key: cord-0873721-gtbhb24z
authors: Moroni, Francesco; Baldetti, Luca
title: COVID-19 and arterial thrombosis: A potentially fatal combination
date: 2020-10-20
journal: Int J Cardiol
DOI: 10.1016/j.ijcard.2020.10.046
sha: f27a3c3302e4c367f68ef8a4177a8edbcc6844ef
doc_id: 873721
cord_uid: gtbhb24z

nan

In this issue of the Journal, Dr. de Roquetaillade et al. report an unusually high rate of arterial thrombosis events in a cohort of COVID-19 European patients , i.e. 24 events in 20 patients, out of a total of 209 cases managed by the Authors during the reference period. 7 While thrombotic and thromboembolic episodes frequently complicate the course of severe infectious diseases, this study, along with similar reports, suggests that several clinical and pathophysiological features differentiate those related to SARS-CoV-2 infection. 8 First, arterial thrombosis is generally a rare complication in infectious diseases. In the present work, however, the rate of arterial thrombotic and thromboembolic events was 9.6%. 7 . This figure is even higher than the 3.7-4.4% reported in the largest previously published cohorts on COVID-19 patients. 9,10 Second, clinical profile of patients who experience these complications is in line with that emerging from similar reports, suggesting that arterial thrombosis events in SARS-CoV-2 infection more frequently involve relatively young males, and occur in large arterial vessels (e.g. the aorta and the mesenteric artery) without significant pre-existing atherosclerotic burden, suggesting a causative mechanism that may be independent of thrombotic superimposition on an unstable atherosclerotic plaque. 9

Third, hemostatic derangements in critically-ill patients usually involve a combination of coagulation pathway alteration, direct platelet consumption or activation, and inflammation-mediated pro-thrombotic state resulting in disseminated intravascular coagulation (DIC). 11 On the contrary, laboratory test alterations typically hallmarking DIC, including low platelet count, prothrombin time prolongation, and fibrinogen consumption are often mild or lacking in COVID-19 patients experiencing thrombotic events. Indeed, in the study by Roquetaillade et al, no significant blood test abnormalities in coagulation parameters were found. 7 In addition, multiple thrombotic events were reported in 20% of patients 7 while no sign of venous or arterial embolism was found to justify these lesions, consistent with a primary, "in situ" phenomenon. Primitive, local thrombosis has also been postulated to relate with pulmonary circulation involvement in COVID-19. 12 Proof of direct endothelial invasion and damage by SARS-CoV-2 provides a pathophysiological backbone to these observations. 13 Indeed, the delicate balance between pro-coagulant and anti-coagulant factors requires an intact endothelium. Disruption of this layer by SARS-CoV-2 infection may thus precipitate a thrombotic cascade, both by means of inflammatory damage and, more importantly, direct cellular invasion. 13 In addition, in severely-ill COVID-19 J o u r n a l P r e -p r o o f patients, the pro-inflammatory milieu may further enhance platelet activation and thrombus formation: indeed, innate-immunity factors (including IL-1, IL-6, and TNF-α) play a proven role in atherothrombosis. 14 Prevention of these potentially fatal complications remains challenging. In this study, 50% of patients were already on prophylactic anticoagulation at the time of the events. 7 Interestingly, previous reports on venous thromboembolism in severe COVID-19 pneumonia have also showed a substantial rate of thrombotic events in spite of adequate prophylactic anticoagulation 11 . Of note, this has led to many to advocate use of therapeutic anticoagulation for thromboembolic prevention in patients with severe COVID-19 pneumonia, while others proposed an "intermediate intensity" anticoagulation regimen (enoxaparin 0.5 mg/kg twice daily). 11 Considerable disagreement on the best anti-thrombotic strategy still subsists: therapeutic anticoagulation and intermediate intensity anticoagulation were advocated by 5.2% and 31.6% of participants, respectively, in a recently published Delphi-method expert consensus on thrombotic complications preventions in severe COVID-19 pneumonia, with the rest supporting standard prophylactic anticoagulation. 15 A whole plethora of clinical trials have been set-up comparing either different anticoagulation approaches or different intensity of the same regimen ( Table 1) . Agents of interest include anti-platelets, parenteral or oral anticoagulants, and even a combination of both. Of note, whether the "in situ" nature of these arterial thrombotic events may be more sensible to anti-aggregation rather than anti-coagulation in unknown. A number of trials exploring the efficacy of aspirin, clopidogrel, dipyridamole, prasugrel and tirofiban may provide precious results to this end.

Grebe Full-dose anticoagulation + antiplatelet therapy: -UFH (targeting an aPTT of x 1.5-2.5) or enoxaparin 1 mg/kg q12h -Clopidogrel 300 mg LD, then 75 md q24h

Full-dose anticoagulation + no antiplatelet therapy: -UFH (targeting an aPTT of x 1.5-2.5) or enoxaparin 1 mg/kg q12h Prophylactic anticoagulation + antiplatelet therapy: -UFH 5000 U q8h or enoxaparin 40 mg q24h -Clopidogrel 300 mg LD, then 75 md qd Prophylactic anticoagulation + antiplatelet therapy: -UFH 5000 U q8h or enoxaparin 40 mg q24h 

Cardiovascular Implications of the COVID-19 Pandemic: A Global Perspective

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection

Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease. Circulation

Into the eye of the cytokine storm

Unusual arterial thrombotic events in Covid-19 patients

The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management

COVID-19 and its implications for thrombosis and anticoagulation

Pulmonary hypertension and right ventricular involvement in hospitalised patients with COVID-19

COVID-19 is, in the end, an endothelial disease

Therapeutic anticoagulation -Enoxaparin 1 mg/kg -UFH (titrated on aPTT or anti-Xa level) -Argatroban (in case of HIT; according to institutional protocol) -Fondaparinux q24h (in case of HIT; weight-adjusted) Rivaroxaban NCT04416048 (COVID-PREVENT) -Rivaroxaban 20 mg q24h (15 mg for subjects with an eGFR ≥30 mL/min/1.73m 2 and <50 mL/min/1.73m 2 ) for at least 7 days -Standard of care