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Contents lists available at ScienceDirect

Advances in Integrative Medicine

journal homepage: www.elsevier.com/locate/aimed

Medical hypothesis

Microparticle clearance theory: An update to the potential mechanisms

of action of cupping therapy
Nurudeen Hassana,* , Rizwhan Sulemana , Waheeb Al-Azzanib , Hisham Jaberc, Ali Mahdid
a
ICAHT Centre of Integrative Medicine, 83-85 Rolleston Street, Leicester, England, United Kingdom
b
Trauma and Orthopaedic Surgery, Prince Philip Hospital, Llanelli, Wales, United Kingdom
c
Radiology Department, University Hospital of Wales, Cardiff, Wales, United Kingdom
d
Haematology Department, Royal Gwent Hospital, Newport, Wales, United Kingdom

A R T I C L E I N F O A B S T R A C T

Article history: Cupping therapy is an ancient medical practice that dates back as far as the earliest records of human
Received 30 June 2019 civilisation. Unlike many other ancient therapies, cupping is still widely practised in different parts of the
Received in revised form 26 June 2020 World. The two main forms of cupping; dry cupping and wet-cupping have recently experienced a
Accepted 13 July 2020
resurgence in popularity in the West due, in part, to high profile athletes and celebrities undergoing the
Available online xxx
treatment. Although cupping is widely used by complementary and holistic therapists to treat many
conditions, its mechanisms of action are not fully understood. In this paper, we review the current
Keywords:
theories and mechanisms through which wet-cupping therapy may exert its effects. We also describe, for
Cupping
Wet-cupping therapy
the first time the microparticle clearance theory as a novel mechanism through which wet-cupping
Holistic therapy therapy may exert anti-inflammatory, anti-thrombotic and afford endothelial protection within tissue
Haemodynamics microvasculature. However, further research is required in order to confirm the exact modes of action of
Immunomodulation cupping to inform targeted clinical research in the field.
Microparticles © 2020 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Methodology: literature search . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Current theories and proposed mechanisms of action .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1. Haemodynamic theory . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2. Blood detoxification and nitric oxide theory . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.3. Immunomodulation theory . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Microparticle clearance theory (MCT) . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
CRediT authorship contribution statement . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction Chinese Medicine texts [2], and works of the Greek physician, and
‘Father of Western medicine’, Hippocrates [3]. In the United
Cupping is a form of therapy that has been employed Kingdom, like many European countries, cupping was widely used
ubiquitously for millennia by different cultures and civilisations. in combination with venesection until the nineteenth century but
There are references to cupping in records of the civilisations of saw a decline with the introduction of the scientific approach and
antiquity such as the Egyptian Ebbers Papyrus [1], Traditional application of medical statistics to medical science [4,5]. However,
the practice of cupping survived in parts of Western Europe such
as Finland, where it is still practised widely by traditional
* Corresponding author at: Cardiff School of Sport and Health Sciences, Cardiff
therapists [6].
Metropolitan University, Llandaff, Cardiff, CF5 2YB, United Kingdom. In recent years there has been a resurgence in the practice of
E-mail address: nhassan@cardiffmet.ac.uk (N. Hassan). cupping in the West due, in part, to high profile celebrities and

https://doi.org/10.1016/j.aimed.2020.07.001
2212-9588/© 2020 Elsevier Ltd. All rights reserved.

Please cite this article in press as: N. Hassan, et al., Microparticle clearance theory: An update to the potential mechanisms of action of cupping
therapy, Adv Integr Med (2020), https://doi.org/10.1016/j.aimed.2020.07.001
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athletes undergoing the treatment. The 2016 Olympics appeared to
mark a watershed moment in the popularisation of cupping
therapy, with many of Olympic athletes sporting the characteristic
cupping marks during the competition.
The two main forms of cupping are dry-cupping and wet-
cupping (also known as bloodletting cupping). These two forms
have been further categorised on the basis of the type of equipment
employed, the power of suction and other characteristics. For a
detailed review of the different types of cupping and indications
see [7].
Even though there has been an increasing body of scholarly
work exploring the effectiveness of cupping therapy in the last
decade, cupping therapy is still widely viewed as a pseudoscience
within large parts of the scientific community, in part due to the
lack of a coherent scientific understanding of cupping's potential
mechanism of action. This warrants the need to explore its
potential modes of action in order to facilitate targeted high-
quality research in the field.
In a highly cited systematic review by Cao and colleagues, 135
randomised controlled trials on cupping published between 1992
and 2010 were reviewed. The authors concluded that cupping
appeared to be effective in treating some pain and inflammatory
conditions such as herpes zoster, acne, facial paralysis, and cervical
spondylosis [8]. Though this review provided an insight into how
cupping could help with a number of conditions, the work did not
discriminate between the different forms of cupping employed in
the studies.
In a more focussed review by Rozenfel and Kalichman, the
authors extensively discussed the various theories and applica-
tions of dry cupping in musculoskeletal medicine [9]. Although
extensive, the paper lacked a discussion on potential mechanisms
of action. This insight was provided to some extent by a seminal
paper by Lowe [10], where the author presents multiple potential
mechanisms through which Haeme-Oxygenase-1 (HO-1) can
mediate therapeutic effects associated with dry cupping. Lowe
purports that the phagocytic action of macrophages at the site of
cupping produce HO-1, that in turn, induces antioxidant, anti-
inflammatory, anti-proliferative and antinociceptive effects. While
further research is required to determine a causal link between the
described theory and reported physiological effects, a randomised
placebo-controlled trial by Lauche et al. [11] provided evidence for
the antinociceptive effect of dry cupping. This study demonstrated
that dry-cupping was more effective than usual care in improving
pain and quality of life in fibromyalgia patients.
Along with dry-cupping, wet-cupping therapy (WCT) is also
gaining popularity in the West, especially in the field of
musculoskeletal medicine. WCT has been shown to be effective
in treating conditions such as hypertension [12], lower back pain
[13,14] and Neck pain [15]. Unlike dry-cupping, there is a lot of
variation in the application of WCT among practitioners. However,
WCT principally involves the application of cups on the skin for
2 5 min (dry cupping stage); followed by superficial incisions
using a surgical blade/ scarificator; then replacement of cups at the
site for about 5 10 min to extract the localised blood.
Given that WCT appears to exert pleiotropic effects and is
employed for multiple indications, this paper focuses on the
current theories and mechanisms of action of WCT by reviewing
peer-reviewed research in the field. Additionally, this paper
presents for the first time, a novel theory by which WCT may
exert its effect at a cellular and molecular level: Microparticle
Clearance Theory.
2. Methodology: literature search
All relevant literature was retrieved through PubMed and
Google Scholar databases using the following keywords: ‘wet
Please cite this article in press as: N. Hassan, et al., Microparticle clearance theory: An update to the potential mechanisms of action of cupping
therapy, Adv Integr Med (2020), https://doi.org/10.1016/j.aimed.2020.07.001
cupping’, ‘wet cupping therapy’, ‘bloodletting cupping’, ‘dry
cupping’ and ‘hijamah’. The search criteria were full-text scientific
papers published in English during or prior to March 2020. Only
full articles discussing and/or supporting the current theories or
proposed theories in cupping therapy were included in this review.
3. Current theories and proposed mechanisms of action
Although the exact mechanisms through which WCT exerts its
effects remains elusive, several theories that have been proposed
by researchers in recent years. This section reviews the most
widely reported theories prima facie.
3.1. Haemodynamic theory
Elsayed et al. [16] proposed a mechanism through which WCT
can clear blood plasma and interstitial fluid of causative
pathological substances such as excessive iron, ferritin and lysed
red blood cells, a theory they termed Taibah theory. In this paper,
we further discuss the proposed haemodynamic effects of WCT in
the context of chronic inflammation–which plays a major role in
the pathophysiology of a myriad of chronic conditions.
During chronic inflammation, the function of tissues is
compromised due to the reduced capillary perfusion and
accompanying activation of leukocytes [17]. The soluble mediators
produced by the leukocytes also increases the tissue pressure,
further compounding the issue. Cupping is understood to cause
localised hyperaemia as a result of the vasodilation of cutaneous
capillaries. The vasodilation is driven by the pressure differential
between the skin and the superficial capillaries [9]. Tham and
colleagues demonstrated that during cupping, the region of the
highest tensile and compressive stress is at the interface between
the rim of the cup and skin. They also demonstrated that the
negative pressure causes the rim of the cup to press against the
skin-potentially occluding superficial microcirculation [18]. The
application and removal of the negative pressure against the
cutaneous microvasculature may also induce post-occlusive
hyperaemia in a fashion analogous to skin blood flux observed
with post-occlusive reactive hyperaemia [19].
The resultant effect of hyperaemia is increased localised
perfusion as characterised by extravasation of blood and ecchy-
mosis observed following cupping treatment. Findings from Liu
et al. [20] support this by demonstrating that a single session of
cupping significantly increased blood flow to the site of application
up to thirty minutes post-application. In another study by Li et al.
[21], they used near-infrared spectroscopy to monitor the oxygen
exchange during cupping and found an increase in the level of
oxyhaemoglobin and decrease in deoxyhaemoglobin, suggesting
active exchange at the level of the microcirculation during cupping.
3.2. Blood detoxification and nitric oxide theory
Studies exploring the blood detoxification effect of WCT have
shown inconclusive results. However, many researchers maintain
that the benefits of WCT is mediated by its ability to ‘filter-out’
deleterious components within blood and modulate the release of
nitric oxide within the microvasculature. For example, Al-Bedah
et al. [22] argue that increased levels of nitric oxide in cupping
blood as reported by Tagil et al. [23], can cause vasodilation,
platelet aggregation and leukocyte adhesion. Previous work by
Niasari et al. [24] also demonstrated that WCT selectively
decreased serum levels of low-density lipoprotein, a major risk
factor of atherosclerosis. In a more recent study by Umar et al. [25],
they also found a significant reduction in systemic levels of heavy
metals (aluminium, zinc and cadmium) up to 30 days following a
session of WCT.
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Taken together, these studies suggest that WCT may have blood
detoxification effects and stimulate the release of nitric oxide.
However, it is still unclear whether these observations are due to
artefacts arising from the cupping process and therefore more
studies in the form of controlled randomised control trials should
be undertaken to confirm these effects.
3.3. Immunomodulation theory
In a study published over a decade ago by Ahmed et al. [26],
they demonstrated that WCT significantly increased levels of the
anti-inflammatory cytokine, Interleukin-4 (IL-4) in patients with
rheumatoid arthritis. Since their early work, other lines of evidence
have emerged to suggest that cupping can improve conditions
characterised by immune system dysregulation such as psoriasis
[27] and asthma [see 8].
More recently, Liu et al. [28] observed a significant difference
between the protein profiles of fluid isolates from cupping blisters
in comparison to burn blisters. Using a 2D-PAGE proteomics
approach they observed higher levels of proteins involved in
immune responses, oxidative stress and metabolic-related pro-
cesses within the cupping group. Although this study gives an
insight into the acute cellular response of the tissues following
cupping, it is still unclear whether the observed immune response
exerts beneficial physiological effects downstream of the cupping
site. Additionally, it is not understood whether the physiological
effects of cupping therapy are mediated through a mechanism of
hormesis in a similar fashion to reactive oxygen species (ROS) and
exercise [29].
Although the cellular and molecular mediators that facilitate
the immune-modulatory effects of cupping remains to be fully
elucidated, Lowe proposed that cupping causes a shift in
macrophage polarisation from a pro-inflammatory (M1) pheno-
type to an immune-regulatory (M2) phenotype [10]. Given that
the polarisation of certain M2 macrophage subtypes is
modulated by the bioavailability of IL-4, this is in congruence
with the findings from Ahmed et al. [26], who reported an
increase in IL-4 levels following WCT. This is further supported
by recent work by Zhang et al. [30] who demonstrated an
increase in anti-inflammatory lipids and the concomitant
decrease in pro-inflammatory lipids in a mouse model following
cupping therapy. They also showed that the addition of the
upregulated lipids attenuated IL-6 induced inflammation in
cultured macrophages.
Collectively, these studies suggest that cupping potentially
exerts immunomodulatory effects at the local site of cupping that
may have systemic effects. However, further research is required to
unravel the exact mechanism(s) through which cupping exerts
these proposed immunomodulatory effects.
4. Microparticle clearance theory (MCT)
Microparticles (also referred to as microvesicles) form part of a
class of submicron (100 1000 nm) membrane-bound vesicles
collectively called extracellular vesicles (EVs). These vesicles are
released by different cell types in response to a patho-/physiologi-
cal stimulus [31]. In this paper, we present for the first time, a
putative mechanism through which cupping may exert beneficial
physiological effects by modulating the bioavailability and tissue
distribution of microparticles.
Red blood cell or Erythrocyte microparticles (EMPs) are the
most widely studied class of microparticles. The release of
microparticles from erythrocytes is a protective mechanism
that occurs with the ageing of erythrocytes to prevent the
activation of the immune system through danger-associated
Please cite this article in press as: N. Hassan, et al., Microparticle clearance theory: An update to the potential mechanisms of action of cupping
therapy, Adv Integr Med (2020), https://doi.org/10.1016/j.aimed.2020.07.001
3
molecular patterns (DAMPS) [32]. However, EMPs have been
associated with systemic inflammatory conditions [33–35].
EMPs have also been shown to be involved in pro-inflammatory
priming of the immune system following transfusion [36],
which may contribute to conditions such as transfusion-
associated lung injury. Microparticles derived from platelets,
endothelial cells and leukocytes have also been associated with
disease processes [see 32]. In a study that underscores the
deleterious effects of microparticles, Danesh et al. [37]
demonstrated that granulocyte-derived EVs potently activated
monocytes ex-vivo and were linked to increased risk of mortality
among intensive care patients.
Within the microcirculation, normal haemodynamic param-
eters cause segregation of blood components, with red blood
cells flowing through the middle of the blood vessel. Other
smaller components and particles flow near the interface of the
blood vessel walls and can interact more readily with the
endothelial cells [38]. Within the blood vessels, microparticles
can initiate and promote disease processes through activation of
inflammatory signals and immune cells [39]. This can, in turn,
decrease endothelial nitric oxide bioavailability [see 40] and
activate the coagulation cascade [41], potentially leading to in
situ thrombosis.
Given the effects of cupping to the local tissue microvasculature
as reviewed in Section 3.1, we herein propose that the process of
WCT could effectively cause the clearance of microparticles at the
local site of application in a fashion akin to apheresis. Apheresis is
an extracorporeal method of separating blood components based
on their physical properties. Given that apheresis has been shown
to reduce circulating microparticles in patients with familial
hypercholesterolemia [42], we hypothesise that cupping may
induce similar effects.
The clearance of microparticles from the local microcirculation
may reduce disease pathophysiology by targeting the major
disease drivers such as chronic inflammation and endothelial
dysfunction. A mechanistic model of how WCT can potentially
exert beneficial physiolgical effects through microparticle clear-
ance is presented in Fig. 1
Microparticles play a major role in the pathogenesis of many
inflammatory disorders and have been shown to activate immune
cells through the activation of NF-kB [43]. The clearance of
microparticles by WCT could reduce the downstream activation of
inflammatory signals.
Microparticles have been shown to promote endothelial
dysfunction through inactivation of endothelial nitric oxide
synthase [44]. Therefore, Cupping-mediated clearance of micro-
particles may afford a protective effect to the tissue vasculature.
Additionally, modulation of the hydrodynamic forces by negative
pressure during WCT could potentially increase the shear stress at
the interface of endothelial lining-which causes eNOS activation
and release of nitric oxide [45,46]. The bioavailable nitric oxide
(NO) can induce vasodilation and can act as a scavenger of free
radicals in the tissue vasculature, further attenuating disease-
causing effects.
Another dimension that remains to be explored is the link
between the reported anti-nociceptive effects of cupping and
microparticles. WCT has been shown to exert analgesic effects
[47,48]. Some researchers have proposed that these effects are
mediated through β-endorphin [49], however, the mechanism
through which WCT mediates these effects remains to be fully
elucidated.
Given that microparticles are known to mediate nociception
[50], we propose that another mechanism through which cupping
may exert its analgesic effects is through the clearance of
microparticles from tissues.
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Fig. 1. Mechanistic model of Microparticle Clearance Theory. Effect of circulating microparticles on inflammation, thrombosis and endothelial dysfunction and proposed
‘clearance’ effect of cupping therapy at a cellular level.
5. Conclusion
Cupping is an ancient medical practice that has seen a
resurgence in popularity in recent years. However, the exact
mechanisms through which it exerts its effects are not fully
understood. Consequently, there is a need to elucidate the modes
of action of cupping in the light of modern medical science. In this
paper, a range of current putative mechanisms through which
cupping therapy may mediate its health-promoting effects have
been reviewed. This paper also presents, for the first time, a novel
theory through which cupping may exert its pleiotropic effects:
microparticle clearance theory. Notwithstanding, further basic
scientific and clinical research is required in order to confirm the
proposed theories through which cupping may be exerting its
effects.
CRediT authorship contribution statement
Nurudeen Hassan: Conceptualization, Writing - original draft.
Rizwhan Suleman: Writing - review & editing. Waheeb Al-
Azzani: Writing - review & editing. Hisham Jaber: Writing - review
& editing. Ali Mahdi: Writing - review & editing.
Declaration of Competing Interest
None.
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