Response to "All these D-dimers in COVID-19".

We appreciate the opportunity to respond to the letter from Dr Thachil, who provided an interesting physiological explanation for coagulation‐fibrinolysis balance shifts of the broncho‐alveolar hemostasis during COVID‐19 infection, and speculated that the extravascular fibrinolysis would be a source of elevated D‐dimers.

Importantly, when we evaluate and use D‐dimer in COVID‐19, we should always be aware that D‐dimer should not be a “stand‐alone test” or a “one‐size‐fits‐all test” in managing COVID‐19.

The COVID‐19 associated coagulopathy would be not only caused by lung‐specific coagulation disorder, but also mainly caused by systemic inflammatory response syndrome. First, even though SARS‐CoV‐2 is primarily a respiratory pathogen, local inflammatory response would release proinflammatory factors into the whole blood circulation to stimulate serial reactions, resulting in coagulation activation, organ damage, etc. Second, hypoxia, which is one of the common symptoms in severe COVID‐19 also can stimulate thrombosis through increasing blood viscosity and a hypoxia‐inducible transcription factor‐dependent signaling pathway. Third, underlying diseases, such as cancer and sepsis et al., are well known as risk factors of venous thromboembolism (VTE). These factors might exacerbate the inflammatory‐thrombotic response.

The extravascular fibrinolysis relevant to COVID‐19 seems to be reasonable. However, in our opinion, among contributions to the elevated D‐dimer, the proportion of extravascular fibrinolysis should be relatively small. The primary source of D‐dimer should still be endovascular fibrinolysis, even just undetectable microthrombus or thrombus but not detected by imaging examination. Of course, this hypothesis needs further pathological studies to verify.

Up to now, D‐dimer has served as one of the most important markers in management of COVID‐19. The potential uses of D‐dimer in COVID‐19 has been revealed in recent studies.

D‐dimer levels on admission might be used to distinguish patients who have potentially high in‐hospital mortality. For COVID‐19 patients who have markedly raised D‐dimers (four‐fold increase), admission to hospital and close monitoring should be considered even in the absence of other severe symptoms.

Serial D‐dimer monitoring might be used to indicate the occurrence of VTE. A rapid increase of D‐dimer levels or a peak D‐dimer might be associated with venous thromboembolism development. , D‐dimer might serve as a screening tool when imaging examination was limited in management of COVID‐19.

D‐dimer might be used to guide whether anticoagulation therapy should be initiated in patients with COVID‐19, and also can be used to evaluate the anticoagulant effect. Whether D‐dimer can be used to guide the dose of anticoagulation needs further studies to confirm. However, our team conducted a randomized clinical trial and found D‐dimer can be used to guide the anticoagulation intensity in patients receiving warfarin therapy.

D‐dimer might be used to monitor disease progression of COVID‐19. Previous studies have observed that continuous raised D‐dimer has been observed to be common in non‐survivors of COVID‐19. , Thus, dynamic monitoring of D‐dimer might be used to evaluate whether the situation is getting worse or better.

We agree with Dr Thachil that future studies are needed to evaluate whether D‐dimer can be used to guide anticoagulation adjustment, initiating mechanical ventilation, de‐escalating critical care support, and indicating prognosis of malignancies. Previous studies have suggested that D‐dimer could be used to determine the duration of oral anticoagulation in patients with VTE; however, whether this application could still work in post‐discharge thromboprophylaxis in the COVID‐19 setting remain unknown. Thus, we are carrying out an observational study involving approximately 200 post‐discharge COVID‐19 patients to evaluate the correlation between laboratory testing (including D‐dimer) and prognosis.

Finally, there are many limitations and uncertainties for D‐dimer in COVID‐19 and other situations; however, we still believe that the use of D‐dimer would not only be limited in the traditional applications, but also it would open a new page in the COVID‐19 era.

CONFLICTS OF INTEREST

The author declares that he has no conflicts of interest regarding this article.