Despite the importance of circulating microparticles in haemostasis and thrombosis, there is limited evidence for potential causative effects of naturally produced cell-derived microparticles on fibrin clot formation and its properties. We studied the significance of blood microparticles for fibrin formation, structure, and susceptibility to fibrinolysis by removing them from platelet-free plasma using filtration. Clots made in platelet-free and microparticle-depleted plasma samples from the same healthy donors were analyzed in parallel. Microparticles accelerate fibrin polymerisation and support formation of more compact clots that resist internal and external fibrinolysis. These variations correlate with faster thrombin generation, suggesting thrombin-mediated kinetic effects of microparticles on fibrin formation, structure, and properties. In addition, clots formed in the presence of microparticles, unlike clots from the microparticle-depleted plasma, contain 0.1–0.5-μm size granular and CD61-positive material on fibres, suggesting that platelet-derived microparticles attach to fibrin. Therefore, the blood of healthy individuals contains functional microparticles at the levels that have a procoagulant potential. They affect the structure and stability of fibrin clots indirectly through acceleration of thrombin generation and through direct physical incorporation into the fibrin network. Both mechanisms underlie a potential role of microparticles in haemostasis and thrombosis as modulators of fibrin formation, structure, and resistance to fibrinolysis.
Whole genome sequencing (WGS) has great potential to explore all possible DNA variants associated with physical performance, psychological traits and health conditions of athletes. Here we present, for the first time, annotation of genomic variants of elite athletes, based on the WGS of 20 Tatar male wrestlers. The maximum number of high-quality variants per sample was over 3.8 M for single nucleotide polymorphisms (SNPs) and about 0.64 M for indels. The maximum number of nonsense mutations was 148 single nucleotide variants (SNVs) per individual. Athletes’ genomes on average contained 18.9 nonsense SNPs in a homozygous state per sample, while non-athletes’ exomes (Tatar controls, n = 19) contained 18 nonsense SNPs. Finally, we applied genomic data for the association analysis and used reaction time (RT) as an example. Out of 1884 known genome-wide significant SNPs related to RT, we identified four SNPs ( KIF27 rs10125715, APC rs518013, TMEM229A rs7783359, LRRN3 rs80054135) associated with RT in wrestlers. The cumulative number of favourable alleles ( KIF27 A, APC A, TMEM229A T, LRRN3 T) was significantly correlated with RT both in wrestlers ( P = 0.0003) and an independent cohort ( n = 43) of physically active subjects ( P = 0.029). Furthermore, we found that the frequencies of the APC A (53.3 vs 44.0%, P = 0.033) and LRRN3 T (7.5 vs 2.8%, P = 0.009) alleles were significantly higher in elite athletes (n = 107) involved in sports with RT as an essential component of performance (combat sports, table tennis and volleyball) compared to less successful (n = 176) athletes. The LRRN3 T allele was also over-represented in elite athletes (7.5%) in comparison with 189 controls (2.9%, P = 0.009). In conclusion, we present the first WGS study of athletes showing that WGS can be applied in sport and exercise science.
Among complications of systemic lupus erythematosus (SLE), thrombotic events are relatively common and contribute significantly to the morbidity and mortality rates. An increased risk of thrombosis in various diseases has been shown to be associated with the lytic stability and mechanical stiffness of the fibrin clot determined by its structure. Here we studied alterations of the fibrin clot properties in relation to disease severity in SLE patients. Plasma clots from 28 SLE patients were characterized by the kinetics of formation and fibrinolytic dissolution (using dynamic turbidimetry), the network and fiber ultrastructure (scanning electron microscopy), viscoelasticity (shear rheometry), and the rate and degree of crosslinking (Western blotting) correlated with the disease activity, blood composition, and compared to clotting of pooled normal human plasma. Clots made from plasma of SLE patients were lysed faster with exogenous t-PA than control clots from normal plasma without a significant difference between those from active (SLEDAI>4) and inactive (SLEDAI<4) SLE patients. Clots from the blood of patients with active SLE were characterized by significantly slower onset, but faster rate of fibrin polymerization and a higher optical density due to thicker fibers compared to those from inactive SLE and control pooled normal plasma. The rheological parameters of the clots (storage and loss moduli) were significantly increased in the active SLE patients along with enhanced fibrin crosslinking and hyperfibrinogenemia. The structural and rheological alterations displayed a strong positive correlation with high fibrinogen levels and other laboratory markers of immune inflammation. In conclusion, changes in the blood composition associated with active systemic inflammation in SLE cause significant alterations in the lytic resistance of fibrin clots associated with changes in polymerization kinetics, viscoelastic properties, and structure. The formation of more rigid prothrombotic fibrin clots in the plasma of SLE patients is likely due to the inflammatory hyperfibrinogenemia and greater extent of crosslinking. However, the higher susceptibility of the SLE clots to fibrinolysis may be a protective and/or compensatory mechanism that reduces the risk of thrombotic complications and improves patient outcomes.
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