Fibrinogen degradation products generation is the major determinant of platelet inhibition induced by plasminogen activators in platelet-rich plasma

Parise, P; Hauert, J; Iorio, Alfonso; Callegari, P.; Nenci, Giuseppe G.

doi:10.1016/0268-9499(93)90062-z

Cited by 8 publications

(4 citation statements)

References 26 publications

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“…This hypoaggregability can be ascribed to a rapid degradation of the fibrinogen present in plasma or secreted by platelets, which may also generate inhibitory FDPs (6-10, 35, 36). However, when fibrinogen levels are returned to normal and FDPs disappear, a normal or even increased platelet aggregability can be observed (6)(7)(8)(9)(10)36). Taken as a whole, these data led us to investi gate what the biological activity of the fibrinogen receptor, the a IIb(33 integrin, would be on strongly activated, but yet nonaggregated plas min-treated platelets, with special emphasis placed on the hypothesis that activation of the receptor may be sustained over time, as suggested by two previous reports (22,28).…”

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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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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“…In vivo, inhibitory effects of plasminogen activators on platelet responses may be partially attributable to fibrinogen degradation products (22)(23)(24)(25)(26) which could bind GPIIbLIIa, but it seems likely that proteolysis of the thrombin receptor on platelets would also play a part in their reduced responsiveness to thrombin.…”

Section: Resuspension In Plasmamentioning

confidence: 99%

“…The effects of plasmin on platelets are influenced by its concentration (1 1, 19), and the time and temperature of incubation of the platelets with plasmin (20). Donor-to-donor variations have also been reported (21), In plasma, the observed inhibition of platelet aggregation by plasmin or plasminogen activators has been attributed mainly to the effects of fibrinogenolysis and fibrinogen degradation products (22)(23)(24)(25)(26), but these changes do not account for its inhibitory effects in artificial media.…”

Section: Introductionmentioning

confidence: 99%

Pretreatment of Human Platelets with Plasmin Inhibits Responses toThrombin, but Potentiates Responses to Low Concentrations of Aggregating Agents, Including the Thrombin Receptor Activating Peptide, SFLLRN

et al. 1997

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SummaryEffects of plasmin on platelets, that influence subsequent responses to aggregating agents, are relevant to attempts to prevent rethrombosis following administration of fibrinolytic agents. We describe plasmin-induced inhibition of platelet responses to thrombin, but potentiation of responses to other aggregating agents. Washed human platelets were labeled with 14C-serotonin, treated for 30 min at 37° C with 0, 0.1 or 0.2 CU/ml of plasmin, followed by aprotinin, washed and resuspended in a Tyrode-albumin solution with apyrase. Incubation with 0.2 CU/ml of plasmin almost completely inhibited thrombin-induced (0.1 U/ml) aggregation, release of 14C-serotonin, and increase in cytosolic [Ca2+]. In contrast, with plasmin-pretreated platelets, aggregation and release of 14C-serotonin were strongly potentiated in response to low concentrations of the thrombin receptor-activating peptide SFLLRN, ADP, platelet-activating factor, collagen, arachidonic acid, the thromboxane mimetic U46619, and the calcium ionophores A23187 and ionomycin. Aspirin or RGDS partially inhibited potentiation. Plasmin-pretreated platelets resuspended in plasma anticoagulated with FPRCH2C1 (PPACK) also showed enhanced responses to aggregating agents other than thrombin. The contrasting effects on responses to thrombin and SFLLRN are noteworthy. Plasmin cleaves GPIIb/IIIa so that it becomes a competent fibrinogen receptor, and binding of 125I-fibrinogen during ADP-induced aggregation was greatly potentiated within 10 s. Potentiation of aggregation by other agonists may be due to increased binding of released fibrinogen. Thus, platelets freed from a thrombus may have increased responsiveness to low concentrations of aggregating agents other than thrombin. These results provide further support for the use of inhibitors of platelet reactions in conjunction with administration of fibrinolytic agents.

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“…Frequent episodesofketosis, resulting from severe insulin deficiency(1) coupledwith aconcomitant rise in counter-regulatory hormones (2),a re relevant determinants of vasculard isease, morbidity and mortality in poorlycontrolled or uncontrolled patients with diabetes mellitus (DM) (3)(4)(5).Clinical studieshave identifiedav arietyofh yperglycaemia-related abnormalities in haemostasis, whichc ould contribute to the development of thrombosis in DM (6)(7)(8). In short, these changes consist of:high plasma levels of several coagulation factors (9), impairedfibrinolysis (10)and endothelial dysfunction (11) as well as platelet hyperactivation (12)(13). Moreover, there is proof thatimpaired haemostatic balanceoften precedes anyevident vascularcomplication and is likelytobeassociatedwith an increased oxidative stress (14)(15)(16)(17).H ypercoagulability, leading to ap rothrombotic tendency, has also beenobservedindiabetic patients with overt ketoacidosis (18).However,nodataisa vailableregarding haemostatic systemchange during the earlyphasesofketoacidosis.…”

Section: Introductionmentioning

confidence: 99%

Impaired endothelial antithrombotic activity following short-term interruption of continuous subcutaneous insulin infusion in type1 diabetic patients

Iorio¹,

Federici²,

Mourvaki³

et al. 2007

Thromb Haemost

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SummaryReview of literature has shown an increased rate of thrombotic complications in diabetic patients with frequent episodes of hyperketonemia. However, the mechanisms by which ketosis promotes vascular disease in diabetic patients are unclear.It was the aim of this study to investigate early changes in haemostatic parameters and oxidative stress markers during the hyperketonemic status which follows the interruption of continuous subcutaneous insulin infusion (CSII) in type I diabetic patients. Eight CSII-treated type I diabetic patients underwent a 4-hour pump arrest. Blood glucose, insulin and 3-hydroxybutirate were measured to verify the metabolic response. A vein-occlusive (VO) test was performed for the determination of tPA and PAI-1 activities and their antigen levels before and after the CSII arrest. Coagulation factor VII and VIII were evaluated by one-stage PT and PTT method, respectively.TF, vWF, tPA and PAI-1 antigens were determined by ELISA, whereas tPA and PAI-1 activities using chromogenic methods. Plasma malondialdehyde (MDA) and protein carbonyl groups (PCG) levels were determined by HPLC and spectrophotometry, respectively. After the insulin deprivation phase, post-VO tPA antigen level significantly decreased (P=0.0391), whereas TF and post-VO PAI-1 activity and antigen levels significantly increased (P=0.0156 and P=0.0234, respectively). Plasma MDA and PCG levels were 1.88-fold and 1.74-fold higher than baseline values, respectively. In conclusion, the impairment of the fibrinolytic potential and the increases in TF, MDA and PCG levels may enhance the risk of both arterial and venous thrombosis during ketosis.Thus, early detection of hyperketonemia in DM patients could contribute to the prevention of life-threatening vascular events.

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Fibrinogen degradation products generation is the major determinant of platelet inhibition induced by plasminogen activators in platelet-rich plasma

Cited by 8 publications

References 26 publications

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

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

Pretreatment of Human Platelets with Plasmin Inhibits Responses toThrombin, but Potentiates Responses to Low Concentrations of Aggregating Agents, Including the Thrombin Receptor Activating Peptide, SFLLRN

Impaired endothelial antithrombotic activity following short-term interruption of continuous subcutaneous insulin infusion in type1 diabetic patients

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