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T. Shimizu
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The Coagulation System
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andRhinosinusitis
TakeshiShimizu andShinoShimizu
2
Abbreviations
APC Activated protein C
AR Allergic rhinitis
BALF Bronchoalveolar lavage uid
CRS Chronic rhinosinusitis
EPCR Endothelial protein C receptor
FDPs Fibrin degradation products
GM-CSF Granulocyte macrophage colony-
stimulating factor
IL Interleukin
LMWH Low-molecular weight heparin
NP Nasal polyp
PAF Platelet-activating factor
PAI-1 Plasminogen activator inhibitor-1
PAR Protease-activated receptor
PDGF Platelet-derived growth factor
TAFI Thrombin activatable brinolysis
inhibitor
TATc Thrombin-antithrombin complex
TF Tissue factor
TFPI Tissue factor pathway inhibitor
TGF Transforming growth factor
TM Thrombomodulin
TNF Tumor necrosis factor
t-PA Tissue plasminogen activator
u-PA Urokinase plasminogen activator
VEGF Vascular endothelial growth factor
Core Message
Local activation of the coagulation system contributes to the pathophysiology of upper airway
inammation, such as allergic rhinitis (AR) and
chronic rhinosinusitis (CRS). Airway inammation is associated with increased vascular permeability. Leakage of plasma coagulation factors
into the tissues induces plasma factor VIIa
(FVIIa) to bind tissue factor (TF) expressed on
endothelial cells, broblasts, epithelial cells, and
leukocytes, which ultimately leads to thrombin
(FIIa) generation and brin deposition. Increased
coagulation activity and decreased brinolytic
activity induce excessive brin deposition in
human nasal polyp (NP) tissues. Thrombin and
coagulation factors play important roles not only
in hemostasis and thrombosis but also in inammation by stimulating the production of cytokines, chemokines, mucin, and extracellular
matrix proteins from nasal epithelial cells and
from broblasts through the protease-activated
receptors (PARs). PAR-mediated responses provide a direct link between coagulation and
inammation, and anticoagulant drugs may have
a therapeutic potential for the treatment of intractable rhinosinusitis.
T. Shimizu (*) · S. Shimizu
Department of Otorhinolaryngology-Head and Neck
Surgery, Shiga University of Medical Science, Otsu,
Shiga, Japan
e-mail: shimizu@belle.shiga-med.ac.jp
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
Ö. Ö. Celebi, T. M. Önerci (eds.), Nasal Physiology and Pathophysiology of Nasal Disorders,
https://doi.org/10.1007/978-3-031-12386-3_2
15
16
(1) Inflammation stimulates the coagulation system by
s
Anti-inflammatory activities of protein C pathway
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T. Shimizu and S. Shimizu
2.1 Introduction
Airway inammation is associated with increased
vascular permeability and leakage of plasma
coagulation factors, leading to the activation of
the coagulation system in the extravascular space.
Procoagulant activity has been demonstrated in
patients with allergic rhinitis (AR) [1], chronic
rhinosinusitis (CRS) [2], bronchial asthma [3],
and lung brosis [4]. The presence of thrombin
activity and thrombin-antithrombin complex
(TATc) in nasal secretions and in bronchoalveolar lavage uid (BALF) is clear evidence of local
activation of the coagulation system. Airway
inammation enhances the activity of tissue factor (TF), an important initial upstream protein of
the extrinsic coagulation cascade, expressed on
airway epithelial cells and inltrating eosinophils
[1, 5].
Airway inammation is characterized by
mucus hypersecretion, inltration of inammatory cells, and tissue remodeling, such as nasal
polyp (NP) formation. Excessive brin deposition is detected in the epithelial mucus layer and
in the lamina propria of NPs [5, 6], and dense
brin networks exacerbate airway inammation
by disturbing the mucociliary activity of the epithelial mucus layer and by providing a scaffold
for proliferating cells such as broblasts and
endothelial cells. Aberrant brin turnover is
induced by an increase in coagulation activity
and a decrease in brinolysis.
Coagulation factors such as thrombin (FIIa),
TF/FVIIa, and FXa play important roles not only
in hemostasis and thrombosis but also in inammation through interactions with proteaseactivated receptors (PARs; PAR-1, PAR-2,
PAR-3, and PAR-4) expressed on epithelial cells,
broblasts, and vascular endothelial cells [7].
Activated coagulation factor–PAR signaling
induces airway inammation by stimulating the
production of cytokines, chemokines, mucin, and
extracellular matrix proteins by airway epithelial
cells and broblasts [1, 8–12].
Figure 2.1 shows the interactions between
coagulation and inammation. The coagulation
system is activated in rhinosinusitis by leakage
of plasma coagulation factors and by enhanced
TF activity expressed on epithelial cells, broblasts, endothelial cells, and leukocytes [5].
Fibrin deposition is facilitated by decreased
activity of the anticoagulant protein C system
[13, 14] and by inhibition of brinolysis following the enhanced production of plasminogen
activator-1 (PAI-1) [15, 16]. Coagulation modulates airway inammation by PAR-mediated
cytokine/chemokine production and by the antiinammatory protein C system. Platelets possess proinammatory mediators such as
thromboxane, histamine, and platelet-activating
factor (PAF), and P-selectin expression on their
surface induces eosinophil inltration [17, 18].
This chapter summarizes the current knowledge
of the role of coagulation, brinolysis, and the
anticoagulant system in the pathophysiology of
rhinosinusitis. The therapeutic potential of anticoagulant drugs for the treatment of intractable
rhinosinusitis is shown.
Fig. 2.1 Interaction
between the coagulation
system and
inammation. Airway
inammation activates
the coagulation system,
and coagulation
modulates inammation
Increased vascular permeability and leakage of plasma coagulation factor
Enhanced tissue factor activity
Increased production of plasminogen activator inhibitor-1
Inflammation Coagulation
(2) Coagulation modulates inflammation by
(1)
(2)
Platelets activation
Coagulation factor-PAR mediated inflammation
Surface contact
Anti-inflammatory
2 The Coagulation System andRhinosinusitis
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17
2.2 The Coagulation System
Hemostasis and thrombosis are controlled by platelet aggregation, coagulation (blood clot forming),
brinolysis (clot lysing), and the anticoagulant
(regulating) system. Platelets immediately form a
plug at the site of injury to the blood vessel, and
then coagulation factors respond in a cascade to
form brin strands, which strengthen the platelet
plug. Fibrinolysis is the process of brin cleavage
by plasmin into brin degradation products (FDPs),
which act to resolve blood clots. Coagulation, brinolysis, and the regulating anticoagulant system
balance their activities and maintain the homeostasis of the coagulation mechanisms (Fig.2.2).
2.2.1 The Coagulation Cascade
The coagulation cascade is classically divided
into the extrinsic (TF) pathway and the intrinsic
Extrinsic pathway Intrinsic pathway
(contact activation) pathway. The extrinsic pathway is the most important primary pathway for
clot formation in the coagulation cascade. The
intrinsic (contact activation) pathway has minor
roles in initiating clot formation, and recent
research has shown that the contact activation
system is more involved in inammation and
innate immunity by activating the complement
system and the kallikrein–kinin pathway [19].
Tissue factor (TF) is an important starting
upstream protein in the extrinsic coagulation cascade, and it is the most potent stimulator of this
cascade [20]. TF is expressed on the cell surface
of epithelial cells, broblasts, endothelial cells,
and leukocytes, including epithelial cells and
inltrating eosinophils in nasal mucosa [1, 5].
Leakage of plasma coagulation factors into tissues induces FVIIa to bind to TF on the cell surface, and this complex binds to factor X (FX),
converting it to the activated form, factor Xa
(FXa). The coagulation factors are generally ser-
XIIa
XII
Regulators
TFPI
Antithrombin
Fibrinolysis
PAI-1
2-antiplasmin
Fig. 2.2 Coagulation cascade. Extrinsic and intrinsic
pathways, brinolysis, regulators, and the anticoagulant
protein C system balance each other’s activities and maintain the homeostasis of the coagulation mechanisms.
Tissue factor is an important starting protein in the extrinsic coagulation cascade, and thrombin plays a fundamental role by converting brinogen to brin. Solid arrow:
t-PA
u-PA
Tissue damage
Prothrombin
Plasminogen
Plasmin
Crosslinked
VIIa
XXa
TM
TAFI
fibrin clot
IXa IXTissue factor (TF)
Va V
XIIIa XIII
XIa XI
VIIIVIIIa
Anticoagulant
X
Thrombin (IIa)
activation, Dotted arrow: Inhibition. EPCR: Endothelial
protein C receptor, FDPs: Fibrin degradation products,
PAI-1: Plasminogen activator inhibitor-1, t-PA: Tissue
plasminogen activator, u-PA: Urokinase plasminogen
activator, TAFI: Thrombin activatable brinolysis inhibitor, TFPI: Tissue factor pathway inhibitor, TM:
thrombomodulin
Protein C pathway
Protein C
TM
Activated protein C (APC)
Protein S
Inactivates
FVa and FVIIIa
activities
FibrinogenFibrinFDPs
EPCR
PAR-1
18
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T. Shimizu and S. Shimizu
ine proteases, which act by cleaving downstream
proteins. The exceptions are TF, FV, FVIII (glycoproteins), and FXIII (transglutaminase). FXa
then leads to eventual thrombin generation and
brin deposition (Fig.2.2).
Thrombin (FIIa) plays fundamental roles in
the coagulation system. Prothrombin is converted
to thrombin by the activation of extrinsic and
intrinsic pathways. Thrombin not only converts
brinogen to brin, but it also has feedback activation roles by activating factors V and VIII.The
brin clot is formed by cross-linking of brin
monomers and is further stabilized by FXIII,
which is activated by thrombin (FXIIIa).
Thrombin also activates their inhibitor, protein C,
in the anticoagulant protein C pathway in the
presence of thrombomodulin (Fig.2.2).
2.2.2 Regulators
TF pathway inhibitor (TFPI) regulates the initial
step of the extrinsic coagulation cascade by targeting the TF-FIIa-FXa complex. TFPI is a serine
protease inhibitor that is secreted by endothelial
cells, leukocytes, platelets, broblasts, smooth
muscle cells, and epithelial cells [21]. TFPI is
produced locally in response to activation of the
coagulation system.
Antithrombin (also called as antithrombin III)
is a serine protease inhibitor that inactivates several coagulation factors, such as thrombin (FIIa),
FIXa, FXa, FXIa, and FXIIa. Antithrombin is a
circulating plasma protein, which is produced in
the liver, and thrombin is rapidly bound to antithrombin by forming thrombin–antithrombin
complex (TATc). Antithrombin is the major
inhibitor, accounting for approximately 80% of
the thrombin inhibitory activity in plasma. The
anticoagulant heparin accelerates antithrombin
activity by the enhanced binding of antithrombin
to thrombin and FXa.
The anticoagulant protein C pathway is activated when thrombin binds to thrombomodulin
on the cell surface, and the thrombin–thrombomodulin complex converts protein C to activated
protein C (APC). APC along with cofactor protein S inactivates FVa and FVIIIa, important pro-
coagulant cofactors in the generation of thrombin.
APC also has cytoprotective and antiinammatory activities through the endothelial
protein C receptor (EPCR) and PAR-1 expressed
on airway epithelial cells and endothelial cells
[22, 23].
2.2.3 Fibrinolysis
Fibrinolysis is a natural mechanism to prevent
excessive brin deposition and to resolve clot
formation. The major brinolytic enzyme, plasmin, cleaves the brin mesh into brin degradation products (FDPs). Plasmin is formed from
plasminogen by tissue plasminogen activator
(t-PA) and urokinase plasminogen activator
(u-PA). Plasminogen, which is produced in the
liver, has afnity for brin and is entrapped
within the clot when it is formed. Plasminogen
activator inhibitor-1 (PAI-1) is a serine protease
inhibitor that acts as a principal inhibitor of both
t-PA and u-PA.Endothelial cells and many different cells produce t-PA, u-PA, and PAI-1, including airway epithelial cells, broblasts, mast cells,
and macrophages [24].
Fibrinolysis is also regulated by endogenous
antibrinolytic proteins, α2-antiplasmin, and
α2-macroglobulin, which inactivate plasmin.
Thrombin activatable brinolysis inhibitor
(TAFI) is another important regulator of brinolysis. TAFI is activated by thrombin and thrombin–thrombomodulin complex and inhibits
brinolysis by removing the binding and activating sites on brin for plasminogen and t-PA [25].
2.3 Activation
oftheCoagulation System
inRhinosinusitis
Activation of coagulation is initiated by plasma
exudation into the tissues in sinonasal inammation, and coagulation steps start through the interaction of plasma coagulation factors with TF, an
initial protein of the coagulation cascade in tissues. Thrombin is generated by the stepwise activation of coagulation factors, and it converts
Mucus layer
Nasal polyp
Epithelial cells
Nasal gland
2 The Coagulation System andRhinosinusitis
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Fig. 2.3 Immunohistochemical staining of brin in nasal polyps (NPs) from patients with CRS with NPs. Fibrin is
strongly expressed in the epithelial mucus layer and lamina propria of NPs
19
brinogen to brin. Enhanced thrombin activity
and elevated concentrations of TATc in nasal
secretions from patients with AR and CRS indicate the local activation of the coagulation system in rhinosinusitis [1, 2]. Activation of the
coagulation system results in excessive deposition of brin in the epithelial mucus layer and in
the lamina propria of NPs [5] (Fig.2.3).
2.3.1 Tissue Factor (TF)
TF is an important upstream protein in the
extrinsic pathway and plays an essential role in
the coagulation cascade. TF and its regulator
TFPI are expressed in nasal epithelial cells and
subepithelial gland cells, and TF is also
expressed in inltrating inammatory cells,
including eosinophils, in nasal mucosa [5]. TF
is a transmembrane glycoprotein, and TF activity is determined as activated FX (FXa) induced
by TF/FVIIa complex on cultured cells.
Thrombin and tumor necrosis factor (TNF)-α
enhance TF activity on cultured airway epithelial cells [2] and on a human eosinophilic leukemia cell line, EoL-1 cells (unpublished data).
These results indicate that inammation activates the local coagulation system through
enhanced TF activity on epithelial cells and on
inltrating eosinophils. TF is strongly expressed
in the basal area of nasal epithelial cells [5]
(Fig.2.4), and it is reportedly important for the
attachment, survival, and proliferation of basal
epithelial cells [26, 27].
TFPI, a major regulator of TF-induced coagulation, is released from cultured nasal epithelial
cells on stimulation with thrombin and TNF-α.
TFPI concentration in nasal secretions is
increased in CRS patients with asthma, and it is
correlated with both thrombin activity and TATc
concentrations in nasal secretions [5]. These
results suggest that TPFI is produced locally in
response to the activation of the coagulation
cascade.
2.3.2 Thrombin
Thrombin activity is determined spectrophotometrically using the synthetic substrate D-Phepiperonyl-Arg-p-nitroanilide, and it is enhanced
in nasal secretions from patients with AR and
CRS with asthma [2]. Thrombin is rapidly bound
by antithrombin and forms TATc invivo, and the
TATc level is a good marker of thrombin generation. The TATc concentration is increased in
nasal secretions from patients with AR and CRS
with asthma [2]. Increased TATc levels are also
reported in nasal lavage uids and in NP tissues
from CRS patients [28], supporting the local activation of thrombin generation and a procoagulant
state in rhinosinusitis.
20
Signal transduction
Protease Tethered ligand
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T. Shimizu and S. Shimizu
a
b
Fig. 2.4 Immunohistochemical staining of tissue factor
(TF) in nasal mucosa from patients with CRS with NPs.
(a) Nasal polyp. (b) Inferior turbinate. TF is expressed in
epithelial cells and inammatory cells including eosinophils. Basal areas of epithelial cells are strongly stained
2.4 Coagulation Contributes
tothePathophysiology
ofRhinosinusitis
Platelets, the cellular component of blood clots,
play important roles in the development of airway inammation. P-selectin expression of platelets is important for eosinophil inltration in
tissues. Thrombin activates platelets and stimulates the release of proinammatory mediators,
such as thromboxane, histamine, serotonin, and
PAF, from platelets [25]. Coagulation factors
such as thrombin (FIIa), TF/FVIIa, and FXa contribute to the inammation through the interaction with PARs expressed on epithelial cells,
broblasts, and endothelial cells [7].
N
CC
Fig. 2.5 Protease activated receptor-1 (PAR-1).
Thrombin stimulates PAR-1 by proteolytic cleavage and
unmasking of an amino-terminal receptor sequence,
which acts as a tethered ligand by binding to the body of
the receptor to initiate transmembrane signaling
N
coagulation factors stimulates PARs by proteolytic cleavage and unmasking of an aminoterminal receptor sequence, which acts as a
tethered ligand by binding to the body of the
receptor to initiate transmembrane signaling
(Fig.2.5). All PARs are expressed in nasal epithelial cells and broblasts [1, 9]. PARs agonist
peptides, synthetic peptides with the same
sequences as the newly formed tethered ligands,
can activate the receptor independently. The three
PARs, PAR-1, PAR-3, and PAR-4, are thrombin
receptors, and FXa may activate PAR-1, PAR-2,
and PAR-329 (Table 2.1). Thrombin and PAR-1
agonist peptide stimulate the secretion of
MUC5AC mucin, PDGF, VEGF, IL-6, IL-8,
CCL-2 [1, 2, 7, 8, 30], and granulocyte macrophage colony-stimulating factor (GM-CSF) [31]
from cultured airway epithelial cells. Thrombin,
FXa, and PAR-1 and PAR-2 agonist peptides
stimulate the secretion of transforming growth
factor (TGF)-β, bronectin, eotaxin-1, IL-6, and
IL-8 from cultured nasal broblasts [9].
2.4.1 Coagulation Factors
andProtease-Activated
Receptors (PARs)
The PAR family consists of four subtypes (PAR1, PAR-2, PAR-3, and PAR-4); each subtype displays a unique activation site that is recognized
by specic proteases [29]. Protease activity of
2.4.2 Tissue Remodeling
Tissue remodeling is an irreversible histologic
change caused by persistent inammation and
aberrant repair mechanisms. Morphological
changes of tissue remodeling in rhinosinusitis
include epithelial sloughing, thickening of the
basement membrane, subepithelial brosis, and
formation of NPs. Goblet cell metaplasia in asso-
2 The Coagulation System andRhinosinusitis
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21
Table 2.1 PARs cleaving proteases
PAR- 1Thrombin, FXa, TF/FVIIa, Activated protein C,
Plasmin
Trypsin, Chymase, MMP-1-3,8,9,12,13,
Cathepsin G,
Neutrophil elastase, Proteinase 3, Granzyme
A,B,K, Der p1
PAR- 2FXa, TF/FVIIa, Plasmin
Trypsin, tryptase, chymase, cathepsin G,S,
Neutrophil elastase, Proteinase 3,
Papain, HDM (Der p1-3,9), Cockroach,
Alternaría, Japanese cedar pollen
PAR- 3Thrombin, FXa, Trypsin
PAR- 4Thrombin, Trypsin, Cathepsin G
Papain, Der p3
ciation with hypersecretion of mucus is an important characteristic of AR and CRS. MUC5AC
mucin is the most predominant gel-forming
mucin expressed in airway goblet cells, and it is
up-regulated in nasal polyposis. PDGF, VEGF,
and TGF-β are probrotic cytokines that promote
tissue remodeling by stimulating the proliferation
of vascular endothelial cells, broblasts, myocytes, and goblet cells, and by increasing the
deposition of extracellular matrix proteins.
Overexpressions of PDGF, VEGF, and TGF-β
and their receptors are commonly observed in
the nasal mucosa of CRS patients [32–35]. IL-6
contributes to tissue remodeling by stimulating
mucus production, broblast proliferation, and
matrix deposition in airways [36]. Fibronectin,
an extracellular matrix protein, is cross-linked
to the brin α chain by FXIIIa [37], and
increased expression of bronectin is reported
in NPs [38, 39].
Activated coagulation factors, thrombin
and FXa, play important roles in tissue remodeling of rhinosinusitis by leading to fibrin
deposition and by stimulating the secretion of
MUC5AC mucin, profibrotic cytokines
(PDGF, VEGF, TGF-β), IL-6, and extracellular matrix protein (fibronectin) from nasal epithelial cells and from nasal fibroblasts via
PAR-1 and PAR-2. Thrombin and FXa are also
involved in the activation, infiltration, and survival of inflammatory cells such as neutrophils, eosinophils, and monocytes in
rhinosinusitis by stimulating the secretion of
IL-8, CCL-2, and GM-CSF from nasal epithelial cells and that of IL-8, and eotaxin-1 from
nasal fibroblasts (Fig.2.6).
2.4.3 Allergic Rhinitis (AR)
The coagulation system is activated by increased
plasma exudation into tissues in AR patients.
Enhanced thrombin activity and elevated concentrations of TATc are reported in nasal secretions
from AR patients [2]. Thrombin activity was signicantly increased in nasal secretions from
patients with house dust mite (HDM) AR 5min
after allergen provocation with an HDM disc,
compared with that before the provocation [1].
Thrombin generation and brin deposition are
more prominent in the nasal mucosa of
ovalbumin- induced AR mice [40]. These results
indicate that allergen stimulation induces thrombin generation and resulting brin deposition in
the nasal mucosa of AR patients.
PAR-2 mediated inammation is important in
allergic inammation. Activated coagulation factor, FXa, TF/FVIIa, and other proteases can activate PAR-2, both derived from the host (mast cell
tryptase and chymase, trypsin, neutrophil elastase, proteinase 3, cathepsin G and S) and from
allergens (HDM, Alternaria, cockroach, and
Japanese cedar pollen) [25]. Allergen-derived
protease-induced PAR-2 activation stimulates
secretion of epithelial cell-derived cytokines,
TSLP and IL-25, from airway epithelial cells,
which induce the initiation and development of
allergic inammation. Protease activity of
Alternaria induces TSLP production from cultured airway epithelial cells, and that of HDM or
Japanese cedar stimulates IL-25 production from
cultured human nasal epithelial cells via PAR-2
[41–43]. PAR-2 is also expressed on mast cells,
eosinophils, and smooth muscle cells in airways.
PAR-2 activation induces histamine release from
mast cells and degranulation and cytokine release
from eosinophils, respectively [44]. FXa and
PAR-2 agonists stimulate the secretion of
eotaxin-1 and IL-8 from cultured nasal broblasts [9], which may induce eosinophil and neutrophil inltration in nasal mucosa. The
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