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Dengue virus NS1 protein is a major pathogenic protein. In this study, we examined the role of NS1 in coagulopathy associated with Dengue infection, a common feature of Dengue virus pathogenesis. Since most coagulation factors are produced by hepatocytes and liver is key organ affected during infection, we conducted transcriptomics using total-RNA extracted from Huh7 cells overexpressing NS1 protein. Coagulation factors 1, 5, 10, and 13 were downregulated and was confirmed using quantitative real-time polymerase chain reaction (RT-PCR) and western blot assays in both adherent and non-adherent cell culture systems across all four serotypes of Dengue. We also determined that downregulation of coagulation factors is a result of reduced expression of transcription activator HNF4α. Furthermore, we demonstrated that phosphorylation of extracellular signal-regulated kinase (ERK) leads to HNF4α downregulation and subsequent downregulation of coagulation factors. The downregulation of HNF4α and the downregulation of subsequent coagulation factors were validated in BALB/c mice by hydrodynamic tail vein injection of NS1 expression plasmids. Western blot assays using plasma from Dengue patients indicated that at least two coagulation factors of the common pathway of coagulation cascade are downregulated during the febrile phase, with levels improving toward the convalescent phase. NS1-mediated downregulation of coagulation factors was observed for both intracellular and secreted NS1. The hypothesis was also validated using virus infection assays. Overall, our study highlights the role of NS1 in mediating coagulopathy by modulating the expression of coagulation factors through transcriptional suppression of HNF4α by elevated phosphorylated ERK. This signaling cascade could be targeted for therapeutic intervention against virus-related coagulopathies., Importance: Thrombocytopenia has been linked to coagulopathy of Dengue infection, and Dengue patients with coagulopathies are often administered platelet transfusion. For coagulopathies without thrombocytopenia, platelet transfusion might not help. We demonstrated the role of NS1 in coagulopathy by downregulating coagulation factors themselves. When thrombocytopenia does not exist or when thrombocytopenia as well as reduced levels of coagulation factors are the causative factors for coagulopathies, only platelet transfusion might not be effective. Alternative strategies, like administration of coagulation factor cocktails or platelet transfusion along with coagulation factor cocktail, might be promising. Our work also leads to a signaling pathway of NS1-mediated downregulation of coagulation factors via phosphorylated ERK and HNF4α. HNF4α is a transcription regulator for many other liver-based metabolic factors and pathways like lipid metabolism, carbohydrate metabolism, etc, and thus, therapeutic targeting of NS1-based downregulation of HNF4α can lead to designing therapeutic candidates for managing other Dengue-based liver dysfunction., Competing Interests: The authors declare no conflict of interest.

COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is associated with hypercoagulability and increased incidence of thrombotic events. In this study, we investigated the levels of neutrophil extracellular trap biomarkers and von Willebrand factor to assess if these could predict the occurrence of a thrombotic event in COVID-19 patients. We enrolled 202 patients hospitalized with symptomatic COVID-19 infection. Of those, 104 patients did not experience any type of thrombotic events before or during their hospitalization. These patients were compared to the other cohort of 98, who experienced thrombotic events before or during their hospitalization. In total, 61 patients who experienced thrombotic events had the event after initial blood collection, so the predictive capacity of biomarkers in these patients was evaluated. Citrullinated histone H3 was the best predictive biomarker for thrombotic events in COVID-19 regardless of age, sex, and race; disease severity was also a significant predictor in most thrombotic event groups. These results may better inform treatment and prophylaxis of thrombotic events in COVID-19 and similar viral illnesses in the future to improve outcomes and reduce mortality.

Coagulation dysfunction has emerged as a significant aspect of COVID-19 pathophysiology, with abnormal coagulation parameters observed in severe cases. This study aimed to investigate the predictive value of coagulation parameters, including prothrombin time (PT), activated partial thromboplastin time (PTT), and international normalized ratio (INR) for mortality in patients with COVID-19. A retrospective analysis was conducted on a cohort of patients diagnosed with COVID-19. Coagulation parameters, including PT, PTT, and INR, were measured upon admission. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performance of these parameters. Sensitivity and specificity were calculated, and the area under the curve (AUC) values were determined. The analysis included 156 patients diagnosed with COVID-19. The t -test revealed a significant difference ( P < 0.05) in PTT, PT, and INR. PTT demonstrated the highest predictive performance, with an AUC value of 0.68, indicating superior discrimination compared with PT and INR. PTT exhibited a sensitivity of 83% and a specificity of 46% for identifying deceased patients. These findings suggest that PTT may serve as a valuable prognostic marker of mortality risk in patients with COVID-19. Coagulation indicators, particularly PTT, predicted COVID-19 mortality. Monitoring coagulation markers may help stratify the risk and guide treatment. Further research and validation studies are needed to corroborate these findings and to establish the clinical importance of coagulation markers in COVID-19 therapy. COVID-19 coagulation dysfunction mechanisms must be understood in order to design targeted therapies to reduce thrombotic consequences., Competing Interests: The authors declare no conflict of interest., (© 2024 by the authors.)

COVID-associated coagulopathy seemly plays a key role in post-acute sequelae of SARS- CoV-2 infection. However, the underlying pathophysiological mechanisms are poorly understood, largely due to the lack of suitable animal models that recapitulate key clinical and pathological symptoms. Here, we fully characterized AC70 line of human ACE2 transgenic (AC70 hACE2 Tg) mice for SARS-CoV-2 infection. We noted that this model is highly permissive to SARS-CoV-2 with values of 50% lethal dose and infectious dose as ~ 3 and ~ 0.5 TCID50 of SARS-CoV-2, respectively. Mice infected with 105 TCID50 of SARS-CoV-2 rapidly succumbed to infection with 100% mortality within 5 days. Lung and brain were the prime tissues harboring high viral titers, accompanied by histopathology. However, viral RNA and inflammatory mediators could be detectable in other organs, suggesting the nature of a systemic infection. Lethal challenge of AC70 hACE2 Tg mice caused acute onset of leukopenia, lymphopenia, along with an increased neutrophil-to-lymphocyte ratio (NLR). Importantly, infected animals recapitulated key features of COVID-19-associated coagulopathy. SARS-CoV-2 could induce the release of circulating neutrophil extracellular traps (NETs), along with activated platelet/endothelium marker. Immunohistochemical staining with anti-platelet factor-4 (PF4) antibody revealed profound platelet aggregates especially within blocked veins of the lungs. We showed that acute SARS-CoV-2 infection triggered a hypercoagulable state coexisting with ill-regulated fibrinolysis. Finally, we highlighted the potential role of Annexin A2 (ANXA2) in fibrinolytic failure. ANXA2 is a calcium-dependent phospholipid-binding protein that forms a heterotertrameric complexes localized at the extracellular membranes with two S100A10 small molecules acting as a co-receptor for tissue-plasminogen activator (t-PA), tightly involved in cell surface fibrinolysis. Thus, our results revealing elevated IgG type anti-ANXA2 antibody production, downregulated de novo ANXA2/S100A10 synthesis, and reduced ANXA2/S100A10 association in infected mice, this protein might serve as druggable targets for development of antithrombotic and/or anti-fibrinolytic agents to attenuate pathogenesis of COVID-19., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Drelich et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Although thrombosis frequently occurs in infectious diseases, the coagulopathy associated with COVID-19 has unique characteristics. Compared with bacterial sepsis, COVID-19-associated coagulopathy presents with minimal changes in platelet counts, normal prothrombin times, and increased D-dimer and fibrinogen levels. These differences can be explained by the distinct pathophysiology of the thromboinflammatory responses. In sepsis-induced coagulopathy, leukocytes are primarily responsible for the coagulopathy by expressing tissue factor, releasing neutrophil extracellular traps, multiple procoagulant substances, and systemic endothelial injury that is often associated with vasoplegia and shock. In COVID-19-associated coagulopathy, platelet activation is a major driver of inflammation/thrombogenesis and von Willebrand factor and platelet factor 4 are deeply involved in the pathogenesis. Although the initial responses are localized to the lung, they can spread systemically if the disease is severe. Since the platelets play major roles, arterial thrombosis is not uncommon in COVID-19. Despite platelet activation, platelet count is usually normal at presentation, but sensitive biomarkers including von Willebrand factor activity, soluble P-selectin, and soluble C-type lectin-like receptor-2 are elevated, and they increase as the disease progresses. Although the role of antiplatelet therapy is still unproven, current studies are ongoing to determine its potential effects., Competing Interests: T.I. has received a research grant from Japan Blood Products Organization and JIMRO. H.W. received grants and personal fees from Asahi Kasei Pharma Corporation and Japan Blood Products Organization. J.H.L. serves on the Steering or Advisory Committees for Instrumentation Laboratories, Merck, Octapharma. This work was supported in part by a Grant-in-Aid for Special Research in Subsidies for ordinary expenses of private schools from the Promotion and Mutual Aid Corporation for Private Schools of Japan., (Thieme. All rights reserved.)

In the early stage of coronavirus disease 2019 (COVID-19), most cases are identified as mild or moderate illnesses. Approximately 20% of hospitalised patients become severe or critical at the middle or late stage of the disease. The predictors and risk factors for prognosis in those with mild or moderate disease remain to be determined. Of 694 patients with COVID-19, 231 patients with mild or moderate disease, who were hospitalised at 10 hospitals in Wenzhou and nearby counties in China, were enrolled in this retrospective study from 17 January to 20 March 2020. The outcomes of these patients included progression from mild/moderate illness to severe or critical conditions. Among the 231 patients, 49 (21.2%) had a poor prognosis in the hospital. Multivariate logistic regression analysis showed that higher inflammation/coagulopathy/immunology responsive index (ICIRI=[c-reactive protein × fibrinogen × D-dimer]/CD8 T cell count) on admission (OR=345.151, 95% CI=23.014-5176.318) was associated with increased odds ratios for poor prognosis. The area under the receiver operating characteristic curve for ICIRI predicting severe and critical condition progression was 0.65 (95% CI=0.519-0.782) and 0.80 (95% CI=0.647-0.954), with cut-off values of 870.83 and 535.44, respectively. Conversely, age, sex, comorbidity, neutrophil/lymphocyte ratio, CD8 T cell count, and c-reactive protein, fibrinogen, and D-dimer levels alone at admission were not good predictors of poor prognosis in patients with mild or moderate COVID-19. At admission, a novel index, ICIRI, tends to be the most promising predictor of COVID-19 progression from mild or moderate illness to severe or critical conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 An, Zhang, Li, Hu, Wang, Chen, Ying, Jin and Li.)

Aims: Coagulopathy and venous thromboembolism are common findings in coronavirus disease 2019 (COVID-19) and are associated with poor outcome. Timely initiation of anticoagulation after hospital admission was shown to be beneficial. In this study we aim to examine the association of pre-existing oral anticoagulation (OAC) with outcome among a cohort of SARS-CoV-2 infected patients., Methods and Results: We analysed the data from the large multi-national Lean European Open Survey on SARS-CoV-2 infected patients (LEOSS) from March to August 2020. Patients with SARS-CoV-2 infection were eligible for inclusion. We retrospectively analysed the association of pre-existing OAC with all-cause mortality. Secondary outcome measures included COVID-19-related mortality, recovery and composite endpoints combining death and/or thrombotic event and death and/or bleeding event. We restricted bleeding events to intracerebral bleeding in this analysis to ensure clinical relevance and to limit reporting errors. A total of 1 433 SARS-CoV-2 infected patients were analysed, while 334 patients (23.3%) had an existing premedication with OAC and 1 099 patients (79.7%) had no OAC. After risk adjustment for comorbidities, pre-existing OAC showed a protective influence on the endpoint death (OR 0.62, P = 0.013) as well as the secondary endpoints COVID-19-related death (OR 0.64, P = 0.023) and non-recovery (OR 0.66, P = 0.014). The combined endpoint death or thrombotic event tended to be less frequent in patients on OAC (OR 0.71, P = 0.056)., Conclusions: Pre-existing OAC is protective in COVID-19, irrespective of anticoagulation regime during hospital stay and independent of the stage and course of disease., (© 2021. The Author(s).)

Introduction: Coronavirus 2 (CoV-2) infection or coronavirus disease 2019 (COVID-19) is frequently associated with microvascular thrombosis.The microthrombosis in COVID-19 is the result of the interplay between inflammation and endotheliopathy. Elevated interleukin-6 (IL-6) characterizes COVID-19 inflammation resulting in endotheliopathy and coagulopathy marked by elevated D-dimer (DD). Aim of this study is to identify and to describe the coagulation changes in 100 moderate COVID-19 patients having lung involvement and to determine the association of coagulopathy with the severity and prognosis., Methods: Inflammation, endothelial and coagulation molecules were measured in moderate and mild disease., Results: IL-6 and tumor necrosis factor-α (TNF-α) and tissue factor (TF), von Willebrand factor (VWF), and tissue factor pathway inhibitor (TFPI) significantly increased in moderate disease as well as D-dimer, thrombin antithrombin complex (TAT), Fibrinogen (Fib), platelet factor-4 (PF4), β-thromboglobulin (β-TG), P-selectin, and platelet adhesion. Shortened clotting time (CT) and clot formation time (CFT), high maximum clot firmness (MCF) and low LY at 30 min were present in 100% of moderate COVID-19 patients compared with mild COVID-19 patients., Conclusions: These findings demonstrate that moderate COVID-19 has a profound inflammation associated with severee ndotheliopathy and intense coagulation activation uncontrolled by TFPI. Attention should be paid to coagulopathy in COVID-19. Closely monitoring of coagulation and application of appropriate anticoagulation may improve the prognosis of moderate COVID-19 and to prevent the progression to severe COVID-19 disease., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as COVID-19, is currently developing into a rapidly disseminating and an overwhelming worldwide pandemic. In severe COVID-19 cases, hypercoagulability and inflammation are two crucial complications responsible for poor prognosis and mortality. In addition, coagulation system activation and inflammation overlap and produce life-threatening complications, including coagulopathy and cytokine storm, which are associated with overproduction of cytokines and activation of the immune system; they might be a lead cause of organ damage. However, patients with severe COVID-19 who received anticoagulant therapy had lower mortality, especially with elevated D-dimer or fibrin degradation products (FDP). In this regard, the discovery of natural products with anticoagulant potential may help mitigate the numerous side effects of the available synthetic drugs. This review sheds light on blood coagulation and its impact on the complication associated with COVID-19. Furthermore, the sources of natural anticoagulants, the role of nanoparticle formulation in this outbreak, and the prevalence of thrombosis with thrombocytopenia syndrome (TTS) after COVID-19 vaccines are also reviewed. These combined data provide many research ideas related to the possibility of using these anticoagulant agents as a treatment to relieve acute symptoms of COVID-19 infection.

Coagulation disturbances are common in severe COVID-19 infection. We examined laboratory markers in COVID-19 patients during the first wave of the pandemic in Finland. We analysed a wide panel of coagulation tests (IL ACL TOP 750/500 ® ) from anonymously collected samples of 78 hospitalized COVID-19 patients in intensive care units (ICUs; n  = 34) or medical wards ( n  = 44) at Helsinki University Hospital in April-May 2020. These coagulation data were supplemented with the laboratory information system results, including complete blood count and C reactive protein (CRP). Coagulation and inflammatory markers were elevated in most: FVIII in 52%, fibrinogen 77%, D-dimer 74%, CRP 94%, platelet count 37%. Anaemia was common, especially in men (73% vs. 44% in women), and overall weakly correlated with FVIII (women R 2 = 0.48, men R 2 = 0.24). ICU patients had higher fibrinogen and D-dimer levels ( p  < .01). Men admitted to the ICU also had higher platelet count, leukocytes and FVIII and lower haemoglobin than the non-ICU patients. None of the patients met the disseminated intravascular coagulation (DIC) criteria, but 31% had a D-dimer level of at least 1.5 mg/L. Presence of both anaemia and high D-dimer together with FVIII is independently associated with ICU admission. Antithrombin was reduced in 47% of the patients but did not distinguish severity. Overall, CRP was associated with coagulation activation. Elevated FVIII, fibrinogen and D-dimer reflected a strong inflammatory response and were characteristic of hospitalized COVID-19 patients. The patients were often anaemic, as is typical in severe inflammation, while anaemia was also associated with coagulation activity.

The influenza A virus (IAV) causes a respiratory tract infection with approximately 10% of the population infected by the virus each year. Severe IAV infection is characterized by excessive inflammation and tissue pathology in the lungs. Platelet and neutrophil recruitment to the lung are involved in the pathogenesis of IAV, but the specific mechanisms involved have not been clarified. Using confocal intravital microscopy in a mouse model of IAV infection, we observed profound neutrophil recruitment, platelet aggregation, neutrophil extracellular trap (NET) production and thrombin activation within the lung microvasculature in vivo . Importantly, deficiency or antagonism of the protease-activated receptor 4 (PAR4) reduced platelet aggregation, NET production, and neutrophil recruitment. Critically, inhibition of thrombin or PAR4 protected mice from virus-induced lung tissue damage and edema. Together, these data imply thrombin-stimulated platelets play a critical role in the activation/recruitment of neutrophils, NET release and directly contribute to IAV pathogenesis in the lung., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kim, Carestia, McDonald, Zucoloto, Grosjean, Davis, Turk, Naumenko, Antoniak, Mackman, Abdul-Cader, Abdul-Careem, Hollenberg and Jenne.)

Purpose of Review: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus-2. Over the past year, COVID-19 has posed a significant threat to global health. Although the infection is associated with mild symptoms in many patients, a significant proportion of patients develop a prothrombotic state due to a combination of alterations in coagulation and immune cell function. The purpose of this review is to discuss the pathophysiological characteristics of COVID-19 that contribute to the immunothrombosis., Recent Findings: Endotheliopathy during COVID-19 results in increased multimeric von Willebrand factor release and the potential for increased platelet adhesion to the endothelium. In addition, decreased anticoagulant proteins on the surface of endothelial cells further alters the hemostatic balance. Soluble coagulation markers are also markedly dysregulated, including plasminogen activator inhibitor-1 and tissue factor, leading to COVID-19 induced coagulopathy. Platelet hyperreactivity results in increased platelet-neutrophil and -monocyte aggregates further exacerbating the coagulopathy observed during COVID-19. Finally, the COVID-19-induced cytokine storm primes neutrophils to release neutrophil extracellular traps, which trap platelets and prothrombotic proteins contributing to pulmonary thrombotic complications., Summary: Immunothrombosis significantly contributes to the pathophysiology of COVID-19. Understanding the mechanisms behind COVID-19-induced coagulopathy will lead to future therapies for patients., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: COVID-19-associated coagulopathy (CAC) is a well-recognized hematologic complication among patients with severe COVID-19 disease, where macro- and micro-thrombosis can lead to multiorgan injury and failure. Major societal guidelines that have published on the management of CAC are based on consensus of expert opinion, with the current evidence available. As a result of limited studies, there are many clinical scenarios that are yet to be addressed, with expert opinion varying on a number of important clinical issues regarding CAC management., Methods: In this review, we utilize current societal guidelines to provide a framework for practitioners in managing their patients with CAC. We have also provided three clinical scenarios that implement important principles of anticoagulation in patients with COVID-19., Conclusion: Overall, decisions should be made on acase by cases basis and based on the providers understanding of each patient's medical history, clinical course and perceived risk.

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 ± 2 and 23 ± 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., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: SARS-CoV-2, the causative agent of COVID-19, attacks the immune system causing an exaggerated and uncontrolled release of pro-inflammatory mediators (cytokine storm). Recent studies propose an active role of coagulation disorders in disease progression. This hypercoagulability has been displayed by marked increase in D-dimer in hospitalized patients., Areas Covered: This review summarizes the pathogenesis of SARS-CoV-2 infection, generation of cytokine storm, the interdependence between inflammation and coagulation, its consequences and the possible management options for coagulation complications like venous thromboembolism (VTE), microthrombosis, disseminated intravascular coagulation (DIC), and systemic and local coagulopathy. We searched PubMed, Scopus, and Google Scholar for relevant reports using COVID-19, cytokine storm, and coagulation as keywords., Expert Opinion: A prophylactic dose of 5000-7500 units of low molecular weight heparin (LMWH) has been recommended for hospitalized COVID-19 patients in order to prevent VTE. Treatment dose of LMWH, based on disease severity, is being contemplated for patients showing a marked rise in levels of D-dimer due to possible pulmonary thrombi. Additionally, targeting PAR-1, thrombin, coagulation factor Xa and the complement system may be potentially useful in reducing SARS-CoV-2 infection induced lung injury, microvascular thrombosis, VTE and related outcomes like DIC and multi-organ failure.

Herein, we demonstrated the development and characterization of a dry powder inhaler (DPI) formulation of edoxaban (EDX); and investigated the in-vitro anticoagulation effect for the management of pulmonary or cerebral coagulopathy associated with COVID-19 infection. The formulations were prepared by mixing the inhalable micronized drug with a large carrier lactose and dispersibility enhancers, leucine, and magnesium stearate. The drug-excipient interaction was studied using X-Ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) methods. The drug and excipients showed no physical inter particulate interaction. The in-vitro drug aerosolization from the developed formulation was determined by a Twin Stage Impinger (TSI) at a flow rate of 60 ± 5 L /min. The amount of drug deposition was quantified by an established HPLC-UV method. The fine particle fraction (FPF) of EDX API from drug alone formulation was 7%, whereas the formulations with excipients increased dramatically to almost 7-folds up to 47%. The developed DPI formulation of EDX showed a promising in-vitro anticoagulation effect at a very low concentration. This novel DPI formulation of EDX could be a potential and effective inhalation therapy for managing pulmonary venous thromboembolism (VTE) associated with COVID-19 infection. Further studies are warranted to investigate the toxicity and clinical application of the inhaled EDX DPI formulation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

COVID-19 primarily affects the respiratory system and may lead to severe systemic complications, such as acute respiratory distress syndrome (ARDS), multiple organ failure, cytokine storm, and thromboembolic events. Depending on the immune status of the affected individual early disease control can be reached by a robust type-I-interferon (type-I-IFN) response restricting viral replication. If type-I-IFN upregulation is impaired, patients develop severe COVID-19 that involves profound alveolitis, endothelitis, complement activation, recruitment of immune cells, as well as immunothrombosis. In patients with proper initial disease control there can be a second flare of type-I-IFN release leading to post-COVID manifestation such as chilblain-like lesions that are characterized by thrombosis of small vessels in addition to an inflammatory infiltrate resembling lupus erythematosus (LE). Mechanistically, SARS-CoV-2 invades pneumocytes and endothelial cells by acting on angiotensin-II-converting enzyme 2 (ACE2). It is hypothesized, that viral uptake might downregulate ACE2 bioavailability and enhance angiotensin-II-derived pro-inflammatory and pro-thrombotic state. Since ACE2 is encoded on the X chromosome these conditions might also be influenced by gender-specific regulation. Taken together, SARS-CoV-2 infection affects the vascular compartment leading to variable thrombogenic or inflammatory response depending on the individual immune response status., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome (HFRS), also called nephropathia epidemica (NE), which is mainly endemic in Europe and Russia. The clinical features include a low platelet count, altered coagulation, endothelial activation, and acute kidney injury (AKI). Multiple connections between coagulation pathways and inflammatory mediators, as well as complement and kallikrein-kinin systems, have been reported. The bleeding symptoms are usually mild. PUUV-infected patients also have an increased risk for disseminated intravascular coagulation (DIC) and thrombosis.

The disease caused by the new coronavirus, initially described in China in December 2019, became known as coronavirus disease 2019 and quickly spread to countries on all continents, becoming a pandemic with an important global impact. Despite being a virus that typically affects the respiratory tract, some studies have already described neurological manifestations associated with this infection, including acute ischaemic vascular insult. We report a case series including 30 patients, who presented with neurological symptoms during admission to our service, being diagnosed with ischaemic stroke and, concomitantly, coronavirus disease 2019. In the subgroup of patients analysed, a state of hypercoagulability and pro thrombosis was observed through laboratory tests, probably related to the cytokine storm syndrome associated with infection by this virus. With that, we discussed the possibility of this finding being an aggravating factor in the occurrence of stroke in these patients.

We report the clinical and laboratory coagulation characteristics of 27 pediatric and young adult patients (2 months to 21 years) treated for symptomatic COVID-19 at a children's hospital in the Bronx, New York, between March 1 and May 31, 2020. D-Dimer was > 0.5 μg/mL (upper limit of normal) in 25 (93%) patients at admission; 11 (41%) developed peak D-dimer > 5 μg/mL during admission. Seven (26%) patients developed venous thromboembolism: three with deep vein thrombosis and four with pulmonary embolism. Requirement of increased ventilatory support was a risk factor for thrombosis (P = 0.006). Three of eight (38%) patients on prophylactic anticoagulation developed thrombosis; however, no patients developed VTE on low-molecular-weight heparin prophylaxis titrated to anti-Xa level. Manifestation of COVID-19 disease was severe or critical in 16 (59%) patients. Four (15%) patients died of COVID-19 complications: all had comorbidities. Elevated D-dimer and increased VTE rate were observed in this young cohort, particularly in those with severe respiratory complications, suggesting thrombotic coagulopathy. More data are needed to guide thromboprophylaxis in this age group., (© 2021 Wiley Periodicals LLC.)

The severe forms and worsened outcomes of COVID-19 (coronavirus disease 19) are closely associated with hypertension and cardiovascular disease. Endothelial cells express Angiotensin-Converting Enzyme 2 (ACE2), which is the entrance door for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The hallmarks of severe illness caused by SARS-CoV-2 infection are increased levels of IL-6, C-reactive protein, D-dimer, ferritin, neutrophilia and lymphopenia, pulmonary intravascular coagulopathy and microthrombi of alveolar capillaries. The endothelial glycocalyx, a proteoglycan- and glycoprotein-rich layer covering the luminal side of endothelial cells, contributes to vascular homeostasis. It regulates vascular tonus and permeability, prevents thrombosis, and modulates leukocyte adhesion and inflammatory response. We hypothesized that cytokine production and reactive oxygen species (ROS) generation associated with COVID-19 leads to glycocalyx degradation. A cohort of 20 hospitalized patients with a confirmed COVID-19 diagnosis and healthy subjects were enrolled in this study. Mechanisms associated with glycocalyx degradation in COVID-19 were investigated. Increased plasma concentrations of IL-6 and IL1-β, as well as increased lipid peroxidation and glycocalyx components were detected in plasma from COVID-19 patients compared to plasma from healthy subjects. Plasma from COVID-19 patients induced glycocalyx shedding in cultured human umbilical vein endothelial cells (HUVECs) and disrupted redox balance. Treatment of HUVECs with low molecular weight heparin inhibited the glycocalyx perturbation. In conclusion, plasma from COVID-19 patients promotes glycocalyx shedding and redox imbalance in endothelial cells, and heparin treatment potentially inhibits glycocalyx disruption., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The COVID-19 pandemic has introduced a global public health threat unparalleled in our history. The most severe cases are marked by ARDS attributed to microvascular thrombosis. Hypercoagulability, resulting in a profoundly prothrombotic state, is a distinct feature of COVID-19 and is accentuated by a high incidence of fibrinolysis shutdown. The aims of this review were to describe the manifestations of fibrinolysis shutdown in COVID-19 and its associated outcomes, review the molecular mechanisms of dysregulated fibrinolysis associated with COVID-19, and discuss potential implications and therapeutic targets for patients with severe COVID-19., (Copyright © 2021 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Aggressive inflammatory response leading to hypercoagulability has been found to be associated with disease severity in COVID-19 patients and portends bad treatment outcome. A state of acute disseminated intravascular coagulation (DIC), along with pulmonary embolism and/or deep vein thrombosis, has been observed in critically ill ICU patients. Autopsy reports of COVID-19 patients demonstrated microthrombi in lungs and in other organs, as well as marked inflammatory changes, characteristic clinicopathological features that exacerbate disease severity. Vitamin D supplementation was recommended by many clinicians across the globe to improve clinical symptoms of COVID-19 patients, mainly because of its immunomodulatory roles on immune cells. Furthermore, vitamin D and its associated molecules are also known to directly or indirectly regulate various thrombotic pathways. We propose that vitamin D supplementation not only attenuates the risk of Acute Respiratory Disease Syndrome (ARDS) but it also may have a role in reducing coagulation abnormalities in critically ill COVID-19 patients. The overarching goal of this review is to discuss the effects of vitamin D on coagulation pathways and other intertwined processes leading to thrombosis. Many clinical trials are currently investigating the efficacy of vitamin D supplementation in reducing the risk of COVID-19 infection. However, randomized placebo control clinical trials are also necessary to ascertain the effect of vitamin D supplementation on reducing the risk of coagulopathy in COVID-19 patients.

Background: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19)., Objective: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival., Design: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used., Setting: 67 hospitals in the United States., Participants: Adults with COVID-19 admitted to a participating ICU., Measurements: Time to death, censored at hospital discharge, or date of last follow-up., Results: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35])., Limitation: Observational design., Conclusion: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation., Primary Funding Source: None.

Introduction: Mortality among critically ill COVID-19 patients remains relatively high despite different potential therapeutic modalities being introduced recently. The treatment of critically ill patients is a challenging task, without identified credible predictors of mortality., Methods: We performed an analysis of 160 consecutive patients with confirmed COVID-19 infection admitted to the Respiratory Intensive Care Unit between June 23, 2020, and October 2, 2020, in University Hospital Center Bezanijska kosa, Belgrade, Serbia. Patients on invasive, noninvasive ventilation and high flow oxygen therapy with moderate to severe ARDS, according to the Berlin definition of ARDS, were selected for the study. Demographic data, past medical history, laboratory values, and CT severity score were analyzed to identify predictors of mortality. Univariate and multivariate logistic regression models were used to assess potential predictors of mortality in critically ill COVID-19 patients., Results: The mean patient age was 65.6 years (range, 29-92 years), predominantly men, 68.8%. 107 (66.9%) patients were on invasive mechanical ventilation, 31 (19.3%) on noninvasive, and 22 (13.8%) on high flow oxygen therapy machine. The median total number of ICU days was 10 (25 th to 75 th percentile: 6-18), while the median total number of hospital stay was 18 (25 th to 75 th percentile: 12-28). The mortality rate was 60% (96/160). Univariate logistic regression analysis confirmed the significance of age, CRP, and lymphocytes at admission to hospital, serum albumin, D-dimer, and IL-6 at admission to ICU, and CT score. Serum albumin, D-dimer, and IL-6 at admission to ICU were independently associated with mortality in the final multivariate analysis., Conclusion: In the present study of 160 consecutive critically ill COVID-19 patients with moderate to severe ARDS, IL-6, serum albumin, and D-dimer at admission to ICU, accompanied by chest CT severity score, were marked as independent predictors of mortality., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Viseslav Popadic et al.)

Coronavirus disease 2019 (COVID-19)-associated coagulopathy is unusual, poorly defined and is linked with significant hypercoagulability and microthrombotic and macrothrombotic complications leading to worse outcomes and higher mortality. Conventional coagulation assays do not always actively reflect these derangements and might fail to detect this coagulopathy. Viscoelastic hemostatic assays (VHA) provide a possible tool that adds to conventional coagulation assays in identifying this hypercoagulable state. VHA has been mostly used in surgery and trauma but it's still not well defined in sepsis patients with lack of large randomized trials. Few studies described VHA findings in patients with COVID-19 showing significant hypercoagulability and fibrinolysis shutdown. Clinicians taking care of these patients might have little experience interpreting VHA results. By reviewing the available literature on the use of VHA in sepsis, and the current knowledge on COVID-19-associated coagulopathy we provide clinicians with a practical guide on VHA utilization in patients with COVID-19., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Patients with coronavirus disease 2019 (COVID-19) have thromboembolic complications. Assessment of coagulation and other markers could be useful to understand their coagulopathy., Methods: We performed a retrospective study of inflammatory and coagulation parameters, including prothrombin fragment 1.2 (PF1.2), thrombin-antithrombin complexes (TATs), fibrin monomers, and D-dimer, in hospitalized patients with COVID-19. We compared the markers in patients with thrombosis, admission to the intensive care unit (ICU), and poor outcome., Results: Of the 81 patients, 9 (11%) experienced an acute thrombotic event (4 with pulmonary embolism, 3 with venous thrombosis, and 2 with stroke). PF1.2 was elevated in 32 (39%) patients, TATs in 54 (67%), fibrin monomers in 49 (60%), and D-dimer in 76 (94%). Statistically significant elevation in PF1.2 and TATs was seen in patients admitted to the ICU, while D-dimer and fibrin monomers were significantly elevated in patients with poor outcomes. The presence of multiple abnormal coagulation parameters was associated with ICU admission. Other parameters with statistically significant results included abnormal WBC counts and elevated C-reactive protein, which were associated with ICU admission and poor outcomes., Conclusions: Our data demonstrate that abnormalities of biomarkers of hemostasis activation and inflammatory markers are associated with poor outcomes in patients with COVID-19., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This paper attempts to explain how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes the complications that make coronavirus disease 2019 (COVID-19) a serious disease in specific patient subgroups. It suggests that cortisol-associated activation of the mineralocorticoid receptor (MR) in epithelial and endothelial cells infected with the virus stimulates the release of adenosine 5'-triphosphate (ATP), which then acts back on purinergic receptors. In the lung this could produce the nonproductive cough via purinergic P2X3 receptors on vagal afferent nerves. In endothelial cells it could stimulate exocytosis of Weibel-Palade bodies (WPBs) that contain angiopoietin-2, which is important in the pathogenesis of acute respiratory distress syndrome (ARDS) by increasing capillary permeability and von Willebrand factor (VWF), which mediates platelet adhesion to the endothelium and hence clotting. Angiopoietin-2 and VWF levels both are markedly elevated in COVID-19-associated ARDS. This paper offers an explanation for the sex differences in SARS-CoV-2 complications and also for why these are strongly associated with age, race, diabetes, and body mass index. It also explains why individuals with blood group A have a higher risk of severe infection than those with blood group O. Dexamethasone has been shown to be of benefit in coronavirus ARDS patients and has been thought to act as an anti-inflammatory drug. This paper suggests that a major part of its effect may be due to suppression of cortisol secretion. There is an urgent need to trial the combination of dexamethasone and an MR antagonist such as spironolactone to more effectively block the MR and hence the exocytosis of WPBs., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a global challenge since December 2019. Although most patients with COVID-19 exhibit mild clinical manifestations, in approximately 5% of these patients, the disease eventually progresses to severe lung injury or even multiorgan dysfunction. This situation represents various challenges to hepatology. In the context of liver injury in patients with COVID-19, several key problems need to be solved. For instance, it is important to determine whether SARS-CoV-2 can directly invade liver, especially when ACE2 appears to be negligibly expressed on hepatocytes. In addition, the mechanisms underlying liver dysfunction in COVID-19 patients are not fully understood, which are likely multifactorial and related to hyperinflammation, dysregulated immune responses, abnormal coagulation and drugs. Here, we systematically describe the potential pathogenesis of COVID-19-associated liver injury and propose several hypotheses about its etiopathogenesis.

Background: Coronavirus disease 2019 (COVID-19) is a novel coronavirus that has typically resulted in upper respiratory symptoms. However, we have encountered acute arterial and venous thrombotic events after COVID-19 infection. Managing acute thrombotic events from the novel virus has presented unprecedented challenges during the COVID-19 pandemic. In our study, we have highlighted the unique treatment required for these patients and discussed the role of anticoagulation for patients diagnosed with COVID-19., Methods: The data from 21 patients with laboratory-confirmed COVID-19 disease and acute venous or arterial thrombosis were collected. The demographics, comorbidities, home medications, laboratory markers, and outcomes were analyzed. The primary postoperative outcome of interest was mortality, and the secondary outcomes were primary patency and morbidity. To assess for significance, a univariate analysis was performed using the Pearson χ 2 and Fisher exact tests for categorical variables and the Student t test for continuous variables., Results: A total of 21 patients with acute thrombotic events met our inclusion and exclusion criteria. Most cases were acute arterial events (76.2%), with the remainder venous cases (23.8%). The average age for all patients was 64.6 years, and 52.4% were male. The most prevalent comorbidity in the group was hypertension (81.0%). Several markers were markedly abnormal in both arterial and venous cases, including an elevated neutrophil/lymphocyte ratio (8.8) and D-dimer level (4.9 μg/mL). Operative intervention included percutaneous angiography in 25.00% of patients and open surgical embolectomy in 23.8%. Most of the patients who had undergone arterial intervention had developed a postoperative complication (53.9%) compared with a 0% complication rate after venous interventions. Acute kidney injury on admission was a factor in 75.0% of those who died vs 18.2% in the survivors (P = .04)., Conclusions: We have described our experience in the epicenter of the pandemic of 21 patients who had experienced major thrombotic events from infection with COVID-19. The findings from our cohort have highlighted the need for increased awareness of the vascular manifestations of COVID-19 and the important role of anticoagulation for these patients. More data are urgently needed to optimize treatment and prevent further vascular complications of COVID-19 infections., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

One of the significant complications of severe COVID-19 infections is a coagulopathy that seems to be related to the occurrence of venous and arterial thromboembolic disease. The coagulation changes mimic but are not identical to disseminated intravascular coagulation (DIC). The vast majority of patients with COVID-19 do not meet the criteria for usual forms of DIC. In addition, there seem to be features of a strong local pulmonary thrombotic microangiopathy and direct endothelial cell infection and injury by the virus that affect the coagulopathic response to severe COVID-19. It seems COVID-19 leads to a distinct intravascular coagulation syndrome that may need separate diagnostic criteria.

Background: Coronavirus Disease-19 (COVID-19) is associated with a high rate of thrombosis, the pathophysiology of which is not well defined. Viscoelastic testing may identify and characterise hypercoagulable states which are not apparent using conventional coagulation assays., Objectives: The objective of this study was to undertake viscoelastic evaluation of the coagulation state in critically ill adults with COVID-19-associated respiratory failure METHODS: This was a single-centre observational point prevalence cohort study of adults with COVID-19-associated respiratory failure requiring respiratory support in the intensive care unit. Coagulation status was evaluated using rotational thromboelastometry (ROTEM®) in conjunction with laboratory markers of coagulation., Results: Six patients fulfilled inclusion criteria. Each patient had one ROTEM® performed. All patients had supranormal clot amplitude at 10 min (A10) and supranormal clot firmness (maximal clot firmness) measured in at least one ROTEM® pathway, and five were supranormal on all pathways. Minimal clot lysis was present on all analyses. Fibrinogen and D-dimer were elevated and routine markers of coagulation within normal ranges in all patients., Conclusion: Patients with COVID-19-associated respiratory failure admitted to the intensive care unit exhibit a hypercoagulable state which is not appreciable on conventional tests of coagulation. Supranormal clot firmness, minimal fibrinolysis, and hyperfibrinogenaemia are key findings. Further research is required into the pathophysiology of this hypercoagulable state, as well as the harms and benefits of different anticoagulation strategies., Competing Interests: Conflict of Interest None of the authors have any interests to declare., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Background: Hypercoagulability and thromboembolism are prominent features of severe COVID-19, and ongoing anticoagulant use might be protective., Methods: We conducted a nationwide register-based cohort study in Sweden, February through May, 2020, to assess whether ongoing direct oral anticoagulant (DOAC) use was associated with reduced risk of hospital admission for laboratory-confirmed COVID-19, or a composite of intensive care unit (ICU) admission or death due to laboratory-confirmed COVID-19., Results: DOAC use (n = 103 703) was not associated with reduced risk of hospital admission for COVID-19 (adjusted hazard ratio [aHR] [95% confidence interval] 1.00 [0.75-1.33] vs. nonuse atrial fibrillation comparator [n = 36 875]; and aHR 0.94 [0.80-1.10] vs. nonuse cardiovascular disease comparator [n = 355 699]), or ICU admission or death due to COVID-19 (aHRs 0.76 [0.51-1.12], and 0.90 [0.71-1.15], respectively)., Conclusion: Ongoing DOAC use was not associated with reduced risk of severe COVID-19, indicating that prognosis would not be modified by early outpatient DOAC initiation., (© 2020 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

A novel coronavirus termed as COVID-19 by WHO has been the causative agent of an unprecedented pandemic in the history of humanity. The global burden of mortality and morbidity associated with this pandemic continues to increase with each passing day as it is progressively leading to multiorgan dysfunction. In most cases, the cause of death has been attributed to respiratory failure, sepsis, cardiac failure, kidney injury, or coagulopathy. As more knowledge is being unfolded, an in-depth understanding of various systemic manifestations and complications of SARS-CoV2 is vital for optimum management of these patients. This novel virus is known to spread faster than its two ancestors, the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), demonstrating a case fatality ranging from 5 to 8% [1]. Hematological abnormalities such as lymphopenia, thrombocytopenia, elevated D-Dimer, elevated fibrinogen, elevated fibrinogen degradation products as well as cytokines such as IL-6 are emerging as important prognostic marker for worse outcome of COVID-19. Among various systemic manifestations, hematological complications such as venous thrombosis causing pulmonary embolism or deep vein thrombosis, and arterial thrombosis causing myocardial infarction, strokes or limb ischemia are being noted to be directly linked to high mortality from COVID-19. An attempt to understand the pathophysiology of various hematological abnormalities including cytokine storm, hypercoagulable state and some rare presentations of this disease hence becomes imperative. Through this review, we aim to provide an up-to-date summary of current evidence-based literature of hematological manifestations, their consequences and management including role of anticoagulation and drugs targeting cytokine storm in patients with SARS-CoV-2., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

COVID-19 is a new pandemic, caused by Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-Cov2) infection and characterized by a broad spectrum of clinical manifestations. Inflammation and the innate immune system have been recently recognized as pivotal players in the most severe forms, characterized by significantly elevated levels of pro-inflammatory cytokines. In this setting, several studies have also reported the presence of abnormalities in coagulation parameters and platelets count, possibly identifying a subgroup of patients with poor prognosis. Some reports of full-blown thromboembolic events are emerging. Among the possible mechanisms underlying coagulation dysfunction, the so-called "cytokine storm" seems to play a pivotal role. Other candidate factors include virus-specific mechanisms, related to the virus interaction with renin angiotensin system (RAS) and the fibrinolytic pathway, but also comorbidities affecting these patients. Coagulation dysfunction is therefore a candidate risk factor for adverse outcomes in COVID-19 and should be carefully addressed in clinical practice., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cardiac injury is a common complication of the coronavirus disease 2019 (COVID-19), and is associated with adverse clinical outcomes. In this study, we aimed to reveal the association of cardiac injury with coagulation dysfunction. We enrolled 181 consecutive patients who were hospitalized with COVID-19, and studied the clinical characteristics and outcome of these patients. Cardiac biomarkers high-sensitivity troponin I (hs-cTnI), myohemoglobin and creatine kinase-myocardial band (CK-MB) were assessed in all patients. The clinical outcomes were defined as hospital discharge or death. The median age of the study cohort was 55 (IQR, 46-65) years, and 102 (56.4%) were males. Forty-two of the 181 patients (23.2%) had cardiac injury. Old age, high leukocyte count, and high levels of aspartate transaminase (AST), D-dimer and serum ferritin were significantly associated with cardiac injury. Multivariate regression analysis revealed old age and elevated D-dimer levels as being strong risk predictors of in-hospital mortality. Interleukin 6 (IL6) levels were comparable in patients with or without cardiac injury. Serial observations of coagulation parameters demonstrated highly synchronous alterations of D-dimer along with progression to cardiac injury. Cardiac injury is a common complication of COVID-19 and is an independent risk factor for in-hospital mortality. Old age, high leukocyte count, and high levels of AST, D-dimer and serum ferritin are significantly associated with cardiac injury, whereas IL6 are not. Therefore, the pathogenesis of cardiac injury in COVID-19 may be primarily due to coagulation dysfunction along with microvascular injury.

Background: The role of coagulation dysfunction in Severe Coronavirus Disease 2019 (COVID-19) is inconsistent. We aimed to explore the impact of coagulation dysfunction amongst patients with COVID-19., Methods: We searched PubMed, Cochrane and Embase databases from December 1, 2019 to April 27, 2020 following Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Data about coagulation (Platelets, PT, APTT, fibrin, fibrinogen degradation products, D-dimer), prevalence of coagulation dysfunction and mortality were extracted. Meta regression was used to explore the heterogeneity., Results: Sixteen observational studies were included, comprising 2, 139 patients with confirmed COVID-19. More severe COVID-19 cases tended to have higher mean D-dimer (SMD 0.78, 95% CI 0.53 to 1.03, P < .001). The similar pattern occurred with PT and fibrin, with a contrary trend for PLTs. Coagulation dysfunction was more frequent in severe cases compared to less severe (SMD 0.46, 95% CI 0.25 to 0.67, P < .001). Higher mortality was associated with COVID-19-related coagulopathy (RR 10.86, 2.86 to 41.24, P < .001). Prevalence of ARDS was increased in more severe patients than less severe cases (RR 16.52, 11.27 to 24.22, P < .001). PT, fibrin and D-dimer levels elevated significantly in non-survivors during hospitalization., Conclusion: Presence of coagulation dysfunction might be associated with COVID-19 severity, and coagulopathy might be associated with mortality. Coagulation markers including PT, fibrin and D-dimer may imply the progression of COVID-19. This illuminates the necessity of effectively monitoring coagulation function for preventing COVID-19-related coagulopathy, especially in severe patients. For the obvious heterogeneity, the quality of the evidence is compromised. Future rigorous randomized controlled trials that assess the correlation between coagulation and COVID-19 are needed., Trial Registration: PROSPERO (CRD42020183514)., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Laboratory testing and the measurement of appropriate biomarkers play a critical role in managing patients with coronavirus disease 2019 (COVID-19), allowing for disease diagnosis, monitoring progression, prognostication, prediction of treatment response, and risk stratification. We sought to characterize these effects on a more detailed, mechanistic level., Methods: We reviewed the literature and identified a multitude of reports that describe the unique effects of this virus and its devastating consequences to multiple organ systems in COVID-19 patients., Results: There are specific alterations in biomarkers related to coagulation, depopulation of T-cell subtypes, the cytokine storm and inflammation, and kidney and cardiac dysfunction., Conclusions: Laboratory measurement of specific parameters and the use of appropriate prognostic, predictive, and monitoring biomarkers afford clinicians the ability to make informed medical decisions and guide therapy for patients afflicted with this dreaded disease., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Coagulopathy has recently been recognized as a recurring complication of COVID-19, most typically associated with critical illness. There are epidemiological, mechanistic and transcriptomic evidence that link Selenium with SARS-CoV-2's intracellular latency. Taking into consideration the vital role of selenoproteins in maintaining an adequate immune response, endothelial homeostasis and a non-prothrombotic platelet activation status, we propose that impairment in selenocysteine synthesis, via perturbations in the aforementioned physiological functions, potentially constitutes a mechanism of coagulopathy in COVID 19 patients other than those developed in critical illness., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

To systematically analyze the blood coagulation features of coronavirus disease 2019 (COVID-19) patients to provide a reference for clinical practice. An electronic search in PubMed, EMbase, Web of Science, Scopus, CNKI, WanFang Data, and VIP databases to identify studies describing the blood coagulation features of COVID-19 patients from 1 January 2020 to 21 April 2020. Three reviewers independently screened literature, extracted data, and assessed the risk of bias of included studies, then, the meta-analysis was performed by using Stata 12.0 software. Thirty-four studies involving 6492 COVID-19 patients were included. Meta-analysis showed that patients with severe disease showed significantly lower platelet count (weighted mean differences [WMD]: -16.29 × 10 9 /L; 95% confidence interval [CI]: -25.34 to -7.23) and shorter activated partial thromboplastin time (WMD: -0.81 seconds; 95% CI: -1.94 to 0.33) but higher D-dimer levels (WMD: 0.44 μg/mL; 95% CI: 0.29-0.58), higher fibrinogen levels (WMD: 0.51 g/L; 95% CI: 0.33-0.69) and longer prothrombin time (PT; WMD: 0.65 seconds; 95% CI: 0.44-0.86). Patients who died showed significantly higher D-dimer levels (WMD: 6.58 μg/mL; 95% CI: 3.59-9.57), longer PT (WMD: 1.27 seconds; 95% CI: 0.49-2.06) and lower platelet count (WMD: -39.73 × 10 9 /L; 95% CI: -61.99 to -17.45) than patients who survived. Coagulation dysfunction is common in severe COVID-19 patients and it is associated with severity of COVID-19., (© 2020 Wiley Periodicals LLC.)

The outbreak of 2019 novel coronavirus disease (COVID-19) has posed a grave threat to the global public health. The COVID-19-induced infection is closely related to coagulation dysfunction in the affected patients. This paper attempts to conduct a meta-analysis and systematically review the blood coagulation indicators in patients with severe COVID-19. A meta-analysis of eligible studies was performed to compare the blood coagulation indicators in patients with severe and nonsevere COVID-19. PubMed, Embase, Web of Science, and the Cochrane Library were searched for studies published between 1 December 2019 and 7 May 2020. A total of 13 studies with 1341 adult patients were enrolled in this analysis. Platelet (weighted mean difference [WMD] = -24.83, 95% confidence interval [CI]: -34.12 to -15.54; P < .001), d-dimer (WMD = 0.19, 95% CI: 0.09-0.29; P < .001), and fibrinogen (WMD = 1.02, 95% CI: 0.50-1.54; P < .001) were significantly associated with the severity in patients with COVID-19. The meta-analysis revealed that no correlation was evident between an increased severity risk of COVID-19 and activated partial thromboplastin time (WMD = -1.56, 95% CI: -5.77 to 2.64; P = .468) or prothrombin time (WMD = 0.19, 95% CI: -0.13 to 0.51; P = .243). The single arm meta-analysis showed that compared with the nonsevere group, the severe group had a lower pooled platelet (165.12 [95% CI: 157.38-172.85] vs 190.09 [95% CI: 179.45-200.74]), higher d-dimer (0.49 [95% CI: 0.33-0.64] vs 0.27 [95% CI: 0.20-0.34]), and higher fibrinogen (4.34 [95% CI: 1.98-6.70] vs 3.19 [95% CI: 1.13-5.24]). Coagulation dysfunction is closely related to the severity of patients with COVID-19, in which low platelet, high d-dimer, and fibrinogen upon admission may serve as risk indicators for increased aggression of the disease. These findings are of great clinical value for timely and effective treatment of the COVID-19 cases., (© 2020 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Although ACE2 (angiotensin converting enzyme 2) is considered the primary receptor for CoV-2 cell entry, recent reports suggest that alternative pathways may contribute. This paper considers the hypothesis that viral binding to cell-surface integrins may contribute to the high infectivity and widespread extra-pulmonary impacts of the SARS-CoV-2 virus. This potential is suggested on the basis of the emergence of an RGD (arginine-glycine-aspartate) sequence in the receptor-binding domain of the spike protein. RGD is a motif commonly used by viruses to bind cell-surface integrins. Numerous signaling pathways are mediated by integrins and virion binding could lead to dysregulation of these pathways, with consequent tissue damage. Integrins on the surfaces of pneumocytes, endothelial cells and platelets may be vulnerable to CoV-2 virion binding. For instance, binding of intact virions to integrins on alveolar cells could enhance viral entry. Binding of virions to integrins on endothelial cells could activate angiogenic cell signaling pathways; dysregulate integrin-mediated signaling pathways controlling developmental processes; and precipitate endothelial activation to initiate blood clotting. Such a procoagulant state, perhaps together with enhancement of platelet aggregation through virions binding to integrins on platelets, could amplify the production of microthrombi that pose the threat of pulmonary thrombosis and embolism, strokes and other thrombotic consequences. The susceptibility of different tissues to virion-integrin interactions may be modulated by a host of factors, including the conformation of relevant integrins and the impact of the tissue microenvironment on spike protein conformation. Patient-specific differences in these factors may contribute to the high variability of clinical presentation. There is danger that the emergence of receptor-binding domain mutations that increase infectivity may also enhance access of the RGD motif for integrin binding, resulting in viral strains with ACE2 independent routes of cell entry and novel integrin-mediated biological and clinical impacts. The highly infectious variant, B.1.1.7 (or VUI 202012/01), includes a receptor-binding domain amino acid replacement, N501Y, that could potentially provide the RGD motif with enhanced access to cell-surface integrins, with consequent clinical impacts.

Coronavirus disease 2019 (COVID-19) causes a spectrum of disease; some patients develop a severe proinflammatory state which can be associated with a unique coagulopathy and procoagulant endothelial phenotype. Initially, COVID-19 infection produces a prominent elevation of fibrinogen and D-dimer/fibrin(ogen) degradation products. This is associated with systemic hypercoagulability and frequent venous thromboembolic events. The degree of D-dimer elevation positively correlates with mortality in COVID-19 patients. COVID-19 also leads to arterial thrombotic events (including strokes and ischemic limbs) as well as microvascular thrombotic disorders (as frequently documented at autopsy in the pulmonary vascular beds). COVID-19 patients often have mild thrombocytopenia and appear to have increased platelet consumption, together with a corresponding increase in platelet production. Disseminated intravascular coagulopathy (DIC) and severe bleeding events are uncommon in COVID-19 patients. Here, we review the current state of knowledge of COVID-19 and hemostasis., (© 2020 S. Karger AG, Basel.)

We present a previously healthy man in his 30s who presented with typical viral prodrome symptoms and worsening abdominal pain. He was found to have portal vein thrombosis, with extensive hypercoagulability workup performed. It was determined that the aetiology of thrombus was secondary to acute cytomegalovirus infection. The patient was started on anticoagulation therapy, with later clot resolution demonstrated on abdominal Doppler ultrasound and abdominal CT scan. Given the atypical presentation of this common virus, we performed a literature review of cytomegalovirus-associated portal vein thrombosis in healthy individuals; we found that most patients present with non-specific symptoms of fever and abdominal pain in the setting of a viral prodrome. This case and literature review suggest physicians must consider cytomegalovirus-associated portal vein thrombosis as a potential diagnosis when patients present with abdominal pain and viral symptoms. The literature highlights the need for a consensus on anticoagulation and antiviral therapy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Coagulation dysfunction in critically ill patients with coronavirus disease 2019 (COVID-19) has not been well described, and the efficacy of anticoagulant therapy is unclear. In this study, we retrospectively reviewed 75 fatal COVID-19 cases who were admitted to the intensive care unit at Jinyintan Hospital (Wuhan, China). The median age of the cases was 67 (62-74) years, and 47 (62.7%) were male. Fifty patients (66.7%) were diagnosed with disseminated intra-vascular coagulation. Approximately 90% of patients had elevated D-dimer and fibrinogen degradation products, which decreased continuously after anticoagulant treatment and was accompanied by elevated albumin (all P <0.05). The median survival time of patients treated with anticoagulant was 9.0 (6.0-14.0) days compared with 7.0 (3.0-10.0) days in patients without anticoagulant therapy ( P =0.008). After anticoagulation treatment, C-reactive protein levels decreased ( P =0.004), as did high-sensitivity troponin ( P =0.018), lactate dehydrogenase ( P <0.001), and hydroxybutyrate dehydrogenase ( P <0.001). In conclusion, coagulation disorders were widespread among fatal COVID-19 cases. Anticoagulant treatment partially improved hypercoagulability, prolonged median survival time, and may have postponed inflammatory processes and cardiac injury.

Physical therapists have a unique role in both prevention of venous thromboembolism (VTE) through the promotion of early mobility and physical activity and diagnosis through discovery of signs and symptoms of VTE. This Perspective updates clinicians on the latest information regarding pathophysiology of coagulopathy associated with COVID-19 and applies VTE clinical practice guidelines to COVID-19 in order to provide guidance on physical therapist management., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)