Microparticles during sepsis: target, canary or cure?
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In the present study, Delabranche et al.  investigated the time course and cellular origin of circulating microparticles (MPs) in patients suffering from sepsis. They enrolled 92 patients with septic shock and performed an extensive investigation on their hemostatic status. They found endothelium-derived MPs to be relevant biomarkers in this context.
The role of MPs during sepsis is complex. It has been shown that circulating levels of MPs are elevated during sepsis and promote tissue injury. However, previous studies describe both protective and deleterious effects [4, 5]. Converging animal and clinical data have emphasized the role of procoagulant MPs in the initiation of disseminated intravascular coagulation (DIC) during sepsis [6, 7, 8]. Patients with meningococcal sepsis display elevated numbers of MPs originating from platelets and granulocytes that are prothrombotic . Since the earliest demonstration of MP generation by platelets, it has been known that MPs contribute to thrombin generation by facilitating the assembly of the prothrombinase complex . Although platelet-derived MPs appear to be a significant part of the number of circulating shed membrane vesicles, particles from other cell types such as red blood cells, leukocytes or endothelial cells also contribute to the plasmatic pool. Their procoagulant properties are based on the combined presence of phosphatidylserine, a procoagulant aminophospholipid exposed after stimulation that supports the assembly of blood-clotting enzyme complexes, and tissue factor, a major initiator of the coagulation cascade. As such, mouse models of endotoxemia confirmed activated coagulation due to increased MP tissue factor activity .
In the study of Delabranche et al. , endothelial- and leukocyte-derived MPs reached higher plasma levels in DIC, while increased soluble glycoprotein V/platelet ratio was delayed. Indeed, they provide new insights on the time course and parent cell origin in septic shock. Leukocytes and endothelial cells were involved in the early stages of sepsis, whereas platelet activation was delayed. These new findings underscore the crucial role of early endothelial injury during sepsis. The role of endothelium-derived MPs as prothrombotic MPs has previously been described: in a mouse model of deep venous thrombosis, E-selectin, expressed by endothelium-derived MPs, reinforces the thrombotic response . In thrombotic thrombocytopenic purpura, endothelium-derived MPs can express very large von Willebrand factor multimers resulting in platelet aggregation . Furthermore, exposure of complement proteins C5b-9 to endothelial cells promotes MP formation with expression of factor Va binding sites and prothrombinase activity . Collectively, these data implicate a specific and early role of endothelium-derived MPs in sepsis-induced DIC.
The authors suggest that very high initial levels of cytokines and chemokines may have prompted endothelial and leukocyte activation prior to septic-shock-induced DIC. Septic shock is a prime example of the link between inflammation and thrombosis, and MPs are crucial effectors in this context. Previous studies have shown that a variety of proinflammatory agents, such as tumor necrosis factor alpha or interleukin-6, can activate endothelial cells and induce the release of MPs. Proinflammatory mediators directly induce tissue factor expression in endothelial cells, and the coagulation protease thrombin can directly induce the expression of proinflammatory mediators in endothelial cells, thus creating a positive feedback loop.
Another level of complexity in the understanding of the role of MPs in patients affected by sepsis stems from the pleiotropic and differential effects depending on target tissues. Hence, a straightforward pharmacological approach on MPs seems unlikely. Mastronardi et al. injected MPs obtained from septic patients into mice, being able to alter recipient inflammatory enzyme systems, nitrosative and oxidative stress; heart and lung tissues were affected to a greater degree by MPs from septic patients, compared with liver and kidney tissues. The same authors had previously reported that circulating MPs from septic patients can exert a protective role against vascular hyporeactivity induced by lipopolysaccharide in mice .
Role of endothelium-derived MPs in sepsis
Role of endothelium-derived MPs in sepsis
Biomarkers in sepsis-induced DIC 
Stratification and allocation to better anticoagulant therapeutic strategies
Deleterious effects of endothelium-derived MPs
Bioeffectors of inflammation and thrombosis → contribute to tissue injury
– Adhere leukocytes → increase phagocytic activity 
– Increase pulmonary endothelial permeability and promote acute lung injury 
Pharmacological control of circulating endothelium-derived MPs in stratified patients = inhibition of the shedding of MPs
Protective effects of endothelium-derived MPs
– Protection against vascular hyporeactivity 
Therapeutic use of endothelium-derived MPs in stratified patients
Another main question raised by the present study is whether MPs should be primarily regarded as a fuel to organ failure in need of treatment and scavenging or rather as an early indicator of coagulatory disturbances. Are MPs a therapeutic target or biomarkers? In this context it could be speculated, for example, that, if MPs are a major contributor to evolving organ failure, then prevention of the release of MPs should be regarded as a major avenue to be explored, whereas if one is to view MPs rather as a biomarker of tissue injury, then other issues are more important and these would be related to diagnostic kits and timing. Finally, there may need to be a combinatorial approach that is biomarker based to heal the cell making MPs and reduce the impact of the MPs once released.
The study by Delabranche et al.  adds a new milestone in MP research during sepsis and underscores the role of endothelial-derived MPs during sepsis-induced DIC. However, further methodological standardization and translational studies are needed to confirm these findings and link these findings to clinical interventions.
This work was supported in part by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
Conflicts of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
- 1.Delabranche X, Boisrame Helms J, Asfar P, Berger A, Mootien Y, Lavigne T, Grunebaum L, Lanza F, Gachet C, Freyssinet JM, Toti F, Meziani F (2013) Microparticles are new biomarkers of septic shock-induced disseminated intravascular coagulopathy. Intensive Care MedGoogle Scholar
- 5.Ogura H, Tanaka H, Koh T, Fujita K, Fujimi S, Nakamori Y, Hosotsubo H, Kuwagata Y, Shimazu T, Sugimoto H (2004) Enhanced production of endothelial microparticles with increased binding to leukocytes in patients with severe systemic inflammatory response syndrome. J Trauma 56:823–830 discussion 830–821PubMedCrossRefGoogle Scholar
- 7.Zafrani L, Gerotziafas G, Byrnes C, Hu X, Perez J, Levi C, Placier S, Letavernier E, Leelahavanichkul A, Haymann JP, Elalamy I, Miller JL, Star RA, Yuen PS, Baud L (2012) Calpastatin controls polymicrobial sepsis by limiting procoagulant microparticle release. Am J Respir Crit Care Med 185:744–755PubMedCrossRefGoogle Scholar