RESUMO
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 (ß = 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.
Assuntos
Aspirina/uso terapêutico , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/metabolismo , Tromboxano A2/biossíntese , Aceleração , Adulto , Idoso , Algoritmos , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/administração & dosagem , Estudos Cross-Over , Estudos Transversais/estatística & dados numéricos , Resistência a Medicamentos/efeitos dos fármacos , Feminino , Meia-Vida , Humanos , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Biossíntese de Proteínas/efeitos dos fármacos , Tromboxano A2/farmacocinéticaRESUMO
Factor XII deficiency is associated with increased risk for both arterial and venous thrombosis. We describe a case of DVT involving superficial femoral and popliteal vein occurred following total hip replacement and despite prophylaxis with low molecular weight heparin in a subject with previous acute myocardial infarction (AMI). Tests of haemostasis documented a slightly prolonged activated partial thromboplastin time (APTT) (45'') due to mild factor XII deficiency (clotting activity 32%). A therapeutic dose of enoxaparin was started, together with warfarin therapy. The patient was advised to continue oral anticoagulation indefinitely. Although cases of both venous and arterial thrombosis in carriers of severe factor XII deficiency have been already reported, to our knowledge this is the first case in the literature occurred in a carrier of partial factor XII deficiency. In conclusion, factor XII deficiency should be suspected if a patient presents with recurrent arterial and/or venous thrombosis and prolonged APTT. If this defect is diagnosed, in the presence of a history of thrombotic events, lifelong anticoagulation could be considered.
Assuntos
Deficiência do Fator XII/complicações , Deficiência do Fator XII/diagnóstico , Infarto do Miocárdio/etiologia , Trombose Venosa/etiologia , Idoso , Arteriopatias Oclusivas/etiologia , Eletrocardiografia , Humanos , Masculino , Tempo de Tromboplastina Parcial , Fatores de Risco , Trombose/etiologiaRESUMO
The methylenetetrahydrofolate reductase (MTHFR) 677 CâT polymorphism may be associated with elevated total homocysteine (tHcy) levels, an independent risk factor for cardiovascular disease. It was the study objective to evaluate in vivo lipid peroxidation and platelet activation in carriers of the MTHFR 677 CâT polymorphism and in non-carriers, in relation to tHcy and folate levels. A cross-sectional comparison of urinary 8-iso-prostaglandin (PG)F(2α) and 11-dehydro-thromboxane (TX)B(2) (markers of in vivo lipid peroxidation and platelet activation, respectively) was performed in 100 carriers and 100 non-carriers of the polymorphism. A methionine-loading test and folic acid supplementation were performed to investigate the causal relationship of the observed associations. Urinary 8-iso-PGF(2α) and 11-dehydro-TXB(2) were higher in carriers with hyperhomocysteinaemia than in those without hyperhomocysteinaemia (p<0.0001). Hyperhomocysteinaemic carriers had lower folate levels (p=0.0006), higher urinary 8-iso-PGF(2α) (p<0.0001) and 11-dehydro-TXB(2) (p<0.0001) than hyperhomocysteinaemic non-carriers. On multiple regression analysis, high tHcy (p<0.0001), low folate (p<0.04) and MTHFR 677 CâT polymorphism (p<0.001) independently predicted high rates of 8-iso-PGF(2α) excretion. Methionine loading increased plasma tHcy (p=0.002), and both urinary prostanoid metabolites (p=0.002). Folic acid supplementation was associated with decreased urinary 8-iso-PGF(2α) and 11-dehydro-TXB2 excretion (p<0.0003) in the hyperhomocysteinaemic group, but not in the control group, with substantial inter-individual variability related to baseline tHcy level and the extent of its reduction. In conclusion, hyperhomocysteinaemia due to the MTHFR 677 CâT polymorphism is associated with enhanced in vivo lipid peroxidation and platelet activation that are reversible, at least in part, following folic acid supplementation. An integrated biomarker approach may help identifying appropriate candidates for effective folate supplementation.