Pulmonary thrombosis in situ is a pathological condition nonrelated to embolism from deep vein thrombosis (DVT) in the lower extremities [13]. Nonpulmonary in situ thrombosis in the right ventricle was also described in COVID-19 patients [14,15]. COVID-19-associated pulmonary intravascular coagulopathy is a complex disease “orchestrated” by a severe and dysregulated proinflammatory response that can lead to immunothrombosis [2,16]. The prothrombotic state in patients with COVID-19 is reminiscent of this immunothrombosis process, a result of the crosstalk between the immune and hemostatic systems and characterized by the production of microthrombi in small capillaries, in which endothelial cells (ECs) adopt a proadhesive phenotype in contact with SARS-CoV-2 [17,18,19]. Pathological studies showed multiple microthrombi in pulmonary capillaries and larger primary thrombi in arterioles considered to be primary in nature [15]. Autopsy lung samples from patients with COVID-19 showed important circulatory changes with inflammation-dependent intravascular thrombosis, direct pathological evidence for immunothrombosis, which were not found in other organs such as heart, brain, and kidneys [15]. There is a concept of a local lung-associated coagulation system, the “bronchoalveolar hemostasis” and the formation of blood clots in the microvasculature of the lungs could be a part of the host immune defense against SARS-CoV-2 [20,21]. Immunothrombosis is an interplay between systemic and lung inflammatory pathways and coagulation/fibrinolysis systems (Figure 1).

In patients with in situ pulmonary thrombosis, in-depth immune pathology analysis by immunohistochemistry supports the inflammatory nature of arterial thrombi composed of white blood cells, especially neutrophils, CD₃⁺ and CD₂₀⁺ lymphocytes, fibrin, red blood cells, and platelets, but not megakaryocytes [16]. Regional thrombosis of the lung microvasculature also showed compressed deformed red blood cells (RBCs), including polyhedrocytes and different morphological types of fibrin structures coated with sparse spherical microparticles, which could comprise virions or cellular ectosomes [15]. Different phenotypes of in situ thrombosis may exist and need different intensity of anticoagulant therapy [22].

Severe COVID-19 is characterized by a proinflammatory state and an associated disbalance in hemostasis, which starts with the disruption of the alveolar epithelium, and involves intrinsic and extrinsic coagulation pathways, neutrophil extracellular traps (NETs) activation and release (NETosis), and impaired fibrinolysis secondary to high plasminogen activator inhibitor 1 (PAI-1) levels [18]. Acute respiratory failure in patients with severe COVID-19 is associated with diffuse alveolar damage, perialveolar microangiopathy, and obstructive neoangiogenesis [18,23,24,25,26,27,28,29,30]. In situ pulmonary thrombosis may appear in COVID-19 pneumonia patients, with peripheral distribution, either within the consolidation lesions of the infected lungs (due to active local inflammation), or in nonconsolidation areas (due to hypercoagulability caused by systemic inflammation) [22]. Systemic inflammatory markers such as C-reactive protein (CRP) have higher values in patients with COVID-19-associated pulmonary artery thrombosis compared with those without pulmonary thrombi [31,32,33,34]. Inflammatory-mediated thrombosis is also supported by the similarity in terms of comorbidities and other classical risk factors for venous thromboembolic disease in patients with and without COVID-19-associated pulmonary thrombosis [31,32]. Elevated serum levels of CRP are associated with thrombotic disease and mortality in COVID-19 patients [35,36,37,38]. Moreover, CRP is an important link between inflammation and thrombosis, as it can activate the complement cascade, induce platelet adhesion to ECs, stimulate tissue factor (TF) expression by blood monocytes, and alter the fibrinolytic balance of ECs [39]. Ferritin, another inflammatory biomarker, is also an independent predictive factor for both venous thrombotic events, especially pulmonary thrombosis, and also mortality, in COVID-19 patients [6,40,41]. Ferritin induces mitochondrial dysfunction in platelets, and this could also contribute to inflammation and thrombosis [2].