COVID‐19 coagulopathy – what should we treat?

Abstract

New Findings What is the topic of this review?Overview of the coagulation abnormalities, including elevated D‐dimers widely reported with COVID‐19, often labelled as COVID coagulopathy. What advances does it highlight?The review highlights the changes in bronchoalveolar haemostasis due to apoptosis of alveolar cells, which contributes to acute lung injury and acute respiratory distress syndrome; the pathophysiological mechanisms, including endothelial dysfunction and damage responsible for thrombosis of pulmonary microcirculation and potential contribution to the hypoxaemia of COVID‐19 acute lung injury; and changes in coagulation proteins responsible for the hypercoagulability and increased risk of thrombosis in other venous and arterial beds. The rationale for anticoagulation and fibrinolytic therapies is detailed, and potential confounders that might have led to less than expected improvement in the various randomised controlled trials are considered. Abstract Coronavirus disease 19 (COVID‐19) causes acute lung injury with diffuse alveolar damage, alveolar–capillary barrier disruption, thrombin generation and alveolar fibrin deposition. Clinically, hypoxaemia is associated with preserved lung compliance early in the disease, suggesting the lack of excessive fluid accumulation typical of other lung injuries. Notably, autopsy studies demonstrate infection of the endothelium with extensive capillary thrombosis distinct from the embolic thrombi in pulmonary arteries. The inflammatory thrombosis in pulmonary vasculature secondary to endothelial infection and dysfunction appears to contribute to hypoxaemia. This is associated with elevated D‐dimers and acquired hypercoagulability with an increased risk of deep vein thrombosis. Hypercoagulability is secondary to elevated plasma tissue factor levels, von Willebrand factor, fibrinogen, reduced ADAMTS‐13 with platelet activation and inhibition of fibrinolysis. Multi‐platform randomised controlled studies of systemic therapeutic anticoagulation with unfractionated and low molecular mass heparins demonstrated a survival benefit over standard care with full‐dose anticoagulation in patients with non‐severe disease who require supplemental oxygen, but not in severe disease requiring ventilatory support. Late intervention and the heterogeneous nature of enrolled patients can potentially explain the apparent lack of benefit in severe disease. Improvement in oxygenation has been demonstrated with intravenous fibrinolytics in small studies. Inhaled anticoagulants, thrombolytic agents and non‐specific proteolytic drugs in clinical trials for decreasing alveolar fibrin deposition might benefit early disease. Essentially, COVID‐19 is a multi‐system disorder with pulmonary vascular inflammatory thrombosis that requires an interdisciplinary approach to combination therapies addressing both inflammation and intravascular thrombosis or alveolar fibrin deposits to improve outcomes.

COVID-19 Biomarkers at the Crossroad between Patient Stratification and Targeted Therapy: The Role of Validated and Proposed Parameters

“…Autoptic studies on COVID-19 deaths have shown a great prevalence of lung microvascular thrombosis: in light of the observed disease-induced coagulopathy, many studies have described elevated D-dimer levels at admission as an independent predictor of negative disease evolution and in-hospital COVID-19 mortality [ 38 , 44 , 45 , 48 , 49 , 50 ]. On the other hand, recent studies have highlighted that D-dimer levels below the standard or age-adjusted threshold in SARS-CoV-2 patients referred to the emergency department could be considered as a predictor of a low risk for pulmonary embolism complications [ 51 , 52 ].…”

“…Even if the involvement of D-dimers in COVID-19 pathophysiology is not fully understood, it has been hypothesized that its increase is a direct consequence of microthrombosis in lung and kidney capillaries, as it should be considered that thromboinflammation is one of the host defense mechanisms commonly activated in response to viral, bacterial, and fungal pathogens [ 38 , 45 , 48 , 49 ].…”

Investigational Use of Mesenchymal Stem/Stromal Cells and Their Secretome as Add-On Therapy in Severe Respiratory Virus Infections: Challenges and Perspectives

“…The severe life-threatening manifestations of influenza and COVID-19 are associated with a dysregulated immune response and hyperproduction of proinflammatory cytokines and chemokines such as interleukin (IL)-1b, IL-6, tumor necrosis factor (TNF)-a, interferon (IFN)-c inducible protein-10, monocyte chemoattractant protein-1, and IL-8 [20][21][22][23][24][25]. The unchecked immunological/inflammatory alterations lead to further tissue damage [20][21][22][23][24][25], in addition to that caused by virus replication alone, and to increased risk of thrombosis [26] not responding to anticoagulation alone [27]. Targeting the immunological/inflammatory dysfunction with glucocorticoids, Janus kinase inhibitors, and humanized monoclonal antibodies against the IL-6 receptor (IL-6R) [28][29][30], in addition to providing maximal supportive therapy [31], significantly reduces the risk of respiratory failure and death in hospitalized patients with severe COVID-19-associated pneumonia, hypoxia, and evidence of systemic inflammation, but the residual numbers of individuals requiring IMV and dying because of respiratory failure remain elevated in the clinical trial setting [28][29][30] and in clinical practice [32].…”

Acid-Base Disturbances in Pediatrics Infected With COVID-19, A Cross Sectional Study

“…This statement is from a subset of pediatric patients who presented with multiple organ failure and severe inflammation and were diagnosed as SARS-CoV-2 positive. One of the most major complications of COVID 19 is the arterial hypoxemia, thus affecting the lung compliance which could require mechanical ventilation (6,7) . Acid base imbalance is a frequent association with patients who suffer from serious viral illnesses including COVID-19 (8) .…”