Keywords
thromboinflammation - immunothrombosis - platelets - coagulation - leukocytes - complement
Schlüsselwörter
Thromboinflammation - Immunthrombose - Blutplättchen - Gerinnung - Leukozyten - Komplement
From Immunothrombosis to Thromboinflammation
From Immunothrombosis to Thromboinflammation
The term immunothrombosis was first coined in 2013 in a review by Engelmann and Massberg,
to describe the mechanisms by which the innate immune system can trigger thrombotic
events.[1] Immunothrombosis involves an interplay of innate immune cells, platelets, and coagulation
factors, which contributes to the local control and clearance of infections.[2] In its physiological form, it represents a process of microcoagulation, which does
not lead to adverse clinical symptoms and simply helps to immobilize invading pathogens
or foreign “danger” structures for subsequent clearance by immune cells. However,
excessive inflammatory reactions can also induce coagulopathies and harmful thrombotic
events, emphasizing a fine-balanced interplay between the immune and the hemostatic
systems ([Fig. 1]).
Fig. 1 From immunothrombosis to thromboinflammation. Activation of the immune system by
PAMPs (e.g., in viral/bacterial infection) or DAMPs (e.g., in hemolytic disease, ischemia/reperfusion
injury) triggers procoagulant NET formation and monocyte TF expression and release
of TF + EVs. Activated platelets act as threshold switch and critically enhance these
processes, which in turn foster thrombin formation and further platelet activation.
Concomitant endothelial dysfunction results in loss of anticoagulant mechanisms and
platelet adhesion, leading to the development of intravascular thrombosis. Thrombotic
processes in turn trigger the dysregulated activation of complement, coagulation,
platelets, and endothelial cells, which leads to disrupted vascular integrity. Aberrant
activation of coagulation factors and platelets mediates inflammation by augmenting
recruitment and extravasation of immune cells, particularly of neutrophils and monocytes.
In addition, dysregulated induction of coagulation may influence immune cell turnover
by impacting on both apoptosis and stem cell functions. DAMP, danger-associated molecular
pattern, EV, extracellular vesicle, NET, neutrophil extracellular trap, PAMP, pathogen-associated
molecular pattern, TF, tissue factor.
The term thromboinflammation was already used prior to immunothrombosis to describe
various aspects of platelet involvement in inflammatory processes. In 2004, it was
first used to describe platelet–leukocyte interactions,[3] whereas in 2009, it referred to platelet activation through toll-like receptors.[4] Additionally, thromboinflammation has been used to describe the underlying causes
of stroke, which is considered a thromboinflammatory disease.[5]
Today, the relationship between immunothrombosis and thromboinflammation is commonly
understood as a cause and effect relationship. Immunothrombosis refers to the influence
of the immune system on the formation of a thrombus, whereas thromboinflammation refers
to the impact of the thrombus on the immune system.
Immunothrombosis, however, is no prerequisite for thromboinflammation, as nonimmunologic
stimuli can also trigger thrombi and subsequently lead to thromboinflammation. While
sepsis and ischemia–reperfusion are well known to cause microvascular thrombi that
fuel inflammatory processes, other diseases are also associated with thromboinflammatory
events including preeclampsia, viral and bacterial infections, as well as hemolytic
diseases like sickle cell disease.[6]
[7] Importantly, certain cancers bear a high risk for immunothrombotic events as well,
and the hemostatic system has been demonstrated to regulate several aspects of tumor-associated
pathologies.[8]
[9] Autoimmune diseases, such as rheumatoid arthritis[10] and antiphospholipid syndrome,[11] also trigger immunothrombosis, with thrombi and activated platelets, in turn, exacerbating
inflammation in autoimmune conditions.
Notably, thromboinflammation is also critically involved in acute ischemic stroke
and coronavirus disease 2019 (COVID-19). Infections triggered by pathogen-associated
molecular patterns (PAMPs) and sterile inflammatory diseases caused by damage-associated
molecular patterns (DAMPs) can lead to thromboinflammatory states. DAMPs are also
released upon tissue injury in situations of ischemia and reperfusion, contributing
to thrombus formation. PAMPs and DAMPs interfere with the antithrombotic and anti-inflammatory
mechanisms of the vasculature and trigger the dysregulated activation of coagulation
factors, platelets, endothelial cells, and complement system. These processes collaborate
and intertwine, resulting in surface expression of P-selectin on platelets and endothelium,
which facilitates recruitment of leukocytes and prompts a thromboinflammatory state.
Furthermore, enhanced release of leukocyte extracellular vesicles (EVs) containing
tissue factor (TF) and formation of neutrophil extracellular traps (NETs) leading
to procoagulant extracellular DNA can trigger a thrombotic response.[12] These processes not only determine the fate of the local microenvironment, where
they lead leads to microthrombi and vessel occlusion, but also have systemic long-term
effects beyond ischemic events and can even cause a state of immunosuppression. Widespread
tissue damage resulting from stroke, trauma, or burns often leads to a phase of weakened
immunity, making the individual more prone to systemic infection, which represents
a significant contributor to mortality following sterile tissue injuries.
Cell-free double-stranded DNA released during tissue injury was recently shown to
promote this immunosuppressive state, as it causes upregulation of interleukin (IL)
1β, which drives differentiation of CD95L+ myeloid cells and thereby causes postinjury
T cell apoptosis and diminished immune responses.[13]
While the causes and consequences of immunothrombosis have been extensively reviewed
elsewhere,[1]
[2]
[14] this review focuses on the effects of the thrombus on immune function and inflammation.
Inflammation-Induced Coagulation and Coagulation-Mediated Inflammation
Inflammation-Induced Coagulation and Coagulation-Mediated Inflammation
Upon vascular injury, the coagulation cascade is initiated by TF. Under quiescent
conditions, TF is expressed in an encrypted form on the cell membrane of fibroblasts,
pericytes, and vascular smooth muscle cells in subendothelial tissue.[15]
[16]
[17] Upon inflammatory processes, monocytes express TF, thereby inducing coagulation
within the circulation and causing immunothrombotic events.[2]
[18] In addition to being membrane associated, TF is also found on EVs shed from monocytes,
which further contributes to thrombus formation.[19] Activated platelets play a pivotal role in the decryption of TF, as they secrete
protein disulfide isomerase and foster its activity in response to interaction with
monocytes.
TF interacts with and activates FVII to FVIIa, which then forms a complex with phospholipids
and Ca2+ that activates FX, a central hub of the coagulation cascade where different pathways
of induction converge. Coagulation can also be triggered by the so-called contact
activation system, which describes the interaction and activation of FXII, FXI, prekallikrein,
and their cofactor high molecular weight kininogen by negatively charged surface,
e.g., activated platelets expressing phosphatidylserine. FXIIa catalyzes the formation
of FXIa from FXI, which then activates FIX to FIXa. FIXa then forms a complex with
its cofactor FVIIIa and phospholipids that activates FX.
Of note, not only TF expression by monocytes or endothelial cells carries a procoagulant
potential but also extracellular DNA, released as extracellular traps (ETs), can initiate
the coagulation cascade via the contact pathway, which represents another central
mechanism in immunothrombosis. While neutrophils are the most studied cells to form
ETs, other cell types, like eosinophils, macrophages, and mast cells represent a source
for extracellular DNA, thereby contributing to immunothrombosis.[20]
[21]
Together with its cofactor FVa, FXa cleaves prothrombin (FII) to thrombin (FIIa),
which catalyzes the cleavage of fibrinogen (FI) to fibrin (FIa). Moreover, thrombin
activates FXI, FVIII, and FV, promoting a positive feedback loop. FXIII is also activated
by thrombin and crosslinks fibrin to an insoluble fibrin network.
Thrombin and other proteases of the coagulation cascade, including FXa and FVIIa,
not only mediate fibrin generation but also regulate cellular functions, which affect
hemostatic and inflammatory processes. Proteases can activate G protein-coupled protease-activated
receptors (PARs) through an irreversible proteolytic event that results in the generation
of a tethered ligand that cannot diffuse away. There are four members of the PAR family.
Thrombin activates PAR1, PAR3, and PAR4, whereas multiple trypsin-like serine proteases
activate PAR2. Signaling regulation by PAR1 has been extensively studied, but less
is known about the other PARs. It has been demonstrated that rapid termination of
PAR1 signaling is crucial in determining the cellular protease response's magnitude
and kinetics.[22] PAR1 is also the main receptor for thrombin on platelets and represents the most
potent pathway of platelet activation. Therefore, PAR1 inhibitors are also clinically
used as antiplatelet agents. However, leukocytes also express PARs, inducing proinflammatory
and proapoptotic responses, and PARs also modulate stem cell functions via enhanced
mobilization of long-term repopulating hematopoietic stem cells.[23]
Endothelial cells express all four PARs and can be activated by FXa, FVIIa, thrombin,
activated protein C, and plasmin (reviewed in[24]). PAR signaling leads to endothelial expression of adhesion markers and proinflammatory
cytokines and reduces nitric oxide production. PAR signaling has therefore been suggested
to contribute to endothelial dysfunction.[25]
Another central mechanism of immunothrombosis is the formation of NETs, which represents
a specialized way of controlled cellular death. Of note, platelets are not only activated
by immunothrombosis, but can also initiate these processes, e.g., binding of platelets
to neutrophils represents a threshold switch for NET formation.[26]
During NET formation, neutrophils not only expel their chromatin, which forms an insoluble
net-like DNA structure that is studded with histones and antimicrobial enzymes (e.g.,
neutrophil elastase) but also retains procoagulant proteins (e.g., von Willebrand
factor [vWF], FXI, FXII). Thus, NET formation during infection serves two purposes:
on one side, NETs capture and kill bacteria and provide a platform where leukocytes
can act more efficiently, which may help to lower bacterial burden.[27]
[28]
[29] On the other side, NETs also serve as a strong prothrombotic and procoagulant stimulus
by providing a negatively charged surface that captures coagulation factors and platelets.[29] Histones and immobilized vWF on NETs activate platelets, while negatively charged
DNA can trigger the activation of the coagulation cascade via FXIIa-induced thrombin
generation (see details above).[30] Additionally, neutrophil elastase on NETs inactivates anticoagulant mechanisms via
cleavage of thrombomodulin and tissue factor pathway inhibitor.[1] NET release is a tightly regulated process involving NADPH oxidases and protein
arginine deiminase type 4 (PAD4) converting arginine residues to citrulline.[31] Inhibition of PAD4 was demonstrated to be sufficient to prevent NETosis of human
and mouse neutrophils.[32] However, PAD4 seems to be only one of several pathways able to induce NET formation
as also PAD4-independent mechanisms are described.[31]
[33] Interestingly, the propensity to form NETs might be an intrinsic property of neutrophil
subpopulations, as aging neutrophils form NETs more frequently than young neutrophils
and possess higher phagocytic function.[34]
[35]
[36] The central physiological role of NETs in bacterial defense is most evident as various
pathogenic bacteria have developed mechanism to circumvent NET formation or reduce
NET function.[37]
FXII also exerts proinflammatory responses in leukocytes and endothelial cells and
contributes to vascular permeability by increasing endothelial dysfunction, immune
cell trafficking, and mitogenic activity.[38] FXIIa can bind to urokinase-type plasminogen activator receptor on endothelial cells
in a platelet-dependent manner and thereby promote activation of the kallikrein–kinin
system, which influences inflammation and blood pressure.[38] NETs-driven FXIIa has been suggested to contribute to COVID-19-associated thromboinflammation,
and inhibition of FXIIa has been shown to reduce NETs, IL-6 levels, and complement
activation in a sepsis model.[39]
The final product of coagulation, fibrin, acts as a scaffold for immune cells and
aids in the recruitment and activation of inflammatory cells. Excessive fibrin deposition
can lead to fibrosis and chronic inflammation. The impact of coagulation on immune
cell functions is summarized in [Fig. 2].
Fig. 2 Impact of coagulation on immune cell functions. Immune-mediated coagulation can be
triggered by TF expression or release of TF-positive EVs from monocytes, leading to
the formation of thrombin, which subsequently catalyzed the cleavage of fibrinogen
to fibrin. By engaging PARs, thrombin also regulates activity and inflammatory responses
of platelets, leukocytes, and endothelial cells, but thrombin also exerts proapoptotic
effects and enhances hematopoiesis. Thrombin generation can also be induced by NETs,
which provide a negatively charged surface that is studded with procoagulant proteins,
e.g., FXII. Thereby, NET-bound coagulation factors elicit proinflammatory responses,
which may involve activation of the kallikrein–kinin system. In addition, FXII(a)
augments leukocyte mobility and contributes to endothelial dysfunction, leading to
enhanced vascular permeability. Finally, the fibrin mesh generated by coagulation
acts as scaffold for immune cells and aids in their activation and recruitment. EV,
extracellular vesicles, FXII(a), (activated) coagulation factor XII; NET, neutrophil
extracellular trap; PAR, protease-activated receptor; PN-1: protease nexin-1; TF,
tissue factor.
The Influence of Inflammation on the Fibrinolytic System and How it Feeds Back
The Influence of Inflammation on the Fibrinolytic System and How it Feeds Back
The fibrinolytic system, responsible for breaking down blood clots, plays a crucial
role in regulating inflammation and maintaining a balance between proinflammatory
and anti-inflammatory processes. Its key role in immunomodulation involves clearing
of proinflammatory fibrin.
Activated by tissue plasminogen activator (tPA) and urokinase (uPA), the fibrinolytic
system ensures effective resolution of the fibrin clot, restoring blood flow after
vessel injury. Endothelial cells, urinary epithelial cells, and monocytes/macrophages
release tPA and uPA, converting plasminogen into plasmin, the major fibrinolytic enzyme.
Fibrin serves as the primary substrate for plasmin, facilitating the interaction of
tPA with plasminogen on its surface and thus promoting its own degradation. Plasmin
binding to fibrin also protects plasmin from rapid inactivation by α2-antiplasmin.
Carboxypeptidase thrombin activatable fibrinolysis inhibitor (TAFI) can counteract
fibrinolysis by removing plasmin binding sites, slowing down plasmin generation, and
linking coagulation to fibrinolysis. During fibrinolysis, multiple fibrin degradation
products, such as D-dimer and fibrinopeptide B, are released, which possess immunomodulatory
and chemotactic functions.
Plasminogen activator inhibitor-1 (PAI-1) and PAI-2, serpins present in plasma, immediately
inhibit tPA and uPA, giving them a short half-life. Endothelial cells synthesize PAI-1
and its release is increased in response to inflammatory cytokines. However, PAI-1
is mostly stored in platelets, which also derive PAI-1 from megakaryocytes.
Another serpin that inhibits both tPA and thrombin is protease nexin-1 (PN-1). While
it is barely detectable in plasma, it is stored within the α-granules of platelets
and released during activation.[40] Platelet PN-1 has the capacity to inhibit both exogenous and endogenous tPA-mediated
fibrinolysis as well as platelet activation via inhibition of thrombin.[41]
Various cell types, including endothelial cells, monocytes, macrophages, and neutrophils,
participate in fibrinolysis. They express cell surface receptors with fibrinolytic
activity, acting as cofactors for plasmin generation and protecting against circulating
fibrinolysis inhibitors.
Fibrinolytic proteins also play a crucial role in regulating the immune response.
PAI-1 is also an acute phase protein, which is upregulated to protect against bacterial
pathogens by promoting bacterial clearance and thereby limiting inflammation.[42] PAI-1 also facilitates neutrophil migration and regulates interferon γ (IFN-γ) responses,[43] whereas PAI-2 dampens proteolytic activity of neutrophils and macrophages.[44]
Plasminogen activators, including tPA and urokinase, modulate the innate immune response,
with actions both dependent and independent of their fibrinolytic activity. Urokinase
enhances monocyte differentiation into macrophages and promotes neutrophil activation
and migration,[44] whereas tPA was found to downregulate inflammation but foster neutrophil adhesion
in ischemia/reperfusion and stroke models.[45]
Plasmin(ogen) has diverse roles in regulating proinflammatory processes. It is essential
for efficient recruitment of monocytes and lymphocytes during inflammation and promotes
macrophage phagocytosis, migration, and differentiation (reviewed in[46]). In ischemia/reperfusion and stroke models, tPA-mediated plasmin activity was also
critical for neutrophil transmigration and disruption of endothelial junctions,[45] while mast cell activation and leukotriene generation were required for neutrophil
recruitment.[45] In addition, plasmin enhances dendritic cell phagocytosis, keeping them in an immature
phenotype and reducing migration to lymph nodes.[47]
TAFI modulates inflammation by removing specific residues from various inflammatory
mediators, including C3a and C5a,[48] dampening neutrophil recruitment and reducing TNF-α and IL-6 levels independently
of its antifibrinolytic function.[49]
The fibrinolytic system's varying roles in immunomodulation, summarized in [Fig. 3], highlight complex interactions that must be carefully balanced to avoid exacerbating
inflammatory responses and promoting a prothrombotic environment.
Fig. 3 Immunomodulatory roles of the fibrinolytic system. Fibrinolysis is a tightly controlled
system subject to multiple layers of regulation, but the involved proteins also have
immunomodulatory effects that may be independent of their (anti-)fibrinolytic function.
Plasmin, the central enzyme of fibrinolysis, is activated by tPA and uPA and degrades
the fibrin mesh into soluble fibrin degradation products (e.g., D-dimer). Exaggerated
fibrinolysis is prevented by PAI-1 and PAI-2, which inhibit both tPA and uPA and thus
determine initial plasmin activation, or by TAFI, which impairs subsequent plasmin-mediated
fibrin degradation. While TAFI has anti-inflammatory effects on leukocytes and downregulates
complement responses, plasmin, uPA, and, in part, also tPA foster proinflammatory
responses, e.g., by enhancing activation, differentiation, and recruitment of various
leukocyte subsets. Plasmin and PAI-1 also facilitate pathogen clearance by promoting
the phagocytic capacity of macrophages and dendritic cells or by augmenting interferon
response of T-cells, respectively, which, in turn, may limit pathogen-induced inflammation.
C3a, complement component 3a; IFN-γ, interferon γ; IL-6, interleukin 6; LT, leukotriene;
PAI, plasminogen activator inhibitor; PN-1: protease nexin-1; TAFI, thrombin-activatable
fibrinolysis inhibitor; TNF-α, tumor necrosis factor α; tPA, tissue plasminogen activator;
uPA, urokinase.
Platelets Modulate Leukocyte Functions and Leukocytes Modulate Platelet Fate and Production
Platelets Modulate Leukocyte Functions and Leukocytes Modulate Platelet Fate and Production
Upon activation, platelets quickly adhere to leukocytes through interactions facilitated
by platelet CD62P and leukocyte P-selectin glycoprotein ligand-1. Monocytes exhibit
the highest affinity for CD62P, followed by granulocytes and lymphocytes. This initial
binding is stabilized by a variety of other receptors (reviewed in[50]) and leads to the targeted release of soluble mediators, mutual activation, and
fine-tuning of immune and inflammatory responses ([Fig. 4]).
Fig. 4 The role of platelets in thromboinflammation. The immune system plays an important
role in thrombopoiesis as neutrophils pluck on proplatelets to assist in their release
from megakaryocytes, thereby contributing to platelet production under physiological
conditions. Under inflammatory conditions, mediators such as IL-1α can further stimulate
thrombopoiesis, which may also convey distinct characteristics to newly produced platelets.
Upon their release into the circulation, platelets can interact with leukocytes either
directly via cell–cell adhesion or indirectly via release of cyto-/chemokines or PEVs,
which allow platelets to modulate immune responses even at distant sites. Thereby,
platelets fine-tune various proinflammatory immune responses, including leukocyte
migration and recruitment, which is also indirectly facilitated by platelet-stimulated
endothelial activation. In addition, platelets contribute to proliferation and differentiation
of T-cells and are important determinants for monocytes/macrophages polarization/differentiation
into proinflammatory and proatherogenic subtypes. Platelet–leukocyte interplay can
further trigger an oxidative burst as well as modulate quality and quantity of released
cytokines. In infectious setting, platelet-mediated immunomodulation also supports
pathogen clearance, by augmenting pathogen phagocytosis and antibody production as
well as inducing NETs. However, under certain conditions, platelet–leukocyte interactions
may also dampen immune responses, e.g., by preventing lymphocyte differentiation,
interfering with neutrophil ROS production, or altering monocyte-derived cyto-/chemokines
toward a more anti-inflammatory profile. 5-HT, serotonin; ATP, adenosine triphosphate;
CCL5, chemokine (C–C motif) ligand 5; CXCL4, chemokine (C–X–C motif) ligand 4; HMGB1,
high mobility group box 1; Ig, immunoglobulin; IL-1α, interleukin 1α; MIF, macrophage
migration inhibitory factor; NET, neutrophil extracellular trap; PAF, platelet activating
factor; PDGF, platelet-derived growth factor; PEV, platelet-derived extracellular
vesicles; ROS, reactive oxygen species; TGF-β, transforming growth factor β; Th1,
T helper cell type 1; Treg, regulatory T cell.
Beyond direct interaction, platelets can also release EVs to communicate with leukocytes.
This communication involves receptor-mediated signaling and transfer of proteins or
nucleic acids (as reviewed in[51]). Through the release of soluble mediators, platelets can further modulate leukocyte
functions at distant sites.
Platelets play a significant role in enhancing immune responses and leukocyte functions.
Platelet-derived chemokines, such as platelet factor 4 (PF4/CXCL4), increase endothelial
adhesion of neutrophils and monocytes. They indirectly promote leukocyte migration
through endothelial cell activation, induced by platelet-derived serotonin (5-HT),
which leads to endothelial CD62P expression and IL-8 release, triggering leukocyte
rolling, adhesion, and extravasation.
Moreover, platelets enhance leukocyte activation, resulting in increased cytokine
release and oxidative burst in neutrophils. They also promote pathogen clearance by
neutrophils and contribute to NET formation. Platelets influence monocyte differentiation,
favoring the switch to CD16-positive monocytes. Furthermore, platelet activation and
CXCL4 release are associated with macrophage phenotype switches. Thereby, platelets
also facilitate foam cell formation and contribute to atherogenesis.[52]
Although platelet–leukocyte interplay generally promotes inflammation, there are also
some reports that suggest an anti-inflammatory role of platelet–leukocyte interplay.
For example, annexin A1 selectively modifies platelet surface determinants, including
phosphatidylserine, to promote platelet phagocytosis by neutrophils, thereby leading
to anti-inflammatory effects and actively driving thrombus resolution.[53]
Platelets also play a crucial role in lymphocyte trafficking to secondary lymphoid
organs and have a significant impact on the function and differentiation of T-lymphocytes
and B-lymphocytes. This highlights their essential role in regulating and modulating
adaptive immune responses.[20]
Increasing evidence suggests an intricate interaction between inflammation and platelet
production. In inflammatory conditions, IL-1α triggers rapid megakaryocyte rupture-dependent
thrombopoiesis, leading to elevated platelet counts.[54] Additionally, neutrophils play a direct role in accelerating proplatelet growth
through plucking, thereby facilitating continuous platelet production.[55] These processes might endow platelets with functional attributes right from their
inception. However, further research is needed to precisely understand the role of
inflammatory drivers in platelet production and their contributions to distinct platelet
subsets.
Complement
The complement system, which is a crucial part of the immune system in defense against
pathogens and for removal of damaged cells, consists of a complex network of plasma
proteins that interact in a cascade-like manner. The complement system can be activated
through three main pathways: the classical pathway, the alternative pathway, and the
lectin pathway. Once activated, the complement system generates a series of reactions,
leading to the formation of membrane attack complexes (MACs) on the surface of pathogens
or infected cells that can destroy invading pathogens, enhance phagocytosis by immune
cells, and trigger inflammation.
The complement system and platelets have intricate interactions with each other, influencing
immune responses and coagulation. Complement proteins can initiate a cascade of reactions
upon binding to platelet receptors, resulting in the recruitment and activation of
immune cells at the site of injury or infection. Platelets express various complement
receptors (cC1qR, gC1qR, C3aR, and C5aR), whereas complement components (C1q, C3,
C4, and C9) can bind to activated platelet surfaces.[56] This binding activates platelets and leads to the surface expression of P-selectin,
which facilitates neutrophil adhesion to the endothelium.[57] Megakaryocytes and platelets store C3 in their granules, releasing it upon activation.[58]
Platelet-associated factors like chondroitin sulfate A or phosphatidylserine exposure
can initiate the complement cascade via C1q/r/s,[56] whereas P-selectin and properdin stabilize C3 and C5 convertases.[59] The subsequent formation of MACs leads to the release of procoagulant EVs from platelets
and endothelial cells.[60]
Platelet-derived ATP and Ca2+ also contribute to the extracellular phosphorylation of C3 and its fragments, prolonging
C3b activity and amplifying complement activation,[61] whereas platelets also express complement control proteins like CD55, CD59, and
factor H to regulate complement activation on their surface to prevent overshooting
responses.[62]
The complement system not only interacts with primary hemostasis but also with secondary
hemostasis, as both cascades share activators and inhibitors. FXIIa can activate C1q,
thereby initiating the classical pathway.[63] C1q esterase inhibitor interferes with all three complement pathways as well as
FXIIa-mediated coagulation.[59] Thrombin can cleave C3 and C5, further amplifying complement activation.[60]
[64]
In turn, complement anaphylatoxins (C3a, C4a, C5a) can directly or indirectly activate
innate immune cells and stimulate endothelial release of proinflammatory mediators
like IL-6, IL-8, and CCL2.[65] In particular, C5a upregulates TF and PAI-1 expression on neutrophils and endothelial
cells[59]
[66] and also mediates vWF secretion from endothelial cells, while C5b induces TF expression
on monocytes.[65]
[67] These interactions illustrate the complex crosstalk between the complement system,
platelets, coagulation, and immune responses ([Fig. 5]).
Fig. 5 Complement interplay with the hemostatic system. (A) Binding of complement factors to respective receptors on platelets leads to their
activation, inducing surface expression of PS and P-selectin, which is essential for
platelet–leukocyte binding and subsequent immunomodulation. Negatively charged CS
and PS can initiate the classic pathway, whereas P-selectin and properdin mediate
the alternative pathway, both of which result in MAC formation on and EV release from
target cells, such as platelets or endothelial cells. Activated platelets also release
C3 from their α-granules, whereas dense granule-derived Ca2+ and ATP mediate phosphorylation of C3 and its fragments, which further amplifies
complement activation. At the same time, platelets express complement control proteins
that prevent overshooting complement responses. (B) Activated coagulation factors FXIIa and thrombin can trigger the complement system
by activating C1q or by cleaving C3 and C5, promoting all three complement pathways.
Notably, the serpin C1 esterase inhibitor targets components of all three complement
pathways as well as FXIIa to regulate both complement and coagulation responses. C3a
and C5a also convey proinflammatory and procoagulant effects by activating leukocyte
and endothelial cells and inducing TF expression and release of procoagulant vWF or
antifibrinolytic PAI-1. ATP, adenosine triphosphate, C1q, complement component 1q;
C1qR, C1q receptor; CCL2, chemokine (C–C motif) ligand 2; CS, chondroitin sulfate
A; EV, extracellular vesicle; FXIIa, activated coagulation factor XII; IL-6, interleukin
6; MAC, membrane attack complex; PAI-1, plasmin activator inhibitor 1; PS, phosphatidylserine;
TF, tissue factor; vWF, von Willebrand factor.
Conclusion
Despite the growing body of evidence that sheds light on how the immune system triggers
thrombotic events, our understanding of how the hemostatic system reciprocally influences
inflammatory and immune responses remains limited. The complexity of these interactions
is amplified by the profound sensitivity of the hemostatic system to factors such
as the underlying disease context, the specific anatomical localization, and the current
state of the disease process.
These dynamic interactions between thrombosis and inflammation can therefore take
on a dual nature, acting either as allies or adversaries depending on the disease
context. In some cases, the involvement of hemostatic elements in immune responses
can be advantageous, aiding in the containment and resolution of infections or injuries.
Conversely, under different circumstances, these same mechanisms can exacerbate inflammatory
processes and foster pathological conditions.
The significant gap in our understanding of thromboinflammation highlights a critical
deficiency in therapeutic approaches, leaving us without precise targets necessary
to effectively address the inflammatory dimension of thrombosis. Extensive research
over the last decade has led to a myriad of innovative approaches directed against
immunothrombosis. These strategies aim to avert potential thrombotic events in high-risk
patients without increasing their risk of bleeding.
Targeting the formation of NETs stands as a promising therapeutic approach. Degradation
of NETs provides a safe treatment option, as seen with drugs like DNase I, which is
already employed in diseases like cystic fibrosis and off-label for COVID-19.[68]
[69] Additionally, the administration of heparin or colchicine offers possibilities to
disrupt NET formation by inhibiting histone-induced coagulation or actin cytoskeleton
rearrangement in NET-forming neutrophils, respectively.[70]
[71]
Finally, novel inhibitors that interfere with myeloperoxidase or PAD4 represent potential
therapeutic drugs to limit NET formation, validated in various inflammatory disease
models such as hepatic ischemia/reperfusion injury, vasculitis, and systemic lupus
erythematosus.[72]
[73]
[74]
Various new antiplatelet agents are currently under examination to prevent inflammation-induced
thrombus formation. Alternative strategies involve impeding platelet–leukocyte interactions,
blocking alternative surface receptors,[75] or inhibition of intracellular signaling pathways such as immunoreceptor tyrosine-based
activation motif signaling or phosphoinositide 3 kinase signaling.[76]
[77]
[78] Likewise, novel methods to inhibit the coagulation cascade are in development. FXI
inhibitors show promising results in clinical trials[79] and also strategies for FXII inhibition are currently under investigation[80].
Current studies are exploring and expanding the utilization of intra-arterial thrombolysis
subsequent to mechanical thrombectomy to initiate tissue reperfusion in acute ischemic
stroke. Tenecteplase, a genetically modified recombinant tPA with increased fibrin
specificity, has been proven to be quicker and more efficient compared with commonly
used Alteplase (recombinant tPA).[81] Further, a recent trial revealed promising results in shielding the brain from tissue
damage, thereby preventing death and disability by the TLR4 antagonist ApTOLL.[82]
Closing this knowledge gap in the near future is of crucial importance, as it holds
the potential to unveil novel strategies for therapeutic intervention, ultimately
leading to more precise and effective treatments for thrombotic disorders with inflammatory
components.
