Leonardo Di Gennaro

The haematocrit and platelet target in polycythemia vera

Polycythemia vera (PV) is a chronic myeloproliferative disorder whose major morbidity and mortality are thrombohaemorragic events and progression to acute leukaemia or myelofibrosis. Whether the haematocrit and platelet count predict such complications remains unclear. The European Collaboration on Low‐dose Aspirin in Polycythemia Vera prospective study included 1638 PV patients. A total of 164 deaths (10%), 145 (8·85%) major thrombosis and 226 (13·8%) total thrombosis were encountered during 4393 person‐years follow‐up (median 2·8 years). In time‐dependent multivariable analysis, a haematocrit in the evaluable range of 40–55% was neither associated with the occurrence of thrombotic events, mortality nor with haematological progression in the studied population. The haematocrit of patients in the highest and lowest deciles at baseline was maintained within a narrow interval of haematocrit values ranging from 40% to 47% throughout follow‐up. High platelet count was associated with a lower progression rate to acute leukaemia/myelofibrosis, whereas it had no significant relationship with thrombotic events or mortality. Our findings do not suggest that the range of haematocrit (<55%) and platelet counts (<600 × 109/l) we encountered in our population had an impact on the outcome of PV patients treated by current therapeutic strategies.

Prevention of thrombosis in polycythemia vera and essential thrombocythemia

Thrombotic events are a dominant clinical feature of polycythemia vera and essential thrombocythemia. Estimating the vascular risk and choosing the best antithrombotic strategy are crucial issues in the management of these disorders. This article reviews the most important risk factors for thrombosis and focuses on the available therapeutic strategies for reducing the vascular risk. See related article on page 372.

Pathophysiology of thrombosis in myeloproliferative neoplasms

Life expectancy of patients with myeloproliferative neoplasms (MPNs) and particularly that of subjects with polycythemia vera (PV) and essential thrombocythemia (ET) has significantly increased over the last three decades, largely due to the use of cytoreductive treatments. Currently, polycythemia

Differential diagnosis of pulmonary embolism in outpatients with non-specific cardiopulmonary symptoms

Most cardiopulmonary diseases share at least one symptom with pulmonary embolism (PE). The aim of this study was to identify the most common acute causes of dyspnea, chest pain, fainting or palpitations, which diagnostic procedures were performed and whether clinicians investigate them appropriately. An Italian multicenter collaboration gathered 17,497 Emergency Department (ED) records of patients admitted from January 2007 to June 2007 in six hospitals. A block random sampling procedure was applied to select 800 hospitalised patients. Results of the overall 17,497 patients were obtained by weighting sampled cases according to the probability of the randomisation block variables in the whole population. The case-mix of enrolled patients was assessed in terms of cardiopulmonary symptoms, and the prevalence of acute disorders. The actual performance of procedures was compared with a measure of their accuracy as expected in the most common clinical presentations. PE occurred in less than 4% of patients with cardiopulmonary symptoms. Acute heart failure, pneumonia and chronic obstructive pulmonary disease exacerbation were the most likely diagnoses in patients with dyspnea. Acute myocardial infarction was present in roughly 10% of patients with chest pain. Atrial fibrillation was the prevalent diagnosis in patients with palpitations. Echocardiography, computed tomographic pulmonary angiography, perfusion lung scan, D-dimer test and B-type natriuretic peptide were performed less than expected from their accuracy. Diagnostic strategies, starting from non-specific symptoms and coping with the eventuality of PE, are likely to benefit from an increased awareness of the examination’s accuracy in discriminating among several competing hypotheses, rather than in testing the single PE suspicion.

Incidence of thromboembolic complications in patients with atrial fibrillation or mechanical heart valves with a subtherapeutic international normalized ratio: A prospective multicenter cohort study

Subtherapeutic international normalized ratio (INR) is frequently encountered in clinical practice, and patients with high‐risk atrial fibrillation (AF) and with mechanical heart valve (MHV) with inadequate anticoagulation may be exposed to an increased risk of thromboembolic events (TE). However, there are no prospective data evaluating this risk. Consecutive patients with a history of stable anticoagulation, but with a subtherapeutic INR, were prospectively included. Data on use and dose of low‐molecular weight heparin (LMWH) bridging therapy were collected. The incidence of objectively confirmed TE and of major bleeding events within 90 days after the index INR was assessed. Five hundred and one patients with INR value 0.5–1 INR units below the lower limit of the patient‐specific target INR were included in the study (280 with MHV and 221 with AF and CHADS2 score ≥3). LMWH was prescribed for 64 patients (12.8%). During follow‐up, seven patients had a TE (1.40%; 95% confidence interval 0.68, 2.86%; 5.58 events for 100 patients year). All the events occurred within 14 days after the index INR. When we consider only patients who did not receive bridging therapy, the incidence of TE was 1.14% (5 of 437 patients; 95% confidence interval 0.49, 2.64%; 4.58 events for 100 patients year). There were no major bleeding events. The risk of TE in this population was not negligible. Given the frequent observation of subtherapeutic INR levels when monitoring vitamin K antagonists, this finding warrants additional investigation to improve the management of these patients. Am. J. Hematol. 2012.

Thrombosis in myeloproliferative and myelodysplastic syndromes

Abstract Myeloproliferative neoplasms (MPNs) and myelodisplastic syndromes (MDs) are clonal disorders caused by mutations of myeloid stem cells. Among MPNs, polycythemia vera and essential thrombocythemia are relatively benign disorders in which arterial and venous thromboses represent the main cause of morbidity and mortality. The natural history of MDs is often complicated by both thromboses and haemorrhages, mainly due to platelet quantitative and quantitative anomalies, as well as to treatment complications. In this short review, we focus the attention on the main aspects of thrombophilia in both disorders.

Leukocyte Activation in Obese Patients: Effect of Bariatric Surgery.

AbstractThe rising prevalence of obesity is a major global health problem. In severe obesity, bariatric surgery (BS) allows to obtain a significant weight loss and comorbidities improvement, among them one of the factors is the thrombotic risk. In this observational study, we measured indices of leukocyte activation in severely obese patients as markers of increased thrombotic risk in relation with serum markers of inflammation before and after BS.Frequency of polymorphonuclear neutrophil-platelet (PLT) and monocyte (MONO)-PLT aggregates as well as of tissue factor (TF) expressing MONOs was measured in the peripheral blood of 58 consecutive obese patients and 30 healthy controls. In 31 of the 58 obese patients, data obtained at the enrollment were compared with those obtained at 3, 6, and 12 months after BS.Compared with healthy controls, obese patients showed a higher frequency of polymorphonuclear leukocyte (PMNL)-PLT aggregates (7.47 ± 2.45 [6.82–8.11]% vs 5.85 ± 1.89 [5.14–6.55]%, P = 0.001), MONO-PLT aggregates (12.31 ± 7.33 [10.38–14.24]% vs 8.14 ± 2.22 [7.31–8.97]%, P < 0.001), and TF expressing MONOs (4.01 ± 2.11 [3.45–4.56]% vs 2.64 ± 1.65 [2.02–3.25]%, P = 0.002). PMNL-PLT and MONO-PLT aggregate frequency was positively correlated with TF expressing MONOs (R2 = 0.260, P = 0.049 and R2 = 0.318, P = 0.015, respectively).BS was performed in 31 patients and induced a significant reduction of the body mass index, and waist and hip circumferences. These effects were associated with a significant decrease of PMNL-PLT aggregates at 12 months (7.58 ± 2.27 [6.75–8.42]% vs 4.47 ± 1.11 [3.93–5.01]%, P < 0.001), and a reduction of TF expressing MONOs at 6 (3.82 ± 2.04 [3.07–4.57]% vs 1.60 ± 1.69 [0.30–2.90]%, P = 0.008) and 12 months (3.82 ± 2.04 [3.07–4.57]% vs 1.71 ± 0.54 [1.45–1.97]%, P = 0.001) after BS.These data suggest that leukocyte-PLT aggregate formation and MONO activation represent an important mechanism underlying the increased thrombotic risk of obese patients. We also show that BS is effective in normalizing these inflammatory indices.

Retrievable filter as an unusual cause of abdominal and lower back pain : A report of an exceptional case

Retrievable filter as an unusual cause of abdominal and lower back pain: A report of an exceptional case -

An old drug for a new application: Carbazochrome‐sodium‐sulfonate in HHT

To the Editor, Hereditary hemorrhagic teleangiectasia (HHT, RenduOsler-Weber Syndrome) is a dominantly inherited genetic vascular disorder in which epistaxis is the most frequent manifestation, responsible for high morbidity and very poor quality of life. Unfortunately, management of epistaxis in this disorder has no standard care and local treatments such as laser procedures, septodermoplasty intervention, or surgical closure of the nostrils are often aggressive. Therefore, the efforts in the approach to management are typically directed to minimize bleeding, as well as administration of blood transfusions avoiding invasive procedures as much possible. In this setting, blood transfusions bound with hormone therapy and antifibrinolytic treatment are used with unclear efficacy. Recently, experimental studies utilizing antiangiogenic drugs are reported as ongoing, but their efficacy has also not been proven. We report a collection of HHT patients showing a good response during treatment with an old hemostatic drug with capillary stabilizing action, carbazochromesodium-sulfonate, never tested before in such patients. Carbazochrome-sodium-sulfonate is used clinically for the treatment of hemorrhage due to capillary fragility. Its mechanism of action is unknown, but it may modulate fibrinolysis through alteration of endothelial cell function. Carbazochrome had various applications in bleeding disorders. With ethics committee approval and after written informed consents, we treated, orally, 10 HHT patients (3 male, 7 female; median range age of 42.8) who had carbazochrome-sodium-sulfonate 50mg twice per day for 2 months. Patients were administered the epistaxis severity score (ESS) questionnaire preand posttreatment. We observed a reduction in the ESS score in all subjects and, in particular, the pretreatment mean score (6.4 2.1) vs. post-treatment score at 1 month (4.9 1.8) and at 2 months (3.4 1.3) showed a statistically, significant difference (P< .05) compared to baseline (9.0 1.6) at both time points. Furthermore, the mean hemoglobin level increased at 1 month (9.9 gr/dL 1.3) compared to baseline (9.0 gr/dL 1.6) and at 2 months (10.9 gr/dL 1.15) statistical analyses showed significance (P< .05) at both time points (Table 1). To our knowledge, this is the first report on the potential beneficial effect of carbazochrome-sodiumsulfonate in treating HHT. Moreover, this observation may relate to an effect on endothelial barrier dysfunction through inhibition of agonist-induced phosphoinositide hydrolysis that may be involved in the pathogenesis of HHT-related epistaxis and these results may lead to further research that may determine safety and The Journal of Clinical Pharmacology 2015, 55(5) 601–602

Hydroxyurea-mediated release of nitric oxide in myeloproliferative neoplasms patients: Effects on platelet–leukocyte interaction

Inmyeloproliferative neoplasms (MPNs), thrombosis is an important cause of morbidity and mortality, and some experimental studies have reported an indirect but significant antithrombotic efficacy of hydroxyurea (HU), currently the most used cytoreductive agent in these disorders. HU was studied in important randomized clinical trials, one carried out in polycythemia vera (PV) and 2 in essential thrombocytemia (ET) patients. In summary, Finazzi describes these last studies, 1 trial comparing HUwith a randomized untreated control group performed in 114 patients with ET and a high risk of thrombosis and another comparing HU plus low-dose aspirin with anagrelide plus low-dose aspirin in 809 ET at high risk. In the first, a significant reduction of the rate of vascular events was observed in the HU arm (1.6% patient-years) compared with the controls (10.7% patientyears;P1⁄4 .003). In the second, patients randomized to HU and aspirin were less likely to reach the composite primary end point of major thrombosis (arterial or venous), major hemorrhage, or death from a vascular cause (P1⁄4 .03). In these randomized studies, HUwas demonstrated to be very effective in preventing thrombosis and thus is considered the drug of choice in high-risk patients. The starting dose of HU usually adopted is 15 to 20mg/kg per day until response is obtained (hematocrit < 0.45 [45%]). In the main trials reported by Finazzi, patients who were assigned to receive HUwere started on 0.5 to 1 g daily. Thereafter, a maintenance dose should be administered to keep hematocrit at response levels without reducing white blood cell count values below 3000 10/L. Notably, the antithrombotic effect of HU may recognize additional mechanisms of action in addition to panmyelosuppression, including qualitative changes in leukocytes, decreased expression of endothelial adhesion molecules, and enhanced nitric oxide generation, as observed in patients with sickle cell disease. In sickle cell disease impaired white blood cell function has a pathogenic role in the onset of vaso-occlusive events. In experimental studies, unstimulated leukocytes showed decreased L-selectin expression and increased H2O2 production, whatever the severity of the disease, reflecting polymorphonuclear cell (PMN) activation. This contributes to endothelial activation reflected by abnormal plasma levels of soluble adhesion molecules (soluble intercellular adhesion molecule-1, sE selectin, and sLselectin). Furthermore, in these patients, tumor necrosis factor induced an H2O2 production significantly higher than in the other patient groups and controls. These impairments immobilize PMNs on the endothelium, thereby inducing reduced blood flow and fostering microvascular occlusion and vascular damage. In contrast, subjects treated with HU show near-normal basal and poststimulation H2O2 production as well as normal L-selectin shedding after stimulation, demonstrating major qualitative changes in PMN abnormalities on HU The Journal of Clinical Pharmacology 2015, 55(10) 1125–1130