Sepsis-induced Coagulopathy Research Articles

Early Coagulation Disorder Is Associated With an Increased Risk of Atrial Fibrillation in Septic Patients.

Background: Atrial fibrillation (AF) and coagulation disorder, two common complications of sepsis, are associated with the mortality. However, the relationship between early coagulation disorder and AF in sepsis remains elusive. This study aimed to evaluate the interaction between AF and early coagulation disorder on mortality.Methods: In this retrospective study, all data were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. Septic patients with coagulation tests during the first 24 h after admission to intensive care units (ICUs) meeting study criteria were included in the analysis. Early coagulation disorder is defined by abnormalities in platelet count (PLT), international normalized ratio (INR) and activated partial thromboplastin time (APTT) within the first 24 h after admission, whose score was defined with reference to sepsis-induced coagulopathy (SIC) and coagulopathy. Patients meeting study criteria were divided into AF and non-AF groups.Results: In total, 7,528 septic patients were enrolled, including 1,243 (16.51%) with AF and 5,112 (67.91%) with early coagulation disorder. Compared with patients in the non-AF group, patients in the AF group had higher levels of INR and APTT (P < 0.001). Multivariable logistic regression analyses showed that stroke, early coagulation disorder, age, gender, congestive heart failure (CHF), chronic pulmonary disease, renal failure, and chronic liver disease were independent risk factors for AF. In addition, AF was related to in-hospital mortality and 90-day mortality. In the subgroup analysis stratified by the scores of early coagulation disorder, AF was associated with an increased risk of 90-day mortality when the scores of early coagulation disorder were 1 or 2 and 3 or 4.Conclusion: In sepsis, coagulation disorder within the first 24 h after admission to the ICUs is an independent risk factor for AF. The effect of AF on 90-day mortality varies with the severity of early coagulation disorder.

Brain-derived extracellular vesicles mediated coagulopathy, inflammation and apoptosis after sepsis

IntroductionThe activation of coagulation, inflammation and other pathways is the basic response of the host to infection in sepsis, but this response also causes damage to the host. Brain-derived extracellular vesicles (BDEVs) have been reported to cause a hypercoagulable state that can rapidly develop into consumptive coagulopathy, which is consistent with the pathophysiological process of sepsis-induced coagulopathy. However, the role of BDEVs in sepsis-induced coagulopathy remains unclear. Materials and methodsMale Sprague-Dawley (SD) rats were used for sepsis modeling using cecal ligation puncture (CLP). Flow cytometry was used to measure the levels of circulating BDEVs. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum levels of plasminogen activator inhibitor type 1 (PAI-1), thrombin-antithrombin (TAT), D-dimer, fibrinogen(Fib), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β and IL-6. Nanoparticle tracking analysis (NTA) and Transmission electron microscopy (TEM) were used to identify BDEVs. Western blot (WB) was used to determine the expression of glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), bax, bcl-2 and cleaved caspase-3. Hematoxylin-eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining were performed to detect tissue injury. Survival was monitored over the course of 168 h. ResultsWe found that a large number of BDEVs were released into the circulating blood in septic rats. Moreover, we observed that BDEVs injection activated the systemic coagulation reaction and induced lung, liver and kidney inflammation and apoptosis(P < .05). Compared with BDEVs from sham-operated rats, BDEVs from septic rats exacerbated this process(P < .05). ConclusionsThis finding suggests that inhibiting BDEVs may yield therapeutic benefits in the treatment of sepsis-induced coagulopathy.

SEPSIS-3.0-Is intensive care medicine ready for ICD-11?

HintergrundIm Januar 2022 wird die 11. Revision der International Classification of Diseases (ICD-11) in Kraft treten. Unter anderem wird darin die SEPSIS-3-Definition implementiert sein, in der Sepsis als „lebensbedrohliche Organdysfunktion, hervorgerufen durch eine fehlregulierte Wirtsantwort auf eine Infektion“ definiert wird. Ziel der vorliegenden Sekundärauswertung einer Umfrage zum Thema „Sepsis-induzierte Koagulopathie“ war es zu evaluieren, ob die SEPSIS-3-Definition (engl. The Third International Consensus Definitions for Sepsis and Septic Shock) 4 Jahre nach ihrer internationalen Einführung im klinischen Alltag anästhesiologisch geführter Intensivstationen in Deutschland angekommen ist und so die Voraussetzungen für die Verwendung des ICD-11 gegeben sind.MethodenIm Rahmen einer deutschlandweiten Umfrage unter ärztlichen Leitern von Intensivstationen, die zwischen Oktober 2019 und Mai 2020 durchgeführt wurde, wurde in einem gesonderten Fragenblock nach der verwendeten Sepsisdefinition gefragt. Zusätzlich wurde gefragt, ob der quick-Sequential (Sepsis-related) Organ Failure Assessment (qSOFA) Score zum Screening auf Sepsis in dem Krankenhaus, zu dem die teilnehmende Intensivstation gehört, verwendet wird.ErgebnisseInsgesamt nahmen 50 ärztliche Leiter von anästhesiologisch geführten Intensivbereichen an der Umfrage teil. In Summe gaben die ausgewerteten Intensivstationen an, etwa 14,0 % der in Deutschland registrierten High-Care-Betten zu führen. An 78,9 % der Universitätsklinika und 84,0 % der teilnehmenden Lehrkrankenhäuser ist die SEPSIS-3-Definition im klinischen Alltag integriert. Im Gegensatz dazu wird der Screening-Test „qSOFA“ nur von 26,3 % der teilnehmenden Universitätsklinika, aber immerhin von 52,0 % der Lehrkrankenhäuser und 80,0 % der „sonstigen“ Krankenhäuser verwendet.SchlussfolgerungUnsere Daten zeigen, dass sowohl SEPSIS‑3 als auch qSOFA im klinischen Alltag deutscher Krankenhäuser angekommen sind. Die zurückhaltende Verwendung des qSOFA an Universitätsklinika bei gleichzeitiger breiter Akzeptanz der SEPSIS-3-Definition kann als Indiz interpretiert werden, dass die Suche nach einem geeigneten Screeningtest für Sepsis noch nicht abgeschlossen ist.

Practice of pharmaceutical thrombosis prophylaxis and anticoagulation in patients with sepsis and pre-existing anticoagulation or heparin-induced type II thrombocytopenia-Results of a nationwide survey in German intensive care units

HintergrundSowohl eine vorbestehende Antikoagulation als auch prädisponierende Vorerkrankungen für Thromboembolien stellen ein häufiges Problem bei Patienten mit Sepsis dar, wenngleich der Umgang mit diesen Rahmenbedingungen von den aktuellen nationalen und internationalen Leitlinien für Sepsis und septischen Schock nicht adressiert wird. Ein Ziel der hier vorliegenden deutschlandweiten Umfrage war es, den Umgang von Intensivmedizinern mit derartigen Problemen zu eruieren.MethodenVon Oktober 2019 bis Mai 2020 führten wir eine deutschlandweite Umfrage unter ärztlichen Leitern von Intensivstationen zum Thema Antikoagulation und medikamentöser Thromboseprophylaxe bei Sepsis und Sepsis-induzierter Koagulopathie durch. Ein Fokus war hierbei, das Vorgehen bei Patienten mit vorbestehender Indikation zur therapeutischen Antikoagulation sowie bei vorbekannter Heparin-induzierter Thrombopenie Typ II (HIT-II) (akut-symptomatisch vs. Jahre zurückliegend) zu eruieren.ErgebnisseDie Umfrageergebnisse zeigen, dass auf den meisten der teilnehmenden Intensivstationen eine vorbestehende Antikoagulation größtenteils mit niedermolekularen Heparinpräparaten oder unfraktioniertem Heparin fortgeführt wird. Bei bekannter HIT-II wird Argatroban bevorzugt, unabhängig davon, ob es sich um eine Jahre zurückliegende oder eine akut-symptomatische HIT-II handelt. Eine hohe Variabilität besteht bei der Festlegung der Zielwerte für die Antikoagulation, wobei diese größtenteils deutlich über dem Bereich einer reinen venösen Thromboembolie(VTE)-Prophylaxe zu liegen kommen.SchlussfolgerungDie Datenlage zur Fortführung einer über die reine VTE-Prophylaxe hinausgehenden Antikoagulation mit konsekutiv erhöhtem Blutungsrisiko bei Patienten mit Sepsis und septischem Schock ist eingeschränkt, und Therapieentscheidungen unterliegen in vielen Fällen einer individuellen Abwägung des Behandlungsteams. Die Ergebnisse unserer Umfrage implizieren die Notwendigkeit einer systematischen Aufarbeitung dieses Themenfeldes, um die auf vielen Intensivstationen gelebte Praxis mit der gebotenen Evidenz zu unterlegen.Zusatzmaterial onlineDie Online-Version dieses Beitrags (10.1007/s00101-021-01011-9) enthält weitere Tabellen, Abbildungen und Auswertungen der Fragebögen.Beitrag und Zusatzmaterial stehen Ihnen auf www.springermedizin.de zur Verfügung. Bitte geben Sie dort den Beitragstitel in die Suche ein oder nutzen Sie den QR-Code auf der ersten Seite des Artikels. Das Zusatzmaterial finden Sie beim Beitrag unter „Ergänzende Inhalte“.

Violation of hemostasis in coronavirus infection

Hemostatic disorders in COVID-19 play an important role in the pathogenesis and clinical implications of the disease. The ability to identify factors and risk of developing thrombotic complications, to interpret the peripheral blood and coagulation dynamics, knowledge of diagnostic criteria possible of hemostatic disorders (DIC, sepsis-induced coagulopathy, antiphospholipid, hemophagocytic, hypercoagulation syndromes, etc.) are necessary to determine the scope of the survey, differentiated prescription of adequate therapy (including anticoagulants, blood components, plasmapheresis), which determines a greater efficiency of complex treatment and prognosis of patients with COVID-19.

DIAGNOSTIC CRITERIA FOR DISSEMINATED INTRAVASCULAR COAGULATION SYNDROME AND SEPSIS-INDUCED COAGULOPATHY

The clinical manifestations of disseminated intravascular coagulation syndrome (DIC) depend on the predominance of the sum of the vectors of hypercoagulation and hyperfibrinolysis and are strongly associated with the underlying disease, against which DIC is formed. The issue of understanding the complex pathogenesis, timely diagnosis of overt DIC and early manifestations of DIC remain an urgent challenge for intensive care physicians and leading specialized societies to study the problems of hemostasis and thrombus formation. This review of the literature analyzes the pathways of DIC development, the current state of the possibility of using diagnostic markers to detect DIC, especially in sepsis. The diagnosis of sepsis-induced coagulopathy against the background of the development of multiple organ failure is highlighted as a separate issue. Diagnostic scales are presented in the form of comparative tables for a more convenient perception of information, memorization and further implementation in clinical practice.

Acute limb ischemia in COVID-19 patients: an overview

COVID-19 causes a wide range of clinical symptoms. COVID-19 hematologic and cardiovascular involvement induces thromboembolic symptoms in various organs, most notably venous thromboembolism (VTE); peripheral arterial involvement is uncommon. Acute limb ischemia (ALI) is a vascular emergency known as a dramatic drop in arterial perfusion of a limb that poses a challenge to the limb's viability. Given routine need for thromboprophylaxis, hospitalised COVID-19 patients are at an elevated risk of ALI, limb loss, or even mortality. Understanding the various specific symptoms of COVID-19 patients, especially extrapulmonary manifests, is crucial for both better patient care and the development of adequate infection prevention methods. Although ALI is a complication of COVID-19 in hospitalized patients, it is now being understood that it can arise in patients with mild COVID-19 symptoms, and that ALI can be the first presenting sign of COVID-19 even in the absence of respiratory symptoms. It is recommended that acutely admitted COVID-19 cases should be given pharmacologic thromboprophylaxis with low molecular weight heparin (LMWH) or fondaparinux unless there is a chance of bleeding or contraindicated. Anticoagulant treatment, primarily with LMWH, correlates strongly with an improved prognosis in serious COVID-19 patients who follow sepsis-induced coagulopathy requirements or have significantly elevated D-dimer levels.

SARS-CoV-2, Endothelial Dysfunction, and the Renin-Angiotensin System (RAS): A Potentially Dangerous Triad for the Development of Pre-Eclampsia

SARS-CoV-2 represents the greatest epidemiological, clinical, and social challenge the human being has had to face in this century. SARS-CoV-2 is not merely a respiratory virus, as its target cells range from upper airway respiratory cells to pulmonary cells but also and above all to the cardiovascular cells, such as pericytes and endothelial cells. Indeed, the pathology related to SARS-CoV-2, COVID-19, may be defined as a thromboinflammatory syndrome in its most severe form, characterized by sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulopathy (DIC), which is prevalent in individuals already presenting a chronic level of inflammation (e.g., obese individuals, elderly) and hypertension. Pregnancy is not only an inflammatory-prone condition but is characterized by a consistent rearrangement of the blood circulation and coagulation profile. Cardiac output increases while arterial systolic and diastolic pressure decrease, regardless of the activation of the RAS system. ACE2, the SARS-CoV-2 entry receptor into the host cells, which transforms Ang II in Ang 1–7, is highly expressed in endothelial, smooth muscle cells and pericytes of placental villi, regulating blood pressure and fetal development. Pre-eclampsia is a pregnancy disorder characterized by hypertension and low levels of ACE2, endothelial dysfunction, and a high production of pro-inflammatory cytokines, resembling COVID-19 manifestations. Whereas pre-eclampsia and COVID-19 have overlapping clinical features, a role for SARS-CoV-2 as a leading cause of pre-eclampsia in COVID-19 positive pregnant women has not been clarified yet. In this mini-review, we will explore the possibility of the existence of such a link, focusing on the role of endothelial dysfunction and RAS in both pre-eclampsia and SARS-CoV-2-induced COVID-19 pathogenesis.

Potential Benefit of Soluble Thrombomodulin in Coping with COVID-19/SARS-CoV-2-Induced Coagulopathy

Researchers should investigate the coagulopathy that accompanies Coronavirus Disease 2019 (COVID-19), as the incidence, as well as the mortality associated with coagulopathy, is higher than expected in COVID-19 patients. We read with interest the article published by Tang N et al. suggesting that elevated plasma levels of the fibrin degradation product D-dimer might be a predictive marker for mortality of patients with COVID-19 [1]. The same authors also reported that the use of heparin improved the prognosis of COVID-19 patients with severe coagulopathy and D-dimer levels &gt;6-fold of the normal upper limit [2]. The high plasma levels of D-dimer suggest that the fibrinolytic system is not inhibited; nonetheless, thrombotic events are frequently noted in COVID-19 patients transferred to intensive care units [3]. Curiously, severe cases of COVID-19 are complicated by cytokine release syndrome in conjunction with Hemophagocytic Lymphohistiocytosis (HLH) [4], suggesting that extremely exaggerated hypercoagulability is induced in COVID-19. The pathophysiology of COVID-19-induced coagulopathy has not been fully elucidated. However, recently, postmortem examination of patients with COVID-19 who died of respiratory failure found thrombi in parallel with the deposition of the C5b-9 complex in the microvasculature, indicating terminal complement activation [5]. These pathological findings are reminiscent of the pathogenesis of Transplant-Associated Thrombotic Microangiopathy (TA-TMA) and atypical Hemolytic Uremic Syndrome (aHUS), in which activation of the complement system plays a role. Other possible factors involved in the pathogenesis of COVID-19-induced coagulopathy may be related to the tropism of Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the pathogen that causes COVID-19, to vascular endothelial cells [6]. SARS-CoV-2 infects vascular endothelial cells via the Angiotensin-Converting Enzyme 2 (ACE2) receptor, leading to vascular derangement, so-called endotheliitis, which may result in coagulopathy and TMA. Thrombomodulin (TM) is a cell-surface expressed glycoprotein comprising six distinct domains, including an NH2-terminal lectinlike region, six tandem Epidermal Growth Factor (EGF)-like structures, an O-glycosylation site-rich domain, a transmembrane domain, and a cytoplasmic tail domain [7]. TM binds to thrombin via its EGF-like region and Converts Protein C (PC) to Activated PC (APC), which inhibits coagulant factors FVIIIa and FVa in the presence of protein S, thereby inhibiting further thrombin generation. Interestingly, TM has an anti-inflammatory effect; the lectin-like domain of TM binds and degrades High Mobility Group Box-1 (HMGB1) and attenuates inflammation. Additionally, after interacting with thrombin, TM converts carboxypeptidase Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) to activated TAFI (TAFIa), which inactivates C3 and C5. Furthermore, the fifth domain of EGF-like region of TM (TME5) interacts with the cell-surface chemokine receptor G protein-coupled receptor protein 15 (GPR15) and then exerts cytoprotective effects on vascular endothelial cells in association with upregulation of antiapoptotic MCl-1 proteins, which is mediated by the activation of extracellular signal-regulated kinase [7]. Recombinant human soluble TM (rhTM) comprises extracellular domains of TM. A clinical trial comparing the efficacy and safety of rhTM with Unfractionated Heparin (UFH) in patients with Intravascular Coagulation (DIC) caused by hematological malignancies or infection found that a greater number of patients treated with rhTM recovered from DIC with acceptable toxicity profiles than those who received UFH. Based on these results, the use of rhTM has been approved for the treatment of DIC in Japan since 2008. The use of rhTM effectively treated many patients with DIC with various types of underlying diseases, including transplant-associated complications such as TA-TMA, hepatic sinusoidal obstruction syndrome/veno-occlusive disease and engraftment syndrome [8]. Importantly, endothliitis plays a role in the development of all of these conditions, suggesting the possible cytoprotective roles of rhTM in vascular endothelial cells. Moreover, prompt improvement of DIC caused by HLH developed in association with immune reconstitution syndrome after initiation of highly active antiretroviral therapy for acquired immunodeficiency syndrome was noted in the individual who received rhTM [9]. Thus, the use of anticoagulant rhTM with additional activities for immune systems and vascular endothelial cells could counteract severe COVID-19 with coagulopathy, although a systematic review and meta-analysis of rhTM therapy for sepsis-induced coagulopathy failed to prove the significant improvement of clinical outcomes of patients with sepsis-induced coagulopathy [10].

Validation of sepsis-induced coagulopathy score in critically ill patients with septic shock: post hoc analysis of a nationwide multicenter observational study in Japan.

Coagulation disorder is a major cause of death in sepsis patients. Recently, sepsis-induced coagulopathy (SIC) scoring was developed as a new criterion for coagulopathy-associated sepsis. We aimed to evaluate the accuracy of the SIC score for predicting the prognosis of septic shock. We analyzed data from a multicenter observational study conducted from 2011 to 2013. We grouped the participants into those who did and did not use vasopressors, and compared the in-hospital mortality rates of SIC and non-SIC patients. Patients who needed vasopressors were considered to have septic shock. We performed survival analysis adjusted by factors independently associated with mortality. SIC developed in 66.4% of patients who used vasopressors and 42.2% of patients who did not. The in-hospital mortality difference between the SIC and non-SIC groups was statistically significant in those who needed vasopressors (35.8% vs 27.9%, p < 0.01). Cox regression analysis indicated that SIC was significantly correlated with mortality risk in patients who used vasopressors (hazard ratio [HR] 1.39; 95% confidence interval [CI] 1.13–1.70; p < 0.01), but not in those who did not (HR 1.38; 95% CI 0.81–2.34; p = 0.23). In conclusion, the SIC score might be a good diagnostic indicator of fatal coagulopathy among sepsis patients who need vasopressors.

D-Dimer as Biomarker for Early Prediction of Clinical Outcomes in Patients With Severe Invasive Infections Due to Streptococcus Pneumoniae and Neisseria Meningitidis.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection; no current clinical measure adequately reflects the concept of dysregulated response. Coagulation plays a pivotal role in the normal response to pathogens (immunothrombosis), thus the evolution toward sepsis-induced coagulopathy could be individuate through coagulation/fibrinolysis-related biomarkers. We focused on the role of D-dimer assessed within 24 h after admission in predicting clinical outcomes in a cohort of 270 patients hospitalized in a 79 months period for meningitis and/or bloodstream infections due to Streptococcus pneumoniae (n = 162) or Neisseria meningitidis (n = 108). Comparisons were performed with unpaired t-test, Mann-Whitney-test or chi-squared-test with continuity correction, as appropriate, and multivariable logistic regression analysis was performed with Bayesian model averaging. In-hospital mortality was 14.8% for the overall population, significantly higher in S. pneumoniae than in N. meningitidis patients: 19.1 vs. 8.3%, respectively (p = 0.014). At univariable logistic regression analysis the following variables were significantly associated with in-hospital mortality: pneumococcal etiology, female sex, age, ICU admission, SOFA score, septic shock, MODS, and D-dimer levels. At multivariable analysis D-dimer showed an effect only in N. meningitidis subgroup: as 500 ng/mL of D-dimer increased, the probability of unfavorable outcome increased on average by 4%. Median D-dimer was significantly higher in N. meningitidis than in S. pneumoniae patients (1,314 vs. 1,055 ng/mL, p = 0.009). For N. meningitidis in-hospital mortality was 0% for D-dimer <500 ng/mL, very low (3.5%) for D-dimer <7,000 ng/mL, and increased to 26.1% for D-dimer >7,000 ng/mL. Kaplan-Meier analysis of in-hospital mortality showed for N. meningitidis infections a statistically significant difference for D-dimer >7,000 ng/mL compared to values <500 ng/mL (p = 0.021) and 500–3,000 ng/mL (p = 0.002). For S. pneumoniae the mortality risk resulted always high, over 10%, irrespective by D-dimer values. In conclusion, D-dimer is rapid to be obtained, at low cost and available everywhere, and can help stratify the risk of in-hospital mortality and complications in patients with invasive infections due to N. meningitidis: D-dimer <500 ng/mL excludes any further complications, and a cut-off of 7,000 ng/mL seems able to predict a significantly increased mortality risk from much <10% to over 25%.

Evolving Paradigm of Prothrombin Time Diagnostics with Its Growing Clinical Relevance towards Cardio-Compromised and COVID-19 Affected Population.

Prothrombin time (PT) is a significant coagulation (hemostasis) biomarker used to diagnose several thromboembolic and hemorrhagic complications based on its direct correlation with the physiological blood clotting time. Among the entire set of PT dependents, candidates with cardiovascular ailments are the major set of the population requiring lifelong anticoagulation therapy and supervised PT administration. Additionally, the increasing incidence of COVID affected by complications in coagulation dynamics has been strikingly evident. Prolonged PT along with sepsis-induced coagulopathy (SIC score > 3) has been found to be very common in critical COVID or CAC-affected cases. Considering the growing significance of an efficient point-of-care PT assaying platform to counter the increasing fatalities associated with cardio-compromised and coagulation aberrations propping up from CAC cases, the following review discusses the evolution of lab-based PT to point of care (PoC) PT assays. Recent advances in the field of PoC PT devices utilizing optics, acoustics, and mechanical and electrochemical methods in microsensors to detect blood coagulation are further elaborated. Thus, the following review holistically aims to motivate the future PT assay designers/researchers by detailing the relevance of PT and associated protocols for cardio compromised and COVID affected along with the intricacies of previously engineered PoC PT diagnostics.

Development of a Nomogram to Predict 28-Day Mortality of Patients With Sepsis-Induced Coagulopathy: An Analysis of the MIMIC-III Database.

Background: Sepsis-induced coagulopathy (SIC) is a common cause for inducing poor prognosis of critically ill patients in intensive care unit (ICU). However, currently there are no tools specifically designed for assessing short-term mortality in SIC patients. This study aimed to develop a practical nomogram to predict the risk of 28-day mortality in SIC patients.Methods: In this retrospective cohort study, we extracted patients from the Medical Information Mart for Intensive Care III (MIMIC-III) database. Sepsis was defined based on Sepsis 3.0 criteria and SIC based on Toshiaki Iba's criteria. Kaplan–Meier curves were plotted to compare the short survival time between SIC and non-SIC patients. Afterward, only SIC cohort was randomly divided into training or validation set. We employed univariate logistic regression and stepwise multivariate analysis to select predictive features. The proposed nomogram was developed based on multivariate logistic regression model, and the discrimination and calibration were verified by internal validation. We then compared model discrimination with other traditional severity scores and machine learning models.Results: 9432 sepsis patients in MIMIC III were enrolled, in which 3280 (34.8%) patients were diagnosed as SIC during the first ICU admission. SIC was independently associated with the 7- and 28-day mortality of ICU patients. K–M curve indicated a significant difference in 7-day (Log-Rank: P < 0.001 and P = 0.017) and 28-day survival (Log-Rank: P < 0.001 and P < 0.001) between SIC and non-SIC groups whether the propensity score match (PSM) was balanced or not. For nomogram development, a total of thirteen variables of 3,280 SIC patients were enrolled. When predicted the risk of 28-day mortality, the nomogram performed a good discrimination in training and validation sets (AUROC: 0.78 and 0.81). The AUROC values were 0.80, 0.81, 0.71, 0.70, 0.74, and 0.60 for random forest, support vector machine, sequential organ failure assessment (SOFA) score, logistic organ dysfunction score (LODS), simplified acute physiology II score (SAPS II) and SIC score, respectively, in validation set. And the nomogram calibration slope was 0.91, the Brier value was 0.15. As presented by the decision curve analyses, the nomogram always obtained more net benefit when compared with other severity scores.Conclusions: SIC is independently related to the short-term mortality of ICU patients. The nomogram achieved an optimal prediction of 28-day mortality in SIC patient, which can lead to a better prognostics assessment. However, the discriminative ability of the nomogram requires validation in external cohorts to further improve generalizability.

Терапевтические мишени при коагулопатии COVID-19

В обзоре представлены сведения о некоторых биохимических и клеточных механизмах патогенеза потенциально смертельного вирусного заболевания, получившего название COVID-19, провоцируемого вирусами из семейства коронавирусов SARS-CoV-2. Наибольшую опасность для жизни и здоровья пациентов представляет коагулопатия, обусловленная ответной реакцией на инфекцию — чрезмерной генерацией клетками пациента внеклеточных мембранных нановезикул (ВМН), которые могут спровоцировать активизацию гемостаза, приводящую к разрушительной полиорганной недостаточности. Вирусы также способны генерировать внеклеточные везикулы, называемые виросомами. Встраивая вирусные компоненты в свои виросомы, вирусы повышают персистентность за счет маскировки своих геномов, умножая вирусную инфекцию. В статье охарактеризованы свойства нейтрофильных гранулоцитов, активирующихся при инфицировании, и представлены сведения о молекулярных механизмах действия их компонентов при попадании во внеклеточное пространство. ВМН уже имеют практическое применение в качестве вакцинных носителей для иммунизации человека и животных против многих инфекционных заболеваний. В настоящее время актуальнейшей темой, обуславливающей большой практический интерес, стала роль ВМН в индуцировании иммунитета против коронавирусной инфекции. Охарактеризованы другие возможные терапевтические мишени. Virus-induced coagulopathy is a typical example of the tight connection between inflammation and thrombosis. These two reactions are linked by pro-inflammatory agents, generated by activated neutrophils and their neutrophil extracellular traps (NETs). Extracellular membrane nanobubbles (EMNs), formed by a wide variety of cell types, have recently been identified as new entrants that play a key role in coagulopathy. EMNs directly and indirectly activate coagulation systems that lead to the further upregulation of inflammation and life-threatening organ dysfunction and thrombosis. EMNs are known to be responsible for the secretion, exchange, and transmission of important active biomolecules in COVID-19. Indeed, EMNs represent an essential mechanism in intercellular communication, and the roles of EMNs in infection and thrombosis have been increasingly recognized. The extracellular microvesicles of viruses, virosomes, represent a new type of infectious agents, which determines new therapeutic goals in solving the problems of controlling viral infections. Understanding the biological nature of all these microvesicles when studying them in vivo is of paramount importance for the development of diagnostic and therapeutic methods.

COVID-19 and hypercoagulability

It has been observed that patients with COVID-19 infection may develop acute pulmonary embolism (APE), acute myocardial infarction, limb thrombosis, and venous and / or arterial thrombosis, including central nervous system. Thrombosis formation in COVID-19 patients can be explained by the virchow triad. Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) can directly attack vascular endothelial cells, causing excessive activation of the immune system and cytokine storm, causing thrombosis. Increased prothrombotic factors such as antiphospholipid antibodies, elevated factor VIII, high fibrinogen, circulating prothrombotic microparticles, neutrophil extracellular traps have been reported in COVID-19 infection. It has been argued that complement-mediated endothelial damage, increase in pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8 and interferon-γ may be the cause of thrombosis. Autopsies of patients with COVID-19 revealed that the causes of death were pneumonia and pulmonary embolism. When monitoring COVID-19 patients, platelet, prothrombin time (PT) and activated partial thromboplastin time (aPTT), fibrinogen and D-dimer monitoring should be initiated every 1-2 days, especially in critically ill patients. High D-dimer levels are associated with high mortality; may indicate infection/sepsis, cytokine storm, and impending organ failure. Disseminated intravascular coagulation (DIC) may be seen in COVID-19 patients, but unlike DIC, fibrinogen is usually high. Clotting times and platelet counts are usually normal. Therefore, it is appropriate to use sepsis-induced coagulopathy (SIC) criteria in the follow-up of COVID-19 patients. Infected areas related to pulmonary embolism can be seen as radiological appearance. Some patients may have enlarged subsegmental pulmonary vessels. Treatment of the underlying disease is the most important treatment for all coagulopathies. Patients with venous thromboembolism, inpatient medical, surgical, and COVID-19 therapy should receive anticoagulant therapy unless there is a contraindication to anticoagulation (for example, active bleeding or severe bleeding within the previous 24 to 48 hours).

Treatment of sepsis-induced coagulopathy : Results of aGermany-wide survey in intensive care units

HintergrundIm Rahmen von Sepsis und septischem Schock kommt es aufgrund der engen Verflechtung von Gerinnung und Entzündung häufig zu einer Koagulopathie. Die sepsisinduzierte Koagulopathie (SIC) stellt hierbei die schwerste, potenziell fatale Form dar. Aufgrund fehlender Evidenz beschränken sich die aktuellen Sepsis-Leitlinien auf Empfehlungen zur medikamentösen Prophylaxe einer venösen Thromboembolie (VTE), während die Behandlung einer SIC nicht thematisiert wird.MethodenUm den Status quo der VTE-Prophylaxe sowie der SIC-Behandlung auf deutschen Intensivstationen zu erheben, wurde von Oktober 2019 bis Mai 2020 eine deutschlandweite Onlineumfrage unter ärztlichen Leitern von Intensivstationen durchgeführt. Diese wurde ab April 2020 durch einen zusätzlichen Fragenblock ergänzt, der sich mit der VTE-Prophylaxe sowie der SIC-Behandlung bei Coronaviruskrankheit(COVID)-19-Patienten befasste.ErgebnisseDie Umfrageergebnisse zeigen eine ausgeprägte Heterogenität in der klinischen Praxis bezüglich Prophylaxe von VTE und Therapie der SIC. Ein systematisches Screening auf SIC findet in den meisten Intensivstationen nicht statt. Bei COVID-19-Patienten fällt v. a. auf, dass bei drei Viertel der teilnehmenden Intensivstationen die gelebte Praxis der medikamentösen VTE-Prophylaxe nicht von Non-COVID-19-Patienten abweicht.SchlussfolgerungDie Heterogenität der in der Umfrage gesammelten Antworten legt nahe, dass es einer systematischen Aufarbeitung dieses Themenfeldes bedarf, um zukünftig über klinische Interventionsstudien die individualisierte Patientenversorgung mit der gebotenen Evidenz zu unterlegen.Zusatzmaterial onlineDie Online-Version dieses Beitrags (10.1007/s00101-021-00916-9) enthält eine Zusammenstellung weiterer Aspekte zum Beitrag und den zugrunde liegenden Fragebogen. Beitrag und Zusatzmaterial stehen Ihnen auf www.springermedizin.de zur Verfügung. Bitte geben Sie dort den Beitragstitel in die Suche ein, das Zusatzmaterial finden Sie beim Beitrag unter „Ergänzende Inhalte“.

Diagnosis and treatment of disseminated intravascular coagulation in COVID-19 patients: a scoping review.

BackgroundDisseminated intravascular coagulation (DIC) is noted in severe cases of coronavirus disease 2019 (COVID-19). Recently, a number of studies evaluating the diagnosis and treatment of DIC in COVID-19 patients have been reported.ObjectiveThe aim of this study is to identify existing gaps where further research is needed on the diagnosis and treatment of DIC complicated by COVID-19.MethodsWe used the PRISMA Extension for Scoping Reviews. MEDLINE, CENTRAL, WHO-ICTRP, ClinicalTrial.gov and PROSPERO were searched from their inception to 6 October 2020.ResultsSeven studies were selected; five were already published and two are ongoing. DIC was diagnosed using the International Society on Thrombosis and Hemostasis (ISTH) DIC score (n = 4) and the sepsis-induced coagulopathy (SIC) DIC score (n = 5). Seven studies examined the effectiveness of low molecular weight heparin (LMWH); of these, four studies used a prophylactic dose and five used a therapeutic dose of LMWH. A prophylactic dose of unfractionated heparin (UFH) was investigated in two studies.ConclusionStudies on DIC diagnostic criteria and anticoagulants were limited to the ISTH or SIC scores and heparinoids, particularly LMWH. Further studies are needed to compare these with other available DIC scoring systems and anticoagulants.

COVID-19-associated coagulopathy: thromboembolism prophylaxis and poor prognosis in ICU

Background Coronavirus disease 2019 (COVID-19) is associated with coagulation abnormalities which are indicators of higher mortality especially in severe cases.Methods We studied patients with proven COVID-19 disease in the intensive care unit of Jinyintan Hospital, Wuhan, China from 30 to 2019 to 31 March 2020.ResultsOf 180 patients, 89 (49.44 %) had died, 85 (47.22 %) had been discharged alive, and 6 (3.33 %) were still hospitalised by the end of data collection. A D-dimer concentration of > 0.5 mg/L on admission was significantly associated with 30 day mortality, and a D-dimer concentration of > 5 mg/L was found in a much higher proportion of non-survivors than survivors. Sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulation (DIC) scoring systems were dichotomised as < 4 or ≥ 4 and < 5 or ≥ 5, respectively, and the mortality rate was significantly different between the two stratifications in both scoring systems. Enoxaparin was administered to 68 (37.78 %) patients for thromboembolic prophylaxis, and stratification by the D-dimer concentration and DIC score confirmed lower mortality in patients who received enoxaparin when the D-dimer concentration was > 2 than < 2 mg/L or DIC score was ≥ 5 than < 5. A low platelet count and low serum calcium concentration were also related to mortality.ConclusionsA D-dimer concentration of > 0.5 mg/L on admission is a risk factor for severe disease. A SIC score of > 4 and DIC score of > 5 may be used to predict mortality. Thromboembolic prophylaxis can reduce mortality only in patients with a D-dimer concentration of > 2 mg/L or DIC score of ≥ 5.

A Machine-Learning Approach for Dynamic Prediction of Sepsis-Induced Coagulopathy in Critically Ill Patients With Sepsis.

Background: Sepsis-induced coagulopathy (SIC) denotes an increased mortality rate and poorer prognosis in septic patients.Objectives: Our study aimed to develop and validate machine-learning models to dynamically predict the risk of SIC in critically ill patients with sepsis.Methods: Machine-learning models were developed and validated based on two public databases named Medical Information Mart for Intensive Care (MIMIC)-IV and the eICU Collaborative Research Database (eICU-CRD). Dynamic prediction of SIC involved an evaluation of the risk of SIC each day after the diagnosis of sepsis using 15 predictive models. The best model was selected based on its accuracy and area under the receiver operating characteristic curve (AUC), followed by fine-grained hyperparameter adjustment using the Bayesian Optimization Algorithm. A compact model was developed, based on 15 features selected according to their importance and clinical availability. These two models were compared with Logistic Regression and SIC scores in terms of SIC prediction.Results: Of 11,362 patients in MIMIC-IV included in the final cohort, a total of 6,744 (59%) patients developed SIC during sepsis. The model named Categorical Boosting (CatBoost) had the greatest AUC in our study (0.869; 95% CI: 0.850–0.886). Coagulation profile and renal function indicators were the most important features for predicting SIC. A compact model was developed with an AUC of 0.854 (95% CI: 0.832–0.872), while the AUCs of Logistic Regression and SIC scores were 0.746 (95% CI: 0.735–0.755) and 0.709 (95% CI: 0.687–0.733), respectively. A cohort of 35,252 septic patients in eICU-CRD was analyzed. The AUCs of the full and the compact models in the external validation were 0.842 (95% CI: 0.837–0.846) and 0.803 (95% CI: 0.798–0.809), respectively, which were still larger than those of Logistic Regression (0.660; 95% CI: 0.653–0.667) and SIC scores (0.752; 95% CI: 0.747–0.757). Prediction results were illustrated by SHapley Additive exPlanations (SHAP) values, which made our models clinically interpretable.Conclusions: We developed two models which were able to dynamically predict the risk of SIC in septic patients better than conventional Logistic Regression and SIC scores.

Assessment of systemic inflammatory reactions and coagulopathy against the background of hormonal therapy in covid-associated lung damage

The mechanisms of COVID-19-associated coagulopathy (CAC) are complex and differ in many ways from the standard mechanisms of thrombosis in critically ill patients. This review presents the pathogenesis, diagnosis, and comparison of various types of coagulopathy with SAS. During COVID-19 infection, the number of sudden deaths outside the hospital increased. One possible reason is the high incidence of serious thrombotic events in patients with COVID-19. However, the pathogenesis of these life-threatening events is multifactorial and requires independent discussion.Deviations in laboratory studies of the hemostatic system in patients infected with SARS-CoV-2 with a severe course indicate the activation of the blood coagulation system corresponding to sepsis-induced coagulopathy (SIC) or DIC. However, hemostasis disorders in COVID-19 have characteristics that distinguish them from DIC in sepsis.The clinical and laboratory features of CAC overlap with hemophagocytic syndrome, antiphospholipid syndrome, and thrombotic microangiopathy. The review presents data on their similarities and differences.Inadequate diagnosis or inadequate treatment of hypercoagulability may explain the high incidence of unexplained deaths from COVID-19. They can be associated with potentially preventable microvascular and macrovascular thrombosis and subsequent cardiovascular complications, including myocardial injury and infarction, as well as insufficient information content of biomarkers for their assessment.Research to identify the most informative biomarkers for decision-making to intensify anticoagulant prophylaxis in patients with severe COVID-19 is progressing rapidly, with increasing focus on TEG and ROTEM.The review presents changes in CAC during hormone therapy for COVID-19-associated lung damage. Pulse therapy with high doses of GCS has a rapid anti-inflammatory effect, but at the same time increases the level of D-dimer, which increases the risk of venous thrombosis and thromboembolism.