This commentary deals with the paper by D. Gorog and colleagues titled “Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium”, recently published in Nature Reviews Cardiology.
Summary of the article (by junior member)
It has been previously well-established that infection with novel Coronavirus (SARS-CoV-2) is associated with significantly increased propensity for microvascular and macrovascular thrombotic and thromboembolic events due to thromboinflammation, endothelial cell activation and injury, platelet activation, and hypercoagulability.1-3 Since thrombotic events are linked to poor clinical prognosis, particularly among hospitalized and ICU-treated COVID-19 patients4, there is an unmet need in developing effective strategies that would prevent thrombosis or aid in the early diagnosis and treatment of thrombotic complications in this vulnerable patient population. Therefore, readily available, as well as novel and experimental circulating biomarkers, might be one of the feasible and effective approaches to facilitate this endeavour.
In the comprehensive consensus statement, issued by the International COVID-19 Thrombosis Biomarkers Colloquium, an aggregate of seventeen international experts in thrombosis provide practical information on the use of various biomarkers for thrombosis risk stratification among patients with COVID-19.5
In their review paper, the authors discuss and evaluate several laboratory biomarkers and diagnostic platforms that reflect distinct mechanistic pathways and pathophysiological processes that are postulated to be operative in COVID-19-provoked thrombosis. They go on by evaluating biomarkers that are implicated in platelet activation and aggregation, endothelial cell activation and injury, as well as haemostasis regulation, coagulation, and fibrinolysis. The authors also include a section on a vaccine-induced immune thrombotic thrombocytopenia (VITT) that is recently recognized as a rare but potentially fatal side-effect of adenoviral vector vaccines that are used against SARS-CoV-2.6
Finally, useful formal recommendations with the level of evidence (LoE) grading are given concerning the usefulness of a particular biomarker in the prognosis, diagnosis, and management of COVID-19-related thrombosis.
Junior commentary
Patients infected with the SARS-CoV-2 virus might develop severe thrombotic events and the initial prothrombotic cascade in this scenario shares similarities with coagulopathies associated with a critical illness such as disseminated intravascular coagulation and consumptive coagulopathy, however, distinct features of laboratory biomarkers and temporal dynamics are present. Since mitigating thrombotic complications in COVID-19 is of exceptional clinical significance, this Consensus statement provides an in-depth and detailed description of thrombotic signatures in COVID-19 and provides relevant information on biomarkers and platforms that might aid in the stratification of thrombotic risk among patients with COVID-19, especially those that are hospitalized or treated in the critical care setting.
The review provides a snapshot of available platforms that are used in the assessment of prothrombotic pathways such as tests of coagulation, tests of fibrinolysis, platelet activation, and platelet aggregation. The authors make practical consensus recommendations on coagulation assays, associated thrombosis biomarkers, and platelet biomarkers in COVID-19. More specifically, they highlight the importance of C-reactive protein (CRP) as a routine biomarker used to guide prognosis and disease severity and also to guide risk assessment of venous thromboembolism (VTE). Similarly, D-dimer is highly recommended to be used for guidance in prognosis and assessment of disease severity and risk of VTE. These observations are largely concordant with real-world clinical practice as these two routinely available biomarkers showed to be useful predictors of VTE and poor clinical outcomes in COVID-19. For example, a recent study by Smilowitz et al. revealed how systemic inflammation, as measured by CRP, was significantly associated with VTE, acute kidney injury (AKI), critical illness, and mortality in COVID-19.7 Similarly, elevated D-dimer levels in COVID-19 were a strong correlate of critical illness, thrombotic events, AKI, and death.8
A particular highlight is put on the role of viscoelastic assays in COVID-19, as these tools can provide global information from the whole blood samples concerning the dynamic changes in clot characteristics, from initiation of clot formation to platelet-fibrin clot generation, subsequent clot stability, and final lysis. In this light, they provide an informative illustration of viscoelastometry tracings obtained from a healthy individual and a critically ill patient with COVID-19 showing the shortened clotting time and clot formation time with the complete absence of fibrinolysis (fibrinolysis shutdown) in the latter case scenario.
Besides the sole focus on markers of thrombosis and its complications in COVID-19, the authors also dedicate a section to the vaccine-induced thrombotic thrombocytopenia (VITT) as an uncommon but serious complication of adenovirus-based COVID-19 vaccination. They go on to provide a brief and up-to-date overview of useful testing schemes to make a VITT diagnosis.
Finally, the authors conclude that the current state of biomarkers for the purpose of thrombosis risk stratification and prognosis in COVID-19 is solid with the potential to improve in the future with the adoption of novel biomarkers while a significantly larger data gap exists with the respect to the usefulness of these tools to guide antithrombotic treatment. Taken together, I hold that this Consensus statement is an important document that will help clinicians worldwide to understand and estimate the risks of thrombosis in patients with COVID-19 as these complications, if unattended, are life-threatening and often fatal.
Senior commentary
COVID-19 disease is known to be associated with increased risk of thrombotic events, mainly venous thromboembolic complications (incidence ranging from 15 to 45% in ICU-admitted patients depending mainly on whether routine screening is used), and antithrombotic prophylaxis and therapy is of utmost relevance in this scenario.9-11 This prothrombotic state is linked with elevated concentrations of numerous biomarkers of thrombosis. Of note, the assessment of these biomarkers may be of help to evaluate thrombotic risk, disease severity and prognosis, but it might also have the potential of guiding thromboprophylaxis and other treatment strategies.
As in many other aspects during the COVID-19 pandemic, there has been an overload of publications on this subject, sometimes of insufficient or doubtful quality from a methodological standpoint, which make it difficult to fully understand or establish the true value of available biomarkers for clinical use in COVID-19 patients. Thus, the authors of this Consensus Statement, led by Professor Diana Gorog, must be commended for providing this thorough and comprehensive manuscript that summarizes the current status of knowledge on biomarkers associated with thrombotic risk, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis, as well as biomarkers of the post-vaccine thrombosis with thrombocytopenia syndrome. Further, available information regarding the specific signature of COVID-19 on platforms and assays used to analyse different pathways involved in thrombotic processes (coagulation, fibrinolysis, platelet activation and aggregation) is also reviewed and presented in this manuscript.
An important feature of this document is that the authors manage to provide consensus recommendations for the clinical use of each and every one of these biomarkers and platforms.12 In particular, C-reactive protein and D-dimer obtained the highest level of evidence and the authors recommended their routine use in COVID-19 patients to guide prognosis and to assess disease severity and risk of VTE.7,8 Conversely, most of the commented biomarkers have not been sufficiently evaluated or prospectively validated and, therefore, their routine adoption in clinical practice cannot be recommended nowadays. Overall, it is fair to acknowledge that there is still a long way to go in terms of research before we can guide our antithrombotic strategy (antiplatelet or anticoagulant regimens) or other therapeutic options for COVID-19 patients solely based on currently available platforms or biomarkers.
Our mission: To reduce the burden of cardiovascular disease.