Scientific Calendar March 2025

Pathology of long COVID

Long COVID – a post-acute consequence of a severe COVID-19 infection – presents with a broad spectrum of relapsing persistent symptoms and variable levels of organ damage, which may be asymptomatic or emerge as acute events such as heart attacks, strokes or recurrent infections. The underlying pathogenic mechanisms are complex. Thrombotic endothelialitis resulting in widespread vascular dysfunction is at the core of these symptoms.

Considering this vascular pathology as a consequence of acute COVID-19 is essential for understanding the vascular abnormalities observed in long COVID, highlighting the key role of vascular injury in both phases of the disease. Persistent thrombotic endothelialitis may be the likely primary pathology driving the chronic course of long COVID, with the dysfunctional vascular endothelium being a source of ‘fibrinaloid microclots’ consisting of fibrin(ogen) molecules which have undergone a structural transformation to an amyloid structure.

These fibrinaloid microclots are small blood clots containing fibrinaloid molecules, other molecules, and other trapped proteins. These microclots exhibit resistance to dissolution as they consist not only of proinflammatory molecules such as serum amyloid A but also α2-antiplasmin and plasminogen activator inhibitor, preventing the breakdown of clots by plasmin, the key enzyme of fibrinolysis.

In addition, the thrombotic endothelialitis leads to a reduction in the density or number of capillaries (referred to as ‘capillary rarefication’). When combined with the circulating fibrinaloid microclots, this capillary rarefication can result in an imbalance between reduced blood supply and increased demand, especially during exercise, and potentially explains much of the symptoms and pathology of long COVID [1,2].

Diagnosis

Currently, the diagnosis of long COVID is mainly based on the symptoms the patient is complaining about, followed by the evaluation of medical history, physical examination, plus blood tests, imaging studies, and/or functional tests, depending on the symptoms described [3]. However, laboratory parameters such as D-dimer, von Willebrand factor, ADAMTS-13, and soluble thrombomodulin, along with flow cytometry-based methodologies to characterise immune cells and to identify, characterise, and quantify the fibrinaloid microclots might help to improve the diagnosis of long COVID and guide treatment strategies [4-6].