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Biomedical subjects

M Mysliwiec

Publications and source records attributed to M Mysliwiec.

At least 37 records · Page 2Linked to original sources
PubMed1998

Long-term effects of erythropoietin on platelet serotonin storage and platelet aggregation in hemodialysis patients with reference to ketanserin treatment.

Correction of uremic platelet serotonin (5-HT) storage pool deficiency is one of the very early hemostatic effects of erythropoietin (Epo) therapy. In this work, platelet 5-HT with relation to primary hemostasis was studied in 15 hemodialysis patients treated with Epo for 8 months. Moreover, effects of ketanserin, a blocker of platelet and vascular smooth muscle cell 5-HT2A receptors, in these patients were followed. The parameters studied were compared with relevant values in healthy controls and in hemodialysis patients not treated with Epo, and remeasured in the long-term Epo patients after a 14-day oral ketanserin trial. Platelet 5-HT content in the eighth month of Epo therapy was not different from the one in untreated patients. Ristocetin- and collagen-induced platelet aggregation were enhanced in comparison with both control groups, as opposed to unaltered response to ADP and arachidonic acid. Fibrinogen concentration was lower than in the untreated group. An inverse correlation between ADP-induced platelet aggregation and the skin bleeding time (r=-0.536, p<0.05) and a positive one between the former and platelet 5-HT (r=0.644, p<0.01) were found. Platelet count correlated positively with both platelet 5-HT (r=0.823, p<0.0002) and ADP-induced platelet aggregation (r=0.596, p<0.02). Ketanserin produced a decrease in ristocetin-induced platelet aggregation, fibrinogen, and prolongation of the bleeding time. The first two of the changes correlated positively with their pre-ketanserin values (r=0.923, p<0.00001 and r=0.839, p< 0.0001, respectively). Post-ketanserin, positive correlations between depressed ristocetin- and arachidonic acid-induced platelet aggregation (r=0.760, p<0.005), and between collagen- and corresponding values of arachidonic acid- (r=0.622, p<0.02), ADP-induced platelet aggregation (r=0.396, p<0.01), and platelet 5-HT (r=0.654, p<0.05) were found. Efficient hemostasis in hemodialysis patients on protracted Epo therapy is, in part, dependent on enhanced platelet aggregability. Correction of platelet 5-HT storage pool deficiency is not evident in this stage but 5-HT still influences complex mechanisms of primary hemostasis. Ketanserin is of anticoagulant value in these patients but its effects must be weighted against possible exacerbation of the anemia.

Adolescent↗
PubMed1998

Modulation of hematopoiesis by ketanserin in erythropoietin-treated uremic patients: evidence from platelet studies.

Recombinant human erythropoietin (EPO) not only ameliorates the anemia of renal failure but also modulates platelet function and corrects uremic platelet serotonin (5-hydroxytryptamine, 5-HT) storage pool deficiency. We studied if ketanserin, a blocker of platelet and vascular smooth muscle receptors for 5-HT, could reverse any EPO-induced changes in hemostasis. A complete blood count, immunoreactive serum EPO concentration, skin bleeding time (BT) and whole blood platelet aggregation (electric impedance method) induced by ristocetin and ADP, and intraplatelet and whole blood 5-HT, were determined in seven chronic hemodialysis (HD) patients before and after 1, 2, 4 and 8 weeks of EPO therapy, and repeated after a 4-week co-treatment with oral ketanserin. Stimulation of erythropoiesis was accompanied by a rise in the platelet count ( P < 0.05), shortening of the BT ( P < 0.02), an increase in platelet aggregability, and by replenished intraplatelet 5-HT store. Ketanserin co-treatment produced an unexpected 33% fall in serum EPO level ( P < 0.02), a decrease in the platelet count ( P < 0.05), prolongation of the BT ( P < 0.05) and depressed platelet aggregation in response to both agonists. There was no change in the amount of intraplatelet 5-HT while whole blood 5-HT concentration decreased significantly ( P < 0.02). Strong positive correlations between the decrease in whole blood 5-HT and the prolongation of the BT ( r = 0.786, P < 0.05), and between the former parameter and the fall in the platelet count ( r = 0.820, P < 0.05) were found. In conclusion, we report dual erythro- and thrombocytopoietic effects of EPO combined with correction of a platelet defect in the storage of 5-HT and enhanced platelet aggregability. The ketanserin-induced falls in serum EPO concentration and the platelet count provide new evidence of the dependency of thrombocytopoiesis on EPO in the initial weeks of the therapy. The 'antiplatelet' effects of ketanserin observed in this study seem to be due to reduction in circulating thrombocyte number rather than from any inhibitory effect on their aggregation.

Journal Article↗
PubMed1998

Vascular and cardiac effects of DV-7028, a selective, 5-HT2-receptor antagonist in rats.

The effect of 5HT2A-receptor antagonist DV-7028 (3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro - 2H-pyrido[1,2,-a]-1,3,5-triazine-2,4(3H)-dione maleate on the rat cardiovascular system was evaluated. DV-7028 (0.1 and 1.0 mg/kg), given intravenously, caused a significant, dose-dependent decrease in mean arterial blood pressure in anesthetized normotensive rats. In vagotomized rats, administration of DV-7028 resulted in a reduction of mean blood pressure, but this effect was less prominent than that seen in nonvagotomized rats. Intravenous administration of DV-7028 induced bradycardia, which was almost completely abolished by vagotomy. In pithed rats, bradycardia and hypotension were not demonstrated after DV-7028 administration. In pithed rats, serotonin administered intravenously caused a dose-dependent increase in blood pressure. In this experimental model, DV-7028 inhibited the pressor effects of serotonin at doses of 0.01 and 0.1 mg/kg, which caused neither hypotension nor bradycardia in anesthetized rats. DV-7028 strongly inhibited the pressor effects of serotonin in the isolated perfused hindlegs of the rat (IC50 = 0.032 +/- 0.004 microM) and caused a concentration-dependent, almost parallel shift to the right of the concentration-response curve to serotonin for its pressor effect in the rat perfused tail artery (pA2 value for DV-7028 was 7.92, a slope 0.94). These data demonstrate that DV-7028 exhibits 5-HT2A-receptor antagonistic property in the rat cardiovascular system. Besides this peripheral action, DV-7028, when applied in high doses, exerts hypotension and bradycardia via an unknown site and mechanism.

Animals↗
PubMed1996

The coagulo-lytic system and endothelial function in cyclosporine-treated kidney allograft recipients.

Since thromboembolic complications in transplanted patients are generally attributed to combined abnormalities in platelets and coagulo-lytic system, some hemostatic parameters tPA (tissue plasmogin activator):Ag and activity, its inhibitor-PAIAg and activity, tPA/PAI, thrombin-antithrombin (TAT) and plasmin-antiplasmin complexes (PAP), urokinase-uPA, euglobulin clot lysis time-ECLT, fibrinogen, plasminogen, protein C activity, D-dimer, prothrombin fragments1+2 (F1+2), fibrin monomers, fibronectin, lipoprotein-a, and von Willebrand factor(vWF), were evaluated using commercially available kits. The studies were performed on kidney transplant recipients treated with CsA, azathioprine and prednisone (n=21), and healthy volunteers (n=21). ECLT was significantly prolonged in kidney transplant recipients together with a rise in F1+2,lipoprotein-a, fibrinogen, fibronectin, and vWF when compared with controls. The TPA level was lower, whereas the PAI level was higher in kidney transplant recipients when compared with controls. In conclusion, CsA-treated kidney transplant recipients show evidence of pronounced impairment in fibrinolysis and endothelial damage in comparison with healthy volunteers.

Adult↗
PubMed1996

Hemostasis, platelet function and serotonin in acute and chronic renal failure.

A pathogenetic role for fibrin deposition and platelet activation in the kidney is thought to play a role in the pathogenesis of acute renal failure (ARF). Thus, some fibrinolytic parameters and platelet function have been studied in 17 patients with ARF and compared to healthy volunteers and subjects with chronic renal failure (CRF). Since serotonin may participate in pathological processes resulting from platelet/vessel wall interactions, its level in the whole blood and plasma was also assayed. In ARF and CRF platelet aggregatory responses in both whole blood and in platelet rich plasma upon stimulation with various agonists (collagen, arachidonic acid, ADP, ristocetin) were lower than those obtained in healthy volunteers. Increased levels of lipoprotein (a), von Willebrand factor (vWF) and fibronectin were found in ARF relative to controls. Protein C activity was significantly lower in patients with ARF. Euglobulin clot lysis time was prolonged in ARF and CRF, reflecting a decreased overall fibrinolytic activity. Activity of tissue plasminogen activator (tPA) inhibitor (PAI) and PAI:Ag were higher in ARF, whereas tPA:Ag, urokinase, tPA/PAI complexes, thrombin-antithrombin complexes (TAT), plasmin-antiplasmin (PAP) complexes, fibrinogen, and F1+2 did not differ between ARF and controls. In CRF elevated levels of TAT, PAP, fibrinogen and prothrombin fragments F1+2 were found, whereas concentration of fibronectin was lowered when compared to controls. In both groups of renal failure patients increased levels of fibrin monomers and d-dimer were found relative to healthy volunteers. Whole blood serotonin was significantly lower, whereas plasma serotonin was significantly higher in patients with ARF and CRF relative to controls. Serotonin uptake and its release from platelets were markedly diminished in patients with ARF and CRF. Chronic renal failure exhibit a slightly different pattern of coagulopathies that acute renal failure.

Acute Kidney Injury↗
PubMed1996

The effect of tacrolimus (FK506) and cyclosporin A (CyA) on peripheral serotonergic mechanisms in uremic rats.

The aim of this study was to investigate the mechanism of hypertension and thromboembolic events induced by cyclosporin (CyA) and tacrolimus (FK506) in respect to their action on the serotonergic blood system. The study was carried out on healthy rats and those with experimental chronic renal failure. CyA injected into healthy and uremic rats caused an increase in serotonin (5-HT) concentration levels in whole blood and platelets. Concomitantly a rise in systolic blood pressure was observed. Platelet aggregation values were significantly higher in uremic rats given CyA. FK506 had no influence on 5-HT blood content, blood pressure or platelet aggregation values. It is concluded that 5-HT may play a role in the development of hypertension and thrombotic events caused by CyA. Furthermore, lower incidence of these complications during FK506 treatment could be the result of this drug's limited effect on the serotonergic blood system.

Animals↗
PubMed1996

Peripheral serotonergic system in uremia.

Several data suggest that platelet-derived serotonin (5-HT), previously classified as a trivial modulator of blood-borne cardiovascular disease (1), may play a decisive role in various pathological processes, resulting from abnormal platelet-vessel wall interactions (2). Following platelet activation upon a contact with a damaged vessel wall, 5-HT, released from platelets upon the activation of 5-HT2 receptors, may amplify the action of other agents on vascular smooth muscle cells and platelets (3,4). Platelets play a unique role in 5-HT metabolism: they take it up, store in their dense granules and release upon stimulation. Platelet dysfunction, alteration in platelet count, their consumption and turnover are common in renal diseases (5). Storage pool deficiency regarding 5-HT and ADP was reported in renal failure (6). Previously we reported that 5HT2 receptor blockers may serve as potent antiplatelet drugs in uremic patients, which are prone to thrombotic complications (7,8). Up to date there have been a few reports dealing predominantly with 5-HT levels in renal patients. Thus, we focused on peripheral serotonergic mechanisms including 5-HT uptake and release and kinetics of its uptake in uremic patients.

Adult↗
PubMed1996

Erythropoietin and uremic platelet aggregation in vivo and in vitro.

Erythropoietin treatment is known to correct anemia and to improve hemostasis. Since platelets may contribute to thromboembolic complications, we assessed platelet aggregation in whole blood and platelet-rich plasma from chronically hemodialyzed patients treated with erythropoietin and evaluated in vitro effects of this drug on aggregatory responses of uremic and normal platelets. Recombinant human erythropoietin was given to uremic patients at a dose of 2,000 IU subcutaneously three times a week. Platelet aggregation in whole blood and platelet-rich plasma was induced by collagen, ADP, arachidonic acid, and ristocetin. In uremic patients, erythropoietin therapy resulted in an enhancement of platelet sensitivity to various agonists, particularly in platelet-rich plasma, reaching values comparable to those of healthy volunteers. In vitro studies we were unable to show any direct effect of erythropoietin, used at concentrations that occurred post intravenous administration, on platelet aggregation both in whole blood and in platelet-rich plasma.

Adenosine Diphosphate↗
PubMed1996

Inverse relationships between haemoglobin and ristocetin-induced platelet aggregation in haemodialysis patients under erythropoietin therapy.

BACKGROUND: Amelioration of the anaemia of chronic renal failure and subsequent improved haemorheology result in correction of bleeding diathesis as evidenced by shortening of the skin bleeding time (BT). However, the relationship between the haematocrit and platelet-vessel wall interactions in haemodialysis (HD) patients under recombinant human erythropoietin (rHuEpo) therapy, assessed by platelet aggregation in response to ristocetin is more complex and somewhat inconsistent. METHODS: We investigated the relationship between haemoglobin (Hb) levels and whole blood ristocetin-induced platelet aggregation (electric impedance method) in 28 HD patients treated with rHuEpo, and with normal BT. The measurements were repeated in 16 subjects after having reduced platelet aggregability with orally administered ketanserin. RESULTS: Ristocetin-induced platelet aggregation in the whole group was comparable to those found in 21 age-matched healthy subjects (normals) and in 25 HD patients not treated with rHuEpo (uraemics). Interestingly, a significant inverse correlation between this aggregation and Hb concentration was found (r = -0.392, P < 0.05). In the group of 16 patients, the pre-ketanserin aggregation was more intensive than in the normals and uraemics (P < 0.05). Ketanserin produced a fall in ristocetin-induced platelet aggregation (P < 0.02), prolongation of the BT (P < 0.02) and, unexpectedly, a decrease in serum Epo concentration (P < 0.0002) and the Hb level (P < 0.001). Again, an inverse correlation between depressed ristocetin-induced platelet aggregation and lowered Hb concentration was found (r = -0.590, P < 0.02). Moreover, a strong positive correlation between the extent of preketanserin platelet aggregation and the decrease in the intensity of this process that followed the trial was observed (r = 0.919, P < 0.000005). There were no changes in other haematological parameters or arterial blood pressure. CONCLUSIONS: Considering the role of von Willebrand factor and fibrinogen in mediating ristocetin-induced platelet aggregation, and enhanced synthesis and/or release of these macromolecules in response to uraemia or inflammation, we suggest that exaggerated whole-blood platelet aggregability to ristocetin points to blunted erythropoiesis in HD patients on rHuEpo therapy.

Adult↗
PubMed1996

Ketanserin: a new perspective in posttransplant erythrocytosis?

We have recently shown that ketanserin, an antagonist of peripheral serotonin 5-HT2 receptors lowers blood erythropoietin (Epo) levels in some chronic hemodialysis patients. Based on this finding, a preliminary study was undertaken to investigate the effect of a 3-week oral ketanserin administration on serum Epo concentration and relevant hematological parameters in 4 renal allograft recipients with posttransplant erythrocytosis (PTE). We found a marked decrease in Epo concentrations following ketanserin administration, from 48% to 76% of the abnormally elevated pretreatment values with subsequent increases at 3 weeks after discontinuation of the drug in all patients studied. In 3 of them a corresponding decrease or no rise in the erythrocyte count were noted. During the 6-week study period, the need for monthly phlebotomies was eliminated in these patients. It is hypothesized that ketanserin diminishes erythropoietin synthesis and may become a new drug in the treatment of posttransplant erythrocytosis.

Adult↗