thromboxane-a2 and Thrombocythemia--Essential

Aspirin has a well established role in the prevention of arterial thrombosis. Discussion on the efficacy and safety of aspirin in the treatment and prophylaxis of thrombosis in essential thrombocythemia (ET) has become an important issue. The rationale for its use in ET comes from the observation that arterial thrombosis and platelet-mediated microcirculatory disturbances are the major causes of morbidity and mortality in ET. Experimental data have shown persistently elevated levels of thromboxane A2 (TXA2) in ET patients probably reflecting an enhanced in vivo platelet activation. Increased TXA2 biosynthesis and platelet activation in vivo in ET are selectively suppressed by repeated low doses of aspirin. ET-related symptoms such as erythromelalgia, transient neurologic and ocular disturbances are sensitive to aspirin. However, the benefit of low-dose aspirin is still uncertain in the primary prevention of thrombosis in ET. Furthermore, aspirin may unmask a latent bleeding diathesis frequently present in ET which may result in severe hemorrhagic complications. Thus, aspirin is contraindicated in ET patients with a bleeding history or a very high platelet count (> 1500 x 10(9)/L) leading to the acquisition of von Willebrand factor deficiency. If indicated, aspirin is presently used in the widely accepted low-dose regimen of 100 mg daily. However, an optimal effective dose has not yet been established. To further evaluate the efficacy and safety of aspirin in ET, prospective clinical trials are needed.

Topics: Abortion, Habitual; Aspirin; Cerebrovascular Disorders; Cohort Studies; Contraindications; Erythromelalgia; Female; Fibrinolytic Agents; Forecasting; Hemorrhage; Humans; Incidence; Middle Aged; Myeloproliferative Disorders; Pilot Projects; Platelet Activation; Platelet Aggregation Inhibitors; Pregnancy; Pregnancy Complications, Hematologic; Retrospective Studies; Safety; Thrombocythemia, Essential; Thrombophilia; Thrombosis; Thromboxane A2; Vision Disorders; von Willebrand Diseases

The role of aspirin in the antithrombotic strategy of patients with polycythemia vera (PV) and essential thrombocythemia (ET) is highly controversial. Long considered unsafe on the basis of a single clinical trial testing very high doses in PV patients, aspirin is being increasingly used at lower dosage. The rationale for the use of aspirin in patients with PV and ET is provided by the efficacy of this agent in the treatment of microcirculatory disturbances of thrombocythemic states associated with myeloproliferative disorders and by recent evidence that asymptomatic PV and ET patients have persistently increased thromboxane (TX) A2-biosynthesis. This increase, which most likely reflects enhanced platelet activation in vivo, is independent of the platelet mass and blood viscosity and largely supressed by a short term low-dose aspirin regimen (50 mg/day for 7 days). Since enhanced TXA2 biosynthesis may play a role in transducing the increased thrombotic risk associated with PV and ET, long-term low-dose aspirin administration has been proposed as a possible antithombotic strategy in these subjects. The safety of this treatment in PV patients has been recently reassessed by the Gruppo Italiano per lo Studio della Policitemia Vera (GISP) which has followed for over one year 112 patients randomized to receive 40 mg/day aspirin or placebo. In the same study, serum TXB2 measurements provided evidence that the low-dose aspirin regimen tested was fully effective in inhibiting platelet cyclooxygenase activity. On this basis, a large scale trial aimed at assessing the antithrombotic efficacy of this approach is currently being organized. In patients with ET both the minimal aspirin dose required for complete inhibition of platelet cyclooxygenase and the safety of long-term aspirin administration need to be established prior to extensive clinical evaluation of this strategy.

Topics: Adult; Aged; Aspirin; Cyclooxygenase Inhibitors; Erythromelalgia; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Platelet Activation; Platelet Aggregation Inhibitors; Polycythemia Vera; Thrombocythemia, Essential; Thromboxane A2

Essential thrombocythaemia (ET) is characterised by enhanced platelet generation and thrombosis. Once daily (od) aspirin incompletely inhibits platelet thromboxane (TX)A2 production in ET. A twice daily (bid) dosing is necessary to fully inhibit TXA2. Whether this dosing regimen affects in vivo prostacyclin (PGI2) biosynthesis is unknown. PGI2 biosynthesis was characterised in 50 ET patients on enteric-coated (EC) aspirin 100 mg od, by measuring its urinary metabolite, 2,3-dinor-6-keto-PGF1α (PGI-M). Moreover, in a crossover study 22 patients poorly responsive to standard aspirin based on serum TXB2 levels (≥4 ng/ml) were randomised to different seven-day aspirin regimens: EC aspirin 100 mg od, 100 mg bid, 200 mg od, or plain aspirin 100 mg od. PGI-M measured 24 hours after the last aspirin intake (EC, 100 mg od) was similar in patients and healthy subjects both on (n=10) and off (n=30) aspirin. PGI-M was unrelated to in vivo TXA2 biosynthesis, and not affected by EC aspirin 100 mg bid or 200 mg od as compared to EC 100 mg od. PGI2 biosynthesis in aspirin-treated ET patients appears unrelated to TXA2 biosynthesis, and not affected by an improved aspirin regimen, demonstrating its vascular safety for future trials.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aspirin; Blood Platelets; Clinical Protocols; Drug Dosage Calculations; Epoprostenol; Female; Humans; Male; Middle Aged; Platelet Aggregation; Thrombocythemia, Essential; Thromboxane A2

Essential thrombocythemia (ET) is characterized by enhanced platelet generation and thrombotic complications. Once-daily low-dose aspirin incompletely inhibits platelet thromboxane A(2) (TXA(2)) in the majority of ET patients. In the present study, we investigated the determinants of aspirin-insensitive platelet TXA(2) biosynthesis and whether it could be further suppressed by changing the aspirin dose, formulation, or dosing interval. In 41 aspirin-treated ET patients, the immature platelet count predicted serum TXB(2) independently of platelet count, age, JAK-2 V617F mutation, or cytoreduction (β = 3.53, P = .001). Twenty-one aspirin-treated patients with serum TXB(2) ≥ 4 ng/mL at 24 hours after dosing were randomized to the following 7-day regimens in a crossover design: enteric-coated aspirin 100 mg twice daily, enteric-coated aspirin 200 mg once daily, or plain aspirin 100 mg once daily. A twice-daily regimen caused a further 88% median (IQR, 78%-92%, P < .001) TXB(2) reduction and normalized the functional platelet response to aspirin, as assessed by urinary 11-dehydro-TXB(2) excretion and the VerifyNow Aspirin assay. Doubling the aspirin dose reduced serum TXB(2) only partially by 39% median (IQR, 29%-54%, P < .05). We conclude that the abnormal megakaryopoiesis characterizing ET accounts for a shorter-lasting antiplatelet effect of low-dose aspirin through faster renewal of platelet cyclooxygenase-1, and impaired platelet inhibition can be rescued by modulating the aspirin dosing interval rather than the dose.

Topics: Acceleration; Adult; Aged; Algorithms; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cross-Over Studies; Cross-Sectional Studies; Cyclooxygenase 1; Cyclooxygenase 2; Drug Resistance; Female; Half-Life; Humans; Male; Metabolic Networks and Pathways; Middle Aged; Molecular Targeted Therapy; Protein Biosynthesis; Thrombocythemia, Essential; Thromboxane A2

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

The role of aspirin in the antithrombotic strategy of patients with polycythemia vera (PV) and essential thrombocythemia (ET) is highly controversial. Long considered unsafe on the basis of a single clinical trial testing very high doses in PV patients, aspirin is being increasingly used at lower dosage. The rationale for the use of aspirin in patients with PV and ET is provided by the efficacy of this agent in the treatment of microcirculatory disturbances of thrombocythemic states associated with myeloproliferative disorders and by recent evidence that asymptomatic PV and ET patients have persistently increased thromboxane (TX) A2-biosynthesis. This increase, which most likely reflects enhanced platelet activation in vivo, is independent of the platelet mass and blood viscosity and largely supressed by a short term low-dose aspirin regimen (50 mg/day for 7 days). Since enhanced TXA2 biosynthesis may play a role in transducing the increased thrombotic risk associated with PV and ET, long-term low-dose aspirin administration has been proposed as a possible antithombotic strategy in these subjects. The safety of this treatment in PV patients has been recently reassessed by the Gruppo Italiano per lo Studio della Policitemia Vera (GISP) which has followed for over one year 112 patients randomized to receive 40 mg/day aspirin or placebo. In the same study, serum TXB2 measurements provided evidence that the low-dose aspirin regimen tested was fully effective in inhibiting platelet cyclooxygenase activity. On this basis, a large scale trial aimed at assessing the antithrombotic efficacy of this approach is currently being organized. In patients with ET both the minimal aspirin dose required for complete inhibition of platelet cyclooxygenase and the safety of long-term aspirin administration need to be established prior to extensive clinical evaluation of this strategy.

Topics: Adult; Aged; Aspirin; Cyclooxygenase Inhibitors; Erythromelalgia; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Platelet Activation; Platelet Aggregation Inhibitors; Polycythemia Vera; Thrombocythemia, Essential; Thromboxane A2

In this issue of Blood, Pascale and colleagues show that biochemical resistance to aspirin in patients with essential thrombocythemia (ET) can be reversed by twice daily dosing.

Topics: Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Female; Humans; Male; Thrombocythemia, Essential; Thromboxane A2

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

Acetylsalicylic acid (ASA) is currently recommended as an antithrombotic for patients with essential thrombocythemia (ET) who are at an increased risk of thrombotic events. However, ASA is also associated with an increased risk of bleeding in these patients as compared to the risk of bleeding in other patients treated with ASA. Recent data suggest that while ASA inhibits platelet thromboxane A2 (TxA2) synthesis in all individuals, ASA has little effect or inhibits the lipoxygenase pathway (i.e., 12-hydroxyeicosatetranoic acid or 12-HETE synthesis) in some individuals, and enhances 12-HETE synthesis in others. These differential effects are associated with a pronounced prolongation of the bleeding time vs. no prolongation of the bleeding time, respectively, i.e., in ASA responders and ASA nonresponders, respectively. To determine if the increased risk of ASA-induced bleeding seen in ET patients is associated with an effect on 12-HETE synthesis, we compared the relative effects of ASA on the bleeding time, platelet TxA2 and 12-HETE synthesis, and platelet aggregation and adhesion in ET patients and healthy volunteers. ASA (300 mg, taken orally) prolonged the bleeding time in 82% of the ET patients but only 27% of the healthy volunteers although platelet TxA2 synthesis and ADP- and collagen-induced aggregation were inhibited significantly in both groups. In contrast, platelet 12-HETE synthesis was unchanged and platelet adhesion was decreased in those patients and volunteers whose bleeding times were prolonged by ASA, whereas platelet 12-HETE synthesis was increased significantly and platelet adhesion was unaffected in those patients and volunteers whose bleeding times were not prolonged, and in some cases shortened by ASA. These results confirm previous data that demonstrate that ASA has different effects on platelet 12-HETE synthesis and platelet adhesion in different individuals, i.e., inhibitory or no effect in ASA responders (in whom ASA prolonged bleeding) vs. enhancing effects in ASA nonresponders (in whom ASA did not prolong bleeding). These results also indicate that there is a greater percentage of ASA responders in patients with ET than that seen in the general population, a difference that is associated with an effect of ASA on the lipoxygenase pathway. This may explain the increased bleeding side effects seen in the ET patient population.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Aspirin; Bleeding Time; Blood Coagulation; Humans; Lipoxygenase; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Thrombocythemia, Essential; Thromboxane A2