Rossella R. Cacciola

Cardiovascular Events and Intensity of Treatment in Polycythemia Vera

BACKGROUND Current treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of less than 45%, but this therapeutic strategy has not been tested in a randomized clinical trial. METHODS We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group). The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. The secondary end points were cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, and hemorrhage. An intention-to-treat analysis was performed. RESULTS After a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.45 to 10.53; P=0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P=0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events. CONCLUSIONS In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT01645124, and EudraCT number, 2007-006694-91.).

Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments

Polycythemia vera and essential thrombocythemia are typically complicated by thrombosis. According to this multicenter study recurrent thrombosis is observed in about one third of patients. Cytoreduction protects against recurrence of thrombosis. The contemporary use of oral anticoagulants or antiplatelet agents further reduce the incidence of re-thrombosis. Background Prior thrombosis is a well-established risk factor for re-thrombosis in polycythemia vera and essential thrombocythemia but scarce data are available on the rate of re-thrombosis and the optimal strategy for prevention of recurrence. Design and Methods We retrospectively estimated the rate of recurrence in a multicenter cohort of 494 patients (poly-cythemia vera/essential thrombocythemia 235/259) with previous arterial (67.6%) or venous thrombosis (31%) or both (1.4%). First thrombosis was cerebrovascular disease in 191 cases, acute coronary syndrome in 106, peripheral arterial thrombosis in 44, and venous thromboembolism in 160. Microcirculatory events were not computed. Results Thrombosis recurred in 166 patients (33.6%), with an incidence of 7.6% patient-years. Sex, diagnosis (polycythemia vera or essential thrombocythemia), and presence of vascular risk factors did not predict recurrence, whereas age >60 years did (multivariable hazard ratio [HR], 1.67; 95% confidence interval [CI] 1.19–2.32). Increased leukocyte count at the time of the first thrombosis was a risk factor for recurrence in patients <60 years old (HR 3.55; 95% CI 1.02–12.25). Cytoreduction halved the risk in the overall cohort (HR 0.53; 95% CI 0.38–0.73) and the combination with antiplatelet agents or oral anticoagulants was more effective than administration of single drugs. Significant prevention of rethrombosis was independently achieved in patients with venous thromboembolism by both oral anticoagulants (HR 0.32; 95% CI 0.15–0.64) and antiplatelet agents (HR 0.42; 95% CI 0.22–0.77), in those with acute coronary syndrome by cytoreduction (HR 0.30; 95% CI 0.13–0.68), and in those with cerebrovascular disease by antiplatelet agents (HR 0.33; 95% CI 0.16–0.66). The overall incidence of major bleeding was 0.9% patient-years and rose to 2.8% in patients receiving both antiplatelet and anti-vitamin K agents. Conclusions In patients with polycythemia vera and essential thrombocythemia, cytoreduction protects against recurrent thrombosis, particularly after acute coronary syndrome. The contemporary use of oral anticoagulants (after venous thromboembolism) or antiplatelet agents (after cerebrovascular disease or venous thromboembolism) further improves the protective effect. Such findings call for prospective studies aimed at investigating whether strategies tailored according to the type of first thrombosis could improve prevention of recurrences.

Increased risk of recurrent thrombosis in patients with essential thrombocythemia carrying the homozygous JAK2 V617F mutation

Evidence suggests that the JAK2 V617F mutation is associated with an increased risk of first thrombosis in patients with essential thrombocythemia (ET). Whether this mutation is also a risk factor for recurrent thrombosis is currently unknown. To investigate the impact of the JAK2 V617F mutation on the risk of recurrent thrombosis in patients with ET, we carried out a multicentre retrospective cohort study. We recruited 143 patients with previous arterial (64.4%) or venous major thrombosis (34.8%) or both (0.8%); 98 of them (68.5%) carried the mutation. Thrombosis recurred in 43 of the patients (30%); overall, after adjustment for sex, age, presence of vascular risk factors, and treatment after the first thrombosis, the presence of the JAK2 mutation did not predict recurrence (multivariable hazard ratio, HR, 0.88, 95% CI 0.46−1.68). Indeed, the individuals homozygous for the JAK2 V617F (allele burden >50%) mutation had an increased risk of recurrence in comparison with wild-type patients (HR 6.15, 95% CI 1.51–24.92). In conclusion, a homozygous JAK2 V617F mutation is an independent risk factor for recurrent thrombosis in patients with ET.

Modifications of coagulation and fibrinolytic parameters in laparoscopic cholecystectomy

Background: The incidence of deep vein thrombosis and pulmonary embolism following laparoscopic surgery is unknown and studies on alterations of hemostasis after laparoscopy are inconclusive. Methods: In this study we prospectively evaluated changes in prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen (Fg), antithrombin III (ATIII), prothrombin fragment F 1 + 2, beta-thromboglobulin (bTG) and D-dimer (D-D), preoperatively and 24 h after laparoscopic surgery in 16 patients. Results: Comparing pre- and postoperative values, no statistical differences were observed in aPTT, F1 + 2, and ATIII measurements. Postoperative PT values increased slightly (p ~ 0.05) after surgery. Conversely, Fg, bTG, and D-D values were statistically higher in the 24-h evaluation (p = 0.008, 0.01, and 0.045, respectively). Conclusions: These data suggest that laparoscopic surgery induces activation of coagulation and fibrinolytic pathways and, additionaly, bTG elevation, which has never been reported and might account for postoperative platelet activation and a greater risk of thrombogenicity. Therefore, routine thromboembolic prophylaxis in patients undergoing laparoscopic surgery is recommended.

Leukocytosis is a risk factor for recurrent arterial thrombosis in young patients with polycythemia vera and essential thrombocythemia

There is evidence that leukocytosis is associated with an increased risk of first thrombosis in patients with polycythemia vera (PV) and essential thrombocythemia (ET). Whether it is a risk factor for recurrent thrombosis too is currently unknown. In the frame of a multicenter retrospective cohort study, we recruited 253 patients with PV (n = 133) or ET (n = 120), who were selected on the basis of a first arterial (70%) or venous major thrombosis (27.6%) or both (2.4%), and who were not receiving cytoreduction at the time of thrombosis. The probability of recurrent thrombosis associated with the leukocyte count recorded at the time of the first thrombosis was estimated by a receiver operating characteristic analysis and a multivariable Cox proportional hazards regression model. Thrombosis recurred in 78 patients (30.7%); multivariable analysis showed an independent risk of arterial recurrence (hazard ratio [HR] 2.16, 95% CI 1.12–4.18) in patients with a leukocyte count that was >12.4 × 109/L at the time of the first thrombotic episode. The prognostic role for leukocytosis was age‐related, as it was only significant in patients that were aged <60 years (HR for arterial recurrence 3.35, 95% CI 1.22–9.19). Am. J. Hematol., 2010.

Relevance of Endothelial-Haemostatic Dysfunction in Cigarette Smoking

Cigarette smoking plays a major role in the development of atherosclerosis and is associated with increased morbidity and mortality for coronary heart disease, stroke and peripheral vascular disease. In spite of the abundance of epidemiological evidence that links cigarette smoking to vascular disease, the pathologic mechanisms for such interaction are not clear. The endothelium is a major target organ that undergoes activation when exposed to common vascular triggers, including hypertension, hypercholesterolemia, hyperglycaemia and smoking. Changes in endothelial function may lead to a dysfunctional vascular phenotype characterized by anomalous responses of the vascular tone, abnormal endothelial proliferation and prothrombotic activation. Several studies have demonstrated that smoking may alter endothelial function by a direct toxic effect and consequently trigger haemostatic activation and thrombosis. In this article we will review the evidence that loss of normal endothelial function may result in a loss of the balance of the haemostatic system and in changes of the platelet physiology that may be relevant for the pathogenic effect of smoking on the development of atherothrombosis.

Portal Vein Thrombosis After Laparoscopic and Open Splenectomy

INTRODUCTION Portal vein thrombosis (PVT) could be a life-threatening complication after splenectomy if not diagnosed promptly and treated properly. Risk factors of PVT are not completely clarified. Spleen size and underlying hematologic diseases are main potential risk factors for this complication. Laparoscopic surgery might increase the risk of developing PVT, as it reduces the blood flow in the portal system due to the pneumoperitoneum but, on the other hand, it seems to be associated with less postoperative modifications of coagulation parameters than open surgery, thus preventing PVT itself. The authors reviewed their series on open and laparoscopic splenectomies, pointing out their experience on PVT and discussing their surveillance and prophylaxis programs to prevent this complication. MATERIALS AND METHODS In this series, the authors report their experience on postsplenectomy PVT in 162 patients who have been splenectomised (102 operated on laparoscopically and 60 by open surgery). RESULTS PVT was clinically observed in 1 case out of 60 open splenectomies and in 3 cases out of 102 laparoscopic procedures. Patients were treated with conservative anticoagulation therapy. In one case, additional ileal resection was needed. Mortality was 0%. CONCLUSION Low-molecular-weight heparin should be administered to all patients who have been splenectomised, especially if they are at high risk of PVT. If symptoms appear, patients need to be treated with high-dose heparin followed, after at least 3 weeks, by oral anticoagulant therapy.

Circulating endothelial-coagulative activation markers after smoking cessation: a 12-month observational study

Eur J Clin Invest 2011; 41 (6): 616–626

Low impact of cardiovascular adverse events on anagrelide treatment discontinuation in a cohort of 232 patients with essential thrombocythemia.

This retrospective study of the thrombocythemia Italian registry (RIT) documented that 71 (30.6%) out of 232 ET patients experienced 88 cardiovascular adverse events (CV-AEs) during anagrelide treatment (522 pt-y). The rate of CV-AEs was: 24.1% for palpitations, 4.3% for angina, 3.5% for arterial hypertension, 3.0% for congestive heart failure, 1.8% for arrhythmia, 0.9% for AMI, 0.4% for pericardial effusion. CV-AEs led to treatment discontinuation in nine (3.9%) patients, while in the remaining cases they were managed by pharmacological intervention and/or patient life style improvement. CV-AEs had no relationship with patient characteristics (including older age). A significant relationship was found only with a higher anagrelide induction dose. In the absence of any agreed protocol, a cardiovascular instrumental evaluation (CV-IE) was performed in 102 (44%) patients before commencement of anagrelide (with higher rate after the anagrelide/Xagrid EMA approval of 2004), and in 84 (36%) patients during treatment. Patients with and without CV-IEs, who resulted completely balanced for all their characteristics, did not significantly differ in the occurrence of CV-AEs. In conclusion, this study on ET patients treated with anagrelide shows that CV-AEs, equally distributed in younger and older subjects, were mostly mild and easily manageable, allowing safe treatment continuation in the majority of cases. Moreover, routinely performing a CV-IE did not appear to anticipate the occurrence of CV-AEs.

Cerebral vein thrombosis in patients with Philadelphia-negative myeloproliferative neoplasms An European Leukemia Net study

To investigate the characteristics and clinical course of cerebral vein thrombosis (CVT) in patients with myeloproliferative neoplasms (MPN) we compared 48 patients with MPN and CVT (group MPN‐CVT) to 87 with MPN and other venous thrombosis (group MPN‐VT) and 178 with MPN and no thrombosis (group MPN‐NoT) matched by sex, age at diagnosis of MPN (±5 years) and type of MPN. The study population was identified among 5,500 patients with MPN, from January 1982 to June 2013. Thrombophilia abnormalities were significantly more prevalent in the MPN‐CVT and MPN‐VT than in MPN‐NoT group (P = 0.015), as well as the JAK2 V617F mutation in patients with essential thrombocythemia (P = 0.059). Compared to MPN‐VT, MPN‐CVT patients had a higher rate of recurrent thrombosis (42% vs. 25%, P = 0.049) despite a shorter median follow‐up period (6.1 vs. 10.3 years, P = 0.019), a higher long‐term antithrombotic (94% vs. 84%, P = 0.099) and a similar cytoreductive treatment (79% vs. 70%, P = 0.311). The incidence of recurrent thrombosis was double in MPN‐CVT than in MPN‐VT group (8.8% and 4.2% patient‐years, P = 0.022), and CVT and unprovoked event were the only predictive variables in a multivariate model including also sex, blood count, thrombophilia, cytoreductive, and antithrombotic treatment (HR 1.97, 95%CI 1.05–3.72 and 2.09, 1.09–4.00, respectively). Am. J. Hematol. 89:E200–E205, 2014.