Immediate Lower Extremity Tourniquet Application to Delay Onset of Reperfusion Injury after Prolonged Crush Injury.

Reperfusion after severe crush injury is an infrequent, but life-threatening condition. It is a unique aspect of prehospital medicine that occurs in the presence of emergency responders attempting to extricate and treat patients who have suffered a crushing injury. These events are unlikely to occur in the hospital setting and, as a result, remain poorly studied. Some evidence exists regarding prophylaxis, but the efficacy of these treatments has not been clearly established. The use of commercial tourniquets to delay the onset of reperfusion injury has previously been described in theory. Extensive literature now exists supporting the safety of tourniquet use in limb trauma and this potential life-saving measure requires further study in patients with crush injury. We present a case of prehospital tourniquet application to delay reperfusion injury after crush injury that resulted in a reduction in morbidity and complete limb salvage.

Pepducin-based intervention of thrombin-receptor signaling and systemic platelet activation.

Transmembrane signaling through G protein-coupled receptors (GPCRs) controls a diverse array of cellular processes including metabolism, growth, motility, adhesion, neuronal signaling and blood coagulation. The numerous GPCRs and their key roles in both normal physiology and disease have made them the target for more than 50% of all prescribed drugs. GPCR agonists and antagonists act on the extracellular side of the receptors, whereas the intracellular surface has not yet been exploited for development of new therapeutic agents. Here, we demonstrate the utility of novel cell-penetrating peptides, termed 'pepducins', that act as intracellular inhibitors of signal transference from receptors to G proteins. Attachment of a palmitate lipid to peptides based on the third intracellular loop of protease-activated receptor 1 (PAR1) or PAR4 (refs. 3-5) yielded potent inhibitors of thrombin-mediated aggregation of human platelets. Infusion of the anti-PAR4 pepducin into mice extended bleeding time and protected against systemic platelet activation, consistent with the phenotype of PAR4-deficient mice. We show that pepducins might be used to ascertain the physiological roles of GPCRs and rapidly determine the potential therapeutic value of blockade of a particular signaling pathway.

Blocking the protease-activated receptor 1-4 heterodimer in platelet-mediated thrombosis.

BACKGROUND: Thrombin is the most potent agonist of platelets and plays a critical role in the development of arterial thrombosis. Human platelets express dual thrombin receptors, protease-activated receptor (PAR) 1 and PAR4; however, there are no therapeutic strategies that effectively target both receptors. METHODS AND RESULTS: Platelet aggregation studies demonstrated that PAR4 activity is markedly enhanced by thrombin-PAR1 interactions. A combination of bivalirudin (hirulog) plus a novel PAR4 pepducin antagonist, P4pal-i1, effectively inhibited aggregation of human platelets to even high concentrations of thrombin and prevented occlusion of carotid arteries in guinea pigs. Likewise, combined inhibition of PAR1 and PAR4 with small-molecule antagonists and pepducins was effective against carotid artery occlusion. Coimmunoprecipitation and fluorescence resonance energy transfer studies revealed that PAR1 and PAR4 associate as a heterodimeric complex in human platelets and fibroblasts. PAR1-PAR4 cofactoring was shown by acceleration of thrombin cleavage and signaling of PAR4 on coexpression with PAR1. CONCLUSIONS: We show that PAR1 and PAR4 form a stable heterodimer that enables thrombin to act as a bivalent functional agonist. These studies suggest that targeting the PAR1-PAR4 complex may present a novel therapeutic opportunity to prevent arterial thrombosis.

Pharmacodynamics and pharmacokinetics of the platelet GPIIb/IIIa inhibitor tirofiban in patients undergoing percutaneous coronary intervention: implications for adjustment of tirofiban and clopidogrel dosage.

INTRODUCTION: Despite extensive data supporting the use of platelet glycoprotein (GP) IIb/IIIa (GPIIb/IIIa) inhibitors in the therapy of patients with acute coronary syndromes (ACS), there is considerable debate as to the optimal choice of antiplatelet regimen. The objective of this study was to conduct a detailed time-resolved analysis of the effects of the GPIIb/IIIa inhibitor tirofiban with concomitant clopidogrel in ACS patients undergoing percutaneous coronary intervention (PCI) to improve the dosing regimen of these two commonly used antiplatelet drugs. METHODS: The study was performed in 14 patients with non-ST-segment elevation (NSTE) ACS who underwent PCI while being treated with the current typically utilized regimen of tirofiban (10 microg/kg bolus, 0.15 microg/kg/min infusion) and clopidogrel (300 mg). Platelet function was assessed before, during, and after tirofiban infusion using a panel of agonists for ADP receptors, PAR1 and PAR4 thrombin receptors, and collagen receptors. RESULTS: Measurements of circulating tirofiban levels demonstrated a trough, which paralleled a reduction in platelet inhibition for all platelet agonists during the time when PCI was being performed. Interestingly, younger ACS patients (<55 years) exhibited less inhibition of platelet function both during the PCI procedure and after termination of the tirofiban infusion. These apparent age differences were primarily attributed to a decreased responsiveness of the younger patients to clopidogrel. CONCLUSIONS: This study shows that the currently utilized tirofiban dosage is suboptimal and suggests that patients may benefit from a higher dose regimen.

Spontaneous pneumomediastinum: diagnostic and therapeutic interventions.

OBJECTIVES: The objective of this case series is to review our experience with spontaneous pneumomediastinum, review the available literature, and refine the current clinical approach to this uncommon condition. METHODS: The case notes of all patients admitted to the George Washington University Medical Center with spontaneous pneumomediastinum from April 2005 to June 2008 were retrospectively reviewed, indentifying seventeen patients on whom various data was collected and analyzed. RESULTS: The typical patient is a young man. The commonest presenting complaint is chest pain. Odynophagia and subcutaneous emphysema are common. Leucocytosis is uncommon. The need for swallow studies, antibiotics, and prolonged hospitalization is uncommon. Most patients have no recurrences or sequelae on long-term follow-up. CONCLUSION: Spontaneous pneumomediastinum is an uncommon, self-limiting condition. Due to concerns for the integrity of the aero-digestive tract, the finding of spontaneous pneumomediastinum usually results in unnecessary radiological investigations, dietary restriction and antibiotic administration with prolonged hospitalization.