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Thrombomodulin as an early marker of endotheliitis in COVID-19

Commented by the ESC WG Thrombosis

Comment: Short description of the paper by Josip A. Borovac, MD, PhD:
Previous clinical studies showed that a notable characteristic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among ICU-hospitalised patients is the development of coagulopathy. Authors of this observational and cross-sectional study hypothesised that endothelial vascular injury might play a central pathogenetic role in the development of COVID-19-associated coagulopathy especially during the inflammatory phase of the disease. For these reasons, they examined biochemical markers of endothelial cell and platelet activation encompassing von Willebrand Factor (VWF) antigen, soluble P-selectin, soluble thrombomodulin, and soluble CD40 ligand along with other relevant hemostasis parameters. The authors examined and compared these parameters in three groups of patients : a) COVID-19 patients in the ICU (mostly intubated and in critical illness), b) non-ICU COVID-19 patients (those on minimal oxygen support requirement) and control healthy patients without COVID-19. This study showed that markers of endothelial cell and platelet activation were significantly higher in ICU vs. non-ICU COVID-19 patients and this was primarily reflected in the elevated percentage of circulating VWF antigen and the concentration of soluble P-selectin. Furthermore, VWF antigen and soluble thrombomodulin significantly correlated with short-term mortality. On the other hand, soluble thrombomodulin concentrations were associated with lower rates of hospital discharge and a lower likelihood of survival, as per Kaplan-Meier analysis. Finally, the authors conclude that their study provides convincing biochemical evidence for endothelial derangement and its contributing role in the onset of COVID-19-associated coagulopathy and critical illness. Such endothelial markers might thus provide prognostic information in patients with COVID-19 and might prompt the initiation of therapeutic strategies that would protect endothelial function in this disease.

COMMENT by Josip A. Borovac, MD, PhD :
This is an important work by Goshua and colleagues that expands our current knowledge of COVID-19-associated coagulopathy. The strength and novelty of this work lie in the fact that reported findings help to integrate the pathophysiological pieces of the puzzle when it comes to critical illness and coagulopathy in hospitalised COVID-19 patients, particularly those with severe forms of the disease requiring mechanical ventilatory support. Previous studies have shown that infection-induced thromboinflammation mediated by „cytokine storm“ is at play in COVID-19 and is marked by hypercoagulability and substantial elevations in laboratory parameters such as D-dimers and fibrin/fibrinogen degradation products accompanied with mild or absent thrombocytopenia and unremarkable changes in prothrombin time or activated partial thromboplastin time.1-3 The incidence of thrombotic complications in ICU-treated COVID-19 patients might be exquisitely high, according to some reports, while abnormal coagulation parameters have been associated with poor in-hospital prognosis.4-6 On the other hand, anticoagulant treatment and pharmacological thrombosis prophylaxis among COVID-19 patients admitted to ICU might mitigate or prevent these complications and improve outcomes.7, 8
The authors of the present study showed that endotheliitis and vascular endotheliopathy might be the „missing link“ required for the staging of the „perfect storm“ in COVID-19. As we know from previous studies, among COVID-19 patients with severe disease, an exuberant virus-induced inflammatory activity might potentiate cytokine storm characterised by upregulation of proinflammatory cytokines such as interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α), and these effects would carry a capacity to induce damage to the endothelium, pulmonary and systemic vasculature, promote coagulopathy and ultimately lead to multiorgan failure and death.9, 10 Results of the present study clearly showed that biochemical markers of endothelial cell and platelet activation such as VWF and soluble P-selectin were significantly higher in COVID-19 patients treated in the ICU vs. non-ICU patients with less severe disease. Importantly, ICU patients with high soluble thrombomodulin levels were discharged from hospital to a significantly lesser degree than those with lower thrombomodulin levels, while in a total patient cohort and ICU-cohort only, high soluble thrombomodulin levels were consistently associated with decreased survival probability. From the pathophysiological perspective, elevated soluble thrombomodulin concentrations likely reflect direct endothelial cell damage, thereby, the concentration of this biomarker in the blood might be the surrogate for the degree of endothelial injury in COVID-19.11 On the other hand, soluble P-selectin is a cell adhesion molecule that is located on the surfaces of activated endothelial cells and activated platelets and is implicated in the complement attack on the endothelium.12 In a murine model of transfusion, development of pulmonary microthrombi was mediated by P-selectin.13 As authors conclude, present results suggest that COVID-19-associated coagulopathy might be triggered by the endothelial injury first that ultimately results in augmented VWF release, platelet activity and hypercoagulability leading to clinical thromboembolic events such as venous, arterial and microvascular thrombosis. Clinical ramifications of these findings are important because we might focus our therapeutic efforts and attention on pharmacologic agents affecting platelet and endothelial function and these could be added to current pharmacologic armamentarium in severe COVID-19 and this paradigm is currently based on traditional anticoagulants targeting thrombin formation. Moreover, a surrogate marker of endothelial injury, thrombomodulin also seems to provide prognostic information in this population. Taken together, authors are to be commended on this fine effort that helps us to elucidate intricate pathophysiological pathways that contribute to systemic deterioration and coagulopathy in patients with a severe form of COVID-19.

COMMENT BY Heleen M.M. van Beusekom, PhD, FESC: The paper on endotheliopathy in COVID-1914, recently published in the Lancet Hematology comes at a time when most European countries are dealing with the second surge in COVID-outbreak. COVID-dedicated ICU-wards are quickly filling up, as are the non-ICU COVID-wards. Therefore, lessons learned during the first surge are definitively worth sharing. Indeed, we already learned that patients with COVID-19 are at high risk for blood clots and strokes (31% complication rate) despite being on preventive doses of anticoagulation. Data that were strongly suggestive of the need to increase prophylaxis towards high-prophylactic doses, even in the absence of randomised evidence6. It was soon speculated that endothelial injury might be involved. In the commented paper, the authors present a single-centre cross-sectional study looking for evidence of endothelial injury in COVID-19 -associated coagulopathy. They compared a range of platelet and endothelial biomarkers, including von Willebrand factor and soluble thrombomodulin. The latter is not only regarded as a reliable marker of endothelial destruction such as in vasculitides, but also as an early marker of initial endothelial cell membrane changes and could therefore be considered a marker of early endothelial damage15. The authors found that both von Willebrand factor and soluble thrombomodulin were significantly related to mortality among all COVID-19 patients. Indeed, soluble thrombomodulin levels greater than 3.26 ng/mL (median levels in their total COVID-19 cohort) were associated with lower rates of hospital discharge in the study period and a lower likelihood of survival (hazard ratio of 5.9, 95%CI 1.9-18). They interpreted this as evidence of endotheliopathy and indicated that early identification might support strategies to mitigate disease progression and improve disease outcome. Since the publication of this paper, a range of papers on endotheliopathy and COVID-19 have been published, and there is no doubt it is related to serious consequences16. Indeed, plasma collected from COVID-19 patients at different disease stages could trigger endothelial damage in vitro, as well as restoration by plasma from convalescent patients as compared to ICU submission17. A new trial to treat endotheliopathy in patients with soluble thrombomodulin levels above 4 ng/mL has started in mechanically ventilated COVID-19 patients18. Results are eagerly awaited.



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2. Terpos E, Ntanasis-Stathopoulos I, Elalamy I, Kastritis E, Sergentanis TN, Politou M, et al. Hematological findings and complications of COVID-19. Am J Hematol. 2020;95(7):834-47. doi: 10.1002/ajh.25829.
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7. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-9. doi: 10.1111/jth.14817.
8. Atallah B, Mallah SI, AlMahmeed W. Anticoagulation in COVID-19. Eur Heart J Cardiovasc Pharmacother. 2020;6(4):260-1. doi: 10.1093/ehjcvp/pvaa036.
9. Buszko M, Park JH, Verthelyi D, Sen R, Young HA, Rosenberg AS. The dynamic changes in cytokine responses in COVID-19: a snapshot of the current state of knowledge. Nat Immunol. 2020;21(10):1146-51. doi: 10.1038/s41590-020-0779-1.
10. Wang T, Du Z, Zhu F, Cao Z, An Y, Gao Y, et al. Comorbidities and multi-organ injuries in the treatment of COVID-19. Lancet. 2020;395(10228):e52. doi: 10.1016/S0140-6736(20)30558-4.
11. López-Aguirre Y, Páramo JA. Endothelial cell and hemostatic activation in relation to cytokines in patients with sepsis. Thromb Res. 1999;94(2):95-101. doi: 10.1016/s0049-3848(98)00200-x.
12. Merle NS, Paule R, Leon J, Daugan M, Robe-Rybkine T, Poillerat V, et al. P-selectin drives complement attack on endothelium during intravascular hemolysis in TLR-4/heme-dependent manner. Proc Natl Acad Sci U S A. 2019;116(13):6280-5. doi: 10.1073/pnas.1814797116.
13. Kim Y, Goodman MD, Jung AD, Abplanalp WA, Schuster RM, Caldwell CC, et al. Microparticles from aged packed red blood cell units stimulate pulmonary microthrombus formation via P-selectin. Thromb Res. 2020;185:160-6. doi: 10.1016/j.thromres.2019.11.028.
14. Goshua G, Pine AB, Meizlish ML, Chang CH, Zhang H, Bahel P, et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol. 2020;7(8):e575-e82. doi: 10.1016/S2352-3026(20)30216-7.
15. Boehme MW, Galle P, Stremmel W. Kinetics of thrombomodulin release and endothelial cell injury by neutrophil-derived proteases and oxygen radicals. Immunology. 2002;107(3):340-9. doi: 10.1046/j.1365-2567.2002.01469.x.
16. Iba T, Connors JM, Levy JH. The coagulopathy, endotheliopathy, and vasculitis of COVID-19. Inflamm Res. 2020. Online ahead of print. doi: 10.1007/s00011-020-01401-6.
17. Rauch A, Dupont A, Goutay J, Caplan M, Staessens S, Moussa M, et al. Endotheliopathy is induced by plasma from critically-ill patients and associated with organ failure in severe COVID-19. Circulation. 2020. Online ahead of print. doi: 10.1161/CIRCULATIONAHA.120.050907.
18. Johansson PI, Bestle M, Søe-Jensen P, Kristiansen KT, Stensballe J, Clausen NE, et al. The effect of prostacyclin (Iloprost) infusion at a dose of 1 ng/kg/min for 72 hours compared to placebo in mechanically ventilated patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial. Trials. 2020;21(1):746. doi: 10.1186/s13063-020-04696-2.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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