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Platelets and platelet adhesion molecules: novel mechanisms of thrombosis and anti-thrombotic therapies

Xiaohong Ruby Xu, Naadiya Carrim, Miguel Antonio Dias Neves and 9 more

Thrombosis Journal · 2016 · Review

doi:10.1186/s12959-016-0100-6

Abstract

Platelets are central mediators of thrombosis and hemostasis. At the site of vascular injury, platelet accumulation (i.e. adhesion and aggregation) constitutes the first wave of hemostasis. Blood coagulation, initiated by the coagulation cascades, is the second wave of thrombin generation and enhance phosphatidylserine exposure, can markedly potentiate cell-based thrombin generation and enhance blood coagulation. Recently, deposition of plasma fibronectin and other proteins onto the injured vessel wall has been identified as a new "protein wave of hemostasis" that occurs prior to platelet accumulation (i.e. the classical first wave of hemostasis). These three waves of hemostasis, in the event of atherosclerotic plaque rupture, may turn pathogenic, and cause uncontrolled vessel occlusion and thrombotic disorders (e.g. heart attack and stroke). Current anti-platelet therapies have significantly reduced cardiovascular mortality, however, on-treatment thrombotic events, thrombocytopenia, and bleeding complications are still major concerns that continue to motivate innovation and drive therapeutic advances. Emerging evidence has brought platelet adhesion molecules back into the spotlight as targets for the development of novel anti-thrombotic agents. These potential antiplatelet targets mainly include the platelet receptors glycoprotein (GP) Ib-IX-V complex, β3 integrins (αIIb subunit and PSI domain of β3 subunit) and GPVI. Numerous efforts have been made aiming to balance the efficacy of inhibiting thrombosis without compromising hemostasis. This mini-review will update the mechanisms of thrombosis and the current state of antiplatelet therapies, and will focus on platelet adhesion molecules and the novel anti-thrombotic therapies that target them.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 23, 2026. Paragraph numbers are ours, so an answer can point at one.

Background

Platelet adhesion, activation and aggregation are critical events in hemostasis and thrombosis. Platelet adhesion molecules, αIIbβ3 integrin and the glycoprotein (GP) Ib-IX-V, are essential for these processes. Other adhesion molecules, such as P-selectin, GPVI and cadherins, are also involved. The important roles of adhesion molecules in normal hemostasis have been well demonstrated in bleeding disorders, for example, Glanzmann thrombasthenia (β3 integrin deficiency) and Bernard-Soulier syndrome (GPIb-IX-V complex deficiency). However, under pathological conditions, excessive platelet function may lead to thrombotic diseases, such as myocardial infarction and ischemic stroke, which cause far more deaths each year than cancer or respiratory diseases. Therefore, antiplatelet agents are vital for the treatment of thrombosis. For over a decade, dual antiplatelet therapy with clopidogrel and aspirin has been considered a key treatment of patients with acute coronary syndrome. Nonetheless, some patients undergoing this combination therapy continue to suffer from recurrent thrombotic events, likely a result of platelet activation and aggregation occurring independently of ADP or thromboxane A2 receptor-mediated signalling pathways. Thus, attenuating platelet adhesion appears to be a desirable strategy in effectively controlling pathological thrombosis. Further understanding of the interactions between platelet adhesion molecules and their binding partners is therefore crucial in developing novel anti-thrombotic therapies. This review briefly summarizes the current knowledge of thrombosis and antiplatelet therapies, introduces a number of major platelet adhesion molecules, and highlights some recent advances in the new mechanisms of thrombosis, and anti-thrombotic therapies that are in clinical trials (unless otherwise indicated). There are several excellent available reviews regarding antiplatelet therapies, such as ADP antagonists (e.g. P2Y12 inhibitors), thromboxane antagonists and PAR-1/4 inhibitors. This mini-review will mainly focus on the therapeutic developments targeting platelet adhesion molecules.

Arterial thrombosis and current state of antiplatelet therapies

Arterial thrombosis at the site of atherosclerotic plaque rupture may lead to uncontrolled vessel occlusion, resulting in life-threatening consequences (e.g. unstable angina, myocardial infarction and ischemic stroke). During plaque rupture, subendothelial matrix proteins, like collagen, von Willebrand factor (VWF), fibrinogen, fibronectin and laminin are exposed to circulation, leading to the rapid response of platelets. Inappropriate platelet adhesion, activation and aggregation promote excessive platelet plug formation. Activated platelets can also provide negatively-charged surfaces that harbor coagulation factors and markedly potentiate cell-based thrombin generation and blood coagulation. The evolving concept of the “protein wave of hemostasis” indicates a potential role of platelet-released plasma fibronectin in thrombosis and hemostasis. Thus, platelets are key mediators of atherothrombosis, which are actively involved in all three waves of thrombus formation: protein wave, platelet accumulation, and blood coagulation.

Current FDA-approved antiplatelet therapies (Fig. 1) mainly aim to (i) inhibit thromboxane A2 synthesis, which inhibits platelet activation (e.g. aspirin and triflusal); (ii) antagonize the function of platelet P2Y12 receptors, (e.g. clopidogrel, prasugrel, and ticagrelor); (iii) inhibit platelet integrin αIIbβ3 activity, which inhibits platelet aggregation, (e.g. abciximab, eptifibatide, and tirofiban); (iv) inhibit phosphodiesterase, which increases platelet cAMP/cGMP levels (e.g. dipyridamole and cilostazol). These antiplatelet drugs have significantly reduced cardiovascular deaths. However, limitations of current therapies, such as weak/poor inhibition of platelet function, excessive bleeding, thrombocytopenia and unexpected platelet activation are concerns that drive therapeutic advances. In 2014, the FDA approved Vorapaxar, a novel antagonist of the thrombin receptor protease-activated receptor 1 (PAR1), which reduces the risk of heart attack and stroke in patients with atherosclerosis or peripheral arterial disease. However, Vorapaxar must not be used in patients who have histories of stroke, transient ischemic attack (TIA) or intracranial hemorrhage, since it increases the risk of intracranial bleeding.

Platelet adhesion molecules in hemostasis and thrombosis: novel mechanisms and therapeutic opportunities

Platelet adhesion molecules are proteins/receptors on the platelet surface that interact with other cells or the extracellular matrix, including the integrin family (e.g. α2β1, α5β1, α6β1, αLβ2, αIIbβ3, and ανβ3), the immunoglobulin superfamily (e.g. GPVI, FcγRIIA, ICAM-2, PECAM-1, JAMs and Cadherin 6), the leucine-rich repeat family (LRR; e.g. GPIb-IX-V complex), and the C-type lectin receptor family (e.g. P-selectin and CLEC-2), etc.. Recent evidence has shown that platelet adhesion molecules play key roles in a variety of pathophysiological processes, such as hemostasis and thrombosis, immune responses, inflammation, atherosclerosis, lymphatic vessel development, angiogenesis, miscarriage, and tumor metastasis. Platelets are versatile cells and the mechanisms of their diverse functions have emerged as hot research topics. This review mainly focuses on their roles in thrombosis and as novel anti-thrombotic targets (Fig. 1).

New insights into the GPIb-IX-V complex

Platelet GPIb-IX-V complex (LRR family protein) has approximately 50,000 copies/platelet. It is composed of one GPIbα subunit disulfide-linked to two molecules of GPIbβ, and non-covalently linked with GPIX and GPV in a 2:4:2:1 ratio. GPIb-IX-V is a key platelet receptor in initiating platelet translocation and adhesion to the vessel wall during vascular injury, especially under high shear stress (e.g. in small or stenosed arteries). Platelet translocation onto the subendothelium is mediated by the binding of GPIbα to the immobilized VWF, a multimeric adhesive protein secreted from activated endothelial cells and platelets. The crystal structure of the GPIbα N-terminal ligand-binding domain and the VWF A1 domain gives useful information regarding their interaction. This interaction induces intracellular signalling events that can activate integrins, leading to platelet stable adhesion and subsequent platelet aggregation. Interestingly, platelet-derived VWF was recently shown not essential for hemostasis and thrombosis, but instead fosters thrombo-inflammatory diseases such as ischemic stroke in mice via a GPIb-dependent mechanism. This suggests that targeting GPIbα-VWF may be a promising anti-thrombotic strategy, particularly in thrombo-inflammatory conditions.

Furthermore, GPIb-IX-V complex has a high affinity for thrombin. Two thrombin binding sites on GPIbα LRR C-terminal flank region have been revealed. Consequently, thrombin can activate platelets via GPIbα in two ways: accelerating the cleavage of PAR-1 and platelet activation, or direct signaling via GPIbα, particularly after cleaving GPV, which is generally considered a “brake” in GPIb-IX-V activation. It is currently unknown but it is reasonable to consider that targeting both VWF and thrombin binding sites of GPIbα might provide additional benefits in effectively controlling thrombosis.

GPIbα can also interact with multiple other ligands, leading to platelet activation (e.g. thrombospondin and P-selectin), pro-coagulant activity (e.g. factors XI, XII, VIIa and kininogen), inflammatory responses (e.g. P-selectin, αMβ2), arterial remodeling and others. Recently, the antibody-GPIbα interaction in immune thrombocytopenia has been highlighted. Some anti-GPIbα antibodies cause platelet activation and desialylation (removal of sugars), followed by the clearance of desialylated platelets via Ashwell-Morell receptors on hepatocytes.

Developing novel antiplatelet agents against GPIbα

Given the critical roles of GPIbα or GPIbα-VWF interactions in platelet adhesion, particularly under stenosis high-shear conditions, they are attractive targets in attenuating thrombosis. Currently, two such agents are in active clinical trials. ALX-0081 (Caplacizumab), an anti-VWF humanized single-variable-domain immunoglobulin (Nanobody), binds to the A1 domains of VWF with high affinity. The phase I and II clinical trials of ALX-0081 in patients with stable angina undergoing percutaneous coronary intervention (PCI) or high risk PCI patients have shown a promising antiplatelet effects, and a relatively safe profile. The phase III clinical trials will investigate its effects on acquired thrombotic thrombocytopenic purpura (TTP). ARC1779, an anti-VWF aptamer, was previously reported as an encouraging agent; however, the clinical trial of ARC1779 was prematurely terminated. These VWF inhibitors may be useful candidates for TTP treatment.

A direct anti-GPIbα drug, Anfibatide, is purified from the snake venom of Agkistrodon acutus. Notably, Anfibatide inhibits both VWF and α-thrombin binding to GPIbα, representing a more potent anti-thrombotic effect. In experimental models, Anfibatide inhibited platelet adhesion, aggregation and thrombus formation, without increasing bleeding time. The phase II human clinical trials have also shown the promise of Anfibatide being utilized as a novel antiplatelet agent in cardiovascular diseases without significantly affecting hemostasis in patients with non-ST segment elevation myocardial infarction (unpublished data). Additionally, anti-GPIbα antibody displayed a strong protective effect in the mouse stroke models without inducing significant intracranial bleeding. Anfibatide has also been shown as a candidate to treat ischemic stroke in experimental models (the same may hold true for anti-VWF therapy) and deserves further investigation. There are some other preclinical agents targeting GPIbα that are under investigation, such as h6B4-Fab, GPG-290, and anti-GPIbα NIT family monoclonal antibodies. The generation of these novel antagonists is reaching the forefront of treatment against heart attack and stroke, although the efficacy and safety of these drugs remain to be further established or evaluated in human clinical trials. Notably, there are currently no clinically available direct GPIbα antagonists.

GPVI: a potential anti-thrombotic target

GPVI (immunoglobulin superfamily protein) is exclusively expressed on platelets and megakaryocytes. It is associated with the Fc receptor γ-chain, which contains an immunoreceptor tyrosine-based activation motif (ITAM). Cross-linking by ligands, such as collagen, leads to ITAM-dependent signalling, and platelet activation. A possible anti-thrombotic benefit of targeting PI3-kinase/Akt pathway on ITAM receptors was suggested. Fibrin has also been identified as a new GPVI ligand. The GPVI ectodomain interacts with immobilized fibrin, which amplifies thrombin generation, and promotes thrombus stabilization.

The role of platelet GPVI in the pathogenesis of ischemic stroke has been gradually acknowledged. Notably, platelet adhesion/activation can enhance infarct growth by promoting an inflammatory response. GPVI-mediated platelet activation can lead to the release of interleukin-1α that drives cerebrovascular inflammation. GPVI may be thus a potential antiplatelet target. In animal models, anti-GPVI protected against thrombosis, ischemia-reperfusion injury and stroke. In phase I clinical trials, Revacept (the humanized Fc fusion protein of the GPVI ectodomain), inhibited collagen-induced human platelet aggregation. Phase II trials of Revacept in patients with carotid artery stenosis, TIA, or stroke are ongoing. The efficacy and safety of Revacept in these patients will be further determined. Some other GPVI targeted agents that are under preclinical development, such as Losartan and scFv9012, have been shown to inhibit the binding of GPVI to collagen.

Platelet integrin receptors

Integrins are heterodimeric transmembrane receptors, which are involved in cell-cell and cell-matrix interactions. There are six different integrins on platelet surfaces: α2β1, α5β1, α6β1, αLβ2, αIIbβ3, and ανβ3. Platelet integrin αIIbβ3 is the dominant integrin expressed on platelets. Given the critical roles of αIIbβ3 integrin in mediating platelet aggregation, αIIbβ3 antagonists have been widely used for nearly two decades.

Integrin αIIbβ3 as anti-thrombotic targets: lessons and opportunities

Approximately 17 % of total platelet surface proteins are αIIbβ3 integrin, which contains both αIIb and β3 subunits. Platelet “outside-in” signals are induced following platelet adhesion and platelet activation (e.g. GPIbα-VWF, GPVI/α2β1-collagen, P2Y12-ADP, PARs-thrombin), resulting in an increased Ca2+ influx and ultimately “inside-out” signaling. These “inside-out” signals further drive the conformational changes of αIIbβ3, from a low to high affinity state for binding to its ligands (e.g. fibrinogen/fibrin, VWF, fibronectin, thrombospondin, vitronectin and unidentified “X” ligands).

Fibrinogen, a major prothrombotic ligand of αIIbβ3, has been documented to be required for platelet aggregation for over 50 years. However, platelet aggregation still occurs in the absence of fibrinogen and VWF, although in the absence of αIIbβ3, aggregation is abolished. The discovery of “fibrinogen-independent platelet aggregation” demonstrates that unidentified αIIbβ3 ligands also mediate platelet aggregation, and have the potential to be novel anti-thrombotic targets. Interestingly, some ligands (e.g. plasma fibronectin, vitronectin) may block prothrombotic ligand (e.g. fibrinogen)-αIIbβ3 interactions and attenuate thrombosis.

Three FDA-approved αIIbβ3 antagonists are available: Abciximab (ReoPro), Eptifibatide (Integrilin) and Tirofiban (Aggrastat). Abciximab is a fragmented antibody that binds close to the ligand binding-pocket on αIIbβ3. Eptifibatide, isolated from snake venom, binds via a KGD sequence and is a competitive inhibitor for fibrinogen-αIIbβ3, whilst tirofiban is a small molecule RGD inhibitor. Currently, αIIbβ3 antagonists are used in patients undergoing PCI and significantly decrease the incidence of myocardial infarction and death. However, these antagonists can induce further conformational changes in the β3 subunit that may have negative consequences, such as exposing previously hidden epitopes, and causing platelet activation. αIIbβ3 antagonists are also associated with intracranial hemorrhage in patients with acute ischemic stroke. Therefore, a safer and more specific on-target drug is required to provide better patient care. Recently, a novel αIIbβ3 antagonist, RUC-4 (a more potent and more soluble congener of RUC-2 that disrupts Mg2+ binding to the metal ion-dependent adhesion site of αIIbβ3), is suggested for prehospital therapy of myocardial infarction in animal models, without significantly priming the receptor to bind fibrinogen. However, the possibility of increased bleeding with therapeutic doses of RUC-4 remains to be evaluated.

The plexin-semaphorin-integrin (PSI) domain, located near the N-terminus of the β3 subunit, is highly conserved across the integrin family in different species, and contains seven cysteine residues which have been implicated in regulating β2 integrin activation. Previous studies described a role for cysteine-derived thiol/disulfide groups in the conformational switches of the β3 integrin. Disulfide bond remodeling is mediated primarily by thiol isomerase enzymatic activity, which is derived from active CXXC thioredoxin motifs and plays a role in the activation of αIIbβ3. Our group has recently identified that integrin PSI domain has endogenous thiol isomerase function and could be a novel target for anti-thrombotic therapy (unpublished data). We found that both CXXC motifs of β3 integrin PSI domain are required to maintain the optimal enzyme function, since mutations to one or both of the CXXC motifs decrease or abolish their protein disulphide isomerase (PDI)-like activity. We developed anti-PSI monoclonal antibodies and found that these antibodies cross-reacted with β3 PSI domains of human and other species and specifically inhibited the PDI-like activity, integrin activation and reduced PAC-1 binding to β3 integrin. Importantly, anti-PSI abrogated murine and human platelet aggregation in vitro and thrombus growth ex vivo and in vivo in both small and large vessels without significantly affecting bleeding time or platelet count. Thus, integrin PSI domain contains endogenous PDI activity and is a key regulator of integrin activation that can be a new target for therapy.

Interestingly, targeting activated platelets αIIbβ3 has been considered into the development of novel fibrinolytic drugs, which may allow effective thrombolysis and thromboprophylaxis. For example, scFvSCE5 (a single-chain urokinase plasminogen activator fused to a small recombinant antibody that binds activated αIIbβ3) directly targets thrombi and exerts an effective thrombolysis. A chimeric platelet-targeted urokinase prodrug (composed of a single-chain version of the variable region of an anti-αIIbβ3 mAb and a thrombin-activatable, low-molecular-weight pro-uPA) selectively targets new thrombus formation.

Other platelet integrins: α2β1, α6β1 and α5β1

Other integrin receptors may also be considered as novel anti-thrombotic targets. Platelet α2β1 promotes stable platelet adhesion to collagen and may be a viable option, since overexpression of α2β1 in humans increases atherothrombotic risk, but lower level of α2β1 does not enhance bleeding risk. Experimental evidence shows that α2β1 inhibitors (e.g. snake venom EMS-16) reduced pathological thrombus formation in vivo. Platelet α6β1, the main receptor for laminin, plays a role in platelet adhesion/activation and arterial thrombosis, and may also be a new target. Platelet α5β1, the major receptor for fibronectin, plays a supplementary role in platelet adhesion, but evidence is lacking regarding the anti-thrombotic benefits of antagonizing α5β1.

Other novel anti-thrombotic candidates: Glucagon-like peptide 1 receptor, P-selectin, CD40/CD40L, and Toll-like receptors

Strategies to target other platelet receptors beyond adhesive proteins have also been developed, such as P2Y12, PAR1, TP, 5HT2A antagonists. Interestingly, some chronic diseases, such as diabetes mellitus and atherosclerosis, are associated with arterial thrombosis. Recently, our group identified that a functional Glucagon-like peptide 1 receptor (GLP-1R) is expressed on human megakaryocytes and platelets. Importantly, GLP-1R agonists (e.g. Exenatide), likely through increasing the intracellular cAMP levels, inhibit platelet function and thrombus formation. This study provides important insights into why diabetic patients who are receiving GLP-1-targeted therapies have a reduced number of cardiovascular events. In addition, given the cross-talks between platelets and immune systems, thrombosis also intensively communicates with the inflammatory pathway. Some anti-inflammatory/anti-atherosclerotic agents may therefore also indirectly inhibit thrombosis, especially in deep vein thrombosis. For example, antagonists of P-selectin/PSGL-1, such as rPSGL-Ig, PSI-697, PSI-421, inhibit platelet-mediated leukocyte attachment and recruitment of procoagulant microparticles, and may represent a safe therapeutic intervention in accelerating thrombolysis. Antagonists of CD40/CD40L, such as CD40 antibody, reduce atherosclerotic burden in a murine model. In addition, as the important roles of Toll-like receptors in atherosclerosis are gradually recognized, they may also be potential targets for the treatment of atherothrombosis.

Conclusions

Arterial thrombotic events, such as myocardial infarction and ischemic stroke, and venous thromboembolism, are three leading causes of morbidity and mortality worldwide. Platelets play a central role in the pathogenesis of atherothrombosis, and contribute profoundly to the pathology of venous thrombosis. Platelet adhesion molecules, act as the contacts between platelets and other cells or extracellular matrix proteins and, to a great extent, may determine the reactivity of platelets and thus are attractive anti-thrombotic targets (Fig. 1). Although evidence-based antiplatelet therapy has markedly improved patient care, on-treatment events and bleeding are still major concerns.

Optimization of the use of currently available therapies, and improvements to the understanding of individual differences in response to anti-platelet treatments are still the most cost-effective treatment strategies. Additionally, improved understanding of the mechanisms of platelet accumulation has been critical for further developing novel antiplatelet therapies, such as the PAR1 antagonist Vorapaxar (recently approved by the FDA), GPIbα/VWF antagonists (e.g. ALX-0081 and Anfibatide; undergoing clinical trials), and GPVI antagonist (e.g. Revacept; undergoing clinical trials) (See section II. A-C). Another cost-effective strategy may be to repurpose already-established drugs by discovering novel mechanisms of action in anti-thrombotic diseases, such as the recently-identified GLP-1R agonist, Exenatide, an anti-diabetic drug that has potential anti-thrombotic effects. Future studies in the areas of atherothrombosis, inflammation, metabolic syndrome, diabetes, lipid metabolism and cancer-related thrombotic diseases in the next few years should advance our knowledge and the application of these and other new anti-platelet agents. Of note, clinical trials provide important evidence regarding the safety and efficacy of the treatments. However, difficulties such as narrow eligibility criteria, low enrollment of patients and the necessity to test the new drugs on top of the current dual antiplatelet therapy (e.g. aspirin and clopidogrel), may add complexity to the development of new drugs and also deserve our attention.

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    Murphy AJ, Bijl N, Yvan-Charvet L, Welch CB, Bhagwat N, Reheman A, et al. Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis. Nat Med. 2013;19:586-94.

    Not in our library10.1038/nm.3150

  41. 41.

    Hess PR, Rawnsley DR, Jakus Z, Yang Y, Sweet DT, Fu J, et al. Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life. J Clin Invest. 2014;124:273-284.

    Not in our library10.1172/jci70422

  42. 42.

    Navarro-Nunez L, Langan SA, Nash GB, Watson SP. The physiological and pathophysiological roles of platelet CLEC-2. Thromb Haemost. 2013;109:991-8.

    Not in our library10.1160/th13-01-0060

  43. 43.

    Osada M, Inoue O, Ding G, Shirai T, Ichise H, Hirayama K, et al. Platelet activation receptor CLEC-2 regulates blood/lymphatic vessel separation by inhibiting proliferation, migration, and tube formation of lymphatic endothelial cells. J Biol Chem. 2012;287:22241-52.

    Not in our library10.1074/jbc.m111.329987

  44. 44.

    Herzog BH, Fu J, Wilson SJ, Hess PR, Sen A, McDaniel JM, et al. Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2. Nature. 2013;502:105-9.

    Not in our library10.1038/nature12501

  45. 45.

    Italiano JE, Richardson JL, Patel-Hett S, Battinelli E, Zaslavsky A, Short S, et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood. 2008;111:1227-33.

    Not in our library10.1182/blood-2007-09-113837

  46. 46.

    Chatterjee M, Huang Z, Zhang W, Jiang L, Hultenby K, Zhu L, et al. Distinct platelet packaging, release, and surface expression of proangiogenic and antiangiogenic factors on different platelet stimuli. Blood. 2011;117:3907-11.

    Not in our library10.1182/blood-2010-12-327007

  47. 47.

    Yougbare I, Lang S, Yang H, Chen P, Zhao X, Tai WS, et al. Maternal anti-platelet beta3 integrins impair angiogenesis and cause intracranial hemorrhage. J Clin Invest. 2015;125:1545-56.

    Not in our library10.1172/jci77820

  48. 48.

    Li C, Piran S, Chen P, Lang S, Zarpellon A, Jin JW, et al. The maternal immune response to fetal platelet GPIbalpha causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies. J Clin Invest. 2011;121:4537-47.

    Not in our library10.1172/jci57850

  49. 49.

    Yougbare I, Wei-She T, Zdravic D, Chen P, Zhu G, Leong-Poi H, et al. Natural killer cells contribute to pathophysiology of placenta leading to miscarriage in fetal and neonatal alloimmune thrombocytopenia. Blood. 2015;126:2254.

    Not in our library10.1182/blood-2015-08-663492

  50. 50.

    Labelle M, Hynes RO. The initial hours of metastasis: the importance of cooperative host-tumor cell interactions during hematogenous dissemination. Cancer Discov. 2012;2:1091-9.

    Not in our library10.1158/2159-8290.cd-12-0329

  51. 51.

    Labelle M, Begum S, Hynes RO. Platelets guide the formation of early metastatic niches. Proc Natl Acad Sci U S A. 2014;111:E3053-61.

    Not in our library10.1073/pnas.1411082111

  52. 52.

    Franco AT, Corken A, Ware J. Platelets at the interface of thrombosis, inflammation, and cancer. Blood. 2015;126:582-8.

    Not in our library10.1182/blood-2014-08-531582

  53. 53.

    Luo SZ, Mo X, Afshar-Kharghan V, Srinivasan S, Lopez JA, Li R. Glycoprotein Ibalpha forms disulfide bonds with 2 glycoprotein Ibbeta subunits in the resting platelet. Blood. 2007;109:603-9.

    Not in our library10.1182/blood-2006-05-024091

  54. 54.

    Jackson SP. The growing complexity of platelet aggregation. Blood. 2007;109:5087-95.

    Not in our library10.1182/blood-2006-12-027698

  55. 55.

    Ruggeri ZM, Mendolicchio GL. Adhesion mechanisms in platelet function. Circ Res. 2007;100:1673-85.

    Not in our library10.1161/01.res.0000267878.97021.ab

  56. 56.

    Huizinga EG, Tsuji S, Romijn RA, Schiphorst ME, de Groot PG, Sixma JJ, et al. Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain. Science. 2002;297:1176-9.

    Not in our library10.1126/science.107355

  57. 57.

    Verhenne S, Denorme F, Libbrecht S, Vandenbulcke A, Pareyn I, Deckmyn H, et al. Platelet-derived VWF is not essential for normal thrombosis and hemostasis but fosters ischemic stroke injury in mice. Blood. 2015;126:1715-22.

    Not in our library10.1182/blood-2015-03-632901

  58. 58.

    Dumas JJ, Kumar R, Seehra J, Somers WS, Mosyak L. Crystal structure of the GpIbalpha-thrombin complex essential for platelet aggregation. Science. 2003;301:222-6.

    Not in our library10.1126/science.1083917

  59. 59.

    Celikel R, McClintock RA, Roberts JR, Mendolicchio GL, Ware J, Varughese KI, et al. Modulation of alpha-thrombin function by distinct interactions with platelet glycoprotein Ibalpha. Science. 2003;301:218-21.

    Not in our library10.1126/science.1084183

  60. 60.

    Andrews RK, Berndt MC, Michelson AD. The GPIb-IX-V Complex. Platelets. 2013;195-213.

    Not in our library

  61. 61.

    De Candia E, Hall SW, Rutella S, Landolfi R, Andrews RK, De Cristofaro R. Binding of thrombin to glycoprotein Ib accelerates the hydrolysis of Par-1 on intact platelets. J Biol Chem. 2001;276:4692-8.

    Not in our library10.1074/jbc.m008160200

  62. 62.

    Ramakrishnan V, DeGuzman F, Bao M, Hall SW, Leung LL, Phillips DR. A thrombin receptor function for platelet glycoprotein Ib-IX unmasked by cleavage of glycoprotein V. Proc Natl Acad Sci U S A. 2001;98:1823-8.

    Not in our library10.1073/pnas.98.4.1823

  63. 63.

    Ni H, Ramakrishnan V, Ruggeri ZM, Papalia JM, Phillips DR, Wagner DD. Increased thrombogenesis and embolus formation in mice lacking glycoprotein V. Blood. 2001;98:368-73.

    Not in our library10.1182/blood.v98.2.368

  64. 64.

    Jurk K, Clemetson KJ, de Groot PG, Brodde MF, Steiner M, Savion N, et al. Thrombospondin-1 mediates platelet adhesion at high shear via glycoprotein Ib (GPIb): an alternative/backup mechanism to von Willebrand factor. FASEB J. 2003;17:1490-2.

    Not in our library10.1096/fj.02-0830fje

  65. 65.

    Baglia FA, Badellino KO, Li CQ, Lopez JA, Walsh PN. Factor XI binding to the platelet glycoprotein Ib-IX-V complex promotes factor XI activation by thrombin. J Biol Chem. 2002;277:1662-8.

    Not in our library10.1074/jbc.m108319200

  66. 66.

    Bradford HN, Pixley RA, Colman RW. Human factor XII binding to the glycoprotein Ib-IX-V complex inhibits thrombin-induced platelet aggregation. J Biol Chem. 2000;275:22756–63.

    Not in our library10.1074/jbc.m002591200

  67. 67.

    Weeterings C, de Groot PG, Adelmeijer J, Lisman T. The glycoprotein Ib-IX-V complex contributes to tissue factor-independent thrombin generation by recombinant factor VIIa on the activated platelet surface. Blood. 2008;112:3227-33.

    Not in our library10.1182/blood-2008-02-139113

  68. 68.

    Chavakis T, Santoso S, Clemetson KJ, Sachs UJ, Isordia-Salas I, Pixley RA, et al. High molecular weight kininogen regulates platelet-leukocyte interactions by bridging Mac-1 and glycoprotein Ib. J Biol Chem. 2003;278:45375-81.

    Not in our library10.1074/jbc.m304344200

  69. 69.

    Romo GM, Dong JF, Schade AJ, Gardiner EE, Kansas GS, Li CQ, et al. The glycoprotein Ib-IX-V complex is a platelet counterreceptor for P-selectin. J Exp Med. 1999;190:803-14.

    Not in our library10.1084/jem.190.6.803

  70. 70.

    Kaplan ZS, Zarpellon A, Alwis I, Yuan Y, McFadyen J, Ghasemzadeh M, et al. Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4. Nat Commun. 2015;6:7835.

    Not in our library10.1038/ncomms8835

  71. 71.

    Simon DI, Chen Z, Xu H, Li CQ, Dong J, McIntire LV, et al. Platelet glycoprotein ibalpha is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med. 2000;192:193-204.

    Not in our library10.1084/jem.192.2.193

  72. 72.

    Chandraratne S, von Bruehl ML, Pagel JI, Stark K, Kleinert E, Konrad I, et al. Critical role of platelet glycoprotein ibalpha in arterial remodeling. Arterioscler Thromb Vasc Biol. 2015;35:589-97.

    Not in our library10.1161/atvbaha.114.304447

  73. 73.
    Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia · 2015
    No notice
  74. 74.

    Li J, Callum JL, Lin Y, Zhou Y, Zhu G, Ni H. Severe platelet desialylation in a patient with glycoprotein Ib/IX antibody-mediated immune thrombocytopenia and fatal pulmonary hemorrhage. Haematologica. 2014;99:e61-3.

    Not in our library10.3324/haematol.2013.102897

  75. 75.

    Gresele P, Momi S. Inhibitors of the interaction between von Willebrand factor and platelet GPIb/IX/V. Handb Exp Pharmacol. 2012;(210):287-309.

    Not in our library10.1007/978-3-642-29423-5_12

  76. 76.

    Ulrichts H, Silence K, Schoolmeester A, de Jaegere P, Rossenu S, Roodt J, et al. Antithrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared with currently marketed antiplatelet drugs. Blood. 2011;118:757-65.

    Not in our library10.1182/blood-2010-11-317859

  77. 77.

    Bartunek J, Barbato E, Heyndrickx G, Vanderheyden M, Wijns W, Holz JB. Novel antiplatelet agents: ALX-0081, a Nanobody directed towards von Willebrand factor. J Cardiovasc Transl Res. 2013;6:355-63.

    Not in our library10.1007/s12265-012-9435-y

  78. 78.

    Muller O, Bartunek J, Hamilos M, Berza CT, Mangiacapra F, Ntalianis A, et al. von Willebrand factor inhibition improves endothelial function in patients with stable angina. J Cardiovasc Transl Res. 2013;6:364-70.

    Not in our library10.1007/s12265-012-9422-3

  79. 79.

    Peyvandi F, Scully M, Kremer Hovinga JA, Cataland S, Knobl P, Wu H, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2016;374:511-22.

    Not in our library10.1056/nejmoa1505533

  80. 80.

    Lammle B. Thrombotic microangiopathy: caplacizumab accelerates resolution of acute acquired TTP. Nat Rev Nephrol. 2016;12:259-60.

    Not in our library10.1038/nrneph.2016.47

  81. 81.

    Von VA. Willebrand factor--a new target for TTP treatment? N Engl J Med. 2016;374:583-5.

    Not in our library10.1056/nejme1515876

  82. 82.

    Blombery P, Scully M. Management of thrombotic thrombocytopenic purpura: current perspectives. J Blood Med. 2014;5:15-23.

    Not in our library10.2147/jbm.s46458

  83. 83.

    Lei X, Reheman A, Hou Y, Zhou H, Wang Y, Marshall AH, et al. Anfibatide, a novel GPIb complex antagonist, inhibits platelet adhesion and thrombus formation in vitro and in vivo in murine models of thrombosis. Thromb Haemost. 2014;111:279-89.

    Not in our library10.1160/th13-06-0490

  84. 84.

    Hou Y, Li BX, Dai X, Yang Z, Qian F, Zhang G, et al. The first in vitro and in vivo assessment of anfibatide, a novel glycoprotein ib antagonist, in mice and in a phase i human clinical trial. Blood. 2013;122:577.

    Not in our library

  85. 85.

    Li B, Dai X, Yang Z, Qian F, Zhang G, Xu Z, et al. First ex vivo and in vivo assessment of anfibatide, a novel glycoprotein Ib-IV-V complex antagonist, in healthy human volunteers in phase I clinical trial. J Thromb Haemost. 2013;11(Suppl. 2):23.

    Not in our library

  86. 86.

    Nieswandt B, Kleinschnitz C, Stoll G. Ischaemic stroke: a thrombo-inflammatory disease? J Physiol. 2011;589:4115-23.

    Not in our library10.1113/jphysiol.2011.212886

  87. 87.

    Stoll G, Kleinschnitz C, Nieswandt B. Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment. Blood. 2008;112:3555-62.

    Not in our library10.1182/blood-2008-04-144758

  88. 88.

    Kleinschnitz C, Pozgajova M, Pham M, Bendszus M, Nieswandt B, Stoll G. Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding. Circulation. 2007;115:2323-30.

    Not in our library10.1161/circulationaha.107.691279

  89. 89.

    Li TT, Fan ML, Hou SX, Li XY, Barry DM, Jin H, Luo SY, Kong F, Lau LF, Dai XR, Zhang GH, Zhou LL. A novel snake venomderived GPIb antagonist, anfibatide, protects mice from acute experimental ischaemic stroke and reperfusion injury. Br J Pharmacol.

    Not in our library10.1111/bph.13178

  90. 90.

    Fontayne A, Meiring M, Lamprecht S, Roodt J, Demarsin E, Barbeaux P, et al. The humanized anti-glycoprotein Ib monoclonal antibody h6B4-Fab is a potent and safe antithrombotic in a high shear arterial thrombosis model in baboons. Thromb Haemost. 2008;100:670-7.

    Not in our library

  91. 91.

    Hennan JK, Swillo RE, Morgan GA, Leik CE, Brooks JM, Shaw GD, et al. Pharmacologic inhibition of platelet vWF-GPIb alpha interaction prevents coronary artery thrombosis. Thromb Haemost. 2006;95:469-75.

    Not in our library10.1160/th05-09-0640

  92. 92.

    Ni H, Zhu G. Novel monoclonal antibodies against platelet GPIb-alpha: potential anti-thrombotic drugs and research reagents for study of thrombosis and hemostasis. 2012.

    Not in our library

  93. 93.

    Moroi AJ, Watson SP. Impact of the PI3-kinase/Akt pathway on ITAM and hemITAM receptors: haemostasis, platelet activation and antithrombotic therapy. Biochem Pharmacol. 2015;94:186-194.

    Not in our library10.1016/j.bcp.2015.02.004

  94. 94.

    Alshehri OM, Hughes CE, Montague S, Watson SK, Frampton J, Bender M, et al. Fibrin activates GPVI in human and mouse platelets. Blood. 2015;126:1601-8.

    Not in our library10.1182/blood-2015-04-641654

  95. 95.

    Mammadova-Bach E, Ollivier V, Loyau S, Schaff M, Dumont B, Favier R, et al. Platelet glycoprotein VI binds to polymerized fibrin and promotes thrombin generation. Blood. 2015;126:683-91.

    Not in our library10.1182/blood-2015-02-629717

  96. 96.

    Bigalke B, Stellos K, Geisler T, Kremmer E, Seizer P, May AE, et al. Expression of platelet glycoprotein VI is associated with transient ischemic attack and stroke. Eur J Neurol. 2010;17:111-7.

    Not in our library10.1111/j.1468-1331.2009.02754.x

  97. 97.

    Induruwa I, Jung SM, Warburton EA. Beyond antiplatelets: the role of glycoprotein VI in ischemic stroke. Int J Stroke. 2016.

    Not in our library10.1177/1747493016654532

  98. 98.

    Al-Tamimi M, Gardiner EE, Thom JY, Shen Y, Cooper MN, Hankey GJ, et al. Soluble glycoprotein VI is raised in the plasma of patients with acute ischemic stroke. Stroke. 2011;42:498-500.

    Not in our library10.1161/strokeaha.110.602532

  99. 99.

    Stoll G, Kleinschnitz C, Nieswandt B. Combating innate inflammation: a new paradigm for acute treatment of stroke? Ann N Y Acad Sci. 2010;1207:149-54.

    Not in our library10.1111/j.1749-6632.2010.05730.x

  100. 100.

    Thornton P, McColl BW, Greenhalgh A, Denes A, Allan SM, Rothwell NJ. Platelet interleukin-1alpha drives cerebrovascular inflammation. Blood. 2010;115:3632-9.

    Not in our library10.1182/blood-2009-11-252643

  101. 101.

    Stegner D, Haining EJ, Nieswandt B. Targeting glycoprotein VI and the immunoreceptor tyrosine-based activation motif signaling pathway. Arterioscler Thromb Vasc Biol. 2014;34:1615-20.

    Not in our library10.1161/atvbaha.114.303408

  102. 102.

    Dutting S, Bender M, Nieswandt B. Platelet GPVI: a target for antithrombotic therapy?! Trends Pharmacol Sci. 2012;33:583-90.

    Not in our library10.1016/j.tips.2012.07.004

  103. 103.

    Pachel C, Mathes D, Arias-Loza AP, Heitzmann W, Nordbeck P, Deppermann C, et al. Inhibition of platelet GPVI protects against myocardial ischemia-reperfusion injury. Arterioscler Thromb Vasc Biol. 2016;36:629-35.

    Not in our library10.1161/atvbaha.115.305873

  104. 104.

    Goebel S, Li Z, Vogelmann J, Holthoff HP, Degen H, Hermann DM, et al. The GPVI-Fc fusion protein Revacept improves cerebral infarct volume and functional outcome in stroke. PLoS One. 2013;8:e66960.

    Not in our library10.1371/journal.pone.0066960

  105. 105.

    Ungerer M, Rosport K, Bultmann A, Piechatzek R, Uhland K, Schlieper P, et al. Novel antiplatelet drug revacept (Dimeric Glycoprotein VI-Fc) specifically and efficiently inhibited collagen-induced platelet aggregation without affecting general hemostasis in humans. Circulation. 2011;123:1891-9.

    Not in our library10.1161/circulationaha.110.980623

  106. 106.

    ClinicalTrials.gov. 2015. https://clinicaltrials.gov/ct2/show/NCT01645306?term=Revacept&rank=1. Accessed 15 June 2016.

    Not in our library

  107. 107.

    Ono K, Ueda H, Yoshizawa Y, Akazawa D, Tanimura R, Shimada I, et al. Structural basis for platelet antiaggregation by angiotensin II type 1 receptor antagonist losartan (DuP-753) via glycoprotein VI. J Med Chem. 2010;53:2087-93.

    Not in our library10.1021/jm901534d

  108. 108.

    Muzard J, Bouabdelli M, Zahid M, Ollivier V, Lacapere JJ, Jandrot-Perrus M, et al. Design and humanization of a murine scFv that blocks human platelet glycoprotein VI in vitro. FEBS J. 2009;276:4207-22.

    Not in our library10.1111/j.1742-4658.2009.07129.x

  109. 109.

    Takagi J, Petre BM, Walz T, Springer TA. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell. 2002;110:599-611.

    Not in our library10.1016/s0092-8674(02)00935-2

  110. 110.

    Li R, Mitra N, Gratkowski H, Vilaire G, Litvinov R, Nagasami C, et al. Activation of integrin alphaIIbbeta3 by modulation of transmembrane helix associations. Science. 2003;300:795-8.

    Not in our library10.1126/science.1079441

  111. 111.

    Vinogradova O, Vaynberg J, Kong X, Haas TA, Plow EF, Qin J. Membrane-mediated structural transitions at the cytoplasmic face during integrin activation. Proc Natl Acad Sci U S A. 2004;101:4094-9.

    Not in our library10.1073/pnas.0400742101

  112. 112.

    Vinogradova O, Velyvis A, Velyviene A, Hu B, Haas T, Plow E, et al. A structural mechanism of integrin alpha(IIb)beta(3) “inside-out” activation as regulated by its cytoplasmic face. Cell. 2002;110:587-97.

    Not in our library10.1016/s0092-8674(02)00906-6

  113. 113.

    Ni H, Denis CV, Subbarao S, Degen JL, Sato TN, Hynes RO, et al. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest. 2000;106:385-92.

    Not in our library10.1172/jci9896

  114. 114.

    Law DA, DeGuzman FR, Heiser P, Ministri-Madrid K, Killeen N, Phillips DR. Integrin cytoplasmic tyrosine motif is required for outside-in alphaIIbbeta3 signalling and platelet function. Nature. 1999;401:808-11.

    Not in our library10.1038/44599

  115. 115.

    Hodivala-Dilke KM, McHugh KP, Tsakiris DA, Rayburn H, Crowley D, Ullman-Cullere M, et al. Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest. 1999;103:229-38.

    Not in our library10.1172/jci5487

  116. 116.

    Reheman A, Yang H, Zhu G, Jin W, He F, Spring CM, et al. Plasma fibronectin depletion enhances platelet aggregation and thrombus formation in mice lacking fibrinogen and von Willebrand factor. Blood. 2009;113:1809-17.

    Not in our library10.1182/blood-2008-04-148361

  117. 117.

    Reheman A, Gross P, Yang H, Chen P, Allen D, Leytin V, et al. Vitronectin stabilizes thrombi and vessel occlusion but plays a dual role in platelet aggregation. J Thromb Haemost. 2005;3:875-83.

    Not in our library10.1111/j.1538-7836.2005.01217.x

  118. 118.

    Topol EJ, Byzova TV, Plow EF. Platelet GPIIb-IIIa blockers. Lancet. 1999;353:227-31.

    Not in our library10.1016/s0140-6736(98)11086-3

  119. 119.

    Phillips DR, Scarborough RM. Clinical pharmacology of eptifibatide. Am J Cardiol. 1997;80:11B-20B.

    Not in our library10.1016/s0002-9149(97)00572-9

  120. 120.

    Egbertson MS, Chang CT, Duggan ME, Gould RJ, Halczenko W, Hartman GD, et al. Non-peptide fibrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp. J Med Chem. 1994;37:2537-51.

    Not in our library10.1021/jm00042a007

  121. 121.

    Schneider DJ. Anti-platelet therapy: glycoprotein IIb-IIIa antagonists. Br J Clin Pharmacol. 2011;72:672-82.

    Not in our library10.1111/j.1365-2125.2010.03879.x

  122. 122.

    Coller BS. alphaIIbbeta3: structure and function. J Thromb Haemost. 2015;13(Suppl 1):S17-25.

    Not in our library10.1111/jth.12915

  123. 123.

    Ciccone A, Motto C, Abraha I, Cozzolino F, Santilli I. Glycoprotein IIb-IIIa inhibitors for acute ischaemic stroke. Cochrane Database Syst Rev. 2014;3:CD005208.

    Not in our library10.1002/14651858.cd005208.pub3

  124. 124.

    Li J, Vootukuri S, Shang Y, Negri A, Jiang JK, Nedelman M, et al. RUC-4: a novel alphaIIbbeta3 antagonist for prehospital therapy of myocardial infarction. Arterioscler Thromb Vasc Biol. 2014;34:2321-9.

    Not in our library10.1161/atvbaha.114.303724

  125. 125.

    Xiong JP, Stehle T, Goodman SL, Arnaout MA. A novel adaptation of the integrin PSI domain revealed from its crystal structure. J Biol Chem. 2004;279:40252-4.

    Not in our library10.1074/jbc.c400362200

  126. 126.

    Zang Q, Springer TA. Amino acid residues in the PSI domain and cysteine-rich repeats of the integrin beta2 subunit that restrain activation of the integrin alpha(X)beta(2). J Biol Chem. 2001;276:6922-9.

    Not in our library10.1074/jbc.m005868200

  127. 127.

    Ni H, Li A, Simonsen N, Wilkins JA. Integrin activation by dithiothreitol or Mn2+ induces a ligand-occupied conformation and exposure of a novel NH2-terminal regulatory site on the beta1 integrin chain. J Biol Chem. 1998;273:7981-7.

    Not in our library10.1074/jbc.273.14.7981

  128. 128.

    Yan B, Smith JW. A redox site involved in integrin activation. J Biol Chem. 2000;275:39964-72.

    Not in our library10.1074/jbc.m007041200

  129. 129.

    Essex DW, Li M. Redox control of platelet aggregation. Biochemistry. 2003;42:129-36.

    Not in our library10.1021/bi0205045

  130. 130.

    Manickam N, Ahmad SS, Essex DW. Vicinal thiols are required for activation of the alphaIIbbeta3 platelet integrin. J Thromb Haemost. 2011;9:1207-15.

    Not in our library10.1111/j.1538-7836.2011.04266.x

  131. 131.

    Wang L, Wu Y, Zhou J, Ahmad SS, Mutus B, Garbi N, et al. Platelet-derived ERp57 mediates platelet incorporation into a growing thrombus by regulation of the alphaIIbbeta3 integrin. Blood. 2013;122:3642-50.

    Not in our library10.1182/blood-2013-06-506691

  132. 132.

    Carrim N, Zhu G, Reddy E, Xu M, Xu X, Wang Y, et al. Integrin PSI domain has endogenous thiol isomerase function and is a novel target for anti-thrombotic therapy. J Thromb Haemost. 2015;13(Supplement S2):60.

    Not in our library

  133. 133.

    Wang X, Palasubramaniam J, Gkanatsas Y, Hohmann JD, Westein E, Kanojia R, et al. Towards effective and safe thrombolysis and thromboprophylaxis: preclinical testing of a novel antibody-targeted recombinant plasminogen activator directed against activated platelets. Circ Res. 2014;114:1083-93.

    Not in our library10.1161/circresaha.114.302514

  134. 134.

    Fuentes RE, Zaitsev S, Ahn HS, Hayes V, Kowalska M, Lambert MP, et al. A chimeric platelet-targeted urokinase prodrug selectively blocks new thrombus formation. J Clin Invest. 2016;126:483-94.

    Not in our library10.1172/jci81470

  135. 135.

    Schaff M, Tang C, Maurer E, Bourdon C, Receveur N, Eckly A, et al. Integrin alpha6beta1 is the main receptor for vascular laminins and plays a role in platelet adhesion, activation, and arterial thrombosis. Circulation. 2013;128:541-52.

    Not in our library10.1161/circulationaha.112.000799

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    Miller MW, Basra S, Kulp DW, Billings PC, Choi S, Beavers MP, et al. Small-molecule inhibitors of integrin alpha2beta1 that prevent pathological thrombus formation via an allosteric mechanism. Proc Natl Acad Sci U S A. 2009;106:719-24.

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