Platelet Aggregation In Microvessels Research Articles

Thromboembolic injury and systemic toxicity induced by nicotine in mice

Nicotine is involved in the pathogenesis of hematological and cardiopulmonary diseases. The understanding of the pathophysiological mechanisms underlying these undesirable effects is however unclear. Cigarette smoking, nicotine gums and patches are common sources for nicotine ingestion. We have investigated the nicotine's effect on cerebral microvessel thrombosis and systemic toxicity. Mice received either nicotine (1 mg/kg, i.p.) or saline (control), once a day for 21 days. Briefly, after bolus intravenous fluorescein injection, a photo insult of cerebral microvessel was done. The platelet aggregation in microvessels was video recorded and analyzed. In conjunction, the plasma levels of superoxide dismutase (SOD), lactate dehydrogenase (LDH), liver enzymes, creatinine and blood urea nitrogen (BUN); and histopathological studies were carried out. Our results revealed a significant prothrombotic effect following nicotine exposure. Significant decrease in SOD indicates the occurrence of oxidative stress involved in the tissue damages and increase in the LDH emphasize the systemic toxicity. Substantial rise in the liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were observed. Lungs histology showed intra-vascular hemorrhagic infarction with necrosis, macrophage and neutrophils infiltration. Liver histology showed intravascular thrombosis and portal inflammation. We conclude that the sub-acute nicotine exposure causes an increase in thrombosis in cerebral microvessels and systemic, hepatic and pulmonary toxicity.

A Potential Role for Plasma Uric Acid in the Endothelial Pathology of Plasmodium falciparum malaria

BackgroundInflammatory cytokinemia and systemic activation of the microvascular endothelium are central to the pathogenesis of Plasmodium falciparum malaria. Recently, ‘parasite-derived’ uric acid (UA) was shown to activate human immune cells in vitro, and plasma UA levels were associated with inflammatory cytokine levels and disease severity in Malian children with malaria. Since UA is associated with endothelial inflammation in non-malaria diseases, we hypothesized that elevated UA levels contribute to the endothelial pathology of P. falciparum malaria.Methodology/Principal FindingsWe measured levels of UA and soluble forms of intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-Selectin), thrombomodulin (sTM), tissue factor (sTF) and vascular endothelial growth factor (VEGF) in the plasma of Malian children aged 0.5–17 years with uncomplicated malaria (UM, n = 487) and non-cerebral severe malaria (NCSM, n = 68). In 69 of these children, we measured these same factors once when they experienced a malaria episode and twice when they were healthy (i.e., before and after the malaria transmission season). We found that levels of UA, sICAM-1, sVCAM-1, sE-Selectin and sTM increase during a malaria episode and return to basal levels at the end of the transmission season (p<0.0001). Plasma levels of UA and these four endothelial biomarkers correlate with parasite density and disease severity. In children with UM, UA levels correlate with parasite density (r = 0.092, p = 0.043), sICAM-1 (r = 0.255, p<0.0001) and sTM (r = 0.175, p = 0.0001) levels. After adjusting for parasite density, UA levels predict sTM levels.Conclusions/SignificanceElevated UA levels may contribute to malaria pathogenesis by damaging endothelium and promoting a procoagulant state. The correlation between UA levels and parasite densities suggests that parasitized erythrocytes are one possible source of excess UA. UA-induced shedding of endothelial TM may represent a novel mechanism of malaria pathogenesis, in which activated thrombin induces fibrin deposition and platelet aggregation in microvessels. This protocol is registered at clinicaltrials.gov (NCT00669084).

Early recovery of microvascular perfusion induced by t-PA in combination with abciximab or eptifibatide during postischemic reperfusion.

GPIIb/IIIa inhibitors abciximab and eptifibatide have been shown to inhibit platelet aggregation in ischemic heart disease. Our aim was to test the efficacy of abiciximab (Reo Pro) or eptifibatide (Integrilin) alone or in combination with plasminogen activator (t-PA) in an experimental model of ischemia reperfusion (I/R) in hamster cheek pouch microcirculation visualized by fluorescence microscopy. Hamsters were treated with saline, or abiciximab or eptifibatide or these drugs combined with t-PA infused intravenously 10 minutes before ischemia and through reperfusion. We measured the microvessel diameter changes, the arteriolar red blood cell (RBC) velocity, the increase in permeability, the perfused capillary length (PCL), and the platelet and leukocyte adhesion on microvessels. I/R elicited large increases in the platelet and leukocyte adhesion and a decrease in microvascular perfusion. These responses were significantly attenuated by abiciximab or eptifibatide (PCL:70 and 65% at 5-10 mins of reperfusion and 85 and 87% at 30 mins of reperfusion, respectively, p < 0.001) while t-PA combined with abiciximab or eptifibatide, was more effective and microvascular perfusion recovered immediately after postischemic reperfusion. Platelets are crucial in I/R injury, as shown by the treatment with abicixmab or eptifibatide, which decreased platelet aggregation in microvessels, and also decreased leukocyte adhesion in venules. Arterial vasoconstriction, decreased arterial RBC velocity and alterations in the endothelial barrier with increased permeability delayed the complete restoration of blood flow, while t-PA combined with inhibition of platelet aggregation speeded up the capillary perfusion after reperfusion.

Platelet aggregation in the cerebral microcirculation: effect of aspirin and other agents.

After a certain period of time filtered ultraviolet light produces platelet aggregation in microvessels on the cerebral surface of the mouse, but only when sodium fluorescein is first injected intravascularly to provide a light-absorbing, heat-generating target. The platelet aggregates fluoresce. They occur only in the illuminated field and adhere to arteriolar and venular walls. Vasoconstriction is not detected prior to or up to 30 seconds after aggregation. Electron microscopy reveals damaged endothelium and undamaged red cells, as well as aggregates consisting almost exclusively of platelets in varying stages of aggregation, pseudopod formation, and degranulation. The time between onset of the noxious stimulus and recognition of the first aggregate can be measured as the vessels are observed microscopically. This "time of aggregation" is prolonged by pentobarbital as opposed to urethane anesthesia, and also is related to time elapsed after craniotomy. We also found that aspirin and indomethacin significantly prolong time to first aggregate, but only on the arteriolar side of the circulation. This is so even though the composition of the aggregates is the same on both the arteriolar and venular sides. Heparin has no effect.