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Assessment of the Impacts of Fibrinaloid Microclots on the Microcirculation and Endothelial Function, Using Laser Speckle and Laser Doppler Imaging

Submitted:

25 June 2025

Posted:

26 June 2025

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Abstract
The microcirculation typically refers to those capillaries less than 100 mm in diameter. Having shown that blood can clot into an anomalous amyloid form that is rather resistant to fibrinolysis, we have previously developed the idea that endothelial dysfunction can both lead to and be caused by the fibrinaloid microclots so formed, such that this can slow or block entirely parts of the microcirculation. The microclots might be thought of as a ‘structural’ manifestation. This impairment of the microcirculation is referred to in Traditional Chinese Medicine (TCM) as ‘blood stasis’. It is thus desirable to have ‘functional’ methods that can measure these effects on the microcirculation directly. As a complement to a recent survey of nailfold capillaroscopy, the present paper provides a wide-ranging review of the utility of laser speckle imaging (LSI) and laser Doppler imaging (LDI) for assessing the microcirculation in a large variety of diseases in which it is considered to be involved, not least Long COVID, sepsis and ischaemic stroke. In all cases in which fibrinaloid microclots have been observed, so too do these methods detect an impairment of the microcirculation. Notably, blood pressure is raised while blood flow in the microcirculation is lower; this clearly speaks to occlusion and/or capillary rarefaction, and indicates that the raised blood pressure is the effect and not the cause of the decrease in flow rate or stasis of the microcirculation. As rapid, information-rich and non-invasive methods, LSI and LDI seem to have outstanding potential for assessing the role of fibrinaloid microclots in affecting blood stasis in the microcirculation, in a huge variety of inflammatory diseases and syndromes.
Keywords: 
clotting
;  
amyloid
;  
fibrinaloid
;  
laser-doppler imaging
;  
cross-seeding
;  
fibrils
;  
microcirculation
Subject: 
Biology and Life Sciences  -   Biochemistry and Molecular Biology

Introduction

The microcirculation and endothelial dysfunction 

The microcirculation represents the terminal elements of the circulation consisting of microvessels, and has been defined as those with diameters less than 20 μm [1] or (more commonly) less than 100 μm [2,3,4,5,6]. As with other blood vessels, the walls of microvessels consist of endothelial cells [7] (we here ignore the glycocalyx [8] and mucins [9]). Endothelial dysfunction, manifesting as effects on the microcirculation (e.g. [10,11]), underpins a large variety of diseases and associated symptoms. Thus, Table 1 provides a list of some diseases or syndromes in which the evidence is especially well established. Further details, in terms of the use of laser imaging methods for assessing the microcirculation in these and many other diseases, and whether or not the presence of fibrinaloid microclots has been tested or observed, is given later in Table 2 (laser speckle imaging) and 3 (laser Doppler imaging).
While it is slightly egregious to pick out specific syndromes, we would comment that some such as ischaemic stroke are among the main causes of human deaths. All these diseases, especially the chronic diseases [249] display multiple, similar observables, and endothelial dysfunction can both cause and be caused by oxidative stress (from hypoxia and/or reactive oxygen species) (e.g. [250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265]), mitochondrial dysfunction [266], and inflammation [254,255,267]. Endothelial dysfunction can itself be caused by cellular senescence [268,269,270,271,272,273,274,275,276], and in particular via infection (see Figure 1).
Disseminated intravascular coagulation (DIC) is commonly an accompaniment to sepsis and is characterised by widespread microvascular thrombosis [277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295] and is associated with a high mortality. A particularly striking recent finding [296] involved the discovery of an unequivocal relationship (odds ratio >50) between DIC and the presence of fibrinaloid microclots. The directions of causality are not yet known, but this does highlight the potential utility of microcirculation measurements in such patients.
Particular attractions of the microcirculation as an object of study are (i) that it is amenable to non-invasive measurements, in particular via the skin, tongue or retina, and (ii) that it reflects the properties of the far less accessible macrovasculature (see e.g. [124,297,298,299,300,301,302,303,304,305,306,307,308]) and is thus effectively a surrogate for assessing the presence, likelihood, and possibly severity, of a large variety of mainly (cardio)vascular diseases.
Fibrinaloid microclots. We discovered long ago that blood can clot into an anomalous amyloid-like form [309,310,311], producing ‘fibrinaloid’ microclots (commonly in the range 2-200 μm in equivalent diameter [312,313,314,315]) that are relatively resistant to degradation. All such diseases in which fibrinaloid microclots formation has been studied are similarly accompanied by the above symptoms. These diseases [316] include acute COVID-19 [317,318,319,320,321,322], Alzheimer’s dementia [309,323,324,325,326], diabetes mellitus type 2 [322,323,327,328,329], Long COVID [313,314,315,330,331,332,333,334,335,336,337,338,339], migraine [340], myalgic encephalopathy/ chronic fatigue syndrome (ME/CFS) [341,342,343,344], Parkinson’s disease [323,345,346], rheumatoid diseases [347,348,349], and sepsis/septic shock [296] (see also [290]). It is obvious that such particulate matter as represented by fibrinaloid microclots can block the microcirculation causing local hypoxia, and (focusing on Long COVID) this readily explains phenomena such as blood stasis [350], fatigue [330], post-exertional system exacerbation (previously post-exertional malaise) [351], auto-antibody formation [352], postural orthostatic tachycardia syndrome (POTS) [336], atrial fibrillation [353] and fibromyalgia [354]. Their amyloid nature, as well as their proteome content [331,332,355], straightforwardly explains the relative resistance of fibrinaloid microclots to fibrinolysis [356,357]. We further showed that the macroclots removed by thrombectomy following an ischaemic stroke are also amyloid in character [358,359].
Although other amyloid stains are available, fibrinaloid microclots are typically measured using the classical fluorogenic amyloid stain thioflavin T [360,361,362,363], and the fluorescence is observed using fluorescence microscopy or flow methods. These may be considered to be ‘structural’ methods, while a variety of more ‘functional’ methods are known. We recently suggested [364] that one ‘functional’ type of methods of assessing abnormalities in the microcirculation, based on nailfold capillaroscopy (see e.g. [365,366,367,368,369,370,371,372]), might make a useful complement to our ‘structural’ microclot assays.
In addition, other functional methods of measuring the microcirculation are known, including indocyanine green fluorescence [373,374,375,376,377,378], optical coherence tomography angiography (OCTA) [28,175,379,380,381,382,383,384,385,386,387,388,389,390,391], and in particular, as we focus on here, here laser speckle (contrast) imaging (LSI or LSCI) [36,392,393,394,395,396,397,398,399,400,401] and laser Doppler imaging (LDI) [235,397,402,403]. From the physics point of view the latter two are considered essentially equivalent [404,405]. The chief purpose of this paper is thus to assess LSI and LDI and the findings made with them when they are applied in diseases known to be accompanied by fibrinaloid microclots. We conclude that, while they are not that cheap, they should prove to be exceptionally useful tools for determining disorders of the microcirculation.

A note on systems biology explanations of cause and effect 

We recognise, for non-systems-biologists, that if one is studying a steady state system in which all steps are proceeding at the same rate it might be seen as odd to argue that some steps are somehow ‘more important’ in determining the speed or course of events than are others. However, this is in fact the case and it can be quantified precisely. Specifically, the answer lies in what is called sensitivity analysis, in which we study the effects of a normalised change in a parameter (such as the kcat of an enzymatic step) on the normalised value of a variable (in metabolism this is usually a concentration or a flux). Metabolic control analysis [406,407,408,409,410] is exactly such a formalism that applies this to biochemistry, and is based on what is called a local sensitivity analysis [411,412]. Even in very simple systems consisting of just three metabolites (e.g. A → B → C) with the two steps catalysed by enzymes E1 and E2, it is surprisingly tricky to do this well unless one is both informed and careful (see e.g. [413,414,415,416,417]).
This said, in an elementary sense, blood pressure (V), peripheral resistance (R) and the rate of blood flow or flux (I) can be seen as straightforwardly related to each other in a manner entirely analogous to the standard and well-known Ohm’s law relation V=IR of DC electricity. Given this relationship, it is worth pointing out that in such systems one can establish a set-up in which external control is either of the voltage or the current (also in AC systems [418]). Consequently it is at least reasonable to ask which of the elements contributing to the observable blood flow then normally exert the greater control. The answer is that it seems clearly to be the case that that blood pressure increases that can be observed [41,74,114,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136] seem to be caused mainly by changes in peripheral resistance i.e. the microcirculation [114,115] rather than anything else controlling the blood pressure more directly. From the perspective of the role of fibrinaloid microclots this is an extremely important recognition.
We next rehearse the role of ‘blood stasis’ in disorders of the microcirculation, before describing LSI.

The microcirculation from the point of view of ‘blood stasis’ in Traditional Chinese Medicine 

The concept of "blood stasis" in TCM is closely related to microcirculatory disorders in modern medicine. Blood stasis is one of the basic pathological mechanisms in TCM, referring to the pathological state of poor blood circulation and stagnant blood. In recent years, multiple studies have shown a high degree of similarity between the concept of blood stasis and microcirculatory disorders in terms of pathophysiology. Our study on the relationship between blood stasis syndrome and microclotting [350] recognised that abnormal amyloid-like clots, known as fibrinaloid microclots, can form in the blood. These microclots appear in various chronic inflammatory diseases, and they can block microvessels, reduce tissue oxygen transport, and lead to various pathological consequences. Microclots provide a simple mechanism for slowing blood flow by obstructing the transport of red blood cells [330,350].
Blood stasis syndrome is commonly seen in various chronic diseases in TCM clinical practice, and its manifestations are highly consistent with the clinical characteristics of microcirculation disorders. Blood stasis constitution is associated with a number of metabolic abnormalities and microcirculation disorders. The complex interactions between host constitution, gut microbiota, and serum metabolites may indicate potential metabolic vulnerability, even in cases of surface health [419].
The main method of treating blood stasis syndrome in TCM is to promote blood circulation. Many TCM herbal formulas have shown significant effects in improving the microcirculation, not least XueFu ZhuYu (reviewed in [350]). Danshen is another commonly used TCM for promoting blood circulation and removing blood stasis, and studies have shown that it has various pharmacological effects on improving microcirculation [420,421]. Salvia miltiorrhiza extract and its pure compounds have many effects, such as anti atherosclerosis, anti arrhythmia, anti thrombosis, anti hypertension, anti ischemia reperfusion injury, and protection of endothelial function [422]. These effects are closely related to improving the microcirculation [423].
Dang-gui-Si-Ni (DGSN) decoction is another typical formula for promoting blood circulation and removing blood stasis. DGSN can prolong clotting time (PT, TT, and APTT) and reduce fibrinogen (FIB) content. In in vivo experiments, low-dose (500 μ g mL-1) DGSN significantly enhanced cardiac output and blood flow velocity. These findings indicate that DGSN can significantly improve hemodynamics and downregulate coagulation factors, thereby improving the microcirculation [424].
In the treatment of chronic coronary syndrome (CCS), the TCM compound Danshen Dripping Pills has shown significant cardioprotective effects. Compared with Western medicine treatment alone, the combination of TCM and Western medicine improved the effectiveness of electrocardiogram by 8318%, the effectiveness of angina by 20%, and the cessation or reduction of nitroglycerin tablet use by 20%. These effects are likely related to improving coronary microcirculation [425]. Overall the microcirculation is seen within TCM as contributing strongly to the phenomena of blood stasis. We now turn to LSI.

Laser speckle (contrast) imaging (LSI/ LSCI) 

When laser light illuminates an object, the scattered light produces a ‘random’ (actually deterministic, but massively complex) interference effect referred to as a speckle pattern. If the object is moving, the speckles necessarily fluctuate in intensity. Similarly, if the speckle pattern is imaged with an exposure time longer than the shortest speckle fluctuation time, the fluctuations cause a blurring of the speckle, leading to a reduction in the local speckle contrast. This thus encodes the velocities and the distributions thereof as speckle contrast variations; for higher velocity the speckle contrast is reduced [392,426,427]. Given the size of the speckles, the magnification used, and the typical blood flow rates (~ 1mm.s-1 in capillaries [428]), exposure times are typically in the range of 1-10 ms [429]. Typically the range thereby covered is 0.1 – 10 mm.s-1. Specific implementations of the general technique are variously referred to as laser speckle imaging (LSI), laser speckle contrast imaging (LSCI), laser speckle contrast analysis (LASCA) and laser speckle flowgraphy (LSFG) (there are slight variations in implementation); we shall normally use the first terminology., and not discriminate them in any real detail A particular attraction is that interrogation can be over a wide area simultaneously (i.e. no scanning or rastering is necessary).
Instruments can be used in ‘spatial mode’ or ‘temporal model’ [392]. Typically, when used in ‘spatial mode’, the speckles are mapped over a small grid of detector pixels (typically 5x5) and the contrast is assessed as the standard deviation (SD) of pixel intensities (average pixel intensity = I); SD is low for fast moving speckles (high blood flow) where the image is blurred, and SD is high for slow moving speckles (low blood flow) where the image is not so blurred. The basic formula for LSCI assessment of tissue is thus Flux ∝ (<Ι>/SD)2. Note that flux differs from velocity as it also takes into account the concentration of the scattering particles.
In ‘temporal mode’, the intensities of individual pixels during at least 25 successive images are used to calculate average intensities and SDs. Compared to a 5x5-pixel set-up this mode is necessarily at least 25 times slower than spatial mode but its linear resolution is of course 5 times greater.
A typical speckle pattern (taken from [392]) is given in Figure 2, while Figure 3 illustrates the general principle.
As with our previous review on nailfold capillaroscopy [364], we think that the most illuminating strategy for our purposes is to compare diseases assessed using LSCI with those in which fibrinaloid microclots are known to exist experimentally, so as to see how much overlap is already documented. Table 2 sets out such an analysis. Note, of course, that many of these syndromes are diseases of ageing, and that microvascular properties do decline with age [431,432,433,434], so a comparison with age-matched controls is (as usual [435]) required.
The widespread occurrence of alterations in the microcirculation, as judged by LSI, also accompanied with inflammation and oxidative stress, indicates how extensive this is in multiple syndromes (Figure 4), and we would argue that they likely share common causes [95]. In particular, where it was tested, all examples in which fibrinaloid microclots have been measured in plasma also show disorders of the microcirculation, as we would expect. This said, despite extensive detection of microclots in diseases such as myalgic encephalopathy/ chronic fatigue syndrome (ME/CFS) and Parkinson’s, laser speckle imaging seems not to have been assessed. This clearly provides some tremendous opportunities.

Laser Doppler Imaging (LDI) 

Detecting properties of moving objects via the Doppler effect is of course a method dating back to the 19th century, and a suite of methods referred to under the term laser Doppler imaging (LDI) has also been applied to the non-invasive estimation of blood flow.
Figure 5 illustrates typical arrangements for LDI. In this case, rastering is required, using either a point scan (Figure 5A) or a line scan (Figure 5B).
Our interest again resides in determining the spatial variation of the microcirculation and assessing diseases in which both LDI has been used to detect microcirculation dysfunction and where microclots have also been observed. To this end, Table 3 is presented in the style of Table 2 but where the measurement technique is laser Doppler imaging rather than laser speckle imaging. As with LSI there is an age dependence in the observables [604], that needs to be taken into account.
From the perspective of the role of fibrinaloid microclots in affecting the microcirculation, at least two features are of particular note. The first is that blood pressure is raised while flow is lower; this clearly speaks to either or both of capillary rarefaction (decreased density) [121] or to occlusion (or both) and that the raised blood pressure is the effect and not the cause of the change in flow rate. (One might comment that in this sense blood pressure [784] corresponds to metabolic fluxes in general, as these tend to be regulated by demand and not by supply [785].) Secondly, many studies indicate – not least in diabetes – that changes in the microcirculation leading to hypoxia precede disease, again consistent with an aetiological role. This of course raises the significance of these phenomena considerably. In a similar vein, the fact that fibrinaloid microclots accompany so many of these diseases is again consistent with them having an aetiological role rather than being a simple side effect of whatever the core component of the diseases might be considered to be.
While the above table focused on disease, it is worth noting that LDI indicated that there are significant differences in local blood flow at acupuncture points relative to surrounding tissue [786,787,788], and that suitable treatments can affect the microcirculation as so measured [789]. Given the significance of blood stasis in a variety of diseases [350], this is definitely noteworthy.

Comparison of the two techniques 

Both laser Doppler Imaging and Laser speckle imaging are capable of measuring the microcirculation effectively, are comparably priced, and in skilled hands generally reasonably reproducible [405,790,791,792,793,794,795] depending on the LSI exposure time (though seemingly not when assessed in boys [796]). They are significantly more expensive than is nailfold capillaroscopy, but do offer real-time measurements. The general feeling is that LSI is more powerful but that LDI penetrates more deeply if that is important, although this depends on a variety of optical and geometric parameters [797,798,799,800]. In one study of dermal blood flow [801] LSI was considered more sensitive.

Discussion

Comparison of technological advantages and innovative breakthroughs 

Laser speckle imaging (LSI) and laser Doppler imaging (LDI) quantify microvascular blood flow in a non-invasive manner, significantly enhancing the clinical value of microcirculation assessment. LSI captures real-time blood flow velocity and distribution with a high spatial resolution of 10 μm, suitable for dynamic monitoring of superficial organs. LDI is known for its ability to penetrate deeper tissues and locate low perfusion areas in deep regions such as the myocardium. The combined application of the two offers functional complementarity and provides a comprehensive analysis for complex microcirculatory disorders. The introduction of artificial intelligence algorithms has further improved the accuracy of blood flow parameter analysis, promoting the transfer of microcirculation imaging techniques and instrumentation from laboratory research to clinical practice.

Unity and specificity of cross-disease mechanisms 

Fibrinaloid microthrombi, as the core pathological mediator of microcirculatory disorders, exhibit both mechanistic unity and significant specificity due to differences in precise phenotypes in various diseases. Its unity is reflected in the fact that whether in acute infection (such as COVID-19), metabolic disorders (such as diabetes) or autoimmune diseases (such as systemic lupus erythematosus), the formation of microthrombosis involves three core links: endothelial cell injury, platelet activation and a systemic imbalance between coagulation and fibrinolysis. The commonality of these pathological processes suggests that microthrombi may be a common hub for the transformation of various diseases into microcirculatory disorders and vice versa.

Opportunities and challenges for further clinical translation 

Laser speckle imaging (LSI) and laser Doppler imaging (LDI) bring new opportunities for the diagnosis, treatment and prognosis of microcirculatory disorders: intraoperative blood flow imaging can optimize the effect of cardiovascular surgery, portable equipment can improve the early screening rate of chronic diseases such as diabetes and foot, and the evaluation of the efficacy of traditional Chinese medicine may be supported by objective blood flow parameters. However, the promotion of the technology still faces obstacles: the blood flow calculation standards of different devices are not unified, imaging of deep organs (such as myocardium) is limited, and high costs constrain grassroots applications.

Future research directions and technological innovation 

Future research may be expected to focus on a number of major directions: precision imaging technology, developing targeted probes and super-resolution microscopes to achieve subcellular-level visualization of microthrombi; intelligent diagnostic systems, using AI algorithms to automatically analyze blood flow patterns and improve the efficiency of recognition of microthrombi and their effects; and multimodal integration, combining optical, ultrasound and other technologies to simultaneously obtain three-dimensional information such as blood flow and vascular elasticity.
Together with biochemical analyses involving multiomics and the data mining thereof, this will greatly promote microcirculation research from "functional observation" to "molecular mechanism analysis", providing new tools for the diagnosis and treatment of cardiovascular and cerebrovascular diseases.

Author Contributions

Conceptualization, DBK, EP, HZ; Formal Analysis, DBK, EP, HZ; Resources, DBK & EP; Writing – Original Draft Preparation, DBK; Writing – Review & Editing, DBK, EP, HZ; Visualization, DBK & EP; Funding Acquisition, DBK & EP.

Funding

DBK thanks the Balvi Foundation (grant 18) and the Novo Nordisk Foundation for funding (grant NNF20CC0035580). EP thanks PolyBio Research Foundation and Kanro Foundation for funding. The content and findings reported and illustrated are the sole deduction, view and responsibility of the researchers and do not reflect the official position and sentiments of the funders. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Acknowledgments

DBK thanks Brian Lock (Moor Instruments) for useful discussions.

Conflicts of Interest

EP is a named inventor on a patent disclosing the use of fluorescence microscopy in Long COVID.

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  794. Roustit, M., Millet, C., Blaise, S., Dufournet, B. and Cracowski, J. L. (2010) Excellent reproducibility of laser speckle contrast imaging to assess skin microvascular reactivity. Microvasc Res. 80, 505-511. [CrossRef]
  795. Sun, S., Hayes-Gill, B. R., He, D., Zhu, Y., Huynh, N. T. and Morgan, S. P. (2016) Comparison of laser Doppler and laser speckle contrast imaging using a concurrent processing system. Optic Lasers Eng. 83, 1-9. [CrossRef]
  796. Hodges, G. J., Klentrou, P., Cheung, S. S. and Falk, B. (2020) Comparison of laser speckle contrast imaging and laser-Doppler fluxmetry in boys and men. Microvasc Res. 128, 103927. [CrossRef]
  797. Fredriksson, I., Larsson, M. and Stromberg, T. (2009) Measurement depth and volume in laser Doppler flowmetry. Microvasc Res. 78, 4-13. [CrossRef]
  798. Jakobsson, A. and Nilsson, G. E. (1993) Prediction of sampling depth and photon pathlength in laser Doppler flowmetry. Med Biol Eng Comput. 31, 301-307. [CrossRef]
  799. O'Doherty, J., McNamara, P., Clancy, N. T., Enfield, J. G. and Leahy, M. J. (2009) Comparison of instruments for investigation of microcirculatory blood flow and red blood cell concentration. J Biomed Opt. 14, 034025. [CrossRef]
  800. Thompson, O. B., Hirst, E. R. and Andrews, M. K. (2011) Is there a difference between laser speckle and laser Doppler in depth sensitivity? Proc SPIE 7898, 7898OE. [CrossRef]
  801. Bamps, D., Macours, L., Buntinx, L. and de Hoon, J. (2020) Laser speckle contrast imaging, the future DBF imaging technique for TRP target engagement biomarker assays. Microvasc Res. 129, 103965. [CrossRef]
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Figure 1. Overview of the relationship between microcirculation disruption and other observables.
Figure 1. Overview of the relationship between microcirculation disruption and other observables.
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Figure 2. A typical ‘instantaneous’ laser speckle pattern, which changes over time in response to particle motion. Taken from the Open Access CC-BY3.0 publication [392] (DOI: 10.1117/1.JBO.18.6.066018).
Figure 2. A typical ‘instantaneous’ laser speckle pattern, which changes over time in response to particle motion. Taken from the Open Access CC-BY3.0 publication [392] (DOI: 10.1117/1.JBO.18.6.066018).
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Figure 3. Schematic representation of laser speckle contrast imaging (LSCI). (A) The technique relies on the interference of light backscattered from an interrogation zone, that may include moving particles, creating distinct dark and bright areas (a speckle pattern) that is captured by a camera. The greater the blur or spatial homogeneity the faster the blood flow. (B) Variations in the speckle pattern, specifically the amount of blur that is observable following a specific imaging window, are predominantly driven by the movement of red blood cells, enabling interpretation as perfusion, whose rate can be estimated. (C) Analysis of speckle-pattern variations yields an image displayed on the monitor, where white and yellow depict areas with high perfusion, contrasting with darker areas indicating lower perfusion areas. Taken from the CC-BY 4.0 publication [396], originally from [430]. For interrogating the subject’s face, only particularly low-power lasers are to be used.
Figure 3. Schematic representation of laser speckle contrast imaging (LSCI). (A) The technique relies on the interference of light backscattered from an interrogation zone, that may include moving particles, creating distinct dark and bright areas (a speckle pattern) that is captured by a camera. The greater the blur or spatial homogeneity the faster the blood flow. (B) Variations in the speckle pattern, specifically the amount of blur that is observable following a specific imaging window, are predominantly driven by the movement of red blood cells, enabling interpretation as perfusion, whose rate can be estimated. (C) Analysis of speckle-pattern variations yields an image displayed on the monitor, where white and yellow depict areas with high perfusion, contrasting with darker areas indicating lower perfusion areas. Taken from the CC-BY 4.0 publication [396], originally from [430]. For interrogating the subject’s face, only particularly low-power lasers are to be used.
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Figure 4. Widespread inflammation, oxidative stress and endothelial dysfunction may cause systemic disease that may affect all organ systems and lead to a plethora of systems disorders. Redrawn in part from the CC-BY 4.0 Open Access paper [255].
Figure 4. Widespread inflammation, oxidative stress and endothelial dysfunction may cause systemic disease that may affect all organ systems and lead to a plethora of systems disorders. Redrawn in part from the CC-BY 4.0 Open Access paper [255].
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Figure 5. Two styles of laser Doppler imaging in which rastering is achieved via (A) a point scan or (B) a line scan. Figure taken, with permission, and redrawn, from a document provided by Moor Instruments at https://www.moor.co.uk/support/theory/. .
Figure 5. Two styles of laser Doppler imaging in which rastering is achieved via (A) a point scan or (B) a line scan. Figure taken, with permission, and redrawn, from a document provided by Moor Instruments at https://www.moor.co.uk/support/theory/. .
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Table 1. A summary of some of the disease or syndromes in which a disruption of the microcirculation is both observed (using any means) and is considered to have aetiological involvement.
Table 1. A summary of some of the disease or syndromes in which a disruption of the microcirculation is both observed (using any means) and is considered to have aetiological involvement.
Disease or syndrome Comments Selected references
Age-related macular degeneration (AMD) Also related to cardiovascular issues. Note that the proteins in drusen, that is the insoluble material often associated with AMD, include amyloid A, amyloid-b, amyloid P, a1-antitrypsin, fibrinogen, etc. [12,13,14], importantly including abundant amyloid structures [15,16,17] that stain with the amyloid stain thioflavin T [18,19] [20,21,22,23,24,25]
Cancers Many vascular changes involved in all aspects of tumorigenesis, etc [26,27,28,29,30,31,32]
Cardiovascular diseases Strong relationship with microcirculation disruption [33,34,35,36,37,38,39,40,41,42,43,44,45,46,47]
Choroid thickness after haemodialysis [48]
Chronic fatigue syndrome Bears some similarities to Long COVID [49,50,51,52,53,54]
Chronic venous insufficiency [55]
COVID and post-COVID The key to recovery [56,57,58,59,60,61,62,63,64,65,66,67,68]
Diabetes, type 2 Recognised as a vascular disease [69,70,71,72,73,74,75,76,77,78,79]
Diabetic complications [80,81,82]
Fibromyalgia Clear likelihood of fibrinaloid microclot deposition [83,84,85,86,87,88,89,90,91,92,93,94]
General reviews of microcirculation disruption [95,96,97,98,99,100,101,102]
Glaucoma Relates to intraocular blood pressure [103,104,105,106,107,108,109,110,111,112,113]
Hypertension Capillary rarefaction seen as a major driver, at least in later stages. Increased blood pressure but lowered flux strongly implies that the latter causes the former. Put another way, there is an increased resistance to flow. This is entirely consistent with the known role of angiogenesis inhibitors in raising blood pressure [114,115]. [41,74,114,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136]
Inflammatory bowel disease [137,138,139,140,141,142]
Metabolic syndrome A comorbidity of many cardiovascular disease [46,47,79,143,144,145,146,147,148,149,150,151]
Obstructive sleep apnoea A common co-morbidity of many of these diseases, which implies the potential for a common aetiology and a common cure [150,152,153,154,155]
Parkinson’s disease [156]
Pre-eclampsia Clear hypertensive disorder, albeit involving cellular senescence [157] and likely an infectious origin [158,159] [160,161,162,163]
Raynaud’s phenomenon Strongly related to systemic scleroderma [137,164,165,166,167,168,169,170]
Sepsis and septic shock One of the most significant examples, with a high level of mortality. Strong evidence that lowered microcirculatory flux relates closely to mortality (and might hence offer protective treatments). [171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200]
Sickle cell disease Significant impacts on the microcirculation [201,202,203,204,205,206,207,208]
Stroke (ischaemic) Very clear evidence for a relation between microcirculation and multiple factors before and after an ischaemic stroke [209,210,211,212,213,214,215,216,217,218,219,220,221]
Subarachnoid haemorrhage Erythrocyte sedimentation rate (ESR) was the only measure predictive of a subsequent stroke in a detailed study [222] [223,224,225,226,227,228,229,230,231,232,233]
Systemic sclerosis (scleroderma) A major focus in the nailfold capillaroscopy field [234,235,236,237,238,239,240,241,242,243]
Traumatic brain injury and other traumas [244,245,246,247,248]
Table 2. Some disorders involving the microcirculation in which laser speckle contrast imaging has been found to have diagnostic utility or where fibrinaloid microclots have been demonstrated. Disorders in which fibrinaloid microclots have been demonstrated are rendered in bold face; note that every disorder in which microclots have been demonstrated has microcirculation anomalies when assessed using laser speckle imaging (where this has been applied).
Table 2. Some disorders involving the microcirculation in which laser speckle contrast imaging has been found to have diagnostic utility or where fibrinaloid microclots have been demonstrated. Disorders in which fibrinaloid microclots have been demonstrated are rendered in bold face; note that every disorder in which microclots have been demonstrated has microcirculation anomalies when assessed using laser speckle imaging (where this has been applied).
Disease or syndrome Comments Selected laser speckle imaging references Selected fibrinaloid microclot references
(where tested)
Acute COVID-19 Significant evidence of microvascular dysfunction [56,436,437] [317,318,319,320,321,322]
Acute respiratory distress syndrome Severity correlates with lowered microcirculation [56,438]
Age-related macular degeneration Also related to glaucoma [439,440]
Alzheimer’s dementia
(including mild cognitive impairment)		 Significantly lowered cerebral blood flow in Alzheimer’s dementia [441,442,443,444,445,446,447,448,449] [309,323,324,325,326]
Antineutrophil Cytoplasmic Antibody-Associated (ANCA) Vasculitis Impaired microvascular function and blunted reactivity after occlusion [450]
Atopic dermatitis Review showing marked differences, and treatment [451]
Behçet’s disease Higher baseline flux [450]
Biliary cirrhosis Significant microcirculation
lesions		 [452]
Burns Lesions can occur at places distal to the burn site. Faster though less common than LDI. Useful in burn depth diagnosis. [453,454,455,456,457,458,459,460,461,462,463,464,465,466,467]
Cancers There is a large literature, indicating issues with the microcirculation. A very small number of reviews at right. [396,468]
Chronic smokers Led to Buerger’s disease, successful diagnosed (and cured) [469]
Cold urticaria Attenuated response to cold challenge in patients with cold urticaria [470]
Connective tissue disorders Includes Ehlers-Danlos syndrome [471,472,473,474,475]
Coronary heart disease [476,477,478,479,480]
Dermatomyositis [474,481]
Diabetes mellitus, type 1 Decreased microcirculation flux. Can be ameliorated by a Chinese herbal formula. [482,483,484,485]
Diabetes mellitus,
type 2 		Impaired microcirculation. Correlates with glycosylated haemoglobin A1c levels [75,486,487,488,489,490] [322,323,327,328,329]
Diabetic complications Review [491]
Diabetic foot [492,493,494]
Diabetic nephropathy Decreased blood flow despite no lowering of vessel diameter (consistent with microclots) [71]
Diabetic neuropathy [489,490,495,496]
Diabetic retinopathy Decreased blood flow despite no lowering of vessel diameter (consistent with microclots). Microcirculation decrease precedes retinopathy. [71,497,498,499]
Digital ulcers [500,501,502,503,504,505,506]
Endothelial (dys)function [507,508,509,510] [338]
Erythromelalgia [511]
Fibromyalgia Seemingly no studies done See [354], and for amyloid deposition in skeletal muscle [512]
Gaucher disease Seemingly no studies done
General reviews [36,242,396,401,426,472,513,514,515,516]
Glaucoma Evidence for vasculopathies [104,105,106,517,518,519,520]
Heart failure [476,521,522,523,524,525]
Hepatitis, viral Seemingly no studies done
Hypertension and hypertensives As expected, raised blood pressure correlates with lower flow rates (implying that the latter is a cause of the former) [526,527,528,529,530,531,532,533]
Long COVID Observable effects on the microcirculation well after the acute phase. Surprisingly few studies. [436,534] [313,314,315,330,331,332,333,334,335,336,337,338]
Lupus (systemic lupus erythematosus, SLE) Functional and morphological microvascular
impairments in patients with SLE		 [472,535,536,537,538]
Migraine Significant microcirculation changes relative to controls [539,540,541,542,543,544] [340]
Myalgic encephalopathy/ chronic fatigue syndrome Despite the fact that is is clearly an endotheliopathy associated with a deranged microcirculation, and with similarities to Long COVID [52,341,545] we have found no relevant studies [275,342,343,344,355]
Obstructive sleep apnoea [150,155,489,546]
Parkinson’s disease Allowed analysis of function of vasomotor small fibers [547] [323,345,346]
Polycythemia vera
 [548]
Polymyositis [474,481]
Port wine stain Convenient non-invasive measurement / diagnostic [549]
Pre-eclampsia Microcirculation impaired [550,551,552]
Psoriasis Perilesional increased perfusion and perfusion inhomogeneity predictive of lesion expansion after two
weeks		 [553,554,555,556]
Pulmonary
arterial hypertension		 [501,502,503,557]
Raynaud’s disease or Raynaud’s phenomenon (a transient digital ischaemia, often related to systemic sclerosis) Laser speckle analysis is little known relative to nailfold capillaroscopy [169]. [241,538,558,559,560,561,562,563]
Rheumatoid arthritis [564,565,566,567] [347,348,349]
Sarcopenia [568,569,570]
Sepsis and septic shock Can discriminate sepsis from septic shock and lowered blood flow is a high predictor of mortality. The odds ratio of predicting survival based on the presence of fibrinaloid microclots was more than 5 [296]. [571,572,573,574,575] [296] and see [290]
Sickle cell disease Microcirculation significantly impaired [201,576,577,578]
Stroke (ischaemic) Very useful technique for monitoring and prediction [570,576,579,580,581,582,583,584,585,586,587,588,589,590]
Subarachnoid
haemorrhage		 [591]
Systemic sclerosis Also the commonest area for nailfold capillaroscopy [237,500,501,502,503,504,505,592,593,594,595,596,597,598,599]
Traumatic brain injury Clear effects in decreasing microcirculation [600,601,602,603]
Table 3. Some disorders involving the microcirculation in which laser Doppler imaging has been found to have diagnostic utility or where fibrinaloid microclots have been demonstrated. Disorders in which fibrinaloid microclots have been demonstrated are rendered in bold face; note again that every disorder in which microclots have been demonstrated has microcirculation anomalies when assessed using laser Doppler imaging (where this has been applied).
Table 3. Some disorders involving the microcirculation in which laser Doppler imaging has been found to have diagnostic utility or where fibrinaloid microclots have been demonstrated. Disorders in which fibrinaloid microclots have been demonstrated are rendered in bold face; note again that every disorder in which microclots have been demonstrated has microcirculation anomalies when assessed using laser Doppler imaging (where this has been applied).
Disease or syndrome Comments Selected laser Doppler imaging references Selected fibrinaloid microclot references
(where tested)
Acute COVID-19 Significant evidence of microvascular dysfunction [57,59,63,605,606,607,608] [317,318,319,320,321,322]
Acute respiratory distress syndrome Few studies but low microcirculation clearly observable [609,610]
Alzheimer’s dementia
(including mild cognitive impairment)		 Significantly lowered cerebral blood flow in Alzheimer’s dementia. Many more studies than with LSI. Care needed with age matching though [604]. Vascular impairment clearly related to Ab deposition. [444,611,612,613,614,615,616,617,618,619,620,621,622,623] [309,323,324,325,326]
Antineutrophil Cytoplasmic Antibody-Associated (ANCA) Vasculitis Impaired microvascular function [624]
Atopic dermatitis Evidence of impaired microvascular function, but surpisingly little recent literature [625,626]
Biliary cirrhosis Significant microcirculation
lesions		 [627,628]
Burns Utility in burn depth assessment for assisting clinical judgement. Microcirculation problems also occur at distal sites. Seemingly more frequently used here than LSI. [456,466,629,630,631,632,633,634,635,636,637,638,639,640,641]
Cancer Somewhat lesser literature than for LSI (given the importance to tumours of vascularisation), but there are issues with the microcirculation in cancer and its treatment. A very small number of articles at right. [642,643,644]
Chronic smokers Impaired microcirculation (many more papers than for LSI) [645,646,647,648,649,650]
Connective tissue disorders [640,651,652,653,654,655]
Coronary heart disease Surprisingly little directly [656,657,658,659]
Dermatomyositis Lowered flow rate correlates with disease severity [170,236,660,661]
Diabetes mellitus, type 1 A large literature implicating microcirculation defects [73,662,663,664]
Diabetes mellitus,
type 2 		Impaired microcirculation. Correlates with glycosylated haemoglobin A1c levels [72,307,646,647,662,664,665,666,667,668,669] [322,323,327,328,329]
Diabetic complications Reviews (note that most complications follow from impaired microcirculation [491,664]
Diabetic foot (ulcers) [397,670,671,672,673]
Diabetic nephropathy Decreased blood flow despite no lowering of vessel diameter (consistent with microclots) [674]
Diabetic neuropathy [675,676]
Diabetic retinopathy Decreased blood flow despite no lowering of vessel diameter (consistent with microclots). Microcirculation decrease precedes retinopathy. [677,678]
Digital ulcers Often coupled to systemic sclerosis [234,505,649,679,680,681]
Endothelial (dys)function generally [608,682,683,684,685,686,687,688] [338]
Fibromyalgia Much more frequent use of LDI than of LSI [88,91,689,690,691] (and for Complex Regional Pain Syndrome [692]) See [354], and for amyloid deposition in skeletal muscle [512]
General reviews [397,516,655,693,694,695,696]
]
Glaucoma [697,698,699]
Heart failure Decreased microcirculation seen as a risk factor (causative) for worse outcomes [700,701,702,703,704,705,706,707,708,709,710]
Hepatitis, viral [711,712]
Hypertension and hypertensives As also seen with LSI, raised blood pressure correlates with lower flow rates (implying that the latter is a cause of the former) [130,679,713,714,715,716]
Inflammatory bowel disease Measured as rectal blood flow [717,718]
Long COVID Observable effects on the microcirculation well after the acute phase. Surprisingly few studies. [52,67] [313,314,315,330,331,332,333,334,335,336,337,338]
Lupus (systemic lupus erythematosus, SLE) Functional and morphological microvascular
impairments in patients with SLE		 [719,720,721]
Migraine [722] [340]
Myalgic encephalopathy/ chronic fatigue syndrome Despite the fact that is is clearly an endotheliopathy associated with a deranged microcirculation, and with similarities to Long COVID [52,341,545] we have found only one relevant study [52] [275,342,343,344,355]
Obstructive sleep apnoea Both improved by treatment [152,723,724,725]
Parkinson’s disease Very few studies [726] [323,345,346]
Peripheral artery disease Often related to diabetes [649,679,727,728,729,730,731]
Polymyositis [170,661]
Port wine stain Convenient non-invasive measurement / diagnostic [549]
Pre-eclampsia Microcirculation impaired [732,733,734,735,736]
Psoriasis [737,738,739,740,741,742]
Raynaud’s disease or Raynaud’s phenomenon (a transient digital ischaemia, often related to systemic sclerosis) [169,170,562,743,744,745,746,747,748]
Rheumatoid arthritis [749,750,751,752,753,754,755,756] [347,348,349]
Sarcopenia [72]
Sepsis and septic shock Microcirculation very important in sepsis. As with LSI, can discriminate sepsis from septic shock and lowered blood flow is a high predictor of mortality. [757,758,759,760,761,762,763,764,765] [296] and see [290]
Sjögren’s syndrome [170]
Sickle cell disease Microcirculation significantly impaired [202,206,766,767,768]
Stroke (ischaemic) Very useful technique for monitoring and prediction [769,770,771]
Subarachnoid
haemorrhage		 Note that impaired blood flow (measured by ESR) was the only predictor of a subsequent stroke [222] [772,773,774,775,776]
Systemic sclerosis [169,234,235,236,241,243,366,504,505,514,557,592,594,595,679,680,681,744,777,778,779]
Traumatic brain injury Clear effects in decreasing microcirculation as a result of damage following the trauma [244,245,780,781]
Urticaria [782,783]
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