Myricetin reduces platelet PANoptosis in sepsis to delay disseminated intravascular coagulation.

Sepsis is a severe inflammatory disease characterized by cytokine storm, often accompanied by disseminated intravascular coagulation (DIC). PANoptosis is a novel form of cell death triggered by cytokine storms, characterized by a cascade reaction of pyroptosis, apoptosis, and necroptosis. It exists in septic platelets and is closely associated with the onset and progression of DIC. However, there remains an unmet need for drugs targeting PANoptosis. The anti-PANoptosis effect of myricetin was predicted using network pharmacology and confirmed through molecular docking. In vitro platelet activation models demonstrated that myricetin significantly attenuated platelet particle release, integrin activation, adhesion, spreading, clot retraction, and aggregation. Moreover, in a sepsis model, myricetin reduced inflammatory infiltration in lung tissue and platelet activation while improving DIC. Additionally, whole blood sequencing samples from sepsis patients and healthy individuals were analyzed to elucidate the up-regulation of the PANoptosis targets. Our findings demonstrate the inhibitory effect of myricetin on septic platelet PANoptosis, indicating its potential as a novel anti-cellular PANoptosis candidate and therapeutic agent for septic DIC. Furthermore, our study establishes a foundation for utilizing network pharmacology in the discovery of new drugs to treat various diseases.

YOD1 protects against MRSA sepsis-induced DIC through Lys33-linked deubiquitination of NLRP3.

Disseminated intravascular coagulation (DIC) is considered to be the most common and lethal complication of sepsis. NLR-family pyrin domain-containing-3 (NLRP3) inflammasome plays an important role in host defense against microbial pathogens, and its deregulation may cause coagulation cascade and should be strictly managed. Here, we identified the deubiquitinase YOD1, which played a vital role in regulating coagulation in a NLRP3 inflammasome-dependent manner in sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA). YOD1 interacted with NLRP3 to remove K33-linked ubiquitination of NLRP3 based on its deubiquitinating enzyme activity and specifically inhibited expression of NLRP3 as well as activation of NLRP3 inflammasome. Deficiency of YOD1 expression enhanced NLRP3 inflammasome activation and coagulation both in vitro and in vivo. In addition, pharmacological inhibition of the NLRP3 effectively improved coagulation and alleviated organ injury in Yod1-/- mice infected with MRSA. Thus, our study reported that YOD1 is a key regulator of coagulation during MRSA infection, and provided YOD1 as a potential therapeutic target for the treatment of NLRP3 inflammasome-related diseases, especially MRSA sepsis-induced DIC.

SURGICAL TREATMENT OF VITREORETINAL COMPLICATIONS DURING DISSEMINATED INTRAVASCULAR COAGULATION SECONDARY TO MENINGOCOCCEMIA.

PURPOSE: To report a case of the surgical management of vitreoretinal complications during disseminated intravascular coagulation secondary to meningococcemia. METHODS: A case report. RESULTS: A 25-year-old man presented with loss of vision due to retinal and vitreous hemorrhages during disseminated intravascular coagulation secondary to meningococcemia. Examination revealed the visual acuity to be counting fingers in the right eye and light perception in the left eye. Bilateral vitreous hemorrhages were found on fundus examination. A dome-shaped lesion overlying the macula consistent with a subinternal limiting membrane hemorrhage was seen on optical coherence tomography. Bilateral vitrectomy was performed. Multiple subinternal limiting membrane hemorrhages were evident in the posterior pole. A membrane forceps was used to peel the internal limiting membrane and remove the fibrin under it. The internal limiting membrane and vitreous samples were sent for anatomopathological examination confirming our hypothesis. The peripheral retina revealed bilateral multiple ischemic areas, and argon laser photocoagulation was performed on it. Both eyes were filled with silicone oil. Eight months after surgery, his vision improved to 70 and 65 on the early diabetic retinopathy study scale in the right and left eyes, respectively. CONCLUSION: Published cases of retinal and vitreous hemorrhages during disseminated intravascular coagulation secondary to meningococcemia are few. There is no specific and codified management of these ocular complications. This case is the first reporting positive visual recovery after surgical treatment. Surgical procedure seems to be effective to treat multiple vitreoretinal hemorrhages secondary to meningococcemia.

Reversible glomerular damage in disseminated intravascular coagulation.

BACKGROUND: Brain death secondary to traumatic brain injury is one of the main sources of organs for transplantation but it can be associated with disseminated intravascular coagulation, which has been considered a relative contraindication for kidney donation. METHODS: We describe two successful pediatric cases of kidney transplantation from a single donor with disseminated intravascular coagulation. RESULTS: A 17-year-old male donor died from head injury and both kidneys were offered to our center. Within 24 h, donor's Hb and platelets dropped to 8.3 g/dl and 32 000/mcl, respectively, serum creatinine reached 2.01 mg/dl, and urinalysis showed proteinuria (300 mg/dl). Pre-implant biopsy showed massive occlusion of glomerular capillaries by fibrin thrombi containing fragmented red blood cells and inflammatory cells, and acute tubular damage. Arterioles and small arteries were spared. A diagnosis of DIC was made. The kidneys were transplanted in a 16-year-old girl and a 13-year-old boy. Slow recovery of graft function was observed in both recipients. On post-operative day 3, platelets dropped to a minimum value of 66 000 and 86 000/mcl, respectively. Diuresis was always present. On day 4, platelets started to rise. Six months later, both recipients attained normal renal function. A six-month protocol biopsy showed no microthrombi or other signs of disseminated intravascular coagulation. CONCLUSIONS: Despite the limited data available in literature, the outcome of these two cases is positive. Thus, pre-implant kidney biopsy, even if it reveals massive thrombotic occlusion of glomerular capillaries compatible with diagnosis of disseminated intravascular coagulation, should not be considered an absolute contraindication to transplantation.

Inflammation/coagulopathy/fibrinolysis: Dynamic indicators of COVID-19 progression in patients with moderate COVID-19 in Wenzhou, China.

BACKGROUND: The majority of the coronavirus disease 2019 (COVID-19) non-survivors meet the criteria for disseminated intravascular coagulation (DIC). Although timely monitoring of clotting hemorrhagic development during the natural course of COVID-19 is critical for understanding pathogenesis, diagnosis, and treatment of the disease, however, limited data are available on the dynamic processes of inflammation/coagulopathy/fibrinolysis (ICF). METHODS: We monitored the dynamic progression of ICF in patients with moderate COVID-19. Out of 694 COVID-19 inpatients from 10 hospitals in Wenzhou, China, we selected 293 adult patients without comorbidities. These patients were divided into different daily cohorts according to the COVID-19 onset-time. Furthermore, data of 223 COVID-19 patients with comorbidities and 22 critical cases were analyzed. Retrospective data were extracted from electronic medical records. RESULTS: The virus-induced damages to pre-hospitalization patients triggered two ICF fluctuations during the 14-day course of the disease. C-reactive protein (CRP), fibrinogen, and D-dimer levels increased and peaked at day 5 (D) 5 and D9 during the 1st and 2nd fluctuations, respectively. The ICF activities were higher during the 2nd fluctuation. Although 12-day medication returned high CRP concentrations to normal and blocked fibrinogen increase, the D-dimer levels remained high on days 17 ±â€¯2 and 23 ±â€¯2 days of the COVID-19 course. Notably, although the oxygenation index, prothrombin time and activated partial thromboplastin time were within the normal range in critical COVID-19 patients at administration, 86% of these patients had a D-dimer level > 500 µg/L. CONCLUSION: COVID-19 is linked with chronic DIC, which could be responsible for the progression of the disease. Understanding and monitoring ICF progression during COVID-19 can help clinicians in identifying the stage of the disease quickly and accurately and administering suitable treatment.

Disseminated intravascular coagulation associated organ failure in obstetric patients admitted to intensive care units: a multicenter study in China.

We aimed to determine disseminated intravascular coagulation (DIC)-associated organ failure and underlying diseases based on data from three ICU wards in tertiary hospitals in China from 2008 to 2016. The diagnosis of DIC was confirmed by an International Society of Thrombosis and Hemostasis score greater than or equal to 5. The maternal outcomes included the changes in organ function 24 h after ICU admission. The durations of hospital stay and ICU stay were recorded as secondary outcomes. Among 297 ICU admissions (median Sequential Organ Failure Assessment score, 4) for obstetric diseases, there were 87 DIC cases, with an estimated DIC incidence of 87 per 87,580 deliveries. Postpartum hemorrhage was the leading disease associated with DIC (71, 81.6%), followed by hypertensive disorders (27, 31.0%), sepsis (15, 17.2%), acute fatty liver of pregnancy (11, 12.6%) and amniotic fluid embolism (10, 11.5%). Compared with patients without DIC, those with DIC had higher rates of multiple organ dysfunction syndrome/death (27.6% vs 4.8%, p = 0.000), organ failure (36.8% vs 24.3%, p = 0.029), among which organ failure included acute renal failure (32.2% vs 10.0%, p = 0.000), respiratory failure (16.1% vs 8.6%, p = 0.057), disturbance of consciousness (12.6% vs 2.4%, p = 0.000) and DIC group also had higher rates of massive transfusion (52.9% vs 21.9%, p = 0.000), hysterectomy (32.2% vs 15.7%, p = 0.001), longer ICU (4 days vs 2 days, p = 0.000) and hospital stays (14 days vs 11 days, p = 0.005). DIC and amniotic fluid embolism were independent risk factors for organ failure in patients admitted to the ICU. Postpartum hemorrhage was the leading cause of DIC associated organ failure in obstetrics admitted to the ICU. The control of obstetric bleeding in a timely manner may improve obstetric prognoses.

Antiphospholipid Antibodies and Infection: Non Nova Sed Nove.

The clinical significance of antiphospholipid antibodies (aPL) in the context of infections has attracted attention since their first discovery in patients with syphilis. In fact, the recognition of aPL in patients with infections has been described in parallel to the understating of the syndrome. Since the first description of aPL-positive tests in three patients with COVID-19 diagnosed in January 2020 in Wuhan, China, a large number of studies took part in the ongoing debate on SARS-2-Cov 2 induced coagulopathy, and many following reports speculated a potential role for aPL. In order to get further insights on the effective role of detectable aPL in the pro-thrombotic status observed in COVID-19 patients, we performed an observational age-sex controlled study to compare the aPL profile of hospitalized patients with COVID with those observed in a) patients with thrombotic APS and b) patients with cultural/serologically-proved infections. Our data showed positive aPL testing in about half of the patients (53%) with COVID-19 and patients with other viral/bacterial infections (49%). However, aPL profile was different when comparing patients with overt APS and patients with aPL detected in the contest of infections. Caution is therefore required in the interpretation and generalization of the role of aPL s in the management of patients with COVID-19. Before introducing aPL testing as a part of the routine testing in patients with COVID-19, larger well-designed clinical studies are required. While the pro-thrombotic status in patients with COVID-19 is now unquestionable, different mechanisms other than aPL should be further investigated.

Retrospective review of 27 European cases of fatal elephant endotheliotropic herpesvirus-haemorrhagic disease reveals evidence of disseminated intravascular coagulation.

Elephant endotheliotropic herpesvirus haemorrhagic disease (EEHV-HD) is widely acknowledged as the most common cause of mortality in young Asian elephants (Elephas maximus) in captivity. The objective of the current study was to perform a blinded, retrospective pathology review of European EEHV-HD fatalities, constituting the largest systematic assessment of EEHV-HD pathology to date. Findings between viral genotypes were compared with the aim to investigate if disseminated intravascular coagulation (DIC) could be substantiated as a significant complicating factor, thereby increasing the understanding of disease pathophysiology. Immunohistochemical staining confirmed endothelial cell (EC) damage and the presence of EC intranuclear inclusion bodies, demonstrating a direct viral cytopathic effect. Microthrombi were observed in 63% of cases in several organs, including lungs, which, together with widespread haemorrhage and thrombocytopenia reported in EEHV-HD case reports, supports the presence of overt DIC as a serious haemostatic complication of active EEHV infection. Death was attributed to widespread vascular damage with multi-organ dysfunction, including severe acute myocardial haemorrhage and subsequent cardiac failure. Systemic inflammation observed in the absence of bacterial infection may be caused by cytokine release syndrome. Findings reinforce the necessity to investigate cytokine responses and haemostatic status during symptomatic and asymptomatic EEHV viraemia, to potentially support the use of anti-inflammatory treatment in conjunction with anti-viral therapy and cardiovascular support.

Specific cytokines in the inflammatory cytokine storm of patients with COVID-19-associated acute respiratory distress syndrome and extrapulmonary multiple-organ dysfunction.

BACKGROUND: To date, specific cytokines associated with development of acute respiratory distress syndrome (ARDS) and extrapulmonary multiple organ dysfunction (MOD) in COVID-19 patients have not been systematically described. We determined the levels of inflammatory cytokines in patients with COVID-19 and their relationships with ARDS and extrapulmonary MOD. METHODS: The clinical and laboratory data of 94 COVID-19 patients with and without ARDS were analyzed. The levels of inflammatory cytokines (interleukin 6 [IL-6], IL-8, IL-10, and tumor necrosis factor α [TNF-α]) were measured on days 1, 3, and 5 following admission. Seventeen healthy volunteers were recruited as controls. Correlations in the levels of inflammatory cytokines with clinical and laboratory variables were analyzed, furthermore, we also explored the relationships of different cytokines with ARDS and extrapulmonary MOD. RESULTS: The ARDS group had higher serum levels of all 4 inflammatory cytokines than the controls, and these levels steadily increased after admission. The ARDS group also had higher levels of IL-6, IL-8, and IL-10 than the non-ARDS group, and the levels of these cytokines correlated significantly with coagulation parameters and disseminated intravascular coagulation (DIC). The levels of IL-6 and TNF-α correlated with the levels of creatinine and urea nitrogen, and were also higher in ARDS patients with acute kidney injury (AKI). All 4 inflammatory cytokines had negative correlations with PaO2/FiO2. IL-6, IL-8, and TNF-α had positive correlations with the APACHE-II score. Relative to survivors, non-survivors had higher levels of IL-6 and IL-10 at admission, and increasing levels over time. CONCLUSIONS: The cytokine storm apparently contributed to the development of ARDS and extrapulmonary MOD in COVID-19 patients. The levels of IL-6, IL-8, and IL-10 correlated with DIC, and the levels of IL-6 and TNF-α were associated with AKI. Relative to survivors, patients who died within 28 days had increased levels of IL-6 and IL-10.

Immunothrombosis in COVID-19: Implications of Neutrophil Extracellular Traps.

SARS-CoV-2 is a member of the family of coronaviruses associated with severe outbreaks of respiratory diseases in recent decades and is the causative agent of the COVID-19 pandemic. The recognition by and activation of the innate immune response recruits neutrophils, which, through their different mechanisms of action, form extracellular neutrophil traps, playing a role in infection control and trapping viral, bacterial, and fungal etiological agents. However, in patients with COVID-19, activation at the vascular level, combined with other cells and inflammatory mediators, leads to thrombotic events and disseminated intravascular coagulation, thus leading to a series of clinical manifestations in cerebrovascular, cardiac, pulmonary, and kidney disease while promoting severe disease and mortality. Previous studies of hospitalized patients with COVID-19 have shown that elevated levels of markers specific for NETs, such as free DNA, MPO, and H3Cit, are strongly associated with the total neutrophil count; with acute phase reactants that include CRP, D-dimer, lactate dehydrogenase, and interleukin secretion; and with an increased risk of severe COVID-19. This study analyzed the interactions between NETs and the activation pathways involved in immunothrombotic processes in patients with COVID-19.

Cardiovascular, hematological and neurosensory impact of COVID-19 and variants.

OBJECTIVE: The purpose of this article was to review our clinical experience with COVID-19 patients observed in the Cardiovascular Division of Pompidou Hospital (University of Paris, France) and the Department of Neurology of the Eastern Piedmont University (Novara, Italy), related to the impact on the cardiovascular, hematological, and neurologic systems and sense organs. PATIENTS AND METHODS: We sought to characterize cardiovascular, hematological, and neurosensory manifestations in patients with COVID-19 and variants. Special attention was given to initial signs and symptoms to facilitate early diagnosis and therapy. Indications of ECMO (extracorporeal membrane oxygenation) for cardiorespiratory support were evaluated. RESULTS: Preliminary neurosensorial symptoms, such as anosmia and dysgeusia, are useful for diagnosis, patient isolation, and treatment. Early angiohematological acro-ischemic syndrome includes hand and foot cyanosis, Raynaud digital ischemia phenomenon, skin bullae, and dry gangrene. This was associated with neoangiogenesis, vasculitis, and vessel thrombosis related to immune dysregulation, resulting from "cytokine storm syndrome". The most dangerous complication is disseminated intravascular coagulation, with mortality risks for both children and adults. CONCLUSIONS: COVID-19 is a prothrombotic disease with unique global lethality. A strong inflammatory response to viral infection severely affects cardiovascular and neurological systems, as well as respiratory, immune, and hematological systems. Rapid identification of acro-ischemic syndrome permits the treatment of disseminated intravascular coagulation complications. Early sensorial symptoms, such as gustatory and olfactory loss, are useful for COVID-19 diagnosis. New variants of SARS-CoV-2 are emerging, principally from United Kingdom, South Africa, and Brazil. These variants seem to spread more easily and quickly, which may lead to more cases of COVID.

Schistocyte quantitation, thrombotic microangiopathy and acute kidney injury in Australian snakebite coagulopathy [ASP28].

INTRODUCTION: The major systemic manifestation of hemotoxicity in human snakebite envenoming is venom-induced consumption coagulopathy (VICC). A subset of patients with VICC develop thrombotic microangiopathy (TMA), in which acute kidney injury (AKI) occurs. We aimed to investigate the association between schistocytosis in snakebite patients with VICC and AKI, compared to non-envenomed patients. METHODS: Serial blood films collected from a prospective cohort of snakebite patients (Australian Snakebite Project) were examined. Cases were classified a priori as non-envenomed snakebites (normal controls), envenomed without VICC, partial VICC without AKI, complete VICC without AKI, and VICC with AKI based on defined clinical and laboratory criteria. The percentage of schistocytes between groups was compared and correlated by Kendall's tau b test. RESULTS: Seven hundred and eighty blood films from 234 snakebite cases were analyzed. There was a statistically significant correlation (τ = .69, SE .03, P < .001) for schistocytosis between the ordered groups of non-envenomed snakebites, envenomed without VICC, partial VICC without AKI, complete VICC without AKI, and VICC with AKI groups. Patients with VICC and AKI had a platelet nadir median of 42 × 109 /L (interquartile range [IQR] :25-130 × 109 /L), hemoglobin nadir of median 107 g/L (IQR 66-122 g/L), and maximum LDH median of 1128 U/L (IQR 474-3255 U/L). A 1.0% threshold for schistocytosis yielded 90% sensitivity (95% CI: 67%-98%) and 71% specificity (95% CI: 62%-79%) for predicting AKI in patients with VICC. CONCLUSION: Schistocyte quantitation has good diagnostic utility in snakebite patients with VICC. A definition of snakebite TMA as MAHA with ≥1.0% schistocytes and thrombocytopenia, would appear to be appropriate.

Bilateral acute renal cortical necrosis after a dog bite: case report.

BACKGROUND: Capnocytophaga canimorsus is a Gram-negative capnophilic rod and part of dogs/cats' normal oral flora. It can be transmitted by bites, scratches, or even by contact of saliva with injured skin. Asplenic patients and patients with alcohol abuse are at particular risk for fulminant C. canimorsus sepsis. However, also immunocompetent patients can have a severe or even fatal infection. This is the first case of a severe C. canimorsus infection in an immunocompromised host complicated by acute renal cortical necrosis with a "reverse rim sign" in contrast-enhanced computed tomography on hospital admission. CASE PRESENTATION: We report the case of a 44-year functionally asplenic patient after an allogeneic stem cell transplantation, who presented with septic shock after a minor dog bite injury 4 days prior. Because of abdominal complaints, epigastric pain with local peritonism, and radiological gallbladder wall thickening, an abdominal focus was suspected after the initial work-up. The patient underwent emergent open cholecystectomy, but the clinical suspicion of abdominal infection was not confirmed. Septic shock was further complicated by cardiomyopathy and disseminated intravascular coagulation. As a causative pathogen, C. canimorsus could be isolated. The clinical course was complicated by permanent hemodialysis and extensive acral necrosis requiring amputation of several fingers and both thighs. CONCLUSION: We present a severe case of a C. canimorsus infection in a functionally asplenic patient after a minor dog bite. The clinical course was complicated by septic shock, disseminated intravascular coagulation, and the need for multiple amputations. In addition, the rare form of acute renal failure - bilateral acute renal cortical necrosis - was visible as "reverse rim sign" on computed tomography scan. This case is an example of the potential disastrous consequences when omitting pre-emptive antibiotic therapy in wounds inflicted by cats and dogs, particularly in asplenic patients.

Protease-activated receptor 1 as a potential therapeutic target for COVID-19.

Acute respiratory disease caused by a novel coronavirus (SARS-CoV-2) has spread all over the world, since its discovery in 2019, Wuhan, China. This disease is called COVID-19 and already killed over 1 million people worldwide. The clinical symptoms include fever, dry cough, dyspnea, headache, dizziness, generalized weakness, vomiting, and diarrhea. Unfortunately, so far, there is no validated vaccine, and its management consists mainly of supportive care. Venous thrombosis and pulmonary embolism are highly prevalent in patients suffering from severe COVID-19. In fact, a prothrombotic state seems to be present in most fatal cases of the disease. SARS-CoV-2 leads to the production of proinflammatory cytokines, causing immune-mediated tissue damage, disruption of the endothelial barrier, and uncontrolled thrombogenesis. Thrombin is the key regulator of coagulation and fibrin formation. In severe COVID-19, a dysfunctional of physiological anticoagulant mechanisms leads to a progressive increase of thrombin activity, which is associated with acute respiratory distress syndrome development and a poor prognosis. Protease-activated receptor type 1 (PAR1) is the main thrombin receptor and may represent an essential link between coagulation and inflammation in the pathophysiology of COVID-19. In this review, we discuss the potential role of PAR1 inhibition and regulation in COVID-19 treatment.

Risk factors for Covid-19 severity and fatality: a structured literature review.

PURPOSE: Covid-19 is a global threat that pushes health care to its limits. Since there is neither a vaccine nor a drug for Covid-19, people with an increased risk for severe and fatal courses of disease particularly need protection. Furthermore, factors increasing these risks are of interest in the search of potential treatments. A systematic literature review on the risk factors of severe and fatal Covid-19 courses is presented. METHODS: The review is carried out on PubMed and a publicly available preprint dataset. For analysis, risk factors are categorized and information regarding the study such as study size and location are extracted. The results are compared to risk factors listed by four public authorities from different countries. RESULTS: The 28 records included, eleven of which are preprints, indicate that conditions and comorbidities connected to a poor state of health such as high age, obesity, diabetes and hypertension are risk factors for severe and fatal disease courses. Furthermore, severe and fatal courses are associated with organ damages mainly affecting the heart, liver and kidneys. Coagulation dysfunctions could play a critical role in the organ damaging. Time to hospital admission, tuberculosis, inflammation disorders and coagulation dysfunctions are identified as risk factors found in the review but not mentioned by the public authorities. CONCLUSION: Factors associated with increased risk of severe or fatal disease courses were identified, which include conditions connected with a poor state of health as well as organ damages and coagulation dysfunctions. The results may facilitate upcoming Covid-19 research.

Clotting disorder in severe acute respiratory syndrome coronavirus 2.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human respiratory viral infection that has rapidly progressed into a pandemic, causing significant morbidity and mortality. Blood clotting disorders and acute respiratory failure have surfaced as the major complications among the severe cases of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection. Remarkably, more than 70% of deaths related to COVID-19 are attributed to clotting-associated complications such as pulmonary embolism, strokes and multi-organ failure. These vascular complications have been confirmed by autopsy. This study summarizes the current understanding and explains the possible mechanisms of the blood clotting disorder, emphasizing the role of (1) hypoxia-related activation of coagulation factors like tissue factor, a significant player in triggering coagulation cascade, (2) cytokine storm and activation of neutrophils and the release of neutrophil extracellular traps and (3) immobility and ICU related risk factors.