Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation (original) (raw)
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Journal of Thrombosis and Haemostasis, 2003
Background: Circulating microparticles of various cell types are present in healthy individuals and, in varying numbers and antigenic composition, in various disease states. To what extent these microparticles contribute to coagulation in vivo, is unknown. Objectives: To examine the in vivo thrombogenicity of human microparticles. Methods: Microparticles were isolated from pericardial blood of cardiac surgery patients and venous blood of healthy individuals. Their numbers, cellular source, and TF exposure were determined using flow cytometry. Their in vitro procoagulant properties were studied in a fibrin generation test, and their in vivo thrombogenicity in a rat model. Results: The total number of microparticles did not differ between pericardial samples and samples from healthy individuals (P = 0.786). In both groups, microparticles from platelets, erythrocytes, and granulocytes exposed TF. Microparticle-exposed TF antigen levels were higher in pericardial compared with healthy individual samples (P = 0.036). Pericardial microparticles were strongly procoagulant in vitro and highly thrombogenic in a venous stasis thrombosis model in rats, whereas microparticles from healthy individuals were not [thrombus weights 24.8 (12.2-41.3) mg versus 0 (0-24.3) mg median and range; P < 0.001]. Preincubation of pericardial microparticles with an inhibitory antibody against human TF abolished their thrombogenicity [0 (0-4.4) mg; P < 0.01], while a control antibody had no effect [19.6 (12.6-53.7) mg; P > 0.05]. The thrombogenicity of the microparticles correlated strongly with their TF exposure (r = 0.9524, P = 0.001). Conclusions: Human cell-derived microparticles promote thrombus formation in vivo in a TF-dependent manner. They might be the direct cause of an increased thromboembolic tendency in various patient groups.
Microparticle analysis in disorders of hemostasis and thrombosis
Cytometry. Part A : the journal of the International Society for Analytical Cytology, 2015
Microparticles (MPs) are submicron vesicles released from the plasma membrane of eukaryotic cells in response to activation or apoptosis. MPs are known to be involved in numerous biologic processes, including inflammation, the immune response, cancer metastasis, and angiogenesis. Their earliest recognized and most widely accepted role, however, is the ability to promote and support the process of blood coagulation. Consequently, there is ongoing interest in studying MPs in disorders of hemostasis and thrombosis. Both phosphatidylserine (PS) exposure and the presence of tissue factor (TF) in the MP membrane may account for their procoagulant properties, and elevated numbers of MPs in plasma have been reported in numerous prothrombotic conditions. To date, however, there are few data on true causality linking MPs to the genesis of thrombosis. A variety of methodologies have been employed to characterize and quantify MPs, although detection is challenging due to their submicron size. F...
Thrombosis Research, 2012
Circulating microparticles (MP) are small membrane vesicles derived from a variety of cell types including platelets, erythrocytes, leukocytes, and endothelial cells. They harbor a large repertoire of cell surface receptors, mRNA and biological activities that are related to their involvement in many biological functions. MP subpopulations are well known for their procoagulant activity that relies mainly on the expression of phosphatidylserine and of tissue factor, the major cellular activator of the clotting system. In this review, we will discuss a new vision of MP as complex and ambivalent structures, expressing both activators and inhibitors of coagulation, but also conveying fibrinolytic properties, counteracting their procoagulant activities and identifying MP as integrative systems tuning the hemostatic balance.
Thrombosis and Haemostasis, 2009
Microparticles (MP) are lipid vesicles from platelets, leukocytes and endothelial cells that are involved in early thrombogenesis. We evaluated a detailed time-course analysis of MPs on thrombogenesis and the associated tissue factor (TF) activity in wild-type, in gene-deleted for E-and P-selectins and with high levels of P-selectin expression after the initiation of venous thrombosis in mice. Inferior vena cava (IVC) ligation was performed on C57BL/6 mice (n =191, 59 = wild-type [WT], 55 = gene-deleted for E-and P -selectins [knock-outs, EPKO] and 77 = elevated levels of soluble P-selectin, named Delta Cytoplasmic Tail (ΔCT). Animals were euthanised at various time points to assess MP production, origin and thrombus weight. MPs were re-injected into separate mice at concentrations of 80,000 and 160,000 units, as well as from different ages. In addition, MPs from thrombosed animals were pooled and TF activity quantitated using a chromogenic assay. Thrombus weight correlated negatively with MPs derived from leukocytes, and positively with MPs derived from platelets for WT animals (p<0.05), while MPs from platelets presented a positive correlation to thrombus weight in the WT and EPKO groups (p<0.01). Total MPs correlated negatively with thrombus weight in the ΔCT group (p<0.05). MP re-injections led to greater thrombus weight, while older MP reinjections tended to form larger thrombus than younger. Finally, TF bearing MPs showed a significant correlation to MP concentrations (R=0.99). In conclusion, MPs appear to be an important element in venous thrombogenesis.
Circulating Microparticles Alter Formation, Structure, and Properties of Fibrin Clots
Scientific Reports, 2015
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. Circulating microparticles (MPs) are 0.1-1-μ m-large phospholipid vesicles 1 released from blood and vascular cells upon activation and apoptosis. The mechanism of MP formation by budding of the outer cell membranes provides them with procoagulant activity, mainly due to phosphatidylserine exposure and tissue factor expression 2,3. Tissue factor-bearing MPs are important for thrombin generation and blood clotting in vitro 4 as well as for thrombus formation in vivo 5-10. MPs are present in the blood under physiological conditions, but the level of circulating MPs is elevated in vascular, infectious, and immune-mediated pathologies 11-16. MPs are heterogeneous in size, composition, density, and cellular origin. MPs derived from different cell types possess unique functional capabilities due to variations of lipids and proteins acquired from parent cells 17-19. The main fraction of circulating MPs in a non-diseased state is reported to be platelet or megakaryocyte-derived MPs 20,21. Circulating MP in the absence of disease likely originate from aging cells 22. Despite many studies on the role of MPs in diseases, the functional importance of normally present MPs is unclear. Circulating MPs in healthy controls were shown to support low-grade thrombin generation by the contact pathway 23. Whether MPs originating under physiological circumstances can provide sufficient activity to support blood coagulation is not clear. Particularly little is known about potential effects of MPs on fibrin clot formation and lysis, the determinant stages of blood clotting. Fibrin is a three-dimensional filamentous
Cytometry. Part B, Clinical cytometry, 2017
Though the presence of platelets-derived microparticles (MPs) have previously been described in heparin-induced thrombocytopenia (HIT), the mechanism of thrombosis in HIT remains poorly understood. We aimed to assess the presence and origin of MPs in patients with HIT and their possible contribution to HIT with thrombosis (HITT). Forty-five patients with HIT and 45 matched hospitalized patients with not confirmed HIT (HIT-negative) were enrolled. Twelve HIT patients (27%) developed HITT. MPs expressing phosphatidylserine (Annexin V-MP), activated platelet-derived (P-Selectin+), activated leukocyte-derived (L-Selectin+), PF4-bearing and tissue factor-bearing (TF+) MPs were measured by flow-cytometry. HIT patients showed significantly higher median levels of P-Selectin+, L-Selectin+, PF4-bearing, L-Selectin+/TF + MPs than HIT-negative; PF4-bearing MP showed the highest statistical difference. As compared to HIT patients, HITT patients showed a trend of higher median levels of all MP s...