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Patients with essential thrombocythemia (ET) are treated with once-daily low-dose aspirin to prevent thrombosis, but their accelerated platelet turnover shortens the antiplatelet effect. The short-term Aspirin Regimens in EsSential Thrombocythemia trial showed that twice-daily aspirin dosing restores persistent platelet thromboxane (TX) inhibition. However, the long-term pharmacodynamic efficacy, safety and tolerability of twice-daily aspirin remain untested. We performed a multicenter, randomized, open-label, blinded-endpoint, phase-2 trial in which 242 patients with ET were randomized to 100 mg aspirin twice- or once-daily and followed for 20 months. The primary endpoint was the persistence of low serum TXB2, a surrogate biomarker of antithrombotic efficacy. Secondary endpoints were major and clinically relevant non-major bleedings, serious vascular events, symptom burden assessed by validated questionnaires, and in vivo platelet activation. Serum TXB2 was consistently lower in the twice-daily versus once-daily regimen on 10 study visits over 20 months: median 3.9 ng/mL versus 19.2 ng/mL, respectively; p < .001; 80% median reduction; 95% CI, 74%-85%. No major bleeding occurred. Clinically relevant non-major bleedings were non-significantly higher (6.6% vs. 1.7%), and major thromboses lower (0.8% vs. 2.5%) in the twice-daily versus once-daily group. Patients on the twice-daily regimen had significantly lower frequencies of disease-specific symptoms and severe hand and foot microvascular pain. Upper gastrointestinal pain was comparable in the two arms. In vivo platelet activation was significantly reduced by the twice-daily regimen. In patients with ET, twice-daily was persistently superior to once-daily low-dose aspirin in suppressing thromboxane biosynthesis and reducing symptom burden, with no detectable excess of bleeding and gastrointestinal discomfort.
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Aspirina , Esquema de Medicación , Hemorragia , Inhibidores de Agregación Plaquetaria , Trombocitemia Esencial , Humanos , Aspirina/administración & dosificación , Aspirina/uso terapéutico , Trombocitemia Esencial/tratamiento farmacológico , Trombocitemia Esencial/sangre , Masculino , Persona de Mediana Edad , Femenino , Anciano , Adulto , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/efectos adversos , Hemorragia/inducido químicamente , Tromboxano B2/sangre , Activación Plaquetaria/efectos de los fármacos , Anciano de 80 o más Años , Resultado del TratamientoRESUMEN
Background: Erythrocytosis is a relatively common condition; however, a large proportion of these patients (70%) remain without a clear etiologic explanation. Methods: We set up a targeted NGS panel for patients with erythrocytosis, and 118 sporadic patients with idiopathic erythrocytosis were studied. Results: In 40 (34%) patients, no variant was found, while in 78 (66%), we identified at least one germinal variant; 55 patients (70.5%) had 1 altered gene, 18 (23%) had 2 alterations, and 5 (6.4%) had 3. An altered HFE gene was observed in 51 cases (57.1%), EGLN1 in 18 (22.6%) and EPAS1, EPOR, JAK2, and TFR2 variants in 7.7%, 10.3%, 11.5%, and 14.1% patients, respectively. In 23 patients (19.45%), more than 1 putative variant was found in multiple genes. Conclusions: Genetic variants in patients with erythrocytosis were detected in about 2/3 of our cohort. An NGS panel including more candidate genes should reduce the number of cases diagnosed as "idiopathic" erythrocytosis in which a cause cannot yet be identified. It is known that HFE variants are common in idiopathic erythrocytosis. TFR2 alterations support the existence of a relationship between genes involved in iron metabolism and impaired erythropoiesis. Some novel multiple variants were identified. Erythrocytosis appears to be often multigenic.
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Patients suffering from chronic anemia can benefit from scheduled transfusions of packed red blood cells (PRBCs), while urgent transfusions have specific indications. These patients frequently seek medical attention in the emergency department (ED), where they can be inappropriately transfused, but research in this field is limited. This study aimed to assess the appropriateness of PRBCs transfusions in chronic anemic patients in the ED. A retrospective analysis was performed on patients who accessed the ED of the Azienda Ospedaliera di Padova (Padova, Italy) between 2016 and 2019 and received PRBCs transfusions. Patients aged ≥ 18 years old and with chronic anemia were included, while those with acute anemia or admitted to the hospital after the transfusion were excluded. Chronic anemia was defined as satisfying one of the following in the past medical history: diagnosis of chronic anemia; two or more previous blood samplings demonstrating anemia; periodic transfusions. As primary outcome, the appropriateness of transfusions was assessed according to the American Association of Blood Banks (AABB) 2016 criteria, using the recommended threshold of 7 g/dL for hemodynamically stable adults and 8 g/dL for patients with pre-existing cardiovascular disease. Out of 1153 transfusions, 344 transfusions were included in the study. According to our criteria, 139 (40.4%) patients were inappropriately transfused, resulting in a total estimated cost of 54,528.71 in the study period. This study showed that transfusions in chronic anemic patients are recurrent events in the ED and are frequently inappropriate. A possible explanation could be the lack of a well-structured primary care network granting periodic transfusions in ambulatory centers. In the future, implementing and improving chronic anemic patients' access to transfusion services through dedicated pathways could reduce the burden on the ED and also decrease costs.
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Anemia , Adulto , Humanos , Adolescente , Estudios Retrospectivos , Anemia/terapia , Transfusión de Eritrocitos , Servicio de Urgencia en Hospital , EritrocitosRESUMEN
BACKGROUND: Incorporating real-world data in the drug development process allows the improvement of health outcomes by providing better representation of actual patterns of drug safety and efficacy. AIMS AND METHODS: Here, we present the results of a retroprospective, observational real-life study of 154 patients with myelofibrosis treated with ruxolitinib in a real-life setting in seven Italian centers of the MYNERVA project. RESULTS: Median drug exposure was 29 (range, 3-98) months. Discontinuation rate was 27% after a median time of 13 (range, 3-61). While hematological toxicities were in line with previous findings, infections occurred frequently, representing a not negligible cause of discontinuation and death. Anemia, symptoms, and spleen responses were obtained at any time in 23%, 91%, and 68% of patients, respectively; most patients achieved their responses by week 24. Larger splenomegaly and delayed treatment initiation correlated with lower spleen response at 24 weeks. Spleen response was associated with a superior overall survival, regardless of DIPSS. Of interest, both achievement and loss of spleen response had prognostic implications. DISCUSSION AND CONCLUSION: Overall, our findings provide insights on the efficacy and safety of ruxolitinib in a real-world, multicenter cohort of Italian MF patients.
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Mielofibrosis Primaria , Humanos , Mielofibrosis Primaria/complicaciones , Nitrilos/uso terapéutico , Pirimidinas/uso terapéutico , Italia , Resultado del TratamientoRESUMEN
Thrombopoietin receptor agonists (TPO-RA) are a valid therapy for immune thrombocytopenia (ITP), due to megakaryocyte stimulation and (poorly characterised) immune-modulatory effects. The spleen is pivotal in the pathogenesis of ITP, yet little is known on its immune microenvironment and on effects of TPO-RA on this organ. To address these topics, we analysed 35 spleens removed for primary refractory ITP. Pre-splenectomy TPO-RA administration correlated with increased splenic regulatory T cells (Tregs), type 2 T-helper cells and histiocyte density and with reduced red pulp sinusoids. Surgical outcome was not associated with TPO-RA administration, other pre-splenectomy therapies and/or Treg density. In conclusion, TPO-RA affect the splenic microenvironment, but this has no impact on splenectomy outcome.
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Púrpura Trombocitopénica Idiopática , Trombocitopenia , Humanos , Púrpura Trombocitopénica Idiopática/etiología , Receptores Fc , Receptores de Trombopoyetina/agonistas , Proteínas Recombinantes de Fusión , Bazo/patología , Linfocitos T Reguladores/patología , Trombocitopenia/complicaciones , Trombopoyetina/farmacología , Trombopoyetina/uso terapéuticoRESUMEN
Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by enhanced platelet production and thrombotic complications. The inhibition of platelet cyclooxygenase (COX) activity by the standard once-daily aspirin is mostly incomplete due to accelerated thrombopoiesis. The phase II Aspirin Regimens in EsSential thrombocythemia (ARES) trial has recently compared the efficacy of once- vs. twice- or three-times daily low-dose aspirin in inhibiting platelet thromboxane (TX) A2 production, as reflected by serum (s) TXB2 measurements. The present substudy characterized the determinants of the highly variable response to the standard aspirin 100 mg once-daily regimen in fully compliant patients with ET and the effects of the experimental dosing regimens on response variability. By multivariable analysis, the platelet count (directly) and cytoreductive treatment (inversely) were significantly associated with sTXB2 values in 218 patients with ET. However, the platelet count positively correlated with sTXB2 in patients not being treated with cytoreductive drugs (ρ = 0.51, P < 0.01, n = 84), but not in patients on cytoreduction. Patients in the lowest sTXB2 quartile were older, more often on cytoreductive drugs, had lower platelet count and Janus-Associated Kinase2 (JAK2)-V617F allele frequency as compared with patients in the upper sTXB2 quartiles. After 2 weeks of a twice- or 3-times daily aspirin regimen, the association between the platelet count and sTXB2 became similar in cytoreduced and non-cytoreduced patients. In conclusion, the platelet count appears the strongest determinant of TXA2 inhibition by once-daily low-dose aspirin in ET, with different patterns depending of cytoreductive treatment. More frequent aspirin dosing restores adequate platelet inhibition and reduces interindividual variability, independently of cytoreduction.
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Aspirina , Trombocitemia Esencial , Tromboxanos , Aspirina/administración & dosificación , Procedimientos Quirúrgicos de Citorreducción , Humanos , Inhibidores de Agregación Plaquetaria , Recuento de Plaquetas , Trombocitemia Esencial/tratamiento farmacológicoRESUMEN
This paper reviews the features of pediatric essential thrombocythemia (ET). ET is a rare disease in children, challenging pediatric and adult hematologists alike. The current WHO classification acknowledges classical Philadelphia-negative MPNs and defines diagnostic criteria, mainly encompassing adult cases. The presence of one of three driver mutations (JAK2V617F, CALR, and MPL mutations) represent the proof of clonality typical of ET. Pediatric ET cases are thus usually confronted by adult approaches. These can fit only some patients, because only 25-40% of cases present one of the driver mutations. The diagnosis of hereditary, familial thrombocytosis and the exclusion of reactive/secondary thrombocytosis must be part of the diagnostic process in children and can clarify most of the negative cases. Still, many children present a clinical, histological picture of ET, with a molecular triple wild-type status. Moreover, prognosis seems more benign, at least within the first few decades of follow-up. Thrombotic events are rare, and only minor hemorrhages are ordinarily observed. As per the management, the need to control symptoms must be balanced with the collateral effects of lifelong drug therapy. We conclude that these differences concert a compelling case for a very careful therapeutic approach and advocate for the importance of further cooperative studies.
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In western countries, about half of the hospitalized patients are anemic. Generally, these patients are old, often with multiple diseases, and anemia worsens the prognosis, finally increasing the risk of death. We describe a monocentric observational study that evaluates 249 consecutive adult patients (160 women and 89 men) with anemia admitted in the internal medicine department over five months. They represent 71.5% of all patients admitted in the study period. Demographic, historical, and clinical data, laboratory tests, duration of hospitalization, readmission at 30 days, and death were recorded. Patients were stratified by age (75-84=old, >85 years=oldest-old), anemia severity, and etiology of anemia. Anemia was found in 67.5% of old and in 77.2% of oldest-old patients. In 37% of old and 32% of oldest-old patients, anemia was mild, in 43% old and 59% of oldest-old moderate and in 20% old and 9% of oldest-old severe in agreement with WHO criteria. Moderate anemia was significantly more common in the oldest-old (p=0.01). The causes of anemia were iron deficiency in 10.6% of patients, other deficiencies in 2.8%, chronic diseases in 38.2%, hematologic neoplasms in 6.1%, multifactorial in 24.1%, and undetermined in 19.9%. The oldest-old have a higher frequency of multifactorial anemia (p=0.04), while hematologic neoplasms were more common in old patients (p=0.03). Most patients with undetermined anemia had mild/moderate forms. An anti-anemic treatment, mainly blood transfusion, was adopted in 100% of oldest-old patients and in 60% of old (p= 0.04). Anemia (and/or its treatment) was reported in the discharge letter in 19% of old and in 28.2% of oldestold patients. From a general point of view, physicians seem to disregard anemia in the context of more important pathologic conditions. In oldest-old patients, multifactorial anemia seems to be considered only "one more cause of disability." When borderline anemia occurs, even if it can represent a relevant adverse condition in frailty, it is poorly considered.
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OBJECTIVE: Immune thrombocytopenia (ITP) is an acquired disorder, characterized by immune-mediated platelet destruction. The spleen plays a key pathogenic role in ITP and splenectomy is a valuable second-line therapy for this disease. Little is known on ITP spleen histology and response to splenectomy is unpredictable. This study aims to characterize ITP spleen histology and assess possible predictors of splenectomy outcome. METHODS: A series of 23 ITP spleens were retrospectively assessed for the following histological parameters: density of lymphoid follicles (LFs), marginal zones (MZs), T helper and cytotoxic T cells; presence of reactive germinal centers (GCs); width of perivascular T cell sheaths; and red pulp features. Clinical and histological data were matched with postsplenectomy platelet counts to assess their prognostic relevance. RESULTS: Three histological patterns were documented: a hyperplastic white pulp pattern, a non-activated white pulp pattern (lacking GCs), and a white pulp-depleted pattern. Poor surgical responses were associated with presplenectomy high-dose steroid administration, autoimmune comorbidities and low T follicular helper cell density. The combination of such parameters stratified patients into different splenectomy response groups. The removal of accessory spleens was also associated with better outcome. CONCLUSION: ITP spleens are histologically heterogeneous and clinical-pathological parameters may help predict the splenectomy outcome.
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Púrpura Trombocitopénica Idiopática/diagnóstico , Bazo/patología , Adolescente , Adulto , Anciano , Autoinmunidad , Biopsia , Terapia Combinada , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Pronóstico , Púrpura Trombocitopénica Idiopática/etiología , Púrpura Trombocitopénica Idiopática/mortalidad , Púrpura Trombocitopénica Idiopática/terapia , Estudios Retrospectivos , Esplenectomía , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
PF4 is a megakaryocyte-derived cationic chemokine that plays a part in innate immunity through its activity on the macrophages. In bacterial sepsis, PF4 binds to glycosaminoglycans (GAGs) on the surface of aerobic bacteria, giving rise to an antigenic complex that induces the early formation of anti-PF4 IgG-IgA-IgM. This triggers the immune response in patients receiving heparin therapy who develop heparin-induced thrombocytopenia (HIT). These antibodies have also been identified in patients with chronic Gram-negative infections. Given the complexity of this innate immune response network, our study on 45 patients with sepsis focused on the immune response mediated by platelet PF4. We analyzed the role of IgG-IgA-IgM against PF4-GAGs, and the presence of specific PF4-bearing platelet microparticles (PMPs). Anti-GAGs/PF4 IgG-IgA-IgM levels were significantly higher in septic patients than in control groups (healthy controls or acute patients without sepsis, p < 0.001). PF4-bearing PMP levels were only significantly higher in septic patients (p < 0.001). The occurrence of IgG-IgA-IgM against PF4-GAGs and PF4+ PMPs correlated with an improvement in patients' sepsis. In conclusion, we demonstrated that, in the course of bacterial sepsis, platelet activation leads to the formation of specific PF4-bearing PMPs. These specific microparticles bind to polyanionic sequences on the surface of aerobic bacteria, giving rise to an antigenic complex that induces the early formation of IgG-IgA-IgM against PF4-GAGs as an innate immune response to infection.
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Anemia is extremely common in hospitalized patients who are old and often with multiple diseases. We evaluated 435 consecutive patients admitted in the internal medicine department of a hub hospital and 191 (43.9%) of them were anemic. Demographic, historic and clinical data, laboratory tests, duration of hospitalization, re-admission at 30 days and death were recorded. Patients were stratified by age (<65, 65-80, >80 years), anemia severity, and etiology of anemia. The causes of anemia were: iron deficiency in 28 patients, vitamin B12 and folic acid deficiencies in 6, chronic inflammatory diseases in 80, chronic kidney disease in 15, and multifactorial in 62. The severity of the clinical picture at admission was significantly worse (p < 0.001), length of hospitalization was longer (p < 0.001) and inversely correlated to the Hb concentration, re-admissions and deaths were more frequent (p 0.017) in anemic compared to non-anemic patients. A specific treatment for anemia was used in 99 patients (36.6%) (transfusions, erythropoietin, iron, vitamin B12 and/or folic acid). Anemia (and/or its treatment) was red in the discharge letter only 54 patients. Even if anemia is common, in internal medicine departments scarce attention is paid to it, as it is generally considered a "minor" problem, particularly in older patients often affected by multiple pathologies. Our data indicate the need of renewed medical attention to anemia, as it may positively affect the outcome of several concurrent medical conditions and the multidimensional loss of function in older hospitalized patients.
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Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2-dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).
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Aspirina/administración & dosificación , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Adulto , Anciano , Aspirina/farmacocinética , Ciclooxigenasa 1/sangre , Inhibidores de la Ciclooxigenasa/farmacología , Método Doble Ciego , Epoprostenol/orina , Humanos , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/farmacocinética , Trombocitemia Esencial/sangre , Trombocitemia Esencial/orinaRESUMEN
Mastocytosis is a rare disease in which heightened amounts of mast cells accumulate in the skin, bone marrow, and other visceral organs. Upon activation, mast cells release a wide variety of preformed or newly synthesized mediators which can induce allergic symptoms and inflammatory reactions. Mastocytosis is diagnosed by biopsy and can be divided into cutaneous and systemic mastocytosis (SM). The first one affects the skin and is relatively benign, whilst SM, which involves bone marrow and other organs, may be aggressive and associate with both myelodisplastic and myeloproliferative diseases. Here we present a case of SM associated with essential thrombocythemia and complicated by severe osteoporosis, successfully treated with hydroxyurea, low-dose aspirin and zolendronic acid.
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Mastocitosis Sistémica/diagnóstico , Trombocitosis/etiología , Biopsia/métodos , Médula Ósea/patología , Humanos , Masculino , Mastocitosis Sistémica/diagnóstico por imagen , Mastocitosis Sistémica/fisiopatología , Persona de Mediana Edad , Trombocitosis/fisiopatologíaRESUMEN
INTRODUCTION: Essential thrombocythemia (ET) is a disease which is extremely rare in children. Only recently, data on pediatric ET have become available. Areas covered: In children with sustained platelet count over 450 x 109/L, secondary thrombocytosis must be ruled out. ET workup comprehends research of JAK2V617F, CALR and MPL mutations and bone marrow biopsy (BM). In asymptomatic children wait and watch is the best option. Aspirin controls headache and other microvascular disturbances. Patients with venous thrombosis need anticoagulation. Cytoreductive drugs in children with ET should be prescribed as a last choice. Hydroxyurea and IFN-a are first-line therapy at any age including children; Anagrelide is not licensed as first-line therapy for ET in Europe. New JAK2-inhibitors are not clearly useful in ET and hence not approved for ET. Expert opinion: The most challenging problem is to understand if a child with prolonged not secondary thrombocytosis really has ET. Diagnostic workup requires molecular and histological studies. The rare children with clonal ET have features like those of adults. Patients with ET have long expected survival and the treatment in children must be long-term efficacious and well tolerated.
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Trombocitemia Esencial/tratamiento farmacológico , Anticoagulantes/uso terapéutico , Aspirina/uso terapéutico , Calreticulina/genética , Niño , Manejo de la Enfermedad , Humanos , Hidroxiurea/uso terapéutico , Interferón-alfa/uso terapéutico , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/genética , Inhibidores de Agregación Plaquetaria/uso terapéutico , Recuento de Plaquetas , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores de Trombopoyetina/genética , Trombocitemia Esencial/diagnóstico , Trombocitemia Esencial/genéticaRESUMEN
INTRODUCTION: ADAMTS13 deficiency results in unusually large von Willebrand factor (ULVWF) multimers in the circulation and a higher risk of microthrombi due to high shear stress. In patients treated for acquired thrombotic thrombocytopenic purpura (TTP), a persistently severe ADAMTS13 deficiency (<10%) in remission is associated with more relapses. A reduced plasma ADAMTS13 activity and increased VWF levels are associated with a higher risk of myocardial infarction. Assessing coronary flow reserve (CFR) enables a better cardiovascular risk stratification: a lower CFR correlates inversely with cardiovascular risk. The aim of the study was to establish whether patients with TTP in remission have an impaired coronary microcirculation, in terms of a lower CFR, and whether there is any correlation between ADAMTS13 activity, the presence of ULVWF multimers, and the occurrence of relapses. METHODS: The clinical information and hemostatic parameters of 24 patients with TTP in remission managed at our center were analyzed. The CFR was assessed in a subgroup of the TTP patients and compared with a control group consisting of 50 healthy volunteers. RESULTS: The CFR was statistically lower in patients in remission of TTP than in controls, but there were no differences between TTP patients with normal and lower CFR. The occurrence of relapses correlated with the presence of ULVWF multimers and with a residual ADAMTS13 activity. CONCLUSIONS: When compared with healthy controls, TTP patients in remission have an impaired coronary microcirculation and the occurrence of relapses in the former reveal the presence of ULVWF multimers.
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Vasos Coronarios/fisiopatología , Microcirculación , Multimerización de Proteína , Púrpura Trombocitopénica Trombótica/fisiopatología , Factor de von Willebrand/análisis , Proteína ADAMTS13/sangre , Adulto , Femenino , Hemostasis , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Púrpura Trombocitopénica Trombótica/sangre , Púrpura Trombocitopénica Trombótica/terapia , Recurrencia , Inducción de RemisiónAsunto(s)
Aborto Espontáneo/etiología , Policitemia Vera/tratamiento farmacológico , Complicaciones Hematológicas del Embarazo/tratamiento farmacológico , Resultado del Embarazo , Adolescente , Adulto , Niño , Femenino , Fibrinolíticos/uso terapéutico , Humanos , Italia , Janus Quinasa 2/genética , Mutación , Embarazo , Estudios Retrospectivos , Adulto JovenRESUMEN
Once-daily (od), low-dose aspirin (75-100 mg) is recommended to reduce the thrombotic risk of patients with essential thrombocytemia (ET). This practice is based on data extrapolated from other high-risk patients and an aspirin trial in polycythemia vera, with the assumption of similar aspirin pharmacodynamics in the two settings. However, the pharmacodynamics of low-dose aspirin is impaired in ET, reflecting accelerated renewal of platelet cyclooxygenase (COX)-1. ARES is a parallel-arm, placebo-controlled, randomized, dose-finding, phase II trial enrolling 300 ET patients to address two main questions. First, whether twice or three times 100 mg aspirin daily dosing is superior to the standard od regimen in inhibiting platelet thromboxane (TX)A2 production, without inhibiting vascular prostacyclin biosynthesis. Second, whether long-term persistence of superior biochemical efficacy can be safely maintained with multiple vs. single dosing aspirin regimen. Considering that the primary study end point is serum TXB2, a surrogate biomarker of clinical efficacy, a preliminary exercise of reproducibility and validation of this biomarker across all the 11 participating centers was implemented. The results of this preliminary phase demonstrate the importance of controlling reproducibility of biomarkers in multicenter trials and the feasibility of using serum TXB2 as a reliable end point for dose-finding studies of novel aspirin regimens.
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Aspirina/administración & dosificación , Protocolos Clínicos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Trombocitemia Esencial/complicaciones , Trombosis/etiología , Trombosis/prevención & control , Biomarcadores , Manejo de la Enfermedad , Femenino , Humanos , Masculino , Selección de Paciente , Proyectos de Investigación , Trombocitemia Esencial/diagnóstico , Trombosis/sangre , Trombosis/diagnóstico , Tromboxano B2/sangreRESUMEN
We analyzed 597 patients with myeloproliferative neoplasms (MPN) who presented transient ischemic attacks (TIA, n = 270) or ischemic stroke (IS, n = 327). Treatment included aspirin, oral anticoagulants, and cytoreductive drugs. The composite incidence of recurrent TIA and IS, acute myocardial infarction (AMI), and cardiovascular (CV) death was 4.21 and 19.2%, respectively at one and five years after the index event, an estimate unexpectedly lower than reported in the general population. Patients tended to replicate the first clinical manifestation (hazard ratio, HR: 2.41 and 4.41 for recurrent TIA and IS, respectively); additional factors for recurrent TIA were previous TIA (HR: 3.40) and microvascular disturbances (HR: 2.30); for recurrent IS arterial hypertension (HR: 4.24) and IS occurrence after MPN diagnosis (HR: 4.47). CV mortality was predicted by age over 60 years (HR: 3.98), an index IS (HR: 3.61), and the occurrence of index events after MPN diagnosis (HR: 2.62). Cytoreductive therapy was a strong protective factor (HR: 0.24). The rate of major bleeding was similar to the general population (0.90 per 100 patient-years). In conclusion, the long-term clinical outcome after TIA and IS in MPN appears even more favorable than in the general population, suggesting an advantageous benefit-risk profile of antithrombotic and cytoreductive treatment.