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BACKGROUND AND OBJECTIVES Several infections and vaccinations can provoke immune thrombocytopenia (ITP) onset or relapse. Information on ITP epidemiology and management during the Covid19 pandemic is scarce. In a large monocenter ITP cohort, we assessed incidence of and risk factors for: 1) ITP onset/relapse after Covid19 vaccination/ infection; 2) Covid19 infection. METHODS Information on date/type of anti-Covid19 vaccine, platelet count before and within 30 days from vaccine and date/grade of Covid19, was collected via phone call or during hematological visits. ITP relapse was defined as a drop in PLT count within 30 days from vaccination, compared to PLT count before vaccination that required a rescue therapy OR a dose increase of an ongoing therapy OR a PLT count

Fostamatinib, a spleen tyrosine kinase (Syk) inhibitor, represents a new therapeutic opportunity for patients with immune thrombocytopenia (ITP) in Europe and Italy. However, the positioning of this drug in patient’s therapeutic sequence is undefined within the most recent international guidelines. The conclusions from a consensus meeting between Italian experts, whose task was to outline the profile of the ideal candidate to receive fostamatinib, are reported here. A modified Delphi methodology was used to achieve shared statements, which were reported in a narrative form. In particular, the panelists examined the strengths and weaknesses of the registration studies in terms of clinical outcomes, the safety profile of fostamatinib, the drug’s impact on the quality of life of patients with chronic ITP, and the potential benefits of its use in the pandemic era. Although the experience with thrombopoietin receptor agonists (TPO-RAs) and the amount of data from real-world studies suggest the preferential use of these drugs as a second-line treatment in most patients, the absence of an increased thrombotic risk in the clinical trials could make fostamatinib a reasonable choice in patients with an increased risk of vascular events. An unstable platelet count during TPO-RAs might also justify a switch to the Syk inhibitor, which is more likely to stabilize the platelet count in responders. Fostamatinib may be preferred to immunosuppressors during the SARS-CoV-2 pandemic, in patients at infectious risk, or in case of contraindication to splenectomy. Finally, the novel mechanism of action makes it an attractive drug in multi-refractory patient.

Fostamatinib is a SYK-inhibitor drug recently approved by the FDA and EMA for treating chronic immune thrombocytopenia.This drug induces a response in about 40% of patients and has a good toxicity profile. It is known that discontinuing thrombopoietin receptor agonists (TRAs) with the maintenance of sustained response off therapy is possible. On fostamatinib, we do not yet have such information.In this case report, we describe the story of a woman with a multirefractory immune thrombocytopenia (steroids, splenectomy, rituximab, both available TRAs). After 16 years from diagnosis, she started fostamatinib therapy within a clinical trial and achieved a complete response. Grade 1–2 headache and diarrhea occurred during the first months of therapy. These adverse events were resolved with dose reduction of fostamatinib. Despite the dose reduction, the platelet count remained steadily above 80 × 109/L. After 4 years, fostamatinib was gradually reduced and finally discontinued with no drop in platelet count.This is the first case in which fostamatinib discontinuation resulted in a sustained response off therapy.

Chimeric antigen receptor (CAR) T-cell therapy is a promising approach for some relapse/refractory hematological B-cell malignancies; however, in most patients, cytokine release syndrome (CRS) may occur. CRS is associated with acute kidney injury (AKI) that may affect the pharmacokinetics of some beta-lactams. The aim of this study was to assess whether the pharmacokinetics of meropenem and piperacillin may be affected by CAR T-cell treatment. The study included CAR T-cell treated patients (cases) and oncohematological patients (controls), who were administered 24-h continuous infusion (CI) meropenem or piperacillin/tazobactam, optimized by therapeutic drug monitoring, over a 2-year period. Patient data were retrospectively retrieved and matched on a 1:2 ratio. Beta-lactam clearance (CL) was calculated as CL = daily dose/infusion rate. A total of 38 cases (of whom 14 and 24 were treated with meropenem and piperacillin/tazobactam, respectively) was matched with 76 controls. CRS occurred in 85.7% (12/14) and 95.8% (23/24) of patients treated with meropenem and piperacillin/tazobactam, respectively. CRS-induced AKI was observed in only 1 patient. CL did not differ between cases and controls for both meropenem (11.1 vs. 11.7 L/h, p = 0.835) and piperacillin (14.0 vs. 10.4 L/h, p = 0.074). Our findings suggest that 24-h CI meropenem and piperacillin dosages should not be reduced a priori in CAR T-cell patients experiencing CRS.

Abstract Background Myelofibrosis (MF) is a clonal disorder of hemopoietic stem/progenitor cells (HSPCs) with high prevalence in elderly patients and mutations in three driver genes (JAK2, MPL, or CALR). Around 10–15% of patients are triple-negative (TN) for the three driver mutations and display significantly worse survival. Circulating extracellular vesicles (EVs) play a role in intercellular signaling and are increased in inflammation and cancer. To identify a biomolecular signature of TN patients, we comparatively evaluated the circulating HSPCs and their functional interplay with the microenvironment focusing on EV analysis. Methods Peripheral blood was collected from MF patients (n = 29; JAK2 V617F mutation, n = 23; TN, n = 6) and healthy donors (HD, n = 10). Immunomagnetically isolated CD34+ cells were characterized by gene expression profiling analysis (GEP), survival, migration, and clonogenic ability. EVs were purified from platelet-poor plasma by ultracentrifugation, quantified using the Nanosight technology and phenotypically characterized by flow cytometry together with microRNA expression. Migration and survival of CD34+ cells from patients were also analyzed after in vitro treatments with selected inflammatory factors, i.e. (Interleukin (IL)-1β, Tumor Necrosis Factor (TNF)-α, IL6) or after co-culture with EVs from MF patients/HD. Results The absolute numbers of circulating CD34+ cells were massively increased in TN patients. We found that TN CD34+ cells show in vitro defective functions and are unresponsive to the inflammatory microenvironment. Of note, the plasma levels of crucial inflammatory cytokines are mostly within the normal range in TN patients. Compared to JAK2V617F-mutated patients, the GEP of TN CD34+ cells revealed distinct signatures in key pathways such as survival, cell adhesion, and inflammation. Importantly, we observed the presence of mitochondrial components within plasma EVs and a distinct phenotype in TN-derived EVs compared to the JAK2V617F-mutated MF patients and HD counterparts. Notably, TN EVs promoted the survival of TN CD34+ cells. Along with a specific microRNA signature, the circulating EVs from TN patients are enriched with miR-361-5p. Conclusions Distinct EV-driven signals from the microenvironment are capable to promote the TN malignant hemopoiesis and their further investigation paves the way toward novel therapeutic approaches for rare MF.

Abstract Recently, treatment of immune‐mediated thrombotic thrombocytopenic purpura (ITTP) has changed with the advent of caplacizumab in clinical practice. The International Working Group (IWG) has recently integrated the ADAMTS‐13 activity/autoantibody monitoring in consensus outcome definitions. We report three ITTP cases during the coronavirus disease 2019 pandemic, that received a systematic evaluation of ADAMTS‐13 activity and autoantibodies. We describe how the introduction of caplacizumab and ADAMTS‐13 monitoring could change the management of ITTP patients and discuss whether therapeutic choices should be based on the clinical response alone. ADAMTS‐13 activity/antibodies were assessed every 5 days. Responses were evaluated according to updated IWG outcome definitions. These kinetics, rather than clinical remission, guided the therapy, allowing early and safe caplacizumab discontinuation and sensible administration of rituximab. Caplacizumab was cautiously discontinued after achieving ADAMTS‐13 complete remission. These cases illustrate that prospective ADAMTS‐13 evaluation and use of updated IWG definitions may improve real‐life patients’ management in the caplacizumab era.

Polycythemia Vera (PV) is a myeloproliferative neoplasm with increased risk of thrombosis and progression to myelofibrosis. Chronic inflammation is commonly observed in myeloproliferative neoplasms including PV. The inflammatory network includes the extracellular vesicles (EVs), which play a role in cell-cell communication. Recent evidence points to circulating microbial components/microbes as potential players in hemopoiesis regulation. To address the role of EVs in PV, here we investigated phenotype and microbial DNA cargo of circulating EVs through multidimensional analysis. Peripheral blood and feces were collected from PV patients (n=38) and healthy donors (n=30). Circulating megakaryocyte (MK)- and platelet (PLT)-derived EVs were analyzed by flow cytometry. After microbial DNA extraction from feces and isolated EVs, the 16S rDNA V3-V4 region was sequenced. We found that the proportion of circulating MK-derived EVs was significantly decreased in PV patients as compared with the healthy donors. By contrast, the proportion of the PLT-derived EVs was increased. Interestingly, PV was also associated with a microbial DNA signature of the isolated EVs with higher diversity and distinct microbial composition than the healthy counterparts. Of note, increased proportion of isolated lipopolysaccharide-associated EVs has been demonstrated in PV patients. Conversely, the gut microbiome profile failed to identify a distinct layout between PV patients and healthy donors. In conclusion, PV is associated with circulating EVs harbouring abnormal phenotype and dysbiosis signature with a potential role in the (inflammatory) pathogenesis of the disease.

Many diseases can induce splenomegaly, however, about 5% of splenomegalies are idiopathic. When there is no underlying treatable cause, and the splenomegaly significantly affects the quality of life, splenectomy is the best therapeutic choice. A 67-year-old woman had idiopathic and asymptomatic splenomegaly. The increase in splenomegaly resulted in hypersplenism with cytopenia and symptoms related to abdominal discomfort. The patient underwent splenectomy which led to clinical improvement. A histological examination showed the presence of hematopoietic tissue. Peripheral blood Next Generation Sequencing with the myeloid panel SOPHiA Genetics showed the following mutations: ASXL1, SRSF2, KRAS and TET2. Three out of these four mutations were also found in the splenic tissue. Next Generation Sequencing could be useful in the diagnosis of splenomegalies associated with myeloproliferative neoplasms otherwise defined as idiopathic, in order to address a therapeutic strategy.

Myelofibrosis (MF) is characterized by chronic inflammation and hyper-activation of the JAK-STAT pathway. Infections are one of the main causes of morbidity/mortality. Therapy with Ruxolitinib (RUX), a JAK1/2 inhibitor, may further increase the infectious risk. Monocytes are critical players in inflammation/immunity through cytokine production and release of bioactive extracellular vesicles. However, the functional behavior of MF monocytes, particularly during RUX therapy, is still unclear. In this study, we found that monocytes from JAK2V617F-mutated MF patients show an altered expression of chemokine (CCR2, CXCR3, CCR5) and cytokine (TNF-α-R, IL10-R, IL1β-R, IL6-R) receptors. Furthermore, their ability to produce and secrete free and extracellular vesicles-linked cytokines (IL1β, TNF-α, IL6, IL10) under lipopolysaccharides (LPS) stimulation is severely impaired. Interestingly, monocytes from RUX-treated patients show normal level of chemokine, IL10, IL1β, and IL6 receptors together with a restored ability to produce intracellular and to secrete extracellular vesicles-linked cytokines after LPS stimulation. Conversely, RUX therapy does not normalize TNF-R1/2 receptors expression and the LPS-driven secretion of free pro/anti-inflammatory cytokines. Accordingly, upon LPS stimulation, in vitro RUX treatment of monocytes from MF patients increases their secretion of extracellular vesicles-linked cytokines but inhibits the secretion of free pro/anti-inflammatory cytokines. In conclusion, we demonstrated that in MF the infection-driven response of circulating monocytes is defective. Importantly, RUX promotes their infection-driven cytokine production suggesting that infections following RUX therapy may not be due to monocyte failure. These findings contribute to better interpreting the immune vulnerability of MF and to envisaging strategies to improve the infection-driven immune response.

Fever of unknown origin (FUO) is a common and challenging clinical condition that can be referred, among others, to infections, drug’s effects, various inflammatory disorders, and cancers. Among the latter, lymphomas can indeed cause fever, which is therefore accounted as a lymphoma-related sign in patients’ staging. Intravascular large B-cell lymphoma (IVLBCL) is a very rare tumor, characterized by lymphoma cell accumulation within sinusoids and, despite a very aggressive course, the evidence of this disease is scarce. Two variants are currently recognized, respectively, occurring in either Western (mainly characterized by neurological symptoms and skin involvement) or Eastern countries (with hemophagocytic syndrome, bone marrow, spleen, and liver involvement). We describe an atypical and unprecedented IVLBCL patient, presenting with pronounced features of Eastern cases as well as skin involvement. Due to the scant amount of neoplastic cells, the diagnosis was very challenging, with FUO being the first and for a certain time unique clinical sign. Although lymphoma was suspected, the lack of evidence for neoplastic cells delayed the final diagnosis. Eventually, only autopsy revealed the extensive involvement of different organs and tissues.

Inflammation may play a role in cancer. However, the contribution of cytokine-mediated crosstalk between normal hemopoietic stem/progenitor cells (HSPCs) and their (inflammatory) microenvironment is largely elusive. Here we compared survival, phenotype, and function of neonatal (umbilical cord blood (CB)) and adult (normal G-CSF-mobilized peripheral blood (mPB)) CD34+ cells after in vitro exposure to combined crucial inflammatory factors such as interleukin- (IL-) 1β, IL-6, tumor necrosis factor- (TNF-) α, or tissue inhibitor of metalloproteinases-1 (TIMP-1). To mimic bone marrow (BM) niche, coculture experiments with normal BM stromal cells (BMSCs) were also performed. We found that combined inflammatory cytokines increased only the in vitro survival of CB-derived CD34+ cells by reducing apoptosis. Conversely, selected combinations of inflammatory cytokines (IL-1β + TNF-α, IL-6 + TNF-α, and IL-1β + TNF-α + TIMP-1) mainly enhanced the in vitro CXCR4-driven migration of mPB-derived CD34+ cells. TNF-α, alone or in combination, upregulated CD44 and CD13 expression in both sources. Finally, BMSCs alone increased survival/migration of CB- and mPB-derived CD34+ cells at the same extent of the combined inflammatory cytokines; importantly, their copresence did not show additive/synergistic effect. Taken together, these data indicate that combined proinflammatory stimuli promote distinct in vitro functional activation of neonatal or adult normal HSPCs.

Myelofibrosis (MF) is a clonal neoplasia associated with chronic inflammation due to aberrant cytokine production. Mutations in Janus Kinase-2 (JAK2), calreticulin (CALR) and myeloproliferative leukemia protein (MPL) genes have been recently associated to MF and they all activate the JAK/STAT signaling pathway. Since this pathway is essential in shaping the immune response, we investigated the role of circulating immune subsets and cytokines in 38 patients (20 carrying JAK2(V617F),13 exon-9 CALR mutation and 5 triple negative). In comparison to healthy donors, patients presented a reduced amount of circulating dendritic cells (DCs) associated with a defective ability of monocytes in differentiating into DCs. In addition, we found a reduction in circulating T-helper (Th)1 and Th17 and hypo-functional innate lymphoid cells (ILC). Results analyzed according to the mutational status showed that patients carrying JAK2(V617F) mutation had a reduction in Th17, myeloid-DCs and effector Tregs as well as increased ILC1 and cytokine producing Tregs. The CALR mutated patients revealed high ILC3 levels, reduced Th1 and their monocytes had a reduced capacity to mature in vitro into fully committed DCs. Their Tregs were also less effective in inhibiting the proliferation of autologous effector T-cells due to an increased proliferative status induced by CALR mutation. Triple negative patients presented a reduced amount of total circulating CD3, effectors Tregs and Th1 with increased ILC1. Overall, we have demonstrated that in MF different mutations lead to phenotypic and functional alterations in different immune subsets that may have a potential role in disease progression and susceptibility to infections.

Myelofibrosis (MF) is a clonal neoplasia of the hemopoietic stem/progenitor cells associated with genetic mutations in the Janus kinase 2 (JAK2), myeloproliferative leukemia virus oncogene (MPL), and calreticulin (CALR) genes. MF is also characterized by a state of chronic inflammation. Calreticulin (CRT), as a multifunctional protein, is involved in a spectrum of cellular processes including inflammation, autoimmunity, and cancer initiation/progression. Based on this background, we hypothesised that in MF circulating CRT might reflect the inflammatory process. In the present study we show that circulating CRT is increased in MF patients compared to healthy controls. Also, in MF, CRT levels highly correlate with bone marrow fibrosis, splenomegaly, and Interleukin-6 (IL-6) plasma levels. In turn, higher IL-6 levels also correlated with disease severity in terms of increased spleen size, bone marrow fibrosis, number of circulating CD34+ cells, and lower hemoglobin values. These results demonstrate that the circulating CRT takes part in the inflammatory network of MF and correlates with aggressiveness of the disease.

Correct definition of the level of risk of invasive fungal infections is the first step in improving the targeting of preventive strategies. We investigated the potential relationship between pre-hospitalization exposure to sources of fungi and the development of invasive fungal infections in adult patients with newly diagnosed acute myeloid leukemia after their first course of chemotherapy. From January 2010 to April 2012, all consecutive acute myeloid leukemia patients in 33 Italian centers were prospectively registered. Upon first admission, information about possible pre-chemotherapy risk factors and environmental exposure was collected. We recorded data regarding comorbid conditions, employment, hygienic habits, working and living environment, personal habits, hobbies, and pets. All invasive fungal infections occurring within 30 days after the first course of chemotherapy were recorded. Of the 1,192 patients enrolled in this study, 881 received intensive chemotherapy and were included in the present analysis. Of these, 214 developed an invasive fungal infection, including 77 proven/probable cases (8.7%). Of these 77 cases, 54 were proven/probable invasive mold infections (6.1%) and 23 were proven yeast infections (2.6%). Upon univariate analysis, a significant association was found between invasive mold infections and age, performance status, diabetes, chronic obstructive pulmonary disease, smoking, cocaine use, job, hobbies, and a recent house renovation. Higher body weight resulted in a reduced risk of invasive mold infections. Multivariate analysis confirmed the role of performance status, job, body weight, chronic obstructive pulmonary disease, and house renovation. In conclusion, several hospital-independent variables could potentially influence the onset of invasive mold infections in patients with acute myeloid leukemia. Investigation of these factors upon first admission may help to define a patient’s risk category and improve targeted prophylactic strategies.

The treatment of choice in steroid-resistant immune thrombocytopenia is still controversial due to the recent advent of new drugs (anti-CD20 antibodies and thrombopoietin mimetics) that have encouraged a generalized tendency to delay splenectomy. Consequently, it is extremely importance to define the efficacy and safety of splenectomy in the long term. We retrospectively analyzed the data of 233 patients affected by immune thrombocytopenia who underwent splenectomy between 1959 and 2001 in 6 European hematologic institutions and who have now a minimum follow up of ten years from surgery. Of the 233 patients, 180 (77%) achieved a complete response and 26 (11%) a response. Sixty-eight of 206 (33%) responsive patients relapsed, mostly (75%) within four years from first response. In 92 patients (39.5%), further treatment was required after splenectomy that was effective in 76 cases (83%). In 138 patients (59%), response was maintained free of any treatment at last contact. No significant association between baseline characteristics and likelihood of stable response was found. Overall, 73 (31%) and 58 (25%) patients experienced at least one infectious or hemorrhagic complication, which was fatal in 2 and 3 patients, respectively. A stable response to splenectomy was associated with a lower rate of infections (P=0.004) and hemorrhages (P

BACKGROUND: A risk score for invasive mold disease (IMD) in patients with hematological malignancies could facilitate patient screening and improve the targeted use of antifungal prophylaxis. METHODS: We retrospectively analyzed 1,709 hospital admissions of 840 patients with hematological malignancies (2005-2008) to collect data on 17 epidemiological and treatment-related risk factors for IMD. Multivariate regression was used to develop a weighted risk score based on independent risk factors associated with proven or probable IMD, which was prospectively validated during 1,746 hospital admissions of 855 patients from 2009-2012. RESULTS: Of the 17 candidate variables analyzed, 11 correlated with IMD by univariate analysis, but only 4 risk factors (neutropenia, lymphocytopenia or lymphocyte dysfunction in allogeneic hematopoietic stem cell transplant recipients, malignancy status, and prior IMD) were retained in the final multivariate model, resulting in a weighted risk score 0-13. A risk score of < 6 discriminated patients with low (< 1%) versus higher incidence rates (> 5%) of IMD, with a negative predictive value (NPV) of 0.99, (95% CI 0.98-0.99). During 2009-2012, patients with a calculated risk score at admission of < 6 had significantly lower 90-day incidence rates of IMD compared to patients with scores > 6 (0.9% vs. 10.6%, P

Immunosuppressive agents are the standard therapeutic approach for immune thrombocytopenia (ITP). Their prolonged use may increase the risk of infectious complications, particularly when the patient is already at higher infectious risk. In this setting, the use of drugs with a mechanism of action alternative to immunosuppression, like thrombopoietin receptor agonists (TRAs), may find particular indication. We report the unique case of a patient with severe immunodeficiency and ITP, who experienced a serious infectious complication while on steroids treatment, and who was successfully treated with Romiplostim second- line. The present experience supports the effectiveness and safety of TRAs as early treatment of ITP patients with drug-induced immunodeficiency or with active infections.

BACKGROUND: The aim of this study was to develop and validate a reliable clinical prediction rule that could be employed to identify patients at higher likelihood of mortality among those with hematological malignancies (HMs) and bacterial bloodstream infections (BBSIs). METHODS AND FINDINGS: We conducted a retrospective cohort study in nine Italian hematological units. The derivation cohort consisted of adult patients with BBSI and HMs admitted to the Catholic University Hospital (Rome) between January 2002 and December 2008. Survivors and nonsurvivors were compared to identify predictors of 30-day mortality. The validation cohort consisted of patients hospitalized with BBSI and HMs who were admitted in 8 other Italian hematological units between January 2009 and December 2010. The inclusion and exclusion criteria were identical for both cohorts, with type and stage of HMs used as matching criteria. In the derivation set (247 episodes), the multivariate analysis yielded the following significant mortality-related risk factors acute renal failure (Odds Ratio [OR] 6.44, Confidential Interval [CI], 2.36-17.57, P

Background Neutropenic patients with persistent fever despite antibiotic therapy are managed with empirical or pre-emptive antifungal therapy. The aim of the present study was to evaluate the current clinical use and efficacy of these two approaches in patients with high risk hematologic conditions.Design and Methods An electronic medical record system, the “Hema e-Chart”, was designed and implemented to collect information prospectively on infectious complications, particularly on invasive fungal diseases, in patients with hematologic malignancies treated with chemotherapy and/or autologous or allogenic hemopoietic stem cell transplantation. The patients were enrolled from Hematology units distributed widely across Italy.Results Three hundred and ninety-seven adults with hematologic malignancies treated with chemotherapy with persistent fever and suspected invasive fungal disease were evaluable for the study (190 treated had been treated with empirical antifungal therapy and 207 with preemptive antifungal therapy). There was a significantly lower incidence of proven/probable invasive fungal diseases in patients treated with empirical antifungal therapy (n=14, 7.4%) than in patients treated with pre-emptive therapy (n=49, 23.7%) (P

Invasive fungal sinusitis (IFS) is a highly aggressive infection that can affect hematologic patients. The classically described general risk factors, however, do not fully explain the development of IFS in a small percentage of cases. This study examined the impact of anatomic sinonasal factors and environmental factors on the development of IFS in high-risk patients. Medical records and computed tomography (CT) scans of patients admitted to our institution who were at high risk of developing IFS were retrospectively reviewed. Twenty-seven patients of 797 fulfilled the inclusion criteria. Patients affected by IFS were compared with patients not affected to identify possible sinonasal and environmental risk factors of IFS. Seven patients were excluded because of the lack of adequate radiological images. Six of the 20 eligible patients were assigned to the study group of patients affected by IFS and the remaining 14 patients were assigned to the control group. All but one case developed the infection during the summer with a significantly higher mean environmental temperature (p = 0.002). Anatomic nasal alterations were found in all patients affected by IFS and were significantly more frequent than in the control group (p = 0.014). It would be advisable to have patients with hematologic risk factors of IFS, especially during the summer period, undergo endoscopic nasal assessment. Furthermore, a CT finding of anatomic nasal alterations, such as anterior nasal septum deviation causing nasal obstruction, should increase the suspicion of IFS in case of the occurrence of nasal symptoms.

Rituximab 375 mg/m2 weekly for four weeks has significant activity in patients with immune thrombocytopenia. We evaluated the activity of lower dose rituximab (100 mg iv weekly for 4 weeks) in 28 adults with idiopathic thrombocytopenic purpura. Overall (platelet count > 50×109/L) and complete responses (platelet count > 100×109/L) were achieved in 21/28 (75%) and 12/28 (43%) patients respectively. The median time to response and time to complete response were 31 and 44 days respectively. After a median follow-up of 11 months (range 3–18), 7/21 (33%) patients relapsed and 3 needed further treatments. In patients with idiopathic thrombocytopenic purpura, lower dose rituximab seems to show similar activity to standard dose.

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