Nicolas Morel

Microparticles: a critical component in the nexus between inflammation, immunity, and thrombosis

Plasma membrane remodeling characterized by phosphatidylserine exposure and consecutive microparticle (MP) shedding is an ubiquitous process enabling the clearance of senescent cells and the maintenance of tissue homeostasis. MPs are released as fragments from the budding plasma membrane of virtually all eukaryotic cell types undergoing stimulation or apoptosis and may be considered a broad primitive response to stress. MP release is dependent on cytoskeleton degradation pathways involving caspases, requires a sustained increase in intracellular calcium triggering K+ and Cl− efflux and is possibly tuned by mitochondria permeability changes. Because they convey a broad spectrum of bioactive molecules, circulating MPs may serve as shuttles promoting cellular cross talk in various pathological settings such as inflammation or immunity-induced thrombotic disorders. If the drastic shedding of procoagulant MPs appears clearly noxious in thrombotic disorders or in some models of inflammation-induced coagulopathy, this does not necessarily endorse their invariably harmful nature. In the vessel, endothelial cytoprotection reported in the early regulation of inflammation-induced coagulopathy is emblematic of the beneficial effects provided by MPs. In addition, MPs would prove beneficial in the prevention of blood leakage. Because of their multiple properties that are characteristic of a private response of the parental cell, MPs could act as cytoprotective and anti-inflammatory agents through the delivery of activated protein C or annexin 1 and could contribute to the limitation of vascular hyporeactivity. Owing to their ability to cargo bioactive signals, MPs could be viewed as an integrated communication network enabling the coordination of complex cellular responses in biological fluids and the maintenance of the homeostasis equation. A better understanding of the molecular mechanisms involved in MP shedding would pave the way of a new pharmacological approach aiming at the control of MP-driven cellular responses.

Platelet microparticles and vascular cells interactions: A checkpoint between the haemostatic and thrombotic responses

Described 40 years ago as cell dust, microparticles (MPs) are now considered a key component in the haemostatic response. Owing to their plasma membrane reactivity, platelets are believed to constitute the main source of circulating procoagulant microparticles and behave as true sensors for the haemostatic response. Erythrocytes, leukocytes and endothelial cells are also able to shed MPs in the blood flow, their respective contribution varying with the pathophysiologic circumstances and extent of the cellular damage. The catalytic properties of MPs rely on a procoagulant anionic phospholipid, phosphatidylserine, made accessible at the outer leaflet following plasma membrane remodelling and on the eventual presence of tissue factor (TF). Under resting conditions, most membrane-bound TF is encrypted. Although able to bind to FVIIa, it does not trigger blood coagulation. Under prothrombotic conditions, TF decryption would occur through intricate pathways involving platelets, monocytes, endothelial cells and derived MPs. P-selectin/P-selectin glycoprotein Ligand-1 (PSGL-1) interactions and reactive oxygen species would promote TF decryption in cell-MP aggregates. At sites of endothelium injury, the swift recruitment of TF+-MPs through P-selectin/PSGL-1 interactions enables the concentration of TF activity above a threshold allowing coagulation to be triggered. Another crucial feature in the initiation of blood coagulation, possibly tuned by MPs, is the balance between TF and TFPI. In specific pathophysiologic contents with elevated levels of circulating TF+-MPs, accessible TFPI at the MP surface would be overwhelmed. Beyond their procoagulant properties demonstrated in vitro, a number of pieces of evidence points to procoagulant MPs as efficient effectors in the haemostatic response, and as pathogenic markers of thrombotic disorders and vascular damage. This review will focus on the pathophysiological significance of platelet-derived MPs and their interaction with vascular cells.

Generation of procoagulant microparticles in cerebrospinal fluid and peripheral blood after traumatic brain injury.

BACKGROUND Traumatic brain injury (TBI) can induce cell damage. Procoagulant microparticles (MPs) are reliable markers of cell stimulation. The aim of this study was to investigate the generation of procoagulant MPs in the cerebrospinal fluid (CSF) and plasma of patients with severe TBI. MATERIAL CSF and plasma MPs of 16 patients with severe TBI were quantified by functional prothrombinase assay (i) on the day of the trauma, (ii) during a 10-day follow-up and compared with control samples. The cellular origin of MP was determined after capture with specific antibodies. RESULTS The CSF and plasma of patients with severe TBI revealed a significantly increased generation of MP compared with control samples on the day of the trauma (CSF: 4.5 +/- 1.8 vs. 0.83 +/- 0.28 nanomolar PhtdSer equivalent; p = 0.01 and plasma 4.1 +/- 3.7 vs. 2.3 +/- 0.19 nanomolar PhtdSer equivalent; p = 0.02). Procoagulant MPs were mainly of platelet and endothelial origin in CSF. MPs decreased significantly in the CSF 10 days after TBI. In CSF, a sustained generation of procoagulant MP was evidenced in two patients presenting a poor clinical outcome. In the blood flow, elevated amounts of procoagulant MPs were detected in three patients presenting disseminated intravascular coagulopathy during the follow-up. CONCLUSION Procoagulant MP testifying to platelet and endothelial activation are produced in the CSF and in the plasma after severe TBI. A sustained generation of procoagulant MP in the CSF could contribute to a poor clinical outcome.

Microparticles in endothelial cell and vascular homeostasis: are they really noxious?

Endothelial damage and release of membrane microparticles are key steps in the pathogenesis of inflammation. In this perspective article, Dr. Morel and co-workers discuss the biological and clinical significance of microparticles in endothelial cells. See related article on page 387.

Evaluation of a new pocket echoscopic device for focused cardiac ultrasonography in an emergency setting

IntroductionIn the emergency setting, focused cardiac ultrasound has become a fundamental tool for diagnostic, initial emergency treatment and triage decisions. A new ultra-miniaturized pocket ultrasound device (PUD) may be suited to this specific setting. Therefore, we aimed to compare the diagnostic ability of an ultra-miniaturized ultrasound device (Vscan™, GE Healthcare, Wauwatosa, WI) and of a conventional high-quality echocardiography system (Vivid S5™, GE Healthcare) for a cardiac focused ultrasonography in patients admitted to the emergency department.MethodsDuring 4 months, patients admitted to our emergency department and requiring transthoracic echocardiography (TTE) were included in this single-center, prospective and observational study. Patients underwent TTE using a PUD and a conventional echocardiography system. Each examination was performed independently by a physician experienced in echocardiography, unaware of the results found by the alternative device. During the focused cardiac echocardiography, the following parameters were assessed: global cardiac systolic function, identification of ventricular enlargement or hypertrophy, assessment for pericardial effusion and estimation of the size and the respiratory changes of the inferior vena cava (IVC) diameter.ResultsOne hundred fifty-one (151) patients were analyzed. With the tested PUD, the image quality was sufficient to perform focused cardiac ultrasonography in all patients. Examination using PUD adequately qualified with a very good agreement global left ventricular systolic dysfunction (κ = 0.87; 95%CI: 0.76-0.97), severe right ventricular dilation (κ = 0.87; 95%CI: 0.71-1.00), inferior vena cava dilation (κ = 0.90; 95%CI: 0.80-1.00), respiratory-induced variations in inferior vena cava size in spontaneous breathing (κ = 0.84; 95%CI: 0.71-0.98), pericardial effusion (κ = 0.75; 95%CI: 0.55-0.95) and compressive pericardial effusion (κ = 1.00; 95%CI: 1.00-1.00).ConclusionsIn an emergency setting, this new ultraportable echoscope (PUD) was reliable for the real-time detection of focused cardiac abnormalities.

Prothrombotic changes in diabetes mellitus.

Although our understanding of vascular pathology has greatly improved in recent years, the cellular and molecular mechanisms underlying the enhanced thrombotic propensity in type 2 diabetes mellitus (T2DM) remain incompletely characterized. Detrimental interactions between activated vascular cells (i.e., platelets, leukocytes, endothelial cells) and the vulnerable atheromatous plaque are a major determinant of the increased atherothrombotic burden in T2DM patients. Endothelial damage and accelerated senescence, impairment of the endothelial progenitor cell repair system, plaque neovascularization and inflammation, decreased clearance of detrimental molecules within the plaque, and increased expression of matrix metalloproteinases may collectively contribute to intraplaque hemorrhage and subsequent rupture. Notably, recent data demonstrates the central importance of the tissue factor-microparticle-mediated pathway in diabetic thrombophilia and cardiovascular complications. Acting as detrimental amplifiers of various biological responses (including thrombogenicity and plaque remodeling), microparticles have also emerged as a key marker of global vascular damage in T2DM patients. Available evidence suggests that targeting the tissue factor-microparticle pathway may be a promising approach for reducing the burden of the atherosclerotic complications of diabetes.

Noninvasive ventilation in blunt chest trauma: beware of missed esophageal injuries!

Dear Editor, For several years, there has been an exponential use of noninvasive ventilation (NIV) for the treatment or prevention of acute respiratory failure, while the actual benefit has not been fully documented for all applications [1–4]. In blunt chest trauma patients, early use of NIV has been shown to prevent intubation and decrease overall complications [4]. However, an inappropriate use in nonselected patients can raise the concern of potentially lethal complications due to initially missed aerodigestive injuries. Thus we report the case of a 26-year-old patient admitted in our trauma center after a blunt chest trauma due to high-speed motorvehicle accident. The whole body computed tomography (CT) scan revealed multiple ribs fractures and pulmonary contusions without sepsis or respiratory failure. Moderate mediastinal air was attributed to the fractures and/or lung trauma, as no obvious aerodigestive perforation was identified (Fig. 1a). The initial management consisted of effective pain control by epidural analgesia and early NIV to prevent secondary respiratory failure. After 48 hours of intensive care, the constitution of a pleural effusion and emergence of a septic shock motivated a second CT scan, which revealed an increase of pneumomediastinum due to a large esophageal perforation (Fig. 1b). The patient was then transferred for suture of esophageal perforation and effective pleural and mediastinal drainage. After treatment of the septic shock, a favourable outcome allowed discharge of the patient after 15 days of intensive care. To our knowledge, this is the first published report of esophageal perforation associated with an inappropriate use of NIV in blunt chest trauma patients. Traumatic esophageal perforation is an extremely rare event associated with an important morbidity and mortality [5]. For the diagnosis, the gold standard remains a water-soluble contrast swallow, but this investigation requires a cooperative patient. In ventilated patients, flexible esophagoscopy should be used. Thoracic CT-scan can also be a useful diagnostic modality when allowing direct visualization of esophageal disruption. However, subtle perforations may be missed, especially at the early stage. CT-scan often provides non-specific signs often ascribed to more common blunt thoracic injuries. Indeed, pneumomediastinum is not uncommon in the polytrauma patients, but has been found to have little clinical significance to predict aerodigestive tract injuries. Thus, it can be difficult to justify a systematic endoscopy in front of a pneumomediastinum in the absence of another argument for esophageal perforation in the initial phase of trauma. Consequently, delayed diagnosis of esophageal perforation is very frequent, reaching 50 % in some series [5]. Then, imaging examinations should be controlled in case of persistent diagnostic uncertainty or clinical worsening. Whatever the diagnosis strategy, it is necessary to avoid iatrogenic injury by improper increase in esophageal pressure, as the diagnosis of esophageal injury is not eliminated. In conclusion, this case emphasizes the need for vigilance in the detection of uncommon esophageal injuries when NIV should be indicated in blunt chest trauma patients. Thus, when CT scan cannot rule out traumatic esophageal injury, NIV should be delayed to perform systematic evaluation with more specific esophageal imaging within 12–24 h.

Ability of a new pocket echoscopic device to detect abdominal and pleural effusion in blunt trauma patients

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Advantage of using a recombinant activated factor VII in traumatic haemorrhagic shock: The Bordeaux experience

Introduction: Several series of patient studies have been published on the use of rFVIIa in traumatic haemorrhagic shock, although to date no international recommendations have been produced. France does not currently recognise traumatic haemorrhagic shock as an appropriate indication for the use of rFVIIa. Materials and methods: In this retrospective study, we present our experience in the use of rFVIIa in traumatic haemorrhagic shock. Results: Twenty-seven patients treated with rFVIIa after a traumatic injury between May 2005 and December 2008 were included. Average age was 46 years old. Eighty per cent of patients were polytransfused. Mortality rate was 33%. Adjusted mortality rate, using the Boffard study criteria, was 8.3%. We observed significant differences between the group of patients who died and the group of survivors in pH, PT, Hb, ionised calcaemia, temperature and platelet count. We observed significant differences between the successful rFVIIa group and the failed rFVIIa group in pH, Hb, platelet count and ionised calcaemia. Ten patients had an rFVIIa injection only and 17 patients had an rFVIIa injection combined with a mechanical procedure to stop the bleeding. Two patients presented with thromboembolic complications. We observed a tendency to recommend an rFVIIa injection before radical treatment is applied. Conclusion: It seems to us legitimate to recommend earlier use of rFVIIa in cases of traumatic haemorrhagic shock in the context of haematological damage control combined with the use of an algorithm to predict the risk involved in polytransfusion and a more aggressive transfusion strategy.

Blood components are essential to regulate microcirculatory blood flow

We read with interest the article by Jacob and colleagues [1] on the regulation of microcirculatory blood flow. In our opinion, the authors missed an important parameter, i.e., blood components and, particularly, red blood cells (RBC). This is regrettable since blood composition is the main parameter that we can influence by our therapies (fluid resuscitation, blood or albumin transfusion) in shocked patients. RBC may use different contradictory pathways to modulate microvascular flow by modifying nitric oxide (NO) bioavailability, which is responsible for precapillary dilatation and capillary perfusion. On the one hand, erythrocytes may reduce NO bioavailability through hemoglobin NO scavenging; on the other hand, enhancing hematocrit may increase viscosity and wall shear stress (WSS), a crucial agonist enabling endothelium NO release. Thus, in hypoxic conditions, RBC may sense tissue oxygen tension and release vasodilatory agents such as NO or ATP. In moderate hemodilution, blood viscosity is reduced, cardiac output increases, wall shear rate (WSR; blood velocity) increases and WSS is unchanged (WSS =WSR× viscosity). NO bioavailability increases because of reduced NO scavenging by erythrocytes, leading to systemic vasoplegia. In extreme hemodilution [2] (hematocrit at 11%), viscosity, WSR, and WSS drop. Functional capillary density (FCD), which reflects microcirculatory flow, decreases. In this model, enhancing blood viscosity with high viscosity-plasma expander increased FCD. In the same way, in a murine model of hemorrhagic shock, transfusion of fresh RBC without oxygen-carrying capacity restored blood viscosity, and enhanced FCD, microvascular flow, and systemic hemodynamics. Recently, Tanaka and colleagues [3] observed that RBC transfusion improved sublingual FCD in humans in hemorrhagic shock with active blood loss. We have known since 1999 from the results of a trial using modified human hemoglobin in traumatic hemorrhagic shock [4] that modifying blood properties could be harmful. Patients in this study had a better blood systolic pressure than control patients, but more of them died. Free hemoglobin scavenges NO, enhancing precapillary vasoconstriction and impairing capillary perfusion. We do not share the authors’ opinion that it is “better to choose hemorrhagic rather than septic shock for yourself”. Guidelines for traumatic hemorrhagic shock management [5] do not consider RBC transfusion for their microcirculatory properties and viscosity improvement, but only for their oxygen-delivering capacity, which is altered for many hours after transfusion, when blood is stored. Recommending a low hemoglobin trigger delays RBC transfusion when microcirculation flow is already impaired.