Thrombotic and bleeding complications in patients with chronic lymphocytic leukemia and severe COVID-19: a study of ERIC, the European Research Initiative on CLL
Authors: Antic Darko , Milic Natasa , Chatzikonstantinou Thomas , Scarfò Lydia , Otasevic Vladimir , Rajovic Nina , Allsup David , Alonso Cabrero Alejandro , Andres Martin , Baile Gonzales Monica , Capasso Antonella , Collado Rosa , Cordoba Raul , Cuéllar-García Carolina , Correa Juan Gonzalo , De Paoli Lorenzo , De Paolis Maria Rosaria , Del Poeta Giovanni , Dimou Maria , Doubek Michael , Efstathopoulou Maria , El-Ashwah Shaimaa , Enrico Alicia , Espinet Blanca , Farina Lucia , Ferrari Angela , Foglietta Myriam , Lopez-Garcia Alberto , García-Marco José A. , García-Serra Rocío , Gentile Massimo , Gimeno Eva , da Silva Maria Gomes , Gutwein Odit , Hakobyan Yervand K. , Herishanu Yair , Hernández-Rivas José Ángel , Herold Tobias , Itchaki Gilad , Jaksic Ozren , Janssens Ann , Kalashnikova Olga B. , Kalicińska Elżbieta , Kater Arnon P. , Kersting Sabina , Koren-Michowitz Maya , Labrador Jorge , Lad Deepesh , Laurenti Luca , Fresa Alberto , Levin Mark-David , Mayor Bastida Carlota , Malerba Lara , Marasca Roberto , Marchetti Monia , Marquet Juan , Mihaljevic Biljana , Milosevic Ivana , Mirás Fatima , Morawska Marta , Motta Marina , Munir Talha , Murru Roberta , Nunes Raquel , Olivieri Jacopo , Pavlovsky Miguel Arturo , Piskunova Inga , Popov Viola Maria , Quaglia Francesca Maria , Quaresmini Giulia , Reda Gianluigi , Rigolin Gian Matteo , Shrestha Amit , Šimkovič Martin , Smirnova Svetlana , Špaček Martin , Sportoletti Paolo , Stanca Oana , Stavroyianni Niki , Te Raa Doreen , Tomic Kristina , Tonino Sanne , Trentin Livio , Van Der Spek Ellen , van Gelder Michel , Varettoni Marzia , Visentin Andrea , Vitale Candida , Vukovic Vojin , Wasik-Szczepanek Ewa , Wróbel Tomasz , Segundo Lucrecia Yáñez San , Yassin Mohamed , Coscia Marta , Rambaldi Alessandro , Montserrat Emili , Foà Robin , Cuneo Antonio , Carrier Marc , Ghia Paolo , Stamatopoulos Kostas 
Published: August 2022

Abstract
Background
Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19.

Methods
This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting.

Results
A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C-reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017–1.109 and OR = 2.438, 95%CI 1.023–5.813, respectively).

Conclusions
Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration.