MINI REVIEW
published: 16 May 2022
doi: 10.3389/fmed.2022.866746
The Therapeutic Potential of
Anticoagulation in Organ Fibrosis
Hanna Oh † , Hye Eun Park † , Min Su Song † , HaYoung Kim † and Jea-Hyun Baek*
School of Life Sciences, Handong Global University, Pohang, South Korea
Fibrosis, also known as organ scarring, describes a pathological stiffening of organs
or tissues caused by increased synthesis of extracellular matrix (ECM) components. In
the past decades, mounting evidence has accumulated showing that the coagulation
cascade is directly associated with fibrotic development. Recent findings suggest
that, under inflammatory conditions, various cell types (e.g., immune cells) participate
in the coagulation process causing pathological outcomes, including fibrosis. These
findings highlighted the potential of anticoagulation therapy as a strategy in organ
fibrosis. Indeed, preclinical and clinical studies demonstrated that the inhibition of blood
coagulation is a potential intervention for the treatment of fibrosis across all major organs
(e.g., lung, liver, heart, and kidney). In this review, we aim to summarize our current
knowledge on the impact of components of coagulation cascade on fibrosis of various
organs and provide an update on the current development of anticoagulation therapy
for fibrosis.
Edited by:
Peter Olinga,
University of Groningen, Netherlands
Reviewed by:
Eliane Pedra Dias,
Fluminense Federal University, Brazil
*Correspondence:
Jea-Hyun Baek
jbaek@handong.edu
† These
authors have contributed
equally to this work
Specialty section:
This article was submitted to
Pathology,
a section of the journal
Frontiers in Medicine
Received: 31 January 2022
Accepted: 13 April 2022
Published: 16 May 2022
Citation:
Oh H, Park HE, Song MS, Kim H
and Baek J-H (2022) The Therapeutic
Potential of Anticoagulation in Organ
Fibrosis. Front. Med. 9:866746.
doi: 10.3389/fmed.2022.866746
Frontiers in Medicine | www.frontiersin.org
Keywords: fibrosis, coagulation, ECM, coagulation factors, hemostasis
INTRODUCTION
Fibrosis (organ scarring) denotes a pathological condition characterized by the elevation of
interstitial fibrous tissue. The hallmarks of fibrosis include the presence and persistence of
myofibroblasts and collagen deposits. Fibrosis is a consequence of failed tissue repair, often
occurring due to a severe incurable, persisting, or repeated injury.
An injured tissue activates a tightly coordinated tissue repair program that is classically divided
into four processes: (1) hemostasis, (2) inflammation, (3) proliferation, and (4) remodeling (1).
Hemostasis induces vasodilation and platelet “plug” activation in response to an injury. Hemostasis
activates blood coagulation, a complex cascade system that leads to fibrin clot formation in the
damaged tissue. The fibrin clot minimizes bleeding as well as traps immune cells and pathogens
facilitating immune response against infection (2). Hemostasis is accompanied by inflammation, a
localized response to tissue damage. Hemostasis and inflammation affect each other: inflammation
activates the hemostatic system that, in turn, controls inflammatory activity (3).
To date, studies have indicated that the persistence of fibrin in the matrix promotes fibrosis (4);
increased levels of fibrinogen or impaired fibrinolysis increases collagen formation and subsequent
fibrosis, while loss of fibrinogen or improved fibrinolysis ameliorates fibrosis (3–9). These findings
led to the identification of coagulation factors as therapeutic targets in organ fibrosis. Indeed,
Abbreviations: ARDS, acute respiratory distress syndrome; BALF, bronchoalveolar lavage fluid; ECM, extracellular
matrix; IPF, idiopathic pulmonary fibrosis; IRI, ischemia-reperfusion injury; LMWH, low-molecular-weight heparin; PAI,
plasminogen activator inhibitor; PAR, protease-activated receptor; SMA, smooth muscle actin; TF, tissue factor; MMP, matrix
metalloprotease; TIMP, tissue inhibitor of metalloprotease.
1
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Oh et al.
Anticoagulants in Organ Fibrosis
growing evidence shows that the inhibition of blood coagulation
is a promising intervention for the treatment of fibrosis across all
major organs (5). However, the precise mechanistic link between
fibrin and collagen formation still deserves further investigations.
COAGULATION FACTORS IN ORGAN
FIBROSIS
MECHANISMS OF BLOOD
COAGULATION
The tissue factor (TF)-FVII/VIIa complex has been studied
as a potential mechanism by which the coagulation cascade
contributes to pulmonary fibrosis development (17). TF
expression is upregulated in the bronchoalveolar lavage fluid
(BALF) of IPF patients and on type II pneumocytes of IPF
patients (18, 19). Concerning IPF, the TF-FVII/VIIa complex
has also been observed in the BALF obtained from patients with
acute respiratory distress syndrome (ARDS); lung injury of which
fluid leakage into the lungs may progress to a fibroproliferative
response (20, 21). FVII has also been linked to intra-alveolar
fibrosis, considered to be involved in the merging of alveolar
walls observed in IPF, as it has been identified in intra-alveolar
fibrosis patients (22, 23).
Increasing amounts of evidence supported that both
FX/Xa and thrombin, other than their role in downstream
coagulation cascade precursor activation, are involved in the
fibro-proliferative response activation in IPF (23–27). Increased
FXa expression has been reported in fibrotic lung tissue (28).
The presence of FX activating procoagulant microparticles has
been identified in the airways of IPF patients (29). Elevated
thrombin levels in BALF samples obtained from pulmonary
fibrosis patients have been reported as well (30, 31). It has been
shown that FX/Xa and thrombin can cleave protease-activated
receptors (PARs) for the activation of fibroblast proliferation
and myofibroblast differentiation (32–35). FX/Xa and thrombinmediated activation of PARs profibrotic effects also induce
proinflammatory cytokine secretion and ECM deposition
stimulation (26, 36).
The involvement of coagulation FVIII/VIIIc, FXIIa, and other
prothrombotic factors may also play important roles in IPF.
Elevated levels of FVIII/VIIIc were observed in IPF patients (35,
37). In one study, IPF patient lung fibroblasts were reported to
have enhanced binding capacity for FXIIa, suggesting a potential
role of FXIIa in fibrosis (38).
Coagulation Factors in Pulmonary
Fibrosis
Blood coagulation is a cascade system of enzymes that collectively
produce fibrin clot in damaged tissues. The fibrin clot provides
a provisional matrix for tissue repair: the fibrin matrix
acts as a reservoir of growth factors and proinflammatory
cytokines, promoting leukocyte migration, and the accumulation,
activation, and proliferation of fibroblasts (6).
The coagulation cascade is divided into three pathways:
the intrinsic, extrinsic, and common pathways (Figure 1)
(10). The extrinsic pathway consists of the extravascular tissue
factor (TF) and coagulation factor VII/VIIa (FVII/FVIIa)
(11). TF is a protein constitutively expressed in tissues
(e.g., by smooth muscle cells, pericytes, and fibroblasts) (7).
Once TF binds to circulating FVIIa, the TF:FVIIa complex
is formed. The TF:FVIIa complex then hydrolyses FX to
its active form FXa. Under inflammatory conditions, TF is
additionally expressed by monocytes, neutrophils, endothelial
cells, and platelets leading to pathologic outcomes (e.g.,
thrombosis) (12). The intrinsic pathway consists of FIX, FXI,
and FXII. The intrinsic pathway is also called the contact
activation pathway because coagulation factors are activated
by an externally charged surface (e.g., collagen). The intrinsic
pathway begins with the binding of three plasma proteins
(FXII, prekallikrein, high molecular weight kininogen) to a
surface (13). The subsequent activation of FXII to FXIIa
converts FXI to FXIa. FXIa, in turn, activates FIX, which
forms a complex with its cofactor FVIIIa, converting FX
to FXa. In the common pathway, FXa and its cofactor FV
activate prothrombin to produce thrombin (FIIa). Thrombin
subsequently converts fibrinogen to form fibrin, and activates
FXIII to FXIIIa, covalently crosslinking the fibrin strands to
form a more stable fibrin network. Once thrombin is activated,
the amplification of coagulation begins. This occurs through
thrombin, which catalysis the activation of FV, FVII, FIX, FX,
and FXI (14).
During normal tissue repair, fibrin is removed by a process,
called fibrinolysis, mediated by the serine protease plasmin,
which is converted from plasminogen by the urokinase-type
(uPA) and tissue-type plasminogen activator (tPA) and regulated
by plasminogen activator inhibitor-1 (PAI-1) (15). PAI-1 is
induced inflammatory cytokines and growth factors (e.g., EGF,
IL-1β, TGF-β) (8). Normally, PAI-1 is significantly elevated in
fibrotic tissues, and PAI-1 deficiency protects organs from fibrosis
in response to injury-related profibrotic signals (8).
Recent studies on the coagulation cascade have revealed that
the function of the coagulation cascade is not limited to fibrin
clot formation and prevention of blood loss, but it is also crucial
in regulating the inflammatory response, tissue repair, and wound
healing process (16).
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Coagulation Factors in Hepatic Fibrosis
Several clinical studies have indicated that anticoagulation may
be a promising therapeutic approach in hepatic fibrosis (39–43).
Congruently, a meta-analysis of preclinical studies also provided
strong evidence that anticoagulants alleviate hepatic fibrosis (44).
Chronic liver diseases are often associated with portal vein
thrombosis (PVT), and anticoagulation is a standard of care for
treating PVT. Thus, studies have assessed the pharmacological
safety of anticoagulants in patients with advanced chronic liver
diseases (45–47).
Coagulation factors, FV, FVII, and FX are particularly
prominent in hepatic fibrosis and cirrhosis (48–50). Due to the
promotion of prothrombic state by these factors, fibrin(ogen)
deposits may obstruct the hepatic sinusoids, which affect the
blood flow and may set the base for fibrosis initiation or
liver disease advancement (48). A connection between TF
2
May 2022 | Volume 9 | Article 866746
Oh et al.
Anticoagulants in Organ Fibrosis
FIGURE 1 | Coagulation cascade and anticoagulants.
and cardiac remodeling, although whether PAR-1 directly
affected myocardial infarction is unclear (57). Also, peptide
agonists of PAR-1 and PAR-2 stimulated cardiac fibroblast
proliferation. These collective data corroborated the role of
PAR signaling mediated by coagulation factors, thrombin and
FXa in cardiac inflammation, fibrotic response, and repair
process.
and hepatic fibrosis is suggested as fibrosis was reduced in
transgenic mice lacking TF (51). In preclinical studies, FXa
played an essential role in CCl4-induced hepatic fibrosis (52).
Furthermore, FXa stimulated proinflammatory and profibrotic
mediator production and thus activated hepatic stellate cells
(HSCs) and the fibrogenic process (52). Also, TF signaling plays
a direct role in CD68+ macrophage activation (53). Macrophages
constitutively express and upregulate TF as macrophages mature
(53). Kupffer cell polarization (M1) may be regulated and
sustained by TF signaling (53).
Coagulation Factors in Renal Fibrosis
The role of coagulation factors in kidney disease beyond normal
hemostasis and thrombosis has been long suspected, and the
increasing clinical utilization of anticoagulants targeting specific
coagulation factors gain deeper insights into the mechanisms
through which the coagulation system modulates renal health
(58). Notably, increased TF expression has been detected in
acute and chronic kidney diseases (59–64). Proinflammatory
stimuli induce glomerular FV expression, whereas kidney IRI
induces tubular fibrinogen expression (63, 65–67). Direct effects
of coagulation proteases such as thrombin or FXa on glomerular
cells have long been known, implying receptor-dependent
modulation of intracellular signaling pathways (63, 68). The
expression of PARs in renal cells provides a molecular link
between coagulation factors and renal cell function (69–72).
Coagulation Factors in Cardiac Fibrosis
A murine cardiac fibrosis model exhibited elevated levels of
locally produced FXa compared to sham-operated mice. FXa
is upregulated in the hypertrophic fibrotic cardiac interstitium
(54). During cardiac fibrosis, PARs are activated by thrombin
and FXa and induce cardiac fibroblast proliferation as well as
myofibroblast activation (55). The infarction size of PAR-2 KO
mice was significantly reduced after 30 min of ischemia on
the heart, and the mRNA transcription of inflammatory genes,
IL-1β, IL-6, and TNF-α, was attenuated in the heart of PAR2 KO mice (56). However, transgenic mice that overexpressed
PAR-1 on cardiomyocytes exhibited increased hypertrophy
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ANTICOAGULANTS IN ORGAN FIBROSIS
of the TF-FVIIa complex may occur on platelets, potentially
after absorbing microvesicles containing TF (86–88). Platelets are
known for their role in accelerating the activation of coagulation
cascade by setting the base for the prothrombinase complex
to form (89). Platelets, by aggregating to the site of fibrosis,
may worsen organ destruction (90). Research has shown that
anti-platelet agents are also effective in attenuating organ fibrosis.
Aspirin inhibits platelets by acetylating serine529 in the active
site of the platelet cyclooxygenase (COX) (91). By changing the
structure of the active site, the platelet-dependent thromboxane
formation is inhibited (91). Aspirin can reduce the severity
of hepatic fibrosis and renal impairment (75, 92). Significant
improvement in hepatic fibrosis was observed at both low- and
high-dose levels of aspirin-treated groups, with a remarkable
improvement in the high-dose aspirin-treated group (75). In
the case of CKD, aspirin has beneficial effects in mild renal
impairment conditions compared to moderate renal impairment
conditions (92).
Clopidogrel is another anti-platelet drug used to treat
thrombosis and has found applications in the treatment of
certain types of fibrosis in mouse models (93). Clopidogrel works
as an anti-platelet drug by preventing ADP from stimulating
P2Y12 , the purinergic receptor of platelets (94). Clopidogrel
combats fibrosis through mechanisms related to angiotensin
II, which has had reports of being a pro-fibrotic factor (93).
Therapeutic effects of clopidogrel when combating fibrosis
are assumed to occur by inhibiting angiotensin II-induced
accumulation of myofibroblasts (93). As a treatment of hepatic
fibrosis, clopidogrel shows a more promising effect compared to
dabigatran, a direct oral anticoagulant, indicated by the difference
between the hydroxyproline expressions: the main component of
collagen and a potential fibrosis marker (95).
Other platelet inhibitors are currently under development for
the treatment of fibrosis. Ticagrelor and prasugrel are P2Y12
antagonists and may also work as platelet antagonists. These
drugs bind to P2Y12 , the adenosine diphosphate (ADP) receptor
of platelets, and prevent blood coagulation (93). A recent
study has shown that ticagrelor may have a positive effect in
ameliorating pulmonary fibrosis in rats (96). Likewise, prasugrel
may have positive effects on relieving hepatic fibrosis (90).
However, further research is necessary for these drugs to be used
in human clinical trials as it is unclear, whether the effects in
animal studies would be translatable to patients is unclear (96).
Heparin and Warfarin
Heparin and its low-molecular-weight derivatives (LMWHs, e.g.,
enoxaparin, nadroparin tinzaparin) are anticoagulants widely
used in the prevention of blood clots (e.g., during hemodialysis,
surgery) and in the prophylaxis and treatment of venous
thromboembolism and myocardial infarction. Heparin inhibits
blood coagulation by increasing the activity of antithrombin III,
an enzymatic inhibitor of thrombin, FXa, and other proteases
(Figure 1). Although heparin does not directly dissolve already
formed clots, heparin may support the body’s natural clot lysis
mechanisms. Therefore, several studies have assessed the antifibrotic activity of heparin and LMWHs using preclinical models.
Consequently, researchers have found that heparin and LMWHs
alleviate experimental pulmonary (73, 74) and hepatic (75–79),
as well as endomysial fibrosis (80). In line with this, clinical
studies corroborated the therapeutic potential of heparin and
LMWHs in organ fibrosis by demonstrating that heparin and
LMWHs inhibit collagen proliferation in the liver with chronic
hepatitis B virus infection (39). Despite positive perspectives,
clinical trials of heparin and LMWHs for organ fibrosis have been
so far without success. Anti-fibrotic therapies with heparin and
LMWHs appeared to pose more risks than benefits (81).
Warfarin is another widely used anticoagulant. As a vitamin
K antagonist, warfarin inhibits vitamin K epoxide reductase,
which is essential for the reactivation of vitamin K1 and, in turn,
for ensuring the activity of vitamin K1 -dependent coagulation
factors such as thrombin, FVII, FIX, and FXa (82) (Figure 1).
In animal studies, warfarin showed protective effects on hepatic
fibrosis following congestive hepatopathy induced by partial
ligation of the inferior vena cava (82) as well as following a
CCl4 challenge (83). Clinical studies revealed that warfarin and
LMWHs ameliorate portal vein thrombosis in patients with
liver cirrhosis reducing de novo occurrence, improving new
hepatic decompensation, and survival of patients with advanced
disease (42). Other studies show that warfarin, heparin, and
LMWHs reduce the proliferation and activation of HSCs limiting
fibrotic areas (75). However, it remains to be clarified whether
warfarin, heparin, and LMWHs have direct effects on HSCs, or
the suppression of HSCs is rather a consequence of the antifibrotic activities of the anticoagulants. Warfarin does not appear
to be effective in IPF. Warfarin was not beneficial in experimental
model of IPF (24). Congruently, a clinical study of warfarin in
IPF was suspended due to a low probability of benefit and an
increase in mortality (84). However, this was contrary to the
result of a precedent clinical study, where patients administered
with warfarin in combination with prednisolone demonstrated
significantly improved survival rates in acute IPF exacerbations
as compared to the group treated with prednisolone alone (85).
Direct Oral Anticoagulants
Direct oral anticoagulants (DOAC)—dabigatran, rivaroxaban,
apixaban, edoxaban, and betrixaban are anticoagulation
pharmacotherapies used for the prevention of thrombosis
(Figure 1). DOACs are categorized into two main classes:
direct FXa inhibitors (rivaroxaban, apixaban, edoxaban, and
betrixaban) and direct thrombin inhibitors (dabigatran).
Rivaroxaban, apixaban, and edoxaban are direct FXa
inhibitors that inhibit FXa by directly binding to the active site
of FXa. Fondaparinux is an indirect FXa inhibitor that binds
to antithrombin and changes its conformation which leads to
inhibition of FXa (97). Dabigatran is a direct thrombin inhibitor
that binds directly to active sites of thrombin and inhibits its
activity (98). Recent studies revealed a correlation between
Anti-platelet
Anti-platelet agents, e.g., aspirin, clopidogrel, ticagrelor, and
prasugrel, serve as potential candidates for thrombosis treatment.
Activated platelets, in combination with FVIIa, mark the
initiation of the coagulation cascade (Figure 1). It is unclear
whether TF is expressed by platelets (86). However, the formation
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Anticoagulants in Organ Fibrosis
Rivaroxaban, co-administered with aspirin alone or with
aspirin plus clopidogrel or ticlopidine, is indicated in the
prevention of atherothrombotic events in patients with acute
coronary syndrome (107). In clinical studies, drugs that
pharmacologically target FX were effective in patients with
cirrhosis of the liver. Rivaroxaban is currently in Phase III trials
for treating patients with liver cirrhosis.
thrombin and FXa with organ fibrosis, and the effectiveness
of DOAC in treating organ fibrosis has emerged as a novel
treatment of organ fibrosis. In an atrial fibrosis-induced model
by transverse aortic constriction, the expression of TNF-α, IL1β, and IL-6 was suppressed by treating rivaroxaban (99). In
addition, collagen III, connective tissue growth factors, and TGFβ, which are upregulated during fibrosis development, were
decreased by rivaroxaban treatment. Rivaroxaban treatment
also inhibited FXa-mediated phosphorylation of NF-κB p65
and STAT3, which are important mediators of myofibroblast
differentiation and fibrosis development (54). In the myocardial
ischemia (MI)-induced fibrosis model, expression of collagen
1a1 and collagen 3a1 was significantly decreased after a
high dosage of direct FXa inhibitor apixaban which indicates
the efficacy of apixaban in attenuating MI-induced fibrosis
(100). In unilateral ureteral obstruction (UUO) mice, which
is the renal tubulointerstitial model, edoxaban treatment
attenuated renal interstitial macrophage infiltration and
release of inflammatory cytokines. Also, the expression of
collagen II and III, TGF-β, and α-smooth muscle actin (SMA)
was significantly attenuated with edoxaban treatment (101).
Treatment of fondaparinux to kidney fibrosis, which was
induced in mice by IRI, reduced macrophage infiltration. Also,
proinflammatory IL-1β mRNA levels decreased in fondaparinuxtreated models (67).
The efficacy of direct thrombin inhibitors in treating
organ fibrosis has been revealed by dabigatran treatment.
Both early and late treatment of dabigatran attenuated the
development of bleomycin-induced pulmonary fibrosis by
significantly reducing thrombin activity and inflammatory
cells and protein concentrations in the bleomycin-induced
pulmonary fibrosis model (102). Additionally, dabigatran
inhibited thrombin-induced cell proliferation, α-SMA expression
and organization, and the in vitro production of collagen and
connective tissue growth factor (CTGF) by lung fibroblasts
(103). Dabigatran attenuates cardiac fibrosis by improving
coronary flow reserve and global cardiac function potentially
by inhibiting thrombin activity and down-regulating PAR-1
expression (104). In the UUO model, dabigatran significantly
inhibited UUO-induced type 1 collagen and tubulointerstitial
fibrosis by inhibiting thrombin-activated PAR-1 expression
in fibrotic kidneys (105). In hepatic IRI mice, dabigatran
treatment significantly improved liver histological damage,
induced sinusoidal protection, and provided both antiapoptotic
and anti-inflammatory effects (106).
DISCUSSION
A large body of evidence has accumulated over the past decades
to support the potential of anticoagulants as a promising
therapeutic strategy for organ fibrosis. The literal meaning of
the term “fibrosis” is “fibrous growth or development in an
organ”; that of “fibrin” is “fibrous substance.” Although these
terms appear to be semantically related, not much attention
was previously paid to the biological link between fibrosis and
coagulation. Preclinical and clinical studies have consistently
demonstrated that the inhibition of coagulation may be beneficial
in organ fibrosis. However, there have been so far only a
few anticoagulation drug approvals/trials for the treatment of
organ fibrosis per se, although anticoagulants are currently being
used for complications, which are frequent in organ fibrosis.
Anticoagulants are effective but have serious adverse effects
making us extra cautious when expanding the application areas of
these therapies. To date, our mechanistic understanding of how
coagulation contributes to organ fibrosis is still largely unclear.
Deeper insights into the precise mechanistic and functional
role of coagulation in fibrotic development will allow us to
better weigh the benefits and risks of anticoagulants in antifibrotic therapy.
AUTHOR CONTRIBUTIONS
All authors listed have made a substantial, direct, and intellectual
contribution to the work, and approved it for publication.
FUNDING
This study was funded by the 2022 University Innovation Support
Project at Handong Global University led by the Ministry of
Education of the Republic of Korea.
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