Search

A b s t r ac t 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

background The use of aspirin for the prevention of thrombotic complications in polycythemia vera is controversial. methods We enrolled 518 patients with polycythemia vera, no clear indication for aspirin treatment, and no contraindication to such treatment in a double-blind, placebo-controlled, randomized trial to assess the safety and efficacy of prophylaxis with low-dose aspirin (100 mg daily). The two primary end points were the cumulative rate of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and the cumulative rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes. The mean duration of follow-up was about three years. results Treatment with aspirin, as compared with placebo, reduced the risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes (relative risk, 0.41; 95 percent confidence interval, 0.15 to 1.15; P=0.09) and the risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (relative risk, 0.40; 95 percent confidence interval, 0.18 to 0.91; P=0.03). Overall mortality and cardiovascular mortality were not reduced significantly. The incidence of major bleeding episodes was not significantly increased in the aspirin group (relative risk, 1.62; 95 percent confidence interval, 0.27 to 9.71). conclusions Low-dose aspirin can safely prevent thrombotic complications in patients with polycythemia vera who have no contraindications to such treatment.

We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials.

Increased mobilization of circulating endothelial progenitor cells may represent a new biological hallmark of myeloproliferative neoplasms. We measured circulating endothelial colony forming cells (ECFCs) in 106 patients with primary myelofibrosis, fibrotic stage, 49 with prefibrotic myelofibrosis, 59 with essential thrombocythemia or polycythemia vera, and 43 normal controls. Levels of ECFC frequency for patient's characteristics were estimated by using logistic regression in univariate and multivariate setting. The sensitivity, specificity, likelihood ratios, and positive predictive value of increased ECFC frequency were calculated for the significantly associated characteristics. Increased frequency of ECFCs resulted independently associated with history of splanchnic vein thrombosis (adjusted odds ratio = 6.61, 95% CI = 2.54-17.16), and a summary measure of non-active disease, i.e. hemoglobin of 13.8 g/dL or lower, white blood cells count of 7.8×10(9)/L or lower, and platelet count of 400×10(9)/L or lower (adjusted odds ratio = 4.43, 95% CI = 1.45-13.49) Thirteen patients with splanchnic vein thrombosis non associated with myeloproliferative neoplasms were recruited as controls. We excluded a causal role of splanchnic vein thrombosis in ECFCs increase, since no control had elevated ECFCs. We concluded that increased frequency of ECFCs represents the biological hallmark of a non-active myeloproliferative neoplasm with high risk of splanchnic vein thrombosis. The recognition of this disease category copes with the phenotypic mimicry of myeloproliferative neoplasms. Due to inherent performance limitations of ECFCs assay, there is an urgent need to arrive to an acceptable standardization of ECFC assessment.

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 x 10(9)/l) we encountered in our population had an impact on the outcome of PV patients treated by current therapeutic strategies.

Thrombopoietin receptor agonists (TPO-RAs) are currently indicated for continuous treatment of chronic primary immune thrombocytopenia (ITP). However, there is growing evidence that TPO-RAs can also trigger sustained response in 10-30% of cases after treatment tapering and discontinuation. Therefore, at least for selected responding patients, it might be rational to plan TPO-RA interruption to exploit off-treatment response. Intriguingly, complete or partial responses with TPO-RAs are frequently observed when treatments are initiated early, suggesting that unknown immune-related mechanisms may be involved in this phenomenon. The sustained responses observed after interruption of TPO-RAs may be interpreted as a recovery of immunological tolerance; thus, the re-establishment of immunological equilibrium might be primarily responsible for the observed off-treatment effect. Importantly, these findings may indicate that anticipated TPO-RA usage can lead to improved responses, and that optimized tapering and interruption in selected patients can furthermore improve prognoses. On the base of this rationale, a series of real-life considerations have been generated by a panel of Experts to elucidate possible novel criteria and modalities to identify subgroups of patients who can benefit from tapering and/or discontinuation of TPO-RAs. Towards this aim, the results of a survey of ITP experts are herein reported, reflecting a snapshot of current real-life experience on early discontinuation of TPO-RA-based therapy. The present manuscript also highlights the importance of future translational studies on novel prognostic and predictive biomarkers that can stratify patients and facilitate the clinical choice for second-line treatment of ITP.

This article presents the results of a group discussion among an ad hoc constituted Panel of experts aimed at highlighting unmet clinical needs (UCNs) in the management of thrombotic risk and thrombotic events associated with Philadelphia-negative myeloproliferative neoplasms (Ph-neg MPNs). With the Delphi technique, the challenges in Ph-neg MPN-associated thrombosis were selected. The most clinically relevant UCNs resulted in: (1) providing evidence of the benefits and risks of direct oral anticoagulants, (2) providing evidence of the benefits and risks of cytoreduction in patients with splanchnic vein thrombosis without hypercythemia, (3) improving knowledge of the role of the mutated endothelium in the pathogenesis of thrombosis, (4) improving aspirin dosing regimens in essential thrombocythemia, (5) improving antithrombotic management of Ph-neg MPN-associated pregnancy, (6) providing evidence for the optimal duration of anticoagulation for prophylaxis of recurrent VTE, (7) improving knowledge of the association between somatic gene mutations and risk factors for thrombosis, and (8) improving the grading system of thrombosis risk in polycythemia vera. For each of these issues, proposals for advancement in research and clinical practice were addressed. Hopefully, this comprehensive overview will serve to inform the design and implementation of new studies in the field.

The safety of raw milk sold in Northern Italy was investigated in relation to hygiene quality parameters and presence of Salmonella spp., Listeria monocytogenes, thermotolerant Campylobacter, and Verocytotoxin producing Escherichia coli O157:H7. The performance of different analytical methods used-official culture method (ISO), modified Bacteriological Analytical Manual cultural method (mBAM), and polymerase chain reaction (PCR)-was evaluated. The presence of Mycobacterium avium subsp. paratuberculosis (Map) was investigated only by PCR. All samples met regulations for alkaline phosphatase and inhibitory substance, while 18% and 44.8% of samples collected from vending machines had, respectively, somatic cell count (SCC) >300,000/mL and total bacterial count (TBC) >50,000 CFU/mL. The correlation between hygienic quality parameters in samples collected from bulk tank and vending machines showed a significant increase of TBC in vending machines meaning that raw milk was mishandled during distribution and sale. All pathogens investigated were detected in raw milk sold at vending machines; a total of five samples (5%) had at least one pathogen, of which two were detected by PCR and three by mBAM. None of the samples was positive by cultural ISO methods. Even if the comparison of analytical methods showed that none performs significantly better than the others, testing a higher volume of milk (25 versus 210 mL) affects significantly the detection rate of pathogens. Three samples (3%) were positive for Map, suggesting that raw milk is a significant source of Map exposure for consumers. The observed TBC increase and the detection of several pathogenic bacteria pose questions on the safety of raw milk; the use of ISO seems inefficient in detecting a low contamination level of pathogens in milk and consequently not appropriate as official method for testing. In order to ensure consumer's safety, a new approach for the raw milk chain is required.

Aims: The aim of the study was to evaluate the behaviour of Listeria monocytogenes in the conditioning liquid of packaged water buffalo mozzarella cheese (WBMC). Methods and Results: The conditioning liquid was contaminated with L. monocytogenes, and the contaminated samples were stored at four different storage temperatures: 5 and 10°C for 22 days; 20°C for 9 days; 20°C for 3 days and then at 5°C for 6 days. The results showed that L. monocytogenes concentration decreased when contaminated samples were stored at 5°C. When WBMC was stored at 20°C and at 10°C, L. monocytogenes started to grow after a lag phase of 3 and 10 days, respectively. When samples were stored at variable temperature conditions, L. monocytogenes numbers showed a lag phase of 5 days. Conclusions: Use of a conditioning liquid characterized by acidity and a correct storage temperature is able to counteract pathogen replication during shelf life. A high concentration of lactic acid bacteria was associated with effective control of L. monocytogenes but the role of lactic acid bacteria in WBMC conditioning liquid requires further investigation. Significance and Impact of the Study: According to European regulations, food producers should be able to justify decision-making on the shelf life assigned to their products, taking into account reasonable storage conditions and use by consumers. The results of the trial yielded information for producers of WBMC and similar cheeses for decision-making on product shelf life.

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.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.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 age60 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 patients60 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.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.

At present, allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only curative treatment for patients with myelofibrosis (MF). Unfortunately a significant proportion of candidate patients are considered transplant ineligible due to their poor general condition and advanced age at time of diagnosis. The approval of the first JAK inhibitor, Ruxolitinib, for patients with advanced MF in 2011 has had a qualified impact on the treatment algorithm. The drug affords substantial improvement in MF-associated symptoms and splenomegaly but no major effect on the natural history. There has, therefore, been considerable support to assess the drug’s candidacy in the peri-transplant period. The drug’s precise impact on clinical outcome following allo-SCT is currently not known; nor is the drug’s long term efficacy and safety known. Considering the rarity of MF and the small proportion of patients who are undergoing allo-SCT, well designed collaborative efforts are required. In order to address some of the principal challenges, an expert panel of laboratory and clinical experts in this field was established, and an independent workshop held during the 54(th) American Society of Hematology’s meeting in New Orleans, USA, on 6(th) December 2013 and the European Hematology Association meeting in Milan, Italy on 13(th) June 2014. This document summarizes the results of these efforts.

ACUTE PROMYELOCYTIC leukemia (APL) is a distinct subtype of acute myelogenous leukemia (AML), identified by the French-American-British classification as AML-M3[1][1] and cytogenetically characterized by the balanced reciprocal translocation between chromosomes 15 and 17. Patients with the common

This study evaluates the functional procoagulant features of plasma microparticle (MP) to explore the MP contribution to the hypercoagulable state of patients with essential thrombocythemia (ET). Platelet-free plasma samples were obtained from 73 ET patients (37 positive for the JAK2V617F mutation) and 72 control subjects. The calibrated automated thrombogram (CAT) was performed in plasma samples to determine thrombin generation of MP-associated tissue factor (TF) and procoagulant phospholipid (PPL) activity, and the STA Procoag PPL assay to measure MP-PPL activity only. Both thrombin generation and PPL procoagulant activities were found significantly elevated in ET patients compared to controls, and were associated to significantly higher levels of TF antigen and FVIIa/AT complex. Thrombin generation was significantly greater in JAK2-V617F positive compared to JAK2-V617F negative patients and normal subjects. Significant correlations were found between the PPL-assay and the different parameters of the CAT assay. No difference was seen between the thrombosis and no thrombosis group. Prospective studies are needed to test whether MP-associated thrombin generation and procoagulant activity may predict for thrombosis in these patients. Am. J. Hematol. 89:68–73, 2014. © 2013 Wiley Periodicals, Inc.

Givinostat, a histone-deacetylase inhibitor (HDACi), inhibits proliferation of cells bearing the JAK2 V617F mutation and has shown significant activity with good tolerability in patients with chronic myeloproliferative neoplasms (MPN). In this multicentre, open-label, phase II study, 44 patients with polycythaemia vera (PV), unresponsive to the maximum tolerated doses (MTD) of hydroxycarbamide (HC), were treated with Givinostat (50 or 100 mg/d) in combination with MTD of HC. The European LeukaemiaNet response criteria were used to assess the primary endpoint after 12 weeks of treatment. Complete or partial response was observed in 55% and 50% of patients receiving 50 or 100 mg of Givinostat, respectively. Control of pruritus was observed in 64% and 67% of patients in the 50 and 100 mg groups, respectively. The combination of Givinostat and HC was well tolerated: eight patients (18%) discontinued, four in each treatment arm; grade 3 adverse events were reported in one patient (4·5%) in each treatment arm. The combined use of Givinostat and HC was safe and clinically effective in HC-unresponsive PV patients.

Hydroxyurea (Hydroxycarbamide; HU) is commonly used for the long-term treatment of patients with Philadelphia-chromosome negative chronic myeloproliferative neoplasms (MPNs). It is considered a first-choice agent for the treatment of these disorders as underlined by the European Leukemia Net Consensus Conference [1], although it is formally approved for this indication in some countries only. The drug is reportedly well tolerated in the large majority of subjects, although systemic and/or localized toxicities have been reported. Consensus criteria for definition of “intolerance” to HU have been described; patients who develop intolerance are candidate for second-line therapy and, more recently, for investigational drugs. However, no epidemiologic information about the occurrence of the most clinically significant HU-associated adverse events is yet available. In this study, the authors report on a multicenter series of 3,411 patients who were treated with HU among which 184, accounting for 5% of total, developed significant drug-related toxicities. These data provide an estimate of the frequency and a detailed characterization of clinically significant HU-related toxicities; these information have relevance for the management of MPN patients who require second-line therapy after developing HU-related intolerance.

Summary. In this overview we address the three phase III studies that compared new oral anticoagulants (dabigatran, rivaroxaban and apixaban) with warfarin in the setting of stroke prevention in atrial fibrillation. Strengths and weaknesses of the studies were examined in detail through indirect comparison. We analyze and comment the inclusion and exclusion criteria, the characteristics of randomized patients, the primary efficacy and safety end points and side effects. All new oral anticoagulants resulted in being non-inferior to vitamin K antagonists in reducing stroke or systemic embolism in patients with atrial fibrillation. Dabigatran 150 mg and apixaban were superior to vitamin K antagonists. Importantly, new oral anticoagulants significantly reduced hemorrhagic stroke in all three studies. Major differences among new oral anticoagulants include the way they are eliminated and side effects. Both dabigatran and apixaban were tested in low- to moderate-risk patients (mean CHADS2 [Congestive heart failure, Hypertension, Age, Diabetes, Stroke] score = 2.1–2.2) whereas rivaroxaban was tested in high-risk patients (mean CHADS2 score = 3.48) and at variance with dabigatran and apixaban was administered once daily. Apixaban significantly reduced mortality from any cause. The choice of a new oral anticoagulant should take into account these and other differences between the new drugs.

The direct sale by farmers of raw milk for human consumption has been allowed in Italy since 2004. The aim of this study was to evaluate the behaviour of selected foodborne pathogens in raw milk sold in vending machines, in field handling conditions, and during shelf-life from production to consumption. Temperature of storage of raw milk in 33 farms authorized to produce and sell raw milk were investigated from farm to vending machine delivery, together with consumer habits in one province of the Emilia-Romagna region of northern Italy. Failure to maintain appropriate low temperatures during shelf-life was recorded and 43% of consumers did not boil milk before consumption. Listeria monocytogenes, Escherichia coli O157:H7, Salmonella Typhimurium and Campylobacter jejuni strains were inoculated into raw milk samples, and the best (4°C as established by law) and worst temperature storage conditions detected (variable temperature) were simulated. Boiling tests were performed for each pathogen considered at high and low levels of contamination. Results showed an increase in L. monocytogenes in milk stored at 4°C and at variable temperatures recorded in shelf-life monitoring, an increase in E. coli O157:H7 and S. Typhimurium at variable temperatures but not at 4°C, and a decrease in C. jejuni in all storage conditions. Boiling milk is effective in making it safe for consumers. This study provides evidence that appropriate handling of raw milk, maintaining low temperatures, together with consumer education concerning boiling raw milk before consumption are key factors in preventing foodborne infections linked to raw milk consumption, and helps assess the risk of foodborne infection linked to raw milk consumption.

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 x 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

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. © Springer-Verlag 2009.

JAK2 617V>F mutation occurs in a homozygous state in 25% to 30% of patients with polycythemia vera (PV) and 2% to 4% with essential thrombocythemia (ET). Whether homozygosity associates with distinct clinical phenotypes is still under debate. This retrospective multicenter study considered 118 JAK2 617V>F homozygous patients (104 PV, 14 ET) whose clinical characteristics were compared with those of 587 heterozygous and 257 wild-type patients. Irrespective of their clinical diagnosis, homozygous patients were older, displayed a higher leukocyte count and hematocrit value at diagnosis, and presented larger spleen volume. Aquagenic pruritus was significantly more common among homozygous PV patients. JAK2 617V>F homozygosity associated with more frequent evolution into secondary myelofibrosis in both PV and ET. After adjustment for sex, age, leukocyte count, and previous thrombosis in a multivariate analysis, homozygous ET patients displayed a significantly higher risk of cardiovascular events (hazard ratio [HR] 3.97, 95% confidence interval [CI] 1.34–11.7; P = .013) than wild-type (HR = 1.0) or heterozygous patients (HR = 1.49). No significant association of JAK2 617V>F homozygosity with thrombosis risk was observed in PV. Finally, JAK2 617V>F homozygous patients were more likely to receive chemotherapy for control of disease. We conclude that JAK2 617V>F homozygosity identifies PV or ET patients with a more symptomatic myeloproliferative disorder and is associated with a higher risk of major cardiovascular events in patients with ET.

Progression to acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) is a possible evolution of polycythemia vera (PV), but whether some patients are at increased natural risk for this complication and how much the contribution of pharmacologic cytoreduction can affect the natural course of the disease remain uncertain. The European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) prospective project included 1638 patients with PV. AML/MDS was diagnosed in 22 patients after a median of 2.5 years from recruitment in the study and a median of 8.4 years from the diagnosis of PV. Variables associated with progression to AML/MDS were assessed using different models of multivariate analysis. Older age was confirmed as the main independent risk factor (hazard ratio [HR], 4.30; 95% confidence interval [95% CI], 1.16-15.94; P = .0294), whereas overall disease duration failed to reach statistical significance (more than 10 years: HR, 1.91; 95% CI, 0.64-5.69; P = .2466). Exposure to P32, busulphan, and pipobroman (HR, 5.46; 95% CI, 1.84-16.25; P = .0023), but not to hydroxyurea (HU) alone (HR, 0.86; 95% CI, 0.26-2.88; P = .8021), had an independent role in producing an excess risk for progression to AML/MDS compared with treatment with phlebotomy or interferon.

SummaryA prospective, randomized, double-blind clinical trial was carried out in a single center to compare the clinical and laboratory quality of oral anticoagulant therapy monitored with recombinant tissue factor (RTF) or with a sensitive, human-derived, conventional thromboplastin (CT) in the PT test. Seven hundred and fifty-seven consecutive patients receiving oral anticoagulation for various indications were randomized to RTF (n = 379) or CT (n = 368) for 6 months. Total follow-up was 167 and 153 patient-years for RTF and TP groups respectively. Fifty-six bleeding events were observed: 31 in the RTF group and 25 in the TP group. The incidence of bleeding was 18.5 and 16.5% pt-yrs for RTF and TP patients respectively (n.s.). The event-free follow-up curves were not significantly different between the two groups. The laboratory quality of oral anticoagulation was evaluated with the “last check in file” method: therapeutic INR was found in the same propor-tipn of RTF and TP patients (70.2% vs 68.8%). Our study shows that RTF is as effective as a sensitive, conventional thromboplastin for monitoring oral anticoagulation.

Objective: To assess the efficacy of intravenous immunoglobulin (IVIG), in comparison with plasma exchange (PE), in the treatment of patients with thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS). © 1992 Wiley-Liss, Inc. Design: Prospective, nonrandomized comparative study. Setting: Hematology department in a general hospital. Patients: 17 consecutive adult patients, six of them pregnant, with diagnosis of TTP/ HUS. Three had a severity score at diagnosis ≦4 and were treated with IVIG and 14 had a severity score of ≧5 and/or were pregnant and received PE. The response was evaluated after 5 days of therapy. Results: Complete remission was obtained in 0/3 cases treated with IVIG and 10/14 (71%) with PE (Fisher's exact test P = 0.05). Three patients died for widespread TTP-HUS, and four had persistent disease. In three of the four resistant patients, complete remission was obtained by further PE but not by further IVIG. The overall remission rate was 76% (13/17). Conclusions: Our study does not confirm the utility of IVIG in the management of TTP-HUS, as suggested by earlier single case reports. © 1992 Wiley-Liss, Inc.

Thrombohemorrhagic complications are a major cause of morbidity and mortality in patients with essential thrombocythemia (ET) and polycythemia vera (PV), The pathogenesis of these complications is not completely clarified, Several studies have described abnormalities of red blood cells and platelets in these patients. However, no studies are available on changes in the polymorphonuclear leukocytes (PMNs), which can play an important role in the activation of the hemostatic System. In patients with ET (n = 37) and PV (n = 34), a series of PMN activation parameters (PMN membrane CD11b and leukocyte alkaline phosphatase [LAP] antigen expression, cellular elastase content, plasma elastase, and myeloperoxidase levels) was evaluated simultaneously with the levels of plasma markers of endothelial damage (thrombomodulin and von Willebrand factor antigen) and hypercoagulation (thrombin-antithrombin complex, prothrombin fragment 1 + 2, and D-dimer). The results show the occurrence of PMN activation in both groups of patients compared with a control group of healthy subjects. An increase in CD11b and LAP expression by PMN membrane was observed, together with a significant increase in cellular elastase content, plasma elastase, and myeloperoxidase levels. In addition, patients had high plasma levels of endothelial and hypercoagulation markers compared with controls, For the first time, these data show that in ET and PV, 2 hematologic conditions that place patients at increased risk for thrombosis, an in vivo leukocyte activation occurs and is associated with laboratory signs of endothelium and coagulation system activation. (C) 2000 by The American Society of Hematology. Thrombohemorrhagic complications are a major cause of morbidity and mortality in patients with essential thrombocythemia (ET) and polycythemia vera (PV). The pathogenesis of these complications is not completely clarified. Several studies have described abnormalities of red blood cells and platelets in these patients. However, no studies are available on changes in the polymorphonuclear leukocytes (PMNs), which can play an important role in the activation of the hemostatic system. In patients with ET (n = 37) and PV (n = 34), a series of PMN activation parameters (PMN membrane CD11b and leuko-cyte alkaline phosphatase [LAP] antigen expression, cellular elastase content, plasma elastase, and myeloperoxidase levels) was evaluated simultaneously with the levels of plasma markers of endothelial damage (thrombomodulin and von Willebrand factor antigen) and hypercoagulation (thrombin-antithrombin complex, prothrombin fragment 1 + 2, and D-dimer). The results show the occurrence of PMN activation in both groups of patients compared with a control group of healthy subjects. An increase in CD11b and LAP expression by PMN membrane was observed, together with a significant increase in cellular elastase content, plasma elastase, and myeloperoxidase levels. In addition, patients had high plasma levels of endothelial and hypercoagulation markers compared with controls. For the first time, these data show that in ET and PV, 2 hematologic conditions that place patients at increased risk for thrombosis, an in vivo leukocyte activation occurs and is associated with laboratory signs of endothelium and coagula-tion system activation. © 2000 by The American Society of Hematology.