thromboxane-b2 and Thrombocythemia--Essential

Once-daily (od), low-dose aspirin (75-100 mg) is recommended to reduce the thrombotic risk of patients with essential thrombocytemia (ET). This practice is based on data extrapolated from other high-risk patients and an aspirin trial in polycythemia vera, with the assumption of similar aspirin pharmacodynamics in the two settings. However, the pharmacodynamics of low-dose aspirin is impaired in ET, reflecting accelerated renewal of platelet cyclooxygenase (COX)-1. ARES is a parallel-arm, placebo-controlled, randomized, dose-finding, phase II trial enrolling 300 ET patients to address two main questions. First, whether twice or three times 100 mg aspirin daily dosing is superior to the standard od regimen in inhibiting platelet thromboxane (TX)A

Topics: Aspirin; Biomarkers; Clinical Protocols; Disease Management; Female; Humans; Male; Patient Selection; Platelet Aggregation Inhibitors; Research Design; Thrombocythemia, Essential; Thrombosis; Thromboxane B2

We tested whether cyclooxygenase 2 (COX-2) expression and unacetylated COX-1 in newly formed platelets might contribute to persistent thromboxane (TX) biosynthesis in aspirin-treated essential thrombocythemia (ET). Forty-one patients on chronic aspirin (100 mg/day) and 24 healthy subjects were studied. Platelet COX-2 expression was significantly increased in patients and correlated with thiazole orange-positive platelets (r = 0.71, P < .001). The rate of TXA(2) biosynthesis in vivo, as reflected by urinary 11-dehydro-TXB(2) (TXM) excretion, and the maximal biosynthetic capacity of platelets, as reflected by serum TXB(2), were higher in patients compared with aspirin-treated healthy volunteers. Serum TXB(2) was significantly reduced by the selective COX-2 inhibitor NS-398 added in vitro. Patients were randomized to adding the selective COX-2 inhibitor, etoricoxib, or continuing aspirin for 7 days. Etoricoxib significantly reduced by approximately 25% TXM excretion and serum TXB(2). Fourteen of the 41 patients were studied again 21 (+/- 7) months after the first visit. Serum TXB(2) was consistently reduced by approximately 30% by adding NS398 in vitro, while it was completely suppressed with 50 microM aspirin. Accelerated platelet regeneration in most aspirin-treated ET patients may explain aspirin-persistent TXA(2) biosynthesis through enhanced COX-2 activity and faster renewal of unacetylated COX-1. These findings may help in reassessing the optimal antiplatelet strategy in ET.

Topics: Adult; Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Drug Therapy, Combination; Etoricoxib; Female; Humans; Immunohistochemistry; Male; Middle Aged; Platelet Aggregation Inhibitors; Pyridines; Sulfones; Thrombocythemia, Essential; Thromboxane A2; Thromboxane B2; Thromboxanes; Treatment Outcome

To observe the influence of the plasma thromboxane B2 (TXB2), 6-keto-PGF1alpha, CD62P and PAC-1 and Thrombus in patients with primary thrombocytosis (ET). To observe the effect of sodium ozagrel to prevent and treat thrombosis in patients with ET.. The subjects including 48 patients with ET. All patients were measured the plasma TXB2, 6-keto-PGF1alpha, CD62P and PAC-1 before and after treatment with or without sodium ozagrel.. The plasma levels of CD62P, PAC-1, TXB2, 6-keto-PGF1alpha and TXA2/PGI2 in the patients with ET were significantly higher than the normal people (P < 0.01). The levels of CD62P, PAC-1, TXB2, TXB2/6-keto-PGF1alpha in patients with treatment of sodium ozagrel were higher than patients without treatment of sodium ozagrel (P < 0.01). The plasma levels of CD62P, PAC-1 and TXA2/PGI2 in patients with treatment of sodium ozagrel and that in normal people had no significant distinction (P < 0.01). All the index of conventional therapy group were higher than normal people (P < 0.01) but had no significant distinction with the patients before conventional treating. The incidence of thrombus in patients treated with sodium ozagrel was lower than patients treated without sodium ozagrel (P < 0.05).. With the treatment of sodium ozagrel in patients with ET, the CD62P, PAC-1, TXB2 and TXA2/PGI2 of plasma could be decreased. And the incidence of thrombus was decreased.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Antibodies, Monoclonal; Blood Platelets; Female; Humans; Male; Methacrylates; Middle Aged; P-Selectin; Receptors, Fibrinogen; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Thrombocythemia, Essential; Thrombosis; Thromboxane A2; Thromboxane B2

We present herein studies carried out in 17 patients with essential thrombocythemia before treatment with anagrelide and on remission. Ten patients had symptoms related to thrombocythemia, 8 of them at the time of starting treatment. The plasmatic levels of TXB2 and PDGF were measured by ELISA technique. Before treatment, PDGF values corrected for the platelet count were lower than controls, 0.48 ng/10(5) platelets (0.13-1.93) and 0.92 ng/10(5) platelets (0.33-1.16) respectively (p = 0.02), and they were not different from the results obtained during remission. Count-corrected TXB2 levels before treatment were higher than the control group, 1.0 ng/10(5) platelets (0.04-14.4) and 0.25 ng/10(5) platelets (0.13-0.39) respectively (p = 0.04); these values decreased during remission 0.86 ng/10(5) platelets (0.07-9.8) (p = 0.04), although they were still above normal values (p = 0.008). Symptoms disappeared with the normalization of platelet counts in all cases. These results show that patients with essential thrombocythemia during remission have a tendency to normalize the count-corrected TXB2 values.

Topics: Adult; Aged; Female; Fibrinolytic Agents; Humans; Immunoenzyme Techniques; Male; Middle Aged; Platelet Count; Platelet-Derived Growth Factor; Quinazolines; Thrombocythemia, Essential; Thromboxane B2

We have evaluated the arachidonic acid (AA) metabolism in patients with myeloproliferative disorders (MPD). In essential thrombocythemia (ET), the generation of thromboxane B2 was found significantly reduced and inversely correlated with platelet count. Polycythemia vera (PV) patients showed an increased formation of this metabolite of AA. Prostaglandin E2 and 6-keto-PGF1 alpha generation were markedly reduced in patients with chronic myelogenous leukemia. Our study confirms that the arachidonate metabolism is frequently deranged in patients with MPD. The opposite changes in thromboxane formation in ET and PV could be one of the factors responsible for the different incidences of thrombotic and hemorrhagic complications in these diseases.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Arachidonic Acid; Arachidonic Acids; Bleeding Time; Dinoprostone; Female; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocyte Count; Male; Middle Aged; Myeloproliferative Disorders; Platelet Count; Polycythemia Vera; Primary Myelofibrosis; Thrombocythemia, Essential; Thromboxane B2

The functional and biochemical characteristics of human megakaryocytic leukemia cells remain unclear. In this study, we examined cytosolic Ca2+ ([Ca2+]i) mobilization and thromboxane (TX) formation in a megakaryocytic leukemia cell line, designated CMK. Stimulation of CMK cells with thrombin resulted in an increase of [Ca2+]i as measured with the fluorescent marker Fura 2-AM. The rise in [Ca2+]i was mostly dependent on extracellular Ca2+. Prostaglandin E1 (PGE1) further increased [Ca2+]i after thrombin addition, thus indicating that PGE1 had a different action on [Ca2+]i in cells of the platelet-megakaryocyte lineage. The addition of thrombin and the calcium ionophore A23178 to CMK cells caused similar rapid formations of TXB2 as measured by RIA. Thrombin plus A23178 had a synergistic effect on TXB2 synthesis in CMK cells. Thrombin had no effect of TX metabolism in the cells with myeloid, erythroid, B-lymphoid, and T-lymphoid lineages. These results indicate that thrombin-induced TX synthesis may serve as a marker of immature megakaryocytes.

Topics: Alprostadil; Antibodies, Monoclonal; Biological Transport; Calcimycin; Calcium; Cell Line; Cytosol; Humans; Osmolar Concentration; Thrombin; Thrombocythemia, Essential; Thromboxane B2; Tumor Cells, Cultured

In the course of an investigation of cyclooxygenase and 12-lipoxygenase activity in platelets of patients with myeloproliferative syndrome receiving treatment with interferon-alpha 2 patients showed unusual results which have not been reported so far. Both patients had thrombocytosis, in one case associated with polycythaemia. In platelets of both patients, a reduced conversion of exogenous 14C arachidonic acid to TXB2 was observed accompanied by a shift in conversion to PGE2 and 12-HETE in one patient and to 12-HETE alone in the other before therapy. These findings were paradoxically associated with evidence of enhanced platelet activation in vivo. Treatment of both patients with interferon-alpha resulted in reversal of the biochemical abnormalities and in clinical remission.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Aged; Arachidonate 12-Lipoxygenase; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Dinoprostone; Humans; Hydroxyeicosatetraenoic Acids; Interferon Type I; Male; Myeloproliferative Disorders; Platelet Activation; Polycythemia Vera; Prostaglandin-Endoperoxide Synthases; Thrombocythemia, Essential; Thromboxane B2

Thirty-two patients with thrombocythemia associated with myeloproliferative syndromes were selected on the basis of normal bleeding time and absence of hemorrhagic or thrombotic history. Twenty-five control subjects were studied simultaneously. They were all given a single intravenous infusion of 500 mg of aspirin (lysine acetylsalicylate), and bleeding time was measured two hours later. Both in the control group and in the patient group, aspirin significantly prolonged the bleeding time, but the average prolongation was significantly more pronounced in the patients. In comparison with the control subjects, the patients had a statistically significant reduction of platelet serotonin content and no difference in the production of platelet lipoxygenase derivative 12-HETE or plasma von Willebrand factor properties. Fourteen patients had abnormal platelet aggregation in response to adenosine diphosphate, adrenaline (epinephrine), or collagen. In six of them, all with very low serotonin content, the bleeding time was prolonged above the upper limit of the post-aspirin values in the control group. Thus, cyclooxygenase inhibition by aspirin unmasked a bleeding tendency in patients with a severe reduction in platelet dense bodies content. These findings might be relevant in relation to the use of antiplatelet drugs.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adolescent; Adult; Aged; Aspirin; Bleeding Time; Blood Platelets; Female; Humans; Hydroxyeicosatetraenoic Acids; Male; Middle Aged; Myeloproliferative Disorders; Polycythemia Vera; Risk; Serotonin; Thrombocythemia, Essential; Thromboxane B2; Time Factors; von Willebrand Factor