Thromboinflammation and the Role of Platelets

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 44, No. 6Thromboinflammation and the Role of Platelets Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBThromboinflammation and the Role of Platelets Andrew Mack, Terry Vanden Hoek and Xiaoping Du Andrew MackAndrew Mack https://orcid.org/0009-0000-7224-7537 Department of Pharmacology and Regenerative Medicine (A.M., X.D.), University of Illinois, Chicago. , Terry Vanden HoekTerry Vanden Hoek https://orcid.org/0000-0002-1684-7850 Department of Emergency Medicine (T.V.H.), University of Illinois, Chicago. and Xiaoping DuXiaoping Du Correspondence to: Xiaoping Du, MD, PhD, Department of Pharmacology and Regenerative Medicine, University of Illinois Chicago, Room E403, 835 S Wolcott Ave, Chicago, IL 60612. Email E-mail Address: [email protected] https://orcid.org/0000-0001-9842-8192 Department of Pharmacology and Regenerative Medicine (A.M., X.D.), University of Illinois, Chicago. Originally published22 May 2024https://doi.org/10.1161/ATVBAHA.124.320149Arteriosclerosis, Thrombosis, and Vascular Biology. 2024;44:1175–1180Thromboinflammation is a pathological condition characterized by the concurrence of thrombosis, inflammation, and vascular leakage/bleeding, which induce and exacerbate each other leading to tissue/organ injury and death. Thromboinflammation may occur in a wide range of inflammatory and cardiovascular/pulmonary diseases, including severe infection (eg, sepsis and severe COVID-19), acute respiratory distress syndrome (ARDS), ischemia-reperfusion injury following myocardial infarction, organ transplant and acute kidney ischemia, cardiac arrest, severe injury, autoimmune diseases, thrombosis (eg, deep vein thrombosis), and atherosclerosis.1,2 Thromboinflammation can be acute and chronic and can be severe with high mortality and morbidity. Despite many years of intensive efforts and development of anti-inflammatory and antithrombotic drugs, there is still no current drug available that is convincingly effective in the treatment of thromboinflammation. The reason for the ineffectiveness of many anti-inflammatory and antithrombotic drugs is unclear. However, past and recent studies and clinical trials shed mechanistic light and raise hopes for new therapeutic concepts and drugs. Here, we briefly discuss our perspectives with an emphasis mainly on severe acute thromboinflammation.GOOD CLOT, BAD CLOT, GOOD INFLAMMATION, AND BAD INFLAMMATIONThromboinflammation is the manifestation of dysregulation of the two most important defensive and wound-healing responses of the body: inflammation and hemostasis.3 Both hemostasis and inflammation are highly regulated processes and are dynamically balanced. Shifting the balance toward either direction causes pathological states. Hemostatic responses to injury or blood vessel leakage activate platelets and the coagulation system, which together form hemostatic thrombi (clots) to seal the wound, minimizing blood loss and microbial invasion. Deficiency in either platelets or coagulation causes blood vessel leakage and bleeding, whereas overreaction of platelets or coagulation causes the formation of thrombi that occlude blood vessels, termed thrombosis. Inflammation as a part of innate immunity can be triggered by molecular patterns from microbial and damaged tissue/cells, antibody-antigen interaction, and cytokines released or generated during hemostatic response. Inflammation involves the activation of immune cells (leukocytes and macrophages) and humoral immune systems (eg, bradykinin, complement), which attack and clear invading microbials, other foreign substances, and damaged tissues/cells to facilitate recovery. Deficiency in inflammation impairs defense against infection and clearance of damaged tissues. However, inflammation also causes friendly fire damage to tissues/cells. Persistent inflammation or overreaction of the inflammatory system causes inflammatory disease. Hemostatic and inflammatory responses are intricately linked. They mutually activate, coordinate, and regulate under normal conditions. Platelets store substantial amounts of proinflammatory and growth factors in granules, which are released or exposed upon platelet activation to stimulate inflammation and promote the regrowth of the cells in the wounded area to facilitate wound healing. Immune cells also stimulate platelet activation and coagulation, for example, by secreting platelet-activating factors and the formation of neutrophil-extracellular traps.2 Activation of the intrinsic pathway of coagulation is directly linked to the activation of proinflammatory pathways of bradykinin and complement. Bradykinin, thrombin generated by coagulation and leukocyte-released factors such as histamine also induce endothelial hyperpermeability, vascular leakage, bleeding, and edema, which are controlled by the hemostatic response. The balanced hemostatic and inflammatory responses are necessary in defense against infection and injury. In thromboinflammation, insults from infection, ischemia, or other injuries seem to disrupt this balance, causing a chaotic and vicious cycle of inflammation, vascular leakage, and thrombosis (Figure). In this process, thrombosis and inflammation independently contribute to poor outcomes and exacerbate each other.4 In grave cases, this leads to disseminated intravascular coagulation, resulting in depletion of platelets and coagulation factors, exacerbated vascular leakage, and extensive bleeding. Extensive vascular leakage and bleeding together with peripheral vessel dilation may lead to circulatory collapse. Thus, the hemostatic and inflammatory systems play not only important beneficial roles in immune defense and wound healing but also pathological roles in the development of thromboinflammation.Download figureDownload PowerPointFigure. Thromboinflammation and important roles of platelets. In thromboinflammation, microbial infection or tissue/cell injuries cause dysregulated thrombosis, inflammation, and vascular leakage/bleeding. These pathological states may distinctly contribute to poor outcomes and exacerbate each other (red arrows). This figure depicts the major causes of thromboinflammation and the key mechanisms of platelet activation. Additionally shown is how platelets play both protective roles in controlling blood vessel leakage and bleeding (hemostasis) as well as pathological roles in thrombosis and exacerbating inflammation. Current antiplatelet and anticoagulant drugs inhibit the pathological role of platelets and coagulation in thromboinflammation (yellow blocking symbol) but also diminish the protective role of platelets (and coagulation) in controlling vascular leakage/bleeding, in modulating inflammation, and in wound healing (yellow arrows). ARDS indicates acute respiratory distress syndrome; DVT, deep vein thrombosis; NET, neutrophil extracellular traps; and TTP, thrombotic thrombocytopenic purpura.GOOD PLATELETS AND BAD PLATELETSPlatelets are blood cells specialized to adhere to the site of vascular injury and aggregate to form a primary hemostatic thrombus.5 Activated platelets, by exposing phosphatidyl serine and releasing coagulation factors/polyphosphates stored in granules, are also important in facilitating thrombin generation and thus coagulation. Together with the coagulation system, platelets play central roles in hemostasis and thrombosis and thus can be both beneficial in controlling vascular leakage and pathological in mediating thrombosis during thromboinflammation.Platelets also respond to inflammatory signals. Platelets express pattern recognition receptors, such as TLRs (toll-like receptors), NOD (nucleotide-binding oligomerization domain)-like receptor 2, and the receptor for advanced glycation end products, which recognize and respond to pathogen-associated molecular patterns from microorganisms and damage-associated molecular patterns from damaged tissues and cells.5,6 Platelets express several isoforms of TLRs. TLR4 is well known for mediating cell responses to bacterial lipopolysaccharide and damage-associated molecular patterns including HMGB1 (high-mobility group box 1). TLR2 (complexed with TLR1 or TLR6) responds to bacterial lipopeptides and oxidized lipid derivatives. TLR7 senses viral ssRNA and TLR9 binds to carboxy(alkylpyrrole) protein adducts generated in oxidative stress. The early signaling pathways of TLRs as well as NOD-like receptor 2 leading to platelet responses show similarities but also differences. They involve MyD88, SFKs (Src family kinases), PI3K (phosphoinositide 3-kinase)-Akt, cGMP, and mitogen-activated protein kinases, which are capable of inducing integrin-independent granule secretion and augmentation of platelet activation/aggregation. TLR4 was shown to stimulate granule secretion via MyD88 and the SFK-PI3K-Akt-cGMP pathway6,7 with minimal direct effect on platelet aggregation but enhanced platelet activation and aggregation together with other agonists. TLR2/6 also requires MyD88 (myeloid differentiation primary response protein 88) and SFK but mediates activation of immune-receptor tyrosine-based activation motif signaling,8 although it is unclear whether this effect requires platelet agonists secreted from granules. Platelets also express Fc receptors such as FcγRIIA (Fcγ receptor II), which induces strong platelet secretion and aggregation through the directly associated immune-receptor tyrosine-based activation motif signaling pathway. Importantly, platelet granules store not only prothrombotic molecules but also numerous proinflammatory cytokines, receptors, and molecules, including serotonin, PF4 (platelet factor 4; CXCL4), β-TG (β-thromboglobulin; CXCL7), CD40 ligand, and P-selectin. Serotonin and PF4 released from platelets have been shown to exacerbate inflammation during myocardial ischemia-reperfusion injury. Platelets also adhere to leukocytes via adhesion receptors glycoprotein Ib-IX complex, integrins, and P-selectin, facilitating leukocyte extravasation and activation. These functions are stimulated by pattern recognition receptors and other platelet agonists. Thus, inflammation signals activate platelets which in turn stimulate inflammation. However, platelets can also play important protective roles in negatively regulating inflammation. During septic shock, platelets were observed to inhibit macrophage-dependent inflammation via the prostaglandin E2 pathway.9 Depletion of platelets enhanced circulating levels of TNF-α (tumor necrosis factor-α) and IL (interleukin)-6 in septic mice. Transfusion of platelets in these mice reduced TNF-α and IL-6, reducing mortality.The roles of platelets in thrombus formation, inflammation, and thromboinflammation have impacts beyond the traditional hemostatic, thrombotic, and inflammatory diseases. For example, cancer cells cause tissue damage and induce inflammation. Cancer cells can directly adhere to and activate platelets and release extracellular vesicles containing cancer cell proteins, RNA, and lipids, which can be taken up by platelets and stimulate platelet activation.10,11 Activated platelets release proinflammatory, prothrombotic, and growth factors, inducing/exacerbating thromboinflammation and promoting cancer cell growth.10 Platelet release of TGFβ stimulates cancer cell metastasis.12 On the other hand, tumor vasculature is leaky and prone to hemorrhage, which requires platelet-dependent hemostasis to control bleeding, Thus, the normally defensive and wound repair functions of platelets and thromboinflammation seem to be utilized by cancer cells to promote cancer growth and spreading.GOOD EFFECT, BAD EFFECT, AND NO EFFECT IN TREATING THROMBOINFLAMMATIONDespite the clear importance of inflammation in the pathophysiology of thromboinflammation, most anti-inflammatory drugs developed thus far failed to convincingly demonstrate therapeutic effects in treating severe thromboinflammatory conditions. One apparent exception is corticosteroids, which reportedly reduce the risk of death due to ARDS associated with COVID-19 and severe sepsis, although this is still controversial.13 Although the reason for this lack of effect is unclear, one could ask whether this is related to the effects of anti-inflammatory drugs in inhibiting both pathological inflammatory overresponses and physiological immune defensive function of inflammation. Furthermore, inflammation and thrombosis distinctly contribute to poor thromboinflammation outcomes.4 Therefore, one would wonder whether anti-inflammation strategies alone are optimally effective as most current anti-inflammatory drugs do not directly inhibit thrombosis, with the exception of nonsteroidal anti-inflammatory drug, such as aspirin, which mildly inhibits both inflammation and platelets. Several antithrombotic drugs, including aspirin and the recombinant activated protein C (Xigris), an inhibitor of thrombin generation, however, show some degrees of anti-inflammatory effects. Several studies in animal models and human patients suggested the beneficial effects of antiplatelet drugs and anticoagulants in improving aspects of thrombo-inflammatory states in sepsis and severe COVID-194 (Table). Unfortunately, no new drug thus far is convincingly effective clinically. The only antithrombotic drug that was approved by the US Food and Drug Administration for treating severe sepsis is Xigris, which showed beneficial effects in clinical trials but also showed significant adverse effects of bleeding.14 In post-FDA approval studies, the adverse effect of bleeding was associated with increased mortality and outweighed its beneficial effect in patients with bleeding tendencies. A second trial of Xigris (REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00604214) was thus performed, in which the drug used did not significantly increase bleeding, but also did not show efficacy, leading to its withdrawal from clinical use. Comparison of the 2 trials seems to suggest that the beneficial therapeutic effect of Xigris in treating sepsis is associated with the adverse effect of bleeding, while a lack of adverse effects on bleeding is associated with a lack of benefit. This is consistent with the fact that Xigris is an anticoagulant, and all current available antiplatelet and anticoagulant drugs inhibit both thrombosis and hemostasis.Table. New Therapeutic Targets and Drugs in Development for Treating Thrombo-Inflammatory ConditionsTarget/mechanismTherapeuticsStudiesFactor XIIa inhibitors/inhibition of both intrinsic coagulation and kallikrein-kinin pathwaysMonoclonal antibody 3F724Reduced bleeding risk. Reduced atherosclerosis and stabilized plaques, attenuated aneurysms, and reduced inflammatory markers in atherosclerosis and stenosis mouse models.24,25Factor XI Inhibitors/inhibition of intrinsic coagulation pathwayAbelacimab,26 3G316Reduced bleeding risk. Improved VTE outcome in clinical trials.26 Protected 100% of baboons from terminal organ failure in a Staphylococcus aureus–induced lethal sepsis model.16Sodium iodide-based catalyst/hydrogen peroxide reduction for treating IRIFDY-530127Reduced MI infarct sizes and improved LVEF in a phase 2 clinical trial.27Platelet-targeted factor Xa inhibitor/selectively inhibiting coagulation on activated plateletsTarg-Tap28Reduced bleeding risk. Improved myocardial function and reduced infarct size in a mouse IRI model.28AKT activator/regulating glucose metabolism to reduce IRITAT-PHLPP9c23Improved survival in mouse and pig models of SCA resuscitation.23ADAMTS13/cleaving VWF to inhibit platelet adhesion and thrombosisrhADAMTS1329,30Improved myocardial ischemia/reperfusion injury and organ trauma animal models.29,30Inhibitors of Gα13-integrin interaction/selective inhibition of integrin outside-in signaling in platelets and leukocytesM3mP6,19 MB2mP64Improved cardiac function and survival in a mouse IRI model.19 Improved survival, thrombosis, and cytokine storm in mouse model of sepsis.4Multivalent serine protease inhibitor/inhibiting coagulation factors and fibrolytic enzymes and other proteasesUlinastatin31Reduced VTE in a postoperative brain tumor surgery clinical trial. Improved coagulation dysfunction and hepatic/kidney functions.31 Phase 3 clinical trial for treating sepsis (NCT05391789).IRI indicates ischemia-reperfusion injury; LVEF, left ventricular ejection fraction; MI, myocardial infarction; SCA, sudden cardiac arrest; VTE, venous thromboembolism; and VWF, von Willebrand factor.ELIMINATE THE BAD BUT KEEP THE GOODPreviously tested drugs have 1 common shortcoming: they do not differentiate bad from good. Anti-inflammatory drugs are immune-suppressive, and antithrombotic drugs exacerbate bleeding. We need anti-inflammatory drugs that minimally inhibit the beneficial effects of inflammation and antithrombotic drugs that minimally affect hemostasis. Fortunately, antithrombotics with reduced bleeding risk are in development (Table). Inhibition of the key intrinsic coagulation pathway enzyme FXI (factor XI) produces only mild bleeding tendencies but demonstrated antithrombotic efficacy in clinical trials and animal studies15 and improved survival in animal models of sepsis and ischemia-reperfusion injury.16 This effect is likely mediated by the mechanism of inhibiting thrombin generation similar to Xigris but with reduced bleeding risk.In addition to coagulation pathways, targeting platelets and leukocytes offers important opportunities to better treat thromboinflammation. Recent studies have shown antiplatelet drugs that have minimal side effects of bleeding and vascular leakage.17,18The function of leukocytes in inflammation and the function of platelets in thrombosis and hemostasis both require integrins. Integrin αIIbβ3 mediates platelet adhesion and formation of hemostatic thrombus. Leukocyte β2 integrins mediate phagocytosis and clearance of microbial and damaged cells. Ligand binding to integrins also induces outside-in signaling, leading to integrin-dependent granule secretion, thrombus expansion, and thrombosis,5 as well as leukocyte migration and cytokine release.4 The β2 and β3 cytoplasmic domains contain conserved sequences that bind the G protein subunit Gα13, which is important for outside-in signaling but not the ligand binding function. Integrin-Gα13 binding also inhibits the Gα13-p115RhoGEF-RhoA pathway and granule secretion.19 An inhibitor of integrin-Gα13 interaction, M3mP6, diminishes integrin outside-in signaling and secretion of prothrombotic and proinflammatory molecules including serotonin.19 M3mP6 inhibits both thrombosis and inflammation without the adverse effects of bleeding and vascular leakage.17 A similar peptide inhibitor blocking Gα13-integrin interaction in platelets and leukocytes inhibited microvascular thrombosis and cytokine storm in a mouse sepsis model without affecting bleeding or bacteria clearance, improving survival rates.4 Thus, it is feasible to inhibit thrombosis without causing bleeding and inhibit inflammation without exacerbating infection.ISCHEMIA-REPERFUSION INJURY AND THROMBOINFLAMMATIONThromboinflammation is usually a secondary pathological condition caused by a variety of pathological states or diseases (Figure), which need to be treated differently. Ischemia-reperfusion injury (IRI) is a major cause of mortality and morbidity following successful rescue of patients from an ischemic state. New drugs are in development that ameliorate organ injury caused by metabolic imbalance and oxidants during ischemia and reperfusion (Table). However, postischemia thromboinflammation has also been increasingly recognized as an important mechanism of IRI, Conditions such as myocardial infarction (MI), ischemic stroke, and cardiac arrest exemplify major diseases causing IRI. Their treatment and outcomes are all affected by an interplay between the metabolic derangements of ischemic organs/cells and subsequent activation of thromboinflammation after reperfusion. In treating patients with MI (heart attack), the use of thrombolytics, percutaneous coronary intervention, and surgical interventions to recannulate occluded coronary arteries, along with antiplatelet drugs, has dramatically reduced mortality in MI patients who reach the emergency department. However, a percentage of successfully treated patients with MI suffer from cardiac IRI resulting in postischemic heart failure with an overall mortality rate close to 20% and significant morbidity.20While often starting as focal ischemia of the heart, out-of-hospital cardiac arrest results in a far more global IRI with a much higher mortality rate (≈90%). Approximately 60% of patients admitted to the hospital after successful resuscitation (ie, reperfusion following global ischemia) with the return of spontaneous circulation die from a post–cardiac arrest syndrome including dysfunction of the heart and brain, exuberant inflammation, and microthrombosis with multiorgan failure.21 There are no drugs available that improve long-term out-of-hospital cardiac arrest survival, despite studies of thrombolytic or anti-inflammatory drugs. There has been a recognition that out-of-hospital cardiac arrest can result in a pronounced platelet hyperfunction, with interest in the possible use of aggressive antiplatelet therapy.22 MI, ischemic stroke, and out-of-hospital cardiac arrest alike, the complexity of IRI highlights the need for new drugs that can promote metabolic recovery and attenuate thromboinflammation without compromising the protective effects of inflammation and/or increasing the risks of vascular leakage and bleeding. As an example of a metabolic recovery approach, a membrane-permeable Akt activating peptide that inhibits the phosphatase PHLPP1, has been shown to improve survival in mouse and pig models of sudden cardiac arrest–resuscitation.23 This effect is likely due to its enhanced glucose utilization with a reduction of tissue lactate. On the other hand, the dual antiplatelet/anti-inflammatory M3mP6 peptide nanoparticles showed marked therapeutic effect in protecting cardiac function and increased survival rate in a mouse myocardial IRI model,17 These studies suggest that protection of organs from primary ischemic injury, and metabolic imbalance following reperfusion, and effective treatment of postischemia thromboinflammation all have potential for novel and complementary IRI treatment.CONCLUDING REMARKSDue to the clinical and social significance of thrombo-inflammatory conditions, enormous investment has been made to develop effective new drugs. The overall results have been disappointing, discouraging many in the field and the pharmaceutical industry. However, lessons from past failures help generate new concepts and targets. In particular, platelets have emerged as an important target for inhibiting thrombosis and inflammation without exacerbating hemorrhage. We think that inhibiting thrombosis and modulating inflammation while minimally impairing the beneficial function of hemostasis and inflammation is not only possible but may facilitate future advances in thromboinflammation treatment.ARTICLE INFORMATIONAcknowledgmentsThe figure was created using www.BioRender.com.Sources of FundingThis work is supported by National Heart, Lung and Blood Institute grants 1R35HL150797 (X. Du) and 1R01HL147031 (T. Vanden Hoek).Disclosures The University of Illinois at Chicago holds patents related to this study. X. Du holds equity interests in DMT, Inc, which licenses University of Illinois at Chicago technology. The other authors report no conflicts.FootnotesThe American Heart Association celebrates its 100th anniversary in 2024. This article is part of a series across the entire AHA Journal portfolio written by international thought leaders on the past, present, and future of cardiovascular and cerebrovascular research and care. To explore the full Centennial Collection, visit https://www.ahajournals.org/centennialFor Sources of Funding and Disclosures, see page 1179.Correspondence to: Xiaoping Du, MD, PhD, Department of Pharmacology and Regenerative Medicine, University of Illinois Chicago, Room E403, 835 S Wolcott Ave, Chicago, IL 60612. Email xdu@uic.eduREFERENCES1. Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms.Blood. 2019; 133:906–918. doi: 10.1182/blood-2018-11-882993CrossrefMedlineGoogle Scholar2. Wagner DD, Heger LA. 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Effects of ulinastatin therapy in deep vein thrombosis prevention after brain tumor surgery: a single-center randomized controlled trial.World J Clin Cases. 2023; 11:7583–7592. doi: 10.12998/wjcc.v11.i31.7583CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails June 2024Vol 44, Issue 6 Advertisement Article InformationMetrics © 2024 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.124.320149PMID: 38776384 Originally publishedMay 22, 2024 Keywordsautoimmune diseasesblood plateletsinflammationmorbiditysepsisthromboinflammationthrombosisPDF download Advertisement