-GPI) is a natural inhibitor of the platelet-VWF interaction.

Thrombomodulin is a stronger indicator of combined oral contraceptives-induced activated protein C pathway resistance in the thrombin generation test than activated protein C.

Background: The mechanism by which combined oral contraceptives (COCs) lead to hypercoagulation is not fully understood, although activated protein C (APC) pathway resistance has been implicated. APC and thrombomodulin (TM) tend to be considered as interchangeable reagents, even though their biological action in coagulation is different. However, it remains unclear which reagent is better suited for the detection of APC pathway resistance.

Low thrombin inactivation capacity is associated with an increased risk of recurrent ischemic events after ischemic stroke at a young age.

Background: Patients with ischemic stroke at a young age (18-50 years) have an increased long-term risk of recurrent ischemic events. Hypercoagulability may contribute to this high risk.

Objectives: To investigate the associations between in vivo and ex vivo hemostatic parameters and recurrent ischemic events after an ischemic stroke or transient ischemic attack (TIA) at a young age.

Impaired whole blood thrombin generation is associated with procedure-related bleeding in acutely decompensated cirrhosis.

Background & Aims: The clinical utility of thrombomodulin-modified thrombin generation (TM-TG) in cirrhosis is uncertain. We conducted a prospective study to evaluate the prognostic value of TM-TG in cirrhosis.

Methods: Patients were recruited during outpatient clinics (compensated and stable decompensated cirrhosis) or if admitted to our inpatient service (acutely decompensated cirrhosis).

Functionally distinct anticoagulant mechanisms of endothelial cells.

Antithrombin and tissue factor pathway inhibitor (TFPI) provide different anticoagulant mechanisms. Having established a potent anticoagulant role of cultured human umbilical vein endothelial cells in vessel-on-a-chip microfluidic models, we now investigated how these cells modulated thrombin generation under stasis through antithrombin and TFPI pathways. We observed that endothelial monolayers in 96 well-plates strongly delayed and suppressed the thrombin generation process induced by tissue factor, regardless of the presence of whole blood, platelet-rich plasma or platelet-free plasma.

An update on laboratory detection and interpretation of antiphospholipid antibodies for diagnosis of antiphospholipid syndrome: guidance from the ISTH-SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies.

Antiphospholipid syndrome (APS) diagnosis is dependent on the accurate detection and interpretation of antiphospholipid antibodies (aPL). Lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-beta2 glycoprotein I antibodies (aβ2GPI) remain the cornerstone of the laboratory part of APS diagnosis. In the 2023 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) APS classification criteria, the type of laboratory parameters remain essentially unchanged compared with the updated Sapporo classification criteria, and aCL and aβ2GPI measurement are still restricted to enzyme-linked immunosorbent assays (ELISAs) with moderate and high titer aPL thresholds defined as 40 and 80 Units, respectively, and a cutoff calculated by the 99th percentile has been abandoned.

Interference of lupus anticoagulant causing antiprothrombin and anti-beta-2-glycoprotein I antibodies on international normalized ratio measurements: comparative analysis of international normalized ratio methods.

Background: Life-long vitamin K antagonist (VKA) therapy is recommended as a standard of care in antiphospholipid syndrome (APS) patients with thrombosis. Concerns have been raised about the validity of international normalized ratio (INR) measurements in lupus anticoagulant (LA)-positive APS patients because LA may interfere with phospholipid-dependent coagulation tests and could elevate INR measurements.

Objectives: Here, we aimed to determine the interference of antigen-specific monoclonal and isolated patient antibodies with LA activity on INR measurements.

Comprehensive functional characterization of a novel ANO6 variant in a new patient with Scott syndrome.

Background: Scott syndrome is a mild platelet-type bleeding disorder, first described in 1979, with only 3 unrelated families identified through defective phosphatidylserine (PS) exposure and confirmed by sequencing. The syndrome is distinguished by impaired surface exposure of procoagulant PS on platelets after stimulation. To date, platelet function and thrombin generation in this condition have not been extensively characterized.

Lipid nanoparticles and siRNA targeting plasminogen provide lasting inhibition of fibrinolysis in mouse and dog models of hemophilia A.

Antifibrinolytic drugs are used extensively for on-demand treatment of severe acute bleeding. Controlling fibrinolysis may also be an effective strategy to prevent or lessen chronic recurring bleeding in bleeding disorders such as hemophilia A (HA), but current antifibrinolytics have unfavorable pharmacokinetic profiles. Here, we developed a long-lasting antifibrinolytic using small interfering RNA (siRNA) targeting plasminogen packaged in clinically used lipid nanoparticles (LNPs) and tested it to determine whether reducing plasmin activity in animal models of HA could decrease bleeding frequency and severity.