Frontiers in medicineOct 8, 2026

Could ongoing buildup of blood clot proteins outside vessels connect small blood vessel and tissue damage in long COVID?

Long Covid Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 9, 2026

Abstract

Long COVID is associated with persistent endothelial dysfunction and microvascular impairment.

Chronic intra- and extravascular coagulation (CIEC) may act as a continuous pathological mechanism following COVID-related endothelial injury.
COVID-associated immunothrombosis could lead to vascular leakage and local formation of fibrin outside blood vessels.
Incomplete resolution of a provisional matrix containing fibrin may contribute to ongoing health issues.
The dual-axis microvascular-interstitial model (DMIM) describes interactions between impaired blood supply and abnormal tissue mechanics.
This framework links microvascular damage with potential extravascular pathology and suggests avenues for further study.

Simplified

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.