Microvascular Thrombosis Research Articles

Infection with SARS-CoV-2 Is Associated with Elevated Levels of IP-10, MCP-1, and IL-13 in Sepsis Patients.

Immunothrombosis, an excessive inflammatory response with simultaneous overactivation of the coagulation system, is a central pathomechanism in sepsis and COVID-19. It is associated with cellular activation, vascular damage, and microvascular thrombosis, which can lead to multiple organ failure and death. Here, we characterized factors related to immunothrombosis in plasma samples from 78 sepsis patients. In the course of routine clinical testing, SARS-CoV-2 was detected in 14 of these patients. Viral infection was associated with a higher mortality. Both, COVID-19 negative and COVID-19 positive sepsis patients showed increased levels of effectors of immunothrombosis, including platelet factor 4, D-dimer, nucleosomes, citrullinated histone H3, high mobility group box-1 protein, as well as phosphatidylserine-expressing platelet-derived extracellular vesicles, compared to healthy controls (n = 25). Using a 27-plex cytokine bead array, we found that Interleukin (IL)-1ra, IL-6, IL-8, IL-13, tumor necrosis factor (TNF)-α, interferon inducible protein (IP)-10, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, and granulocyte-colony stimulating factor (G-CSF) were elevated in both, COVID-19 negative and COVID-19 positive sepsis patients, as compared to healthy controls. SARS-CoV-2 infection was associated with elevated levels of IP-10, MCP-1, and IL-13, while all other mediators widely overlapped between COVID-19 negative and COVID-19 positive patients.

Nintedanib as an Antifibrotic in Post Covid Lung Fibrosis: Are we Really Overestimating?

Antifibrotics were exuberantly used to treat post covid lung complications. Lung is the primary target organ in COVID-19 disease with diverse clinical and radiological presentations and outcome. It has caused minimal to moderate lung disease in some patients and in some cases caused deadly acute respiratory distress syndrome (ARDS). COVID-19 disease caused lung damage by direct virus induced alveolar damage, cytokine induced alveolar and vascular damage and microvascular thrombosis resulting into acute hypoxic respiratory failure. COVID-19 pneumonia evolved over period of three weeks in cases with ARDS as natural course of illness. Usually, ARDS resolves by fibrosis or resolution as final outcome. Similarly, in COVID-19 recovered cases of advanced disease or those suffering from ARDS are having post covid lung disease. Lung fibrosis is final radiological outcome of COVID-19 pneumonia documented in proportionately majority of cases. Post COVID lung fibrosis is considered as worrisome radiological complication observed during early phase of pandemic. Antifibrotics such as Nintedanib and Pirfenidone were used to treat post covid lung complications such as fibrosis. Both drugs were shown good antifibrotic property in clinical trials for fibrotic lung disease and observed positive outcome in restoring lung parenchyma. Time trends of final radiological outcome has evolved over months with or without treatment with antifibrotics and steroids. Importantly, Post covid lung fibrosis resolved more than fifty percent cases in six months and nearly in all cases after one year. Thus, antifibrotics were used irrationally in fibrosing lung condition of reversible type. Actually, we have overestimated post covid lung fibrosis and overtreated with antifibrotics.

Plasminogen activator inhibitor 1 is not a major causative factor for exacerbation in a mouse model of SARS-CoV-2 infection

Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global pandemic. Although several vaccines targeting SARS-CoV-2 spike proteins protect against COVID-19 infection, mutations affecting virus transmissibility and immune evasion potential have reduced their efficacy, leading to the need for a more efficient strategy. Available clinical evidence regarding COVID-19 suggests that endothelial dysfunction with thrombosis is a central pathogenesis of progression to systemic disease, in which overexpression of plasminogen activator inhibitor-1 (PAI-1) may be important. Here we developed a novel peptide vaccine against PAI-1 and evaluated its effect on lipopolysaccharide (LPS)-induced sepsis and SARS-CoV-2 infection in mice. Administration of LPS and mouse-adapted SARS-CoV-2 increased serum PAI-1 levels, although the latter showed smaller levels. In an LPS-induced sepsis model, mice immunized with PAI-1 vaccine showed reduced organ damage and microvascular thrombosis and improved survival compared with vehicle-treated mice. In plasma clot lysis assays, vaccination-induced serum IgG antibodies were fibrinolytic. However, in a SARS-CoV-2 infection model, survival and symptom severity (i.e., body weight reduction) did not differ between vaccine- and vehicle-treated groups. These results indicate that although PAI-1 may promote the severity of sepsis by increasing thrombus formation, it might not be a major contributor to COVID-19 exacerbation.

Real-time intelligent classification of COVID-19 and thrombosis via massive image-based analysis of platelet aggregates.

Microvascular thrombosis is a typical symptom of COVID-19 and shows similarities to thrombosis. Using a microfluidic imaging flow cytometer, we measured the blood of 181 COVID-19 samples and 101 non-COVID-19 thrombosis samples, resulting in a total of 6.3 million bright-field images. We trained a convolutional neural network to distinguish single platelets, platelet aggregates, and white blood cells and performed classical image analysis for each subpopulation individually. Based on derived single-cell features for each population, we trained machine learning models for classification between COVID-19 and non-COVID-19 thrombosis, resulting in a patient testing accuracy of 75%. This result indicates that platelet formation differs between COVID-19 and non-COVID-19 thrombosis. All analysis steps were optimized for efficiency and implemented in an easy-to-use plugin for the image viewer napari, allowing the entire analysis to be performed within seconds on mid-range computers, which could be used for real-time diagnosis.

Autoantibodies enhance ADAMTS-13 clearance in patients with immune thrombotic thrombocytopenic purpura

BackgroundSevere deficiency in ADAMTS-13 (<10%) and the loss of von Willebrand factor–cleaving function can precipitate microvascular thrombosis associated with thrombotic thrombocytopenic purpura (TTP). Patients with immune-mediated TTP (iTTP) have anti-ADAMTS-13 immunoglobulin G antibodies that inhibit ADAMTS-13 function and/or increase ADAMTS-13 clearance. Patients with iTTP are treated primarily by plasma exchange (PEX), often in combination with adjunct therapies that target either the von Willebrand factor-dependent microvascular thrombotic processes (caplacizumab) or the autoimmune components (steroids or rituximab) of the disease. ObjectivesTo investigate the contributions of autoantibody-mediated ADAMTS-13 clearance and inhibition in patients with iTTP at presentation and through the course of the PEX therapy. Patients/MethodsAnti-ADAMTS-13 immunoglobulin G antibodies, ADAMTS-13 antigen, and activity were measured before and after each PEX in 17 patients with iTTP and 20 acute TTP episodes. ResultsAt presentation, 14 out of 15 patients with iTTP had ADAMTS-13 antigen levels of <10%, suggesting a major contribution of ADAMTS-13 clearance to the deficiency state. After the first PEX, both ADAMTS-13 antigen and activity levels increased similarly, and the anti-ADAMTS-13 autoantibody titer decreased in all patients, revealing ADAMTS-13 inhibition to be a modest modifier of the ADAMTS-13 function in iTTP. Analysis of ADAMTS-13 antigen levels between consecutive PEX treatments revealed that the rate of ADAMTS-13 clearance in 9 out of 14 patients analyzed was 4- to 10-fold faster than the estimated normal rate of clearance. ConclusionThese data reveal, both at presentation and during PEX treatment, that antibody-mediated clearance of ADAMTS-13 is the major pathogenic mechanism that causes ADAMTS-13 deficiency in iTTP. Understanding the kinetics of ADAMTS-13 clearance in iTTP may now enable further optimization of treatment of patients with iTTP.

Microvascular lung vessels obstructive thromboinflammatory syndrome in patients with COVID-19: Insights from lung intravascular optical coherence tomography.

Microvascular lung vessels obstructive thromboinflammatory syndrome has been proposed as a possible mechanism of respiratory failure in COVID-19 patients. However, it has only been observed in post-mortem studies and has never been documented in vivo, probably because of a lack of CT scan sensitivity in small pulmonary arteries. The aim of the present study was to assess the safety, tolerability, and diagnostic value of optical coherence tomography (OCT) for the assessment of patients with COVID-19 pneumonia for pulmonary microvascular thromboinflammatory syndrome. The COVID-OCT trial was a multicenter, open-label, prospective, interventional clinical study. Two cohorts of patients were included in the study and underwent pulmonary OCT evaluation. Cohort A consisted of patients with COVID-19 with a negative CT scan for pulmonary thrombosis and elevated thromboinflammatory markers (D-dimer > 10,000 ng/mL or 5,000 < D-dimer < 10,000 ng/mL and one of: C-reactive Protein > 100 mg/dL, IL-6 > 6 pg/mL, or ferritin > 900 ng/L). Cohort B consisted of patients with COVID-19 and a CT scan positive for pulmonary thrombosis. The primary endpoints of the study were: (i) to evaluate the overall safety of OCT investigation in patients with COVID-19 pneumonia, and (ii) to report on the potential value of OCT as a novel diagnostic tool for the diagnosis of microvascular pulmonary thrombosis in COVID-19 patients. A total of 13 patients were enrolled. The mean number of OCT runs performed in each patient was 6.1 ± 2.0, both in ground glass and healthy lung areas, achieving a good evaluation of the distal pulmonary arteries. Overall, OCT runs identified microvascular thrombosis in 8 patients (61.5%): 5 cases of red thrombus, 1 case of white thrombus, and 2 cases of mixed thrombus. In Cohort A, the minimal lumen area was 3.5 ± 4.6 mm2, with stenosis of 60.9 ± 35.9% of the area, and the mean length of thrombus-containing lesions was 5.4 ± 3.0 mm. In Cohort B, the percentage area obstruction was 92.6 ± 2.6, and the mean thrombus-containing lesion length was 14.1 ± 13.9 mm. No peri-procedural complications occurred in any of the 13 patients. OCT appears to be a safe and accurate method of evaluating the distal pulmonary arteries in hospitalized COVID-19 patients. Here, it enabled the first in vivo documentation of distal pulmonary arterial thrombosis in patients with elevated thromboinflammatory markers, even when their CT angiogram was negative for pulmonary thrombosis. ClinicalTrial.gov, identifier NCT04410549.

Blocking of PI3-kinase beta protects against cerebral ischemia/reperfusion injury by reducing platelet activation and downstream microvascular thrombosis in rats

Phosphoinositide 3-kinase beta (PI3Kβ) plays an important role in platelet activation and thrombosis, but its role in stroke pathology remains unknown. In this study, we investigated whether inhibition of PI3Kβ protects against cerebral ischemia/reperfusion (I/R) injury by preventing circulating platelet activation and downstream microvascular thrombosis. We used a rat intraluminal filament model of transient middle cerebral artery occlusion (tMCAO) because the rapid restoration of cerebral blood flow to the ischemic area in both tMCAO and endovascular thrombectomy provides clinical relevance for this model. The results showed that TGX221, a selective PI3Kβ inhibitor, treatment immediately before the onset of reperfusion dose-dependently reduced infarct volume and improved neurological function. The protective effects were associated with blocking platelet activation and thrombotic response, thereby reducing downstream microvascular thrombosis, and maintaining reperfusion efficiency. These results suggest that PI3Kβ might be a promising target for treating downstream microvascular thrombosis induced by cerebral I/R injury and offer a novel adjunctive treatment to improve reperfusion therapy for acute ischemic stroke.

Microvascular Thrombosis as a Critical Factor in Severe COVID-19.

Platelet-endothelial interactions have a critical role in microcirculatory function, which maintains tissue homeostasis. The subtle equilibrium between platelets and the vessel wall is disturbed by the coronavirus disease 2019 (COVID-19), which affects all three components of Virchow's triad (endothelial injury, stasis and a hypercoagulable state). Endotheliitis, vasculitis, glycocalyx degradation, alterations in blood flow and viscosity, neutrophil extracellular trap formation and microparticle shedding are only few pathomechanisms contributing to endothelial damage and microthrombosis resulting in capillary plugging and tissue ischemia. In the following opinion paper, we discuss major pathological processes leading to microvascular endothelial activation and thrombosis formation as a possible major adverse factor driving the deterioration of patient disease course in severe COVID-19.

Atrial inflammation and microvascular thrombogenicity are increased in deceased COVID-19 patients

BackgroundHistopathological studies have shown inflammation, cardiomyocyte injury, and microvascular thrombosis in the ventricular myocardium of patients with coronavirus disease 2019 (COVID-19). However, although atrial dysfunction is common in COVID-19, little is known about histopathological changes in the atria of the heart. We therefore analyzed inflammation, cardiomyocyte injury, and microvascular thrombogenicity in the atria of deceased patients with COVID-19. MethodsAtrial tissue was obtained from autopsied COVID-19 (n=16) patients and control patients (n=10) and analyzed using immunohistochemistry. The infiltration of CD45+ leukocytes, CD3+ T lymphocytes, CD68+ macrophages, MPO+ neutrophils, and Tryptase+ mast cells were quantified as well as cardiomyocyte damage and microvascular thrombosis. In addition, Tissue Factor (TF) and Factor XII (FXII) were quantified as markers of microvascular thrombogenicity. ResultsThe numbers of lymphocytes, macrophages, and neutrophils were significantly increased in the atrial myocardium and epicardial atrial adipose tissue of COVID-19 patients compared with the control group. This was accompanied by dispersed cardiomyocyte injury, the occasional presence of microvascular thrombosis, and an increased presence of TF and FXII in the microvascular endothelium. ConclusionsSevere COVID-19 induces inflammation, cardiomyocyte injury, and microvascular thrombosis in the atria of the heart.

Microvascular significance of TGF-β axis activation in COVID-19.

As 2023 approaches, the COVID-19 pandemic has killed millions. While vaccines have been a crucial intervention, only a few effective medications exist for prevention and treatment of COVID-19 in breakthrough cases or in unvaccinated or immunocompromised patients. SARS-CoV-2 displays early and unusual features of micro-thrombosis and immune dysregulation that target endothelial beds of the lungs, skin, and other organs. Notably, anticoagulation improves outcomes in some COVID-19 patients. The protein transforming growth factor-beta (TGF-β1) has constitutive roles in maintaining a healthy microvasculature through its roles in regulating inflammation, clotting, and wound healing. However, after infection (including viral infection) TGF-β1 activation may augment coagulation, cause immune dysregulation, and direct a path toward tissue fibrosis. Dysregulation of TGF-β signaling in immune cells and its localization in areas of microvascular injury are now well-described in COVID-19, and such events may contribute to the acute respiratory distress syndrome and skin micro-thrombosis outcomes frequently seen in severe COVID-19. The high concentration of TGF-β in platelets and in other cells within microvascular thrombi, its ability to activate the clotting cascade and dysregulate immune pathways, and its pro-fibrotic properties all contribute to a unique milieu in the COVID-19 microvasculature. This unique environment allows for propagation of microvascular clotting and immune dysregulation. In this review we summarize the physiological functions of TGF-β and detail the evidence for its effects on the microvasculature in COVID-19. In addition, we explore the potential role of existing TGF-β inhibitors for the prevention and treatment of COVID-19 associated microvascular thrombosis and immune dysregulation.

Rozchynni fibryn-monomerni kompleksy i D-dymery yak pokaznyky tiazhkosty hostroho pankreatytu

Introduction. Local and systemic inflammation, disorders in the hemostatic system are among the key components of acute pancreatitis (AP) pathogenesis already in its early stages, and in future development of thrombohemorrhagic complications. The degree of systemic hemostatic disorders in AP varies from subclinical activation of coagulation, which can only be detected using sensitive markers of activation of coagulation factors, to fulminant disseminated intravascular coagulation syndrome, characterized by multiple systemic microvascular thrombosis and profuse bleeding from different sites. It has been proven that D-dimers and soluble fibrin-monomeric complexes (SFMK) are valuable markers of coagulation and fibrinolysis activation. The aim of the study. To study the dynamics of D-dimers, soluble fibrin-monomeric complexes in the blood of patients with acute pancreatitis, depending on the severity of the disease. Materials and methods. A prospective examination of 206 patients with AP was carried out. According to the criteria of the International Classification, mild pancreatitis was verified in 51 patients, moderate – in 98, severe – in 57. The concentration of SFMK, D-dimers was determined in 66 patients with AP on the first, third, seventh and fourteenth days of conservative treatment. The reference values were estimated in 11 healthy individuals. Results. The enhansed concentration of SFMK and D-dimers were detected in the blood of all patients under examination. Their content directly correlated with the severity of AP course as determined by the Ranson and BISAP score, the severity of the patient’s condition by the APACHE II score and organ dysfunction by the SOFA score, and the degree of damage to the pancreas by the Balthazar criteria. The concentration of SFMK and D-dimers significantly increased with the occurrence of respiratory, cardiovascular, renal, and metabolic dysfunction. A reliable direct correlation was determined between the amount of SFMK and the concentration of creatinine and glucose in the blood of patients with AP. The increase in the level of D-dimers significantly directly correlated with the concentration of creatinine in the blood serum. The sensitivity of SFMK determination (cut-of value 137.50 ng/L) for predicting pulmonary dysfunction was 86.20 %, and the specificity was 83.80 %, with positive and negative predictive values of 80.65 and 88.57 % respectively. Conclusions. The course of acute pancreatitis is accompanied by local or systemic inflammation, changes in the hemostatic system, severity of which correlating with the severity of the disease. Characteristic feature for patients with severe acute pancreatitis is the combination of systemic inflammation with procoagulant changes. The severity of acute pancreatitis, the severity of patient’s condition and organ dysfunction, the severity of pancreatic lesions are associated with an increase of fibrin degradation products. The concentration of soluble fibrin-monomeric complexes can be used to predict pulmonary dysfunction in patients with acute pancreatitis.

Diagnosis, management and prevention of thrombotic complications in microsurgical breast reconstruction: a review of the literature

Autologous free tissue transfer is a safe and effective option for breast reconstruction. It is an increasingly utilized technique with well-demonstrated improved patient satisfaction and quality of life. Microvascular thrombosis is a rare but significant complication of microsurgical breast reconstruction, often resulting in flap failure. Proper diagnosis and timely management of this complication are essential to free flap salvage. While microvascular thrombosis poses a threat to flap survival, several methods may be employed to mitigate its more devastating effects. Here, we present a comprehensive review of arterial and venous thrombotic complications in both the intraoperative and postoperative settings. We discuss preoperative risk assessment, methods for flap monitoring, and operative and medical management of thrombotic complications. We present an updated algorithm for the intraoperative management of microvascular thrombosis adapted to reflect the most recent literature and our novel algorithm for the postoperative management of microvascular thrombosis.

An Outcome Analysis of Asymptomatic COVID-19 Patients Presenting with Angina- A Retrospective Study

Introduction: Cardiovascular disorders have long been considered as one of the leading causes of mortality in India, which when presented with concurrent Coronavirus Disease (COVID-19) infection becomes even more fatal. Evidence suggests that COVID-19 affects the cardiovascular system by causing exuberant cytokinaemia, which results in endothelial inflammation and microvascular thrombosis, leading to multiorgan failure. Aim: To analyse the outcome of the asymptomatic COVID-19 patients presenting with cardiac angina during the second wave of COVID-19 in India. Materials and Methods: This is a retrospective data analysis of asymptomatic COVID-19 patients hospitalised with angina was conducted between April 2021 to June 2021 at Bardhhaman Medical College and Hospital located at Bardhdhaman district of West Bengal, India. A total of 1235 patients underwent all regular biochemical, haematological and cardiac investigations after undergoing test for COVID-19 test. Data was retrospectively collected. The outcome of these patients was analysed. Estimation of mean, standard deviation, percentage, p-value (from Pearson’s correlation) was performed to establish the aim of the study. Results: Seventy six out of 1235 patients tested positive for asymptomatic COVID-19. The mean age of this study population was 55.075±10.95 years, of which were 55 male and 21 female. Hypertension was the most prevalent co-morbidity followed by diabetes, 73 (96%) presented with chest pain. A total of 47(62%) of these 76 patients had ST Elevated Myocardial Infarction (STEMI). Eleven (14.4%) underwent Percutaneous Coronary Intervention (PCI) whereas 36 (47.3%) underwent fibrinolytic therapy with tenecteplase, followed by secondary PCI in 27 (75%) of them. Rest 29 (38%) were medically managed for unstable angina. Mortality rate was as low as 6.5%. Age and comorbidity were the contributing factors for STEMI among asymptomatic COVID-19 patients. Conclusion: The results indicate that age and comorbidity are the factors, which lead to death or increases the life risk among patients with asymptomatic COVID-19. In this study, we have established that for the current patient population STEMI and age are negatively corelated. Medical management with thrombolytic agent became a lot more accepted in this scenario. PCI still remains the gold standard to treat myocardial infarction. It is recommended that there should be an ICMR guided protocol for the management of such cases with the concurrent COVID-19.

Influence of traumatic brain injury on ipsilateral and contralateral cortical perfusion in mice

Traumatic brain injury (TBI) is one of the most important causes of death in young adults. After brain injury cortical perfusion is impaired by cortical spreading depression, cerebral microvasospasm or microvascular thrombosis and contributes to secondary expansion of lesion into surrounding healthy brain tissue. The present study was designed to determine the regional cortical perfusion pattern after experimental TBI induced by controlled cortical impact (CCI) in male C57/BL6N mice. We performed a longitudinal time series analysis by Laser speckle contrast imaging (LSCI). Measurements were carried out before, immediately and 24 h after trauma. Immediately after CCI cortical perfusion in the lesion core dropped to 10 % of before injury (baseline; %BL) and to 21–24 %BL in the cortical area surrounding the core. Interestingly, cortical perfusion was also significantly reduced in the contralateral non-injured hemisphere (41–58 %BL) matching the corresponding brain region of the injured hemisphere. 24 h after CCI perfusion of the contralateral hemisphere returned to baseline level in the area corresponding to the lesion core, whereas the lateral area of the parietal cortex was hyperperfused (125 %BL). The lesion core region itself remained severely hypoperfused (18 to 26 %BL) during the observation period. TBI causes a maldistribution of both ipsi- and contralateral cerebral perfusion immediately after trauma, which persist for at least 24 h. Higher perfusion levels in the lesion core 24 h after trauma were associated with increased tissue damage, which supports the role of reperfusion injury for secondary brain damage after TBI.

Diagnosis of Disseminated Intravascular Coagulation in Patients Suffering from Sepsis using the Modified International Society of Thrombosis and Haemostasis Criteria and Japanese Association of Acute Medicine Criteria

Introduction: The international task force defines sepsis as ‘life- threatening organ dysfunction caused by a dysregulated host response to infection’. Disseminated Intravascular Coagulation (DIC) is a coagulopathy syndrome that causes microvascular and macrovascular thrombosis and increases the risk of bleeding due to consumptive coagulopathy. Sepsis causes dysfunction in coagulation due to release of inflammatory markers which leads to inappropriate deposition of intravascular fibrin. In order to facilitate the diagnostic process for detecting DIC, the scoring system recommended by International Society of Thrombosis and Haemostasis (ISTH) and Japanese Association of Acute Medicine (JAAM) were used which are based on the global coagulation tests such as the platelet count, Prothrombin time, International Normalised Ratio (INR) and Fibrin Degradation Products (FDPs)/D-dimer. Aim: To determine the prevalence and outcome of DIC in patients suffering from sepsis using ISTH criteria and JAAM criteria. Materials and Methods: A prospective cohort was carried out from January 2021 to July 2022 in the haematology section of pathology department of Government Medical College and Hospital, Aurangabad, Maharashtra, India. Hundred patients suffering from clinically suspected sepsis were included in the study. Venous blood was collected from patients in Ethylene Diamine Tetra-acetic Acid (EDTA) and Citrate bulbs. The tests performed were Complete Blood Count (CBC), Prothrombin Time (PT), INR and D-Dimer. CBC was performed on Fully automated three part cell counter. PT, INR, D-Dimer testing was done on fully automated coagulometer. The above test results were used to diagnose DIC in patients suffering from sepsis using the modified ISTH and JAAM criterias. The results were analysed using Microsoft excel 2019 i.e., chi-square test was applied for p-value calculation. Results: Out of 100 patients with clinically suspected sepsis 35 patients (35%) suffered from Overt DIC using ISTH criteria and 58 patients (58%) suffered from DIC using JAAM criteria. The total mortality in patients with sepsis in the present study was 40%. The mortality in patients with DIC in sepsis using the ISTH criteria was 26 patients (74.28%) and 37 patients (63.79%) using the JAAM criteria. Conclusion: Coagulation abnormalities are widely prevalent in patients with sepsis and are likely to play a key role in multi- organ dysfunction. Both ISTH and JAAM criteria are good predictors of mortality.

Coagularea intravasculară diseminată în obstetrică: mini-review

Disseminated intravascular coagulation (DIC) represents a major challenge in obstetrics. The prognosis is influenced by the severity of the coagulopathy and its underlying condition. Early recognition of DIC, if possible, is important because of the potential for end-organ microvascular thrombosis and/or major blood loss. Obstetric DIC manifests mainly with bleeding. In order to facilitate the diagnosis and management of disseminated intravascular coagulation, a pregnancy-specific DIC score was developed. The therapy aims at treating the condition that triggers DIC, the hemorrhagic complications and the coagulopathy.

Regulating Neutrophil PAD4/NOX-Dependent Cerebrovasular Thromboinflammation.

Background: Neutrophil extracellular trap (NET) production has been implicated in the pathogenesis of thromboinflammatory conditions such as Sickle Cell Disease (SCD), contributing to heightened risk for ischemic stroke. NETs are catalyzed by the enzyme Peptidyl Arginine Deiminase 4 (PAD4) and neutrophil derived reactive oxygen species (ROS), especially NADPH oxidase (NOX) which interacts with PAD4 and is therefore critical for neutrophil function. However, the role that NOX-dependent ROS and NETs play in the accelerated cerebral microvascular thrombosis associated with thromboinflammatory conditions, such as SCD, has not been fully elucidated and is the aim of this study. Methods: The in-vitro effects of targeting PAD4 and NOX were examined using physiologically relevant NET assays with neutrophils isolated from healthy volunteers (control) and SCD patients. In addition, in-vivo intravascular effects of targeting PAD4 and NOX in the cerebral microcirculation of C57BL/6 and sickle transgenic mice (STM) were assessed using a photoactivation thrombosis model (light/dye) coupled with real-time fluorescence intravital microscopy. Results: We found that targeting PAD4 and NOX in human neutrophils significantly inhibited ionomycin dependent H3cit+ neutrophils. Targeting PAD4 and NOX in-vivo resulted in prolonged blood flow cessation in cerebrovascular arterioles as well as venules. Moreover, we were able to replicate the effects of PAD4 and NOX targeting in a clinical model of accelerated thromboinflammation by increasing blood flow cessation times in cerebral microvessels in STM. These findings concurred with the clinical setting i.e. neutrophils isolated from SCD patients, which possessed an attenuation of H3cit+ neutrophil production on targeting PAD4 and NOX. Conclusions: Taken together, our compelling data suggests that PAD4 and NOX play a significant role in neutrophil driven thromboinflammation. Targeting PAD4 and NOX limits pathological H3cit+ neutrophils, which may further explain attenuation of cerebral thrombosis. Overall, this study presents a viable pre-clinical model of prevention and management of thromboinflammatory complications such as ischemic stroke.

Disseminated Intravascular Coagulation Associated With SARS-COV-2 Infection: A Post- Mortem Case Study

The mechanisms of coagulation disorder in COVID-19 are complex. However, it is already postulated that endotheliopathy and platelet activation may be important factors, causing direct damage to endothelial cells and the imbalance of inflammatory response, manifesting by venous arterial or microvascular thrombosis. The present study aims to describe a clinical case of an 8-year-old female patient with disseminated intravascular coagulation due to sepsis of viral etiology.

COVID-19 Hastalarında İnme Sıklığının Değerlendirilmesi

Objective: Neurological symptoms occur due to central and peripheral nervous system involvement with different mechanisms in coronavirus disease 2019 (COVID-19). Microvascular thrombosis develops with prothrombotic activation along with the increase in cytokines in COVID-19 infection. We aimed to investigate the incidence of cerebrovascular disease and concomitant risk factors in COVID-19 positive patients.Materials and Methods: Acute and temporally related cerebrovascular diseases with a diagnosis of COVID-19 were evaluated. Cerebrovascular events were assessed in 4 groups as ischemic and hemorrhagic events, transient ischemic attacks, and cerebral venous thrombosis. Risk factors for cerebrovascular disease in these patients were also assessed, and which risk factors for cerebrovascular diseases in COVID-19 patients are high risk were examined.Results: Of the 1000 patients with COVID-19 disease were evaluated. Ischemic cerebrovascular disease and/or transient ischemic attack were found in 14 patients (1.4%). The most common symptoms related to COVID-19 were fever and respiratory distress in 14 patients with acute ischemic stroke diagnosed with COVID-19.Conclusion: COVID-19 increases the risk of stroke in patients with multiple risk factors. Close follow-up should be performed more carefully, especially in patients with pulmonary involvement and acute ischemic stroke, because mortality is likely to be higher.

Disseminated Intravascular Coagulation (DIC): Old player creates new perspectives on the polymicrobial sepsis model of CASP.

Disseminated Intravascular Coagulation (DIC) is a life-threatening complication of sepsis. In surgical ICUs, DIC is frequently caused by abdominal sepsis, and the disarranged coagulation and complications often lead to death. The severity of sepsis is associated with a higher DIC score according to the parameters proposed by the International Society of Hemostasis and Thrombosis (ISTH) in 2001: platelet count, bleeding time (Quick), D-dimer, and fibrinogen. One problem in studying DIC is finding an adequate animal model that reflects the clinical situation of polymicrobial overwhelming infection. We investigated whether a well-established polymicrobial sepsis model of colon ascendens stent peritonitis (CASP) is suited to investigate the complexity of DIC. For this purpose, CASP-operated mice were examined 20 h after the operation with regard to coagulation parameters using cell counts, bleeding times, rotational thromboelastometry (ROTEM), ELISAs for D-dimer and fibrinogen, and platelet accumulation in affected organs via immunohistochemistry to see if the mice develop a coagulation disorder that meets the definition of DIC proposed by the ISTH 2001 consensus conference. Herein, we showed that the CASP model is an all-encompassing animal model to analyze the complexity of systemic DIC in murine abdominal sepsis. There is highly reproducible thrombocytopenia, a significant prolongation of the bleeding time, and a loss of fibrinogen in plasma. We also observed microvascular thrombosis due to platelet accumulation in the microcirculation of the liver. The CASP model seems superior to other artificial models, e.g., injecting substances, for inducing DIC. CASP is one of the best true-to-life models for analyzing the complexity of disseminated intravascular coagulation in polymicrobial sepsis.