ReviewCirculating microparticles: pathophysiology and clinical implications
Introduction
Microparticles are intact vesicles derived from cell membranes; they vary in size from 0.2–2.0 μm. They arise mainly through cell membrane activation processes, and from apoptosis. Microparticles originating from platelets, endothelial cells and monocytes have been most extensively studied, though similar particles can arise from red cells and granulocytes.
Platelet microparticles (PMP) were originally studied because of their procoagulant activity. More recent studies have investigated their involvement in the pathophysiology of disease, in particular in vascular disorders.
Chargaff et al. in 1949 first recognised that platelet-free plasma contains a precipitable factor that could accelerate thrombin generation.1 Later, in 1967, Wolf noted the presence of sudanophilic lipid-rich, cell-membrane derived material in platelet free plasma obtained by ultra-centrifugation, capable of generating thrombin.2 He demonstrated a linear correlation between the levels of PMP (which he termed “platelet dust”) and the original platelet count of the blood samples: he noted that high levels of platelet microparticles were present in polycythaemic patients with high platelet counts, and low levels in thrombocytopenic patients. By electron microscopy it was possible to confirm that these small microvesicles originated from activated platelets: numerous tendrils were seen from activated platelets with budding at the distal ends.
In 1999 Combes et al. described microparticles derived from human umbilical vein endothelial cells (HUVECs) stimulated by TNFα.3 These microparticles were detectable in healthy individuals and in patients with a prothrombotic coagulation abnormality. Combes’ group showed by electron microscopy that bleb formation occurs on the membrane of TNFα-stimulated HUVECs, leading to increased numbers of released microparticles. These endothelial microparticles expressed the same antigens as the corresponding cell surface, both in resting and activated conditions.
Later in 1994, Satta et al. described circulating microparticles originating from monocyte.4 They observed that monocyte microparticles could be generated after stimulation of monocytes by lipopolysaccharide (LPS).
In common with platelets, monocytes and endothelial cells, red blood cell membranes form microparticles in response to Ca++ influx into the cytosol. Ca++ influx occurs in red cells in a focal manner in response to complement terminal complex attack5, 6 and globally in association with a number of pathological conditions, including sickle cell disease7 and hereditary spherocytosis.8
Microparticle formation in red blood cells occurs physiologically in normal erythrocyte maturation and aging and is also marked during storage of red cells for transfusion.8 Red cell microparticles are generally smaller in size than those described for other cell types above. They are approximately 0.15 μm in diameter, and are accompanied by a smaller type of vesicle of approximately 0.06 μm, termed nanovesicles.9
Section snippets
Cell membrane phospholipids and the control of asymmetry
The composition and the distribution of cell membrane phospholipids are highly specific: phosphatidylcholine (PC) and sphingomyelin (SM) are located on the external membrane layer, while phosphatidylserine (PS) and phosphatidyl-ethanolamine (PE) are found on the inner side of the cell membrane. The preservation of this asymmetry is essential and is maintained through a complex transmembrane enzymatic balance. Loss of phospholipid asymmetry arises during platelet activation, apoptosis and
Blood collection
The choice of method for collection of the blood sample is important: a clean venepuncture
Platelet microparticles
During platelet activation, two types of vesicles are generated in the circulation: platelet microparticles and exosomes. Exosomes are simply secretional granules of activated platelets; they are generally smaller. The average size of microparticles is
Procoagulant activity
The ability to form microparticles is an essential part of physiological coagulation: a defect in this pathway causes a bleeding disorder called Scott syndrome. The aminophospholipids on the surface of microparticles from platelets and endothelial cells provide a large number of binding sites for factors IXa, VIII, Va and IIa.48, 53, 54, 55 In addition, endothelial cell derived microparticles express ultra large von Willebrand factor multimers (ULvWf), which promote platelet aggregates, and
Sickle cell disease
Microparticles can be detected in the circulation of patients with sickle cell disease (SCD) both during chronic phases and in crises.36 Chronic phase is characterised by chronic haemolysis, along with chronic activation of coagulant pathways. This results in low-grade thrombin generation, with depletion of anticoagulants, and activation of leucocytes and platelets. These pro-coagulant and pro-inflammatory processes are associated with endothelial damage and consequent detachment of endothelial
Acknowledgement
We would like to thank Mr Anthony Edward for his artistic contribution to the creation of Fig. 1a.
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