Interactions between thrombolytic agents and platelets: Effects of plasmin on platelet glycoproteins Ib and IIb/IIIa

Hoffmann, J. J. M. L.; Janssen, W C M

doi:10.1016/0049-3848(92)90075-l

Cited by 15 publications

(6 citation statements)

References 22 publications

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“…Instead, plasmin might have cleaved platelet surface receptors important for adhesion. Supporting this, plasmin has been shown to severely impair the functional integrity of, for example, platelet surface glycoproteins Ib and IIb/IIIa [ 56 ]. All in all, we propose that impaired control over thrombus growth either through diminished fibrinolysis [ 9 ] or enhanced platelet aggregation explains the newly described link between lack of plasminogen and aHUS.…”

Section: Discussionmentioning

confidence: 99%

Minor Role of Plasminogen in Complement Activation on Cell Surfaces

Hyvärinen

Jokiranta

2015

PLoS ONE

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Atypical hemolytic uremic syndrome (aHUS) is a rare, but severe thrombotic microangiopathy. In roughly two thirds of the patients, mutations in complement genes lead to uncontrolled activation of the complement system against self cells. Recently, aHUS patients were described with deficiency of the fibrinolytic protein plasminogen. This zymogen and its protease form plasmin have both been shown to interact with complement proteins in the fluid phase. In this work we studied the potential of plasminogen to restrict complement propagation. In hemolytic assays, plasminogen inhibited complement activation, but only when it had been exogenously activated to plasmin and when it was used at disproportionately high concentrations compared to serum. Addition of only the zymogen plasminogen into serum did not hinder complement-mediated lysis of erythrocytes. Plasminogen could not restrict deposition of complement activation products on endothelial cells either, as was shown with flow cytometry. With platelets, a very weak inhibitory effect on deposition of C3 fragments was observed, but it was considered too weak to be significant for disease pathogenesis. Thus it was concluded that plasminogen is not an important regulator of complement on self cells. Instead, addition of plasminogen was shown to clearly hinder platelet aggregation in serum. This was attributed to plasmin causing disintegration of formed platelet aggregates. We propose that reduced proteolytic activity of plasmin on structures of growing thrombi, rather than on complement activation fragments, explains the association of plasminogen deficiency with aHUS. This adds to the emerging view that factors unrelated to the complement system can also be central to aHUS pathogenesis and suggests that future research on the mechanism of the disease should expand beyond complement dysregulation.

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Section: Discussionmentioning

confidence: 99%

Minor Role of Plasminogen in Complement Activation on Cell Surfaces

Hyvärinen

Jokiranta

2015

PLoS ONE

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“…Follow ing this protocol, we observed that plasmin-treated platelets exhibit a marked capacity to aggregate when stirred with intact fibrinogen in the range 1 to 1.5 mg/ml, and that this aggregability is maximum for pre-incubation of 20 min with plasmin activities in the range 0.25 to 0.75 CU/ml. Such activities are readily attainable in v itr o in a plasma milieu in which plasminogen has been converted into plasmin by addi tion of pharmacological concentrations of PA (9,20,37,38), and have been recently reported to be detectable in the plasma of patients under going thrombolytic therapy (39). This aggregability is clearly depen dent on the availability of the a IIb(33 integrin, as indicated by the potent inhibition observed with the monoclonal antibody AP2, the divalent cation chelator EDTA, and the peptide GRGDS.…”

Section: Discussionmentioning

confidence: 99%

Exposure of Human Platelets to Plasmin Results in the Expression of Irreversibly Active Fibrinogen Receptors

Rabhi-Sabile

Pidard

1995

Thromb Haemost

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SummaryAlthough plasmin can trigger strong platelet responses such as shape change and exocytosis of internal granules, limited platelet aggregation is induced by this proteinase, owing to its capacity to rapidly proteolyse secreted adhesive proteins. In this context, we have investigated the state of activation of the fibrinogen receptor, the integrin αIIbβ3, on platelets exposed to plasmin. Following incubation with plasmin at 37 °C, washing, and resuspension, platelets exhibit a moderate, low-velocity aggregation when stirred in the presence of fibrinogen. Optimum aggregability is observed when platelets have been exposed to plasmin activity of ≈0.5 CU/ml for 20 min, and aggregation is insensitive to the presence of antagonists such as prostaglandin (PG) E1 and apyrase. Plasmin-induced platelet aggregability is associated with the expression of active fibrinogen receptors on the cell surface, which, using a l25I-fibrinogen binding assay, can be quantified to ≈2,300 molecules per platelet. Exposure of active αIIbβ3 receptors appears to depend partially, but not totally on a metabolic activation and granule exocytosis at the time of incubation with plasmin. In contrast with a-thrombin, plasmin-induced activation of αIIbβ3 is sustained and cannot be reversed by exposure of platelets to PGE1. Immunoblotting analysis of the receptor subunits shows no extensive proteolytic modification of αIIbβ3 by plasmin, and only reveals a limited proteolysis of the aminoterminal domain of the αIIb subunit. In addition to their capacity to aggregate in the presence of fibrinogen alone, plasmin-treated platelets also show a potentiated aggregability in response to low doses of ADP. Thus, plasmin has the potential to activate the platelet fibrinogen receptor in such a way that it remains irreversibly available to fibrinogen on the surface of nonaggregated cells, a feature that may participate to pathological states of in vivo platelet hyperaggregability.

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“…The benefit of thrombolytic therapy for myocardial infarction (MI) with plasminogen activators is at present limited by the relatively high incidence of reocclusion and resistance to reperfusion despite anticoag- ulation with heparin (1,2). There is evidence that both events are medi ated by an increased procoagulant activity resulting from plasmin gen eration and from continued thrombin formation as evidenced by elevat ed plasma fibrinopeptide A-or thrombin-antithrombin levels in patients with myocardial infarction (3,4,5). Another important factor respon sible for resistance against reperfusion are platelet aggregates develop ing as a result of shear stress in areas of vascular injury and disturbed blood flow.…”

Section: Introductionmentioning

confidence: 99%

Prevention of Early Reocclusion after Thrombolysis of Copper Coil-induced Thrombi in the Canine Carotid Artery: Comparison of PEG-Hirudin and Unfractionated Heparin

Rübsamen¹,

Hornberger²

1996

Thromb Haemost

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SummaryCofactor-independent thrombin inhibitors as adjunctive treatment to thrombolysis have been found to enhance reperfusion and reduce the incidence of early reocclusion more effectively than heparins. However, all thrombin inhibitors presently available are rapidly cleared from the circulation which may cause rebound effects after cessation of treatment. To evaluate the effect of PEG-hirudin (LU 87981) a new, long acting derivative of hirudin as adjunctive treatment to rt-PA, a thrombotic occlusion of the carotid artery was induced in mongrel dogs by means of a copper coil. Vessel patency was continuously monitored with an electromagnetic flow probe. Thrombolysis of the occluded artery was induced by administration of 40 Μg × kg−1 + 240 Μg × kg−1 × h−1 rt-PA (low dose) or 80 Μg × kg−1 + 480 Μg × kg−1 × h−1 rt-PA (high dose). With high dose rt-PA treatment, patency was achieved in all animals within 50 min (range 24 to 75), with low dose rt-PA treatment only in 6 out of 8 animals after 73 min (range 26 to 117). Concomitant administration of PEG-hirudin (0.3 mg × kg−1 bolus + 0.15 mg × kg−1 × h−1 infusion) increased the incidence of reperfusion in the low dose rt-PA group to 100% while the reperfusion time was shortened from 73 min in the corresponding control group to 38 min (range 20 to 75 min) in the group given PEG-hirudin (p = 0.065, Mann-Whitney U-test). The carotid artery blood flow, which rapidly declined to zero within 18 to 27 min after discontinuing low or high dose rt-PA infusions remained at a sustained level for the whole observation period of 4 h only in the group given PEG-hirudin. Only one animal reoccluded after 229 min. Unfractionated heparin (UFH) given at a dose of 0.3 mg × kg−1 bolus + 0.3 mg × kg−1 × h−1 infusion did not improve the incidence of reperfusion or lower the incidence of reocclusion. Buccal bleeding time was prolonged after high dose rt-PA treatment and after low dose rt-PA with adjunctive UFH- or PEG-hirudin treatment. Buccal blood loss was not significantly affected by either treatment.In conclusion, these experiments indicate that early reocclusion after thrombolysis can effectively be diminished by concomitant treatment with the long acting thrombin inhibitor PEG-hirudin with moderate effects on bleeding time and aPTT.

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Interactions between thrombolytic agents and platelets: Effects of plasmin on platelet glycoproteins Ib and IIb/IIIa

Cited by 15 publications

References 22 publications

Minor Role of Plasminogen in Complement Activation on Cell Surfaces

Minor Role of Plasminogen in Complement Activation on Cell Surfaces

Exposure of Human Platelets to Plasmin Results in the Expression of Irreversibly Active Fibrinogen Receptors

Prevention of Early Reocclusion after Thrombolysis of Copper Coil-induced Thrombi in the Canine Carotid Artery: Comparison of PEG-Hirudin and Unfractionated Heparin

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