Human neutrophil elastase modulates platelet function by limited proteolysis of membrane glycoproteins.

Brower, Mark S.; Levin, Richard I.; Garry, Kimberly E.

doi:10.1172/jci111744

Cited by 114 publications

(56 citation statements)

References 64 publications

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“…Proteolysis of platelet surface glycoproteins, in vivo, has been associated with cirrhosis of the liver (36). After the studies reported here were completed, Brower et al (37) have reported that platelets treated with human neutrophil elastase lose the ability to aggregate in response to thrombin and ristocetin. However, spontaneous aggregation to added fibrinogen was not tested by Brower et al (37).…”

Section: Discussionmentioning

confidence: 76%

Exposure of fibrinogen receptors in human platelets by surface proteolysis with elastase.

Kornecki¹,

Ehrlich²,

Mars³

et al. 1986

J. Clin. Invest.

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Human platelets that were preincubated with porcine elastase aggregated spontaneously upon the addition of fibrinogen. Maximal aggregation to fibrinogen was observed with platelets pretreated with an elastase concentration of 111 tg/ml, and halfmaximal aggregation occurred after treatment with 11 ,ug/ml elastase. Binding of radiolabeled fibrinogen to elastase-treated platelets was specific, saturable, and showed a single class of 48,400±9,697 fibrinogen-binding sites per platelet with a dissociation constant of 6.30±1.48 X i0-M. ATP, apyrase, and the stimulators of platelet adenylate cyclase forskolin, prostaglandin El, prostacyclin, and N6, 2'-O-dibutyryl cyclic AMP did not inhibit the fibrinogen-induced aggregation of elastase-treated platelets. EDTA completely blocked the initiation of aggregation and reversed the fibrinogen-induced aggregation of elastasetreated platelets. Monoclonal and polyclonal antibodies directed against glycoproteins (GP) Ilb and II1a completely blocked the fibrinogen-induced aggregation of elastase-treated platelets. Immunoprecipitates with these antibodies obtained from detergent extracts of surface-radiolabeled, intact, and elastase-treated platelets contained the glycoproteins IUb and IIIa. We conclude that surface proteolysis by low concentrations of elastase can expose fibrinogen-binding sites associated with GPIIb and GPIIIa on the platelet surface, resulting in spontaneous aggregation upon the addition of fibrinogen. These findings may be relevant to hemostatic changes observed in patients with increased levels of circulating elastase.

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Section: Discussionmentioning

confidence: 76%

Exposure of fibrinogen receptors in human platelets by surface proteolysis with elastase.

Kornecki¹,

Ehrlich²,

Mars³

et al. 1986

J. Clin. Invest.

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“…[29][30][31] Like thrombin, CG potently stimulates platelet aggregation through structurally related proteaseactivated receptors. 32,33 Although NE2 does not activate platelets by itself, [34][35][36][37] it significantly enhances the platelet aggregating property of CG, especially at lower concentrations. 30 CG and NE2 can proteolytically cleave the integrin ␣ IIb ␤ 3 , the mediator of platelet aggregation.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory derivatives induce PU.1 down-regulation, myeloid maturation arrest, and neutropenia

Pal

Monaghan

Hassett

et al. 2010

Blood

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The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide yield high response rates in patients with multiple myeloma, but the use of IMiDs in multiple myeloma is associated with neutropenia and increased risk for venous thromboembolism (VTE) by mechanisms that are unknown. We show that IMiDs downregulate PU.1, a key transcription factor involved in granulocyte differentiation in vitro and in patients treated with lenalidomide. Loss of PU.1 results in transient maturation arrest with medullary accumulation of immature myeloid precursors and subsequent neutropenia. Accumulation of promyelocytes leads to high levels of the platelet aggregation agonist, cathepsin G stored in the azurophilic granules of promyelocytes. High levels of cathepsin G subsequently may increase the risk of VTE. To our knowledge, this is the first report investigating the underlying mechanism of IMiD-induced neutropenia and increased risk of VTE in multiple myeloma. (Blood. 2010;115:605-614) IntroductionThalidomide and its immunomodulatory derivatives (IMiDs), such as lenalidomide (CC-5013) and pomalidomide (CC-4047), represent a novel class of agents with potent activity against multiple myeloma (MM). However, the use of IMiDs has been associated with 2 major adverse effects: (1) higher incidence of neutropenia that is the most common reason for holding or termination of treatment, and (2) increased risk for venous thromboembolism (VTE) that is further amplified with combination therapy.In 2 multicenter randomized trials including 353 patients with MM, 23% of patients experienced grade 3 or 4 neutropenia. 1,2 In patients receiving pomalidomide, the rate of grade 3 or 4 neutropenia was 32% in a phase 2 trial 3 and 58% in a phase 1 trial. 4 Clinical trials on myelodysplastic syndrome have shown that the frequency of lenalidomide-induced neutropenia is dose dependent and increases with duration of treatment. 5,6 The mechanism of induction of neutropenia is unclear, especially because IMiDs are not stem cell toxic and in vitro induce the expansion of CD34 ϩ cells. 7 Previous studies have shown that thalidomide/IMiDs increase the risk of VTE in patients with MM, especially if used in combination with dexamethasone. In 2 phase 3 trials comparing lenalidomide plus dexamethasone versus dexamethasone alone, the incidence of VTE in the absence of thromboembolic prophylaxis was 4 times greater in the lenalidomide/dexamethasone group, 16% versus 4%. 1,2,8 In a phase 1 trial evaluating pomalidomide alone, in 24 patients with refractory and/or relapsed MM, 4 (17%) developed VTE without thromboembolic prophylaxis during the first year of therapy. 4 The observation that aspirin is effective in preventing IMiD-induced VTE, 9 however, sharply contrasts with the lack of efficacy of aspirin in VTE prevention, suggesting that the pathogenesis in IMiD-induced VTE is different from that of "standard" VTE and, moreover, that platelet activation might contribute to thalidomide/IMiD-induced VTE.In this study, we analyzed the effect of IMiDs on granulocytic pr...

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“…The complexities involved in studying effects of neutrophils on platelets are emphasized by recent contradictory reports in the literature. These range from neutrophil promotion of platelet reactivity (2)(3)(4)(5) to neutrophil blockage of platelet responsiveness (6)(7)(8)(9)(10)(11)(12). The reasons for these differences are not completely understood, but must in part be attributable to methodology.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of human platelet reactivity by neutrophils. Participation of lipoxygenase derivatives and adhesive proteins.

Vallés¹,

Santos²,

Marcus³

et al. 1993

J. Clin. Invest.

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Unstimulated neutrophils inhibited activation and recruitment of thrombin-or collagen-stimulated platelets in an agonist-specific manner. This occurred under conditions of close physical cell-cell contact, although biochemical adhesion between the cells as mediated by P-selectin was not required. Moreover, in the presence of monoclonal P-selectin antibodies that blocked biochemical platelet-neutrophil adhesion, thrombin-stimulated platelets were more efficiently downregulated by neutrophils. This suggested a prothrombotic role for P-selectin under these circumstances. The neutrophil downregulatory effect on thrombin-stimulated platelets was amplified by lipoxygenase inhibition with 5,8,11,14-eicosatetraynoic acid. In contrast, the neutrophil inhibitory effect on platelets was markedly reduced by platelet-derived 12S-hydroxy-5,8-cis, 10-trans, 14-cis-eicosatetraenoic acid (12S-HETE), as well as by the platelet-neutrophil transcellular product, 12S,20-dihydroxy-5,8,10,14-eicosatetraenoic acid (12S,20-DiHETE), but not by another comparable metabolite, 5S,12S-dihydroxy-6-trans, 8-cis, 10-trans, 14-cis-eicosatetraenoic acid (5S,12S-DiHETE), or the neutrophil-derived hydroxy acid leukotriene B4. The neutrophil downregulatory effect on thrombin-induced platelet reactivity was enhanced by aspirin treatment. This may represent a novel action of aspirin as an inhibitor of platelet function. These results provide in vitro biochemical and functional evidence for the thromboregulatory role of neutrophils and emphasize the multicellular aspect of hemostasis and thrombosis. (J. Clin.

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Human neutrophil elastase modulates platelet function by limited proteolysis of membrane glycoproteins.

Cited by 114 publications

References 64 publications

Exposure of fibrinogen receptors in human platelets by surface proteolysis with elastase.

Exposure of fibrinogen receptors in human platelets by surface proteolysis with elastase.

Immunomodulatory derivatives induce PU.1 down-regulation, myeloid maturation arrest, and neutropenia

Downregulation of human platelet reactivity by neutrophils. Participation of lipoxygenase derivatives and adhesive proteins.

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