Preprint Inflammatory Triggers, Cell Death, Membrane Damage and Lipid Asymmetry That Shape Procoagulant Surfaces for Amyloidogenic Microclotting,2025,Pretorius

[mariovitali]

Etheresia Pretorius,Chantelle Venter,Jean M. Nunes,Alain R. Thierry,Douglas B. Kell​

Abstract​

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.


Link : https://www.preprints.org/manuscript/202510.1460

 

[mariovitali]

@DMissa and @TamaraRC please have a look at this. Extensive content on the role of Phosphatidylserine (PS) and phospholipids. Also mentions efferocytosis.

 

[DMissa]

@DMissa and @TamaraRC please have a look at this. Extensive content on the role of Phosphatidylserine (PS) and phospholipids. Also mentions efferocytosis.

we have an efferocytosis lab or two next door, i will have to chat with them

 

[Violeta]

Do you think the pro resolving mediators would help dissolve the fibrinaloid microclot complexes. Or if it can't break up the clots, at least perhaps decrease the amount formed.

Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia.

The T-series of resolvins (RvTs) reduce the formation of neutrophil extracellular traps (NETs) and enhance NET clearance by macrophages​

 

[Jonathan Edwards]

Do you think the pro resolving mediators would help dissolve the fibrinaloid microclot complexes. Or if it can't break up the clots, at least perhaps decrease the amount formed.

As far as I know we still have no evidence for the existence of microclots in human beings. If they were there in blood samples they would have been centrifuged out when plasma is prepared. The 'microclots' reported appear to be in vitro artefacts. The abstract in the first post makes no sense in terms of the biology I was taught. I am not sure that anyone except Pretorius believes in it.

 

[Violeta]

Do you think the pro resolving mediators would help dissolve the fibrinaloid microclot complexes. Or if it can't break up the clots, at least perhaps decrease the amount formed.

Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia.

​

The T-series of resolvins (RvTs) reduce the formation of neutrophil extracellular traps (NETs) and enhance NET clearance by macrophages​

Neutrophil activation and neutrophil extracellular traps (NETs) in COVID‐19 ARDS and immunothrombosis​

Neutrophil activation and neutrophil extracellular traps (NETs) in COVID-19 ARDS and immunothrombosis - PubMed

Acute respiratory distress syndrome (ARDS) is an acute inflammatory condition with a dramatic increase in incidence since the beginning of the coronavirus disease 19 (COVID-19) pandemic. Neutrophils play a vital role in the immunopathology of severe acute respiratory syndrome coronavirus 2...

pubmed.ncbi.nlm.nih.gov

Acute respiratory distress syndrome (ARDS) is an acute inflammatory condition with a dramatic increase in incidence since the beginning of the coronavirus disease 19 (COVID‐19) pandemic. Neutrophils play a vital role in the immunopathology of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection by triggering the formation of neutrophil extracellular traps (NETs), producing cytokines including interleukin‐8 (CXCL8), and mediating the recruitment of other immune cells to regulate processes such as acute and chronic inflammation, which can lead to ARDS. CXCL8 is involved in the recruitment, activation, and degranulation of neutrophils, and therefore contributes to inflammation amplification and severity of disease. Furthermore, activation of neutrophils also supports a prothrombotic phenotype, which may explain the development of immunothrombosis observed in COVID‐19 ARDS. This review aims to describe hyperinflammatory ARDS due to SARS‐CoV‐2 infection. In addition, we address the critical role of polymorphonuclear neutrophils, inflammatory cytokines, and the potential targeting of CXCL8 in treating the hyperinflammatory ARDS population.

 

[Violeta]

As far as I know we still have no evidence for the existence of microclots in human beings. If they were there in blood samples they would have been centrifuged out when plasma is prepared. The 'microclots' reported appear to be in vitro artefacts. The abstract in the first post makes no sense in terms of the biology I was taught. I am not sure that anyone except Pretorius believes in it.

https://polybio.org/new-study-polybio-supported-study-identifies-microclots-endothelial-injury-markers-and-neutrophil-activation-in-children-and-young-adults-with-long-covid/

 

[Jonathan Edwards]

I am not sure what that URL is intended to imply but I am aware that there are some others teaming up with Pretorius and Kell, apparently oblviious of the fact that we have no evidence for any of this being relevant to Long Covid. All the evnets that are supposed to be involved are in the wrong tissue compartments to be so.

 

[Amw66]

As far as I know we still have no evidence for the existence of microclots in human beings. If they were there in blood samples they would have been centrifuged out when plasma is prepared. The 'microclots' reported appear to be in vitro artefacts. The abstract in the first post makes no sense in terms of the biology I was taught. I am not sure that anyone except Pretorius believes in it.

Is ttp not micro clots?

 

[Violeta]

https://polybio.org/new-study-polybio-supported-study-identifies-microclots-endothelial-injury-markers-and-neutrophil-activation-in-children-and-young-adults-with-long-covid/

"The team found that participants with Long COVID had a significantly increased burden of fibrin amyloid microclots in the blood. They also observed abnormal endothelial signaling, including increased markers of angiogenesis and vascular remodeling such as FGF-2, which correlated with microclot burden. At the same time, cell-free DNA – a marker consistent with intravascular neutrophil extracellular trap formation, or NETosis – was elevated and positively correlated with serum amyloid A, a component of microclots.

FGF-2, a cytokine involved in angiogenesis and wound healing, was significantly increased in Spike-positive versus Spike-negative patients. Importantly, the study went beyond correlation. In vitro co-culture assays showed that SARS-CoV-2 Spike protein immune complexes can trigger NETosis, which in turn contributes to endothelial injury. Taken together, the findings suggest that intravascular neutrophil activation may be a key driver of endovascular pathology in Long COVID.

The pediatric and young adult focus of the study is especially important. Because younger individuals are less likely to have the cardiometabolic and inflammatory comorbidities that often complicate interpretation in older adult cohorts, these findings strengthen the case that microclots and endothelial abnormalities are directly related to Long COVID biology rather than background age-related disease."

 

[Violeta]

Detection of Long COVID Microclots using Pulsed Speckle Contrast Optical Spectroscopy​

https://www.biorxiv.org/content/10.1101/2025.08.06.669007v1.full

"Microclots have been consistently identified in the plasma of long COVID patients and suggest a sustained imbalance in coagulation and clearance.
Similar fibrin amyloid microclots have been reported in other inflammatory and metabolic diseases, including Alzheimer’s, Parkinson’s, and type 2 diabetes, where they may impair microvascular perfusion and promote chronic inflammation.
In these contexts, microclots may act as upstream drivers of inflammation and tissue stress, through a shared mechanism of vascular occlusion and impaired perfusion."

 

[Violeta]

I am not sure what that URL is intended to imply but I am aware that there are some others teaming up with Pretorius and Kell, apparently oblviious of the fact that we have no evidence for any of this being relevant to Long Covid. All the evnets that are supposed to be involved are in the wrong tissue compartments to be so.

It's a link with some information about the topic that people who want to learn more about the topic can read.

 

[Jonathan Edwards]

Is ttp not micro clots?

Microthrombi rather than clots I think but yes microthingies. But I was referring to Long Covid and ME/CFS, where there are no clinical signs of such microthingies. If you take TTP blood and spin it I doubt you will find thingies in the plasma.

It's a link with some information about the topic that people who want to learn more about the topic can read.

Or be misinformed about it!
The things you are li'ble to read in 'scientific papers', ain't necessarily so, I am afraid.
I am not the only sceptic here. A group of eminent haemtologists wrote a letter to nature pointing out the problem with claiming there are 'clots' that I pointed out. Papers by some of these authors claim complete nonsense.

The essence of science is being critical.

 

[Jonathan Edwards]

In these contexts, microclots may act as upstream drivers of inflammation and tissue stress, through a shared mechanism of vascular occlusion and impaired perfusion."

No competent clinical pathologist would write a sentence like that. It is not just speculation, it is biological make-believe. We know what microclots do - they produce the clinical picture of diffuse intravascular coagulation, which has been well documented for decades and does not occur in Parkinson's disease, diabetes, rheumatoid arthritis or long Covid.