COVID‐19, thromboembolic risk, and Virchow's triad: Lesson from the past

Abstract COronavirus Infectious Disease which started in 2019 (COVID‐19) usually presents with the signs and symptoms of pneumonia. However, a growing number of recent reports highlight the fact that the infection may be by far more than only a respiratory disease. There is evidence of an increased thromboembolic risk in COVID‐19 patients, with a variety of manifestations in terms of ischemic stroke, deep vein thrombosis, acute pulmonary embolism, acute myocardial infarction, systemic arterial embolism, and placental thrombosis. The German physician Rudolph Virchow, about two centuries ago, described three pivotal factors contributing together to thromboembolic risk: endothelial injury, hypercoagulability, and blood stasis. COVID‐19‐associated hypercoagulability is unique and distinctive, and has its own features involving the immune system. Many of the drugs proposed and currently undergoing evaluation for the treatment of COVID‐19 have one or more of the Virchow's triad elements as a target. The three factors outlined by Virchow are still able to explain the venous and arterial hypercoagulable state in the dramatic COVID‐19 setting. Nowadays, we have decidedly more sophisticated diagnostic tools than Virchow had, but many of the challenges that we are facing are the same as Virchow faced in the 19th century.


| INTRODUCTION
Since its outbreak in December 2019, the world is facing a rapidly expanding pandemic owing to a new coronavirus, now named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
The SARS-CoV-2-related disease  usually presents with the signs and symptoms of pneumonia. However, several recent reports highlight the fact that the infection may be far more than only a respiratory disease, with the involvement of other organs.
The mechanism why some affected people suffer from disproportionate effect of the virus is still under debate. The patients present with or develop acute myocardial infarction, acute renal and liver injury, acute gastro-intestinal issues, skin manifestations, neurologic damage, and other pathologies. Especially among older sicker patients, a worsening clinical presentation with acute respiratory distress syndrome and multi-organ failure is seen quite often. 1

| COVID-19 AND THROMBOEMBOLIC EVENTS
There is evidence of an increased risk of intravascular clot formation and disseminated intravascular coagulation (DIC) in patients with COVID-19. Oxley et al were the first to report five cases of largevessel ischemic stroke in COVID-19 patients aged less than 50 years, with a 7-fold increase than what is normally expected. The patients had either no, or mild COVID-19 symptoms. 2 3 After that, a number of reports from around the world provided confirmation of an increased thromboembolic risk in COVID-19 patients, although with different estimates due to the different settings where the related data were gathered, that is, outpatient departments, hospital wards, or intensive care units, which influenced also the type of screening and diagnostic tests that were performed. 4 Nevertheless, the rates of all thromboembolic events appear to be quite high among patients with COVID-19, most of all in the most severe cases requiring admission to intensive care unit. [5][6][7] When focusing on each specific thrombotic event, the rate of adverse venous thromboembolic events seems to be much higher in patients with COVID-19 compared to those with non-COVID-19 infection and with acute respiratory disease syndrome (ARDS) (18.0% vs 6.0%). This difference remained statistically significant even with multivariate analysis, that is, after correcting for potential confounding factors. 8 Furthermore, studies carried out in deceased COVID-19 individuals revealed pulmonary embolism in large as well as small lung vessels, along with microangiopathy and alveolar capillary microthrombi. 9,10 At macrovascular level, deep vein thrombosis was found at autopsy in about 60% of the cases, and consequent pulmonary embolism proved to be the direct cause of death in more than a third of the patients with a diagnosis of COVID-19. Deep vein thrombosis involved the proximal and distal portion of the legs equally. 11 Even though thrombosis affects peripheral deep vein vessels the most, other regions of the body appear to be involved in patients suffering from COVID-19 pneumonia. In this respect, the incidence of peripheral arterial thrombosis inducing acute limb ischemia was reported to be significantly increased in northern Italy, one of the worst early epicenters of the pandemic in the world, with worse outcomes than would be expected. Administering antiplatelet or anticoagulant therapy was not as effective as expected. Free-floating thrombi in the thoracic aorta were described as well in these patients. 12 With respect to stroke, an incidence rate ranging from 2.5% to 6.4% has been described in COVID-19 patients. 2,3,13 Cardiovascular complications are frequent in patients with COVID-19 and a possible link between SARS-CoV-2 and acute myocardial infarction has been suggested. The latter may be the first clinical manifestation of the disease. A majority of patients with COVID- 19 have ST segment elevation on electrocardiogram, thus implying a severe transmural ischemia caused by coronary artery obstruction or rupture of a preexisting atherosclerotic plaque. 14,15 Finally, systemic thromboembolism is not rare in patients with COVID-19. A recent study carried out in the United States found that the placenta of mothers affected by COVID-19 showed thrombi in its large vessels, reduced tissue perfusion and atrophic villi. All babies were born full-term and tested COVID-19 negative-suggesting lack of a direct maternal-fetal transmission; these features were indicative of a systemic hypercoagulable state associated with COVID-19 infection. 16 All the cited studies are summarized in Table 1.

| VIRCHOW'S TRIAD
When looking for a possible pathophysiologic explanation of these observations, one should bear in mind what the eminent German physician Rudolph Ludwig Karl Virchow (1821-1902) described, about two centuries ago, three broad categories of factors contributing to thrombosis and, hence, thromboembolic risk, namely: endothelial injury, hypercoagulability, and blood stasis. 17 The definition of "Virchow's triad" was then coined later.
Coronavirus binds to the angiotensin-converting enzyme 2 (ACE-2) enzyme, which is widely expressed in multiple organs, including the lung, heart, kidney, and intestine. ACE-2 receptors are also expressed on the endothelium of blood vessels, thus allowing the virus to enter the bloodstream. 18 The presence of SARS-CoV-2 elements within endothelial cells of different organs was recently demonstrated by Varga et al. 19 Thus, the first element suggested by Virchow, that is, an endothelial injury, which is caused by SARS-CoV-2 virus occurs in One may certainly argue that Virchow's triad explains venous thromboembolic events (venous thrombosis, pulmonary embolism) better than the arterial (ischemic stroke, myocardial infarction, acute limb ischaemia), but this is not completely true. In fact, the majority of arterial thromboembolic events share the same origin, that is, the formation of a clot over an underlying atherosclerotic plaque. In most cases, the thrombus overlies a ruptured plaque or an intact plaque with superficial endothelial erosion. 23 In this respect, the first element of Virchow's triad is still in place, since SARS-CoV-2 can infect arterial endothelial cells directly, thus causing endothelial injury. For example, viral particles have been detected in endothelial cells of injured artery in a patient with past medical history of renal transplantation who passed away from COVID-19-induced multi-organ failure. 19 As soon as arterial wall is damaged, the innate immune system is activated. In particular, macrophages begin to secrete collagenases which in turn degrade collagen, a major constituent of the fibrous cap on atherosclerotic plaques, thus causing plaque rupture. Activated macrophages also release tissue factor, a potent procoagulant factor which triggers clot formation when the plaque is broken. 24 Patients with COVID-19 often have comorbidities leading to atherosclerosis, like hypertension and diabetes, and arterial plaques constitute a major risk factor for platelet adhesion leading to arterial thrombosis. SARS-CoV-2 infection is associated with platelets hyperreactivity in terms of increased aggregation, which can partially be attributed to increased mitogenactivated protein kinase activation and thromboxane generation 25 (hypercoagulability). While venous thrombi mainly consist of fibrin and red blood cells, and less by platelets, the latter are essential in arterial thrombus formation in an attempt to repair the damaged endothelium, which in turn is the main stimulus triggering platelets activation and arterial hypercoagulability. 26 As to the third element of Virchow's triad (blood stasis), there is no doubt that, when an arterial lumen is occluded partially or in entirety by an atherosclerotic plaque, blood flow at that levels slows down or is completely shut down. 27

| THERAPEUTIC OPTIONS: DO THEY HAVE VIRCHOW'S TRIAD ELEMENTS AS A TARGET?
Some of the drugs proposed for COVID-19, and others currently undergoing evaluation, may have a beneficial effect on the COVID-19-related coagulopathy, having one or more of the Virchow's triad elements as a target.

| CONCLUSION
On balance, COVID-19, the pandemic disease caused by SARS-CoV-2, is increasingly being recognized as a systemic thrombotic illness with systemic activation of the coagulation cascade and secondary DIC as well. It causes multi-organ involvement, which dramatically worsen patients' outcome.
Hypercoagulability is probably the reason why many investigators worldwide are suggesting prophylactic use of pharmacological agents against thrombosis-at a very high-dose-in COVID-19 patients especially those who are very sick, even in the absence of evidence from randomized clinical trials. 34 We suggest that the three components of the classic Virchow's triad are the basis of thrombosis in COVID-19 patients.