ME/CFS is a debilitating chronic condition that often develops after viral or bacterial infection. Insight from the study of Long COVID/Post Acute Sequelae of COVID-19 (PASC), the post-viral syndrome associated with SARS-CoV-2 infection, might prove to be useful for understanding pathophysiological mechanisms of ME/CFS. Disease presentation is similar between the two conditions, and a subset of Long COVID patients meet the diagnostic criteria for ME/CFS. Since Long COVID is characterized by significant vascular pathology - including endothelial dysfunction, coagulopathy, and vascular dysregulation - the question of whether or not the same biological abnormalities are of significance in ME/CFS arises. Cardiac abnormalities have for a while now been documented in ME/CFS cohorts, with recent studies demonstrating major deficits in cerebral blood flow, and hence vascular dysregulation. A growing body of research is demonstrating that ME/CFS is accompanied by platelet hyperactivation, anomalous clotting, a procoagulant phenotype, and endothelial dysfunction. Endothelial damage and dysregulated clotting can impair substance exchange between blood and tissues, and result in hypoperfusion, which may contribute to the manifestation of certain ME/CFS symptoms. Here we review the ME/CFS literature to summarize cardiovascular and haematological findings documented in patients with the condition, and, in this context, briefly discuss the potential role of previously-implicated pathogens. Overall, cardiac and haematological abnormalities are present within ME/CFS cohorts. While atherosclerotic heart disease is not significantly associated with ME/CFS, suboptimal cardiovascular function defined by reduced cardiac output, impaired cerebral blood flow, and vascular dysregulation are, and these abnormalities do not appear to be influenced by deconditioning. Rather, these cardiac abnormalities may result from dysfunction in the (autonomic) nervous system. Plenty of recently published studies are demonstrating significant platelet hyperactivity and endothelial dysfunction in ME/CFS, as well as anomalous clotting processes. It is of particular importance to determine to what extent these cardiovascular and haematological abnormalities contribute to symptom severity, and if these two systems can be targeted for therapeutic purposes. Viral reservoirs of herpesviruses exist in ME/CFS, and most likely contribute to cardiovascular and haematological dysfunction directly or indirectly. This review highlights the potential of studying cardiac functioning, the vasculature, and coagulation system in ME/CFS.

Understanding the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is critical for advancing treatment options. This review explores the novel hypothesis that a herpesvirus infection of endothelial cells (ECs) may underlie ME/CFS symptomatology. We review evidence linking herpesviruses to persistent EC infection and the implications for endothelial dysfunction, encompassing blood flow regulation, coagulation, and cognitive impairment—symptoms consistent with ME/CFS and Long COVID. This paper provides a synthesis of current research on herpesvirus latency and reactivation, detailing the impact on ECs and subsequent systemic complications, including latent modulation and long-term maladaptation. We suggest that the chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be partly attributable to herpesvirus-induced endothelial maladaptation. Our conclusions underscore the necessity for further investigation into the prevalence and load of herpesvirus infection within the ECs of ME/CFS patients. This review offers conceptual advances by proposing an endothelial infection model as a systemic mechanism contributing to ME/CFS, steering future research toward potentially unexplored avenues in understanding and treating this complex syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are two post-viral diseases, which share many common symptoms and pathophysiological alterations. Yet a mechanistic explanation of disease induction and maintenance is lacking. This hinders the discovery and implementation of biomarkers and treatment options, and ultimately the establishment of effective clinical resolution. Here, we propose that acute viral infection results in (in)direct endothelial dysfunction and senescence, which at the blood-brain barrier, cerebral arteries, gastrointestinal tract, and skeletal muscle can explain symptoms. The endothelial senescence-associated secretory phenotype (SASP) is proinflammatory, pro-oxidative, procoagulant, primed for vasoconstriction, and characterized by impaired regulation of tissue repair, but also leads to dysregulated inflammatory processes. Immune abnormalities in ME/CFS and long COVID can account for the persistence of endothelial senescence long past the acute infection by preventing their clearance, thereby providing a mechanism for the chronic nature of ME/CFS and long COVID. The systemic and tissue-specific effects of endothelial senescence can thus explain the multisystem involvement in and subtypes of ME/CFS and long COVID, including dysregulated blood flow and perfusion deficits. This can occur in all tissues, but especially the brain as evidenced by findings of reduced cerebral blood flow and impaired perfusion of various brain regions, post-exertional malaise (PEM), gastrointestinal disturbances, and fatigue. Paramount to this theory is the affected endothelium, and the bidirectional sustainment of immune abnormalities and endothelial senescence. The recognition of endothelial cell dysfunction and senescence as a core element in the aetiology of both ME/CFS and Long COVID should aid in the establishment of effective biomarkers and treatment regimens.

Hypercoagulability, immunothrombosis, and protein misfolding are deeply interconnected processes that converge on cell membranes as central orchestrators of thrombo-inflammation. In health, membrane lipid asymmetry, intact glycocalyx, and regulated receptor activity maintain vascular homeostasis. During inflammation or cell death, however, phosphatidylserine (PS) externalization, protein unfolding, and damage to glycosaminoglycans expose negatively charged, amyloidogenic surfaces that attract coagulation factors, inflammatory mediators, and adhesion proteins. These events generate catalytic sites for prothrombinase assembly. We review how cellular debris, microparticles, immune complexes such as neutrophil extracellular traps, and amyloidogenic plasma proteins, including serum amyloid A, interact with fibrinogen to form circulating (heterogeneous) procoagulant complexes, we term fibrinaloid microclot complexes (FMCs). Distinct from canonical fibrin clots, these FMCs display β-sheet–rich features, ThT-binding, and resistance to fibrinolysis, implicating them as key drivers of vascular pathology in inflammatory (and post-viral) syndromes. Recognizing different FMC phenotypes, mechanisms, and biochemical composition of these circulating complexes provides new insights into the pathogenesis of systemic inflammatory diseases, and highlights their potential as both diagnostic markers and therapeutic targets.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are two post-viral diseases, which share many common symptoms and pathophysiological alterations. Yet a mechanistic explanation of disease induction and maintenance is lacking. This hinders the discovery and implementation of biomarkers and treatment options, and ultimately the establishment of effective clinical resolution. Here, we propose that acute viral infection results in (in)direct endothelial dysfunction and senescence, which at the blood-brain barrier, cerebral arteries, gastrointestinal tract, and skeletal muscle can explain symptoms. The endothelial senescence-associated secretory phenotype (SASP) is proinflammatory, pro-oxidative, procoagulant, primed for vasoconstriction, and characterized by impaired regulation of tissue repair, but also leads to dysregulated inflammatory processes. Immune abnormalities in ME/CFS and long COVID can account for the persistence of endothelial senescence long past the acute infection by preventing their clearance, thereby providing a mechanism for the chronic nature of ME/CFS and long COVID. The systemic and tissue-specific effects of endothelial senescence can thus explain the multisystem involvement in and subtypes of ME/CFS and long COVID, including dysregulated blood flow and perfusion deficits. This can occur in all tissues, but especially the brain as evidenced by findings of reduced cerebral blood flow and impaired perfusion of various brain regions, post-exertional malaise (PEM), gastrointestinal disturbances, and fatigue. Paramount to this theory is the affected endothelium, and the bidirectional sustainment of immune abnormalities and endothelial senescence. The recognition of endothelial cell dysfunction and senescence as a core element in the aetiology of both ME/CFS and Long COVID should aid in the establishment of effective biomarkers and treatment regimens.

Coagulation, although primarily regulated by platelets, endothelial cells, and clotting factors, can also be influenced by molecules that are not traditionally seen as related to coagulation, including cytokines, hormones, metabolites, reactive oxygen species, acute phase reactants, and more. Here, we derive pseudoserum or clotting factor-depleted fractions from control, type II diabetes mellitus, and Long COVID platelet-poor plasma (PPP) samples, and expose them to purified, exogenous fibrinogen obtained from healthy donors. Thrombin-induced fibrin networks were then formed and visualized using light and scanning electron microscopy. The results demonstrate that pseudoserum can greatly influence the organization, density, and ultrastructure of fibrin networks formed from purified fibrinogen, emphasizing the role of non-clotting factors in fibrin formation. Fibrin networks formed from purified fibrinogen exposed to control pseudoserum appear homogeneous, exhibiting organised architecture with few regions of unusual density or aggregates, whereas the networks formed using patient pseudoserum show disorganisation, regions of density, fibre-like strands, and anomalous aggregates. These abnormalities are also observed in patient PPP samples, suggesting that fibrin network characteristics in PPP samples are also significantly influenced by non-clotting factors and are somewhat independent of endogenous fibrinogen. Furthermore, fibrinolysis was significantly reduced in the patient groups, demonstrating the ability of pseudoserum to influence the susceptibility of fibrin networks to plasmin-induced degradation. The ability of pseudoserum to drive these changes, despite the essential absence of endogenous fibrinogen and other classical clotting factors, suggests that soluble molecules retained in pseudoserum can directly modify fibrinogen's structural conformation and functionality, influence thrombin-mediated fibrin formation and polymerization, and/or impact Factor XIII's crosslinking capabilities. This study provides a systems-level perspective on the influence of pseudoserum on fibrin networks and highlights the potential of serum and other clotting factor-depleted fractions to yield deeper mechanistic and diagnostic insights into coagulation.