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Cellular & Molecular Immunology (2016) 13, 432–442

& 2016 CSI and USTC All rights reserved 1672-7681/16 $32.00
www.nature.com/cmi

REVIEW

Aberrant coagulation causes a hyper-inflammatory


response in severe influenza pneumonia
Yan Yang1 and Hong Tang1,2
Influenza A virus (IAV) infects the respiratory tract in humans and causes significant morbidity and mortality
worldwide each year. Aggressive inflammation, known as a cytokine storm, is thought to cause most of the damage
in the lungs during IAV infection. Dysfunctional coagulation is a common complication in pathogenic influenza,
manifested by lung endothelial activation, vascular leak, disseminated intravascular coagulation and pulmonary
microembolism. Importantly, emerging evidence shows that an uncontrolled coagulation system, including both the
cellular (endothelial cells and platelets) and protein (coagulation factors, anticoagulants and fibrinolysis proteases)
components, contributes to the pathogenesis of influenza by augmenting viral replication and immune
pathogenesis. In this review, we focus on the underlying mechanisms of the dysfunctional coagulatory response in
the pathogenesis of IAV.
Cellular & Molecular Immunology (2016) 13, 432–442; doi:10.1038/cmi.2016.1; published online 4 April 2016

Keywords: anticoagulant; coagulation; inflammation; influenza A virus

Influenza A virus (IAV) is a genus of the family Orthomyx- thrombosis, hemorrhage and diffuse alveolar damage are
oviridae that contains a negative-sense, single-stranded, seg- observed in severe influenza pneumonia, indicating disordered
mented RNA genome and is categorized into subtypes based on coagulation.6,7 Severe IAV also causes multiple organ dysfunc-
the expression of hemagglutinin (HA; H1–H18) and neurami- tion syndrome and disseminated intravascular coagulation
nidase (NA; N1–N11) on the surface of the viral envelope.1 (DIC).5,8,9
Seasonal flu, which is caused by different subtypes of IAV, IAV primarily targets the airway and alveolar epithelial cells
usually leads to the death of half a million people each year. by binding to sialic acid residues through HA. The internalized
Pandemic flu is caused by the genetic reassortment and viral RNA in the cytosol activates pattern recognition receptors,
transmission of IAV in the chain of wild birds/poultry/pigs including Toll-like receptors (TLRs; primarily TLR3 and TLR7)
and has become one of the most imminent dangers to human and retinoic acid inducible gene-1 (RIG-I) to initiate the innate
beings.2 Because of the lack of immune memory, these immune responses. Recognition of viral RNA by RIG-I and
zoonotic viruses often cause high morbidity and mortality in TLRs activates IRF3/7 to induce robust type I and III interferon
infected people; for example, the notorious 1918 H1N1 (IFN-α/β and -λ) responses, which induce the transcription
pandemic killed up to 50 million people globally and the and release of hundreds of interferon-stimulated genes (ISGs)
2009 H1N1 pandemic had a death toll of up to 284 500 and trigger the activation of nuclear factor kappa B (NF-κB) to
people.3,4 induce the production of pro-inflammatory cytokines and
Severe IAV, involving either seasonal or pandemic influenza chemokines (for example, interleukin (IL)-6, TNF-α, MCP-1,
virus, infects the upper respiratory tracts and induces acute MIP-1α/β and RANTES).10,11 In addition, the viral RNA and
respiratory distress syndrome (ARDS).5 Clinically, the char- proteins can also activate inflammasomes, resulting in the
acteristic alveolar changes of influenza virus pneumonia release of IL-1β and IL-18.12–14 IFNs and pro-inflammatory
include capillary thrombosis, focal necrosis and hyperemia of cytokines and chemokines are important for viral clearance and
the alveolar wall, inflammatory infiltration, the formation of also induce the recruitment and activation of circulating
hyaline membranes and pulmonary edema.6 Small vessel neutrophils, monocytes and lymphocytes (natural killer (NK)

1
Division of Viral Pathology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China and 2Institute Pasteur of Shanghai, Chinese
Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China
Correspondence: Professor H Tang, PhD, Institute Pasteur of Shanghai, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
E-mail: [email protected] or [email protected]
Received: 28 September 2015; Revised: 6 January 2016; Accepted: 6 January 2016; published online 4 April 2016
Coagulation and inflammation in influenza pneumonia
Y Yang and H Tang

433

cells, natural killer T cells and T cells) into the site of recent advances in understanding the hyper-inflammatory
infection.15 In addition to further activating the innate immune response that is caused by aberrant coagulation in IAV
response and priming the adaptive immune response to infection.
eradicate the virus, innate immune cells are often overactivated
in IAV-induced ARDS and contribute to its high morbidity and OVERVIEW OF THE COAGULATION SYSTEM
mortality.16 The overproduction of pro-inflammatory cyto- Coagulation is the formation of a blood clot. Coagulation is a
kines and the overactivation of immune cells during IAV highly ordered process that involves three components
infection is known as a cytokine storm.17 Although the general (endothelial cells, platelets and coagulation factors) in a
concept of a cytokine storm is well known (reviewed in ref. 17), sequential action of primary hemostasis, secondary hemostasis
the precise constitution and molecular mechanisms of the IAV- and fibrinolysis.21 Typically, coagulation is initiated by an
associated hyper-inflammatory response in ARDS is largely injury to the vascular endothelial cells (ECs) (Figure 1b).
unclear. Primary hemostasis is characterized by platelets that bind to
Emerging lines of evidence indicate that an aggressive injured and/or activated ECs and the immediate formation of a
immune response in severe influenza is augmented by dysfunc- platelet plug (Figure 1c). Secondary coagulation has two
tional coagulation, which is manifested by lung endothelial separate initial pathways, the contact activation pathway
activation, vascular leak, disseminated intravascular coagulation (intrinsic pathway) and the tissue factor (TF) pathway (extrin-
and pulmonary microembolism.18–20 This review summarizes sic pathway) (Figures 1d and e). Both pathways result in the

Figure 1 Cascades of the coagulation system. (a) Resting ECs provide natural anticoagulants (TM, AT and TFPI and ADPase) to inhibit
coagulation and keep platelet activation and the coagulation cascade in check. (b) Coagulation is typically initiated by an injury to the
vascular ECs, which results in the exposure of TF and collagen from the sub-endothelial tissue to the blood and the release of vWF.
(c) Platelets are activated when they are exposed to TF, collagen and vWF. Activated platelets release a number of mediators, such as ADP
and vWF stores within their granules, leading to further platelet recruitment, activation, aggregation and plug formation, which is a process
termed primary hemostasis. (d) The interaction between TF and factor VII initiates the extrinsic pathway. (e) The exposure of collagen to
blood starts the intrinsic pathway. (f) Both the extrinsic and intrinsic pathways result in the initiation of a common pathway, which
contains the cascades involved in the production of activated Factor X and thrombin and the formation of fibrin strands. (g) Fibrin strands
strengthen the platelet plug and lead to the formation of a stable platelet–fibrin clot. This process is termed secondary hemostasis.
(h) Kallikrein, uPA or tPA activate plasminogen to plasmin, which then degrades and reabsorbs the polymerized fibrin strands. It is the
eventual process of fibrinolysis that heals wounds. AT, antithrombin; ECs, endothelial cells; TF, tissue factor; TFPI, tissue factor pathway
inhibitors; TM, thrombomodulin; tPA, tissue plasminogen activator; uPA, urokinase plasminogen activator; vWF, von Willebrand factor.

Cellular & Molecular Immunology


Coagulation and inflammation in influenza pneumonia
Y Yang and H Tang

434

production of factor X, which induces thrombin and the complex is increased in both pandemic and HPAI-H5N1
formation of fibrin strands to strengthen the platelet plug and virus-infected ferrets, while intra-capillary fibrin deposition is
form a stable platelet–fibrin clot (Figures 1f and g). The especially evident in HPAI-H5N1 infection.49
coagulation process is tightly controlled by anticoagulants, More importantly, such a pro-thrombotic state induced by
which can limit the clot to avoid thrombus propagation, and influenza virus infection will inevitably downregulate the
fibrinolysis, which is responsible for the degradation of the anticoagulant components and inhibit fibrinolysis.33,50–52
platelet–fibrin clot as the wound heals (Figures 1a and h). In turn, abnormal coagulation promotes hemorrhage and
thrombosis, which is often associated with the overzealous
COAGULATION DISORDER IS ASSOCIATED WITH inflammation observed during a severe IAV infection.20,33,53
INFLUENZA INFECTION
Thrombosis, which often leads to hemorrhage, is a common THE ABERRANT ACTIVATION OF ECS IS RESPONSIBLE
clinical complication of severe influenza. Patients with a severe FOR BOTH ABNORMAL COAGULATION AND HYPER-
IAV infection, such as an H7N9 viral infection,6,22 often show INFLAMMATION IN INFLUENZA
typical alterations of coagulation, including hyperemia of the Resting ECs provide a non-thrombogenic barrier that prevents
alveolar wall, pulmonary capillary and small vessel thrombosis, the inappropriate activation of coagulation by producing
fibrin deposition and DIC, and hemorrhage. The coagulation numerous anticoagulant components and inhibiting platelet
abnormalities (coagulopathy) are characterized by a prolonged activation54 (Figure 1a). Once activated or injured, ECs initiate
activated partial thromboplastin time, prothrombin time and coagulation by activating platelets and the expression of
thrombin time, and decreased platelet counts in the blood in coagulation components, as well as by down-regulating
patients infected with H7N923–25 or highly pathogenic physiological anticoagulant components and suppressing fibri-
H5N1.26,27 Both thrombotic and hemorrhagic complications nolytic activity55 (Figure 1b). At the same time, the activation
were reported in the 2009 H1N1 influenza (‘swine flu’), such as of ECs can result in an increase in local blood circulation,
microscopic thrombi, thromboemboli, pulmonary arterial localized plasma leakage and the recruitment and activation of
thrombi and pulmonary hemorrhage with hemoptysis, hema- leukocytes to promote inflammation.56,57 IAV can directly and/
temesis and petechial rash.28–31 Thus, an influenza virus or indirectly induce EC activation and vascular hyperperme-
infection results in disorders, including both overactivated ability (Figure 2a). Certain IAV subtypes, such as H3N2 and
coagulation that leads to uncontrolled thrombosis and coagu- H5N1, may infect lung endothelial cells, which also express α2,
lopathy that leads to pulmonary hemorrhage and edema. 6-linked sialic acid and are adjacent to the primary target cells
The overactivation of coagulation by influenza exacerbates of the respiratory epithelia. Recognition of damage-associated
the risk of pulmonary and cardiac diseases.32–37 IAV infections molecular patterns, such as HMGB1 or oxidized phospholipids
also cause a transient increased risk of deep venous thrombosis via TLR4, also activates ECs to drive lung injury.53,58,59 Direct
and pulmonary embolism,32 acute coronary syndromes,37 acute stimulation of TLR3 by viral RNA results in the upregulation of
cardiac injury,38 acute myocardial infarction (AMI)39,40 and TF and the downregulation of thrombomodulin in endothelial
other cardiovascular diseases.41,42 For example, H1N1 infection cells.60 Human IAV has been reported to induce pulmonary
elevates the expression of genes that promote hemostasis microvascular leakage through the degradation of the tight
and/or platelet aggregation and the signature platelet genes junction protein claudin-5.61 In vivo, D-dimer and tissue fibrin
associated with AMI.43 Such acute thrombosis in an already- deposition are elevated.60
diseased coronary artery can cause a subcritical level of stenosis Inflammatory cytokines, produced by leukocytes, the lung
attributable to the development of acute coronary syndromes.37 epithelium and pulmonary endothelium, mainly contribute to
Therefore, reducing the risk of infection by vaccination against endothelium dysfunction. Elevated TNF-α levels have been
influenza effectively reduces the risk of stroke hospitalization,44 shown to induce EC apoptosis. TNF-α, IL-1β and IL-6 can
AMI rates39 and other cardiovascular events,45 with beneficial upregulate trypsin in ECs, which results in the loss of zonula
cardiovascular outcomes41 and increased survival among occludens-1 (ZO-1; a tight junction protein) and vascular
patients with acute heart failure.46 Clinical trials using oselta- hyperpermeability via protease-activated receptor-2 (PAR-2).62
mivir (Tamiflu) have shown that a reduction in viral load is Hypoxia, which is found in flu patients, contributes to EC
associated with a decrease in the incidence of cardiac activation to induce the release of pro-inflammatory IL-1, IL-6,
disorders.47 platelet-activating factor (PAF), intercellular adhesion molecule
Animal studies have partly explained the mechanism of 1 (ICAM-1), P-selectin and vWF.63 Thus, an IAV infection can
activated coagulation by IAV infection.48,49 IAV activates induce pulmonary hemorrhage and alveolar edema through the
coagulation by increasing thrombin generation, fibrin deposi- activation and damage of ECs via several mechanisms, includ-
tion and fibrinolysis in C57BL/6 mice.48 D-dimer (a circulating ing direct damage, loss of tight junctions and hyperpermeability
marker for enhanced coagulation and fibrinolysis) concentra- induced by inflammatory factors and the apoptosis of
tions and von Willebrand factor (vWF) activity are both endothelial cells.
increased in ferrets after infection with seasonal, pandemic or At the same time, the activation of and damage to ECs leads
highly pathogenic avian influenza (HPAI)-H5N1 viruses.49 The to the activation of the pro-coagulatory cascade. The expression
activation marker of coagulation thrombin–antithrombin of TF and vWF by activated ECs, the exposure of collagen to

Cellular & Molecular Immunology


Coagulation and inflammation in influenza pneumonia
Y Yang and H Tang

435

Figure 2 Interactions between coagulation and inflammation during IAV infection. (a) Airway and alveolar epithelial cells are the primary
targets of IAV infection. IAV can directly infect ECs and/or indirectly induce EC activation and vascular hyperpermeability through PAMPs,
DAMPs and inflammatory cytokines. (b) The activation of ECs induces a pro-thrombotic state by down-regulating the anticoagulant
components (TM, AT, TFPI and ADPase), the expression of TF and vWF and the exposure of collagen to blood. Thrombin, FXa and FVIIa,
produced by the coagulation cascade, augment the inflammatory response by activating platelets, endothelial cells, monocytes, neutrophils,
NKT and T cells through PARs. (c) Platelets are activated by exposure to thrombin, TF, collagen and vWF. Then, the coagulation cascades
and thrombi formation are initiated. (d) The downregulation of tight junction protein on ECs and apoptosis of ECs induced by inflammatory
cytokines lead to vascular hyperpermeability, which results in leakage of plasma and blood cells into the bronchoalveoli (hemorrhage).
Decompensated thrombocytopenia is another reason for hemorrhage during an IAV infection. (e) Activated platelets act as pro-inflammatory
cells by releasing inflammatory cytokines and promoting the activation, transmigration and cytokine release of neutrophils, T, B and NK
cells, DC and monocytes. Activated platelets also modulate EC function to promote an inflammatory response. (f) The cytokine storm of
overactivated neutrophils, monocytes and lymphocytes (NK cell, NKT cell and T cell), as well as the overproduction of inflammatory
cytokines by these cells, contributes to the high morbidity and mortality during IAV infection. AT, antithrombin; DAMPs, damage-associated
molecular patterns; DC, dendritic cell; EC, endothelial cell; IAV, influenza A virus; NK, natural killer; NKT, natural killer T cells; PAMPs,
pathogen-associated molecular patterns; PAR, protease-activated receptor; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TM,
thrombomodulin; vWF, von Willebrand factor.

blood as a result of disruption of the endothelial barrier, and Pulmonary ECs subsequently play a crucial role in the
increased platelet binding to ECs induces platelet activation and initiation and amplification of the cytokine storm during an
aggregation, which then activates the extrinsic coagulation IAV infection. By activating sphingosine-1-phosphate-1 (S1P1)
cascade (Figure 2b).21 EC activation reduces the expression signaling in the pulmonary endothelium, S1P1 receptor ago-
or secretion of components of anticoagulation and fibrinolysis, nists (CYM-5442 and RP-002) inhibit the cytokine storms and
and facilitates microthrombosis in the lung.18 Impaired coa- protect the host from pathogenic influenza virus challenge.53
gulation then leads to DIC and triggers decompensated Moreover, IL-1R signaling and MyD88/TRIF signaling are
thrombocytopenia, which is induced by overactivation and necessary for the early amplification of the cytokine storm,
excessive aggregation and passive exhaustion of platelets (dis- and S1P1 receptor agonist treatment blunts the cytokine storm
cussed below). Pulmonary thrombosis results in passive con- mainly by inhibiting the MyD88 signaling pathway.67 Innate
gestion, limiting compensatory ventilation responses and then cytokine and chemokine production and innate immune cell
exacerbates vascular leakage and alveolar edema, contributing infiltration are separable events, with the pulmonary endothe-
to widespread hemorrhaging, severe hypoxia, multiple organ lium at the center of both processes.53 The innate immune cell
failure and death during severe IAV infection (Figure 2d).64–66 infiltration is regulated by ECs, which express adhesion

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Coagulation and inflammation in influenza pneumonia
Y Yang and H Tang

436

molecules (P-selectin, E-selectin, ICAM-1 and VCAM-1) and Massive infiltration of activated and aggregated platelets in
facilitate the binding and migration of leukocytes during an the lungs may be associated with thrombocytopenia, which is
influenza virus infection (Figure 2e).68,69 An activated EC– often observed in highly pathogenic influenza virus infections
platelet–leukocyte interaction feeds forward to amplify the but is rare for other human viruses, such as adenovirus,
overall inflammatory response (Figure 2e).18 Thus, pulmonary metapneumovirus, coronavirus or bocavirus infections.85
ECs might be a potential therapeutic target because of their Thrombocytopenia has been observed in 73% of patients
critical role in the amplification of the cytokine storm. infected by avian origin H7N9 and is a risk factor for acute
respiratory failure in H1N1 influenza.86–88 The overactivation
MASSIVE INFILTRATION AND THE ACTIVATION OF of platelets by influenza viruses causes thrombosis in the lung,
PLATELETS CONTRIBUTES TO THE PATHOGENESIS which can passively exhaust platelets, and lead to
OF INFLUENZA IN THE LUNGS thrombocytopenia.20
The primary function of platelets is to sense the injured vessel Therefore, blockade of platelet overactivation and aggrega-
endothelia and initiate blood clotting for hemostasis.70 Recent tion can reduce the severity of acute respiratory syndrome.20
studies show that, in addition to their important roles in For example, the administration of the PAR-1 antagonist
damage repair, platelets are also an integral part of the innate SCH79797, which inhibits the activation of platelets induced
immune system as pro-inflammatory cells.71–73 After the by thrombin, decreases inflammation and improves survival
activation of and damage to ECs, platelets are activated by after IAV infection in mice.89 A deficiency in the major platelet
numerous factors, including collagen, thromboxane A2, vWF, receptor glycoprotein IIIa (GPIIIa) or treatment with anti-
thrombin, ADP and pro-inflammatory cytokines or PAF platelet compounds (eptifibatide, MRS 2179, clopidogrel,
(Figure 1c).52 Influenza virus H1N1 also activates platelets acetylsalicylic acid/aspirin and ticlopidine) protects mice from
through FcγRIIA on platelets by the IgG–virus immune lethal influenza virus infection.20,90 Aspirin also acts as an anti-
complex.52 influenza virus agent in vitro by inhibiting pro-inflammatory
Moreover, activated platelets release a number of mediators NF-κB activity and improving the influenza outcome in vivo.91
and cytokines from stores within their α- and dense-granules However, whether aspirin inhibits platelet activation in vivo is
for further platelet recruitment, activation and aggregation controversial because it may have increased the mortality of the
(Figure 1c). Platelets are major pro-inflammatory cells under 1918–1919 pandemic influenza92 and influenza virus infection
inflammatory conditions.71,74–77 Upon activation, platelets in animal models.93 Larger scale clinical studies are needed to
change from smooth discs to spiny spheres and rapidly release exclude strain variation in influenza viruses, various antipyretic
inflammatory and coagulatory mediators stored in their regimes and models of meta-analysis.94,95 For example, treat-
granules and express a number of receptors for adhesion and ment with aspirin and dicrofenac sodium aggravates the
clotting molecules.77 The interaction of P-selectin on activated hematogenous spread of IAV to the central nervous system
in chicken but does not affect transneural infection in mice.96
platelets and P-selectin glycoprotein ligand expressed on
Interestingly, aspirin does not significantly increase mortality in
neutrophils leads to the activation of neutrophils in the
an influenza B virus mouse model of Reye’s syndrome.97
circulation and the redistribution of Mac-1 and CXCR2, which
Aspirin and acetaminophen have the potential to exacerbate
guide neutrophil intravascular crawling and transmigration and
the consequences of influenza B virus infection in neonatal
the initiation of inflammation (Figure 2e).69 Such platelet–
mice but not in weanling mice.98 Therefore, anti-platelet
neutrophil aggregates contribute to a variety of inflammatory
compounds should be explored as a potential treatment for
settings, including acute lung injury, acute hepatic injury, sepsis
influenza, but more studies are needed, and the data must be
and atherosclerosis.78–80 Platelet–neutrophil aggregation is also
carefully interpreted.
responsible for the generation of reactive oxygen species (ROS)
by neutrophils, modulating the phagocytic capacity of neutro- COAGULATION FACTORS AUGMENT THE
phils and the formation of neutrophil extracellular traps (webs INFLAMMATORY RESPONSE TO AN IAV INFECTION
of extracellular DNA and histones).79,80 Activated platelets also The plasma coagulation cascade is primarily initiated by TF
interact with T cells, B cells, NK cells, dendritic cells (DCs) and during an influenza infection.19 Under physiological condi-
monocytes and induce their homing, activation and recruit- tions, TF is present in the sub-endothelial tissue, fibroblasts
ment, and cytokine release (Figure 2e).81 More importantly, the and circulatory blood cells or ECs do not express TF
cytokines and chemokines released from the activated platelets, (Figure 1a). Inflammation caused by IAV infection causes
including CD40L, IL-1β, CCL5, CXCL4, CXCL7 and TGF-β, disruption of the vessel walls that exposes TF to the
are profoundly involved in the modulation of endothelial cell circulation.33,65 ECs and monocytes begin producing TF in
function, leukocyte trafficking and immune response response to various pro-inflammatory cytokines (such as
(Figure 2c).81 For example, CD40L, released from activated TNF-α, IL-1, IL-6, IL-8 and MCP-1) and pathogen-
platelets, can activate CD40 on endothelial cells to upregulate associated molecular pattern (such as viral RNA).60,99 The
ICAM-1, VCAM-1, E-selectin and P-selectin and to release coagulation cascade is initiated quickly once TF has been
IL-6, MCP-1, CCL2 and TF, thereby promoting leukocyte exposed to the blood (Figure 1d). The activated coagulation
recruitment to lesions and immune activation.82–84 cascade generates thrombin protease (factor IIa), which

Cellular & Molecular Immunology


Coagulation and inflammation in influenza pneumonia
Y Yang and H Tang

437

converts fibrinogen into fibrin (Figure 1f). Thrombin is inhibit inflammation and pulmonary coagulopathy, it also
involved in the feedback activation of coagulation by activating facilitates neutrophil influx and protein leakage into the
coagulation factors V, VIII, XI and XIII (Figures 1e and f). As bronchoalveolar.114,115 Additionally, anti-PC antibody treat-
one of the strongest platelet activators, thrombin also induces ment results in delayed mortality,114 but recombinant activated
platelet aggregation and clot formation.100 Furthermore, fibri- PC treatment does not affect the outcome.115 Therefore, the
nogen and fibrin also activate macrophages and cytokine function of PC during influenza virus infection remains
production through TLR4.101,102 uncertain.
In addition to their roles in coagulation, activated AT (also known as antithrombin III) is a serine protease
coagulatory factors, such as thrombin, FXa and FVIIa, also inhibitor produced by the liver. AT functions as an
augment the initial inflammatory response. Treatment with a anticoagulant by inhibiting thrombin, as well as FXa, FIXa,
recombinant inhibitor of the FVIIa/TF complex attenuates the FIa and FXIIa, and its activity is increased by heparin.116 By
pro-inflammatory response and prolongs survival rates in a binding to thrombin, AT directly suppresses the activation of
rhesus monkey model of Ebola hemorrhagic fever.103 The pro- pro-inflammatory cells (leukocytes, ECs and platelets).117
inflammatory function of coagulation factors is mediated Furthermore, AT inhibits leukocyte rolling, adhesion and
through their activation of PARs (PAR-1, -2, -3 and -4), which activation directly by binding to receptors on the leukocyte
are mainly expressed in platelets and other cell types, including or indirectly by endothelial cell-released PGI(2) that tethers AT
ECs, macrophages, mast cells, eosinophils, myocytes and to cell surface glycosaminoglycan.118,119 Of further interest,
gastrointestinal and bronchial epithelial cells.19,89,104 PAR-1, AT possesses antiviral activity against HIV,120,121 HSV122,123
-3 and -4 are activated by thrombin, whereas PAR-2 is and HCV.124 The antiviral activities of AT reside in its serine
activated by FVIIa and FXa but not by thrombin. PAR-1 is protease inhibitor activity against the hemagglutinin of influ-
also responsible for FXa signaling.19 PAR signaling activates enza A virus H1N1 in vitro and in vivo.125 In line with this,
ECs, platelets and leukocytes to express pro-inflammatory several proteases (Gzma, Tmprss4, Elane, Ctrl, Gzmc and
cytokines and chemokines, and increases the permeability of Gzmb) are upregulated in the lung after mice are infected
ECs and the adhesion and chemotaxis of leukocytes with the H1N1 virus, and treatment with serine protease
(Figure 2b).19 The TF/thrombin/PAR-1 pathway promotes inhibitors protects mice from the fatal infection.126
the deleterious innate inflammatory response to an influenza TFPI is another serine protease inhibitor present in endothe-
virus infection in mice.89,104 PAR-2 plays both a protective and lia and platelets. By targeting the TF-FVIIa complex, it inhibits
a pathogenic role in response to an H1N1 infection.105,106 The coagulation cascades and modulates platelet pro-coagulant
activation of PAR-4 exacerbates acute lung injury, inflamma- activity.127 However, the function of TFPI in inflammation
tion and death through platelet activation and a PAR-4 or viral infection remains largely unknown.
antagonist (pepducin p4pal-10) protects mice during influenza ADAMTS13 is an anticoagulant protease that cleaves vWF.
virus infection.20 Taken together, these results suggest that It is produced in liver stellate cells and endothelial cells and is
coagulation factors mainly play pathogenic roles through also present in platelets. Systemic inflammation reduces
PAR-1 and PAR-4, which may serve as therapeutic targets ADAMTS13 activity,128 resulting in the formation of high-
against IAV infection. molecular weight vWF multimers and increased platelet
activation.129 Acute IAV infections reduce the level of
THE HOMEOSTASIS OF THE INFLAMMATORY ADAMTS13 and elevate the level of anti-ADAMTS13 anti-
RESPONSE IS MAINTAINED BY INTRINSIC bodies, which are associated with thrombotic thrombocytope-
ANTI-COAGULANT COMPONENTS IN IAV INFECTION nic purpura.35,36 A markedly high ratio of vWF to ADAMTS13
To keep the platelet activation and coagulation cascade in in the circulation has been found in H1N1 influenza patients
check, coagulation is well regulated by three major antic- with thrombotic microangiopathy.51 The decreased level of
oagulant mechanisms, which are protein C (PC), antithrombin ADAMTS13 might result from the influenza virus-induced
(AT) and the tissue factor pathway inhibitor (TFPI; cytokine storm. However, whether ADAMTS13 takes part in
Figure 1a).107 A deficiency in anticoagulants may result in the initiation and amplification of the inflammatory response is
acquired thrombophilia, a condition in which there is an unknown.
increased tendency to form blood clots.
PC, a major endogenous anticoagulant, is activated by FIBRINOLYSIS IS INVOLVED IN BOTH LUNG
thrombin.108 Activated PC cleaves the activated FVa and FVIIIa INFLAMMATION AND THE INFLUENZA A VIRUS
to inhibit the coagulation cascades.108 In addition to its anti- LIFE CYCLE
coagulatory role, activated PC also exerts anti-inflammatory Coagulation is resolved by fibrinolysis, a process that involves a
activity by inhibiting pro-inflammatory cytokine production distinct enzymatic cascade. In the physiological state, fibrino-
and leukocyte infiltration.109–113 Reduced PC, on the other lysis is initiated by three serine proteases: tissue plasminogen
hand, increases the generation of thrombin during an influenza activator (tPA), urokinase plasminogen activator (uPA) and
virus infection.48 However, because of the complex network kallikrein (Figure 1h).130 uPA and tPA initiate the conversion
that regulates coagulation, contradictory effects of PC are of the zymogen plasminogen to the serine proteinase plasmin,
often observed in lethal H1N1 influenza in mice: while it can which dissolves the polymerized fibrin strands. Fibrinolysis is

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Coagulation and inflammation in influenza pneumonia
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438

regulated by other molecules, including α2-antiplasmin, α2- also been implicated in influenza encephalitis.138,139 Therefore,
macroglobulin, plasminogen activator inhibitor-1 (PAI-1) and plasminogen-dependent cleavage of HA is used by influenza
thrombin-activatable fibrinolysis inhibitor.131 In addition to its viruses to increase their replication rates and infectivity
fibrinolysis activity, plasmin plays a critical role in a variety of (Figure 3b). On the other hand, the binding of NA of the
processes, including inflammation.132,133 Plasminogen binds to influenza virus A/WSN/33 to plasminogen helps to sequestrate
different receptors on monocytes, macrophages, DCs and other plasminogen on the cell surface and increases the cleavage of
immune cells and generates plasmin, which is responsible for HA. This further helps in the dissemination of the virus and
the migration and recruitment of inflammatory immune cells the efficient replication of IAV in the brains of mice.135,136
to lesions and subsequently stimulates the production of pro- Binding of plasminogen to NA seems to rely on the unique
inflammatory cytokines and chemokines and ROS.132 In fact, sequence motif of the WSN strain.135 The activation of
excessive activation of plasmin exacerbates the pathogenesis of plasminogen also helps with the replication of other influenza
different inflammatory diseases.132 virus strains in an NA-independent fashion. In this case,
Plasminogen and plasmin play critical roles in the infectivity annexin II of the host cell binds to plasminogen and activates
of influenza viruses. The proteolytic cleavage of HA by trypsin- HA cleavage.134,140,141 Moreover, viral HA itself seems to be
able to recruit plasminogen for HA cleavage.142 Bacterial
like proteases in the respiratory tract can process the HA
staphylokinase can activate plasminogen to plasmin and
precursor protein into two disulfide bond-linked subunits,
thereby induce cleavage of HA of the MS96 (H9N2) virus.
HA1 and HA2. This is an essential step in the life cycle and is
This mechanism may partly explain why bacterial infection can
required for IAV infectivity.134 Influenza viruses use the
enhance influenza infectivity.143
conversion of plasminogen into plasmin, and the latter
Plasminogen not only facilitates the infection of IAV but also
possesses a trypsin-like protease activity to cleave HA
contributes to the pathogenicity of the viral infection.144
(Figure 3b).135,136 Moreover, mini-plasmin, which is generated Fibrinolysis (fibrinogen degradation) is one of the underlying
by the sequential processing of plasminogen by a plasminogen mechanisms of plasminogen-driven lung inflammation and
activator and elastases, has been found in the epithelial cells of mortality. A blockade of plasminogen fibrinolysis by 6-
the bronchioles and is reported to process HA.137 The aminohexanoic acid (6-AHA) treatment, for example, protects
accumulation of mini-plasmin in the cerebral capillaries has mice from influenza virus lethality.144 Increased vascular
permeability, induced by plasminogen, helps in the recruitment
of inflammatory cells to the site of IAV infection and also
contributes to the inflammation response.144 Plasminogen
might also interact with PAR-1 to decrease survival and
increase lung inflammation after an influenza infection.89
PAI-1, encoded by the SERPINE1 gene, is a serine protease
inhibitor that inhibits the activation of tPA and uPA and,
hence, fibrinolysis (Figure 1h).145 Recently, PAI-1 was identi-
fied as an unconventional ISG that targets extracellular airway
proteases to inhibit viral glycoprotein cleavage and reduce the
infectivity of progeny viruses in vitro and in vivo (Figure 3a).146
Influenza virus infection can increase the production of PAI-1
from ECs and airway epithelial cells, which inhibits the spread
of the IAV.146,147 Increased PAI-1 expression may not protect
hosts against an IAV infection under certain circumstances; for
example, passive cigarette smoke exposure can induce PAI-1
expression, but it promotes alveolar epithelial cell apoptosis
and exacerbates lung inflammation after an IAV infection.148

Figure 3 The role of the fibrinolytic components in the IAV life


BACTERIAL SUPERINFECTION AFFECTS INFLUENZA
cycle. (a) The release of influenza virus particles from the host cell PATHOGENESIS THROUGH THE HYPER-ACTIVATION
is mediated by NA through the cleavage of sialic acid from OF COAGULATION
glycoproteins. PAI-1 inhibits viral glycoprotein cleavage, reducing Bacterial superinfection during influenza, primarily by Strepto-
the spread of the virus from the host cell to uninfected surrounding coccus pneumoniae, often results in hospitalization and even the
cells. (b) HA of the IAV is typically cleaved by trypsin-like proteases death of patients.149–151 IAV-S. pneumoniae co-infection in
to gain viral fusion capacity. Certain influenza viruses can hijack
mice causes a markedly more severe disease and hyper-
plasmin for cleaving their HA to increase their viral infectivity and
spread. PAI-1 acts as an anti-influenza molecule through the
activation of coagulation compared with IAV infection
inhibition of HA cleavage by plasmin, as PAI-1 is the main inhibitor alone.64 Widespread pulmonary thrombosis and the extensive
of the plasminogen activators. HA, hemagglutinin; IAV, influenza A expression of TF on the endothelial, epithelial and immune
virus; NA, neuraminidase; PAI, plasminogen activator inhibitor-1. cells is found in the lung sections of S. pneumoniae-positive

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1918 H1N1 autopsies and co-infected mice.64 A secondary ACKNOWLEDGEMENTS


S. pneumoniae infection is held accountable for the over- This work is supported by grants from the National Natural Sciences
expression of TF, the initiation of the coagulation cascade and Foundation of China (NSFC) to HT (No. 81590764) and YY (No.
thrombus formation, which contribute to severe hypoxia 31400755).
and death.64
Unlike the pathogenic bacterial superinfection, the coloniza-
tion of commensal bacteria or pretreatment with probiotic
1 Tong S, Zhu X, Li Y, Shi M, Zhang J, Bourgeois M et al. New world
bacteria can dampen influenza-mediated acute lung injury.
bats harbor diverse influenza A viruses. PLoS Pathog 2013; 9:
Staphylococcus aureus, one of the most common commensal e1003657.
bacterium colonized in the airways, induces the polarization of 2 Kuiken T, Riteau B, Fouchier RA, Rimmelzwaan GF. Pathogenesis of
M2 alveolar macrophages and inhibits the lethal inflammatory influenza virus infections: the good, the bad and the ugly. Curr Opin
Virol 2012; 2: 276–286.
response to an IAV infection.152 Furthermore, both oral and 3 Wu A, Su C, Wang D, Peng Y, Liu M, Hua S et al. Sequential
nasal pretreatment with the probiotic lactic acid bacteria strains reassortments underlie diverse influenza H7N9 genotypes in China.
(Lactobacillus rhamnosus CRL1505) protects mice from PR8 Cell Host Microbe 2013; 14: 446–452.
4 Gao R, Cao B, Hu Y, Feng Z, Wang D, Hu W et al. Human infection
lethality.153,154 Pretreatment with L. rhamnosus significantly with a novel avian-origin influenza A (H7N9) virus. New Engl J Med
reduces coagulatory activation mainly through the downregu- 2013; 368: 1888–1897.
lation of TF and the restoration of thrombomodulin levels.154 5 Short KR, Kroeze EJ, Fouchier RA, Kuiken T. Pathogenesis of
influenza-induced acute respiratory distress syndrome. Lancet Infect
Taken together, these studies show that bacteria in the airways Dis 2014; 14: 57–69.
affect the outcome of IAV pneumonia, and precise targeting of 6 Taubenberger JK, Morens DM. The pathology of influenza virus
the bacteria should be considered in the treatment of influenza. infections. Annu Rev Pathol 2008; 3: 499–522.
7 Rosen DG, Lopez AE, Anzalone ML, Wolf DA, Derrick SM, Florez LF
et al. Postmortem findings in eight cases of influenza A/H1N1.
CONCLUSION Mod Pathol 2010; 23: 1449–1457.
Influenza virus infection causes excessive activation of ECs and 8 Davison AM, Thomson D, Robson JS. Intravascular coagulation
complicating influenza A virus infection. Br Med J 1973; 1:
platelets, which triggers a coagulation cascade with concur- 654–655.
rently impaired anti-coagulatory and fibrinolytic signaling. 9 Watanabe T. Renal complications of seasonal and pandemic influenza
Such a pro-coagulant state can cause hemorrhagic fever and A virus infections. Eur J Pediatr 2013; 172: 15–22.
10 Pang IK, Pillai PS, Iwasaki A. Efficient influenza A virus replication in
is often associated with ARDS in severe flu patients. The the respiratory tract requires signals from TLR7 and RIG-I. Proc Natl
aberrant coagulation system contributes to the severity of Acad Sci USA 2013; 110: 13910–13915.
influenza at multiple levels. The activated ECs and platelets 11 Gao R, Bhatnagar J, Blau DM, Greer P, Rollin DC, Denison AM et al.
Cytokine and chemokine profiles in lung tissues from fatal cases of
first produce pro-inflammatory cytokines and chemokines that 2009 pandemic influenza A (H1N1): role of the host immune
enhance inflammatory cell infiltration and increase vascular response in pathogenesis. Am J Pathol 2013; 183: 1258–1268.
permeability. Platelets are further activated under these cir- 12 McAuley JL, Tate MD, MacKenzie-Kludas CJ, Pinar A, Zeng W,
Stutz A et al. Activation of the NLRP3 inflammasome by IAV virulence
cumstances. Second, coagulation factors are activated, which protein PB1-F2 contributes to severe pathophysiology and disease.
further augment the inflammation via PARs on ECs, platelets PLoS Pathog 2013; 9: e1003392.
and leukocytes. Third, the expression of anticoagulant compo- 13 Ichinohe T, Pang IK, Iwasaki A. Influenza virus activates
inflammasomes via its intracellular M2 ion channel. Nat Immunol
nents decreases as the ECs are activated. And last, fibrinolytic 2010; 11: 404–410.
proteases (such as plasmin) are activated by the upregulated 14 Lupfer C, Thomas PG, Anand PK, Vogel P, Milasta S, Martinez J et al.
coagulation, which has been hijacked by the influenza virus for Receptor interacting protein kinase 2-mediated mitophagy regulates
inflammasome activation during virus infection. Nat Immunol 2013;
viral replication and infectivity. 14: 480–488.
Understanding the cellular and molecular events of 15 Iwasaki A, Pillai PS. Innate immunity to influenza virus infection.
coagulation will contribute to the development of more Nat Rev Immunol 2014; 14: 315–328.
16 Brandes M, Klauschen F, Kuchen S, Germain RN. A systems analysis
precise therapeutics against IAV infections. Drugs that target identifies a feedforward inflammatory circuit leading to lethal influ-
endothelial cell activation (S1P1 agonists CYM-5442 and enza infection. Cell 2013; 154: 197–212.
RP-002), anti-platelet agents (eptifibatide, aspirin, MRS 2179 17 Liu Q, Zhou YH, Yang ZQ. The cytokine storm of severe influenza and
development of immunomodulatory therapy. Cell Mol Immunol 2016;
and clopidogrel), anticoagulants (recombinant activated PC 13: 3–10.
and Ancrod) and protease inhibitors (6-AHA, PAI-1 and 18 Armstrong SM, Darwish I, Lee WL. Endothelial activation and
aprotinin155) effectively hamper pathogenic IAV infection in dysfunction in the pathogenesis of influenza A virus infection.
Virulence 2013; 4: 537–542.
mice. Nevertheless, the detailed mechanisms of how coagula- 19 Antoniak S, Mackman N. Multiple roles of the coagulation protease
tion contributes to the pathogenesis of severe influenza, cascade during virus infection. Blood 2014; 123: 2605–2613.
especially in humans, remains to be investigated. A better 20 Le VB, Schneider JG, Boergeling Y, Berri F, Ducatez M, Guerin JL
et al. Platelet activation and aggregation promote lung inflammation
understanding of coagulatory homeostasis would definitely and influenza virus pathogenesis. Am J Respir Crit Care Med 2015;
benefit the development of more precise treatments for 191: 804–819.
epidemic and pandemic influenza. 21 Palta S, Saroa R, Palta A. Overview of the coagulation system.
Indian J Anaesth 2014; 58: 515–523.
22 To KK, Song W, Lau SY, Que TL, Lung DC, Hung IF et al. Unique
CONFLICT OF INTEREST reassortant of influenza A(H7N9) virus associated with severe disease
The authors declare no conflict of interest. emerging in Hong Kong. J Infect 2014; 69: 60–68.

Cellular & Molecular Immunology


Coagulation and inflammation in influenza pneumonia
Y Yang and H Tang

440

23 Chen E, Wang F, Lv H, Zhang Y, Ding H, Liu S et al. The first avian 47 Dobson J, Whitley RJ, Pocock S, Monto AS. Oseltamivir treatment for
influenza A (H7N9) viral infection in humans in Zhejiang Province, influenza in adults: a meta-analysis of randomised controlled trials.
China: a death report. Front Med 2013; 7: 333–344. Lancet 2015; 385: 1729–1737.
24 Chen Y, Liang W, Yang S, Wu N, Gao H, Sheng J et al. Human 48 Keller TT, van der Sluijs KF, de Kruif MD, Gerdes VE, Meijers JC,
infections with the emerging avian influenza A H7N9 virus from wet Florquin S et al. Effects on coagulation and fibrinolysis induced by
market poultry: clinical analysis and characterisation of viral genome. influenza in mice with a reduced capacity to generate activated
Lancet 2013; 381: 1916–1925. protein C and a deficiency in plasminogen activator inhibitor type 1.
25 Lu S, Li T, Xi X, Chen Q, Liu X, Zhang B et al. Prognosis of 18 H7N9 Circ Res 2006; 99: 1261–1269.
avian influenza patients in Shanghai. PLoS One 2014; 9: e88728. 49 Goeijenbier M, van Gorp EC, Van den Brand JM, Stittelaar K,
26 Wiwanitkit V. Hemostatic disorders in bird flu infection. Blood Coagul Bakhtiari K, Roelofs JJ et al. Activation of coagulation and tissue
Fibrinolysis 2008; 19: 5–6. fibrin deposition in experimental influenza in ferrets. BMC Microbiol
27 Claas EC, Osterhaus AD, van Beek R, De Jong JC, Rimmelzwaan GF, 2014; 14: 134.
Senne DA et al. Human influenza A H5N1 virus related to a highly 50 Herold S, Becker C, Ridge KM, Budinger GR. Influenza virus-induced
pathogenic avian influenza virus. Lancet 1998; 351: 472–477. lung injury: pathogenesis and implications for treatment. Eur Respir J
28 Harms PW, Schmidt LA, Smith LB, Newton DW, Pletneva MA, 2015; 45: 1463–1478.
Walters LL et al. Autopsy findings in eight patients with fatal H1N1 51 Akiyama R, Komori I, Hiramoto R, Isonishi A, Matsumoto M, Fujimura
influenza. Am J Clin Pathol 2010; 134: 27–35. Y. H1N1 influenza (swine flu)-associated thrombotic microangiopathy
29 Soto-Abraham MV, Soriano-Rosas J, Diaz-Quinonez A, Silva-Pereyra with a markedly high plasma ratio of von Willebrand factor to
J, Vazquez-Hernandez P, Torres-Lopez O et al. Pathological changes ADAMTS13. Intern Med 2011; 50: 643–647.
associated with the 2009 H1N1 virus. New Engl J Med 2009; 361: 52 Boilard E, Pare G, Rousseau M, Cloutier N, Dubuc I, Levesque T et al.
2001–2003. Influenza virus H1N1 activates platelets through FcgammaRIIA
30 Gilbert CR, Vipul K, Baram M. Novel H1N1 influenza A viral infection signaling and thrombin generation. Blood 2014; 123: 2854–2863.
complicated by alveolar hemorrhage. Respir Care 2010; 55: 53 Teijaro JR, Walsh KB, Cahalan S, Fremgen DM, Roberts E, Scott F
623–625. et al. Endothelial cells are central orchestrators of cytokine amplifica-
31 Mauad T, Hajjar LA, Callegari GD, da Silva LF, Schout D, Galas FR tion during influenza virus infection. Cell 2011; 146: 980–991.
et al. Lung pathology in fatal novel human influenza A (H1N1) 54 van Hinsbergh VW. Endothelium—role in regulation of coagulation
infection. Am J Respir Crit Care Med 2010; 181: 72–79. and inflammation. Semin Immunopathol 2012; 34: 93–106.
32 Smeeth L, Cook C, Thomas S, Hall AJ, Hubbard R, Vallance P. Risk of 55 Vallet B, Wiel E. Endothelial cell dysfunction and coagulation.
deep vein thrombosis and pulmonary embolism after acute infection Crit Care Med 2001; 29(7 Suppl): S36–S41.
in a community setting. Lancet 2006; 367: 1075–1079. 56 Pober JS, Sessa WC. Evolving functions of endothelial cells in
33 Marsden PA. Inflammation and coagulation in the cardiovascular inflammation. Nat Rev Immunol 2007; 7: 803–815.
system: the contribution of influenza. Circ Res 2006; 99: 57 Pate M, Damarla V, Chi DS, Negi S, Krishnaswamy G. Endothelial cell
1152–1153. biology: role in the inflammatory response. Adv Clin Chem 2010; 52:
34 Rothberg MB, Haessler SD, Brown RB. Complications of viral 109–130.
influenza. Am J Med 2008; 121: 258–264. 58 Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van
35 Kosugi N, Tsurutani Y, Isonishi A, Hori Y, Matsumoto M, Fujimura Y. Loo G et al. Identification of oxidative stress and Toll-like receptor 4
Influenza A infection triggers thrombotic thrombocytopenic purpura signaling as a key pathway of acute lung injury. Cell 2008; 133:
by producing the anti-ADAMTS13 IgG inhibitor. Intern Med 2010; 235–249.
49: 689–693. 59 Tsai SY, Segovia JA, Chang TH, Morris IR, Berton MT, Tessier PA
36 Jonsson MK, Hammenfors D, Oppegaard O, Bruserud O, Kittang AO. et al. DAMP molecule S100A9 acts as a molecular pattern to
A 35-year-old woman with influenza A-associated thrombotic throm- enhance inflammation during influenza A virus infection: role of
bocytopenic purpura. Blood Coagul Fibrinolysis 2015; 26: 469–472. DDX21-TRIF-TLR4-MyD88 pathway. PLoS Pathog 2014; 10:
37 Corrales-Medina VF, Madjid M, Musher DM. Role of acute infection in e1003848.
triggering acute coronary syndromes. Lancet Infect Dis 2010; 10: 60 Shibamiya A, Hersemeyer K, Schmidt Woll T, Sedding D, Daniel JM,
83–92. Bauer S et al. A key role for Toll-like receptor-3 in disrupting
38 Ludwig A, Lucero-Obusan C, Schirmer P, Winston C, Holodniy M. the hemostasis balance on endothelial cells. Blood 2009; 113:
Acute cardiac injury events p30 days after laboratory-confirmed 714–722.
influenza virus infection among U.S. veterans, 2010-2012. BMC 61 Armstrong SM, Wang C, Tigdi J, Si X, Dumpit C, Charles S et al.
Cardiovasc Disord 2015; 15: 109. Influenza infects lung microvascular endothelium leading to
39 Barnes M, Heywood AE, Mahimbo A, Rahman B, Newall AT, microvascular leak: role of apoptosis and claudin-5. PLoS One
Macintyre CR. Acute myocardial infarction and influenza: a meta- 2012; 7: e47323.
analysis of case-control studies. Heart 2015; 101: 1738–1747. 62 Wang S, Le TQ, Kurihara N, Chida J, Cisse Y, Yano M et al. Influenza
40 Warren-Gash C, Smeeth L, Hayward AC. Influenza as a trigger for virus-cytokine-protease cycle in the pathogenesis of vascular hyper-
acute myocardial infarction or death from cardiovascular disease: a permeability in severe influenza. J Infect Dis 2010; 202: 991–1001.
systematic review. Lancet Infect Dis 2009; 9: 601–610. 63 Pinsky DJ, Naka Y, Liao H, Oz MC, Wagner DD, Mayadas TN et al.
41 Clar C, Oseni Z, Flowers N, Keshtkar-Jahromi M, Rees K. Influenza Hypoxia-induced exocytosis of endothelial cell Weibel-Palade bodies.
vaccines for preventing cardiovascular disease. Cochrane Database A mechanism for rapid neutrophil recruitment after cardiac preserva-
Syst Rev 2015; 5: CD005050. tion. J Clin Invest 1996; 97: 493–500.
42 Kwok CS, Aslam S, Kontopantelis E, Myint PK, Zaman MJ, Buchan I 64 Walters KA, D'Agnillo F, Sheng ZM, Kindrachuk J, Schwartzman LM,
et al. Influenza, influenza-like symptoms and their association with Kuestner RE et al. 1918 pandemic influenza virus and Streptococcus
cardiovascular risks: a systematic review and meta-analysis of pneumoniae co-infection results in activation of coagulation and
observational studies. Int J Clin Pract 2015; 69: 928–937. widespread pulmonary thrombosis in mice and humans. J Pathol
43 Rose JJ, Voora D, Cyr DD, Lucas JE, Zaas AK, Woods CW et al. 2016; 238: 85–97.
Gene expression profiles link respiratory viral infection, platelet 65 Visseren FL, Bouwman JJ, Bouter KP, Diepersloot RJ, de Groot PH,
response to aspirin, and acute myocardial infarction. PLoS One Erkelens DW. Procoagulant activity of endothelial cells after infection
2015; 10: e0132259. with respiratory viruses. Thromb Haemost 2000; 84: 319–324.
44 Lin HC, Chiu HF, Ho SC, Yang CY. Association of influenza 66 Goeijenbier M, van Wissen M, van de Weg C, Jong E, Gerdes VE,
vaccination and reduced risk of stroke hospitalization among the Meijers JC et al. Review: viral infections and mechanisms of
elderly: a population-based case-control study. Int J Environ Res thrombosis and bleeding. J Med Virol 2012; 84: 1680–1696.
Public Health 2014; 11: 3639–3649. 67 Teijaro JR, Walsh KB, Rice S, Rosen H, Oldstone MB. Mapping the
45 Granwehr B. ACP Journal Club. Review: influenza vaccination reduces innate signaling cascade essential for cytokine storm during influenza
cardiovascular events in adults. Ann Intern Med 2014; 160: JC2. virus infection. Proc Natl Acad Sci USA 2014; 111: 3799–3804.
46 Kopel E, Klempfner R, Goldenberg I. Influenza vaccine and survival in 68 Perrone LA, Plowden JK, Garcia-Sastre A, Katz JM, Tumpey TM.
acute heart failure. Eur J Heart Fail 2014; 16: 264–270. H5N1 and 1918 pandemic influenza virus infection results in early

Cellular & Molecular Immunology


Coagulation and inflammation in influenza pneumonia
Y Yang and H Tang

441

and excessive infiltration of macrophages and neutrophils in the lungs systematic review and meta-analysis. J R Soc Med 2010; 103:
of mice. PLoS Pathog 2008; 4: e1000115. 403–411.
69 Sreeramkumar V, Adrover JM, Ballesteros I, Cuartero MI, Rossaint J, 94 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring
Bilbao I et al. Neutrophils scan for activated platelets to initiate inconsistency in meta-analyses. BMJ 2003; 327: 557–560.
inflammation. Science 2014; 346: 1234–1238. 95 Yang Y, Sun R, Yang H, Zheng F, Gong F. -308 G 4 A of TNF-alpha
70 Semple JW, Italiano JE Jr., Freedman J. Platelets and the immune gene promoter decreases the risk of multiple sclerosis: a
continuum. Nat Rev Immunol 2011; 11: 264–274. meta-analysis. Mult Scler 2011; 17: 658–665.
71 Tamagawa-Mineoka R. Important roles of platelets as immune cells in 96 Sunden Y, Park CH, Matsuda K, Anagawa A, Kimura T, Ochiai K et al.
the skin. J Dermatol Sci 2015; 77: 93–101. The effects of antipyretics on influenza virus encephalitis in mice
72 Vieira-de-Abreu A, Campbell RA, Weyrich AS, Zimmerman GA. and chicks. J Vet Med Sci 2003; 65: 1185–1188.
Platelets: versatile effector cells in hemostasis, inflammation, and 97 Davis LE, Green CL, Wallace JM. Influenza B virus model of
the immune continuum. Semin Immunopathol 2012; 34: 5–30. Reye's syndrome in mice: the effect of aspirin. Ann Neurol 1985; 18:
73 Esmon CT, Xu J, Lupu F. Innate immunity and coagulation. J Thromb 556–559.
Haemost 2011; 9(Suppl 1): 182–188. 98 Crocker JF, Digout SC, Lee SH, Rozee KR, Renton K, Field CA et al.
74 Stokes KY, Granger DN. Platelets: a critical link between Effects of antipyretics on mortality due to influenza B virus in a mouse
inflammation and microvascular dysfunction. J Physiol 2012; 590: model of Reye's syndrome. Clin Invest Med 1998; 21: 192–202.
1023–1034. 99 Bouwman JJ, Visseren FL, Bosch MC, Bouter KP, Diepersloot RJ.
75 Klinger MH, Jelkmann W. Role of blood platelets in infection and Procoagulant and inflammatory response of virus-infected monocytes.
inflammation. J Interferon Cytokine Res 2002; 22: 913–922. Eur J Clin Invest 2002; 32: 759–766.
76 Gawaz M, Langer H, May AE. Platelets in inflammation and 100 Heemskerk JW, Bevers EM, Lindhout T. Platelet activation and blood
atherogenesis. J Clin Invest 2005; 115: 3378–3384. coagulation. Thromb Haemost 2002; 88: 186–193.
77 Morrell CN, Aggrey AA, Chapman LM, Modjeski KL. Emerging roles 101 Smiley ST, King JA, Hancock WW. Fibrinogen stimulates macrophage
for platelets as immune and inflammatory cells. Blood 2014; 123: chemokine secretion through toll-like receptor 4. J Immunol 2001;
2759–2767. 167: 2887–2894.
78 Rondina MT, Garraud O. Emerging evidence for platelets as immune 102 Szaba FM, Smiley ST. Roles for thrombin and fibrin(ogen) in
and inflammatory effector cells. Front Immunol 2014; 5: 653. cytokine/chemokine production and macrophage adhesion in vivo.
79 Zarbock A, Polanowska-Grabowska RK, Ley K. Platelet- Blood 2002; 99: 1053–1059.
neutrophil-interactions: linking hemostasis and inflammation. Blood 103 Geisbert TW, Hensley LE, Jahrling PB, Larsen T, Geisbert JB,
Rev 2007; 21: 99–111. Paragas J et al. Treatment of Ebola virus infection with a recombinant
80 Li J, Kim K, Barazia A, Tseng A, Cho J. Platelet-neutrophil inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys.
interactions under thromboinflammatory conditions. Cell Mol Life Lancet 2003; 362: 1953–1958.
Sci 2015; 72: 2627–2643. 104 Antoniak S, Owens AP 3rd, Baunacke M, Williams JC, Lee RD,
81 Rossaint J, Zarbock A. Platelets in leucocyte recruitment and Weithauser A et al. PAR-1 contributes to the innate immune response
function. Cardiovasc Res 2015; 107: 386–395. during viral infection. J Clin Invest 2013; 123: 1310–1322.
82 Siegel-Axel DI, Gawaz M. Platelets and endothelial cells. Semin 105 Khoufache K, LeBouder F, Morello E, Laurent F, Riffault S, Andrade-
Thromb Hemost 2007; 33: 128–135. Gordon P et al. Protective role for protease-activated receptor-2
83 Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, against influenza virus pathogenesis via an IFN-gamma-dependent
Muller-Berghaus G et al. CD40 ligand on activated platelets triggers pathway. J Immunol 2009; 182: 7795–7802.
an inflammatory reaction of endothelial cells. Nature 1998; 391: 106 Nhu QM, Shirey K, Teijaro JR, Farber DL, Netzel-Arnett S, Antalis TM
591–594. et al. Novel signaling interactions between proteinase-activated
84 Danese S, Scaldaferri F, Papa A, Pola R, Gasbarrini A, Sgambato A receptor 2 and Toll-like receptors in vitro and in vivo. Mucosal
et al. CD40L-positive platelets induce CD40L expression de novo in Immunol 2010; 3: 29–39.
endothelial cells: adding a loop to microvascular inflammation. 107 Delvaeye M, Conway EM. Coagulation and innate immune responses:
Arterioscler Thromb Vasc Biol 2004; 24: e162. can we view them separately? Blood 2009; 114: 2367–2374.
85 Kim JK, Jeon JS, Kim JW. Correlation between abnormal platelet 108 Jackson CJ, Xue M. Activated protein C–an anticoagulant that does
count and respiratory viral infection in patients from Cheonan, Korea. more than stop clots. Int J Biochem Cell Biol 2008; 40: 2692–2697.
J Clin Lab Anal 2014. 109 Okajima K. Regulation of inflammatory responses by natural antic-
86 Gao HN, Lu HZ, Cao B, Du B, Shang H, Gan JH et al. Clinical findings oagulants. Immunol Rev 2001; 184: 258–274.
in 111 cases of influenza A (H7N9) virus infection. New Engl J Med 110 Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF,
2013; 368: 2277–2285. Lopez-Rodriguez A et al. Efficacy and safety of recombinant
87 Lopez-Delgado JC, Rovira A, Esteve F, Rico N, Manez Mendiluce R, human activated protein C for severe sepsis. New Engl J Med
Ballus Noguera J et al. Thrombocytopenia as a mortality risk factor in 2001; 344: 699–709.
acute respiratory failure in H1N1 influenza. Swiss Med Wkly 2013; 111 Nick JA, Coldren CD, Geraci MW, Poch KR, Fouty BW, O'Brien J et al.
143: w13788. Recombinant human activated protein C reduces human
88 Rondina MT, Brewster B, Grissom CK, Zimmerman GA, Kastendieck endotoxin-induced pulmonary inflammation via inhibition of
DH, Harris ES et al. In vivo platelet activation in critically ill neutrophil chemotaxis. Blood 2004; 104: 3878–3885.
patients with primary 2009 influenza A(H1N1). Chest 2012; 141: 112 Toltl LJ, Swystun LL, Pepler L, Liaw PC. Protective effects
1490–1495. of activated protein C in sepsis. Thromb Haemost 2008; 100:
89 Khoufache K, Berri F, Nacken W, Vogel AB, Delenne M, Camerer E 582–592.
et al. PAR1 contributes to influenza A virus pathogenicity in mice. 113 Pestana D, de la Oliva P. Nebulized activated protein C in a
J Clin Invest 2013; 123: 206–214. paediatric patient with severe acute respiratory distress syndrome
90 Sugiyama MG, Gamage A, Zyla R, Armstrong SM, Advani S, Advani A secondary to H1N1 influenza. Br J Anaesth 2011; 107: 818–819.
et al. Influenza virus infection induces platelet-endothelial adhesion 114 Schouten M, de Boer JD, van der Sluijs KF, Roelofs JJ, van't Veer C,
which contributes to lung injury. J Virol 2015; 90: 1812–1823. Levi M et al. Impact of endogenous protein C on pulmonary
91 Mazur I, Wurzer WJ, Ehrhardt C, Pleschka S, Puthavathana P, coagulation and injury during lethal H1N1 influenza in mice. Am J
Silberzahn T et al. Acetylsalicylic acid (ASA) blocks influenza virus Respir Cell Mol Biol 2011; 45: 789–794.
propagation via its NF-kappaB-inhibiting activity. Cell Microbiol 115 Schouten M, Sluijs KF, Gerlitz B, Grinnell BW, Roelofs JJ, Levi MM
2007; 9: 1683–1694. et al. Activated protein C ameliorates coagulopathy but does not
92 Starko KM. Salicylates and pandemic influenza mortality, influence outcome in lethal H1N1 influenza: a controlled
1918-1919 pharmacology, pathology, and historic evidence. Clin laboratory study. Crit Care 2010; 14: R65.
Infect Dis 2009; 49: 1405–1410. 116 Allen KS, Sawheny E, Kinasewitz GT. Anticoagulant modulation of
93 Eyers S, Weatherall M, Shirtcliffe P, Perrin K, Beasley R. The effect inflammation in severe sepsis. World J Crit Care Med 2015; 4:
on mortality of antipyretics in the treatment of influenza infection: 105–115.

Cellular & Molecular Immunology


Coagulation and inflammation in influenza pneumonia
Y Yang and H Tang

442

117 Margetic S. Inflammation and haemostasis. Biochem Med 2012; 22: 138 Yao D, Kuwajima M, Kido H. Pathologic mechanisms of influenza
49–62. encephalitis with an abnormal expression of inflammatory cytokines
118 Ostrovsky L, Woodman RC, Payne D, Teoh D, Kubes P. Antithrombin and accumulation of mini-plasmin. J Med Invest 2003; 50: 1–8.
III prevents and rapidly reverses leukocyte recruitment in ischemia/ 139 Yao D, Chen Y, Kuwajima M, Shiota M, Kido H. Accumulation of
reperfusion. Circulation 1997; 96: 2302–2310. mini-plasmin in the cerebral capillaries causes vascular invasion of
119 Mizutani A, Okajima K, Uchiba M, Isobe H, Harada N, Mizutani S the murine brain by a pneumotropic influenza A virus: implications
et al. Antithrombin reduces ischemia/reperfusion-induced renal for influenza-associated encephalopathy. Biol Chem 2004; 385:
injury in rats by inhibiting leukocyte activation through promotion 487–492.
of prostacyclin production. Blood 2003; 101: 3029–3036. 140 LeBouder F, Lina B, Rimmelzwaan GF, Riteau B. Plasminogen
120 Congote LF. The C-terminal 26-residue peptide of serpin A1 is an promotes influenza A virus replication through an annexin 2-
inhibitor of HIV-1. Biochem Biophys Res Commun 2006; 343: dependent pathway in the absence of neuraminidase. J Gen Virol
617–622. 2010; 91(Pt 11): 2753–2761.
121 Elmaleh DR, Brown NV, Geiben-Lynn R. Anti-viral activity of human 141 Sun X, Tse LV, Ferguson AD, Whittaker GR. Modifications to the
antithrombin III. Int J Mol Med 2005; 16: 191–200.
hemagglutinin cleavage site control the virulence of a neurotropic
122 Whitney JB, Asmal M, Geiben-Lynn R. Serpin induced antiviral
H1N1 influenza virus. J Virol 2010; 84: 8683–8690.
activity of prostaglandin synthetase-2 against HIV-1 replication. PLoS
142 Tse LV, Marcano VC, Huang W, Pocwierz MS, Whittaker GR.
One 2011; 6: e18589.
123 Quenelle DC, Hartman TL, Buckheit RW, Prichard MN, Lynn RG. Plasmin-mediated activation of pandemic H1N1 influenza virus
Anti-HSV activity of serpin antithrombin III. Int Trends Immun 2014; hemagglutinin is independent of the viral neuraminidase. J Virol
2: 87–92. 2013; 87: 5161–5169.
124 Asmal M, Seaman M, Lin W, Chung RT, Letvin NL, Geiben-Lynn R. 143 Tse LV, Whittaker GR. Modification of the hemagglutinin cleavage
Inhibition of HCV by the serpin antithrombin III. Virol J 2012; 9: site allows indirect activation of avian influenza virus H9N2 by
226. bacterial staphylokinase. Virology 2015; 482: 1–8.
125 Smee DF, Hurst BL, Day CW, Geiben-Lynn R. Influenza Virus H1N1 144 Berri F, Rimmelzwaan GF, Hanss M, Albina E, Foucault-Grunenwald
inhibition by serine protease inhibitor (serpin) antithrombin III. ML, Le VB et al. Plasminogen controls inflammation and pathogen-
Int Trends Immun 2014; 2: 83–86. esis of influenza virus infections via fibrinolysis. PLoS Pathog 2013;
126 Bahgat MM, Blazejewska P, Schughart K. Inhibition of lung serine 9: e1003229.
proteases in mice: a potentially new approach to control influenza 145 Yasar Yildiz S, Kuru P, Toksoy Oner E, Agirbasli M. Functional
infection. Virol J 2011; 8: 27. stability of plasminogen activator inhibitor-1. ScientificWorldJournal
127 Peraramelli S, Rosing J, Hackeng TM. TFPI-dependent activities of 2014; 2014: 858293.
protein S. Thromb Res 2012; 129(Suppl 2): S23–S26. 146 Dittmann M, Hoffmann HH, Scull MA, Gilmore RH, Bell KL,
128 Wang Y, Chen J, Ling M, Lopez JA, Chung DW, Fu X. Hypochlorous Ciancanelli M et al. A serpin shapes the extracellular environment
acid generated by neutrophils inactivates ADAMTS13: an oxidative to prevent influenza A virus maturation. Cell 2015; 160: 631–643.
mechanism for regulating ADAMTS13 proteolytic activity during 147 Visseren FL, Verkerk MS, Bouter KP, Diepersloot RJ, Erkelens DW.
inflammation. J Biol Chem 2015; 290: 1422–1431. Interleukin-6 production by endothelial cells after infection with
129 Schwameis M, Schorgenhofer C, Assinger A, Steiner MM, Jilma B. influenza virus and cytomegalovirus. J Lab Clin Med 1999; 134:
VWF excess and ADAMTS13 deficiency: a unifying pathomechanism 623–630.
linking inflammation to thrombosis in DIC, malaria, and TTP. Thromb 148 Bhandary YP, Shetty SK, Marudamuthu AS, Midde KK, Ji HL,
Haemost 2015; 113: 708–718. Shams H et al. Plasminogen activator inhibitor-1 in cigarette smoke
130 Draxler DF, Medcalf RL. The fibrinolytic system-more than exposure and influenza A virus infection-induced lung injury. PLoS
fibrinolysis? Transfus Med Rev 2015; 29: 102–109. One 2015; 10: e0123187.
131 Cesarman-Maus G, Hajjar KA. Molecular mechanisms of fibrinolysis. 149 Rynda-Apple A, Robinson KM, Alcorn JF. Influenza and bacterial
Br J Haematol 2005; 129: 307–321. superinfection: illuminating the immunologic mechanisms of disease.
132 Godier A, Hunt BJ. Plasminogen receptors and their role in the
Infect Immun 2015; 83: 3764–3770.
pathogenesis of inflammatory, autoimmune and malignant disease.
150 McCullers JA. The co-pathogenesis of influenza viruses with bacteria
J Thromb Haemost 2013; 11: 26–34.
in the lung. Nat Rev Microbiol 2014; 12: 252–262.
133 Syrovets T, Lunov O, Simmet T. Plasmin as a proinflammatory cell
151 McCullers JA. Insights into the interaction between influenza virus
activator. J Leukoc Biol 2012; 92: 509–519.
134 LeBouder F, Morello E, Rimmelzwaan GF, Bosse F, Pechoux C, and pneumococcus. Clin Microbiol Rev 2006; 19: 571–582.
Delmas B et al. Annexin II incorporated into influenza virus particles 152 Schuliga M. The inflammatory actions of coagulant and fibrinolytic
supports virus replication by converting plasminogen into plasmin. proteases in disease. Mediators Inflamm 2015; 2015: 437695.
J Virol 2008; 82: 6820–6828. 153 Zelaya H, Tsukida K, Chiba E, Marranzino G, Alvarez S, Kitazawa H
135 Goto H, Kawaoka Y. A novel mechanism for the acquisition of et al. Immunobiotic lactobacilli reduce viral-associated pulmonary
virulence by a human influenza A virus. Proc Natl Acad Sci USA damage through the modulation of inflammation-coagulation
1998; 95: 10224–10228. interactions. Int Immunopharmacol 2014; 19: 161–173.
136 Goto H, Wells K, Takada A, Kawaoka Y. Plasminogen-binding activity 154 Zelaya H, Tada A, Vizoso-Pinto MG, Salva S, Kanmani P, Aguero G
of neuraminidase determines the pathogenicity of influenza A virus. et al. Nasal priming with immunobiotic Lactobacillus rhamnosus
J Virol 2001; 75: 9297–9301. modulates inflammation-coagulation interactions and reduces influ-
137 Murakami M, Towatari T, Ohuchi M, Shiota M, Akao M, Okumura Y enza virus-associated pulmonary damage. Inflamm Res 2015; 64:
et al. Mini-plasmin found in the epithelial cells of bronchioles triggers 589–602.
infection by broad-spectrum influenza A viruses and Sendai virus. 155 Zhirnov OP, Klenk HD, Wright PF. Aprotinin and similar protease
Eur J Biochem 2001; 268: 2847–2855. inhibitors as drugs against influenza. Antiviral Res 2011; 92: 27–36.

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