Coagulation and Rheological Abnormalities
1 Hypercoagulability
Converging evidence from haematology, proteomics, and functional assays documents a prothrombotic, procoagulant state in ME/CFS.
Nunes et al. (2022) (Nunes et al. 2022) provided the first quantitative characterisation of haematological pathology in ME/CFS specifically. Key findings in 25 ME/CFS patients vs. controls:
- Platelet hyperactivation: Mean spreading score 2.72 ± 1.24 vs. 1.00 for healthy controls — confirmed by PAC-1 and CD62P markers, indicating pre-activated platelets circulating in the blood
- Fibrinaloid microclots: Amyloid-resistant fibrin microclots present at more than 10-fold greater area than in healthy controls, establishing that microclot pathology is not unique to Long COVID
- Thromboelastography: Hypercoagulable state detected in approximately 50% of ME/CFS participants across multiple parameters
Plasma proteomics by Nunes et al. (2024) (Nunes et al. 2024) (15 ME/CFS patients vs. 10 controls, data-independent LC-MS/MS) identified 24 significantly elevated proteins, with a coherent procoagulant pattern:
- Thrombospondin-1 (THBS1) elevated: Produced by activated endothelial cells and platelets; promotes endothelial dysfunction via pro-oxidative and proinflammatory mechanisms
- Platelet factor 4 (PF4) elevated: A platelet-released chemokine that potentiates coagulation
- P-selectin elevated: Reflects platelet and endothelial activation
- Protein S decreased: An endogenous anticoagulant; its reduction predisposes to pathological clotting
These findings were corroborated by Heng et al. (2025) (Heng et al. 2025), whose multi-omics study in 61 ME/CFS patients independently identified VWF (von Willebrand factor), THBS1, and FN1 (fibronectin 1) among the top discriminating biomarkers — convergence across independent cohorts and analytical platforms strengthens confidence in this prothrombotic signature.
2 Fibrin Deposition and Microclot Biology
Kruger et al. (2022) (Kruger et al. 2022) characterised the proteome of Long COVID microclots, finding 27 distinct immunoglobulin variants trapped within fibrin microclots absent from controls, alongside elevated VWF (2.6-fold), PF4 (3.5-fold), and reduced plasma kallikrein (4.4-fold). Entrapped pro-inflammatory molecules impair fibrinolysis from within the clot, and microclots exceeding capillary diameter (\(<\) 10~\(\mu\)m) physically obstruct capillary flow, limiting red blood cell transit and oxygen exchange.
Nunes et al. (2023) (Nunes, Kell, and Pretorius 2023) reviewed cardiovascular and haematological pathology in ME/CFS, documenting a 26% mean reduction in cerebral blood flow and orthostatic intolerance prevalence exceeding 95% in some cohorts, with microclot and platelet pathology at lower levels than Long COVID but significantly above healthy controls. Viral reservoirs (EBV, HHV-6, HHV-7) are proposed as maintenance factors that continuously reactivate coagulation through direct endothelial infection and proinflammatory cytokine release.
- Fibrinolysis resistance: Amyloid conformation renders microclots resistant to normal fibrinolytic clearance
- Oxygen delivery deficit: Modelling of comparable RBC rheological disruption in COVID-19 indicates maintaining equivalent oxygen delivery would require a \(\sim\) 135% increase in cardiac output (Rogers et al. 2024) — a physiologically impossible compensation
- Treatment implications: Anticoagulation and fibrinolytic agents have been investigated in preliminary Long COVID case series; no controlled trial data exist specifically in ME/CFS
3 Red Blood Cell Deformability and Oxygen Delivery Failure
Red blood cells must deform to traverse narrow capillaries (5–8~\(\mu\)m, smaller than the unstressed RBC diameter of \(\sim\) 8~\(\mu\)m). Impaired deformability directly reduces capillary transit velocity and oxygen delivery independently of haemoglobin concentration or cardiac output.
Saha et al. (2019) (Saha et al. 2019) demonstrated ME/CFS RBCs show approximately 12% longer capillary entry time, 17% reduced transit velocity, and 14% reduced membrane deformability, alongside 30% elevated ROS production — creating a self-amplifying cycle of oxidative membrane damage and further deformability reduction.
Guo et al. (2025) (Guo et al. 2025) provided direct capillary-level evidence using microfluidic channels (5.05\(\\times\)5.94~\(\mu\)m, matching real capillary dimensions) under controlled hypoxia (PO2 = 0–34~mmHg): ME/CFS patient RBCs showed significantly compromised capillary velocity compared to healthy controls under low oxygen tension. Critically, the hypoxia-sensing mechanism — which normally triggers local vasodilation and increased RBC flow to hypoxic tissue — was impaired in ME/CFS RBCs. This is a cell-autonomous defect in the oxygen delivery feedback loop: ME/CFS RBCs not only transit capillaries more slowly but also fail to signal for increased local perfusion when tissue oxygen falls.
Grau et al. (2024) (Grau et al. 2024) documented persistent RBC morphological abnormalities in Long COVID at mean 42 weeks post-infection — beyond the 120-day RBC lifespan — indicating ongoing production of morphologically abnormal RBCs rather than survival of initially damaged ones. Echinocytes and acanthocytes constituted 16.0 ± 9.9% vs. 2.3 ± 1.4% in controls (p \(<\) 0.0001). RBC morphological abnormality correlated with fatigue severity (r = \(-\) 0.51, p = 0.006), establishing a quantitative haematological-symptom link.
The combined picture is of multi-level oxygen delivery failure: microclots obstruct capillary lumina mechanically, abnormal RBC morphology reduces membrane flexibility for transit, impaired hypoxia-sensing prevents compensatory vasodilation, and accumulated ROS further damage already-impaired RBC membranes. Scheibenbogen and Wirth (2024) (Scheibenbogen and Wirth 2024) proposed that this chronic capillary hypoperfusion — initiating in the post-COVID or post-infectious phase — is the upstream event that eventually drives mitochondrial calcium toxicity in skeletal muscle, with ME/CFS representing the chronic phase in which mitochondrial damage has become structurally fixed (see Energy Metabolism and Mitochondrial Function, WASF3–DRP1 Convergence: Two Routes to the Same Mitochondrial Failure).