Mechanisms of thrombosis and cardiovascular complications in COVID-19

Abstract

Background: The novel coronavirus SARS-CoV-2, responsible for the 2019-2020 global (COVID-19) pandemic, is a respiratory virus associated with the development of thromboembolic complications and respiratory failure in severe cases. Increased risk of pulmonary embolism and thrombosis has been identified in COVID-19 patients, alongside accompanying elevations in potential prognostic biomarkers, including D-dimer, IL-6 and cardiac specific troponins. Our aim was to provide a scoping review of the available literature regarding thrombosis risk, other cardiovascular implications, and their biomarkers in COVID-19 to highlight potential disease mechanisms.

Methods: Authors conducted a literature search in PubMed using MeSH headings "disseminated intravascular coagulation", "pulmonary embolism", "thromb*", "stroke", "myocardial infarction" and "acute lung injury", as well as terms "COVID-19", "SARS-CoV-2", "2019 novel coronavirus" and "2019-nCoV".

Results and conclusions: COVID-19 disease is characterised by the interactions between hyperactive coagulation and complement systems - induced by hyper-inflammatory conditions, resulting in a pro-thrombotic state and diffuse tissue injury. There are several promising prognostic markers of disease severity, with D-dimer the most significant. The presence of thrombocytopenia appears to be a key indicator of patient deterioration. Further research is required to understand the underlying pathophysiology in COVID-19 and its implications in disease progression and patient management. Randomised trials are urgently needed to determine the safety of proposed therapeutic anticoagulation with heparin and the role for anti-platelet agents, such as Ticagrelor, in patient management.

Keywords: COVID-19; Cardiovascular complications; D-dimer; SARS-CoV-2; Thromboembolism.

Graphical abstract

Fig. 1

Proposed mechanisms of immunothrombosis in COVID-19 and the interactions of the inflammation and coagulation systems. Direct SARS-CoV-2 – platelet interaction results in high levels of platelet activation, promoting a pro-thrombotic state. Direct viral trauma and resultant inflammation leads to fibrinogen elevations through IL-6, leukocyte activation, NETosis, endothelial cell activation and inflammatory mediator release. Subsequent activation of both the tissue factor and contact activation pathways of the coagulation cascade further potentiates a hyper-coagulable state, which leads to the development of thromboembolic complications in patients. CRP = C-Reactive Protein, IL-6 = Interleukin 6, IL-8 = Interleukin 8, TNF-α = Tumour necrosis factor α, TF = Tissue factor, FXII = coagulation factor XII, FXIIa = activated coagulation factor XII, FX = coagulation factor X, FXa = activated coagulation factor X.

Fig. 2

Proposed mechanisms behind the changes in prognostic biomarkers observed in COVID-19. Increased fibrin network turnover results in clotting factor consumption and prolonged standard clotting tests (PT and APTT), as well as raised D-dimer and fibrin degradation products as a result of plasmin activity. Inflammatory markers CRP and IL-6, as well as myocardial damage markers CTnT and CTnI, are elevated in COVID-19. Thrombocytopenia results from a combination of increased activation, reduced production and increased destruction due to the direct effects of SARS-CoV-2 viral interactions and the development of DIC/SIC in severe disease. PT = Prothrombin Time, APTT = Activated Partial Thromboplastin Time, IL-6 = Interleukin 6, CRP = C-Reactive Protein, CTnT = Cardiac Specific Troponin T, CTnI = Cardiac Specific Troponin I, DIC = Disseminated Intravascular Coagulation, SIC = Sepsis-Induced Coagulopathy.