Importance of individual residues in hydrophobic patch PLVIVGL (1481-1487) in FV-Short for synergistic TFPIα cofactor activity with protein S, an alanine-scanning study: AlphaFold-mediated prediction of FV-Short/TFPIα/protein S trimolecular complex structure.

Background: In the splice variant factor (F)V-Short, 702 residues are deleted from the B domain, resulting in exposure of an acid region (AR2; 1493-1537) that binds TFPIα. FV-Short and protein S serve as synergistic TFPIα cofactors in inhibition of FXa. In the preAR2 region, a hydrophobic patch PLVIVGL (1481-1487) is crucial for synergistic TFPIα-cofactor activity and assembly of FV-Short, TFPIα, and protein S.

Corrigendum to 'The Hemophilia Joint Health Score version 2.1 Validation in Adult Patients Study: A multicenter international study' [Research and Practice in Thrombosis and Haemostasis, 6/2, (2022) e12690].

[This corrects the article DOI: 10.1002/rth2.12690.

Natural anticoagulant discovery, the gift that keeps on giving: finding FV-Short.

The complex reactions of blood coagulation are balanced by several natural anticoagulants resulting in tuned hemostasis. During several decades, the knowledge base of the natural anticoagulants has greatly increased and we have also learned about antiinflammatory and cytoprotective activities expressed by antithrombin and activated protein C (APC). Some coagulation proteins have also been found to function as anticoagulants; e.

Diagnosis and management of severe congenital protein C deficiency (SCPCD): Communication from the SSC of the ISTH.

Severe congenital protein C deficiency (SCPCD) is rare and there is currently substantial variation in the management of this condition. A joint project by three Scientific and Standardization Committees of the ISTH: Plasma Coagulation Inhibitors, Pediatric/Neonatal Thrombosis and Hemostasis, and Women's Health Issues in Thrombosis and Hemostasis, was developed to review the current evidence and help guide on diagnosis and management of SCPCD. We provide a summary of the clinical presentations, differential diagnoses, appropriate investigations to confirm the diagnosis, approaches for management of the acute situation, and options for long-term management including subsequent pregnancies.

A hydrophobic patch (PLVIVG; 1481-1486) in the B-domain of factor V-short is crucial for its synergistic TFPIα-cofactor activity with protein S and for the formation of the FXa-inhibitory complex comprising FV-short, TFPIα, and protein S.

Background: Factor V-short (FV756-1458) is a natural splice variant functioning in synergy with protein S as tissue factor pathway inhibitor alpha (TFPIα)-cofactor in inhibition of factor Xa (FXa). An exposed acid region (AR2; 1493-1537) in the B domain binds TFPIα. The preAR2 (1458-1492) is crucial for the synergistic TFPIα-cofactor activity between FV-short and protein S and for assembly of a trimolecular FXa-inhibitory complex among FV-short, protein S, and TFPIα.

Classic Thrombophilias and Thrombotic Risk Among Middle-Aged and Older Adults: A Population-Based Cohort Study.

Background Five classic thrombophilias have been recognized: factor V Leiden (rs6025), the prothrombin G20210A variant (rs1799963), and protein C, protein S, and antithrombin deficiencies. This study aimed to determine the thrombotic risk of classic thrombophilias in a cohort of middle-aged and older adults. Methods and Results Factor V Leiden, prothrombin G20210A and protein-coding variants in the (protein C), (protein S), and (antithrombin) anticoagulant genes were determined in 29 387 subjects (born 1923-1950, 60% women) who participated in the Malmö Diet and Cancer study (1991-1996).

The preAR2 region (1458-1492) in factor V-Short is crucial for the synergistic TFPIα-cofactor activity with protein S and the assembly of a trimolecular factor Xa-inhibitory complex comprising FV-Short, protein S, and TFPIα.

Background: Factor V-Short (FV756-1458) is a natural splice variant in which 702 residues are deleted from the B domain. It exposes an acid region (AR2; 1493-1537) that binds tissue factor pathway inhibitor alpha (TFPIα). Protein S also interacts with TFPIα and serves as TFPIα-cofactor in factor Xa (FXa) inhibition.

Pleiotropic anticoagulant functions of protein S, consequences for the clinical laboratory. Communication from the SSC of the ISTH.

Hereditary deficiencies of protein S (PS) increase the risk of thrombosis. However, assessing the plasma levels of PS is complicated by its manifold physiological interactions, while the large inter-individual variability makes it problematic to establish reliable cut-off values. PS has multiple physiological functions, with only two appearing to have significant anticoagulant properties: the activated protein C (APC) and tissue factor pathway inhibitor alpha (TFPIα) cofactor activities.

Genetic risk factors for venous thromboembolism.

Introduction: Venous thromboembolism (VTE) is a complex disease that aggregates in families. Both acquired and genetic risk factors are important. Proper recognition and management of high-risk individuals are important.

Reduced Apolipoprotein M and Adverse Outcomes Across the Spectrum of Human Heart Failure.

Background: Apo (apolipoprotein) M mediates the physical interaction between high-density lipoprotein (HDL) particles and sphingosine-1-phosphate (S1P). Apo M exerts anti-inflammatory and cardioprotective effects in animal models.

Methods: In a subset of PHFS (Penn Heart Failure Study) participants (n=297), we measured apo M by Enzyme-Linked ImmunoSorbent Assay (ELISA).

Advances in Understanding Mechanisms of Thrombophilic Disorders.

Venous thromboembolism constitutes a major medical problem afflicting millions of individuals worldwide each year. Its pathogenesis is multifactorial, involving both environmental and genetic risk factors. The most common genetic risk factor known to date is a mutation in the factor V (FV) gene (R506Q or FV Leiden), which impairs the normal regulation of FV by activated protein C (APC).

Plasma apoM and S1P levels are inversely associated with mortality in African Americans with type 2 diabetes mellitus.

apoM is a minor HDL apolipoprotein and carrier for sphingosine-1-phosphate (S1P). HDL apoM and S1P concentrations are inversely associated with atherosclerosis progression in rodents. We evaluated associations between plasma concentrations of S1P, plasma concentrations of apoM, and HDL apoM levels with prevalent subclinical atherosclerosis and mortality in the African American-Diabetes Heart Study participants (N = 545).

New functional test for the TFPIα cofactor activity of Protein S working in synergy with FV-Short.

Essentials Protein S and FV-Short are synergistic cofactors to Tissue Factor Pathway Inhibitor α (TFPIα). An assay for the TFPIα synergistic cofactor activity of protein S with FV-Short was developed. The assay was specific for the synergistic TFPIα-cofactor activity of free protein S.

Factor V-short and protein S as synergistic tissue factor pathway inhibitor (TFPIα) cofactors.

Background: FV-Short is a normal splice variant of Factor V (FV) having a short B domain, which exposes a high affinity-binding site for tissue factor pathway inhibitor α (TFPIα). FV-Short and TFPIα circulate in complex in plasma.

Objectives: The aim was to elucidate whether FV-Short affects TFPIα as inhibitor of coagulation FXa and to test whether the TFPIα-cofactor activity of protein S is influenced by FV-Short.

Lean ApoM Mice with Hyperactive Brown Adipose Tissue.

In Cell Reports, Christoffersen et al. [1] demonstrate that sphingosine 1-phosphate (S1P) bound to apolipoprotein M (apoM) regulates the activity and mass of brown adipose tissue (BAT). They found mice lacking apoM to have hyperactive BAT with high triglyceride (TG) utilization, resulting in low white adipose tissue (WAT) mass and low body weight.

High-density lipoprotein from end-stage renal disease patients exhibits superior cardioprotection and increase in sphingosine-1-phosphate.

Background: Chronic kidney disease (CKD) exacerbates the risk of death due to cardiovascular disease (CVD). Modifications to blood lipid metabolism which manifest as increases in circulating triglycerides and reductions in high-density lipoprotein (HDL) cholesterol are thought to contribute to increased risk. In CKD patients, higher HDL cholesterol levels were not associated with reduced mortality risk.

Evaluation of Expression Level of Apolipoprotein M as a Diagnostic Marker for Primary Venous Thromboembolism.

Recently, decreased levels of apolipoprotein M (ApoM) were shown to be associated with higher risk of recurrent venous thromboembolism (VTE) in male patients. However, the role of ApoM in primary VTE is unknown. We aimed in our study to analyze the plasma levels of ApoM in patients with VTE in order to evaluate the diagnostic importance of ApoM in primary VTE.

Vitamin K-Dependent Protein S: Beyond the Protein C Pathway.

Protein S is a vitamin K-dependent plasma glycoprotein circulating in plasma at a concentration of around 350 nM. Approximately 60% of protein S in human plasma is bound to the complement regulatory protein C4b-binding protein (C4BP) in a high-affinity, high-molecular-weight complex. Protein S in plasma has multiple anticoagulant properties and heterozygous protein S deficiency is associated with increased risk of venous thrombosis.

Novel insights into the regulation of coagulation by factor V isoforms, tissue factor pathway inhibitorα, and protein S.

Factor V (FV) is a regulator of both pro- and anticoagulant pathways. It circulates as a single-chain procofactor, which is activated by thrombin or FXa to FVa that serves as cofactor for FXa in prothrombin activation. The cofactor function of FVa is regulated by activated protein C (APC) and protein S.

The nanoparticle protein corona formed in human blood or human blood fractions.

The protein corona formed around nanoparticles in protein-rich fluids plays an important role for nanoparticle biocompatibility, as found in several studies during the last decade. Biological fluids have complex compositions and the molecular components interact and function together in intricate networks. Therefore, the process to isolate blood or the preparation of blood derivatives may lead to differences in the composition of the identified protein corona around nanoparticles.