A Possible Role of Amyloidogenic Blood Clotting in the Evolving Haemodynamics of Female Migraine-With-Aura: Results From a Pilot Study

Abstract

Introduction: Migraine is a debilitating primary headache disorder with a poorly understood aetiology. An extensive body of literature supports the theory of migraine as a systemic vascular inflammatory disorder characterised by endothelial dysfunction. It is also well-known that chronic inflammation results in an excessive burden of oxidative stress and therefore cellular dysfunction. In this study the effects of excessive oxidative stress through the phases of female migraine-with-aura (FMA) were evaluated by examining the health of the systems of haemostasis.Methods: Blood was obtained from 11 FMA patients at baseline and during the headache phase of migraine, as well as from 8 healthy age-matched female controls. Samples were analysed using thromboelastography (TEG) to evaluate viscoelastic profiles, light microscopy for erythrocyte morphology, Scanning Electron Microscopy (SEM) for erythrocyte and fibrin clot structure, confocal microscopy for β-amyloid detection in fibrin clots.Results: Viscoelastic profiles from platelet poor plasma showed decreased clot reaction times in FMA at baseline (95% CI [5.56, 8.41]) vs. control (95% CI [7.22, 11.68]); as well as decreased time to maximum thrombus generation for the same comparison (95% CI [6.78, 10.20] vs. [8.90, 12.96]). Morphological analysis of erythrocytes indicated widespread macrocytosis, poikilocytosis and eryptosis in the migraineurs. Analysis of fibrin networks indicated that this hypercoagulability may be a result of aberrant fibrin polymerisation kinetics caused by the adoption of a β-amyloid conformation of fibrin(ogen).Conclusion: The results reaffirm the hypercoagulable state in migraine, and would suggest that this state is most likely a result of a systemic inflammatory state which induces oxidative damage to both erythrocytes and fibrin(ogen) in female episodic migraine-with-aura. Furthermore, if the amylodogenic changes to fibrin(ogen) were observed in a larger cohort, this would support theories of micro-embolisation in migraine-with-aura.

Erythrocyte, Platelet, Serum Ferritin, and P-Selectin Pathophysiology Implicated in Severe Hypercoagulation and Vascular Complications in COVID-19

“…In our current research, it comes as no surprise that serum ferritin levels are increased in COVID-19 blood samples, as it is known as a marker of damaged cells [31]. Its presence in the circulation may cause pathology to platelet erythrocytes, as well as the plasma protein fibrinogen [18][19][20][21][22][23][32][33][34][35][36][37][38]. Iron can also leak into the circulation due to cellular damage to not only erythrocytes but, also, endothelial and other cells.…”

The Atypical Fibrin Fibre Network in Rheumatoid Arthritis and its Relation to Autoimmunity, Inflammation and Thrombosis

“…It is apparent that our investigation into the structural properties of fibrin networks in RA and its relation to hemostatic function has a rather deceptive appearance. Our group has previously shown that fibrin networks in multiple inflammatory conditions (113,(121)(122)(123) and in plasma exposed to inflammatory stimuli (26,114,124) stain positive for amyloid-specific dyes. This constitutes the appearance of misfolded, protein aggregates with enriched β -sheet content that confers a higher degree of insolubility (125).…”

Prevalence of amyloid blood clots in COVID-19 plasma

“…Strongly bound up with the coagulopathies accompanying severe COVID-19 disease is the presence of hyperferritinaemia (in cases such as the present it is a cell damage marker (28)) and a cytokine storm, (29)(30)(31)(32)(33) which usually occurs in the later phase of the disease (16). Excess iron has long been known to cause blood to clot into an anomalous form (34), later shown to be amyloid in nature (18)(19)(20)(21)(22)(23)(24). These kinds of phenomena seem to accompany essentially every kind of inflammatory disease (e.g.…”