COVID-19-associated coagulopathy and antithrombotic agents-lessons after 1 year.

COVID-19 is associated with a high incidence of thrombotic complications, which can be explained by the complex and unique interplay between coronaviruses and endothelial cells, the local and systemic inflammatory response, and the coagulation system. Empirically, an intensified dose of thrombosis prophylaxis is being used in patients admitted to hospital with COVID-19 and several guidelines on this topic have been published, although the insufficiency of high quality and direct evidence has led to weak recommendations. In this Viewpoint we summarise the pathophysiology of COVID-19 coagulopathy in the context of patients who are ambulant, admitted to hospital, and critically ill or non-critically ill, and those post-discharge from hospital. We also review data from randomised controlled trials in the past year of antithrombotic therapy in patients who are critically ill. These data provide the first high-quality evidence on optimal use of antithrombotic therapy in patients with COVID-19. Pharmacological thromboprophylaxis is not routinely recommended for patients who are ambulant and post-discharge. A first ever trial in non-critically ill patients who were admitted to hospital has shown that a therapeutic dose of low-molecular-weight heparin might improve clinical outcomes in this population. In critically ill patients, this same treatment does not improve outcomes and prophylactic dose anticoagulant thromboprophylaxis is recommended. In the upcoming months we expect numerous data from the ongoing antithrombotic COVID-19 studies to guide clinicians at different stages of the disease.

Therapeutic strategies in patients with coagulopathy and disseminated intravascular coagulation: awareness of the phase-dependent characteristics.

INTRODUCTION: Disseminated intravascular coagulation (DIC) has long been understood as a condition where both thrombotic and hemostatic abnormalities coexist. DIC is a difficult complication for clinicians to manage as it is due to multiple underlying complications of pathophysiologic abnormalities in diverse disease states. Ongoing research continues to define the meaning of DIC, evaluate therapeutic options, and how it presents with the complex paradigm of systemic activation of coagulation. In this review we introduce the current topics regarding this difficult situation. EVIDENCE ACQUISITION: Online search of published medical literature through MEDLINE and Web of Science using the term "disseminated intravascular coagulation," "coagulopathy," "coagulation disorder," "hemostasis," "fibrinolysis," "thrombus" and "anticoagulants." EVIDENCE SYNTHESIS: Articles were chosen for inclusion based on their relevance to disseminated intravascular coagulation, coagulopathy, hemostasis and thrombosis in sepsis, COVID-19, trauma, and obstetrics. Reference lists were reviewed to identify additional relevant articles. CONCLUSIONS: DIC is recognized as a pathologically triggered and dysregulated systemic activation of coagulation in response to various noxious stimuli. DIC's phenotype and clinical manifestations can vary from prothrombotic to hemorrhagic, depending on the underlying diseases. However, the fundamental mechanisms of systemic and vascular endothelial dysfunction can be explained as different phases of the acute response, with an initial prothrombotic phase that can commonly change to hemostatic insufficiency. Thrombin is the key initiator of the pathophysiologic process along with endothelial injury and initially fibrinolysis activation followed by fibrinolysis suppression. There is no established approach for managing DIC beyond initially treating the underlying disease and replacement therapy for the management of coagulopathy. Targeting anticoagulation therapy with antithrombin concentrates and recombinant thrombomodulin for the prevention of microthrombus formation, and antifibrinolytic therapy using tranexamic acid for the coagulopathy after massive bleeding, continue to be studied as therapeutic options.

Clinical Update for Physical Therapists: Coagulopathy and COVID-19.

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.

COVID-19-associated coagulopathy and disseminated intravascular coagulation.

The pathology of coronavirus disease 2019 (COVID-19) is exacerbated by the progression of thrombosis, and disseminated intravascular coagulation (DIC), and cytokine storms. The most frequently reported coagulation/fibrinolytic abnormality in COVID-19 is the increase in D-dimer, and its relationship with prognosis has been discussed. However, limits exist to the utility of evaluation by D-dimer alone. In addition, since the coagulation/fibrinolytic condition sometimes fluctuates within a short period of time, regular examinations in recognition of the significance of the examination are desirable. The pathophysiology of disseminated intravascular coagulation (DIC) associated with COVID-19 is very different from that of septic DIC, and both thrombotic and hemorrhagic pathologies should be noted. COVID-19 thrombosis includes macro- and microthrombosis, with diagnosis of the latter depending on markers of coagulation and fibrinolysis. Treatment of COVID-19 is classified into antiviral treatment, cytokine storm treatment, and thrombosis treatment. Rather than providing uniform treatment, the treatment method most suitable for the severity and stage should be selected. Combination therapy with heparin and nafamostat is expected to develop in the future. Fibrinolytic therapy and adsorption therapy require further study.

Fulminant Bacillus cereus food poisoning with fatal multi-organ failure.

This case represents a rare fulminant course of fried-rice associated food poisoning in an immunocompetent person due to pre-formed exotoxin produced by Bacillus cereus, with severe manifestations of sepsis, including multi-organ (hepatic, renal, cardiac, respiratory and neurological) failure, shock, metabolic acidosis, rhabdomyolysis and coagulopathy. Despite maximal supportive measures (continuous renal replacement therapy, plasmapheresis, N-acetylcysteine infusion and blood products, and broad-spectrum antimicrobials) and input from a multidisciplinary team (consisting of infectious diseases, intensive care, gastroenterology, surgery, toxicology, immunology and haematology), mortality resulted. This case is the first to use whole genome sequencing techniques to confirm the toxigenic potential of B. cereus It has important implications for food preparation and storage, particularly given its occurrence in home isolation during the COVID-19 pandemic.

Coronavirus Disease 2019-Associated Coagulopathy.

Patients with the severe form of coronavirus disease 2019 (COVID-19) have been frequently found to suffer from both arterial and venous thrombotic events due to the perpetuation of a hypercoagulable state. This phenomenon, termed COVID-19-associated coagulopathy, is now considered a major component of the pathophysiology of this novel infectious disease, leading to widespread thrombosis. While at first, the vascular insults may be limited to the pulmonary microvasculature, as the disease progresses, systemic involvement occurs, culminating in distant organ thrombosis and multiorgan dysfunction syndrome. In this review article, we discuss recent insights into the pathophysiologic mechanisms of COVID-19-associated coagulopathy and review the clinical, histopathologic, and laboratory evidence, which leads us to conclude that COVID-19 is both a pulmonary and vascular disorder.

Viscoelastic Tests in the Evaluation of Haemostasis Disturbances in SARS-CoV2 Infection.

COVID-19 associated coagulopathy is a dysfunction of severe SARS-CoV-2 infection, characterized by significantly increased fibrinogen, D-dimer and C reactive protein and normal to near-normal prothrombin time, activated partial thromboplastin time and platelet count. Hypercoagulopathy and hypofibrinolysis coexist and are detected by viscoelastic tests. These features, when associated with immobilization and intrinsic risk factors (age, obesity, comorbidities, drugs) of the patient, can trigger thromboembolic events, despite thromboprophylaxis. The lungs are the first and most severely damaged organ. To date, most patients have exhibited hypercoagulability on viscoelastic tests not detected by standard coagulation tests. A high rate of thrombotic events was reported, suggesting that it should be considered as a cause of clinical deterioration in intensive care and potentially other clinical settings. In advanced stage, COVID-19 associated coagulopathy, fibrinogen and platelet count can decrease significantly, depending on the severity of clinical status resembling consumptive coagulopathy. In this stage, bleeding events can occur, especially if the patient is under extracorporeal membrane oxygenation (ECMO). Viscoelastic tests are very useful tools to assess hypercoagulability and hypofibrinolysis (not detectable by standard coagulation tests) in critically ill SARS-CoV-2 patients with COVID-19 associated coagulopathy and look like very promising tools for anticoagulation management. However, further research needs to be carried out to determine whether abnormal viscoelastic tests alone or in combination with other clinical or laboratory findings can identify patients at increased thrombotic risk. Clinical trials to evaluate hypercoagulability using viscoelastic tests and the need for personalized dosage of anticoagulation in SARS-CoV-2 patientsare quickly emerging.

A coagulopatia associada à COVID-19 é uma disfunção associada à infeção SARS-CoV-2 grave, caraterizada por aumento significativo do fibrinogénio, D-dímeros e Proteína C reativa, e por valores normais/muito pouco alterados do tempo de protrombina, tempo de tromboplastina parcial ativado, e número de plaquetas. A hipercoagulabilidade e a hipofibrinólise coexistem e são detetadas por testes viscoelásticos. Quando associadas à imobilização e aos fatores de risco intrínsecos do doente (idade, obesidade, comorbilidades, drogas) potenciam eventos tromboembólicos, apesar da tromboprofilaxia. Os pulmões são o órgão inicialmente e mais gravemente afetado. Até à data, a maioria dos doentes apresentou hipercoagulabilidade nos testes viscoelásticos, não detetada pelos testes de coagulação de rotina, e foi reportada uma elevada taxa de eventos trombóticos, sugerindo que esta deveria ser considerada uma das causas de deterioração clínica, não só em cuidados intensivos. Na coagulopatia associada à COVID-19 avançada, o número de plaquetas e o fibrinogénio podem diminuir significativamente, dependendo da gravidade clínica da infeção, assemelhando-se o quadro a uma coagulopatia de consumo. Nesta fase pode haver hemorragia, especialmente se o doente estiver sob extracorporeal membrane oxygenation. Os testes viscoelásticos afiguram-se muito úteis para avaliar a hipercoagulabilidade e a hipofibrinólise em doentes críticos SARS-CoV-2 com coagulopatia associada à COVID-19, parecendo também promissores para a gestão da anticoagulação. No entanto, é necessária mais investigação para determinar se testes viscoelásticos alterados, individualmente ou quando combinadoscom outros resultados clínicos/laboratoriais, podem identificar os doentes com risco trombótico acrescido. Estão a emergir rapidamente ensaios clínicos para avaliação da hipercoagulabilidade por testes viscoelásticos e da necessidade de personalização da anticoagulação em doentes SARS-CoV-2.

Complement activation and coagulopathy - an ominous duo in COVID19.

INTRODUCTION: COVID-19 has similarities to the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks, as severe patients and non-survivors have frequently shown abnormal coagulation profiles. Immune-mediated pathology is a key player in this disease; hence, the role of the complement system needs assessment. The complement system and the coagulation cascade share an intricate network, where multiple mediators maintain a balance between both pathways. Coagulopathy in COVID-19, showing mixed features of complement-mediated and consumption coagulopathy, creates a dilemma in diagnosis and management. AREAS COVERED: Pathophysiology of coagulopathy in COVID-19 patients, with a particular focus on D-dimer and its role in predicting the severity of COVID-19 has been discussed. A comprehensive search of the medical literature on PubMed was done till May 30th, 2020 with the keywords 'COVID-19', 'SARS-CoV-2', 'Coronavirus', 'Coagulopathy', and 'D-dimer'. Twenty-two studies were taken for weighted pooled analysis of D-dimer. EXPERT OPINION: A tailored anticoagulant regimen, including intensification of standard prophylactic regimens with low-molecular-weight heparin is advisable for COVID-19 patients. Atypical manifestations and varying D-dimer levels seen in different populations bring forth the futility of uniform recommendations for anticoagulant therapy. Further, direct thrombin inhibitors and platelet inhibitors in a patient-specific manner should also be considered.

The clinical course of COVID in pregnancy.

The 2019 novel coronavirus disease (COVID-19) pandemic poses unique challenges to the medical community as the optimal treatment has not been determined and is often at the discretion of institutional guidelines. Pregnancy has previously been described as a high-risk state in the context of infectious diseases, given a particular susceptibility to pathogens and adverse outcomes. Although ongoing studies have provided insight on the course of this disease in the adult population, the implications of COVID-19 on pregnancy remains an understudied area. The objective of this study is to review the literature and describe clinical presentations among pregnant women afflicted with COVID-19.

Commonalities Between COVID-19 and Radiation Injury.

As the multi-systemic components of COVID-19 emerge, parallel etiologies can be drawn between SARS-CoV-2 infection and radiation injuries. While some SARS-CoV-2-infected individuals present as asymptomatic, others exhibit mild symptoms that may include fever, cough, chills, and unusual symptoms like loss of taste and smell and reddening in the extremities (e.g., "COVID toes," suggestive of microvessel damage). Still others alarm healthcare providers with extreme and rapid onset of high-risk indicators of mortality that include acute respiratory distress syndrome (ARDS), multi-organ hypercoagulation, hypoxia and cardiovascular damage. Researchers are quickly refocusing their science to address this enigmatic virus that seems to unveil itself in new ways without discrimination. As investigators begin to identify early markers of disease, identification of common threads with other pathologies may provide some clues. Interestingly, years of research in the field of radiation biology documents the complex multiorgan nature of another disease state that occurs after exposure to high doses of radiation: the acute radiation syndrome (ARS). Inflammation is a key common player in COVID-19 and ARS, and drives the multi-system damage that dramatically alters biological homeostasis. Both conditions initiate a cytokine storm, with similar pro-inflammatory molecules increased and other anti-inflammatory molecules decreased. These changes manifest in a variety of ways, with a demonstrably higher health impact in patients having underlying medical conditions. The potentially dramatic human impact of ARS has guided the science that has identified many biomarkers of radiation exposure, established medical management strategies for ARS, and led to the development of medical countermeasures for use in the event of a radiation public health emergency. These efforts can now be leveraged to help elucidate mechanisms of action of COVID-19 injuries. Furthermore, this intersection between COVID-19 and ARS may point to approaches that could accelerate the discovery of treatments for both.

Nervous system complications of COVID-19 with a focus on stroke.

As a severe and highly contagious infection, coronavirus disease (COVID-19) affects all aspects of society and has become a global public health problem. Because of the complexity of the pathology of COVID-19, it is difficult to treat. An increasing number of reports have indicated that COVID-19 may have neurological complications, including stroke. The nervous system complications of COVID-19 have gradually attracted research attention. In this review, we summarize the latest findings related to COVID 19, elaborate on the possible mechanism of COVID 19 related onset of stroke, and summarize current treatment options because an improved understanding and appropriate treatments may improve the prognosis of patients with COVID-19-related stroke.

Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation.

The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.

Analysis of dynamic disturbance in blood coagulation function of patients with Coronavirus Disease 2019: A retrospective observational study.

Coronavirus Disease 2019 (COVID-19) has became a major problem affecting global health security.To assess the differences and dynamic changes of blood coagulation function in COVID-19 patients with different severity.A total of 261 COVID-19 patients from January 24 to March 25, 2020 in Huangshi, Hubei Province were enrolled.We designed a retrospective observational study. Clinical information, including age, blood routine and blood coagulation function, were collected. According to the Diagnosis and Treatment Guidelines for COVID-19 (seventh version) that issued by the National Health Committee of the People's Republic of China, patients were divided into 3 subgroups: 186 ordinary, 45 severe and 30 critical ones. We compared the differences in blood coagulation factors among groups.Average age in critical group (71.47 ±â€Š11.48 years) was the oldest of 3 subgroups. At admission, statistically differences could be observed among ordinary, severe and critical patients in D-dimer (0.18 ±â€Š0.33, 0.63 ±â€Š1.13 and 1.16 ±â€Š1.58 mg/L), fibrinogen/fibrin degradation products (FDP) (3.11 ±â€Š5.30, 9.82 ±â€Š23.91 and 21.94 ±â€Š40.98 µg/ml), platelet [(169 ±â€Š62.85), (188 ±â€Š71.56) and (117 ±â€Š38.31) × 10/L)] and lymphocyte count [(1.18 ±â€Š0.46), (0.82 ±â€Š0.35) and (0.75 ±â€Š0.39) × 10/L)], respectively (P < .05). During hospitalization, the peak values of coagulation and valley values of blood routine were monitored. There were significant differences among ordinary, severe and critical patients in D-dimer (0.26 ±â€Š0.46, 1.39 ±â€Š1.51 and 2.89 ±â€Š1.68 mg/L), FDP (3.29 ±â€Š5.52, 23.68 ±â€Š39.07 and 56.11 ±â€Š49.94 µg/ml), platelet [(164 ±â€Š55.53), (171 ±â€Š69.96) and (84 ±â€Š57.80) × 10/L)] and lymphocyte count [(1.10 ±â€Š0.46), (0.65 ±â€Š0.35) and (0.55 ±â€Š0.31) × 10/L)], respectively (P < .001). D-dimer and FDP in the course of disease in severe/critical groups showed a first upward and then downward trend.We concluded that coagulation function indexes such as D-dimer and FDP could be served as markers to estimate COVID-19 patients condition. Close monitoring of coagulation function may be helpful for early diagnosis of severe patients and guidance of treatments.

Endothelial dysfunction contributes to COVID-19-associated vascular inflammation and coagulopathy.

Great attention has been paid to endothelial dysfunction (ED) in coronavirus disease 2019 (COVID-19). There is growing evidence to suggest that the angiotensin converting enzyme 2 receptor (ACE2 receptor) is expressed on endothelial cells (ECs) in the lung, heart, kidney, and intestine, particularly in systemic vessels (small and large arteries, veins, venules, and capillaries). Upon viral infection of ECs by severe acute respiratory syndrome coronarvirus 2 (SARS-CoV-2), ECs become activated and dysfunctional. As a result of endothelial activation and ED, the levels of pro-inflammatory cytokines (interleukin -1, interleukin-6 (IL-6), and tumor necrosis factor-α), chemokines (monocyte chemoattractant protein-1), von Willebrand factor (vWF) antigen, vWF activity, and factor VIII are elevated. Higher levels of acute phase reactants (IL-6, C-reactive protein, and D-dimer) are also associated with SARS-CoV-2 infection. Therefore, it is reasonable to assume that ED contributes to COVID-19-associated vascular inflammation, particularly endotheliitis, in the lung, heart, and kidney, as well as COVID-19-associated coagulopathy, particularly pulmonary fibrinous microthrombi in the alveolar capillaries. Here we present an update on ED-relevant vasculopathy in COVID-19. Further research for ED in COVID-19 patients is warranted to understand therapeutic opportunities.

A Retrospective Analysis of the Coagulation Dysfunction in COVID-19 Patients.

To discuss the coagulation dysfunction in COVID-19 patients and to find new biomarkers to separate severe COVID-19 patients from mild ones. We use a retrospective analysis of 88 COVID-19 patients, and compare the coagulation function between severe and mild groups. We found the prothrombin time (PT), thrombin time (TT), D-dimer were significantly higher in the severe group (P < 0.05), and the highest area under the curve (AUC) is 0.91 for D-dimer, while the AUC of PT and TT were 0.80 and 0.61 respectively. We identified that D-dimer has a better value in predicting patients who are likely to develop into severe cases, with the sensitivity and specificity were 84.4% and 88.8%, respectively. D-dimer may be a good biomarker to separate the severe COVID-19 patients from the mild ones.

Correlation analysis of coagulation dysfunction and liver damage in patients with novel coronavirus pneumonia: a single-center, retrospective, observational study.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) is currently breaking out worldwide. COVID-19 patients may have different degrees of coagulopathy, but the mechanism is not yet clear. We aimed to analyse the relationship between coagulation dysfunction and liver damage in patients with COVID-19. METHODS: A retrospective analysis of 74 patients with COVID-19 admitted to the First People's Hospital of Yueyang from 1 January to 30 March 2020 was carried out. According to the coagulation function, 27 cases entered the coagulopathy group and 47 cases entered the control group. A case control study was conducted to analyse the correlation between the occurrence of coagulation dysfunction and liver damage in COVID-19 patients. RESULTS: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), markers of liver damage, were positively correlated with coagulopathy (p = 0.039, OR 2.960, 95% CI 1.055-8.304; and p = 0.028, OR 3.352, 95% CI 1.137-9.187). Alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GT), and total bilirubin (TBIL) were not statistically correlated with coagulopathy. According to the diagnosis and treatment plan, the included cases were classified into mild, moderate, severe, and critical. The results showed that the occurrence of coagulation dysfunction had no statistical correlation with the severity of COVID-19. CONCLUSION: Coagulation dysfunction in patients with COVID-19 is closely related to liver damage. A longer course of the disease may cause a vicious circle of coagulopathy and liver damage. Clinicians need to closely monitor coagulation and liver function tests and to give prophylactic or supportive therapy when needed.

COVID-19 Associated Coagulopathy and Thrombotic Complications.

The SARS-CoV-2 virus caused a global pandemic within weeks, causing hundreds of thousands of people infected. Many patients with severe COVID-19 present with coagulation abnormalities, including increase D-dimers and fibrinogen. This coagulopathy is associated with an increased risk of death. Furthermore, a substantial proportion of patients with severe COVID-19 develop sometimes unrecognized, venous, and arterial thromboembolic complications. A better understanding of COVID-19 pathophysiology, in particular hemostatic disorders, will help to choose appropriate treatment strategies. A rigorous thrombotic risk assessment and the implementation of a suitable anticoagulation strategy are required. We review here the characteristics of COVID-19 coagulation laboratory findings in affected patients, the incidence of thromboembolic events and their specificities, and potential therapeutic interventions.

Current Overview on Hypercoagulability in COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought many unique pathologies, such as coagulopathy, prompting a desperate need for effective management. COVID-19-associated coagulopathy (CAC) can cause various thromboembolic complications, especially in critically ill patients. The pathogenesis is likely due to endothelial injury, immobilization, and an increase in circulating prothrombotic factors. Data on treatment are limited, although prophylactic anticoagulation is advised in all hospitalized patients. Herein, we have comprehensively reviewed the current literature available on CAC and highlight the pathogenesis, clinical features, and management of CAC.