Tuesday, September 1, 2009
MICROPARTICLES: What are they? What do they do? How are they involved in coagulation?
First described 40 years ago as the "coagulant material in minute particle form" in platelet-poor plasma (otherwise termed platelet dust), microparticles have been the subject of considerable debate and controversy over the years, particularly in the context of blood coagulation in healthy individuals
Cell-derived microparticles (MP)are small membranous vesicles released from the plasma membranes of platelets, leukocytes, red cells and endothelial cells in response to diverse biochemical agents or mechanical stresses. They are the main carriers of circulating tissue factor, the principal initiator of intravascular thrombosis, and are implicated in a variety of thrombotic and inflammatory disorders. Circulating MP provide an additional procoagulant phospholipid surface enabling the assembly of the clotting enzyme complexes and thrombin generation. Their procoagulant properties rely on the exposure of phosphatidylserine and on the possible presence of tissue factor, the main initiator of blood coagulation. Microparticles constitute the main reservoir of blood-borne tissue factor. Derived from various cells, most notably platelets, erythrocytes, leucocytes and endothelial cells, circulating MP are detectable in the circulation of healthy subjects. Elevated levels are encountered in diseases with vascular involvement and hypercoagulability such as disseminated intravascular coagulation, diabetes, immune-mediated thrombosis, kidney diseases, acute coronary syndromes or systemic inflammatory disease, where they appear indicative of a poor clinical outcome.There is evidence suggesting that cell-derived microparticles are involved predominantly with microvascular, as opposed to macrovascular, thrombosis. Cell-derived microparticles may substantially contribute to ischemic brain disease in several settings, as well as to neuroinflammatory conditions.
GENERATION OF MICROPARTICLES:
The finding of localized biomechanical generation of microparticles on thrombogenic surfaces is interesting and potentially important and should stimulate further investigation into the relationship between shear and microparticle formation. Platelets in travel through vessels in vitro by sheer stress. The shedding of procoagulant microparticles from the surface of platelets and other cell types involves proteolytic shedding mechanisms linked to cell stimulation by potent agonists or following apoptosis. It remains to be seen whether proteolytic shedding is the predominant mechanism of microparticle generation under lower shear conditions and whether biomechanically derived particles become progressively more important at higher shear. Nonetheless, these findings raise interesting issues and should stimulate further investigation into the precise relationship between the earliest events of platelet adhesion and the subsequent initiation of blood coagulation, a topic that remains as uncertain today as it did when microparticles were first discovered.
Elevated levels of MPs appear to play a role in the pathogeneisis of thrombosis in sepsis. Both events of thrombosis and sepsis, can be orchestrated by the interaction between circulating and vascular cells that under activation release microparticles. Circulating levels of microparticles and platelet- and endothelial-derived microparticles were increased in septic patients. Sepsis and trauma lead to a sustained activation of monocytes and endothelium. In the vascular compartment, stimulated cells release microparticles. At sites of endothelium injury, enhanced release or recruitment of procoagulant MP through P-selectin-PSGL-1 pathway could concentrate TF activity above a threshold allowing blood coagulation to be triggered. Converging evidences from experimental or clinical data highlight a role for MP harboring tissue factor in the initiation of disseminated intravascular coagulation. In these settings, the pharmacological modulation of MP levels or biological functions through activated protein C or factor VIIa allows challenging issues.
Platelet MPs are submicormeter fragments resulting from the remodeling of the platelet membrane in relation to several conditions. These MP are increased in several prothrombotic and inflammatory disorders including cardiovascular disease, autoimmune and infectious diseases and cancer. Clinically, you can use platelet microparticles for identifying patients with vascular risk and monitoring response to treatment. Little is known about the processes by which platelet microparticles are generated in vivo. However observing video microscopy of live mouse megakaryocytes demonstrated that microparticles form as submicron beads and are CD41+, CD42b+. They express surface phosphatidylserine. To determine whether circulating microparticles are derived primarily from activated platelets or megakaryocytes, markers were identified that distinguish between these 2 populations. CD62P and LAMP-1 were found only on mouse microparticles from activated platelets. In contrast, full-length filamin A was found in megakaryocyte-derived microparticles, but not microparticles from activated platelets. Circulating microparticles isolated from mice were CD62P-, LAMP-1 and expressed full-length filamin A, indicating a megakaryocytic origin. Similarly, circulating microparticles isolated from healthy volunteers were CD62P- and expressed full-length filamin A. Cultured human megakaryocytes elaborated microparticles that were CD41+, CD42b+, and express surface phosphatidylserine. These results indicate that direct production by megakaryocytes represents a physiologic means to generate circulating platelet microparticles.
WOMEN AND MENOPAUSE:
The risk for symptomatic atherosclerotic disease increases after menopause, currently recognized risk factors do not identify ongoing disease processes in low-risk women. This study tested the hypothesis that circulating cell-derived microparticles may reflect disease processes in women defined as low risk by the Framingham risk score. The concentration and phenotype of circulating microparticles were evaluated in a cross-sectional study of apparently healthy menopausal women, screened for enrollment into the Kronos Early Estrogen Prevention Study. Microparticles were evaluated by flow cytometry, and coronary artery calcification (CAC). The procoagulant activity of isolated microparticles was determined with a sensitive fluorescent thrombin generation assay. Chronological age, body mass index, serum lipids, systolic blood pressure (Framingham risk score < 10%, range 1-3%), and high-sensitivity C-reactive protein did not differ significantly among women with low (0 < 35; range, 0.3-32 Agatston units) or high (>50; range, 93-315 Agatston units) CAC compared with women without calcification. The total concentration and percentage of microparticles derived from platelets and endothelial cells were greatest in women with high CAC scores. The thrombin-generating capacity of the isolated microparticles correlated with phosphatidylserine expression, which also was greatest in women with high CAC scores. The percentages of microparticles expressing granulocyte and monocyte markers were not significantly different among groups. Therefore, the characterization of platelet and endothelial microparticles may identify early menopausal women with premature CAC who would not otherwise be identified by the usual risk factor analysis.
MP has been found to be markedly increased in patients with both breast and pancreatic cancer who present with VTE. A study looked at various malignancies and their corresponding levels of MP. It was observed that there is a relationship between elevated MP activity and VTE in patients with cancer. It appears that is the contribution of the cancer cells that cause the elevated MPs. It was determined that patients that develop VTE during cancer did not have elevated microparticles. Therefore, the VTE doesn't cause the increase in MP, but the cancer cells.
So, there you have it, microparticles do correlate with several disease states, and appear that increased levels correlate with phosphatidylserine expression. Early identification of this process may aid in the diagnosis and early intervention for several disorders. So stay tuned for more research in this area and outcomes in coagulation disorders.
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