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A Direct Relationship Between ‘Blood Stasis’ and Fibrinaloid Microclots in Chronic, Inflammatory and Vascular Diseases, and Some Traditional Natural Products Approaches to Treatment

A peer-reviewed article of this preprint also exists.

Submitted:

19 February 2025

Posted:

20 February 2025

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Abstract
‘Blood stasis’ (syndrome) (BSS) is a fundamental concept in Traditional Chinese Medicine (TCM), where it is known as Xue Yu (血瘀). Similar concepts exist in Traditional Korean Medicine ('Eohyul') and in Japanese Kampo medicine (Oketsu). Blood stasis is considered to underpin a large variety of inflammatory diseases, though an exact equivalent in western systems medicine is yet to be described. Some time ago we discovered that blood can clot into an anomalous amyloid form, creating what we have referred to as fibrinaloid microclots. These microclots occur in a great many chronic, inflammatory diseases, are comparatively resistant to fibrinolysis, and thus have the ability to block microcapillaries and hence lower oxygen transfer to tissues, with multiple pathological consequences. We here develop the idea that it is precisely the fibrinaloid microclots that relate to, and are largely mechanistically responsible for, the traditional concept of blood stasis (a term also used by Virchow). First, the diseases known to be associated with microclots are all associated with blood stasis. Secondly, fibrinaloid microclots provide a simple mechanistic explanation for the physical slowing down (‘stasis’) of blood flow. Thirdly, Chinese herbal medicine formulae proposed to treat these diseases, especially Xue Fu Zhu Yu and its derivatives, are known mechanistically to be anticoagulatory and anti-inflammatory, consistent with the idea that they are actually helping to lower the levels of fibrinaloid microclots, plausibly in part by blocking the catalysis of the polymerisation of fibrinogen into an amyloid form. We rehearse some of the known actions of its constituent herbs and specific bioactive molecules that they contain. Consequently, such herbal formulations (and some of their components), that are comparatively little known to Western science and medicine, would seem to offer the opportunity to provide novel, safe and useful treatments for chronic inflammatory diseases that display fibrinaloid microclots, including Myalgic Encephalopathy/ Chronic Fatigue Syndrome and Long COVID.
Keywords: 
blood stasis
;  
clotting
;  
amyloid
;  
fibrinaloid
;  
proteomics
;  
natural products
;  
bioactive molecules
;  
Chinese Herbal Medicine
;  
inflammation
Subject: 
Biology and Life Sciences  -   Biochemistry and Molecular Biology
Preprints 149892 i020

Introduction

Preamble, Audience, and Scope

This review integrates concepts of systems medicine from both Eastern and Western systems medicine. It is intended to be read (and readable) by scientists, clinicians and patients from very different intellectual and cultural backgrounds, and will necessarily include subsections that are completely familiar to some but entirely arcane to others. We hope that at the end readers will recognise that the discovery of fibrinaloid microclots provides a ready general explanation for the traditional, if molecularly ill-defined concept of ‘Blood Stasis’. Equivalently, the concepts (and extensive traditional knowledge) of blood stasis may provide extremely useful insights into the biology of fibrinaloid microclots and the means of treating them and the diseases with which they are associated. Our focus is on Chinese Herbal Medicine, and we acknowledge (but for reasons of scope we mainly do not rehearse) the underlying principles of Traditional Chinese Medicine (TCM) such as 5-element theory, and the analysis of pulses, meridians and Qi 1, nor do we directly consider other adjunctive treatment elements of TCM such as acupuncture, moxibustion, cupping, massage, and so on, since the focus is the mode of action of relevant Chinese herbal formulae as they relate to blood stasis. We then focus on a particular herbal formulation used to treat blood stasis, and the nature and mechanisms of the bioactive chemicals that it contains.

A Note on Systems and Personalised Medicine

Modern western medicine, especially that based on pharmaceuticals, has tended to assume (incorrectly) that a particular drug will be efficacious in all patients. Given the existence of some 25,000 genes, each with many alleles, leave aside phenotypic variations such as those based on lifestyle effects, it has always been obvious that this could not be the case (e.g. 2). As phrased by the 18th century physician Caleb Parry (quoted in 3), “It is much more important to know what kind of patient has a disease than to know what kind of disease a patient has”. This principle of personalised medicine (e.g. 4, 5) lies at the heart of TCM, and is intimately linked with equivalent western concepts such as systems biology 6-12, systems medicine 13, 14, polypharmacology 15-26, and network pharmacology 27-30. A subset of systems biology known as metabolic control analysis (e.g. 31-38) describes explicitly how and why individual reactions contribute only weakly to the control of metabolic fluxes, and why, to have big effects, one must modulate multiple reactions simultaneously. Natural evolution selects for robustness to individual insults 39, and the kinetic and architectural 40 properties of such networks tend to provide it; indeed, the interlinked kinetics of reaction networks mean that it is easy to find circumstances in which two inhibitors individually have negligible effects on a metabolic flux whereas together their effect can be massive 41, 42.
As a systems approach, Chinese herbal medicine adheres to the Jun-Chen-Zuo-Shi principle 43-47 (Westerners will find some minor variations of the Chinese characters). As phrased by 44 “The Jun (emperor) component is the principal phytocomplex targeting the major symptom of the disease. There are only a few varieties of Jun medicinals that are administered as a single formula, usually in large doses. The Chen (minister) herbs synergize with Jun to strengthen its therapeutic effects, and may also treat secondary symptoms. The Zuo (assistant) medicinal reduces or eliminates possible adverse or toxic effects of the Jun and/or Chen components, while also enhancing their effects and sometimes treating secondary symptoms. Finally, the Shi (courier) herbs facilitate delivery of the principal components to the lesion sites, or facilitate the overall action of the other components”. It is particularly interesting that the last component effectively relates to the significance of pharmaceutical drug transporter proteins, something finally being recognised more widely (e.g. 48-52) and that in fact had evolved precisely to transport natural products 53.
While recognising that TCM practitioners will vary treatments precisely to suit the individual, we do not normally have access to such information for our scientific purposes. Equally, we rarely know the multiple targets of even single pharmaceutical drugs (in 2008 the average number of known targets per drug molecule was six 54). Consequently, this review will seek to paint a big picture, recognising in particular that it is combinations of herbs affecting multiple processes that have the greatest chance of having useful effects 30, 55-59, while seeking to bring together the biochemistry of microclots (see below) with what is known of blood stasis.

Blood Stasis

“Blood stasis” (or blood stasis syndrome, BSS) is a fundamental concept in Traditional Chinese Medicine (TCM), where it is known as Xue Yu (血瘀)60. BSS refers to conditions in which the circulation of blood is not smooth or is slowed down in some way (e.g. 61, 62, and see later). It has been known (using other terms) at least from the time of The Yellow Emperor's Inner Classic (Huang Di Nei Jing) 60, 63. The same concept exists in many other traditional medicines, including Traditional Korean Medicine (where blood stasis is known as 'Eohyul' or ‘Ouhyul’) 12, 64, and in Japanese Kampo medicine (where it is termed Oketsu). Even within TCM there are similar variants (e.g. 65). Blood stasis can be caused by vascular obstruction, abnormal flow of blood, blood congestion in a viscous, and contaminated blood, has at least four subtypes 66, and is regarded as the cause or the result of a great many chronic, inflammatory diseases 67-69, that we summarise later.
Many general reviews of blood stasis exist, e.g. 61, 67, 70-75.
Traditionally, BSS is measured somewhat subjectively by a practitioner’s observation of symptoms or manifestations such as tongue colour and the results of palpations. More recently attempts have been made to objectify or quantify the extent of BSS using various kinds of scores (e.g. 63, 76-87). Blood stasis is fundamentally related to haemorheology measurements (i.e. viscosity) 80, 88, 89. We rehearse explicitly this point about scoring BSS, as such quantitative measurements (as used e.g. for scoring fatigue in long COVID 90) will be highly desirable for future studies that seek to relate microclot burden to BSS. However, such data presently do not exist.
It is also worth rehearsing here that the 19th-century physiologist Virchow recognised three factors (known as Virchow’s Triad 91-95) that contribute to the development of venous thrombosis, and these are stasis of blood flow, hypercoagulability, and endothelial injury. The significance of the terminology of the first one is not lost on us.

Fibrinaloid Microclots

Fibrinogen, one of the most abundant plasma proteins (2-4 g.L-1), has dimensions of some 5x45 nm giving a length:diameter ratio of ~9. As is well known, a key part of blood clotting involves the removal from fibrinogen by the protease thrombin of two fibrinopeptides (FpA and FpB), leading to a remarkable self-organisation in which fibrinogen molecules accrete to form far larger fibrils and protofibrils via a ‘knobs and stalks’ mechanism (Figure 1A-C). In normal clotting, the fibrinogen molecules are essentially oriented in the direction of the growing chain, that looks somewhat like cooked spaghetti in the electron microscope (EM) (Figure 1B). Other things such as erythrocytes and platelets may also be trapped, along with non-fibrin proteins whose concentrations in the clot roughly correlate with those in normal soluble plasma 96, 97.
Over a decade ago, it was discovered was that certain small molecules such as specific oestrogens 98, 99 or unliganded iron 100-105 could cause fibrinogen to form highly anomalous clots that in the EM appeared like claggy aggregations of partly boiled spaghetti, and that were referred to at the time as ‘dense matted deposits’ 102, 103, 106-108 (Figure 1C).
Subsequent studies, using the well-established 110-112 amyloid stain thioflavin T (Figure 2), as well as the commercial oligothiophene ‘Amytracker™’ stains 113, 114, showed that this anomalous clotting (i) was actually due to the conversion of the fibrin(ogen) into amyloid forms, that are characterised by crossed-b motifs that bind these stains and effect their observable fluorescence, (ii) could be induced by minuscule amounts of bacterial cell wall components (e.g. one molecule of bacterial lipopolysaccharide per 100 million fibrinogen molecules 113), and (iii) could be observed in a large variety of chronic, inflammatory diseases (e.g. 115 and Table 1). Much as with prion and other amyloid proteins 116, 117, there is no thermodynamic problem; the clotting will happen anyway and these molecules simply catalyse a different route of self-organisation that maintains the necessary close packing in the relevant macrostates.
Clearly such insoluble microclots (like other microparticulates 119, 120) can straightforwardly interfere with the flow of blood through microcapillaries, leading to a loss of O2 transfer, hypoxia, and other pathological consequences 121.
**Diseases Involving Blood Stasis in Which Raised Levels of Fibrinaloid Microclots Have Been Detected
Over the years, we and others have assessed the raised presence of fibrinaloid microclots in a series of chronic, inflammatory diseases, each of which, it transpires, is considered to involve blood stasis. Table 1 provides a summary. Note of course that many of these syndromes, especially those (as here) involving vascular issues, exhibit comorbidities because they have common causes. Diabetes and Alzheimer’s disease provide one such example 115, 122-136 of many. TCM of course recognises this explicitly, where it is known as “Treating Different Diseases with the Same Treatment” 75, 137-139.

Diseases Involving Blood Stasis Where Fibrinaloid Microclots Are Yet to Be Measured Directly

In a similar vein, effectively the converse of the above, there are many diseases involving blood stasis in which microclots have yet to be assessed, but which would make obvious objects of study from this point of view. The basic reasoning is as per the paired papers 258, 259 on amyloid clot proteomics. In the first 258, we showed that known amyloid microclots had proteomes that differed markedly from those of known (‘normal’) clots. Besides fibrin they contained various proteins that were in low concentration in soluble plasma yet lacked many that were in high concentration there. Indeed, normal clots had a proteome that roughly mirrored the soluble plasma proteome, implying a relatively weak binding or sequestration (see Figure 3). The proteins ‘enriched’ in the microclots were highly amyloidogenic, suggesting that they were actually incorporated into the fibrils via the cross-b motifs common to all amyloids. The second paper 259 asked the ‘inverse’ question, i.e. if we know the composition of the clot proteome in various thrombotic diseases can we predict whether or not the clot is amyloid(ogenic)? In all cases the answer was that these clots should indeed be amyloid, which can thus be tested (and in the case of ischaemic stroke had been 236).
Table 2 gives a listing of various vascular and thrombotic diseases that are known from TCM to be associated with blood stasis but are not in Table 1, along with some mechanistic comments that suggest that such studies to assess whether or not the microclots were both present and amyloid in character in these diseases would likely be attended with success.
These all tend to be systems diseases, and so the different components of herbal preparations will tend to interrogate different elements of what has been disrupted. An example from traumatic brain injury 363 is given in Figure 4, and one from Long COVID, showing the multiplicity of symptoms, in Figure 5.

Cancer and Classical Amyloidoses

We did not include the classical amyloidoses in the above Table (though Alzheimer’s and Parkinson’s, listed in Table 1, would certainly fall into those categories), not least because there are a great variety of them 366, 367, cross-seeding is commonplace (e.g. 258, 368), and they deserve a separate treatment in their own right. Similarly, cancer is a topic that is so broad and massive that it too deserves (and will receive) a separate treatment. Consequently, we here note only three things:
(i)
Cancer, particularly pancreatic cancer (PDAC), is strongly linked to thromboembolic states 369-386, with thrombotic events often leading to a worse outcome.
(ii)
Cancer is strongly associated (as is Long COVID) with fatigue 387-394
(iii)
Unsurprisingly, therefore, cancers are strongly associated with blood stasis 62, 65, 71, 300, 395-402

Amyloid Nature of the Blood Clots in Blood Stasis

While we are not aware of any measurement of the amyloid nature (or otherwise) of microclots in samples characterised by CHM practitioners as involving blood stasis, proteomics can on its own predict whether a clot is likely to be normal or amyloid in character 258, 403, and all the recent assessments of the microclots occurring in these various diseases shows that they are amyloid in character. Such proteins (that include prions and prionoids) are well known, because of the cross-b sheet motifs, to be rather resistant to most proteases 404-410. This, together with the presence of various anti-fibrinolytics trapped in such clots 168, 169, provides a ready explanation for the failure to remove them, such that they can contribute strongly to the phenomena of blood stasis.

A focus on Xue Fu Zhu Yu

Having established the consonance between cases (accompanied by inflammation and coagulopathies) where fibrinaloid microclots have been measured, and the co-existence of blood stasis as defined within TCM, it is of interest to begin to understand what these various herbs may be doing. As mentioned, even single pharmaceutical drugs have multiple known targets 54; in some cases (such as statins, reviewed in 411) the so-called ‘off-target’ effects are actually largely responsible for the efficacy of the drug in terms of increasing longevity. Consequently, deconvolving accurately what everything is doing within a Chinese herbal medicine cocktail is going to be very difficult. However, this does not mean that some progress cannot be made in terms of establishing components that e.g. are anti-inflammatory or anti-oxidant, and 296 provides a nice example for pulmonary fibrosis. To rehearse again, it is by hitting these multiple targets simultaneously that one can expect and find that the formulae are efficacious.
Xue-Fu-Zhu-Yu (sometimes XueFu ZhuYu, Zuefuzhuyu) is a herb combination designed to boost Qi and remove blood stasis 412-417. Xuefu Zhuyu Decoction (Xuefu zhuyu tang, XFZYD) is used explicitly for a variety of coronary diseases 263, 268, 270, 271, 301, 303, 312, 418-434 (notably a decreased mortality from ischaemic heart disease more than 4-fold 435), as well as traumatic brain injury 45, 361, 436-447, NAFLD 331, 448, deep vein thrombosis 316, fibrosis 449, ischaemic stroke 431, 450, 451, COPD 295, sepsis 196(including a five-herb injectable variant known as Xuebijing (XBJ, see below) 197 , 198-205, 206 , 207-216, 217 , 218-222), amyloidogenesis 144, myocardial fibrosis 421, dysmenorrhea 317, 319, 320, hypertension 452, and tumours 453.
For illustrative purposes, we are therefore going to concentrate on Xue Fu Zhu Yu (血府逐瘀); ‘Blood stasis-expelling decoction’ or Stasis in the mansion of blood’), since – while others such as Danshen-Chuanxiong) are certainly in use against some diseases of blood stasis (e.g. 454-456) this formula https://sys02.lib.hkbu.edu.hk/cmfid/details.asp?lang=eng&id=F00115 (accessed 6/2/2025) is among those most commonly used to treat blood stasis 414, 457, 458.
The aim is to indicate the kind of knowledge we presently have of the most significant chemical components in each herb, while recognising that some modest variations would likely be prescribed for individuals who are physically seen by a Chinese Medical Herbalist.
Xue Fu Zhu Yu, also known as Xuefu Zhuyu, has 11 herbal components 459-461. Proportions vary, but we give the percentages in a particular preparation of which we are aware. The ingredients are Semen persicae aka Prunus persica = peach seed (Tao Ren) 16%, Radix rehmanniae from Rehmannia glutinosa Libosch (Di Huang or Sheng Di depending on whether dried or fresh) 12%, Radix Achyranthis Bidentata or Cyathulae Radix (Niu Xi) 12%, Radix Angelicae sinensis (Chinese angelica)(Dang Gui) 12%, Flos carthami aka safflower (Hong Hua) 12%, Fructus aurantia (Zhi Qiao) 8%, Radix paeoniae rubra Chi Shao) 8%, Radix platycodonis (Jie Geng) 6%, Rhizoma chuanxiong (= Ligusticum chuanxiong) or Szechaun lovage roots 6%, Radix glycorrhizae (Chinese licorice)(Gan Cao) 4%, Radix Bupleuri (Chinese Thorawax Root)(Chai Hu) 4%. We note also that Angelica sinensis also houses endophytic fungi that can have great effects on the metabolome 462. (Xuebijing is an injectable subset of Xue Fu Xhu Yu plus Danshen (Salviae Miltiorrhizae Radix et Rhizoma).composed of five Chinese herbs, which are Honghua (Carthami Flos), Chishao (Paeoniae Radix Rubra), Chuanxiong (Chuanxiong Rhizoma), Danggui (Angelicae Sinensis Radix) and Danshen (Salviae Miltiorrhizae Radix et Rhizoma), particularly used against sepsis 207, 216. A recent study 219 selected hydroxysaffron yellow A (HSYA), vanillin, ligustilide, paeoniflorin and other substances as the main active ingredients of XueBijing through a comprehensive analysis of metabolomics and network pharmacology. Among them, HSYA showed outstanding performance in promoting endothelial cell proliferation 219.
According to https://sys02.lib.hkbu.edu.hk/cmfid/details.asp?lang=eng&id=F00115 (and using slightly different names), within the Jun-Chen-Zuo-Shi (Emperor-Minister-Assistant-Courier) principle mentioned above, the components are considered to be: Tao Ren and Hong Hua as Emperor; Chi Shao, ChuanXiong and Niu Xi as Minister; Sheng Di, Danggui, Jie Geng, Zhi Qiao and Chai Hu as Assistant; and Gan Cao as Courier.
**Bioactive molecules in Xue Fu Zhu Yu
We now look at some of the molecules that are considered to be actives within the different herbs (Table 3). While this is likely to be far from complete, it shows clearly the known and multiple effects of some of the major bioactive components in the herbs comprising Xue Fu Zhu Yu.
What is also clear is that there is a wealth of literature in some cases and a dearth in others, and comparing subsets of the mixtures leads to an infeasible combinatorial explosion 566. There are also some consonances, with molecules or classes being common to more than one of the herbs (Table 3), and of course it is well known that natural products can make for successful drugs, even in western medicine (e.g. 567-571). It is also of interest that the triterpenoid saponins (platycodins, saikosaponins and glycyrrhizin), molecules of increasing importance in natural products drug discovery 572-575, can also contain most or all of a steroid nucleus 576-580, and have good bioavailability 581(probably through their chemical relatedness to steroids and bile acids 582, 583 584). Importantly, such triterpenoids may inhibit toxic amyloidogenesis (e.g. 585-616), and indeed appear in other herbal formulae for stimulating blood circulation in blood stasis syndrome (e.g. 617-621).
To avoid cluttering up Table 3, chemical structures of some of the main components of the herbs in Xue Fu Zhu Yu are given in Table 4.
What is also clear from Table 4 is the large number of different chemical structures of even the main, known bioactives in Xue Fu Zhu Yu, as well as their multiple targets (Table 3). Natural products tend to be larger than purely chemical drugs 622-631, which may imply that they have even more targets than the average of six mentioned above for pharmaceutical drugs 54. While little is known of the transporters responsible for their uptake into cells, it is known that pharmaceutical drugs that are taken up do mimic natural products 53.

Mechanism(s) of Action of Xuefu Zhuyu Decoction

For illustrative purposes, these include at least the following:
1.Neuroprotective effects: XFZYD may exert neuroprotective effects by regulating miRNA expression and promoting synaptic remodelling. A study found that XFZYD could reverse the reduction of BDNF and TrkB in the hippocampus caused by Traumatic Brain Injury, and increase the number of synaptic connections, as well as the expression of synaptic-related protein PSD95, axon-related protein GAP43, and neuron-specific protein TUBB3 446.
2.Anti-inflammatory effects: Multiple studies have shown that XFZYD has anti-inflammatory effects. In an alopecia model, XFZYD can significantly inhibit the levels of IL-6, IL-1β, and TNF-α in serum and skin tissue 632.
3.Promoting angiogenesis: A study evaluated the angiogenic effect of XFZYD using a PTK787-induced segmental vascular injury zebrafish model. Through various analytical methods, seven active components promoting angiogenesis were identified, including ferulic acid, paeoniflorin, and hesperidin 633.

Summarising and Concluding Remarks

The concept of blood stasis is exceptionally important in traditional Asian medicines, and we have here argued that it reflects the fibrinaloid microclots that two of us had discovered. The recognition that herbal formulae such as Xue Fu Zhu Yu are well known (by relevant practitioners) to be of value in treating blood stasis, as well as some of the bioactive molecules that it contains, thus opens up the area of microclots to focused pharmacological analyses. It also offers the hope of effective treatments.

Author Contributions

All authors contributed to the conceptualisation, analyses, funding acquisition, drafting, and final editing. All authors have read and agreed to the published version of the manuscript.

Acknowledgments

DBK thanks a great many people for useful discussions, including Yisheng Chen, Amanda Crist, Meng Li, Linghui Lu, Michael Moran and Louanne Richards.

Conflicts of Interest

E.P. is a named inventor on a patent application covering the use of fluorescence methods for microclot detection in Long COVID. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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Figure 1. Structure and dimensions of fibrinogen and its folding into healthy and pathological amyloid fibrin(ogen). A) Fluorescence microscopy of healthy plasma (with and witout spike protein), with thioflavin T (to shown amyloid areas in fibrin(ogen)) and added thrombin. B) Scanning electron microscopy of fibrin(ogen) with and without lipopolysaccharide (LPS) and thrombin C). Scanning electron microscopy of human plasma with FeCl3 and thrombin. (Adapted from 103, 109. Generated with Biorender.com.
Figure 1. Structure and dimensions of fibrinogen and its folding into healthy and pathological amyloid fibrin(ogen). A) Fluorescence microscopy of healthy plasma (with and witout spike protein), with thioflavin T (to shown amyloid areas in fibrin(ogen)) and added thrombin. B) Scanning electron microscopy of fibrin(ogen) with and without lipopolysaccharide (LPS) and thrombin C). Scanning electron microscopy of human plasma with FeCl3 and thrombin. (Adapted from 103, 109. Generated with Biorender.com.
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Figure 2. Representative confocal images of human plasma with three amyloid markers (cyan: Amytracker™ 480; red: Amytracker™ 680; green: ThT). (A to C) Naïve human plasma; (D to F) Plasma exposed to Lipopolysaccharide (LPS); (G to I) Plasma exposed to iron; (J to L) Plasma exposed to lipoteichoic acid-1; (M to O) Plasma exposed to lipoteichoic acid-1. (Taken from a CC-BY Open Access publication 118.).
Figure 2. Representative confocal images of human plasma with three amyloid markers (cyan: Amytracker™ 480; red: Amytracker™ 680; green: ThT). (A to C) Naïve human plasma; (D to F) Plasma exposed to Lipopolysaccharide (LPS); (G to I) Plasma exposed to iron; (J to L) Plasma exposed to lipoteichoic acid-1; (M to O) Plasma exposed to lipoteichoic acid-1. (Taken from a CC-BY Open Access publication 118.).
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Figure 3. Weak binding or sequestration. Different classes or types of protein co-aggregation: Titration; Sequestration; Axial and lateral. (Figure adapted from Open Access papers 258, 259, which was based on 260.) Generated with Biorender.com.
Figure 3. Weak binding or sequestration. Different classes or types of protein co-aggregation: Titration; Sequestration; Axial and lateral. (Figure adapted from Open Access papers 258, 259, which was based on 260.) Generated with Biorender.com.
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Figure 4. Multipotential drug treatment strategies for Traumatic Brain Injury. Redrawn from 363. Generated with Biorender.com.
Figure 4. Multipotential drug treatment strategies for Traumatic Brain Injury. Redrawn from 363. Generated with Biorender.com.
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Figure 5. Long COVID symptoms (taken from 171). Generated with Biorender.com.
Figure 5. Long COVID symptoms (taken from 171). Generated with Biorender.com.
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Figure 6. Blood stasis-expelling decoction’ or Stasis in the mansion of blood’, based on the material at https://sys02.lib.hkbu.edu.hk/cmfid/details.asp?lang=eng&id=F00115.
Figure 6. Blood stasis-expelling decoction’ or Stasis in the mansion of blood’, based on the material at https://sys02.lib.hkbu.edu.hk/cmfid/details.asp?lang=eng&id=F00115.
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Table 1. Some diseases or syndromes in which fibrinaloid microclots have been observed, and which are considered to involve blood stasis.
Table 1. Some diseases or syndromes in which fibrinaloid microclots have been observed, and which are considered to involve blood stasis.
Disease or Syndrome Selected References Showing Microclot Formation Selected References Relating the Disease to Blood Stasis
Alzheimer’s disease 140-143 71, 144-146
(Acute) COVID-19 infection 147-151 152-159
Diabetes type 2 141, 151, 160-162 68, 71, 74, 163-166
Long COVID 117, 121, 167-173 155, 174, 175
Migraines 176 71 177
Myalgic Encephalopathy/ Chronic Fatigue Syndrome 178, 179 175, 180-183 (see also 184)
Parkinson’s disease 141, 185-187 61, 188-190
Rheumatoid arthritis 167, 191, 192 71, 166, 193, 194
Sepsis 195 196, 197 , 198-216, 217 , 218-222
Septic shock 195 223-235
Stroke 236 75, 79, 237-257
Table 2. Diseases involving blood stasis where fibrinaloid microclots are yet to be measured directly. These diseases are mostly vascular or thrombotic. We here ignore classical amyloidoses and cancer.
Table 2. Diseases involving blood stasis where fibrinaloid microclots are yet to be measured directly. These diseases are mostly vascular or thrombotic. We here ignore classical amyloidoses and cancer.
Disease or Syndrome Selected References Relating the Disease to Blood Stasis Comments
Angina pectoris 71, 261-277 A very obvious example, as vasodilators are the main treatment. The tightening of the chest and shortness of breath are easily explained by microclots blocking capillaries.
Atherosclerosis 278-283 Another very obvious example of fibrinaloid microclots resisting fibrinolysis contributing to atherosclerotic plaques (and later to stroke 236). The pairing Danshen-Chuanxiong is often used 284 281.
Atrial Fibrillation (AF) 12 At one level, atrial blood stasis is seen as synonymous as an effect of AF 285, 286. Evidence that fibrinaloid microclots are more a cause than an effect of AF was summarised in 287
Attention deficit hyperactivity disorder (ADHD) 288-291 Plausibly due to decreased blood flow caused by microclots.
Chronic kidney disease 70, 292, 293 Less likelihood of kidneys excreting microclots if diseased.
Chronic obstructive pulmonary disease (COPD) 294-298 Strong hint in the term ‘obstructive’
Coronary heart disease 83, 84, 271, 274, 299-307 308-310 Xue Fu Zhu Yu (a formula to overcome blood stasis) helps 301, 303, 311-313.
Deep vein thrombosis (DVT) 314-316 TCM classifies DVT as blood stasis in the category of “pulse closed” and “femoral swelling”. Xue Fu Zhu Yu helps, and there is evidence 259 that the thromboses are likely to be amyloid in nature.
Dysmenorrhoea 317-322 Note that 17-b-oestradiol was one of the first small molecules discovered to induce anomalous clotting 98
Fibromyalgia syndrome (FMS) 180, 323 We consider it likely that FMS (and fibrosis 296) is caused by the deposition of fibrin caused by fibrinaloid microclots 109. There is little actual work on BSS here.
Heart failure and Ischaemic heart disease 324-327 Various formulas used for this kind of blood stasis
Metabolic syndrome (MS) 71, 80, 328, 329 MS covers a variety of different syndromes; at this stage we do not seek to deconvolve it.
Non-alcoholic fatty liver disease (NAFLD) (since mid-2023 it is called metabolic dysfunction-associated steatotic liver disease (MASLD) 330) 166, 331, 332
Postural Orthostatic Tachycardia Syndrome (POTS) 333 Capillary blocking by fibrinaloid microclots provides a ready explanation for POTS 334 (see also 335)
Pre-eclampsia (PE) 336-339 PE has a microbial origin 340, 341 and is significantly prothrombotic 342
Pulmonary embolism 91, 343
Sub-arachnoid haemorrhage 344, 345 The only predictor of a later stroke 346 was ESR, a measure of blood stasis
Thrombotic diseases generally 347-349 High likelihood of the clots involved being amyloid in nature 259
Tinnitus 74, 350 A common accompaniment to diseases (such as Long COVID) where microclots are involved and where both can be induced by spike protein (cf. 147 and 351-353).
Transient ischaemic attack (TIA) 248, 354, 355 TIA is of course a common precursor to ischaemic stroke 356, where amyloid clotting has been demonstrated 236
Traumatic brain injury (TBI) 357-363 Blood stasis is seen as a core component of (the sequelae of) TBI, that include coagulopathy 364. Most significantly, Xue Fu Zhu Yu ameliorated neurological deficiencies without impairing blood coagulation in a rat model 361.
Traumatic injury generally 365 65
Table 3. Constituent herbs of Xue Fu Zhu Yu, some known bioactives it contains, and some known activities.
Table 3. Constituent herbs of Xue Fu Zhu Yu, some known bioactives it contains, and some known activities.
Herb Some Known Bioactive Molecules Therein Some Known Targets or General Properties
Tao Ren; Semen persicae; peach kernel (Emperor) Amygdalin 463, 464 Follistatin induction 463; ERK1/2 activation 464
Hong Hua; Flos carthami; Carthamus tinctorius L.; safflower (Emperor) (Hydroxy)safflor yellow A 465-470 Antithrombotic, angiogenic, anticoagulant, antiplatelet. Reviews: 471-476
Kaempferol, quercetin Antioxidants/ anti inflammatory 465
Endothelial cell protection Enhances HIF1-a 465
Chi Shao; Radix paeoniae rubra; Paeonia lactiflora Pall; red peony root (Minister) Oxypaeoniflorin Anti-thrombin 348
Paeoniflorin 477 Anti-inflammatory 478, 479 and antioxidant 480; blocks TGF1b signalling, ERK1/2, JNK1/2, NF-kB, etc 477, 481, 482; deactivation of STAT3 483; Akt/Nrf2/GPX4 190
Paeonol Anti-inflammatory, antioxidant, protects endothelium 484; endothelium-protecting and antiplatelet 485; antioxidant and anti-inflammatory 486
Rhizoma chuanxiong (= Ligusticum chuanxiong); Szechaun lovage roots (Minister) Reviews 487-490
Ligustrazine Anti-inflammatory 491 492. Dilates
blood vessels, inhibits platelet aggregation and prevents thrombopoiesis 492. Anti-anginal 493. Multiple roles 494.
Ligustilide (also in Dang Gui and Niu Xi) Anti-inflammatory and anti-oxidant 495. Improves lipid metabolism,
antioxidant and anti-inflammatory, protects vascular endothelium, inhibits vascular endothelial fibrosis 496. Cannabinoid receptor 2 activation
Sekyunolide I (SEI) Reviews on antioxidant and anti-inflammatory properties 497-499. Other targets of SEI include Nrf2 500, activity vs NAFLD 501, UVB damage 502, NET formation 503, ischaemia-reperfusion injury 504-507, It occurs in appreciable concentrations in both ChuanXiong 508, 509. and Angelica sinensis (Danggui) 510.
Ferulic acid Anti-thrombin activity 511
Radix Achyranthis Bidentata (Niu Xi), also Cyathulae Radix (Minister ; may also be a Courier 512) Achyranthine, but no real stand-outs Seemingly not well understood 513, 514
Radix rehmanniae (Di Huang or Sheng Di) (Assistant) Reviews: 515-517 Multiple effects, including
anti-inflammation, antioxidation, anti-tumor, immunomodulation, cardiovascular and cerebrovascular regulation 517. Hypoglycaemic 518
iridoid glycosides (such as catalpol and aucuboside), Catalpol blocks AMPK signalling 519 and promotes angiogenesis 520 and cell migration 521. Antioxidant via Nrf2/HO-1 522 and NF-kB 523, Many other references, reviewed in 524-526. Aucuboside is an immunomodulator 527.
phenylpropanoid glycosides (such as acteoside), Acteoside e.g. stimulates amyloid degradation 528 and ameliorates ischaemia-reperfusion injury 529, and has many other effects 530 including anticancer 531.
Radix Angelicae sinensis (Chinese angelica) (Dang Gui) (Assistant)
Z-lingustilide (see above)
Ferulic acid Antioxidant and anti-inflammatory 532. Nephroprotective 533. Ameliorates lipid metabolism
via AMPK/ACC and PI3K/AKT pathways 534.
Sekyunolide I (see above)
Radix platycodonis (Balloonflower root) (Jie Geng) (Assistant; may also be a Courier 512) Platycodins 535 536 (triterpenoid saponins) Many activities 537, 538 including anti-inflammatory and antioxidant 535, 539, 540, vasodilatory541, antiviral 542,
Fructus aurantia (Citrus aurantium L.) Bitter orange (Zhi Qiao) (Assistant) Flavones and flavonoids, including sinensetin, tangeretin, 5-demethylnobiletin and chrysin. Antioxidant, anti-inflammatory 543 and other activities via JAK-STAT3n and PI3K-AKT signalling 544
Radix Bupleuri (Chinese Thorawax Root) (Chai Hu) (Assistant) Quercetin 271 Antioxidant and other properties (some not at all newly discovered 545, 546)
Saikosaponins (triterpenoid saponins) Many activities including antioxidant and anti-inflammatory 547-550
Radix glycyrrhizae (Glycyrrhiza uralensis Fisch; Chinese licorice) (Gan Cao) (Courier) Flavanones Liquiritigenin and Isoliquiritigenin Anti-oxidant 551, also anti-amyloid 552 and transporter inducers. Reviews 553, 554.
Triterpene saponins including glycyrrhizin Antiviral and other 555-561 562-565
Table 4. Chemical structures of some of the constituents in Xue Fu Zhu Yu as mentioned in Table 3.
Table 4. Chemical structures of some of the constituents in Xue Fu Zhu Yu as mentioned in Table 3.
Molecule Structure
Acteoside Preprints 149892 i001
Amygdalin Preprints 149892 i002
Aucuboside Preprints 149892 i003
Catalpol Preprints 149892 i004
Glycyrrhizin Preprints 149892 i005
Hydroxysafflor yellow A Preprints 149892 i006
Isoliquiritigenin
(2',4,4'-Trihydroxychalcone)		 Preprints 149892 i007
(Z-)Ligustilide Preprints 149892 i008
Ligustrazine (2,3,5,6-tetramethylpyrazine) Preprints 149892 i009
Liquiritigenin 4’, 7- dihydroxyflavanone Preprints 149892 i010
Oxypaeoniflorin Preprints 149892 i011
Paeniflorin Preprints 149892 i012
Paeonol Preprints 149892 i013
Platycodins: variants of structure at right. One example is below, in which R1 is glucose and R2 is arabinose-rhamnose-xylose-apifuranosyl Preprints 149892 i014
Platycodin D Preprints 149892 i015
Quercetin Preprints 149892 i016
Safflor yellow A Preprints 149892 i017
Saikosaponin nucleus Preprints 149892 i018
Saikosaponin A As above, R1 = b-OH, R2 = CH2OH
Sekyunolide I Preprints 149892 i019
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