Pathophysiological Processes Underlying the High Prevalence of Deep Vein Thrombosis in Critically Ill COVID-19 Patients

Abstract

Coronavirus disease 2019 (COVID-19) predisposes to deep vein thrombosis (DVT) and pulmonary embolism (PE) particularly in mechanically ventilated adults with severe pneumonia. The extremely high prevalence of DVT in the COVID-19 patients hospitalized in the intensive care unit (ICU) has been established between 25 and 84% based on studies including systematic duplex ultrasound of the lower limbs when prophylactic anticoagulation was systematically administrated. DVT prevalence has been shown to be markedly higher than in mechanically ventilated influenza patients (6-8%). Unusually high inflammatory and prothrombotic phenotype represents a striking feature of COVID-19 patients, as reflected by markedly elevated reactive protein C, fibrinogen, interleukin 6, von Willebrand factor, and factor VIII. Moreover, in critically ill patients, venous stasis has been associated with the prothrombotic phenotype attributed to COVID-19, which increases the risk of thrombosis. Venous stasis results among others from immobilization under muscular paralysis, mechanical ventilation with high positive end-expiratory pressure, and pulmonary microvascular network injuries or occlusions. Venous return to the heart is subsequently decreased with increase in central and peripheral venous pressures, marked proximal and distal veins dilation, and drops in venous blood flow velocities, leading to a spontaneous contrast "sludge pattern" in veins considered as prothrombotic. Together with endothelial lesions and hypercoagulability status, venous stasis completes the Virchow triad and considerably increases the prevalence of DVT and PE in critically ill COVID-19 patients, therefore raising questions regarding the optimal doses for thromboprophylaxis during ICU stay.

Keywords: COVID-19; D-dimer; deep vein thrombosis; hemostasis disorder; venous stasis.

FIGURE 1

Factors favoring deep vein thrombosis in COVID-19 patients. (A) SARS-CoV-2 invades the endothelial cell and produces systemic and vascular inflammation leading to increased fibrinogen, CRP, IL-6, and coagulation factor V, as well as antiphospholipid antibodies possibly through molecular mimicry. Mononuclear cell inflammation, apoptosis, and necrosis were documented in the lungs; in veins, their presence was not specifically studied. SARS-CoV-2 invades the endothelial cell and determines directly and/or through systemic inflammation the exocytosis of von Willebrand factor and factor VIII from Weibel–Palade granules. (B) SARS-CoV-2 involves endothelial cells injuries (apoptosis and necrosis). (C) Mechanical ventilation, high PEEP, and immobility decrease the blood velocities of the venous return. (A–C) Complete the Virchow triad and increase the risk of thrombosis. SARS-CoV-2, severe acute respiratory syndrome–coronavirus 2 virus; IL-6, interleukin-6; CRP, C-reactive-protein; FV, coagulation factor V; FVIII, coagulation factor VIII; VWF, von Willebrand factor; PEEP, positive end-expiratory pressure; ACE2, angiotensin-converting enzyme type 2.

FIGURE 2

Ultrasound imaging of the popliteal vein. (A) The flow is characterized by the presence of a sludge consisting in the increased echogenicity of blood due to the “brightness” of the erythrocyte aggregates occurring in vessels with low blood flow velocities. (B) A calf compression is performed that provokes a sudden increase in blood flow velocities in the popliteal vein; blood becomes anechoic with the disappearance of the sludge pattern. The sludge pattern is recovered in less than 20 s after compression. In both panels, the blood is anechoic in the popliteal artery because blood flow velocities are elevated compared to the popliteal vein.