One of the most consistent abnormal hemostatic laboratory markers in COVID‐19 is raised D‐dimers. Increased D‐dimers have also been observed in several studies published in the Journal of Thrombosis and Haemostasis to have prognostic implications.1., 2. But, some of the perplexing questions in this regard are what may be the reasons for such marked elevation in D‐dimers and may it have any “useful” purpose apart from prognostication?
SARS‐CoV‐2 is primarily a respiratory pathogen. An overlooked host defence mechanism to counter this virus is the activation of lung‐specific coagulation system, otherwise termed broncho‐alveolar hemostasis.3 In healthy individuals, the coagulation‐fibrinolysis balance of the broncho‐alveolar hemostasis is shifted toward fibrinolysis.4 This high fibrinolytic activity (predominantly urokinase plasminogen activator) diligently clears fibrin deposited in alveolar compartments and allows uninterrupted gas exchange.4 However, in patients who develop acute lung injury secondary to COVID‐19 (and other infectious states), this balance shifts toward the procoagulant side, with the purpose of creating pulmonary thrombi possibly to limit viral invasion.3., 4., 5. Of course, the breakdown of these thrombi would cause an increase in D‐dimers. But may there be other causes of these elevated D‐dimers?
Coagulation and fibrinolysis do not always occur in the intravascular space, especially in the lungs. Wagers and colleagues have shown that one of the prominent features of airway inflammation is the leakage of plasma proteins including fibrinogen and thrombin into the airway lumen.6 This elegant study demonstrated extravascular thrombin to convert fibrinogen into fibrin, which contributed to airway hyper‐responsiveness.6 The physiological purpose of this extravascular fibrin is possibly to serve as a matrix on which inflammatory cells can attach and function.7 This extravascular fibrin breakdown could also explain the marked increase in D‐dimers noted in patients with malignancies even in the absence of clots in the circulation.8
How is the extravascular fibrinolysis relevant to COVID‐19? The intense lung inflammation caused by SARS‐CoV‐2 is associated with elevated fibrinogen levels. Cross‐linked fibrin generated from the markedly increased fibrinogen that leaks into the extravascular space would be broken down by plasmin or proteolytic enzymes released from activated neutrophils.9 D‐dimers formed in this manner may not signify thrombus formation but could predict the need for mechanical ventilation, because they arise from lung exudates.
D‐dimers have always been considered a diagnostic rule‐out test with well‐established roles in the exclusion of venous thromboembolism. Serial D‐dimer monitoring was not a common practice in the pre COVID‐19 era except in critically ill patient for whom a possible diagnosis of DIC would be considered. But, based on intravascular and extravascular D‐dimer generation in COVID‐19, it would be worthwhile examining the following in future studies.
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Is it appropriate and safe to increase the dose of anticoagulation if the D‐dimer increase was not caused by pulmonary or systemic thrombi?
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Could serial D‐dimer monitoring predict who may require mechanical ventilation even in the absence of thrombus formation?
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In a similar manner, could serial D‐dimer monitoring be helpful in de‐escalating critical care support?
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Could D‐dimers be used to guide the duration of post‐discharge thromboprophylaxis in the COVID‐19 setting (persistent raised levels suggest continued lung inflammation)?
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In patients with underlying malignancies, could D‐dimer monitoring be helpful as a prognostic indicator?
CONFLICT OF INTEREST
None.
Footnotes
Manuscript handled by: David Lillicrap
Final decision: David Lillicrap, 19 May 2020
REFERENCES
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