key: cord-0973259-matfhcdk
authors: Kessler, Chiara; Stricker, Hans; Demundo, Daniela; Elzi, Luigia; Monotti, Rita; Bianchi, Giorgia; Llamas, Michael; Spinedi, Luca; Rossi, Davide; Chiesa, Alessandro Felice; Pagnamenta, Alberto; Conti, Marco; Casso, Gabriele; Stoira, Elisa; Valenti, Elisa; Colucci, Giuseppe; Stussi, Georg; Gerber, Bernhard; Previsdomini, Marco
title: Bleeding prevalence in COVID-19 patients receiving intensive antithrombotic prophylaxis
date: 2020-08-14
journal: J Thromb Thrombolysis
DOI: 10.1007/s11239-020-02244-y
sha: 48ca86e24a5b6bfd4eb9201a1b60d43d4ead1cb2
doc_id: 973259
cord_uid: matfhcdk

nan

In-hospital patients with severe acute respiratory syndrome coronavirus 2-induced disease (COVID-19) have a high risk of thrombosis [1] [2] [3] [4] . Pharmacological thromboprophylaxis is strongly encouraged, and several experts even suggest the use of high-dose prophylaxis or full anticoagulation for patients with severe disease at low risk of bleeding, but up to now, data on safety of this approach are lacking [1, [5] [6] [7] [8] .

Here, we report observational single-center prevalence of major bleeding events (ISTH definition, Table S1) in patients with COVID-19 receiving intensive thromboprophylaxis [9] . We included all consecutive adult patients with laboratoryproven COVID-19 treated between April 1st and May 6th 2020 at the Hospital La Carità, Locarno, Switzerland. On April 1st 2020, we have implemented the following intensive thromboprophylaxis scheme: Patients with COVID-19 with an estimated glomerular filtration rate (eGFR) ≥ 30 ml/ min/1.73 m 2 received subcutaneous enoxaparin twice daily (BID) at a dose of 40 mg (< 80 kg), or 60 mg (≥ 80 kg) for a minimum of 14 days (dose level 1). Dose escalation to 60 mg BID (< 80 kg), or 80 mg BID (≥ 80 kg) was discussed if D-dimer levels increased during follow-up > 2.0 mg/L, irrespective of the presence of thromboembolic complications (dose level 2). Patients with COVID-19 with an eGFR < 30 ml/min/1.73 m 2 received subcutaneous UFH at a dose of 5000 IU three times a day in the regular ward, or continuous intravenous UFH in the intensive care unit (ICU) with a target anti-Xa activity of 0.3-0.5 U/ml. The study was approved by the Ethical Committee Ticino, Switzerland (2020-00838 RIF.CE 3621).

A total of 270 inpatients with confirmed COVID-19 were eligible for this analysis. 22 (8.2%) patients received regular thromboprophylaxis with once daily enoxaparin 40 mg or UFH 5000 IU two times a day, 183 (67.8%) patients received the intensified thromboprophylaxis, and 65 (24%) patients had full anticoagulation (Table 1) . Of the 65 patients with therapeutic anticoagulation, 20

Bernhard Gerber and Marco Previsdomini contributed equally and are listed alphabetically.

The online version of this article (https ://doi.org/10.1007/s1123 9-020-02244 -y) contains supplementary material, which is available to authorized users. Table 1 Characteristics of patients with COVID-19 with and without major bleedings WHO World Health Organization, ARDS acute respiratory distress syndrome, UFH unfractionated heparin, LMWH low molecular weight heparin, DOAC direct oral anticoagulant, VKA vitamin K antagonist, OD once daily, BID two times per day, TID three times per day, INR international normalized ratio, anti-Xa anti-activated coagulation factor X activity, ICU intensive care unit (30.7%) patients had prior anticoagulation for atrial fibrillation (Afib) (n = 17, 26.2%) and for venous thromboembolism (VTE) (n = 3, 4.6%) unrelated to COVID-19. During follow-up, 73 (27%) patients underwent dose escalation from regular prophylaxis or dose level 1 to dose level 2, or to full anticoagulation. Reasons for dose escalation were increasing d-dimer levels (n = 31, 11.5%), acute VTE (n = 36, 13.3%), and newly diagnosed Afib (n = 6, 2.2%). Four (2.2%) bleedings, all retroperitoneal, were observed in the 183 patients receiving intensified prophylaxis (Table S2 ). Three out of these four patients had concomitant anti-platelet therapy. 10 (16.6%) bleedings occurred in patients receiving full anticoagulation because of Afib, catheter-associated thrombosis or pulmonary embolism (Table S2) . No patient had overt disseminated intravascular coagulation or heparin-induced thrombocytopenia. Fatal bleeding occurred in none of the 183 patients receiving intensive thromboprophylaxis, and in three (4.6%) of the 65 patients with full anticoagulation.

The observed bleeding prevalence in patients with COVID-19 receiving high-dose thromboprophylaxis is two-fold higher when compared to medically ill patients receiving standard dose thromboprophylaxis, but lower than the 5.5% major bleeding rate in critically ill medical patients receiving standard dose thromboprophylaxis [10, 11] . Patients with COVID-19 who receive full-dose anticoagulation are at higher risk of major bleeding. Preventing the need for therapeutic anticoagulation is therefore a major goal of thromboprophylaxis. The predominance of intramuscular hemorrhage with two thirds of the bleedings localized in the retroperitoneum, the gluteal and the thigh muscles warrants further investigation (Table S2) . SARS-CoV-2 induced muscle necrosis, and vasculopathy might contribute to this bleeding phenotype [12] [13] [14] .

In conclusion, our data are reassuring and supportive of intensive thromboprophylaxis for hospitalized patients with COVID-19. Most major bleedings occurred after two weeks of hospitalization, and dose de-escalation after the first 10 to 14 days might be considered in patients with a favorable clinical course. Prospective trials are required to optimize patient selection, dosing and treatment duration for patients with COVID-19.

COVID-19 and its implications for thrombosis and anticoagulation

Coagulation abnormalities and thrombosis in patients with COVID-19

Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia

Incidence of venous thromboembolism in hospitalized patients with COVID-19

COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients

Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients

Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis

Dalteparin versus unfractionated heparin in critically ill patients

Autopsy findings and venous thromboembolism in patients with COVID-19

Endothelial cell infection and endotheliitis in COVID-19

Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19

Clinical Management of COVID-10 -Interim guidance

The authors thank all colleagues and staff mem-