Lifestyle factors and risk of myeloproliferative neoplasms in the NIH-AARP diet and health study.

The etiology of Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) is largely unknown. We assessed potential associations between lifestyle factors and MPN risk in the NIH-AARP Diet and Health Study. In this prospective cohort with 463,049 participants aged 50-71 years at baseline (1995-1996) and a median follow-up of 15.5 years, we identified 490 MPN cases, including 190 with polycythemia vera (PV) and 146 with essential thrombocythemia (ET). Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Smoking was not associated with MPN risk in the overall cohort, but analyses stratified by sex suggested that smoking increased the risk of MPN in women (former smoker vs. nonsmokers, HR = 1.43, 95% CI: 1.03-2.00, p = 0.03; current smokers vs. nonsmokers, HR = 1.71, 95% CI: 1.08-2.71, p = 0.02). Coffee consumption was inversely associated with the risk of PV (high vs. low intake, HR = 0.53, 95% CI: 0.33-0.84, p-trend < 0.01), but not the risk of ET or MPN overall. Further analysis revealed an inverse association between the amount of caffeine intake and PV risk (high vs. low intake, HR = 0.55, 95% CI: 0.39-0.79, p-trend < 0.01). While the consumption of caffeinated coffee appeared to confer a protective effect against PV, the consumption of decaffeinated coffee did not. This large prospective study identified smoking as a risk factor for MPN in women and suggests that caffeine intake is associated with a lower risk of PV.

Platelet activation and inhibition in polycythemia vera and essential thrombocythemia.

Persistently enhanced platelet activation has been characterized in polycythemia vera (PV) and essential thrombocythemia (ET) and shown to contribute to a higher risk of both arterial and venous thrombotic complications. The incidence of major bleeding complications is also somewhat higher in PV and ET than in the general population. Although its efficacy and safety was assessed in just 1 relatively small trial in PV, low-dose aspirin is currently recommended in practically all PV and ET patients. Although for most patients with a thrombosis history the benefit/risk profile of antiplatelet therapy is likely to be favorable, in those with no such history this balance will depend critically on the level of thrombotic and hemorrhagic risks of the individual patient. Recent evidence for a chemopreventive effect of low-dose aspirin may tilt the balance of benefits and harm in favor of using aspirin more broadly, but the potential for additional benefits needs regulatory scrutiny and novel treatment guidelines. A clear pharmacodynamic rationale and analytical tools are available for a personalized approach to antiplatelet therapy in ET, and an improved regimen of low-dose aspirin therapy should be tested in a properly sized randomized trial.

Platelet-mediated proteolytic down regulation of the anticoagulant activity of protein S in individuals with haematological malignancies.

The natural anticoagulant protein S contains a so-called thrombin- sensitive region (TSR), which is susceptible to proteolytic cleavage. We have previously shown that a platelet-associated protease is able to cleave protein S under physiological plasma conditions in vitro . The aim of the present study was to investigate the relation between platelet-associated protein S cleaving activity and in vivo protein S cleavage, and to evaluate the impact of in vivo protein S cleavage on its anticoagulant activity. Protein S cleavage in healthy subjects and in thrombocytopenic and thrombocythaemic patients was evaluated by immunological techniques. Concentration of cleaved and intact protein S was correlated to levels of activated protein C (APC)-dependent and APC-independent protein S anticoagulant activity. In plasma from healthy volunteers 25% of protein S is cleaved in the TSR. While in plasma there was a clear positive correlation between levels of intact protein S and both APC-dependent and APC-independent protein S anticoagulant activities, these correlations were absent for cleaved protein S. Protein S cleavage was significantly increased in patients with essential thrombocythaemia (ET) and significantly reduced in patients with chemotherapy-induced thrombocytopenia. In ET patients on cytoreductive therapy, both platelet count and protein S cleavage returned to normal values. Accordingly, platelet transfusion restored cleavage of protein S to normal values in patients with chemotherapy-induced thrombocytopenia. In conclusion, proteases from platelets seem to contribute to the presence of cleaved protein S in the circulation and may enhance the coagulation response in vivo by down regulating the anticoagulant activity of protein S.

Hydroxyurea in old patients with essential thrombocythemia.

BACKGROUND AND AIMS: A previous thrombotic event and advanced age are well-known risk factors for thrombosis in essential thrombocythemia (ET). In these patients, therefore, cytotoxic drugs are needed to reduce platelet count. In spite of this convincing idea, in clinical practice, some old patients do not use platelet-reducing drugs, for a variety of causes, and few specific studies in old patients with ET are available. Our retrospective study reports single-center experience in 54 old ET patients with long follow-ups. METHODS: We compared the clinical outcome of 27 ET old patients not taking cytotoxic drugs (group A) with 27 cases treated with hydroxyurea (HU) (group B), evaluating the incidence of thrombosis and thrombosis-free survival. In 16 patients in group A and in 18 in group B, V617FJak2 mutation was sought. About 20% of HU-treated patients developed major side-effects. RESULTS: No significant difference was found in the occurred thrombosis between the 2 groups in either clinical or laboratory features. V617FJak2 was equally common in groups A and B, and in patients with or without thrombosis. CONCLUSIONS: This study is not randomised and includes a small number of patients. However, it shows that it is necessary to identify better patients who really need treatment, as the side-effects of HU are relatively common in old people and their treatment should be discontinued. V617FJak2 does not define the thrombotic risk in old ET patients.

Thrombosis and bleeding in polycythemia vera and essential thrombocythemia: pathogenetic mechanisms and prevention.

Polycythemia vera and essential thrombocythemia are chronic myeloproliferative disorders, the benign clinical course of which can be complicated by both thrombotic and hemorrhagic diatheses. Thrombotic diathesis is characterized by microcirculatory disturbances and by an increased risk of arterial and venous thromboses. Thrombotic accidents often manifest at diagnosis or in the preclinical phase of the disease so that the search for a latent myeloproliferative disorder has become widely recommended in screenings for acquired thrombophilia, particularly when venous thromboses manifest at an unusual site. Hemorrhagic diathesis is more rare, less ominous and mostly affects patients with a very high platelet count. In these subjects, an altered degradation and function of von Willebrand factor can cause minor mucocutaneous hemorrhages, which are sometimes a prelude to major gastrointestinal bleedings. The bleeding tendency can be effectively treated by cytoreduction. Pathogenesis and treatment of thrombotic diathesis are still controversial. The nature of disease-related hemostatic abnormalities and the role of common risk factors are far from being elucidated. In polycythemic subjects, treatment of blood hyperviscosity is essential and low-dose aspirin, which has an established antithrombotic efficacy, should always be used in the absence of contraindications. These are mostly constituted by conditions of increased bleeding risk, which, in particular, have to be evaluated when considering aspirin use in patients with essential thrombocythemia. Future clinical research should primarily aim to assess the risk/benefit ratio of aspirin use in this disease, to better characterize the determinants of vascular risk and to reduce the high incidence of leukemias in patients with these diseases. This might require either the availability of safer cytoreductive agents or, alternatively, the use of more aggressive antiplatelet regimens in patients at high thrombotic risk.

[Anagrelide in the treatment of thrombocythemia essential (ET)]. / Anagrelid w leczeniu nadplytkowosci samoistnej (NS).

Essential thrombocythaemia (ET), the most often occurring myeloproliferative disorder is a clonal malignant disorder arising from stem cell. The course of the disease is complicated by some severe thrombotic events and far less commonly by haemorrhagic phenomena. Treatment of ET consist of antiplatelet drugs (e.g. aspirin) and lowering platelet count (hydroxyurea or interferon alpha). Anagrelide (anagrelide hydrochloride) is an imidazoquinazoline derivative which lowers platelet count probably by inhibiting thrombopoiesis and reduces platelet aggregation. The aim of the study was to evaluate the efficacy and side effects of anagrelide in patients with ET refractory to prior treatment with hydroxyurea. Anagrelide (Agrylin or Thromboreductin) was used in 40 patients with ET from Jan. 1999 to June. 2003. Out of 40 patients, there were 29 females and 11 males, (median age 52.0 +/- 14.25 years; range, 21-72). Median follow up was 23 months (range, 8 to 54 months). Anagrelide in the average dose of 2,0 mg (range, 1,0-3,5 mg) reduced platelet count in all patients. Median time of response was 3-4 weeks. Complete remission (platelet count < or =450 G/l) achieved 22 persons (55%) and partial remission 17 persons, and only one patient had platelet count slightly above 600 G/l (627 G/l). There was a significant (p < 0.05) reduction in platelet count from a mean of 1136.05 +/- 295.09 G/l to 480.98 +/- 72.26 G/l (56%) Despite platelet count reduction <500 G/l in 3 patients reappeared symptoms of low extremities deep venous thrombosis and in one transient ischaemic cerebral stroke was found. Hemoglobin level in a single case was lower than 12 g/dL (10.8 g/dL), and neither leukopenia nor disturbances of hepatic or renal function were observed. During the first two months of treatment with anagrelide some mild and transient side effects were noticed, eg. headache in 10 (25%), fluid retention in 8 (20%), palpitations in 4 (10%), and diarrhoea in 2 (5%) patients, but all of them continued therapy. Achieved platelet count reduction allowed in 2 ET patients safe performance of planned surgery (cholecystectomy, partial thyroidectomy) and in 1 balloon coronary angioplasty. Anagrelide proved to be an effective drug for of ET patients refractory to hydroxyurea.

[Management of patients with coagulation disorder in oral and maxillofacial surgery. I. Management of patients with hypocoagulation caused by primary thrombocytopathy]. / Il trattamento del paziente con difetto di coagulazione in chirurgia orale e maxillo-facciale. Nota II. Il management dei pazienti in stato ipocoagulativo a causa di una patologia primaria trombocitopatica.

Any oral and maxillo-facial surgical treatment, however urgent it may be, must not include pathological states in which the patient's life may be particularly at risk as, for example, with Disseminated Intravascular Coagulation (DIC) or throm-botic thrombocytopenic purpura. In this article the authors present the result of studies carried out on the nosology of thrombocytopathy from an odontostomatological point of view. Thrombocytopathy can be divided into two groups: the first including the pathologies with a predominant defective number of thrombocytes (i.e.: thrombocytopenia, thrombocythemia, thrombocyto-sis), the second including forms with predominant qualitative defects (commonly known as thrombocytopathies). The authors, after having presented in short the physiopathologic functions of thrombocytes, illustrate the clinical and therapeutic aspects of the most important thrombocytopathies. Morbus Maculosus Werhofii, Glanzmann's disease, Bernard-Soulier syndrome, thrombocytopathies from defective reaction of release, Thrombocytopathies from defective procoagulant activity of blood plaques, thrombocytopathies in linkage to other genetic anomalies, von Willebrand's pseudodisease and a lot of acquired thrombocytopathies are identified. In the last part the authors illustrate the most opportune clinical steps corresponding to the most important thrombocytopathies. The results obtained suggest the necessity of keeping to the management that was described, Actually a low percentage of accidents occurred only when the above-mentioned clinical processes were completely performed.

Thrombotic and hemorrhagic complications in chronic myeloproliferative disorders.

Bleeding and thrombosis are major causes of morbidity and mortality in patients with chronic myeloproliferative disorders. We retrospectively evaluated 101 consecutive patients affected by primary thrombocytosis (46 male, 55 female, aged 18-84 years; mean +/- SD 61 +/- 15) followed for a period ranging from 6 months up to 10 years (median 5 years) at our hematological unit. At the time of diagnosis 48 patients were asymptomatic; 26 had clinical evidence of atherothrombosis (cerebral ischemic attacks, ischemic heart disease, peripheral occlusive arterial disease), ten had venous thrombosis, four experienced major hemorrhages, 23 presented microvascular ischemic manifestations namely erythromelalgia, paresthesias, acrocyanosis and dizziness. At presentation 51.2% of the patients had elevated serum lactic dehydrogenase, 34.5% hyperuricemia, and 23.4% serum creatinine > 1.2 mg/dL. Color Doppler ultrasound provided evidence of vascular stenosis or medium-intimal hyperplasia of epiaortic vessels in 48.9% of patients studied, and similar alterations of lower limb arteries in 23.8% of cases. Therapy modality included an antiplatelet agent (picotamide 300 mg/bid); a cytoreductive agent (busulphan, hydroxyurea, pipobroman or melphalan) was used when platelet count was > 800000/microL. Symptoms due to microvascular ischemia promptly regressed after picotamide and cytoreductive therapy. During follow-up. nine patients suffered from atherothrombotic events (transient ischemic attacks, ischemic stroke, unstable angina pectoris) and five developed deep vein thrombosis or superficial thrombophlebitis. Five patients experienced major hemorrhages (two melena, two hematuria, one perioperative bleeding); the two gastrointestinal hemorrhages occurred in patients self-medicated with non steroidal anti-inflammatory drugs, and the two episodes of hematuria occurred on oral anticoagulant therapy and aspirin respectively. No major bleeding occurred in patients on continuative therapy with picotamide, even in the presence of upper digestive tract disorders. Seven patients died: mortality resulted from one sudden coronary death, three solid neoplasia, one blast crisis, one anile, and one massive hemorrhage due to abdominal aortic prosthesis tearing. Our study suggests that a long-term antithrombotic prophylaxis with picotamide may be of benefit in patients affected by primary thrombocytosis; a controlled clinical trial is warranted to assess whether picotamide can ameliorate the natural history of the disease.