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Published on: February 14, 2017
Differential contributions of monocyte- and platelet-derived microparticles towards thrombin generation and fibrin
M M Aleman1, C Gardiner, P Harrison
1Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
Background:
Microparticles (MPs) are sub-micron vesicles shed by activated or apoptotic cells, including platelets and monocytes. Increased circulating MPs are associated with thrombosis; however, their role in thrombogenesis is poorly understood.
Objective:
To determine how MPs promote thrombin generation and modulate fibrin density and stability.
Methods:
Platelets and monocytes were isolated from healthy donors. Platelets were stimulated with calcium ionophore, thrombin receptor agonist peptide (TRAP) or TRAP/convulxin. Monocytes and human monocytic THP-1 cells were stimulated with lipopolysaccharide (LPS). MPs were isolated, washed by high-speed centrifugation and assessed using the following: transmission electron microscopy (TEM), Nanoparticle Tracking Analysis (NTA), flow cytometry, tissue factor (TF) activity, prothrombinase activity, thrombin generation, and clot formation, density and stability.
Results:
MPs from monocytes (M-MPs) and platelets (PMPs) had similar shapes and diameters (100-300 nm). M-MPs had TF activity (16.7 ± 2.4 pm TF per 10(6) MP), supported prothrombinase activity and triggered shorter thrombin generation lag times than buffer controls (5.4 ± 0.5 vs. 84.2 ± 4.8 min, respectively). Compared with controls, M-MPs supported faster fibrin formation (0.24 ± 0.24 vs. 76.7 ± 15.1 mOD min(-1) , respectively), 38% higher fibrin network density and higher clot stability (3.8-fold higher turbidity in the presence of tissue plasminogen activator). In contrast, PMPs did not have TF activity and supported 2.8-fold lower prothrombinase activity than M-MPs. PMPs supported contact-dependent thrombin generation, but did not independently increase fibrin network density or stability. Interestingly, PMPs increased rates of thrombin generation and fibrin formation (1.7- and 1.3-fold, respectively) when mixed with THP-1-derived MPs.
Conclusion:
MPs from platelets and monocytes differentially modulate clot formation, structure and stability, suggesting unique contributions to thrombosis.
Insights
Microparticles (MPs) from monocytes and platelets differentially impact blood clot formation. Monocyte-derived MPs promote thrombin generation and fibrin clot stability, while platelet-derived MPs have distinct roles, suggesting unique contributions to thrombosis.
Area of Science:
- Hematology
- Vascular Biology
- Biochemistry
Background:
- Microparticles (MPs) are vesicles shed by activated or apoptotic cells.
- Elevated circulating MPs are linked to thrombosis, but their precise role is unclear.
Purpose of the Study:
- To investigate how MPs influence thrombin generation.
- To determine the effect of MPs on fibrin clot density and stability.
Main Methods:
- Isolated MPs from human monocytes and platelets.
- Assessed MP characteristics using TEM, NTA, and flow cytometry.
- Measured tissue factor activity, prothrombinase activity, thrombin generation, and clot formation dynamics.
Main Results:
- Monocyte-derived MPs (M-MPs) exhibited tissue factor activity, enhanced prothrombinase activity, and accelerated thrombin generation.
- M-MPs increased fibrin network density and clot stability.
- Platelet-derived MPs (PMPs) lacked tissue factor activity and showed lower prothrombinase activity than M-MPs.
- PMPs enhanced thrombin generation and fibrin formation when combined with monocyte-derived MPs.
Conclusions:
- MPs derived from monocytes and platelets have distinct effects on clot formation, structure, and stability.
- These findings suggest unique roles for different MP types in the pathogenesis of thrombosis.
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