Effect of progressive haemodilution with hydroxyethyl starch, gelatin and albumin on blood coagulation.
Egli G A,Zollinger A,Seifert B,Popovic D,Pasch T,Spahn D R
British journal of anaesthesia
We have compared the effects of progressive (30% and 60%) in vitro haemodilution with hydroxyethyl starch (HES), gelatin (GEL) and albumin (ALB) with haemodilution using 0.9% saline in 96 patients by thrombelastography. Haemodilution with HES, GEL and ALB significantly (P < 0.05) compromised coagulation time (k), angle alpha and maximal amplitude (MA), with HES having the most negative effect at 30% and 60% haemodilution (P < 0.05). Haemodilution with saline significantly affected all variables of blood coagulation and clot lysis measured by thrombelastography, resulting in an increased coagulability at 30% haemodilution. To specifically assess the intrinsic effect of plasma expander molecules on blood coagulation and clot lysis, we analysed the difference between saline diluted blood (same degree of haemodilution) and plasma expander diluted blood. Prolongation of reaction time (r) was found for HES at 30% and 60% haemodilution and for ALB at 60% haemodilution and an increase in clot lysis by HES, GEL and ALB became evident. We conclude that HES, GEL and ALB compromised blood coagulation, while the maximum effect was found with HES.
10.1093/bja/78.6.684
Albumin Infusion in Critically Ill COVID-19 Patients: Hemodilution and Anticoagulation.
Ramadori Giuliano
International journal of molecular sciences
Hypercoagulation is one of the major risk factors for ICU treatment, mechanical ventilation, and death in critically ill patients infected with SARS-CoV-2. At the same time, hypoalbuminemia is one risk factor in such patients, independent of age and comorbidities. Especially in patients with severe SARS-CoV-2-infection, albumin infusion may be essential to improve hemodynamics and to reduce the plasma level of the main marker of thromboembolism, namely, the D-dimer plasma level, as suggested by a recent report. Albumin is responsible for 80% of the oncotic pressure in the vessels. This is necessary to keep enough water within the systemic circulatory system and for the maintenance of sufficient blood pressure, as well as for sufficient blood supply for vital organs like the brain, lungs, heart, and kidney. The liver reacts to a decrease in oncotic pressure with an increase in albumin synthesis. This is normally possible through the use of amino acids from the proteins introduced with the nutrients reaching the portal blood. If these are not sufficiently provided with the diet, amino acids are delivered to the liver from muscular proteins by systemic circulation. The liver is also the source of coagulation proteins, such as fibrinogen, fibronectin, and most of the v WF VIII, which are physiological components of the extracellular matrix of the vessel wall. While albumin is the main negative acute-phase protein, fibrinogen, fibronectin, and v WF VIII are positive acute-phase proteins. Acute illnesses cause the activation of defense mechanisms (acute-phase reaction) that may lead to an increase of fibrinolysis and an increase of plasma level of fibrinogen breakdown products, mainly fibrin and D-dimer. The measurement of the plasma level of the D-dimer has been used as a marker for venous thromboembolism, where a fourfold increase of the D-dimer plasma level was used as a negative prognostic marker in critically ill SARS-CoV-2 hospitalized patients. Increased fibrinolysis can take place in ischemic peripheral sites, where the mentioned coagulation proteins can become part of the provisional clot (e.g., in the lungs). Although critically ill SARS-CoV-2-infected patients are considered septic shock patients, albumin infusions have not been considered for hemodynamic resuscitation and as anticoagulants. The role of coagulation factors as provisional components of the extracellular matrix in case of generalized peripheral ischemia due to hypoalbuminemia and hypovolemia is discussed in this review.
10.3390/ijms22137126
NLRP3 inflammasome activation in platelets in response to sepsis.
Physiological reports
Sepsis is a complex syndrome characterized by organ dysfunction and a dysregulated immune host response to infection. There is currently no effective treatment for sepsis, but platelets have been proposed as a potential therapeutic target for the treatment of sepsis. We hypothesized that the NLRP3 inflammasome is activated in platelets during sepsis and may be associated with multiorgan injury in response to polymicrobial sepsis. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in 12- to 13-week-old male Sprague-Dawley rats. The necrotic cecum was removed at 24 h post-CLP. At 72 h post-CLP, activated platelets were significantly increased in CLP versus Sham rats. Colocalization of NLRP3 inflammasome components was observed in platelets from CLP rats at 72 h post-CLP. Plasma, pulmonary, and renal levels of IL-1β and IL-18 were significantly higher in CLP rats compared to Sham controls. Soluble markers of endothelial permeability were increased in CLP versus Sham. Renal and pulmonary histopathology were markedly elevated in CLP rats compared to Sham controls. NLRP3 is activated in platelets in response to CLP and is associated with inflammation, endothelial permeability and multiorgan injury. Our results indicate that activated platelets may play a role to cause multiorgan injury in sepsis and may have therapeutic potential for the treatment of sepsis multiorgan injury.
10.14814/phy2.14073
Coagulation abnormalities in critically ill patients.
Levi Marcel,Opal Steven M
Critical care (London, England)
Many critically ill patients develop hemostatic abnormalities, ranging from isolated thrombocytopenia or prolonged global clotting tests to complex defects, such as disseminated intravascular coagulation. There are many causes for a deranged coagulation in critically ill patients and each of these underlying disorders may require specific therapeutic or supportive management. In recent years, new insights into the pathogenesis and clinical management of many coagulation defects in critically ill patients have been accumulated and this knowledge is helpful in determining the optimal diagnostic and therapeutic strategy.
10.1186/cc4975
NLRP3 inflammasome contributes to endotoxin-induced coagulation.
Thrombosis research
INTRODUCTION:Excessive activation of the coagulation cascades leads to life-threatening disseminated intravascular coagulation (DIC) in sepsis. Two recent studies by our group and others have both demonstrated the noncanonical inflammasome is pivotal for the endotoxin or gram-negative bacterial-induced coagulation. Based on this, we further evaluated the function of the NLRP3 inflammasome, the most studied inflammasome, in endotoxin-induced coagulation. MATERIALS AND METHODS:We established an endotoxin-induced coagulation model by intraperitoneal injection of sublethal doses of LPS in mice. Mice were sacrificed 8 h after injection and blood was collected for thrombin-antithrombin (TAT), plasminogen activator inhibitor-1 (PAI-1), prothrombin time (PT), D-dimer, IL-1β and tissue factor (TF) measurements by commercial ELISA. Lungs and livers were examined via HE staining images to determine injury scores and immunohistochemistry for TF expression and fibrin deposits. The role of NLRP3 activation was evaluated in wild-type (WT), Nlrp3, Asc (apoptosis-associated speck-like protein containing a CARD), Caspase-11 mice and 30 min after treatment with MCC950, a potent inhibitor of NLRP3. Western blotting and Q-PCR were performed to assess TF expression in the lungs and livers. To uncover the different effects of NLRP3 and Caspase-11, we also compared the time-dependent IL-1β release in LPS-treated Nlrp3 and Caspase-11 mice. Correlation analysis of TAT, PAI-1 were estimated the relationship of coagulation and release of IL-1β, as well as IL-1β and TF. RESULTS:Inhibition of NLRP3 by MCC950 as well as NLRP3 or ASC deficiency decreased TAT, PAI-1, PT, D-dimer, and TF levels in blood and impaired the thrombus formation and fibrin deposition, as well as declined expression of TF in the liver and lung in endotoxin-induced coagulation but not caspase-11 deficiency. Impressively, IL-1β release is increased in LPS-treated Caspase-11 mice, but not in Nlrp3 mice. Moreover, the correlation analysis is indicated that downstream of the NLRP3 inflammasome, IL-1β expression, is positively correlated with TAT, PAI-1 and TF in blood circulation. CONCLUSIONS:The NLRP3 inflammasome contributes to endotoxin-induced coagulation by promoting TF expression at least in part through the induction of IL-1β release. These findings broadened our understanding of the mechanism of coagulation and implicated a possible therapeutic strategy for preventing coagulation in sepsis.
10.1016/j.thromres.2022.04.001
Sphingosine 1-phosphate (S1P) carrier-dependent regulation of endothelial barrier: high density lipoprotein (HDL)-S1P prolongs endothelial barrier enhancement as compared with albumin-S1P via effects on levels, trafficking, and signaling of S1P1.
The Journal of biological chemistry
Sphingosine 1-phosphate (S1P) is a blood-borne lysosphingolipid that acts to promote endothelial cell (EC) barrier function. In plasma, S1P is associated with both high density lipoproteins (HDL) and albumin, but it is not known whether the carriers impart different effects on S1P signaling. Here we establish that HDL-S1P sustains EC barrier longer than albumin-S1P. We showed that the sustained barrier effects of HDL-S1P are dependent on signaling by the S1P receptor, S1P1, and involve persistent activation of Akt and endothelial NOS (eNOS), as well as activity of the downstream NO target, soluble guanylate cyclase (sGC). Total S1P1 protein levels were found to be higher in response to HDL-S1P treatment as compared with albumin-S1P, and this effect was not associated with increased S1P1 mRNA or dependent on de novo protein synthesis. Several pieces of evidence indicate that long term EC barrier enhancement activity of HDL-S1P is due to specific effects on S1P1 trafficking. First, the rate of S1P1 degradation, which is proteasome-mediated, was slower in HDL-S1P-treated cells as compared with cells treated with albumin-S1P. Second, the long term barrier-promoting effects of HDL-S1P were abrogated by treatment with the recycling blocker, monensin. Finally, cell surface levels of S1P1 and levels of S1P1 in caveolin-enriched microdomains were higher after treatment with HDL-S1P as compared with albumin-S1P. Together, the findings reveal S1P carrier-specific effects on S1P1 and point to HDL as the physiological mediator of sustained S1P1-PI3K-Akt-eNOS-sGC-dependent EC barrier function.
10.1074/jbc.M112.423426
Structural and functional characteristics of S1P receptors.
Sanchez Teresa,Hla Timothy
Journal of cellular biochemistry
The sphingosine-1-phosphate (S1P) family of G protein-coupled receptors (GPCR) regulates essential cellular processes such as proliferation, migration, cytoskeletal organization, adherens junction assembly, and morphogenesis. S1P, a product from the breakdown of sphingomyelin, binds to the five members of this receptor family, S1P(1), S1P(2), S1P(3), S1P(4), and S1P(5), previously referred to as endothelial differentiation gene (EDG)-1, -5, -3, -6, and -8. S1P receptors are widely expressed in different tissues, so it is not surprising that the S1P receptor family regulates many physiological processes, such as vascular maturation, cardiac development, lymphocyte trafficking, and vascular permeability. FTY720, a new S1P receptor agonist, is undergoing clinical trials as an immunosuppressor. Understanding the physiological role of these receptors and the basics of the ligand-receptor interaction will potentially provide new therapies to control a variety of diseases.
10.1002/jcb.20127
Barrier maintenance by S1P during inflammation and sepsis.
Tissue barriers
Sphingosine 1-phosphate (S1P) is a multifaceted lipid signaling molecule that activates five specific G protein-coupled S1P receptors. Despite the fact that S1P is known as one of the strongest barrier-enhancing molecules for two decades, no medical application is available yet. The reason for this lack of translation into clinical practice may be the complex regulatory network of S1P signaling, metabolism and transportation.In this review, we will provide an overview about the physiology and the network of S1P signaling with the focus on endothelial barrier maintenance in inflammation. We briefly describe the physiological role of S1P and the underlying S1P signaling in barrier maintenance, outline differences of S1P signaling and metabolism in inflammatory diseases, discuss potential targets and compounds for medical intervention, and summarize our current knowledge regarding the role of S1P in the maintenance of specialized barriers like the blood-brain barrier and the placenta.
10.1080/21688370.2021.1940069
S1P and the birth of platelets.
Hla Timothy,Galvani Sylvain,Rafii Shahin,Nachman Ralph
The Journal of experimental medicine
Recent work has highlighted the multitude of biological functions of sphingosine 1-phosphate (S1P), which include roles in hematopoietic cell trafficking, organization of immune organs, vascular development, and neuroinflammation. Indeed, a functional antagonist of S1P(1) receptor, FTY720/Gilenya, has entered the clinic as a novel therapeutic for multiple sclerosis. In this issue of the JEM, Zhang et al. highlight yet another function of this lipid mediator: thrombopoiesis. The S1P(1) receptor is required for the growth of proplatelet strings in the bloodstream and the shedding of platelets into the circulation. Notably, the sharp gradient of S1P between blood and the interstitial fluids seems to be essential to ensure the production of platelets, and S1P appears to cooperate with the CXCL12-CXCR4 axis. Pharmacologic modulation of the S1P(1) receptor altered circulating platelet numbers acutely, suggesting a potential therapeutic strategy for controlling thrombocytopenic states. However, the S1P(4) receptor may also regulate thrombopoiesis during stress-induced accelerated platelet production. This work reveals a novel physiological action of the S1P/S1P(1) duet that could potentially be harnessed for clinical translation.
10.1084/jem.20122284
Sphingosine-1-Phosphate (S1P) and S1P Signaling Pathway Modulators, from Current Insights to Future Perspectives.
Cells
Sphingosine-1-phosphate (S1P) and S1P receptors (S1PR) are bioactive lipid molecules that are ubiquitously expressed in the human body and play an important role in the immune system. S1P-S1PR signaling has been well characterized in immune trafficking and activation in both innate and adaptive immune systems. Despite this knowledge, the full scope in the pathogenesis of autoimmune disorders is not well characterized yet. From the discovery of fingolimod, the first S1P modulator, until siponimod, the new molecule recently approved for the treatment of secondary progressive multiple sclerosis (SPMS), there has been a great advance in understanding the S1P functions and their involvement in immune diseases, including multiple sclerosis (MS). Modulation on S1P is an interesting target for the treatment of various autoimmune disorders. Improved understanding of the mechanism of action of fingolimod has allowed the development of the more selective second-generation S1PR modulators. Subtype 1 of the S1PR (S1PR1) is expressed on the cell surface of lymphocytes, which are known to play a major role in MS pathogenesis. The understanding of S1PR1's role facilitated the development of pharmacological strategies directed to this target, and theoretically reduced the safety concerns derived from the use of fingolimod. A great advance in the MS treatment was achieved in March 2019 when the Food and Drug Association (FDA) approved Siponimod, for both active secondary progressive MS and relapsing-remitting MS. Siponimod became the first oral disease modifying therapy (DMT) specifically approved for active forms of secondary progressive MS. Additionally, for the treatment of relapsing forms of MS, ozanimod was approved by FDA in March 2020. Currently, there are ongoing trials focused on other new-generation S1PR1 modulators. This review approaches the fundamental aspects of the sphingosine phosphate modulators and their main similarities and differences.
10.3390/cells11132058
Sphingosine 1-phosphate (S1P): Physiology and the effects of S1P receptor modulation.
Hla Timothy,Brinkmann Volker
Neurology
Sphingosine 1-phosphate (S1P) and 5 specific high-affinity S1P receptor (S1PR) subtypes, S1P(1-5), have important regulatory functions in normal physiology and disease processes, particularly involving the immune, central nervous, and cardiovascular systems. Within the immune system, downmodulation of S1P(1) prevents the egress of B and T cells from lymph nodes (LN) into the lymphatic circulation. This is especially relevant in certain autoimmune diseases, including multiple sclerosis (MS), in which demyelination and brain atrophy occur due to the presence of autoreactive lymphocytes within the CNS. Accordingly, S1P(1)-directed pharmacologic interventions that aim to retain these autoreactive lymphocytes in the LN and thus prevent their recirculation and subsequent infiltration into the CNS have been investigated as a means of preventing disease progression in patients with MS. Fingolimod (FTY720), a structural analog of sphingosine, is phosphorylated in vivo into fingolimod phosphate by sphingosine kinase-2. Fingolimod phosphate, which binds to S1PRs, has been shown to modulate the activity of S1P(1) in patients with MS and to reduce immune cell infiltration into the CNS, consistent with its previously established effects in animal models of the disease. Preclinical studies also suggest that fingolimod has beneficial effects within the CNS that are independent of its immune cell trafficking activity. This review highlights the normal physiologic processes modulated by S1P and S1PRs, and the therapeutic effects of S1PR modulation in the immune, central nervous, and cardiovascular systems.
10.1212/WNL.0b013e31820d5ec1
Molecular Mechanism of S1P Binding and Activation of the S1P Receptor.
Jiang Zhenyan,Zhang Hansi
Journal of chemical information and modeling
Sphingosine-1-phosphate (S1P) is a lipidic mediator in mammals that functions either as a second messenger or as a ligand. In the latter case, it is transported by its HDL-associated apoM carrier and circulated in blood where it binds to specific S1P receptors on cell membranes and induces downstream reactions. Although S1P signaling pathways are essential for many biological processes, they are poorly understood at the molecular level. Here, the solved crystal structures of the S1P receptor were used to evaluate molecular dynamics (MD) simulations to generate greater detailed molecular insights into the mechanism of S1P signaling. The MD simulations provided observations at the coarse-grained and atomic levels indicating that S1P may access the receptor binding pocket directly from solvents. Lifting of the bulky N-terminal cap region of the receptor precedes initial S1P binding. Glu121 guides S1P penetration, and together with Arg292 is responsible for the stabilization of S1P in the binding pocket, which is consistent with experimental predictions. The complete binding of S1P is followed by receptor activation, wherein Trp269 moves toward the transmembrane helix (TM) 7, resulting in the formation of an enhanced hydrogen bond network in the lower region of TM7. The distance between TM3 and TM6 is subsequently increased, resulting in the opening of the intracellular binding pocket that enables G protein binding. Further analysis of the force distribution network in the receptor yielded a detailed molecular understanding of the signal transmission network that is activated upon agonist binding.
10.1021/acs.jcim.9b00642
S1P control of endothelial integrity.
Xiong Yuquan,Hla Timothy
Current topics in microbiology and immunology
Sphingosine 1-phosphate (S1P), a lipid mediator produced by sphingolipid metabolism, promotes endothelial cell spreading, vascular maturation/stabilization, and barrier function. S1P is present at high concentrations in the circulatory system, whereas in tissues its levels are low. This so-called vascular S1P gradient is essential for S1P to regulate much physiological and pathophysiological progress such as the modulation of vascular permeability. Cellular sources of S1P in blood has only recently begun to be identified. In this review, we summarize the current understanding of S1P in regulating vascular integrity. In particular, we discuss the recent discovery of the endothelium-protective functions of HDL-bound S1P which is chaperoned by apolipoprotein M.
10.1007/978-3-319-05879-5_4
National incidence and mortality of hospitalized sepsis in China.
Critical care (London, England)
BACKGROUND:Sepsis is a leading cause of preventable death around the world. Population-based estimation of sepsis incidence is lacking in China. In this study, we aimed to estimate the population-based incidence and geographic variation of hospitalized sepsis in China. METHODS:We retrospectively identified hospitalized sepsis from the nationwide National Data Center for Medical Service (NDCMS) and the National Mortality Surveillance System (NMSS) by ICD-10 codes for the period from 2017 to 2019. In-hospital sepsis case fatality and mortality rate were calculated to extrapolate the national incidence of hospitalized sepsis. The geographic distribution of hospitalized sepsis incidence was examined using Global Moran's Index. RESULTS:We identified 9,455,279 patients with 10,682,625 implicit-coded sepsis admissions in NDCMS and 806,728 sepsis-related deaths in NMSS. We estimated that the annual standardized incidence of hospitalized sepsis was 328.25 (95% CI 315.41-341.09), 359.26 (95% CI 345.4-373.12) and 421.85 (95% CI 406.65-437.05) cases per 100,000 in 2017, 2018 and 2019, respectively. We observed 8.7% of the incidences occurred among neonates less than 1 year old, 11.7% among children aged 1-9 years, and 57.5% among elderly older than 65 years. Significant spatial autocorrelation for incidence of hospitalized sepsis was observed across China (Moran's Index 0.42, p = 0.001; 0.45, p = 0.001; 0.26, p = 0.011 for 2017, 2018, 2019, respectively). Higher number of hospital bed supply and higher disposable income per capita were significantly associated with a higher incidence of hospitalized sepsis. CONCLUSION:Our study showed a greater burden of sepsis hospitalizations than previous estimated. The geographical disparities suggested more efforts were needed in prevention of sepsis.
10.1186/s13054-023-04385-x
Incidence and mortality of hospital- and ICU-treated sepsis: results from an updated and expanded systematic review and meta-analysis.
Fleischmann-Struzek C,Mellhammar L,Rose N,Cassini A,Rudd K E,Schlattmann P,Allegranzi B,Reinhart K
Intensive care medicine
PURPOSE:To investigate the global burden of sepsis in hospitalized adults by updating and expanding a systematic review and meta-analysis and to compare findings with recent Institute for Health Metrics and Evaluation (IHME) sepsis estimates. METHODS:Thirteen electronic databases were searched for studies on population-level sepsis incidence defined according to clinical criteria (Sepsis-1, -2: severe sepsis criteria, or sepsis-3: sepsis criteria) or relevant ICD-codes. The search of the original systematic review was updated for studies published 05/2015-02/2019 and complemented by a search targeting low- or middle-income-country (LMIC) studies published 01/1979-02/2019. We performed a random-effects meta-analysis with incidence of hospital- and ICU-treated sepsis and proportion of deaths among these sepsis cases as outcomes. RESULTS:Of 4746 results, 28 met the inclusion criteria. 21 studies contributed data for the meta-analysis and were pooled with 30 studies from the original meta-analysis. Pooled incidence was 189 [95% CI 133, 267] hospital-treated sepsis cases per 100,000 person-years. An estimated 26.7% [22.9, 30.7] of sepsis patients died. Estimated incidence of ICU-treated sepsis was 58 [42, 81] per 100,000 person-years, of which 41.9% [95% CI 36.2, 47.7] died prior to hospital discharge. There was a considerably higher incidence of hospital-treated sepsis observed after 2008 (+ 46% compared to the overall time frame). CONCLUSIONS:Compared to results from the IHME study, we found an approximately 50% lower incidence of hospital-treated sepsis. The majority of studies included were based on administrative data, thus limiting our ability to assess temporal trends and regional differences. The incidence of sepsis remains unknown for the vast majority of LMICs, highlighting the urgent need for improved epidemiological sepsis surveillance.
10.1007/s00134-020-06151-x
Challenges of assessing the burden of sepsis.
Medizinische Klinik, Intensivmedizin und Notfallmedizin
BACKGROUND:Sepsis is one of the most frequent causes of death worldwide, but the recording of population-based epidemiology is challenging, which is why reliable data on sepsis incidence and mortality are only available in a few, mostly highly-resourced countries. OBJECTIVE:The aim of this narrative review is to provide an overview of sepsis epidemiology worldwide and in Germany based on current literature, to identify challenges in this research area, and to give an outlook on future developments. MATERIALS AND METHODS:Selective literature review. PubMed and Google Scholar were searched for current literature. The results were processed narratively. RESULTS:Based on modeling studies or meta-analyses of prospective studies, global annual sepsis incidence was found to be 276-678/100,000 persons. Case fatality ranged from 22.5 to 26.7%. However, current data sources have several limitations, as administrative data of selected individual countries-mostly with high income-were used as their basis. In these administrative data, sepsis is captured with limited validity. Prospective studies using clinical data often have limited comparability or lack population reference. CONCLUSION:There is a lack of reliable data sources and definitions to monitor the epidemiology of sepsis and collect reliable global estimates. Increased policy efforts and new scientific approaches are needed to improve our understanding of sepsis epidemiology, identify vulnerable populations, and develop and target effective interventions.
10.1007/s00063-023-01088-7
Epidemiology of sepsis and septic shock.
Chiu Catherine,Legrand Matthieu
Current opinion in anaesthesiology
PURPOSE OF REVIEW:The epidemiology of sepsis and septic shock has been challenging to study for multiple reasons. These include changing diagnostic definitions, as well a high concentration of sepsis-related studies published from high-income countries (HICs), despite a large global burden. This section attempts to address the incidence of sepsis throughout the years and worldwide. RECENT FINDINGS:The incidence of sepsis and septic shock has continued to increase since the first consensus definitions (Sepsis-1) were established in 1991, and the latest definitions (Sepsis-3) provide a better reflection of mortality risk for a diagnosis of sepsis. Several studies argue that the incidence of sepsis is overreported in HICs, based on billing and coding practices, and may lead to overutilization of resources. However, recent estimates of the true global burden of sepsis, including low-income countries, are likely much higher than reported, with calls for better allocation of resources. SUMMARY:The true epidemiology of sepsis worldwide continues to be a highly debated subject, and more research is needed among low-income countries and high-risk subpopulations.
10.1097/ACO.0000000000000958