Changes in haemostasis and inflammatory markers after mRNA BNT162b2 and vector Ad26.CoV2.S SARS-CoV-2 vaccination.

INTRODUCTION: Reported thromboembolic events after SARS-CoV-2 vaccinations are still raising concerns, predominantly in non-scientific population. The aim of our study was to investigate the differences between haemostasis and inflammatory markers in the subjects vaccinated with mRNA BNT162b2 and vector Ad26.CoV2.S vaccine. MATERIALS AND METHODS: The study included 87 subjects vaccinated with mRNA BNT162b2 and 84 with Ad26.CoV2.S vaccine. All the laboratory parameters (TAT, F 1 + 2, IL-6, CRP, big endothelin-1, platelets, fibrinogen, D-dimers, VWF activity) were investigated for the mRNA vaccine at five (before the first dose, 7 and 14 days after the first and second vaccine dose), and three time points (before the first dose, 7 and 14 days after) for the vector vaccine, respectively. All the markers were measured by well-established laboratory methods. RESULTS: Our results have shown statistically higher CRP levels in the vector group 7 days after vaccination (P = 0.014). Furthermore, study has revealed statistically significant rise in D-dimers (P = 0.004) between tested time points in both vaccine groups but without clinical repercussions. CONCLUSION: Although statistically significant changes in haemostasis markers have been obtained, they remained clinically irrelevant. Thus, our study implicates that there is no plausible scientific evidence of a significant disruption in the coagulation and inflammatory processes after vaccination with BNT162b2 mRNA and Ad26.CoV2.S vector SARS-CoV-2 vaccines.

COVID-19 Critical and Intensive Care Medicine Essentials

This book provides healthcare professionals in Critical Care setting an easy consultation guide to fight against COVID-19. The book is divided into sections: Fundamentals of COVID-19, Pneumological critical care, Neurological manifestations, Cardiovascular manifestations, Renal manifestations, Haemostasis and coagulation, Other multi-organs involvement, Principles of therapy. Each section includes: · brief pathophysiology of COVID-19 (ventilation, neurological, cardiovascular, etc.);· principles of management (enriched with flowcharts and figures);· principles of therapy;· tips and key messages. Readers can find the most updated advices on how to face the ongoing pandemic: from principles of conventional oxygen therapy, assisted and invasive mechanical ventilation in critically ill COVID-19 patients to the complications sometimes underestimated. Tables and flowcharts provided are based on current knowledge in COVID-19 to help the clinician managing COVID-19 patients by a multiple-organs prospective. Written by international key opinion leaders of each field, the book represents a point of reference for all professionals involved in the management of COVID-19 pandemic. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

Dysregulated haemostasis in thrombo-inflammatory disease.

Inflammatory disease is often associated with an increased incidence of venous thromboembolism in affected patients, although in most instances, the mechanistic basis for this increased thrombogenicity remains poorly understood. Acute infection, as exemplified by sepsis, malaria and most recently, COVID-19, drives 'immunothrombosis', where the immune defence response to capture and neutralise invading pathogens causes concurrent activation of deleterious prothrombotic cellular and biological responses. Moreover, dysregulated innate and adaptive immune responses in patients with chronic inflammatory conditions, such as inflammatory bowel disease, allergies, and neurodegenerative disorders, are now recognised to occur in parallel with activation of coagulation. In this review, we describe the detailed cellular and biochemical mechanisms that cause inflammation-driven haemostatic dysregulation, including aberrant contact pathway activation, increased tissue factor activity and release, innate immune cell activation and programmed cell death, and T cell-mediated changes in thrombus resolution. In addition, we consider how lifestyle changes increasingly associated with modern life, such as circadian rhythm disruption, chronic stress and old age, are increasingly implicated in unbalancing haemostasis. Finally, we describe the emergence of potential therapies with broad-ranging immunothrombotic functions, and how drug development in this area is challenged by our nascent understanding of the key molecular and cellular parameters that control the shared nodes of proinflammatory and procoagulant pathways. Despite the increasing recognition and understanding of the prothrombotic nature of inflammatory disease, significant challenges remain in effectively managing affected patients, and new therapeutic approaches to curtail the key pathogenic steps in immune response-driven thrombosis are urgently required.

Should Anticoagulant Drugs Be Advised in Every Future Pandemic Guideline?Ourcovid-19 Comparative Analysis

Background: Covid-19 is a viral disease that has been declared a pandemic by the World Health Organization.[ 1,2]. The most frequent complication has been reported to be sepsis[3]. Disseminated intravascular coagulation (DIC) has been observed in majority of mortalities.[4,5].While Disseminated Intravascular Coagulation is widely used to describe sepsis associated coagulopathy, ISTH has recently started using Sepsis Associated Coagulopathy in its definition. SIC is actually considered the early stage of DIC, and research has found that anticoagulant treatment is effective in patients meeting SIC criteria.[6,7]. Anticoagulant treatment has been shown to be beneficial in patients who do not exhibit clinical DIC, but meet SIC criteria. (Figure 1). Contemporary guidelines recommend anticoagulant treatment. Method(s): The patient groups, who were followed up with Covid-19 in Necmettin Erbakan University hospital, with and without anticoagulant treatment, will be analyzed retrospectively and comparative. Result(s): This study assessed the data of 2028 patients diagnosed with COVID-19 and subsequently given (Group1 (n=1008)) or not given (Group2 (n=1020)) anticoagulant treatment. The demographic characteristics displayed on the table exhibited similarities;D-dimer, SOFA and SIC scores demonstrated significant changes. (Table 1).Patients who developed DVT, arterial embolism and pulmonary embolism were included in the THROMBOSIS'' study. While group 1 had a thrombosis development rate of 5.15% (n=52), this rate was 19.21% (n=196) in group2.THROMBOSIS patients in group1 and 2 demonstrated a mortality rate of 38.46%(n=20) and 65.5% (n=128), respectively (p<0.001).THROMBOSIS patients in group1 and 2 were divided into subgroups according to SIC scores and their mortality rates were analyzed with respect to SICDIC scores;significant results were observed (SIC>5 was accepted as DIC).Patients who receive anticoagulant treatment subsequent to COVID-19 diagnosis have reduced disposition to thrombosis. According to SIC-DIC scores obtained through SOFA scores and clinical parameters, patients who reach DIC levels (SIC>5) have an increased rate of mortality. (Table 2).However, in group 2 patients who were diagnosed with COVID-19 and not given anticoagulant treatment due to no recommendation in prior guidelines, the mortality rate was high with every SIC score. Patients with a SIC score of 4 had a substantially high mortality rate;this is probably due to not receiving anticoagulants because DIC had not manifested.It was observed that compared to group 1, patients in group 2 who had not yet reached a DIC score, but had a SIC score of 4, had mortality rates reduced by 97% with anticoagulant treatment (p<0.001). According to SIC-DIC scores obtained through SOFA scores and clinical parameters, patients who reach DIC levels (SIC>5) have an increased rate of mortality (Tables 2 and 3). According to SIC-DIC scores obtained through SOFA scores and clinical parameters, patients who reach DIC Conclusion(s): Through our findings, we wanted to describe when COVID-19 patients who are hospitalized should receive anticoagulant treatment. Patients should be monitored with respect to their SIC scores, and clinicians should consider anticoagulant administration as it can potentially decrease mortality rate, regardless of DIC development.

Illustration: Thromboelastography - A useful tool to monitor COVID-19-associated coagulopathy.

COVID 19 is caused by Severe Acute Respiratory Syndrome Corona Virus-2 which results in wide range of manifestations. Systemic hypercoagulation is a typical feature of COVID-19. We present a case of COVID-19 in whom TEG was performed on admission and hypercoagulability was diagnosed and hence patient was started on Enoxaparin sodium 6000 IU twice daily. TEG was repeated after 5 days which showed normal coagulation status and the patient was discharged without any thrombotic complications.

Non-Coding RNAs in COVID-19: Emerging Insights and Current Questions.

The highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as the causative agent of coronavirus disease 2019 (COVID-19) in late 2019, igniting an unprecedented pandemic. A mechanistic picture characterising the acute immunopathological disease in severe COVID-19 is developing. Non-coding RNAs (ncRNAs) constitute the transcribed but un-translated portion of the genome and, until recent decades, have been undiscovered or overlooked. A growing body of research continues to demonstrate their interconnected involvement in the immune response to SARS-CoV-2 and COVID-19 development by regulating several of its pathological hallmarks: cytokine storm syndrome, haemostatic alterations, immune cell recruitment, and vascular dysregulation. There is also keen interest in exploring the possibility of host-virus RNA-RNA and RNA-RBP interactions. Here, we discuss and evaluate evidence demonstrating the involvement of short and long ncRNAs in COVID-19 and use this information to propose hypotheses for future mechanistic and clinical studies.

DIC, SIC or CAC - the haemostatic profile in COVID-19 patients hospitalised in the intensive care unit: a single-centre retrospective analysis.

INTRODUCTION: Infection with SARS-CoV-2 in its most severe form leads to acute respiratory distress syndrome requiring mechanical ventilation under the conditions of the Intensive Care Unit (ICU). The state of hypercoagulation described in COVID-19 may deepen respiratory failure, leading to increased mortality. The aim of the presented study is to characterise the haemostatic profile based on the results of clotting system parameters and risk assessment of thromboembolic complications of patients hospitalised in the ICU. MATERIAL AND METHODS: This retrospective study covered the first 10 adult patients hospitalised in the ICU of the Hospital for Infectious Diseases in Warsaw in the second quarter of 2020. Demographic, clinical and laboratory parameters of the coagulation system and the risk of thromboembolic complications were assessed. Well known criteria of haemostatic disorders were used to classify the observed derangements. RESULTS: The most frequently observed deviations in the coagulation system were high concentrations of D-dimer and fibrinogen. In select cases the clotting time was prolonged. No severe thrombocytopenia was observed. All patients presented a high risk of thromboembolic complications as assesed by the Padua score. The observed clotting abnormalities did not meet the criteria for DIC (disseminated intravascular coagulation) and SIC (sepsis-induced coagulopathy) diagnosis. CONCLUSIONS: The main elements of coagulopathy that were observed in our cases differ from those usually seen in patients with recognised sepsis. The unique haemostatic profile of COVID-19 patients treated in the ICU has been described as CAC (COVID-19-associated coagulopathy).

The Impact of the Renin-Angiotensin-Aldosterone System on Inflammation, Coagulation, and Atherothrombotic Complications, and to Aggravated COVID-19.

Atherosclerosis is considered a disease caused by a chronic inflammation, associated with endothelial dysfunction, and several mediators of inflammation are up-regulated in subjects with atherosclerotic disease. Healthy, intact endothelium exhibits an antithrombotic, protective surface between the vascular lumen and vascular smooth muscle cells in the vessel wall. Oxidative stress is an imbalance between anti- and prooxidants, with a subsequent increase of reactive oxygen species, leading to tissue damage. The renin-angiotensin-aldosterone system is of vital importance in the pathobiology of vascular disease. Convincing data indicate that angiotensin II accelerates hypertension and augments the production of reactive oxygen species. This leads to the generation of a proinflammatory phenotype in human endothelial and vascular smooth muscle cells by the up-regulation of adhesion molecules, chemokines and cytokines. In addition, angiotensin II also seems to increase thrombin generation, possibly via a direct impact on tissue factor. However, the mechanism of cross-talk between inflammation and haemostasis can also contribute to prothrombotic states in inflammatory environments. Thus, blocking of the renin-angiotensin-aldosterone system might be an approach to reduce both inflammatory and thrombotic complications in high-risk patients. During COVID-19, the renin-angiotensin-aldosterone system may be activated. The levels of angiotensin II could contribute to the ongoing inflammation, which might result in a cytokine storm, a complication that significantly impairs prognosis. At the outbreak of COVID-19 concerns were raised about the use of angiotensin converting enzyme inhibitors and angiotensin receptor blocker drugs in patients with COVID-19 and hypertension or other cardiovascular comorbidities. However, the present evidence is in favor of continuing to use of these drugs. Based on experimental evidence, blocking the renin-angiotensin-aldosterone system might even exert a potentially protective influence in the setting of COVID-19.

Hypercoagulopathy, acquired coagulation disorders and anticoagulation before, during and after extracorporeal membrane oxygenation in COVID-19: a case series.

BACKGROUND: Thromboembolism and bleeding contribute to Coronavirus disease 2019 (COVID-19)'s morbidity and mortality and are also frequent complications of venovenous extracorporeal membrane oxygenation (vvECMO). As the interaction of the underlying pathologies caused by vvECMO in COVID-19 is barely understood, we designed this study to better differentiate coagulation disorders in COVID-19 patients before, during and after vvECMO-support. METHODS: Observational case series, six consecutive patients with Coronavirus acute respiratory distress syndrome supported with vvECMO treated in the anaesthesiologic ICU in a third level University ECMO-centre. We measured routine coagulation parameters and assessed coagulation factors. We also conducted advanced von Willebrand factor (VWF) multimer analysis, platelet aggregometry and immunological screening. RESULTS: We identified various phases of coagulation disorders: Initially, intensely activated coagulation with highly increased VWF and factor VIII activity in acute COVID-19, then severe acquired von Willebrand syndrome and platelet dysfunction during vvECMO leading to spontaneous bleeding and finally, hypercoagulopathy after vvECMO explantation. Five of six patients developed immunological abnormalities enhancing coagulation. CONCLUSIONS: Coronavirus-induced coagulopathy and bleeding disorders during vvECMO cannot be discriminated via 'routine' coagulation tests. Precise and specific analyses followed by the appropriate treatment of coagulation disorders may help us develop tailored therapeutic concepts to better manage the phases described above.

Effects of Omega-3 Polyunsaturated Fatty Acids and Their Metabolites on Haemostasis-Current Perspectives in Cardiovascular Disease.

The beneficial effects of long-chain polyunsaturated omega-3 fatty acids (omega-3 PUFAs) in cardioprotection are widely known and generally accepted. In this literature review, we have focused on the known and postulated mechanisms of action of omega-3 PUFAs and their metabolites on various components of the haemostatic system, in particular on blood platelets and endothelium. We have also made an attempt to provide a comprehensive review of epidemiological studies with particular regard to clinical trials. Notably, the results of these studies are contradictory, and some of them failed to report the beneficial effects of taking or supplementing omega-3 PUFAs in the diet. A potential explanation, in our opinion, could be the need to use higher doses of omega-3 PUFAs and a proper ratio of omega-3 and omega-6 PUFAs. An additional problem which is difficult to solve is the use of a proper neutral placebo for interventional studies. Despite some controversies regarding the beneficial effects of supplementation of omega-3 PUFAs in cardiovascular disease, our review suggests that a promising aspect of future studies and applications is to focus on the anti-thrombotic properties of these compounds. An argument supporting this assumption is the recent use of omega-3 PUFAs as a supporting tool for the treatment of COVID-19 complications.

SARS-CoV-2 Infected Patient: from a Hematologist's Perspective.

INTRODUCTION: According to the World Health Organization (WHO), COVID-19 has become a Public Health Emergency of International Concern (PHEIC). Understanding patients' hematologic findings in SARS-CoV-2 infection is essential to doing their prognosis, so adjusting care and improving outcomes. OBJECTIVE: In this review, we aim at summarizing changes in the hematopoietic system and hemostasis that occur in SARS-CoV-2 infected patients. FINDINGS: COVID-19 infection is often associated with laboratory hematologic features that can have important clinical implications. Careful revision of baseline hematologic data at diagnosis can predict the severity of illness and help clinicians tailoring the approach and management of patients whose condition can be guarded or critical. The levels of hematologic markers like D-dimer, procalcitonin, C-reactive protein, viral load, inflammatory cytokines, differential blood cell count, and peripheral smear are fundamental for the prognosis. Studies have also shown an association between some of these markers and severe COVID-19 infection requiring admission to the intensive care unit or complicated by acute respiratory distress syndrome (ARDS). Since, so far, a vaccine is not available, prevention of the infection is based on the avoiding people affected and the spreading of the virus; the treatment, in the absence of an effective antiviral agent, is symptomatic, and, in addition to oxygen support, finds in the anti-inflammatory drugs and anticoagulation fundamental therapeutic lines. According to the American Society of Hematology (ASH), all hospitalized patients with COVID-19 should receive pharmacologic thromboprophylaxis with LMWH.