Coagulopathy of Coronavirus Disease 2019

Toshiaki Iba

Jerrold Levy

Marcel Levi

Jean Connors

Jecko Thachil

^{Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.}

^{Department of Anesthesiology, Critical Care, and Surgery, Duke University School of Medicine, Durham, NC.}

^{Department of Medicine and Cardio-metabolic Programme-NIHR UCLH/UCL BRC, University College London Hospitals NHS Foundation Trust, London, United Kingdom.}

^{Hematology Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.}

^{Department of Haematology, Manchester Royal Infirmary, Manchester, United Kingdom.}

^{Corresponding author.}

For information regarding this article, E-mail: pj.ca.odnetnuj@abiihsot

This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

Objectives:

Recent studies have reported a high prevalence of thrombotic events in coronavirus disease 2019. However, the significance of thromboembolic complications has not been widely appreciated. The purpose of this review is to provide current knowledge of this serious problem.

Design:

Narrative review.

Data Sources:

Online search of published medical literature through PubMed using the term “COVID-19,” “SARS,” “acute respiratory distress syndrome,” “coronavirus,” “coagulopathy,” “thrombus,” and “anticoagulants.”

Study Selection and Data Extraction:

Articles were chosen for inclusion based on their relevance to coagulopathy and thrombosis in coronavirus disease 2019, and anticoagulant therapy. Reference lists were reviewed to identify additional relevant articles.

Data Synthesis:

Coronavirus disease 2019 is associated with a strikingly high prevalence of coagulopathy and venous thromboembolism that may contribute to respiratory deterioration. Monitoring coagulation variables is important, as abnormal coagulation tests are related to adverse outcomes and may necessitate adjuvant antithrombotic interventions. In the initial phase of the infection, d-dimer and fibrinogen levels are increased, while activated partial prothrombin time, prothrombin time, and platelet counts are often relatively normal. Increased d-dimer levels three times the upper limit of normal may trigger screening for venous thromboembolism. In all hospitalized patients, thromboprophylaxis using low-molecular-weight heparin is currently recommended. The etiology of the procoagulant responses is complex and thought to be a result of specific interactions between host defense mechanisms and the coagulation system. Although the coagulopathy is reminiscent of disseminated intravascular coagulation and thrombotic microangiopathy, it has features that are markedly distinct from these entities.

Conclusions:

Severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019 frequently induces hypercoagulability with both microangiopathy and local thrombus formation, and a systemic coagulation defect that leads to large vessel thrombosis and major thromboembolic complications, including pulmonary embolism in critically ill hospitalized patients. d-dimers and fibrinogen levels should be monitored, and all hospitalized patients should undergo thromboembolism prophylaxis with an increase in therapeutic anticoagulation in certain clinical situations.

Keywords: coagulopathy, coronavirus, coronavirus disease 2019, disseminated intravascular coagulation, hypercoagulability, thromboembolism

Objectives:

Increasing communications worldwide have reported that hospitalized, critically ill coronavirus disease 2019 (COVID-19) patients are frequently developing laboratory abnormalities compatible with hypercoagulability and clinically a high prevalence of thromboembolic events (1). In addition to deep vein thrombosis (DVT) and pulmonary embolism (PE), thrombosis in extracorporeal circuits and arterial thrombosis have been reported (2). Patients with COVID-19 often present with dyspnea, hypoxemia, and hemodynamic instability with acute respiratory distress syndrome (ARDS), and in such clinical condition, venous thromboembolism (VTE) may be overlooked (3, 4). Standard imaging in critically ill patients utilizing contrast-enhanced CT may not always be feasible, and additionally, concerns exist with disease transmission to health-care staff.

Ranucci et al (5) recently reported comprehensive coagulation analyses including d-dimers, fibrinogen levels, and viscoelastic testing in the COVID-19 patients with ARDS, and reported the procoagulant profile on ICU admission with median d-dimer levels of 5.5 mg/L (10 times the upper limit of normal), fibrinogen levels of 7.8 g/L, and increased clot strength by thromboelastometry. Panigada et al (6) performed a similar analysis and also noted increased fibrinogen levels, enhanced platelet activation, and increased viscoelastic variables. Beyond VTE, the relevance of microthrombus formation to organ dysfunction and acro-ischemic change has also been suggested (7–9). Although the number of postmortem pathologic reports are limited, Luo et al (10) described vascular wall thickening, stenosis of the vascular lumen, and microthrombus formation accompanying the findings of ARDS. Similar pathologic findings are found in small vessels of other organs (8–11). Magro et al (12) reported the deposition of C5b-9 (membrane attack complex), C4d, and mannose-binding lectin-associated serine protease-2 in the lung capillaries and the skin microvasculature. Notably, the deposition was co-localized with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein. A recent report also noted mononuclear and polymorphonuclear leukocyte infiltration and pulmonary microcirculation along with apoptosis as induced by caspase 3 staining (13).

In critically ill COVID-19 patients, there appear to be at least two separate pathologic coagulation pathologic processes that are important in producing clinical manifestations. In the microcirculation of the lung and potentially other organs, there is local direct vascular and endothelial injury producing microvascular clot formation and angiopathy (13, 14). Post mortem biopsy of the lung revealed mononuclear and polymorphonuclear infiltration along with apoptosis of endothelial and mononuclear cells (13). In the systemic circulation, due to hypercoagulability with hyperfibrinogenemia, there is also the potential for large vessel thrombosis and major thromboembolic sequelae including PE that is reported in 20–30% of ICU patients (15–17) (Fig. Fig.11). Because of the important role of coagulation activation in critically ill COVID-19 patients, this review summarizes the current knowledge about the coagulopathy and role of anticoagulation in these patients.

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Figure 1.

Various types of thrombus formation in coronavirus disease 2019 (COVID-19). Venous thrombosis and pulmonary thromboembolism are common complications in COVID-19. Increased fibrinogen and factor VIII, activated coagulation, direct viral endothelial infection and endothelial injury, and increased platelet-vessel wall interaction activation play roles in the development of thrombotic complications. In addition, there may be pulmonary microvascular coagulation in COVID-19. The prevalence of arterial thrombosis is also high and involvement of antiphospholipid antibodies has been suggested.

Footnotes

Dr. Levy received funding from research, data safety, or advisory committees for CSL Behring, Instrumentation Labs, Janssen, Merck, and Octapharma. Dr. Connors’ institution received funding from CSL Behring; received funding from Abbott (consulting), Bristol-Myers Squibb (consulting), and Portola (scientific advisory board). The remaining authors have disclosed that they do not have any potential conflicts of interest.

Footnotes

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