Major bleeding complications in critically ill patients with COVID-19 pneumonia

Abstract

As patients with COVID-19 pneumonia admitted to intensive care unit (ICU) have high rates of thrombosis, high doses of thromboprophylaxis have been proposed. The associated bleeding risk remains unknown. We investigated major bleeding complications in ICU COVID-19 patients and we examined their relationship with inflammation and thromboprophylaxis. Retrospective monocentric study of consecutive adult patients admitted in ICU for COVID-19 pneumonia requiring mechanical ventilation. Data collected included demographics, anticoagulation status, coagulation tests and outcomes including major bleeding and thrombotic events. Among 56 ICU COVID-19 patients, 10 (18%) patients had major bleeding and 16 (29%) thrombotic events. Major bleeding occurred later than thrombosis after ICU admission [17(14–23) days versus 9(3–11) days respectively (p = 0.005)]. Fibrinogen concentration always decreased several days [4(3–5) days] before bleeding; D-dimers followed the same trend. All bleeding patients were treated with anticoagulants and anticoagulation was overdosed for 6 (60%) patients on the day of bleeding or the day before. In the whole cohort, overdose was measured in 22 and 78% of patients receiving therapeutic anticoagulation during fibrinogen increase and decrease respectively (p < 0.05). Coagulation disorders had biphasic evolution during COVID-19: first thrombotic events during initial hyperinflammation, then bleeding events once inflammation reduced, as confirmed by fibrinogen and d -dimers decrease. Most bleeding events complicated heparin overdose, promoted by inflammation decrease, suggesting to carefully monitor heparin during COVID-19. Thromboprophylaxis may be adapted to this biphasic evolution, with initial high doses reduced to standard doses once the high thrombotic risk period ends and fibrinogen decreases, to prevent bleeding events.

Preventing Thrombohemorrhagic Complications of Heparinized COVID-19 Patients Using Adjunctive Thromboelastography: A Retrospective Study

“…Moreover, the early hypercoagulable state of CAC is associated with increased fibrinogen and D-dimer, and fibrinolytic shutdown has been demonstrated on TEG [ 45 , 46 , 47 , 48 ]. The hemorrhagic phenotype of CAC may correspond to the later reduction in fibrinogen synthesis as the acute inflammatory response abates, coupled with the rebalancing of the fibrinolytic system [ 10 , 16 , 26 , 46 ]. Fibrin-thrombin complexes protect thrombin from inactivation by antithrombin and have been shown to require twenty times more heparin for inactivation when compared to free thrombin [ 43 ].…”

“…In addition, low levels of antithrombin have been demonstrated in hospitalized COVID-19 patients upon admission. Because these levels also return to normal with the dissipation of the acute inflammatory response, these patients would be expected to exhibit increased heparin sensitivity [ 16 , 26 , 47 , 48 ]. We hypothesize that these combined hemostatic derangements in fibrinogen and antithrombin levels may in part explain the late development of increased heparin sensitivity and resulting hemorrhage demonstrated in some hospitalized COVID-19 patients treated with heparinoids.…”

“…Our analysis corroborates the interim findings of the mpRCT, demonstrating that full therapeutic anticoagulation may be harmful [ 17 , 52 ]. In the mpRCT, ICU level of care was defined as any patient who required high flow nasal oxygen, invasive or noninvasive mechanical ventilation, vasopressor support, or ECMO [ 16 ]. The risks of bleeding are far greater in the sicker, mechanically ventilated, and ECMO populations.…”

“…In vivo models of coronavirus infection support the concept that UFH behaves as a “decoy receptor/sink to reduce viral infectivity and potentially augment viral clearance” [ 10 , 11 ]. Despite the frequent hypercoagulable state of hospitalized COVID-19 patients and the attractive therapeutic hypothesis of heparinoids, anticoagulation is often complicated by the rapid evolution from heparinoid resistance to heparinoid hypersensitivity, which may result in major hemorrhage [ 9 , 12 , 13 , 14 , 15 , 16 ]. With little evidence early in the pandemic, institutions offered conflicting guidelines for the empiric escalation of prophylactic anticoagulation to intermediate or therapeutic doses for hospitalized patients with COVID-19 pneumonitis and without macrovascular thrombosis [ 17 , 18 , 19 , 20 , 21 ].…”

Prevention of venous thromboembolism and haemostasis monitoring in patients with COVID-19: Updated proposals (April 2021)

“…Fibrinogen, as an acute phase reactant, can decrease the efficacy of heparin infusion and lead to increased dose requirements. The decrease in fibrinogen levels can lead to unfractionated heparin overdose and bleeding complications [43] . In critically ill patients, we suggest monitoring those parameters [platelet count, prothrombin time, fibrinogen] frequently in the acute phase of the disease, for instance every 24−72 h. In ward patients, the platelet count should be monitored once or twice a week to detect heparin-induced thrombocytopaenia if standard dose unfractionated heparin is used [44] .…”