Abstract Emerging as a new epidemic, long COVID or post-acute sequelae of coronavirus disease 2019 (COVID-19), a condition characterized by the persistence of COVID-19 symptoms beyond 3 months, is anticipated to substantially alter the lives of millions of people globally. Cardiopulmonary symptoms including chest pain, shortness of breath, fatigue, and autonomic manifestations such as postural orthostatic tachycardia are common and associated with significant disability, heightened anxiety, and public awareness. A range of cardiovascular (CV) abnormalities has been reported among patients beyond the acute phase and include myocardial inflammation, myocardial infarction, right ventricular dysfunction, and arrhythmias. Pathophysiological mechanisms for delayed complications are still poorly understood, with a dissociation seen between ongoing symptoms and objective measures of cardiopulmonary health. COVID-19 is anticipated to alter the long-term trajectory of many chronic cardiac diseases which are abundant in those at risk of severe disease. In this review, we discuss the definition of long COVID and its epidemiology, with an emphasis on cardiopulmonary symptoms. We further review the pathophysiological mechanisms underlying acute and chronic CV injury, the range of post-acute CV sequelae, and impact of COVID-19 on multiorgan health. We propose a possible model for referral of post-COVID-19 patients to cardiac services and discuss future directions including research priorities and clinical trials that are currently underway to evaluate the efficacy of treatment strategies for long COVID and associated CV sequelae.

https://academic.oup.com/eurheartj/advance-article-pdf/doi/10.1093/eurheartj/ehac031/42541089/ehac031.pdf

Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus

Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and D-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research. 

/pdf/current-and-novel-biomarkers-of-thrombotic-risk-in-covid-19-egg083xg.pdf

Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium

COVID-19-associated coagulopathy (CAC) is a life-threatening complication of SARS-CoV-2 infection. However, the underlying cellular and molecular mechanisms driving this condition are unclear. Evidence supports the concept that CAC involves complex interactions between the innate immune response, the coagulation and fibrinolytic pathways, and the vascular endothelium, resulting in a procoagulant condition. Understanding of the pathogenesis of this condition at the genomic, molecular and cellular levels is needed in order to mitigate thrombosis formation in at-risk patients. In this Perspective, we categorize our current understanding of CAC into three main pathological mechanisms: first, vascular endothelial cell dysfunction; second, a hyper-inflammatory immune response; and last, hypercoagulability. Furthermore, we pose key questions and identify research gaps that need to be addressed to better understand CAC, facilitate improved diagnostics and aid in therapeutic development. Finally, we consider the suitability of different animal models to study CAC. 

/pdf/understanding-covid-19-associated-coagulopathy-2q0r3rxs.pdf

Understanding COVID-19-associated coagulopathy

Post-acute sequelae of COVID (PASC), usually referred to as 'Long COVID' (a phenotype of COVID-19), is a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, 'brain fog', tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection. It bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many regulatory health bodies still do not recognize this syndrome as a separate disease entity, and refer to it under the broad terminology of 'COVID', although its demographics are quite different from those of acute COVID-19. A few years ago, we discovered that fibrinogen in blood can clot into an anomalous 'amyloid' form of fibrin that (like other β-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope. Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored 'triple' anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders. 

A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

Though the acute effects of SARS-CoV-2 infection have been extensively reported, the long-term effects are less well described. Specifically, while clinicians endure to battle COVID-19, we also need to develop broad strategies to manage post-COVID-19 symptoms and encourage those affected to seek suitable care. This review addresses the possible involvement of the lung, heart and brain in post-viral syndromes and describes suggested management of post-COVID-19 syndrome. Post-COVID-19 respiratory manifestations comprise coughing and shortness of breath. Furthermore, arrhythmias, palpitations, hypotension, increased heart rate, venous thromboembolic diseases, myocarditis and acute heart failure are usual cardiovascular events. Among neurological manifestations, headache, peripheral neuropathy symptoms, memory issues, lack of concentration and sleep disorders are most commonly observed with varying frequencies. Finally, mental health issues affecting mental abilities and mood fluctuations, namely anxiety and depression, are frequently seen. Finally, long COVID is a complex syndrome with protracted heterogeneous symptoms, and patients who experience post-COVID-19 sequelae require personalized treatment as well as ongoing support.

/pdf/post-covid-19-syndrome-involvement-and-interactions-between-3vo9nh1e.pdf

Post-COVID-19 Syndrome: Involvement and Interactions between Respiratory, Cardiovascular and Nervous Systems

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jth.15490

James S. O’ Donnell

Papers

Persistent Endotheliopathy in the Pathogenesis of Long COVID Syndrome.