The last research roundup provided you with an overview of recent research on end-of-life care in a global pandemic. In the last 9 months, there have been many rapidly published studies around COVID-19, and I feared I would struggle to find a relevant topic for this month's roundup. However, as I was reading the information around coagulopathy in COVID-19 from a personal perspective, it seemed appropriate to carry this further for the journal piece. There is emerging evidence that changes to coagulation and embolic events are linked with more serious cases of COVID-19 and may be prognostic of the outcome, as these events contribute to morbidity and mortality. This month, I am looking at three publications on this subject, including one that explains the coagulation process to help contextualise the problem. There is little related to prescribing choices as, initially, low molecular weight heparin was used, but now other anticoagulant medications are being trialled and hopefully results from these will be available in the near future.
Coagulopathy and COVID-19
This review article from Tokyo in Japan was published in March 2020 and outlined what was being seen by clinicians dealing with ill patients in the first wave of the COVID-19 pandemic (Iba et al, 2020). It was recognised fairly early on that many of the patients who were hospitalised with COVID-19 were also presenting with coagulopathy issues.
This paper also outlines the coagulation process, highlighting what the changes were doing to the normal clotting cascade mechanisms and how that may be used to understand what was compromised. The authors report that the most seriously ill patients with coronavirus exhibited clinical signs of varying thrombo-embolic conditions, including disseminated intravascular coagulation-like symptoms, pulmonary embolism and large intravascular embolism. They report that bleeding tendency and haemorrhage are rare but that end-organ function is often affected.
These changes can be seen clinically but also in altered blood and biochemical biomarkers. The authors speculatively relate these biomarker changes to altered clotting cascade and end outcome events. There is a good discussion on coagulation therapy around both the need for it and the choice of low molecular weight heparin as an initial intervention. This paper helps sets the scene as one of the earliest published discussions of hypercoagulopathy and COVID-19.
An in-depth analysis of the coagulation system
This original research paper, published in August 2020, reports on a study of 206 Spanish patients who presented with COVID-19 (Martin-Rojas et al, 2020). The aim of the study was to analyse the normal bloods taken and the coagulation parameters of patients with COVID-19. This was used to determine whether coagulation factor derogation occurs and identify potential prognostic biomarkers of the disease. This was a retrospective study examining already collected data on patients hospitalised with COVID-19 between 3 April and 3 May 2020. Participant inclusion was determined by the following criteria; being a patient diagnosed with COVID-19, who was hospitalised and was over 18 years old. Anyone receiving Vitamin K therapy was excluded. COVID-19 diagnosis was defined by ‘positive polymerase chain reaction in nasopharyngeal swab’ or by ‘radiologic and analytical findings highly suggestive of the disease’. The bloods that were taken were analysed according to the COVID-19 protocol in place in that hospital at the time of the study. These included red and white cell blood counts, biochemistry, C-reactive protein, procalcitonin, ferritin, and interleukin 6. In addition, D-dimer and coagulation factors were also analysed.
Of the 206 participants, 18 died. The main finding of the study was an elevated d-dimer with 69.4% of the patients' above normal range. Factor VII levels also showed an increasing trend but did not reach statistical significance. They conclude that abnormal coagulation and other routine laboratory parameters were associated with poor prognosis. Notably, D-dimer levels were significantly higher in non-survivors, who also showed changes to prothrombin.
Endothelial cells orchestrate COVID-19 coagulopathy
This comment piece in the Lancet Haematology section links endothelial cells to COVID-19 associated coagulopathy (O'Sullivan et al, 2020). They report that in COVID-19 patients, coagulation activation is widely seen and postmortem reports have identified many cases of widespread microthrombi disseminated throughout the pulmonary vasculature, suggesting that vasculopathy is important in COVID-19 pathogenesis. These post-mortem studies also show substantial endothelial cell damage, with evidence of apoptosis (cell death) and loss of tight junctions.
Collectively, these data suggest that endothelial cells play a key role in orchestrating the unusual pulmonary intravascular coagulopathy associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There is a good discussion and visual interpretation of the potential activation cascade from endothelium to aid understanding. There is also a good discussion around the significance of elevated von Willebrand Factor and disease severity, with more patients who display this symptom being admitted to intensive care settings. Von Willebrand Factor can bind to platelet receptors causing platelet adhesion and aggregation, leading to hypercoagulability. Normal blood vessels are lined by an endothelial cell monolayer that plays a crucial role in preventing the formation of pathological thrombosis. Thrombomodulin on endothelial cells has anticoagulant properties. If thrombomodulin is shed, which it can occur in response to cytokine activation, then this anticoagulant property of endothelial cells is compromised.
The authors conclude that further studies will be required to define the different mechanisms through which SARS-CoV-2 infection causes such marked endothelial cell effects, and how this can be ameliorated or managed pharmacologically.
Conclusions
There seems to be a growing body of evidence to support potentially significant numbers of patients who contract COVID-19 having some vascular and coagulopathy symptoms, which may or may not cause morbidity and mortality. These range from simple elevated D-dimer with no clinical correlation, to patients experiencing fatal embolic events. What is evident is that this is an area for significant further research and coagulopathy should be assessed in all patients presenting with symptomatic COVID-19 and appropriate anticoagulation therapy should be prescribed to prevent significant embolic events.