Could persistent extravascular fibrin deposition link microvascular and interstitial pathology in long COVID?

Long COVID is associated with persistent endothelial dysfunction, microvascular impairment, coagulation abnormalities, impaired fibrinolysis, and tissue hypoxia. Although these intravascular abnormalities are increasingly documented, less attention has been paid to whether vascular injury may also generate persistent pathology in the extravascular interstitial compartment. We propose chronic intra- and extravascular coagulation (CIEC) as a continuous pathological mechanism in which COVID-associated immunothrombosis and endothelial injury may be followed by vascular leakage, local extravascular fibrin formation, and incomplete resolution of a fibrin-containing provisional matrix. At a different level, the dual-axis microvascular-interstitial model (DMIM) describes how abnormalities on both sides of the vascular wall may interact functionally: impaired microvascular tissue supply (Axis 1) together with abnormal interstitial mechanics and diffusion (Axis 2) may contribute to tissue dysfunction and symptoms. This framework links established microvascular pathology with a proposed extravascular component and provides testable predictions for histological, biochemical, molecular-imaging, microcirculatory, and biomechanical studies in long COVID.