Ikewaki et al. Thrombosis Journal(2020) 18:27
https://doi.org/10.1186/s12959-020-00239-6

REVIEW

Open Access

Coagulopathy associated with COVID-19 –Perspectives & Preventive strategies using a
biological response modifier Glucan
Nobunao Ikewaki1,2, Kosagi-Sharaf Rao3, Armando Durant Archibold3, Masaru Iwasaki4, Rajappa Senthilkumar5,
Senthilkumar Preethy5, Shojiro Katoh6 and Samuel J. K. Abraham4,6,7,8*

Abstract
Direct endothelial injury by viruses and dysregulation of clotting mechanisms due to cytokine storm are the major
precipitating factors of mortality in COVID-19; both are attributed to a fundamental dysregulation of the immune
system. While immune dysregulation can be attributed to several factors, the risk of associated thrombogenic
disruption varies across individuals. This variation depends on several factors, such as comorbidities, including
diabetes, hypertension, and cardiovascular diseases. When considering ethnic variations, the vulnerability of
Caucasians, African Americans and Hispanics needs to be addressed before arriving at strategies to handle
thromboembolic complications, which have been identified in recent reports as the leading causes of mortality in
COVID-19. Although evaluation of D-dimer and prothrombin during admission is considered to predict prognosis
and mortality, there are no preventive or prophylactic strategies before hospital admission. Herein, we present ourperspectives on the effect of regular supplementation with the biological response modifier beta glucan based on
its relevance to immune modulation. This effect is of paramount importance in decreasing the development ofsevere COVID-19 and reducing mortality against the background of coagulopathy, especially in vulnerable
populations.

Introduction
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), the novel virus behind the coronavirus
disease (COVID-19) pandemic, is wreaking havoc
around the world [1]. Efforts are ongoing to understand the pathophysiological processes underlying thedisease to mitigate complications. While severe acuterespiratory distress syndrome is the major cause ofdeath, other organ failures, such as acute kidney failure and acute cardiac injury, have also been associated with the disease [1].
* Correspondence: drsam@nichimail.jp
4
II Department of Surgery & Centre for Advancing Clinical Research (CACR),
Yamanashi University- School of Medicine, Chuo, Japan
6
Edogawa Evolutionary Laboratory of Science (EELS), Edogawa Hospital,
Tokyo, Japan
Full list of author information is available at the end of the article

The inflammatory response is highly increased during
COVID-19 infection, and this process sets the stage fororgan failure. Elevation of Th1 cytokine interferon(IFN)-gamma; inflammatory cytokines interleukin (IL)-1,
IL-6, and IL-12; neutrophil chemokine IL-8; monocyte
chemoattractant protein-1 (MCP-1); and Th1 chemokine
IFN-gamma-inducible protein-1 [2] leads to a cytokine
storm (CS) called macrophage activation syndrome(MAS) or secondary haemophagocytic lymphohistiocytosis (sHLH), which causes tissue damage [3]. Other immune dysregulation-related phenomena, including
complement activation, also play a role in the organ failure caused by the virus. The host’s innate and adaptive
immunity must come into play, encompassing different
aspects, including the production of various proinflammatory cytokines and the activation of CD4 and© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.

Ikewaki et al. Thrombosis Journal(2020) 18:27

CD8+ T cells for controlling viral infection and downregulating inflammation [3].
Coagulopathy has been reported in patients with
SARS-CoV-2. Coagulation changes in patients with
COVID-19 have been reported to include both disseminated intravascular coagulopathy (DIC) andsepsis-induced coagulopathy (SIC) [4]. During theearly phase of COVID-19 infection, there is no clinical bleeding despite coagulation test abnormalities.
Several factors, including certain treatments, havebeen found to culminate in the later development of
SIC or DIC. The term COVID-19-associated coagulopathy (CAC) has been used to describe the coagulation changes occurring in COVID-19 patients [4].
Coagulopathy leading to venous thromboembolic
events, end-organ failure secondary to a microangiopathy similar to disseminated intravascular coagulation (DIC), and stroke have all been reported in
COVID-19 but with distinct features, wherein thiscoagulopathy in COVID-19 is associated with an increased risk of death [5]. However, it should be
noted that even in the absence of advanced COVID19, large artery stroke has been reported [6]. ACE2
receptors are expressed widely within endothelial
cells, which could explain their vulnerability to
SARS-CoV-2 binding, membrane fusion, and viralentry, thereby leading to infection and direct vascular injury [7] and giving rise to the coagulopathyassociated sequence in COVID-19.
Comorbidities such as diabetes, hypertension [8],and cardiovascular diseases [9] have been associatedwith a higher risk of complications and mortality due
to COVID-19 [10]. Pre-existing increased plasmin activity occurring in hypertension, diabetes, and cardiovascular disease enhances the virulence and infectivityof the SARS-CoV-2 virus by cleaving its spike proteins, which in turn aggravates this coagulationrelated process [11].
Herein, we report our perspectives on how people
predisposed to coagulopathy and thrombogenic events
could be the main target at high risk of complications
due to COVID-19, and preventive measures can possibly be undertaken to allow predisposed people tosuccessfully defend against complications due to
COVID-19.
Coagulopathy and COVID-19 – pathological mechanisms

In COVID-19, two separate pathologic processes havebeen found to play a role in producing clinical manifestations of coagulopathy: (i) local direct vascular andendothelial injury by invasion of the virus producing
microvascular clot formation and angiopathy and (ii)mononuclear and polymorphonuclear infiltration alongwith apoptosis of endothelial and mononuclear cells as

Page 2 of 8

consequence of inflammation. Hypercoagulability withhyperfibrinogenaemia causing large vessel thrombosis
and major thromboembolic sequelae should also be considered. The most common and critical feature observedin patients with coagulopathy-related predisposition to
COVID-19 is abnormally elevated D-dimer levels. Elevated D-dimer levels have been associated with a poor
prognosis. Increased prothrombin times (PTs) and activated partial thromboplastin times (aPTTs), lower platelet counts, and increased levels of lactate dehydrogenase(LDH) and ferritin are other factors associated with apoor prognosis in several studies [10].
A review article that provides guidance for the haemostasis laboratory in the management of the thrombotic
risk associated with COVID-19 [12] suggests that themost seriously affected individuals have slightly longer
PT than patients with more favourable prognosis. APTT
is generally proportionally less prolonged than PT, probably due to an increase in plasma concentration of factor
VIII and a low platelet count at admission (i.e., < 200 ×
109/L), but it has also been associated with increased
risk of death. The authors recommend monitoring theplasma concentration of PT, fibrinogen, D-dimers andplatelet count every 48 h to continuously assess thethrombotic risk and identify timely warning signs of possible venous thrombotic events [12].
Hardy et al. [13] suggest that studies reporting on
haemostasis in COVID-19 should ensure the careful
reporting of laboratory methods to enable a correct interpretation of the thrombo-embolic risk and effects in
COVID-19. For instance, a high variability in heparin
plasma level measurement between the available measurement kits has been reported. The authors mention
that the reagents designed to measure thrombin potentials require standardization. Some patients exhibit heparin resistance, which may be due to the normal
thrombin generation profiles, which would have been reported as abnormal levels due to the methodologies
employed. They also question whether viscoelastometrictests (VETs) recommended for studying thrombogenic
profiles are truly standardized on a global scale [13].
Iba et al. [11] describe the four pathways ofcoagulation-related events and thrombus formation in
COVID-19: (i) CS and pro-inflammatory cytokines suchas interleukin (IL)-1β and IL-6 stimulate the expressionof tissue factor on immune cells, thereby initiating extrinsic coagulation cascade activation; (ii) suppression of
the fibrinolytic system by the decreased activity ofurokinase-type plasminogen activator and increased release of plasminogen activator inhibitor-1; (iii) activationof platelets by various pro-inflammatory cytokines andthe damaged endothelium readily binding with the activated platelets; and (iv) direct endothelial damage induced by inflammation.

Ikewaki et al. Thrombosis Journal(2020) 18:27

Coagulopathy and COVID-19 – incidence and vulnerable
populations

Because the thrombogenesis associated with COVID-19
is complex and very little understood, a potential distinct“COVID-19-induced coagulopathy pattern” has been
postulated [14]. The first report of haemostasis disorders
in patients with COVID-19 was by Guan et al. on 28
February 2020 [15]. In this initial cohort of 1099 hospitalized patients with COVID-19, an increased D-dimer
level above 0.5 mg/L was seen in 46.4% of the patientsduring initial presentation [15, 16]. In 191 hospitalized
patients with COVID-19, 81% of non-survivors had Ddimer levels greater than 1 mg/L on admission [17]. A
higher D-dimer level was identified in 59.6% of severe
infections compared to 43.2% of non-severe COVID-19
patients. In fact, DIC has emerged as a strong predictor
of mortality, with 71.4% of non-survivors meeting thecriteria for DIC compared to only 0.6% of survivors [18].
Therefore, regular monitoring of D-dimer, prothrombin,and fibrinogen in COVID-19 is recommended because asignificant increase in D-dimer and prothrombin with adecrease in fibrinogen has been observed at days 10–14
in non-survivors, and an elevated D-dimer level (above 1
mcg/mL) has been reported to be a strong independentrisk factor in this vulnerable population [16, 19]. Caution
should be exercised when interpreting plasma D-dimer
values and unfavourable prognosis in COVID-19 because different thresholds have been proposed for stratifying the risk of mortality (i.e., between 1000 and 3000
ng/mL), and in the presence of significant pulmonary inflammation, fibrin deposits can occur within alveoli andthe pulmonary extravascular space, whose lysis may also
contribute to the rise of D-dimers [13]. Nevertheless, theworking group on perioperative haemostasis considers
patients with plasma D-dimer levels > 3000 ng/mL as
having a very high thromboembolic risk; these patientsmight benefit from increased doses of heparin, and continued thromboprophylaxis is recommended after hospital discharge for a maximum of 45 days [20].
Other reports on the incidence of coagulopathy in
COVID-19 include one with 150 patients with
COVID-19, among whom 25 (16.7%) experienced apulmonary embolism and two had three thrombotic
circuit occlusions [21]. Lupus anticoagulants were detected in 50 of 57 patients tested (87.7%) [22]. Oxley
et al. reported five patients with acute large vessel occlusion with ischaemic stroke [23]. In the originalcases reported from Wuhan, China, stroke was seen
in 5% of patients [24]. Another report indicated anincidence of thrombotic complications of 16–49% in
patients with COVID-19 admitted to intensive care[13]. With regard to deep-vein thrombosis (DVT), of
143 patients hospitalized with COVID-19, 66 developed lower extremity DVT [25].

Page 3 of 8

Because most of the COVID-19 coagulopathy data arefrom Chinese patients owing to the first reporting of
COVID-19 being from China and because the incidenceof venous thromboembolism is approximately 3- to 4fold lower in Chinese patients [26], coagulopathy andthrombo-embolic events have been less important in
Chinese hospitals, and the use of thromboprophylaxis isalso less common. However, with the disease having affected Caucasian individuals at a magnitude several
times greater than it has affected Chinese individuals, it
is essential to know the ethnicity-related risk ofthrombogenic events. Caucasians have higher thrombotic risk than Chinese and other Asian populations,and the risk is even higher in African-American and Hispanic patients in the USA [27–29]. Consistent with thispattern, a study conducted on COVID-19 coagulopathy
in Caucasian patients showed that although the risk ofcoagulopathy was higher in Caucasians, because the patients included in the study were on low-molecularweight heparin (LMWH) thromboprophylaxis, theyrarely developed overt DIC, and in cases where DIC developed, it was during the later stages of the disease
only. The study also reported a novel pulmonary-specificvasculopathy, which we term pulmonary intravascular
coagulopathy (PIC), associated with COVID-19, that is
distinct from DIC [30, 31]. Table 1 presents the racebased risk for COVID-19 coagulopathy, which confirmsthat the risk of coagulopathy is higher in Caucasians,
African-Americans and Hispanics who should be treatedwith caution when affected with COVID-19 [32–40].
Activation of innate immunity with older age and agerelated coagulation cascade changes are also factors thathave been reported to contribute to the vulnerability ofelderly people to COVID-19 coagulopathy [41]. Alveolar
macrophages (AMs) increase during ageing, but theirplasticity to convert between pro- and anti-inflammatory
states is greatly reduced. This accelerates COVID-19 in
its early stages in the elderly and in advanced stages,
causing excessive lung damage. A decline in neutrophil
activity during ageing causes these cells to lose theirability to migrate to sites of infection and kill infected
cells. The production and diversity of mucins and protective glycoproteins contributing to mucosal barriers
also change during ageing [42]. The immunosenescenceof the adaptive immune system in the aged also contributes to progression to severe COVID-19 in this population. A decline in the production of fresh naïve T cells, aless expansive T cell receptor (TCR) repertoire, T cell
metabolic dysfunction, and weaker activation of T cells
also contribute to immune vulnerability of the aged to
COVID-19. An exploration of the link between the immune system and coagulopathy in the aged, whichmakes them a vulnerable population, identified that one
in two fatal cases of COVID-19 experience a CS, amongIkewaki et al. Thrombosis Journal(2020) 18:27

Page 4 of 8

Table 1 Factors pre-disposing a specific Race/Ethnicity for increased risk of coagulopathy
S.No Race/Ethnicity Factor V Leiden
Non-O
Lower Protein
Blood
C levels
andprothrombin
gene polymorphism Group [32, 34] [32, 35, 36][32, 33]
1

Caucasians/
Europeans

High prevalence2

Afro-Americans Intermediate
prevalence3

Hispanics

4

Africans

5

AsiansHighprevalenceHigh levels of
Procoagulant
proteins FVIII
andvon Willebrandfactor [32, 37]Highprevalence

Elevatedlevels of
D-Dimer[32, 38]

UndergoingObesitysurgery [32, 39] [32, 40]HighprevalenceHigh prevalenceHigh prevalenceIntermediate
prevalence

Low prevalenceHigh prevalence(Japanese,
Taiwaneseand Thai)

whom 82% are over the age of 60 [43]. Inflammaging isa major driver for this increased CS occurring in aged
individuals, exacerbated by obesity, poor diet and oral
health, microbial dysbiosis, and sedentary lifestyle [43].
Age-related correlation of higher basal circulating levelsof pro-inflammatory cytokines, including IL-6, TNF-α,
IL-1α, and CRP, is a reported phenomenon. During ageing, there is a gradual decline in immune function called
immunosenescence and a chronic increase in systemic
overactive but ineffective inflammation, a process known
as inflammaging. Immunosenescence is characterized by
impairment of both arms of immunity, innate and adaptive, and is characterized by ineffective pathogen recognition, macrophage activation, a reduction in naturalkiller (NK) cell cytotoxicity, thymic atrophy and accumulation of anergic memory lymphocytes [41]. The
inflammaging process in older patients underlies the
rapid progression to cytokine storms, whose key player
is NLRP3, which is the major protein component of theinflammasome and is abundant in older individuals.
NLRP3 priming induced by TLRs or tumour necrosis
factor receptor activation leads to pro-inflammatory
cytokine production, and activation is triggered by arange of stimuli that emerge during infections, such as
tissue damage, nucleic acids, and invading pathogen proteins [41]. This process is further aggravated by decreased activity of sirtuin 2 (SIRT2) in the aged, as
SIRT2 directly controls NLRP3 [41]. This cytokine storm
disrupts the feedback control mechanisms of thrombin
generation by antithrombin III, a tissue factor pathway
inhibitor, and the protein C system, which predisposes
individuals to the development of microthrombosis andDIC [43].
Coagulopathy seems to be the central factor predicting
the progression of COVID-19. It also explains why children rarely experience severe illness due to COVID-19,
as thrombotic complications in the paediatric age groupHighprevalenceHighprevalence

Low prevalence

are rare in the absence of an underlying cancer or a central venous access device. While pregnant women should
be expected to have high vulnerability to coagulopathy,
they have, in fact, been found to have only milder illness
because of immune suppression during the gestational
period to avoid foetal rejection, and thus, immunothrombosis does not come into play [43].
The vulnerability of patients with cardiovascular risk
factors such as obesity, hypertension, and diabetes to thedisease severity of COVID-19 is well established [7–9,44]. Imbalance between coagulation and fibrinolysis withincreased levels of clotting factors and relative inhibitionof the fibrinolytic system, endothelial dysfunction, andenhanced platelet aggregation and activation, which arecomplications of diabetes, favour the development of a
hypercoagulable pro-thrombotic state, thus explaining
the high risk of diabetes patients to COVID-19 in termsof disease severity [44]. With regard to hypertension,other cardiovascular diseases, in addition to alterations
in vascular and thrombogenic factors, pulmonary andperipheral endothelial injury due to direct viral attack,and CS have been indicated as inducers of hypercoagulation in these patients [45]. Another factor of concern ismicroparticles (MPs) [14]. These MPs are shed due tocell blebbing induced by activation of circulating blood
cells, including platelets and leukocytes, and of endothelial cells by the COVID-19-induced cytokine storm. The
membrane proteins on these MPs carry proteins andmiRNAs to transmit the activator signal to distant cells
propagating the disease and promote pro-coagulant responses due to the exposure of tissue factors and the activation of the coagulation cascade, ultimately leading tothrombin generation. Elevated levels of procoagulant
MPs have been described in conditions such as arterial
hypertension, diabetes mellitus, dyslipidaemia, obesity,
pulmonary embolism, arterial hypertension, acute coronary syndromes, heart failure, etc. Thus, these individuals

Ikewaki et al. Thrombosis Journal(2020) 18:27

are at high risk of COVID-19-associated coagulopathy[14]. In the case of cardiovascular comorbidities, it has
been hypothesized that damage mediated by the releaseof inflammation mediators acts on the vascular endothelium, leading to hypercoagulability and hypoxic damage
by alterations of perfusion (acute coronary syndrome,
thromboembolism, DIC) [46]. The immune response isalso responsible for myocarditis with myocardial damage. Imbalance of the normal circulatory and inflammatory homeostasis due to alterations in the ACE2
receptor adds to the pathogenetic mechanisms of thedamage, which is exacerbated by certain drugs used inpeople with hypertension, diabetes, and vascular disease,thus making these individuals at high risk of cardiovascular and thrombogenic events [46].
Preventive and therapeutic aspects of coagulopathy in
COVID-19

Having identified the various populations vulnerable tocoagulopathy-associated severity of COVID-19, we now
turn towards possible therapeutic solutions and preventive strategies. Recent guidelines recommend thromboprophylaxis for all hospitalized COVID-19 patients orfull therapeutic-intensity anticoagulation [47]. Antiplatelet drugs, thrombolysis, immunomodulatory agents, andanti-complement drugs are suggested approaches. For
anticoagulation, the drug of choice is low molecularweight heparin, and in patients who might have severe
renal impairment or extremely high risk of bleeding,unfractionated heparin is recommended [48]. Preventive
aspects deal with treating the comorbidities and end
with a maximum level of thromboprophylaxis, but all ofthese measures are suggested after a patient is hospitalized. We explored whether any other preventive strategy
is available. Supplementation with the biological response modifier beta glucan (BRMG) could be a solution
in the vulnerable population. Beta glucans are potent
biological response modifiers.
The effects of BRMG in infections and septic shock
have been reported in both in vivo animal models andclinical studies [49]. BRMGs such as the soluble beta 1,3
glucans have been found to decrease septic complications and improve survival by acting on cytokine production and regulating coagulation activation [50] in a
rat model. Preventive supplementation by BRMG prior
to infection with S. aureus prevented sepsis in a guinea
pig model [49]. Macrophage activation by BRMG has
been shown to significantly reduce septic morbidity andmortality in human patients [51, 52]. In a randomized
phase I/II trial, BRMG supplementation as an immune
prophylaxis helped reduce postoperative infectious complications in patients undergoing major surgery bystimulating leucocytosis and phagocytic activity [52].
BRMG recognizes and interacts with the innate immune

Page 5 of 8

system in humans to help combat infections [53]. Radiation exposure and/or diabetes-induced oxidative stress,
which causes disturbances in the measured clotting parameters by enhancing platelet aggregation and increasing thrombin levels, were reversed by yeast BRMG [50].
A BRMG from a black yeast, Aureobasidium pullulans (AFO-202), has been reported to be a potent
immune modulator acting through its receptor,
Dectin-1, which cooperates with pattern recognition
receptors (PRRs) and Toll-like receptors (TLRs) in
the innate immune response [54]. This BRMG reduces the levels of IL-1β, IL-2, IL-4, IL-6, IL-12,
TNF-α, IFN-γ, and sFasL while increasing IL8 andsFAS [34], thereby balancing an effective optimal defence against viral infection without hyperinflammation. Anti-viral defence activities of BRMG occur
through increased IL8, which causes activation, migration, and chemotaxis of neutrophils to kill virusinfected cells; increased type-I IFN production,
which helps kill virus-infected cells; increased IL-7
production, which leads to development and survivalof mature T-cells to maintain homeostasis; activationof B-cells, which results in production of virusspecific antibodies (IgG, IgM and sIgA) for
neutralization of virus toxicity; and increased NK cell
activity and macrophage activity [7]. Prevention of
hyperinflammation occurs by preventing the onset of
apoptosis through increased sFAS production, regulation and suppression of CS through activation ofTreg cells and decreased IL6, and prevention of chemoattraction of monocytes and macrophages, T cells,
NK cells, and dendritic cells through a decrease in
CXCL10 and CCL2 (monocyte chemotactic protein
1; MCP-1) [7]. AFO-202 BRMG was found to enhance NK activity and cellular immunity in Leishmania amazonensis-infected mice [55]. AFO-202
BRMG has been demonstrated to protect mice infected with a lethal titre of the A/Puerto Rico/8/34(PR8; H1N1) strain of influenza virus, and the mechanism of action was found to be through inhibitionof viral replication [56].
The effects of this BRMG in acting as a prophylactic
supplement to help combat coagulopathy associatedwith COVID-19 are illustrated in Fig. 1.
SARS-CoV-2 infection triggers a cascade of events that
result in a gradually increasing hyperinflammatory state,
which in turn provokes thrombogenicity culminating ina potentially devastating microangiopathy, contributing
to COVID-19-induced acute respiratory distress syndrome (ARDS) and organ damage [57]. AFO-202 BRMG
has been proven to attenuate CS caused by proinflammatory cytokines such as IL-6 while mounting
anti-viral defence [54] by upregulating NK cells, macrophages and factors such as IL8, sFAS, type I IFN, IL andIkewaki et al. Thrombosis Journal(2020) 18:27

Page 6 of 8

Fig. 1 A schematic illustration of the implications of the COVID-19 coagulopathy cascade and the stepwise mechanism that leads to organ
damage. Various risk factors modulated by the biological response modifier (BRM) glucan at various steps of this cascade are listed and gradedantibodies. AFO-202 BRMG has also been proven efficacious in lifestyle diseases in East Asian and South Asian
populations with maintenance of blood glucose and lipid
levels [58–60]. Since comorbidities such as hypertension,
diabetes mellitus, dyslipidaemia and obesity have a verystrong correlation to coagulopathies due to the presenceof a dysregulated inflammatory system [61], BRMG will
be beneficial in decreasing the risk of coagulopathy inthese individuals with dual risk (COVID-19-induced risk
and comorbidity-induced risk). BRMGs have been reported to have direct antiplatelet, antioxidative, anticoagulant and antithrombotic actions, which further
supports their beneficial effects as a supplement to prevent COVID-19-associated coagulopathy. Due to these
attributes of BRMG, although it has not been tested inpeople with COVID-19 or those with ethnic or otherpredispositions to coagulopathy, it is worth considering
its efficacy in controlling a pathophysiology that maytrigger coagulopathy due to hyperinflammation.

Conclusion
The proposed mechanisms for multiorgan dysfunction in COVID-19 are multifactorial, and a

hypercoagulable state with micro- and macrocirculatory thrombosis has been identified as a key factor
determining the clinical course and disease severity.
Ethnically vulnerable populations such as Caucasians,
African Americans, Hispanics, the elderly population,and patients with comorbidities are at high risk andrequire prevention during this hypercoagulable state.
D-dimer and prothrombin have emerged as the mostimportant biomarkers to be analysed at the time of
hospital admission due to COVID-19. In the present
scenario, where there is no definite pharmacologicalremedy for prevention or treatment presently available, a biological response modifier beta glucan foodsupplement that has several advantages in modulating the immune response is considered to be worth
recommendation for clinical studies of COVID-19,
especially in vulnerable populations.
Acknowledgements
We thank Mr. Takashi Onaka, (Sophy Inc., Kochi, Japan), for necessary
technical clarifications. KR & AD are thankful to National Science System (SNI62-2019) of SENACYT, Panama for the support. RS & SP are thankful to
Loyola-ICAM College of Engineering & Technology (LICET), Loyola Campus,
Chennai, India for their support.

Ikewaki et al. Thrombosis Journal(2020) 18:27

Page 7 of 8

Authors’ contributions
NI, KR, SK, and SA contributed to conception and design of the study. RS
performed the literature search and data analysis. SA & SP drafted themanuscript. AD, MI, KR & SA performed critical revision of the manuscript. All
the authors read, and approved the submitted version.

8.

Funding
The article did not receive any external funding.

10.

Availability of data and materials
Not applicable.

11.

Ethics approval and consent to participate
Not applicable.

12.

Consent for publication
Not applicable.
Competing interests
1. Nobunao Ikewaki is an employee of Dept. of Medical Life Science, Kyushu
University of Health and Welfare, Japan & Institute of Immunology, Junsei
Educational Institute, Nobeoka, Miyazaki, Japan
2. Rao Kosagi-Sharaf and Armando Durant Archibold are employees of INDI
CASAT AIP, Panama
3. Masaru Iwasaki is a faculty in Yamanashi University, Japan
4. Rajappa Senthilkumar and Senthilkumar Preethy are employees of NCRM,
India
5. Shojiro Katoh is a faculty of EELS & employee of Edogawa Hospital, Japan
6. Samuel Abraham is a faculty in Yamanashi University, EELS, Edogawa
Hospital, Japan & NCRM, India, as well as shareholder in GN Corporation,
Japan which in turn is a shareholder in the manufacturing company of the
AFO 202 Beta Glucan.
Author details
1
Department of Medical Life Science, Kyushu University of Health andWelfare, Nobeoka, Miyazaki, Japan. 2Institute of Immunology, Junsei
Educational Institute, Nobeoka, Miyazaki, Japan. 3Instituto de Investigaciones
Científicas y Servicios de Alta Tecnología (INDICASAT AIP), City of Knowledge,
Panama City, Panama. 4II Department of Surgery & Centre for Advancing
Clinical Research (CACR), Yamanashi University- School of Medicine, Chuo,
Japan. 5The Fujio-Eiji Academic Terrain (FEAT), Nichi-In Centre forRegenerative Medicine (NCRM), Chennai, India. 6Edogawa Evolutionary
Laboratory of Science (EELS), Edogawa Hospital, Tokyo, Japan. 7The
Mary-Yoshio Translational Hexagon (MYTH), Nichi-In Centre for Regenerative
Medicine (NCRM), Chennai, India. 8GN Corporation Co. Ltd, Kofu, Japan.

9.

13.

14.
15.
16.

17.

18.

19.

20.

21.

22.
Received: 22 July 2020 Accepted: 22 September 2020

References
1. Nahum J, Morichau-Beauchant T, Daviaud F, Echegut P, Fichet J, Maillet JM,
Thierry S. Venous thrombosis among critically ill patients with coronavirus
disease 2019 (COVID-19). JAMA Netw Open. 2020;3:e2010478.
2. Quartuccio L, Semerano L, Benucci M, Boissier MC, De Vita S. Urgent
avenues in the treatment of COVID-19: targeting downstream inflammation
to prevent catastrophic syndrome. Joint Bone Spine. 2020;87:191–3.
3. Tufan A, Avanoğlu Güler A, Matucci-Cerinic M. COVID-19, immune system
response, hyperinflammation and repurposing antirheumatic drugs. Turk J
Med Sci. 2020;50:620–32.
4. Connors JM, Levy JH. COVID-19 and its implications for thrombosis andanticoagulation. Blood. 2020;135:2033–40.
5. Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis
in patients with COVID-19. Lancet Haematol. 2020;7:e438–40.
6. Fara MG, Stein LK, Skliut M, Morgello S, Fifi JT, Dhamoon MS.
Macrothrombosis and stroke in patients with mild Covid-19 infection. J
Thromb Haemost. 2020. https://doi.org/10.1111/jth.14938.
7. Rao KS, Suryaprakash V, Senthilkumar R, Preethy S, Katoh S, Ikewaki N,
Abraham S. Role of immune dysregulation in increased mortality among a
specific subset of COVID- 19 patients and immune-enhancement strategies
for combatting through nutritional supplements. Front Immunol. 2020.
https://doi.org/10.3389/fimmu.2020.01548.

23.

24.

25.
26.
27.

28.
29.

30.

Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes
mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020;8:
e21.
Wang B, Li R, Lu Z, Huang Y. Does comorbidity increase the risk of patientswith COVID-19: evidence from meta-analysis. Aging (Albany NY). 2020;12:6049–57.
Monteil V, Kwon H, Prado P, et al. Inhibition of SARS-CoV-2 Infections inEngineered Human Tissues Using Clinical-Grade Soluble Human ACE2. Cell.
2020;181:905–913.e7.
Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of coronavirus
disease 2019. Crit Care Med. 2020. https://doi.org/10.1097/CCM.
0000000000004458.
Hardy M, Douxfils J, Bareille M, et al. Studies on hemostasis in COVID-19
deserve careful reporting of the laboratory methods, their significance andtheir limitations [published online ahead of print, 2020 Aug 13]. J Thromb
Haemost. 2020;https://doi.org/10.1111/jth.15061.
Hardy M, Lecompte T, Douxfils J, et al. Management of the thrombotic risk
associated with COVID-19: guidance for the hemostasis laboratory.
Thrombosis J. 2020;18:17. https://doi.org/10.1186/s12959-020-00230-1.
Marchandot B, Sattler L, Jesel L, et al. COVID-19 related coagulopathy: adistinct entity? J Clin Med. 2020;9:E1651.
Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease2019 in China. N Engl J Med. 2020;382:1708–20.
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters areassociated with poor prognosis in patients with novel coronavirus
pneumonia. J Thromb Haemost. 2020. https://doi.org/10.1111/jth.14768.
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality ofadult inpatients with COVID19 in Wuhan, China: a retrospective cohort
study. Lancet. 2020;395:1054–62. https://doi.org/10.1016/S01406736(20)30566-3.
Lillicrap D. Disseminated intravascular coagulation in patients with 2019nCoV pneumonia. J Thromb Haemost. 2020;18:786–7. https://doi.org/10.
1111/jth.14781.
Becker RC. COVID-19 update: Covid-19-associated coagulopathy [published
online ahead of print, 2020 May 15]. J Thromb Thrombolysis. 2020:1–14.
https://doi.org/10.1007/s11239-020-02134-3.
Susen S, Tacquard CA, Godon A, Mansour A, Garrigue D, Nguyen P, et al.
Prevention of thrombotic risk in hospitalized patients with COVID19 andhemostasis monitoring: proposals from the French working group on
perioperative Haemostasis (GIHP) the French Sdy group on thrombosis andHaemostasis (GFHT), in collaboration with the French Society for
Anaesthesia and Intensive Care (SFAR). Crit Care. 2020;24(1):364.
Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic
complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;
191:145–7.
Leonard-Lorant I, Delabranche X, Severac F, et al. Acute pulmonary
embolism in COVID-19 patients on CT angiography and relationship to Ddimer levels. Radiology. 2020;201561. https://doi.org/10.1148/radiol.
2020201561.
Oxley TJ, Mocco J, Majidi S, et al. Large-vessel stroke as a presenting featureof Covid-19 in the young. N Engl J Med. 2020;382(20):e60. https://doi.org/
10.1056/NEJMc2009787.
Zhang L, Feng X, Zhang D, et al. Deep vein thrombosis in hospitalized
patients with coronavirus disease 2019 (COVID-19) in Wuhan, China:
prevalence, risk factors, and outcome. Circulation. 2020. https://doi.org/10.
1161/CIRCULATIONAHA.120.046702.
COVID-19 coagulopathy: an evolving story. Lancet Haematol. Editorial. 2020:
7. https://doi.org/10.1016/S2352-3026(20)30151-4.
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019
novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.
Liao S, Woulfe T, Hyder S, Merriman E, Simpson D, Chunilal S. Incidence ofvenous thromboembolism in different ethnic groups: a regional directcomparison study. J Thromb Haemost. 2014;12:214–9.
White RH, Keenan CR. Effects of race and ethnicity on the incidence ofvenous thromboembolism. Thromb Res. 2009;123(Suppl 4):S11–7.
Gurumurthy G, Gaddam A, Patel V, Patel RS. Coagulopathy and hospitaloutcomes in patients with spontaneous bacterial peritonitis: a call for action
to improve Care of Inpatients. Cureus. 2020;12(6):e8926.
Fogarty H, Townsend L, Ni Cheallaigh C, et al. More on COVID-19
coagulopathy in Caucasian patients. Br J Haematol. 2020. https://doi.org/10.
1111/bjh.16791.

Ikewaki et al. Thrombosis Journal(2020) 18:27

31. McGonagle D, O'Donnell JS, Sharif K, Emery P, Bridgewood C. Immune
mechanisms of pulmonary intravascular coagulopathy in COVID-19
pneumonia. Lancet Rheumatol. 2020. https://doi.org/10.1016/S26659913(20)30121-1.
32. Zakai NA, McClure LA. Racial differences in venous thromboembolism. J
Thromb Haemost. 2011;9:1877–82. https://doi.org/10.1111/j.1538-7836.2011.
04443.x.
33. Margaglione M, Grandone E. Population genetics of venous
thromboembolism. A narrative review. Thromb Haemost. 2011;105:221–31.
34. Folsom AR, Wu KK, Conlan MG, Finch A, Davis CE, Marcucci G, Sorlie PD,
Szklo M. Distributions of hemostatic variables in blacks and whites:
population reference values from the atherosclerosis risk in communities(ARIC) study. Ethn Dis. 1992;2:35–46.
35. Cushman M. Epidemiology and risk factors for venous thrombosis. Semin
Hematol. 2007;44:62–9.
36. Angchaisuksiri P, Atichartakarn V, Aryurachai K, Archararit N, Rachakom B,
Atamasirikul K, Tiraganjana A. Risk factors of venous thromboembolism inthai patients. Int J Hematol. 2007;86:397–402.
37. Lutsey PL, Cushman M, Steffen LM, Green D, Barr RG, Herrington D, Ouyang
P, Folsom AR. Plasma hemostatic factors and endothelial markers in four
racial/ethnic groups: the MESA study. J Thromb Haemost. 2006;4:2629–35.
38. Cushman M, Folsom AR, Wang L, Aleksic N, Rosamond WD, Tracy RP,
Heckbert SR. Fibrin fragment D-dimer and the risk of future venous
thrombosis. Blood. 2003;101:1243–8 10.1182/blood-2002-05-1416 2002-051416.
39. White RH, Zhou H, Romano PS. Incidence of symptomatic venous
thromboembolism after different elective or urgent surgical procedures.
Thromb Haemost. 2003;90:446–55.
40. Centers for Disease Control and Prevention. Differences in prevalence ofobesity among black, white, and Hispanic adults – United States, 2006–
2008. MMWR Morb Mortal Wkly Rep. 2009;58:740–4.
41. Mueller AL, McNamara MS, Sinclair DA. Why does COVID-19
disproportionately affect older people? Aging (Albany NY). 2020;12(10):9959–81.
42. Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between
inflammation and coagulation. Lancet Respir Med. 2020;8:e46-7.
43. Thachil J, Agarwal S. Understanding the COVID-19 coagulopathy spectrum.
Anaesthesia. 2020. https://doi.org/10.1111/anae.15141.
44. Hussain A, Bhowmik B. Do Vale Moreira NC. COVID-19 and diabetes:
knowledge in progress. Diabetes Res Clin Pract. 2020;162:108142.
45. Cao W, Li T. COVID-19: towards understanding of pathogenesis. Cell Res.
2020;30:367–9.
46. Mansueto G, Niola M, Napoli C. Can COVID 2019 induce a specificcardiovascular damage or it exacerbates pre-existing cardiovasculardiseases? Pathol Res Pract. 2020;216:153086.
47. Kollias A, Kyriakoulis KG, Dimakakos E, Poulakou G, Stergiou GS, Syrigos K.
Thromboembolic risk and anticoagulant therapy in COVID-19 patients:
emerging evidence and call for action. Br J Haematol. 2020;189:846–7.
48. Engstad CS, Engstad RE, Olsen JO, Osterud B. The effect of soluble beta-1,3glucan and lipopolysaccharide on cytokine production and coagulation
activation in whole blood. Int Immunopharmacol. 2002;2:1585–97. https://doi.org/10.1016/s1567-5769(02)00134-0.
49. Kernodle DS, Gates H, Kaiser AB. Prophylactic anti-infective activity of poly[1-6]-beta-D-glucopyranosyl-[1-3]-beta-D-glucopryanose glucan in a Guinea
pig model of staphylococcal wound infection: antimicrobial agents andchemotherapy. Antimicrob Agents Chemother. 1998;42:545–9.
50. El-Kashoury, Fattah SM, Ramadan L, El-Denshary ES. The Role of Yeast Beta
Glucan on Blood Coagulation in Streptozotocin-Induced Diabetes andIrradiated Rats. 2016. Available from https://www.semanticscholar.org/
paper/The-Role-of-Yeast-Beta-Glucan-on-Blood-Coagulation-El-KashouryFattah/6f68a9067831eebb0015c2961882d1e91a89e84f . Accessed, June 18,
2020.
51. Williams DL, Mueller A, Browder W. Glucan-Based Macrophage Stimulators.
Clin Immunother. 5:392–9. https://doi.org/10.1007/BF03259335.
52. Babineau TJ, Marcello P, Swails W, Kenler A, Bistrian B, Forse RA.
Randomized phase I/II trial of a macrophage-specific immunomodulator(PGG-glucan) in high-risk surgical patients. Ann Surg. 1994;220:601–9.
53. Sissener EC, Engstad RE, Olsen JO, Østerud B. The effect of soluble h-1, 3glucan and lipopolysaccharide on cytokine production and coagulation
activation in whole blood. Int Immunopharmacol. 2002;2:1585–97.

Page 8 of 8

54. Ikewaki N, Fujii N, Onaka T, Ikewaki S, Inoko H. Immunological actions ofSophy beta-glucan (beta-1,3-1,6 glucan), currently available commercially asa health food supplement. Microbiol Immunol. 2007;51:861–73.
55. Yatawara L, Wickramasinghe S, Nagataki M, et al. Aureobasidium-derived
soluble branched (1,3-1,6) beta-glucan (Sophy beta-glucan) enhances
natural killer activity in Leishmania amazonensis-infected mice. Korean J
Parasitol. 2009;47:345–51.
56. Muramatsu D, Iwai A, Aoki S, et al. β-Glucan derived from Aureobasidium
pullulans is effective for the prevention of influenza in mice. PLoS One.
2012;7:e41399.
57. Henry BM, Vikse J, Benoit S, Favaloro EJ, Lippi G. Hyperinflammation andderangement of renin-angiotensin-aldosterone system in COVID-19: a novel
hypothesis for clinically suspected hypercoagulopathy and microvascularimmunothrombosis. Clin Chim Acta. 2020;507:167–73.
58. Dedeepiya VD, Sivaraman G, Venkatesh AP, Preethy S, Abraham SJ. Potential
effects of nichi glucan as a food supplement for diabetes mellitus andhyperlipidemia: preliminary findings from the study on three patients from
India. Case Rep Med. 2012;2012:895370.
59. Ganesh JS, Rao YY, Ravikumar R, et al. Beneficial effects of black yeast
derived 1-3, 1-6 Beta Glucan-Nichi Glucan in a dyslipidemic individual ofIndian origin--a case report. J Diet Suppl. 2014;11:1–6.
60. Ikewaki N. Results of oral consumption of AFO-202 Beta Glucan in elderly
volunteers and cancer patients through NK cell activity. Abstract presented
at 28th Annual Meeting of Japanese Society for Parenteral and Enteral
Nutrition; 2013.
61. Pretorius L, Thomson GJA, Adams RCM, Nell TA, Laubscher WA, Pretorius E.
Platelet activity and hypercoagulation in type 2 diabetes. Cardiovasc
Diabetol. 2018;17:141.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.