thromboxane-b2 and Polycythemia-Vera

In this pilot study, aimed at exploring the feasibility of a large-scale trial of low-dose aspirin in polycythaemia vera (PV), 112 PV patients (42 females, 70 males. aged 17-80 years) were selected for not having a clear indication for, or contraindication to, aspirin treatment and randomized to receive oral aspirin (40 mg/d) or placebo. Follow-up duration was 16 +/- 6 months. Measurements of thromboxane A2 production during whole blood clotting demonstrated complete inhibition of platelet cyclooxygenase activity in patients receiving aspirin. Aspirin administration was not associated with any bleeding complication. Within the limitations of the small sample size, this study indicates that a biochemically effective regimen of antiplatelet therapy is well tolerated in patients with polycythaemia vera and that a large-scale placebo-controlled trial is feasible.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aspirin; Blood Platelets; Cyclooxygenase Inhibitors; Female; Humans; Male; Middle Aged; Pilot Projects; Platelet Count; Polycythemia Vera; Thromboxane B2

Polycythemia vera (PV) is associated with high morbidity and mortality for thrombosis. We hypothesized that in PV altered sensitivity to aspirin might be related to dysfunction of the endothelial repair and/or of the nitric oxide (NO) system. Urinary thromboxane (TX) A(2) metabolite (TXM), endothelial colony-forming cells (ECFCs), plasma asymmetric dimethylarginine (ADMA) and von Willebrand factor (VWF) were measured in 37 PV patients on low-dose aspirin and 12 healthy controls. Patients showed an approximately 2-fold increase in median TXM and plasma ADMA levels (P < .001), while ECFC numbers were reduced by approximately 7-fold (P < .001) as compared with non-aspirinated control. These differences were more pronounced in patients with previous thrombosis. An 8-week course of aspirin did not affect ECFCs in 6 controls. VWF and TXM correlated directly with ADMA, and inversely with ECFCs. By multiple regression analysis, lower ECFC quartiles (beta = -0.39; SE = 0.17; P = .028) and higher VWF levels (beta = 0.338, SE = 0.002, P = .034) were independent predictors of higher TXM quartiles (R(2) = 0.39). Serum TXB(2), measured in 22 patients, was approximately 10-fold higher than aspirin-treated controls. PV patients appear to have an unbalanced ECFC/NO axis, and an apparent altered sensitivity of platelet TXA(2) production, all potentially contributing to aspirin-insensitive TXM formation. Thus, additional antithrombotic strategies may be beneficial in PV.

Topics: Adult; Aged; Aged, 80 and over; Arginine; Aspirin; Blood; Case-Control Studies; Colony-Forming Units Assay; Endothelial Cells; Female; Humans; Male; Middle Aged; Polycythemia Vera; Stem Cells; Thromboxane A2; Thromboxane B2; Thromboxanes

Increased thromboxane (TX) production and modified aspirin sensitivity has been detected in vitro in platelets isolated from patients with polycythemia vera. To verify the relevance of these capacity-related measurements to the actual rate of TXA2 biosynthesis in vivo and its suppression by oral aspirin, we have investigated the urinary excretion of major enzymatic metabolites of TXB2 in 17 patients with polycythemia vera and 23 gender- and age-matched controls. Urinary 11-dehydro-TXB2 and 2,3-dinor-TXB2 were measured by previously validated radioimmunoassays. In addition, urinary immunoreactive leukotriene (LT) E4 was measured to explore the 5-lipoxygenase pathway of arachidonate metabolism. Polycythemic patients had significantly (P < .001) higher excretion rates of both 11-dehydro-TXB2 (1,033 +/- 1,050 v 117 +/- 45 pmol/mmol creatinine; mean +/- SD) and 2,3-dinor-TXB2 (725 +/- 676 v 82 +/- 43 pmol/mmol creatinine) than controls. In contrast, urinary LTE4 was not significantly different. Enhanced metabolite excretion did not correlate with the platelet count or with the hematocrit value, and was not related to the current treatment or to a clinical history of thrombotic complications. Platelet TX receptor studies did not show any significant changes in the binding characteristics of two different ligands. A platelet-selective regimen of aspirin therapy (50 mg/d for 7 to 14 days) was associated with greater than 80% suppression in metabolite excretion in nine patients. These results are consistent with abnormal stimuli operating in polycythemia vera to induce a selective enhancement in the platelet biosynthesis of TXA2 without changes in receptor binding. This in vivo abnormality in platelet biochemistry can be largely suppressed by low doses of aspirin.

Topics: Adult; Aged; Aspirin; Blood Platelets; Female; Humans; Kinetics; Leukotriene E4; Male; Middle Aged; Platelet Activation; Polycythemia Vera; SRS-A; Thromboxane A2; 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

Patients with the myeloproliferative syndrome (MPS) often show morphological and functional platelet abnormalities and an increased incidence of lowered cyclooxygenase- and/or lipoxygenase activity. We present the case history of a 68-year-old male patient with polycythaemia vera in whom an absolute absence of platelet lipoxygenase activity has been detected for the first time in the literature.

Topics: Aged; Blood Platelets; Humans; Lipoxygenase; Male; Malondialdehyde; Multiple Myeloma; Platelet Aggregation; Platelet Function Tests; Polycythemia Vera; 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

Patients with polycythemia vera have been described to have hemorrhagic as well as thrombotic tendencies. In a patient with polycythemia vera and angina pectoris, we observed markedly decreased platelet aggregation response to epinephrine but increased platelet and whole-blood thromboxane A2 generation compared with normal subjects. Electron microscopy mostly showed partially activated forms of platelets, which may account for decreased aggregation response in vitro and hemorrhagic tendencies. Young and large platelets found in this disease, however, can generate large amounts of vasoconstrictor and platelet proaggregatory prostanoid thromboxane A2 in response to endogenous thrombin, which may be a basis for thrombotic tendencies.

Topics: Angina Pectoris; Blood Platelets; Humans; Male; Microscopy, Electron; Middle Aged; Platelet Aggregation; Polycythemia Vera; Thromboxane A2; 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