Pulmonary embolism in patients with coronavirus disease-2019 (COVID-19) pneumonia: a narrative review

The hypercoagulable state in COVID-19 was confirmed in a study by Han et al., in which higher levels of d-dimer, fibrinogen, and fibrinogen degradation products [46], prolonged prothrombin time (PT), international normalized ratio (INR), and thrombin time (TT) were also noted in patients with COVID-19 [47]; these abnormalities have been associated with poor prognosis in patients infected with SARS-CoV-2 [48]. Oudkerk et al. suggest that the very high d-dimer levels observed in COVID-19 patients are not only secondary to systemic inflammation, but also reflect true thrombotic disease, possibly induced by cellular activation that is triggered by the virus [50]. Furthermore, Cui et al. demonstrated that a cut-off value of 3.0 μg/mL for d-dimer had sensitivity, specificity and negative predictive values of 76.9%, 94.9% and 92.5% to predict VTE, respectively [51]. After receiving anticoagulant therapy, the level of d-dimer decreased gradually, showing that d-dimer levels may not only predict thrombosis but also monitor the effectiveness of anticoagulant therapy. Nonetheless, d-dimer levels may not be a reliable predictor of VTE but rather a marker of poor overall outcome [4, 9] [52]. Indeed, Lionard-Lorant et al. showed that d-dimer greater than 2660 μg/L is highly sensitive (100%, 95% CI 88–100) but not specific (67%, 95% CI 52–79) to detect PE in COVID-19 patients [30]. Therefore, routine screening for VTE based on elevated d-dimer levels was not recommended in the most recent guidelines of the ISTH [49].

Viral infections may predispose to VTE [51], activating systemic inflammatory response that in turn causes an imbalance between procoagulant and anticoagulant effects [52]. Coagulation pathways and immune system are strictly linked. Clot formation should limit the loss of blood and immune components [53]. Meanwhile, a blood clot can slow down microorganism invasion of the circulation [53]. Indeed, immunocompromised individuals have been suggested to have had less pulmonary complications when infected with COVID-19 [53]. Thrombin and platelets play a key role in the relationship between immune system and coagulation. On the one hand, thrombin directly links the clotting pathways to the innate immune response [54]. On the other hand, various granular constituents of the platelets show antimicrobial and chemotactic properties [55]. The interaction between coagulation and inflammatory pathways in the bronchoalveolar compartment, also known as the “bronchoalveolar hemostasis” [56] could partially explain thrombotic complications in COVID-19 patients.

At least two main phenotypes of COVID-19 patients with thrombotic lung injury can be identified: patients affected by “ordinary” VTE and patients showing pulmonary microthrombosis (PMT). Since DVT or other sources of VTE were not consistently found in COVID-19 patients with PE, PMT could be the result of local hypercoagulability rather than secondary to embolization from the lower limbs [53]. Formation of thrombi in the microvasculature may be a part of the physiological effort to limit the viral load. Indeed, viral invasion induces an intense inflammation of the lungs which in turn triggers a local activation of hemostasis driven by the interaction between platelets and endothelium [53]. It has been speculated that a possible cornerstone of microthrombi generation during COVID-19 is related to endothelial cells’ dysfunction [57, 58].

Interestingly, the coagulation activation pattern in COVID-19 ARDS patients in the ICU was not the same as in non-COVID-19 ARDS patients [31]. Whereas d-dimers levels were less elevated, PT, activated partial thromboplastin time (aPTT), and AT were within normal ranges, and fibrinogen was higher. This pattern differs also from that observed in patients with septic shock, who frequently develop disseminated intravascular coagulation (DIC) [59], Helms et al. reported that no COVID-19 patient was diagnosed with DIC using ISTH “overt” score [31]. The underlying mechanisms of COVID-19-induced coagulopathy may be, therefore, different from that reported in other patients with sepsis. This may also explain the different phenotypes observed in COVID-19 patients, with predominant thromboembolic manifestations rather than bleeding tendency.

Several mechanisms may contribute to a hypercoagulable state [60] and PMT during COVID-19 [46] (Fig. 1). First, the direct and indirect pathologic consequences of COVID-19, such as severe hypoxia, preexisting comorbidities, and associated organ dysfunction can predispose to hemostatic abnormalities, including DIC [47]. Hypoxia can predispose to thrombosis by increasing blood viscosity and via a hypoxia-inducible transcription factor-dependent signaling pathway [61]. The risk of VTE is also associated with individual patient-related risk factors, such as age, immobilization, obesity, past history of personal or familial VTE, cancer, sepsis, respiratory or heart failure, pregnancy, stroke, trauma, or recent surgery. ICU-specific risk factors may also contribute to this risk, including but not limited to sedation, immobilization, vasopressor administration, and use of central venous catheters [60]. Second, endothelial dysfunction, von Willebrand factor (vWF) elevation, Toll-like receptor activation, and tissue-factor pathway activation [62] may induce proinflammatory and procoagulant effects through complement activation and cytokine release [50], resulting in a dysregulation of the coagulation cascade with the subsequent formation of intra-alveolar or systemic fibrin clots. This may be explained, at least in part, by the increased plasminogen activator inhibitor 1 (PAI-1) levels with subsequent decrease of the fibrinolytic activity in these patients [63]. Helms et al. analyzed the occurrence of thromboembolic events in all patients admitted to four French ICUs for COVID-19-associated ARDS [31]. They noted that vWF activity and vWF antigen (vWF:Ag) were considerably increased, as was factor VIII. Furthermore, 50 of the 57 patients tested (87.7%) had positive lupus circulating anticoagulants during their ICU stay. Third, the release of high plasma levels of proinflammatory cytokines (IL-2, IL-6, IL-7, IL-8, granulocyte colony-stimulating factor, interferon gamma-induced protein 10 (IP10), monocyte chemotactic protein-1 (MCP1), macrophage inflammatory protein 1A (MIP1A) and tumor necrosis factor (TNF-α)—the so-called “cytokine storm”, which is a common feature of sepsis—cause secondary development of hemophagocytic lymphohistiocytosis with activation of blood coagulation, increased risk of intravascular microthrombosis and secondary local consumption coagulopathy [50], promoting the occurrence of VTE. Finally, the interactions between different types of blood cell (macrophages, monocytes, endothelial cells, platelets and lymphocytes) could play a critical role in the procoagulant effect of viral infections. For example, platelet activation upon antigen recognition may facilitate the pathogen’s clearance by white blood cell activation and clot formation [62]. This may be modulated by the neutrophil extracellular traps (NETs), which are induced by platelets and play an important role in sepsis-associated hypercoagulability [64]. In agreement with this assumption, Middeldorp et al. found that white blood cell count, higher neutrophil-to-lymphocyte ratio and a higher d-dimer level are independent risk factors associated with VTE [37].

Endothelial cells represent almost a third of the cells in the broncho-alveolar units [65]. Endothelial dysfunction refers to a systemic condition in which the endothelium loses some its physiological properties such as promoting vasodilation, fibrinolysis, and anti-aggregation [65]. This condition could be induced in COVID-19 patients through general and virus-related factors. Comorbid conditions, such as hypertension, diabetes and acute kidney injury are usually linked to endothelial damage and may, therefore, promote COVID-19-related complications [65]. Virus-related factors may also induce endothelial damage through direct viral penetration in endothelial cells, the effects of cytokines on the endothelium, and the release of von Willebrand factor by endothelial cells. Endothelial cells possess the key receptors for the SARS-CoV-2 (i.e., the angiotensin-converting enzyme-2 receptors), that facilitate viral penetration [66]. They also express other receptors shared with SARS-CoV-2, such as serine protease 2 and sialic acid receptors [58]. Accordingly, endothelial cell infection results in some cytopathic modifications following viral penetration. In particular, vascular obliteration and thrombosis of small and middle size vessels are common findings in PMT secondary to COVID-19. Furthermore, the proinflammatory cytokines released in patients with COVID-19 promote vascular endothelial cell apoptosis, PMT, vascular leakage, alveolar edema, and ultimately hypoxia [66]. Proinflammatory cytokines can also increase the expression of adhesion molecules that in turn results in endothelial activation, procoagulant effects and pro-adhesive changes [67]. All these molecular changes can impaire microvascular flow and, consequently, alter ventilation/perfusion ratio. It has been also postulated that endothelial damage and PMT could be induced by an imbalance between insufficient ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) and excessive exocytosis of ultra large von Willebrand factor multimers (ULVWF) from Weibel–Palade bodies present in endothelial cells [57]. ULVWF are anchored to the endothelial surface and can recruit platelets inducing microthrombogenesis [57]. Subsequently, platelets are rapidly activated causing platelet aggregation and leukocytes recruitment in a P-selectin-dependent manner [57]. These aggregates continue to grow until they become sufficiently large to induce extended PMT.