Search PubMed⌕ Search

Biomedical subjects

M Gawaz

Publications and source records attributed to M Gawaz.

At least 37 records · Page 2Linked to original sources
PubMed2000

Incomplete inhibition of platelet aggregation and glycoprotein IIb-IIIa receptor blockade by abciximab: importance of internal pool of glycoprotein IIb-IIIa receptors.

Resting platelets contain a substantial internal pool of GPIIb-IIIa complexes that is exposed on the surface of activated platelets. Whether the exposure of internal GPIIb-IIIa complexes on the activated platelet surface affects therapy with GPIIb-IIIa antagonists is poorly understood. We addressed this issue in thirteen patients who underwent elective coronary stenting and received abciximab. Platelet aggregation, surface expression of GPIIb-IIIa and P-selectin, receptor blockade of GPIIb-IIIa, and platelet release in response to ADP and thrombin-receptor activating peptide (TRAP) were determined ex vivo by Lumi-aggregometry and flow cytometry before, during and after abciximab administration. We found that inhibition of aggregation and GPIIb-IIIa blockade of ADP-stimulated platelets was almost complete during abciximab administration. In contrast, when TRAP was used to stimulate platelets ex vivo aggregation was only partially inhibited, most likely due to release of internal pool of unblocked GPIIb-IIIa complexes. Using electron microscopy we found that 7E3-occupied GPIIb-IIIa complexes are internalized into the surface connected system (SCS) and the alpha-granules of washed platelets which was associated with a reduced degranulation of the alpha-granula membrane protein P-selectin. We conclude, that despite internalization of abciximab into the internal pool of GPIIb-IIIa, upon strong platelet activation with thrombin a significant amount of unblocked internal GPIIb-IIIa can be exposed on the platelet surface and mediate platelet aggregation. Incomplete blockade of the internal GPIIb-IIIa pool may limit clinical efficacy of abciximab.

Abciximab↗
PubMed1999

Polymorphism of platelet glycoprotein IIb and risk of thrombosis and restenosis after coronary stent placement.

Both glycoprotein (GP) IIb and IIIa of platelet fibrinogen receptor are polymorphic proteins. Unlike GPIIIa, there is little information about the clinical significance of the GPIIb polymorphism. We designed this prospective study to assess whether patients with the human platelet antigen (HPA)-3 polymorphism of GPIIb are more susceptible to developing thrombosis and restenosis after coronary stent placement. We included 2,178 consecutive patients with coronary artery disease who underwent intracoronary stent implantation, 789 (36.2%) with HPA-3a/a, 1,023 (47.0%) with HPA-3a/b, and 366 (16.8%) with HPA-3b/b genotype. The incidence of stent thrombosis was 1.7% in HPA-3a/a, 1.7% in HPA-3a/b, and 1.6% in HPA-3b/b patients (p = 0.999). The incidence of stent restenosis was 37.3% in HPA-3a/a, 36.2% in HPA-3a/b, and 34.6% in HPA-3b/b patients (p = 0.724). Event-free survival 1 year after stent placement was 76.1% for HPA-3a/a, 76.5% for HPA-3a/b, and 76.4% for HPA-3b/b patients (p = 0.968). We conclude that the HPA-3 polymorphism of platelet GPIIb is not associated with an increase in the risk of thrombosis and restenosis over 1 year after coronary stent placement. These data indicate that unlike the HPA-1 polymorphism of GPIIIa, the HPA-3 polymorphism of GPIIb may not serve as a useful genetic marker for the risk assessment of patients treated with intracoronary stenting.

Adult↗
PubMed1999

Effect of glycoprotein IIb/IIIa receptor blockade on platelet-leukocyte interaction and surface expression of the leukocyte integrin Mac-1 in acute myocardial infarction.

OBJECTIVES: This prospective randomized study investigated platelet-induced upregulation of Mac-1 on monocytes and its inhibition by glycoprotein (GP) IIb/IIIa blockage in patients with acute myocardial infarction (AMI). BACKGROUND: In experimental AMI, Mac-1 on leukocytes is the pivotal adhesion molecule for detrimental inflammatory responses. In vitro, platelet adhesion to monocytes upregulates Mac-1. METHODS: Patients undergoing stenting in AMI within 48 h after onset of symptoms were randomly assigned to receive either standard-dose heparin (n = 50) or abciximab plus low-dose heparin (n = 50). In serial blood samples, we assessed platelet-monocyte interaction and Mac-1 surface expression by triple color immunofluorescence flow cytometry. RESULTS: Compared with platelet-negative monocytes, Mac-1 surface expression on monocytes with attached platelets was upregulated (median fluorescence intensity [interquartile range]: 259 [179 to 367] vs. 135 [78 to 195] arbitrary units, p < 0.001). As an indicator of platelet-monocyte interaction, mean fluorescence of the platelet marker GP Ib alpha in the monocytes population decreased after abciximab, although it remained unaffected by heparin alone. Abciximab achieved this effect by a reduction in platelet mass attached to monocytes (GP Ib alpha fluorescence intensity of heterotypic aggregates at 24 h [arbitrary units]: 187 [143 to 236] after abciximab vs. 228 [156 to 332] after heparin, p = 0.02), whereas it did not affect the percentage of monocytes with adherent platelets. Reduction of platelet-monocyte interaction resulted in decreased Mac-1 surface expression (fluorescence intensity at 24 h [arbitrary units]: 116 [68 to 153] after abciximab vs. 162 [117 to 239] after heparin, p = 0.001). CONCLUSIONS: In patients with AMI, platelet-leukocyte interactions modulate Mac-1 expression on monocytes. Glycoprotein IIb/IIIa blockade is a therapeutic option to interfere with this mechanism.

Abciximab↗
PubMed1998

Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction.

BACKGROUND: Apart from its established effects on vessel patency after percutaneous coronary revascularization, glycoprotein IIb/IIIa receptor blockade by abciximab may improve myocardial perfusion by inhibition of the interaction of platelets and platelet aggregates with the microvasculature. We investigated the effect of abciximab with stent placement in acute myocardial infarction. METHODS AND RESULTS: In a prospective randomized trial, patients undergoing stenting in acute myocardial infarction within 48 hours after onset of symptoms were randomly assigned to receive either standard-dose heparin or abciximab plus low-dose heparin. Immediately after the procedure and at 14-day angiographic follow-up, we assessed flow velocity in the recanalized vessel with the Doppler wire and regional wall motion by the centerline method. End points were changes in papaverine-induced peak flow velocities and in wall motion indices. We assigned 98 patients to standard heparin and 102 to abciximab. We obtained 152 paired flow measurements and 151 paired left ventricular function studies. Residual stenoses of the treated lesions did not differ between the 2 groups. Improvement of peak flow velocity (mean [95% CI]: 18.1 cm/s [13.6 to 22.6 cm/s], n=80, versus 10.4 cm/s [5.4 to 15.4 cm/s], n=72, P=0.024) and wall motion index (0.44 SD/chord [0.29 to 0.59 SD/chord], n=79 versus 0. 15 SD/chord [0.00 to 0.30 SD/chord], n=72, P=0.007) was significantly greater in patients assigned to abciximab than in those on heparin alone. At follow-up, the abciximab group had a higher global left ventricular ejection fraction than the heparin group (62% [59% to 65%] versus 56% [53% to 59%], P=0.003). CONCLUSIONS: Abciximab had important effects beyond the maintenance of large-vessel patency. It improved the recovery of microvascular perfusion and concomitantly enhanced the recovery of contractile function in the area at risk.

Abciximab↗
PubMed1998

Procoagulant inflammatory responses of monocytes after direct balloon angioplasty in acute myocardial infarction.

This study sought to investigate monocyte procoagulant activity and Mac-1 expression after successful percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction (AMI). An increased leukocyte count is an important risk factor for subsequent adverse cardiac events in AMI. Cellular procoagulant responses may contribute to the risk of thrombotic events after AMI. In 20 patients with AMI serial venous blood samples were obtained before, 4, 8 hours, and daily after direct PTCA. Twenty patients with elective PTCA served as a control group. We measured leukocyte procoagulant activity with a 1-stage clotting assay, Mac-1 expression of monocytes by flow cytometry, concentrations of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and IL-8 using immunoassays. Forty-eight hours after PTCA in patients with AMI, an increase in systemic IL-6 and C-reactive concentrations was found (p = 0.001, p = 0.008) associated with an increase in monocyte Mac-1 expression by 49 +/- 18% (p = 0.04) and followed by an increase in monocyte procoagulant activity by 140 +/- 63% 72 hours after PTCA (p = 0.01). None of these changes were detectable in the control group. No changes in the concentrations of the cytokines IL-1beta, tumor necrosis factor-alpha, or IL-8 were found. The present study demonstrates an increase in procoagulant activity along with an increase in Mac-1 expression on circulating monocytes after successful PTCA in AMI associated with an increase in systemic IL-6. These cellular procoagulant responses may limit the clinical benefit from timely reperfusion.

Aged↗
PubMed1998

Changes in platelet membrane glycoproteins before bone marrow transplantation and after engraftment--a pilot study.

Thrombotic complications are observed in patients undergoing bone marrow transplantation despite thrombocytopenia and impaired coagulation due to liver function disturbances. Endothelial cell damage which is involved in the pathogenesis of major transplant related complications like graft-versus-host disease, veno-occlusive disease, sepsis or microangiopathy may be a contributing factor. Little is known about platelet function in bone marrow transplant recipients. In order to study functional alterations in circulating platelets we investigated unstimulated and ADP-stimulated platelets of 10 bone marrow transplant recipients ex vivo by flow cytometry in a pilot study using a panel of monoclonal antibodies to characterize changes in membrane glycoproteins. Samples were collected before and during conditioning and at three timepoints after engraftment. 10 healthy volunteers served as controls. Platelets of bone marrow transplant recipients showed partly a significant, higher expression of surface bound fibrinogen, activated fibrinogen receptor, and glycoprotein Ib as compared to controls. P-selectin, a marker of platelet degranulation was significantly elevated after ADP-induced stimulation at all timepoints compared to controls. Only marginal differences were found for GP IIb/IIIa surface expression. The data point to an increased platelet activation state in bone marrow transplant recipients which might contribute to the thrombotic phenomena observed in these patients.

Adenosine Diphosphate↗
PubMed1998

Activated platelets induce monocyte chemotactic protein-1 secretion and surface expression of intercellular adhesion molecule-1 on endothelial cells.

BACKGROUND: Platelet/endothelium interaction plays an important role in the pathophysiology of inflammation and atherosclerosis. The role of platelets for monocyte chemotactic protein-1 (MCP-1) secretion and surface expression of intercellular adhesion molecule-1 (ICAM-1) on endothelial cells has been assessed. METHODS AND RESULTS: Monolayers of human umbilical vein endothelial cells were incubated with nonstimulated or ADP-activated platelets for 6 hours, and secretion of MCP-1 and surface expression of ICAM-1 were determined by ELISA and flow cytometry, respectively. In the presence of ADP-activated platelets, both MCP-1 secretion and ICAM-1 surface expression were significantly increased compared with nonstimulated platelets (P<0.02). Activation of the transcription factor nuclear factor-kappaB (NF-kappaB) determined by electrophoretic mobility shift assay and kappaB-dependent transcriptional activity was enhanced in the presence of activated platelets. In addition, ADP-activated platelets induced MCP-1 and ICAM-1 promoter-dependent transcription. Liposomal transfection of a double-stranded kappaB phosphorothioate oligonucleotide, but not of the mutated form, inhibited MCP-1 secretion and surface expression of ICAM-1 on activated endothelium (P<0.05). CONCLUSIONS: The present study indicates that activated platelets modulate chemotactic (MCP-1) and adhesive (ICAM-1) properties of endothelial cells via an NF-kappaB-dependent mechanism. Platelet-induced activation of the NF-kappaB system might contribute to early inflammatory events in atherogenesis.

Arteriosclerosis↗
PubMed1998

Effect of glycoprotein IIb-IIIa receptor antagonism on platelet membrane glycoproteins after coronary stent placement.

Platelet membrane glycoproteins play a crucial role in ischemic complications after coronary stenting. Glycoprotein IIb-IIIa blockade reduces adverse clinical events after angioplasty but is associated with rare but profound thrombocytopenia that might increase hemorrhagic complications. Changes in platelet membrane glycoproteins of patients with angina who underwent coronary stenting and were treated with the GPIIb-IIIa antagonist abciximab (n=20) or with heparin (n=23) were studied. GPIb-IIIa receptor blockade and membrane glycoproteins were evaluated with immunological markers in venous blood samples taken before. 10, 24, 48, 72, and 96 h after initial treatment with either abciximab or heparin. Patients receiving abciximab therapy showed a rapid inhibition of binding of fluorochrome-conjugated mAb CD41 and c7E3 concomitant with a reduction in platelet aggregation which was restored in part in the days after termination of abciximab infusion. Induction of ligand-induced binding sites on GPIIb-IIIa was increased in patients receiving abciximab. The expression of ligand-induced binding sites correlated inversely with platelet count. No significant change in platelet membrane markers were found in the heparin group. In vitro studies showed that abciximab induces ligand-induced binding sites on isolated platelets and on nuclear cells bearing recombinant GPIIb-IIIa. Abciximab rapidly achieves GPIIb-IIIa receptor blockade after coronary stent placement that might be beneficial in high-risk settings to bridge the delayed action of ticlopidine. Significant alterations of platelet membrane glycoproteins during GPIIb-IIIa antagonism might contribute to development of acute profound thrombocytopenia.

Abciximab↗
PubMed1997

Recovery of myocardial perfusion in acute myocardial infarction after successful balloon angioplasty and stent placement in the infarct-related coronary artery.

OBJECTIVES: This study sought to investigate changes in myocardial perfusion after direct percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction (MI). BACKGROUND: After initially successful recanalization of the infarct-related artery, coronary perfusion may deteriorate as a result of reocclusion, distal embolization of platelet aggregates formed at the dilated plaque or microvascular reperfusion injury. This change could offset the benefit from early intervention. METHODS: The study included 19 patients in whom the infarct-related artery was successfully recanalized by PTCA with Palmaz-Schatz stent placement within 24 h after the onset of pain. Basal and papaverine-induced coronary blood flow were assessed by Doppler flow velocity measurements and quantitative coronary angiography. In addition, basal and adenosine-induced myocardial blood flow were measured by nitrogen-13 ammonia positron emission tomography (PET). RESULTS: Immediately after completion of the intervention, the average coronary flow reserve (CR) in the recanalized vessel was 1.56 +/- 0.51; it increased to 2.04 +/- 0.65 at 1 h (p = 0.013) and to 2.66 +/- 0.72 at 2 weeks after reperfusion (p = 0.008, n = 16). PET studies in 12 patients revealed that perfusion defect size and CR in the infarct region (2.19 +/- 0.89 vs. 2.33 +/- 0.86) did not change significantly between day 2 after recanalization and 2 weeks. However, we found significant (p < 0.03) increases in basal (by 26%) and adenosine-induced (by 40%) blood flow in the infarct region. CONCLUSIONS: Despite the persistence of a perfusion defect after successful recanalization of the occluded artery in acute MI, CR of the infarct region improves in most patients within 1 h and further improves within 2 weeks.

Adult↗
PubMed1997

Vitronectin receptor (alpha(v)beta3) mediates platelet adhesion to the luminal aspect of endothelial cells: implications for reperfusion in acute myocardial infarction.

BACKGROUND: Platelet interaction with endothelium plays an important role in the pathophysiology of coronary microcirculation. We assessed the role of the vitronectin receptor (integrin alpha(v)beta3) in platelet/endothelium adhesion. METHODS AND RESULTS: We investigated the effect on platelet/endothelium adhesion of plasma obtained from patients with acute myocardial infarction during reperfusion (before and 8, 24, 48, and 72 hours and 5 to 7 days after direct angioplasty) and with pretreatment with alpha-thrombin (2 U/mL) and recombinant human interleukin-1beta. Platelet/endothelium adhesion was significantly enhanced by approximately 20% after pretreatment of endothelium with patient plasma for 4 hours (P<.05) compared with endothelium treated with pooled control plasma. Plasma-induced platelet/endothelium adhesion was, in part, RGD peptide dependent. Pretreatment of endothelial cells with alpha-thrombin or recombinant human interleukin-1beta enhanced platelet/endothelium adhesion and surface expression of alpha(v)beta3 on the luminal aspect of endothelium (P<.05). The adhesion of platelets, isolated platelet microparticles, and Chinese hamster ovary cells bearing human recombinant alpha(IIb)beta3 (platelet glycoprotein IIb-IIIa) to activated endothelial cells was inhibited by antiadhesive peptides GRGDSP and c(RGDfV) and monoclonal antibodies 4F10, LM609, and 7E3. CONCLUSIONS: The expression of vitronectin receptor exposed on the luminal aspect of activated endothelium is enhanced and mediates platelet/endothelium adhesion. Vitronectin receptor-mediated platelet attachment to activated endothelium during reperfusion may contribute to reperfusion injury and could be a target for antiadhesive therapy.

Adult↗
PubMed1997

Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets.

BACKGROUND: Activated platelets tether and activate myeloid leukocytes. To investigate the potential relevance of this mechanism in acute myocardial infarction (AMI), we examined cytokine induction by leukocyte-platelet adhesion and the occurrence of leukocyte-platelet conjugates in patients with AMI. METHODS AND RESULTS: We obtained peripheral venous blood samples in 20 patients with AMI before and daily for 5 days after direct percutaneous transluminal coronary angioplasty (PTCA) and in 20 patients undergoing elective PTCA. Throughout the study period, CD41 immunofluorescence of leukocytes (flow cytometry) revealed increased leukocyte-platelet adhesion in patients with AMI compared with control patients (mean +/- SE of fluorescence [channels] before PTCA: 77 +/- 16 versus 35 +/- 9; P = .003). In vitro, thrombin-stimulated fixed platelets bound to neutrophils and monocytes. Within 2 hours, this resulted in increased mRNA for interleukin (IL),1 beta, IL-8, and monocyte chemoattractant protein (MCP)-1 in unfractionated leukocytes. After 4 hours, IL-1 beta and IL-8 concentration of the cell-free supernatant had increased by 268 +/- 36% and 210 +/- 7%, respectively, and cellular MCP-1 content had increased by 170 +/- 8%. Addition of activated platelets to adherent monocytes had a similar effect and was associated with nuclear factor-kappa B activation. Inhibition of binding by anti-P selectin antibodies reduced the effect of activated platelets on cytokine production. CONCLUSIONS: In patients with AMI, leukocyte-platelet adhesion is increased. Binding of activated platelets induces IL-1 beta, IL-8, and MCP-1 in leukocytes. Our findings suggest that leukocyte-platelet adhesion contributes to the regulation of inflammatory responses in AMI.

Adult↗
PubMed1997

Platelet function in septic multiple organ dysfunction syndrome.

OBJECTIVE: Altered platelet function plays a role in the pathophysiology of multiple organ failure in sepsis. The purpose of the present study was to evaluate various aspects of platelet adhesive function in septic patients and its putative relevance for prognosis. DESIGN: Prospective clinical study. SETTING: Intensive Care Unit of the University Hospital. PATIENTS AND METHODS: A total of 41 patients admitted to the medical Intensive Care Unit were studied. On the day of admission, patients were evaluated by intensive care scoring systems (Elebute, APACHE II) to assess the severity of sepsis and multiple organ dysfunction syndrome (MODS), and platelet function tests were performed. All patients were observed for 28 days to assess their clinical outcomes. Eleven patients revealed septicemia without MODS (Elebute > or = 12, APACHE II < 20) and 20 septic patients suffered from MODS (Elebute > or = 12, APACHE II > or = 20). Ten non-septic patients without MODS served as a control group (Elebute < 12, APACHE II < 20). Flow cytometric determination of the activated fibrinogen (fg) receptor GPIIb-IIIa and as well as thrombospondin (TSP) on platelets and platelet-neutrophil adhesion (CD 41 immunofluorescence) ex vivo was performed using monoclonal antibodies. The effect of plasma obtained from patients on normal platelet aggregation in vitro, and adhesion to cultured endothelial cells was evaluated. RESULTS: The surface expression of TSP on platelets was increased in septic patients with MODS compared to controls (p < 0.03). Platelet-neutrophil adhesion was not significantly altered in septicemia (p < 0.09) but decreased significantly in the presence of MODS (p < 0.05) when compared to controls. Logistic regression analysis showed that platelet-neutrophil adhesion was an independent predictor for poor clinical outcome (p < 0.01). Plasma from septic patients sensitized normal platelets to hyperaggregate and to adhere to cultured endothelium (p < 0.01). CONCLUSION: In septic patients platelets become activated and are hyperadhesive to other vascular cells including neutrophils and endothelium. This may induce sequestration of platelets and microcirculatory arrest, thus the development of MODS.

APACHE↗
PubMed1997

Antiplatelet effect of ticlopidine after coronary stenting.

OBJECTIVES: This study sought to investigate the contribution of ticlopidine to the inhibition of platelet activation after coronary stent placement. BACKGROUND: After coronary stenting, antiplatelet therapy with aspirin and ticlopidine improves stent patency compared with anticoagulation. However, the specific role of ticlopidine has not been elucidated. METHODS: After successful coronary stent placement, we randomized 22 patients to receive ticlopidine and aspirin (ticlopidine group) and 25 to receive aspirin alone (aspirin group). Surface expression on platelets of the activated fibrinogen receptor and of P-selectin was assessed by flow cytometry. RESULTS: In the aspirin group the percent of platelets with activated fibrinogen receptors increased between days 1 and 5 (p = 0.001), whereas there were no substantial changes in the ticlopidine group. The percent of P-selectin-positive platelets did not change significantly in the aspirin group but decreased in the ticlopidine group (p = 0.019). At day 5 after the intervention, the percent of platelets with activated fibrinogen receptors in the ticlopidine group was significantly lower (median [interquartile range]: 8.5 [3.1 to 17.8] vs. 18.1 [8.5 to 35.5], p = 0.025), and there was a trend to fewer P-selectin-positive platelets than in the aspirin group (5.8 [3.4 to 9.5] vs. 8.8 [4.0 to 15.8], p = 0.073). CONCLUSIONS: Combined antiplatelet therapy with ticlopidine plus aspirin is superior to treatment with aspirin alone in suppressing platelet activation after coronary stenting.

Aged↗
PubMed1997

Induction of cytokine expression in leukocytes in acute myocardial infarction.

OBJECTIVES: This study sought to investigate whether cytokine expression in leukocytes may be induced by plasma from the reperfused heart of patients with an acute myocardial infarction (MI). BACKGROUND: Reperfusion in acute MI is associated with deleterious local and systemic inflammatory responses that are regulated by cytokines. Induction of cytokine expression in resident leukocytes could contribute to inflammatory responses of the ischemic and reperfused heart. METHODS: Blood samples of 10 patients with an acute MI were obtained simultaneously from the coronary sinus and the aorta before and 5 min after recanalization of the coronary occlusion. Ten patients with elective percutaneous transluminal coronary angioplasty served as a control group. We incubated leukocytes from healthy donors with plasma samples and analyzed mRNA expression of interleukin (IL)-1 beta, IL-6, IL-8 and tumor necrosis factor-alpha (TNF-alpha) by Northern blot analysis. RESULTS: In patients with an acute MI, plasma obtained from the coronary sinus after recanalization increased the mRNA expression of IL-1 beta and IL-8 compared with that of plasma before recanalization (median [quartiles] difference before vs. after recanalization: 34.5 [4, 137], p = 0.017, for IL-1 beta; 18.5 [4, 35], p = 0.032, for IL-8) and simultaneously obtained aortic plasma (median [quartiles] coronary sinus-aortic differences after recanalization: 45.5 [-3, 115], p = 0.021, for IL-1 beta; 16 [4, 52], p = 0.005, for IL-8). No induction of IL-6 and TNF-alpha expression could be observed. No changes found in the study patients were detectable in the control group. CONCLUSIONS: Plasma from the ischemic and reperfused heart stimulates the expression of IL-1 beta and IL-8 in leukocytes. Therefore, leukocyte-derived cytokines may contribute to the regulation of cardiac inflammatory responses in patients with an acute MI.

Adult↗
PubMed1997

Reduction of monocyte-platelet interaction and monocyte activation in patients receiving antiplatelet therapy after coronary stent implantation.

BACKGROUND: Monocyte activation induces different procoagulant and proadhesive inflammatory responses and thus may play a role in thrombotic complications after coronary interventions. Monocyte-platelet interaction may trigger these effects inducing monocyte activation. AIMS: To characterize the effect of antiplatelet vs anticoagulation therapy on monocyte-platelet interaction and monocyte function after intracoronary stenting. METHODS AND RESULTS: Immediately before, and during the first 12 days after successful coronary stenting, monocyte-platelet conjugates and monocyte function were assessed by flow cytometric detection of GPIIb/IIIa (CD41) on monocytes and by monocyte surface exposure of Mac-1 (CD11b/CD18) and L-selectin (CD62L). Twenty patients receiving combined antiplatelet therapy (ticlopidine, aspirin) were compared to 20 patients with standard anticoagulation (phenprocoumon, overlapping heparin, aspirin). Before stenting, monocyte-platelet conjugates and Mac-1 surface expression in both groups were significantly increased, while L-selectin was significantly diminished. Anticoagulation did not change these variables significantly during the subsequent 12 days. In contrast, antiplatelet therapy reduced platelet-monocyte conjugates by 46 +/- 9.3% (mean +/- SEM, P = 0.0019) within 4 days, which was associated with a decrease in Mac-1 expression (28 +/- 6.7%, P = 0.0013) and an increase in L-selectin (56 +/- 15.0%, P = 0.0061). CONCLUSION: After intracoronary stenting, combined antiplatelet therapy, but not anticoagulation, causes reduction of monocyte-platelet interaction, which is associated with monocyte deactivation. This may contribute to a decreased risk for thrombotic events.

Adult↗
PubMed1997

Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity.

Interleukin (IL)-6 and IL-8 are important regulators of inflammatory responses in myocardial infarction. Induction of monocyte procoagulant activity (PCA) by these cytokines could present a mechanism that links inflammatory responses to thrombotic events. We therefore investigated the effect of IL-6 and IL-8 on monocyte tissue factor (TF) expression. Recombinant human IL-6 and IL-8 caused a time- and dose-dependent increase in PCA (recalcification time) of monocytic U937 cells and of mononuclear leukocytes. Using blocking anti-TF monoclonal antibodies and factor VII-deficient control plasma, this PCA was shown to be TF dependent. Compared with unstimulated cells, mononuclear cell PCA increased by 4.5-fold to 17 +/- 2 mU/5x10(5) cells after exposure to 100 ng/L IL-6 for 4 hours and by 6.6-fold to 27 +/- 4 mU/5x10(5) cells after exposure to IL-8 under the same conditions. Northern blot analysis showed an increase in TF mRNA after stimulation with IL-6 or IL-8 for 2 hours, and after 4 hours an increase in cellular TF protein content was found by immunoassay. Flow cytometry demonstrated that IL-6 and IL-8 induced an increase in TF surface expression on monocytes. Thus, IL-6 and IL-8 induce monocyte PCA by increasing mRNA, protein content, and surface expression of TF.

Blood Coagulation Factors↗