thromboxane-b2 and Myeloproliferative-Disorders

In myeloproliferative neoplasms (MPN), aspirin reduces the thrombotic risk. Nevertheless, aspirin resistance may be due to excessive platelet production ("turnover" resistance). Aspirin resistance can also result from a lack of effect of aspirin; this second component is called "intrinsic resistance". Two biological tests are considered reference methods for the assessment of aspirin resistance: TXB2 assay and Light Transmittance Aggregometry (LTA) with arachidonic acid.. We have compared a third method, the Multiple Electrode Aggregometry (MEA), performed with arachidonic acid on the Multiplate® analyzer, with both reference methods. Thirty-six patients with MPN were assessed for aspirin resistance with all three techniques. 30 patients devoid of MPN were used as controls.. The three methods were statistically equivalent: LTA and TXB2 were comparable methods (ROC curve AUC=0.844>0.7; LTA cutoff=67%). At this threshold, LTA had a sensitivity of 73% and a specificity of 96%. MEA (without added aspirin) and TXB2 were also comparable (ROC curve AUC=0.782; MEA cutoff=31U), but at this threshold, 11 patients (30%) were falsely positive with MEA. Last, MEA and LTA were comparable (ROC curve AUC=0.888; MEA cutoff=56U), with a sensitivity of 90% and a specificity of 84.6%. Besides, MEA gave an insight into the mechanism of aspirin resistance (turnover and/or intrinsic).. MEA is both rapid and reliable as compared to reference methods. Clinical correlation with risk of re-thrombosis should definitively validate this method and the best cutoff value.

Topics: Adult; Aged; Aged, 80 and over; Arachidonic Acid; Aspirin; Blood Platelets; Drug Resistance; Electrodes; Female; Humans; Male; Middle Aged; Myeloproliferative Disorders; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Thrombosis; Thromboxane B2; Young Adult

Topics: Humans; Myeloproliferative Disorders; Platelet Activation; Syndrome; Thrombosis; 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

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

In 2 out of 29 patients suffering from the myeloproliferative syndrome a lack of thromboxane conversion by platelets from exogenous arachidonic acid was discovered. In one patient PGE2 (30.9%) and 12-HETE (12-Hydroxyeicosatetraenoic acid) (42.8%) were formed instead, whilst in the other patient 12-HETE (72.9%) was the main metabolic product. In both the patients, serum and plasma TXB2, as well as malondialdehyde, were quite low. It is claimed that this phenomenon is due to the expression of a pathological population of platelets related to the disease.

Topics: Aged; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Humans; Male; Malondialdehyde; Myeloproliferative Disorders; Platelet Function Tests; Polycythemia Vera; Thrombocytosis; 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

Platelet functions were studied in 64 patients with various myeloproliferative diseases. The characteristic alterations were prolonged bleeding time, decreased platelet aggregation (but normal results induced by ristomycin), elevated level of BTG, high production of MDA, increased level of TXB2 with almost normal level of 6-keto-PGF1. However, considering the bleeding time and the amount of BTG in relation to the whole blood platelet count, no differences could be detected.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Aged, 80 and over; beta-Thromboglobulin; Blood Platelets; Female; Humans; Male; Malondialdehyde; Middle Aged; Myeloproliferative Disorders; Platelet Aggregation; Platelet Count; Platelet Function Tests; Thromboxane B2

19 patients with MPD have been studied. As described in normals, an age-related increase in beta thromboglobulin (beta TG) release is observed. Such release, however, is greater in patients with myeloproliferative disorders (MPD). MPD seem therefore to cause platelet activation, allowing an earlier and more evident manifestation of physiologic ageing phenomena. PF 4 levels are near zero both in controls and patients, regardless of platelet number. This suggests that increased levels of PF 4 represent only a laboratory artifact, caused by platelet activation in vitro. Mean ability in producing thromboxane B2 (TxB2) is increased, but is perfectly normal in patients with normal platelet count and decreased in 3 thrombocythaemic patients, who seem to present an increased thrombotic risk. TxB2 is reduced almost to zero by the administration of aspirin plus dipyridamole; contrarily, all other parameters were unaffected, either by such drugs or by AD 6, a new coumarin derivative with antiplatelet properties.

Topics: Adult; Age Factors; Aged; Aspirin; Beta-Globulins; beta-Thromboglobulin; Dipyridamole; Female; Humans; Male; Middle Aged; Myeloproliferative Disorders; Platelet Count; Platelet Factor 4; Thromboxane B2

Platelet alpha-adrenoceptor status was examined in 35 patients with myeloproliferative disorders (MPD) and 35 normal controls by means of radioligand binding studies with 3H-yohimbine (3H-YOH) and in vitro platelet function tests. A group of 'adrenaline insensitive' MPD patients identified in the functional studies were found to be identical to normal controls and other MPD patients with respect to their alpha 2-adrenoceptor status as assessed by the binding studies. Possible explanations for the dissociation between radioligand binding studies and functional responses in the platelet are discussed.

Topics: Adenine Nucleotides; Adolescent; Adult; Aged; Blood Platelets; Epinephrine; Humans; Middle Aged; Myeloproliferative Disorders; Platelet Aggregation; Receptors, Adrenergic, alpha; Thromboxane B2; Yohimbine

A group of patients with myeloproliferative disorders was studies with respect to platelet aggregation responses, release of beta-thromboglobulin and incorporated 5-hydroxy-tryptamine, and synthesis of thromboxane b 2. In all patients the resting plasma beta-thrombo-globulin was elevated. Aggregation responses were frequently impaired to adrenaline, arachidonic acid, A23187 and the prostaglandin endoperoxide analogue, U44069. Both 5-hydroxy-tryptamine and beta-thromboglobulin release were greater with patients' platelets than with those of controls in response to adrenaline, ADP and U44069. The patients' platelets produced more thromboxane B2 than did controls, irrespective of the agonist used, yet those aggregating agents which are thought to act by generating thromboxane A2 were relatively ineffective in causing aggregation. This might reflect resistance to thromboxane A2 action in these patients, which is met by increased thromboxane formation.

Topics: Adenosine Diphosphate; Adult; Aged; Arachidonic Acid; Arachidonic Acids; beta-Thromboglobulin; Blood Platelets; Calcimycin; Collagen; Epinephrine; Female; Humans; Male; Middle Aged; Myeloproliferative Disorders; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Ristocetin; Serotonin; Thromboxane B2; Thromboxanes

Bleeding and abnormal platelet aggregation occur in patients with myeloproliferative disorders. In this study, twenty patients were examined, some sequentially, and a proportion found to have defective aggregation toward adrenaline, adenosine diphosphate (ADP), and collagen. In these seven patients, the abnormality in platelet response with defective collagen-induced [14C]serotonin release correlated with poor collagen-stimulated thromboxane B2 (TXB2) production. In contrast, five of these patients showed a normal threshold aggregation response to arachidonic acid. The combined results suggest that in these patients, there is a defect between receptor-stimulus coupling and the mobilization of arachidonic acid from membrane phospholipid.

Topics: Blood Platelets; Humans; Leukemia, Myeloid; Membrane Lipids; Myeloproliferative Disorders; Platelet Aggregation; Platelet Count; Polycythemia Vera; Serotonin; Syndrome; Thrombocytosis; Thromboxane B2

Topics: Adenine Nucleotides; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Humans; Lipoxygenase; Myeloproliferative Disorders; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Radioimmunoassay; Thromboxane B2

Platelet lipoxygenase and cyclo-oxygenase pathways were investigated by the incubation of 1(-14) C-arachidonic acid with washed platelets in 33 patients with myeloproliferative disorders, including 14 patients with chronic myeloid leukemia (CML), 12 with polycythemia vera (PV), 4 with essential thrombocythemia (ET), and 3 with myelofibrosis (MF). In patients with MF and CML, mean activities of the lipoxygenase pathway were significantly lower when compared with normal controls (p less than 0.001 and p less than 0.01, respectively). When a normal range of the activity was defined as mean +/- 2 SD, all patients with MF, 8 with CML, 6 with PV, and 1 with ET showed decreased lipoxygenase activities, while activities of the cyclo-oxygenase pathway were decreased in one of each patient with CML, PV, and ET. In 4 of 10 patients with a selective lipoxygenase deficiency, platelets were aggregated by lower concentrations of arachidonic acid than those necessary to induce normal platelet aggregation. It is suggested that the lipoxygenase activity could modulate platelet functions through its effect on arachidonate metabolism by the cyclo-oxygenase pathway and that a selective lipoxygenase deficiency could offer a mechanism for hyperfunction of the platelet, which may lead to a thrombotic tendency, one of the common features of myeloproliferative disorders.

Topics: Adult; Aged; Arachidonic Acids; Aspirin; Blood Platelets; Female; Humans; Lipoxygenase; Male; Middle Aged; Myeloproliferative Disorders; Platelet Aggregation; Prostaglandins E; Prostaglandins F; Thromboxane B2; Time Factors