Protein S deficiency and novel oral anticoagulants: An intriguing case

Peer Reviewe

Vitamin K-dependent proteins GAS6 and Protein S and TAM receptors in patients of systemic lupus erythematosus: correlation with common genetic variants and disease activity

INTRODUCTION: Growth arrest-specific gene 6 protein (GAS6) and protein S (ProS) are vitamin K-dependent proteins present in plasma with important regulatory functions in systems of response and repair to damage. They interact with receptor tyrosine kinases of the Tyro3, Axl and MerTK receptor tyrosine kinase (TAM) family, involved in apoptotic cell clearance (efferocytosis) and regulation of the innate immunity. TAM-deficient mice show spontaneous lupus-like symptoms. Here we tested the genetic profile and plasma levels of components of the system in patients with systemic lupus erythematosus (SLE), and compare them with a control healthy population. METHODS: Fifty SLE patients and 50 healthy controls with matched age, gender and from the same geographic area were compared. Genetic analysis was performed in GAS6 and the TAM receptor genes on SNPs previously identified. The concentrations of GAS6, total and free ProS, and the soluble forms of the three TAM receptors (sAxl, sMerTK and sTyro3) were measured in plasma from these samples. RESULTS: Plasma concentrations of GAS6 were higher and, total and free ProS were lower in the SLE patients compared to controls, even when patients on oral anticoagulant treatment were discarded. Those parameters correlated with SLE disease activity index (SLEDAI) score, GAS6 being higher in the most severe cases, while free and total ProS were lower. All 3 soluble receptors increased its concentration in plasma of lupus patients. CONCLUSIONS: The present study highlights that the GAS6/ProS-TAM system correlates in several ways with disease activity in SLE. We show here that this correlation is affected by common polymorphisms in the genes of the system. These findings underscore the importance of mechanism of regulatory control of innate immunity in the pathology of SLE

Host-Derived Molecules as Novel Chagas Disease Biomarkers: Hypercoagulability Markers in Plasma

The most severe clinical symptomatology of Chagas disease affects ~30% of those chronically infected with the Trypanosoma cruzi parasite. The pathogenic mechanisms that lead to life-threatening heart and gut tissue disruptions occur "silently" for a longtime in a majority of cases. As a result, despite there are several serological and molecular methods available to diagnose the infection in its acute and chronic stages, diagnosis is often achieved only after the onset of clinical symptoms in the chronic phase of the disease. Furthermore, although there are two drugs to treat it, the assessment of their performance is impractical with current parasite-derived diagnostics, and therapeutic efficacy cannot be acknowledged in a timely manner.In this chapter we present two procedures to measure host-derived molecules as surrogates of therapeutic response against chronic T. cruzi infection. Their outputs relate to the generation and activity of thrombin, a major component of the blood coagulation cascade. This is due to the fact that a hypercoagulability state has been described to occur in chronic Chagas disease patients and revert after treatment with benznidazole

Contribution of the mRNA binding protein CPEB4 in platelet biology through translational control

Trabajo presentado en el European Congress on Thrombosis and Haemostasis (ECTH), celebrado en Glasgow (Reino Unido), del 2 al 4 de octubre de 2019Platelets are anucleated cells, lacking the mechanism of nuclear transcription. However, there are increasing data showing that platelets have post-transcriptional mechanisms that allow them to regulate the expression of a specific set of proteins, modulating platelet activation. Among the components of platelets, the abundant presence of messenger RNA (mRNA) is striking. This mRNA repertoire is specific and can be translated into proteins, however the mechanisms responsible for the translation of mRNA and its biological implications are unknown. Among these regulatory mechanisms, CPEBs (Cytoplasmic Polyadenylation Element Binding proteins) are a family of proteins that control mRNA translation by binding to the 3'UTR region and regulating the length of the poly (A) tail. These proteins were originally discovered to regulate the translation of maternal RNAs during embryonic development, but it is now known that they also regulate up to 20% of the transcriptome in the adult organism. AIMS The main objective of the project is to analyze the role of the CPEB4 protein in hemostasis and platelet functions. Physiological role of CPEB4 in platelets. Role does CPEB4 play in thrombosis and vascular pathology Molecular mechanism underlying the functions of CPEB4 in platelets. METHODS We have generated conditional knockout mice in order to study the role of CPEB4 in platelets (mouse Pf4-Cre:CPEB4lox/lox). Using in vitro (platelet activation and aggregation tests), in vivo (tail bleeding, TPO levels, megakaryocytopoiesis analysis, experimental pulmonary embolism) and high throughput (proteomics) strategies we have analyzed the functional effects and underlying molecular mechanism of CPEB4 absence in platelets. RESULTS CPEB4 is readily detected in both human and mouse platelet extracts. Animals with a platelet-specific deficiency in CPEB4 show a normal platelet counts in blood, but increased concentration of TPO in plasma, and increased megakaryocyte area and number in the bone marrow. These results suggest an increased platelet turn-over in the absence of CPEB4 in vivo. Moreover, CPEB4-deficient platelets have a tendency to lower activation and aggregation. In animal models of hemostasis and venous and arterial thrombosis, platelet CPEB4-deficient animals showed slightly increased bleeding times and less tendency to thrombus formation. Proteomic data comparing platelets WT or lacking CPEB4 suggest mechanisms of action of this regulatory pathway and possible relevant targets. SUMMARY/CONCLUSION Control of RNA translation by CPEB4 represents a novel regulatory mechanism of platelet function. The absence of CPEB4 reduces platelet activation by thrombin. Mice deficient in CPEB4 in platelets showed less thrombosis and increased bleeding. These results underscore the importance of the mRNA pool in platelet biology.Fundació Marató de TV3; SET

Control de la traducción por la proteína de unión A mRNA CPEB4 en la biología plaquetar

Trabajo presentado en el LXIII Congreso Nacional de la SEHH (Sociedad Española de Hematología y Hemoterapia) y XXXVII Congreso Nacional de la SETH (Sociedad Española de Trombosis y Hemostasia), celebrado en Pamplona (España) del 14 al 16 de octubre de 2021

Predictive value of the adjusted global anti-phospholipida syndrome score on clinical recurrence in APS patients. A longitudinal study

Objective: To assess the effect of the average adjusted global APS score (aGAPSS) over time on recurrence of clinical manifestations in APS patients through a retrospective longitudinal study. Methods: The study included 200 patients with APS. The aGAPSS was calculated for each patient at baseline and on a yearly basis for either up to 6 years (minimum 3 years) or just before the clinical event in patients who experienced clinical recurrence. The mean score per patient was computed. In patients under vitamin K antagonists (VKA) the percentage of time spent within the therapeutic range (TTR) was calculated. Cox-regression analysis was performed to determine the cut-off value of the aGAPSS with the strongest association with clinical recurrence. Results: Higher average aGAPSS values were found in patients who experienced clinical recurrence in comparison to patients who did not [8.81 (95% C.I. 7.53-10.08) vs 6.38 (95% C.I. 5.64-7.12), p = 0.001], patients with thrombotic recurrence compared to patients with obstetric recurrence [9.48 (95% C.I. 8.14-10.82) vs 4.25 (95% C.I. 0.85-7.65), p = 0.006], and patients with arterial thrombosis compared to patients with venous thrombosis [10.66 (S.D. 5.48) vs 6.63 (S.D. 4.42), p = 0.01]. aGAPSS values > 13 points were associated with the highest risk of recurrence in multivariate analysis [HR = 3.25 (95% C.I. 1.93-5.45, p < 0.0001]. TTR was not statistically different between patients who had thrombosis recurrence and patients who had not. Conclusions: Our data support the role of periodic (annual) monitoring of the aGAPSS score in predicting clinical recurrence in patients with APS