Identification of FcγRIIa as the ITAM-bearing receptor mediating αIIbβ3 outside-in integrin signaling in human platelets

Boylan, Brian; Gao, Cunji; Rathore, Vipul; Gill, Joan Cox; Newman, Debra K.; Newman, Peter J.

doi:10.1182/blood-2008-02-142125

Cited by 155 publications

(155 citation statements)

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“…As the only IgG FcR expressed by human platelets, FcγRIIA contributes to the pathophysiology of diseases such as heparininduced and antibody-mediated thrombocytopenias and to antiphospholipid antibody syndrome-mediated arterial thrombosis. In addition, FcγRIIA has been shown to stimulate platelets through interaction with other molecules and receptors, including α2bβ3, GP1b-IX-V and von Willebrand factor [25][26][27]. Furthermore, FcγRIIA and PECAM-1 are physically and functionally associated on the surface of human platelets [28].…”

Section: A Spoonful Of Antibodies Makes the Platelets Go Down?mentioning

confidence: 99%

Platelet power: sticky problems for sticky parasites?

Pleass

2009

Trends in Parasitology

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Platelets might have a crucial role in the pathogenesis of both human and rodent malarias by assisting in the sequestration of infected erythrocytes within the cerebral vasculature. However, recent elegant work by McMorran et al. suggests that they are also involved in innate protection during the early stages of infection. Here, we discuss the implications of their important findings in the context of immunity to malaria. Platelet: friend or foe?The platelet, traditionally known for its role in blood clotting, is also known for its putative involvement in malaria pathology [1,2]. However, a recent study using C57BL6 mice genetically deficient in the megakaryocyte growth and differentiation factor C-mpl (encoded by the Mpl gene), and resulting in mice with 90% fewer platelets, showed that these animals were significantly more susceptible to death when infected with Plasmodium chabaudi [3]. Furthermore, the authors went on to show that purified human platelets killed Plasmodium falciparum parasites within red blood cells when added to in vitro cultures and that various platelet antagonists, including aspirin, reversed this antiparasitic activity both in vitro and in vivo. This result raises concerns over the use of aspirin as an antipyretic in patients with malaria. Using specific receptor antagonists, the authors demonstrated that killing and control of parasite growth in P. falciparum cultures was dependent on platelet activation via P2Y1, an ADP-dependent metabotrophic puronergic receptor (Figure 1).These results in animals seem counterintuitive, in that platelets are believed to be involved in pathological disease states that hasten death, such as cerebral malaria [1,2]. For example, mice with significantly compromised platelet function (CXCL4 or CXCR3 deficient) have been shown to survive longer than their wild-type counterparts [4]. By contrast, platelet depletion by anti-CD41 monoclonal antibody injection early, but not late, in the course of disease is known to protect C57BL6 mice from Plasmodium berghei ANKA-induced severe experimental cerebral malaria (ECM) by altering levels of pathogenic cytokines [5]. Unfortunately, the study by McMorran et al. used P. chabaudi, a rodent malaria thatalthough capable of sequestering to a number of organs -is not known to develop ECM. It should also be noted that non-sequestering Plasmodium species also give rise to ECM in some inbred mouse strains, Plasmodium yoelii 17XL in BALB/c mice being a good example Europe PMC Funders Group A cornucopia of receptorsThe first of these questions is easier to explain for P. falciparum than for Plasmodium vivax or the murine malarias. Platelet-mediated clumping is common in P. falciparum field isolates, is distinctive from other adhesive phenotypes and involves the host receptors CD36[7] and gC1qR/HABP1/p32 [8]. Whether these are the only platelet receptors involved is debatable and worth exploring. Although GPIIb/IIIa (CD41/CD61) and GPIb/IX (CD42a/ CD42b)-deficient platelets still clump to infected erythrocytes [7], the...

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Section: A Spoonful Of Antibodies Makes the Platelets Go Down?mentioning

confidence: 99%

Platelet power: sticky problems for sticky parasites?

Pleass

2009

Trends in Parasitology

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“…10 The importance of Fc␥RIIA in pathophysiologic disorders such as HIT is well established, 26 but it may also play a role in physiologic platelet activation processes. 27,28 Fc␥RIIA cross-linking by the specific antibody IV.3 induced an efficient aggregation of washed platelets that was fully inhibited by 50 nM dasatinib ( Figure 6A). Interestingly, dasatinib also inhibited platelet aggregation induced by sera from HIT patients in a dose-dependent manner ( Figure 6B).…”

Section: Dasatinib Prevents Platelet Activation By Serum From Hit Patmentioning

confidence: 99%

The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo

Gratacap

Martin

Valera

et al. 2009

Blood

111

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Dasatinib is an oral potent adenosine triphosphate (ATP)-competitive inhibitor of BCR-ABL, cKIT, platelet-derived growth factor receptor, and SRC family kinases (SFKs), which has demonstrated high efficiency in patients with imatinib-resistant chronic myelogenous leukemia. Here, we show that dasatinib weakly affects platelet activation by thrombin or adenosine diphosphate but is a potent inhibitor of platelet signaling and functions initiated by collagen or Fc␥RIIA cross-linking, which require immunoreceptor tyrosinebased activation motif phosphorylation by SFKs. Accordingly, dasatinib treatment rapidly decreases the volume of thrombi formed under arterial flow conditions in whole blood from patients or mice perfused over a matrix of collagen. Moreover, treatment of mice with dasatinib increases the tail bleeding time in a dose-dependent manner. Interestingly, these effects are rapidly reversible after interruption of the treatment. Our data clearly demonstrate that, in contrast to imatinib, dasatinib affects platelet functions in vitro and in vivo, which has important implications in clinic and could explain increased risks of bleeding observed in patients. Moreover, dasatinib efficiently prevents platelet activation mediated by Fc␥RIIA cross-linking and by sera from patients with heparin-induced thrombocytopenia, suggesting that reversible antiplatelet agents acting as ATP-competitive inhibitors of SFKs may be of therapeutic interest in the treatment of this pathology.

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“…Another explanation is that signals originated from GPVI or IIb3 contribute to the thrombin signaling cascade. Boylan et al (2006) have reported that platelets that lost GPVI after in vivo injection of an anti-GPVI antibody had diminished functional responses to thrombin and that outside-in signaling downstream of IIb3 engagement also uses an ITAM-based pathway (Boylan et al, 2008). Older studies have shown that Syk is phosphorylated and activated after platelet stimulation with thrombin (Taniguchi et al, 1993;Clark et al, 1994).…”

Section: Bleeding Time Assaymentioning

confidence: 99%