key: cord-0912393-w3jpi5sb
authors: Seitz, Rainer; Schramm, Wolfgang
title: DIC in COVID‐19: Implications for Prognosis and Treatment?
date: 2020-04-28
journal: J Thromb Haemost
DOI: 10.1111/jth.14878
sha: 6137b4d45b3832607d8f7fa4ace94e155767c3f8
doc_id: 912393
cord_uid: w3jpi5sb

The ongoing COVID‐19 pandemic is an exceptional challenge for the health systems throughout the world. So far, no causative therapy nor protective vaccines are available. In several countries, the capacities for intensive care and for support in case of acute respiratory distress syndrome (ARDS) are overstretched, and the mortality is considerable. In this situation, useful prognostic parameters and targeted supportive treatment are urgently needed.

Moreover, it appears reasonable to formulate the hypothesis that DIC might not only be a concomitant finding, but even a pathophysiological process contributing to circulatory and organ failure, in COVID-19 particularly pulmonary damage. As well know from DIC e.g. in bacterial sepsis, disseminated fibrin deposits occur in the microvasculature, impairing the perfusion and thus performance of vital organs. In this context, it is of interest that in three patients with severe COVID-19 pneumonia induced ARDS Tissue Plasminogen Activator (tPA) treatment resulted in documented but transient improvement of pulmonary function parameters 4. . This would be compatible with the assumption that during tPA infusion the pulmonary microvasculature was partially reopened, but after terminating tPA the microthrombi inceased again, due to the ongoing inflammatory stimulus perpetuating DIC.

If the above hypothesis would be correct, it might be warranted to think about possible interventions to attenuate DIC and prevent further obstruction of organ microvasculature by fibrin deposits. The key player in the generation of fibrin deposits is thrombin. Thus, for decades several approaches of anticoagulation have been evaluated for beneficial effects in DIC, particularly in sepsis. These trials have been admittedly so far frustrating. For none of the approaches could a clear and proven survival benefit be demonstrated, as shown in a recent meta-analysis 5 . However, some of the clinical studies conducted so far had considerable flaws. For instance, the large randomized multicenter KyberSept trial 6 used exceedingly high Antithrombin III (AT) doses, in many patients accompanied by effective heparin doses, resulting in excessive bleeding. In their meta-analysis 5 , Umemura et al. showed that AT nevertheless did show a small reduction of mortality (risk ratio 0.63; 95% CI 0.45; 0.90) in the subgroup of sepsis patients with DIC. Also a recent summary 7 of systematic reviews found some evidence, albeit with low certainty for a beneficial effect in sepsis-induced DIC, and mentioned that the Japanese Clinical Practice Guidelines for Management of Sepsis and Septic shock weakly recommended the use of antithrombin for DIC patients with reduced antithrombin activities.

Thus, it might be time for reconsidering the interaction and modulating of different connected systems e.g. coagulation, fibrinolysis, Kallikrein-Kinin, Complement and immunity (cytokine storm). A rationale for developing strategies for attenuating DIC in COVID-19. If such efforts would be successful, it might have immense benefit also for intensive care patients far beyond the current crisis.

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/JTH.14878 This article is protected by copyright. All rights reserved

Rainer Seitz wrote the manuscript

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation

Disseminated intravascular coagulation in patients with 2019-nCoV pneumonia

Tissue Plasminogen Activator (tPA) Treatment for COVID-19

Associated Acute Respiratory Distress Syndrome (ARDS): A Case Series

Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta-analysis of randomized controlled trials

KyberSept Trial Study Group. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial

A Systematic Summary of Systematic Reviews on Anticoagulant Therapy in Sepsis

This article is protected by copyright. All rights reserved Accepted Article