History Of Arterial Thrombosis Research Articles

Abstract 15274: STEMI as Initial Manifestation of Essential Thrombocythemia

Background: Essential thrombocythemia (ET) is a myeloproliferative neoplasm of myeloid cell expansion, mainly excessive platelet production, associated with thrombotic complications. Myocardial infarction (MI) in the setting of ET can result from thrombosis in the absence of coronary atherosclerosis. Here we present a case of ST elevation MI in the setting of previously undiagnosed ET. Case Report: A 59-year-old male with hypertension presented to the ED with left upper extremity weakness which started upon waking. On exam, he was in acute distress and diaphoretic. EKG revealed sinus rhythm with ST elevation in II, III, aVF, V5, and V6 suggesting inferolateral STEMI (Figure 1A). Labs were notable for Hgb 8.5g/dL, white blood cell count 33k/μL, and platelets 1.9million/μL. Decision Making: He was loaded with aspirin and clopidogrel (dual antiplatelet therapy-DAPT) and taken for coronary angiogram which revealed 80-90% thrombotic occlusion of the left circumflex artery (Figure 1b). Thrombectomy was performed and a drug-eluting stent was placed. A bone marrow biopsy showed JAK2 positive ET with myelofibrosis. He was immediately started on hydroxyurea. Platelets remained elevated, thus pegylated IFN alpha-2a was started which normalized platelet count. He remained on DAPT through discharge with no recurrent ischemic events or in-stent thrombosis during the 45-day hospitalization post stent placement. Conclusion: Patients with ET are at high risk for arterial thrombosis regardless of the presence of traditional atherosclerotic risk factors. High-risk patients, which includes those age over 60 with JAK2 mutation or history of arterial thrombosis, should be treated prophylactically with aspirin and hydroxyurea for cytoreduction. MI may be the first clinical manifestation of ET, even in patients without atherosclerotic risk factors. Initial management in patients with ET presenting with STEMI includes PCI with DAPT and early cytoreductive therapy.

Association of anti-β2-glycoprotein I/HLA-DR complex antibody with arterial thrombosis in female patients with systemic rheumatic diseases

Backgroundβ2-glycoprotein I (β2GPI) complexed with human leukocyte antigen DR (β2GPI/HLA-DR) was found to be a major autoantibody target in antiphospholipid syndrome (APS). This study aimed to reveal the association between anti-β2GPI/HLA-DR antibodies and vascular thromboses in women with systemic rheumatic diseases.MethodsWe conducted a retrospective longitudinal study. We measured anti-β2GPI/HLA-DR antibodies and compared them with anti-phospholipid antibody (aPL) profiles and the adjusted global antiphospholipid syndrome score (aGAPSS). Using receiver operating characteristic (ROC) analysis, we determined the best cut-off value for arterial thrombosis. We also evaluated the validity of anti-β2GPI/HLA-DR antibodies by adding to conventional cardiovascular risk factors in multivariate logistic analysis.ResultsWe evaluated 704 patients, including 66 (obstetric or thrombotic) APS, 13 primary APS, and 78 asymptomatic aPL carriers. Seventy-seven patients had a history of arterial thrombosis, and 14 patients had both arterial and venous thrombosis. These 14 patients, as well as patients with aGAPSS > 10 or triple-positive aPL profiles, displayed high anti-β2GPI/HLA-DR antibody titers. The ROC curve showed a sensitivity, specificity, and area under the curve (AUC) for arterial thrombosis of 33.8%, 91.4%, and 0.6009, respectively, with a cut-off value of 172.359 U/mL. The anti-β2GPI/HLA-DR antibody positivity using this cut-off value yielded an odds ratio of 5.13 (95%CI: 2.85–9.24), significantly improving the AUC from 0.677 to 0.730.ConclusionAnti-β2GPI/HLA-DR antibodies are associated with arterial thrombosis in female patients with systemic rheumatic diseases.

Hereditary Antithrombin Deficiency Pilot Project Registry from the American Thrombosis and Hemostasis Network (ATHN)

Background: Hereditary antithrombin deficiency (HAD) is a severe rare thrombophilia with an estimated prevalence of 0.02% to 0.2% in the general population. Patients with HAD have a high risk of developing arterial and venous thromboembolism (VTE). The purpose of ATHN 12: HAD Pilot Project is to collect data on participants diagnosed with HAD across the United States to better understand this rare thrombophilia and to develop guidelines regarding timing of screening for HAD, type of antithrombotic therapy, and indications for using antithrombin concentrate. The ATHN 12 study is sponsored by the American Thrombosis and Hemostasis Network (ATHN). ATHN will leverage its existing data collection infrastructure and its ATHN-affiliated network of 146 hemostasis and thrombosis treatment centers in the United States to identify a cohort of approximately 100 patients with HAD who are receiving care in these centers. Methods: We designed a national HAD registry to collect clinical, laboratory, and treatment data for participants with HAD with the goal of optimizing their management. The ongoing prospective HAD registry project (ATHN 12) was created in 2020 to identify a cohort of 100 adult and pediatric participants with HAD receiving care at thrombosis centers affiliated with ATHN. We collected information on demographics, laboratory data, thrombotic events, risk factors, antithrombotic therapy, and use of antithrombin (AT) concentrate during pregnancy and procedures. Results: 71 participants have been enrolled, 47 (66.2%) are female; mean age is 35 years (1-82); the majority 58 (82%) are White and 31 (43.6%) have type 1 HAD; 62 (87.32%) had a known diagnosis of HAD; 45 (63.38%) had a history of VTE (Table 1). The most common VTE locations included: lower extremity deep vein thrombosis 51 events (57%) and pulmonary embolisms 23 events (26%). 23 participants (51%) had recurrent VTEs. 4 participants (5.5%) had history of arterial thrombosis (AT) and 1 (25%) had a recurrent event. Of 45 participants, 17 (38%) had no other known risk factors for VTE; 21 (46.5%) were estrogen-related; 11 (24.4%) occurred after surgery, prolonged immobilization, hospitalization, travel, or trauma (Table 1). A total of 173 anticoagulants were prescribed on 45 (63.38%) participants (Table 2) There were 87 pregnancies in 37 women. Low molecular weight heparin (LMWH) was administered in 46% of the pregnancies and in 3 women LMWH was switched to UFH between 36 to 38 weeks of gestation. AT concentrate was administered in 22 (25%) of the pregnancies before delivery and in 14 pregnancies 24 hours post-delivery. 31 women (36%) restarted anticoagulation post-delivery. The earliest initiation of anticoagulation was 6 hours after delivery. Overall, there were 34 (39%) pregnancy complications: 23 pregnancy losses mainly in first trimester, 4 thrombosis, 4 pre-eclampsia, and 6 other complications (Table 2). 59 participants (83%) had a total of 171 surgeries or procedures. The most frequent surgeries were gastrointestinal, and the most common procedures were vascular (Table 2). Overall, 28 (39.4%) have received AT concentrate without adverse events. Conclusions: VTE was the most frequent clinical manifestation with DVT accounting for 57% of events and PE 26%. Oral factor Xa inhibitors were the most common anticoagulants prescribed. LMWH was administered in almost half of the pregnancies and AT concentrates in 25% of the pregnancies before delivery, and in 39.4% overall in pregnancies and procedures without reported adverse events. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association of Genetic Variability in Selected Genes with Platelet Hyperaggregability and Arterial Thrombosis

Abstract Introduction: Inherited platelet hyperaggregability, so called “Sticky platelet syndrome” (SPS), is a prothrombotic platelet disorder. The syndrome contributes more often to arterial than venous thrombosis. The most common localization of arterial occlusion involves cerebral or coronary arteries. However, SPS may also lead to thrombosis in the atypical sites of the circulation. This qualitative platelet alteration causes platelet hyperaggregability after a very low concentration of platelet inducers – adenosine diphosphate (ADP) and/or epinephrine (EPI). The precise genetic background of the syndrome has not been defined. In the present study we aimed to determine the association between selected single nucleotide polymorphisms (SNPs) within genes for platelet endothelial aggregation receptor 1 (PEAR1) and murine retrovirus integration site 1 (MRVI1) and the risk for arterial thrombosis in patients with SPS. The products of these selected genes play an important role in platelet aggregation. Patients and methods: We examined 69 patients with SPS and a history of arterial thrombosis and 69 healthy blood donors who served as controls. SPS was confirmed by a light transmission aggregometry (LTA) according to the method and criteria described by Mammen and Bick. We assessed two SNPs within PEAR1 gene (rs12041331, rs1256888) and two SNPs within MRVI1 gene (rs1874445, rs7940646). Results: Selected PEAR1 and MRVI1 polymorphisms seem not to be a risk factor for the development of SPS as the syndrome with an arterial thrombosis phenotype. However, in the subgroup of SPS1 patients there was found a decreased frequency of the minor A allele of SNP rs12041331 in PEAR1 gene (borderline p value, p=0.061) that can be hypothesized as protective against arterial thrombosis. In the same SPS1 subgroup the haplotype TA in PEAR1 gene also showed a decreased frequency with a borderline insignificance (p=0.056). We can theorize also about its protective role in SPS1 patients. We did not confirm the protective effect of polymorphism (T/T of rs 12566888) in PEAR1 against arterial thrombosis in SPS patients and SPS subgroups. Conclusion: Our results support the idea that examined genetic variability of the selected SNPs in PEAR1 and MRVI1 genes is not associated with platelet hyperaggregability manifested as arterial thrombosis. The possible protective role of the minor A allele of SNP rs12041331 as well as a role of haplotype TA in PEAR1 gene related to the arterial thrombosis found in the subgroup of SPS1 patients needs to be verified in further research.

Cytogenetic abnormalities in essential thrombocythemia: Clinical and molecular correlates and prognostic relevance in 809 informative cases

Cytogenetic studies among 809 consecutive patients with essential thrombocythemia (ET; median age 59 years; 65% females) revealed normal karyotype in 754 (93%), loss of chromosome Y only (-Y) in 16 (2%), and abnormalities other than -Y in 39 (4.8%), the most frequent being sole 20q- (n = 8). At presentation, abnormal karyotype, excluding -Y, was associated with older age (p = 0.04), higher leukocyte count (p = 0.03) and arterial thrombosis history (p = 0.02); no associations were apparent for JAK2/CALR/MPL mutations whereas ASXL1 mutations clustered with normal karyotype/-Y and TP53 with abnormal karyotype. Survival was significantly shorter in patients with abnormal karyotype or -Y, compared to those with normal karyotype (median 12, 10, and 21 years, respectively; p < 0.0001). During multivariable analysis that included IPSET (international prognostic score for ET) variables, abnormal karyotype (p < 0.01, HR 2.0), age >60 years (p < 0.01, HR 4.5), leukocytosis >11 × 109/L (p < 0.01, HR 1.5), and male gender (p < 0.01, HR 1.4) were independently associated with inferior survival; abnormal karyotype and age >60 years remained significant, along with SF3B1/SRSF2/U2AF1/TP53 mutations (p = 0.04; HR 2.9), when the latter was included in the multivariable model. The current study suggests prognostic relevance for karyotype in ET.

The 1.5 Million Platelet Count Threshold in Essential Thrombocythemia: Phenotype and Genotype Correlates and Relevance to Vascular Events

▪BackgroundCurrent NCCN and ELN guidelines lack supporting evidence in regards to initiation of cytoreductive therapy in essential thrombocythemia (ET) with extreme thrombocytosis (ExT) ≥1500 x 10 9/L (NCCN guidelines: myeloproliferative neoplasms, version 2. 2019, Barbui, Leukemia, 2018).; we sought to determine prevalence and establish phenotype and genotype correlates for ET with ExT and assess its impact on thrombotic and bleeding events, in the context of aspirin therapy or cytoreduction.Methods1,249 WHO-defined ET patients evaluated over five decades (1967-2021) were retrospectively recruited from the Mayo Clinic. Conventional criteria were used to define major arterial and venous thrombosis and major hemorrhage. Conventional statistical methods were applied using JMP Pro 14.0.0 software package, SAS Institute, Cary, NC.Results 1.i) Phenotype and genotype correlatesAmong 1,249 consecutive patients with ET, 104 (8%) displayed Ext ≥1500 x 10 9/L, at time of initial diagnosis; these patients were characterized by younger age (median 47 vs 59 years; p<0.001) female gender (80% vs 62%; p<0.001), CALR mutation (39% vs 25%; p=0.004), lower hemoglobin (median 13.1 vs 13.7 g/dl; p<0.0001), leukocytosis ≥11 x 10 9/l (42% vs 23%; p<0.0001), and palpable splenomegaly (22% vs 14%; 0.03); multivariable analysis confirmed associations with age, anemia, leukocytosis, and CALR mutation. Acquired von Willebrand syndrome was reported in 4/9 (44%) vs 27/78 (35%) tested patients, with or without Ext ≥1500 x 10 9/L, respectively (p=0.57); however, comparison using platelet ≥1000 x 10 9/L resulted in near-signficant difference (46% vs 29%; p=0.11). NGS was performed in 297 patients and showed a non-sigificant association with U2AF1 mutations (5% vs 0.4%; p=0.11). ExT ≥1500 x 10 9/L was present in 25/986 (3%), 42/891 (5%), and 15/558 (3%) in the validation cohort; the limited number of cases precluded comparative analyses. 1.ii )Correlation with vascular events at/prior to diagnosisArterial or venous thrombosis at/prior to diagnosis occurred in 190 (15%) and 111 (9%) patients, respectively, and major hemorrage in 50 (4%). Ext ≥1500 x 10 9/L was associated with major hemorrhage (HR 2.9; 1.3-6.3), but not with arterial (p=0.15) or venous (p=0.41) thrombotic events, at/prior to diagnosis. Instead, multivariable analysis for events at/prior to diagnosis identified male gender (p=0.02), JAK2 mutation (p=0.01), and cardiovascular risk factors (p=0.001) as risk factors for arterial thrombosis and JAK2 mutation (HR 2.8; 1.4-5.7) as a risk factor for venous thrombosis.iii )Correlation with vascular events after diagnosisAt median follow-up of 10 years, arterial or venous thrombosis occurred in 222 (18%) and 97 (8%) patients, respectively, and major hemorrage in 128 (11%). Ext ≥1500 x 10 9/L at diagnosis was not associated with arterial (p=0.35) or venous (p=0.23) thrombosis-free survival or hemorrhage-free survival (p=0.24). Instead, multivariable analysis identified age >60 years, presence of cardiovascular risk factors, and history of arterial thrombosis, as risk factors for arterial thrombosis-free survival; and male gender and history of venous thrombosis as risk factors for venous thrombosis-free survival; and age >60 years and leukocytosis of ≥11 x 10 9/L as risk factors for hemorrhage-free survival. In addition, aspirin therapy was idependently protective of venous thrombosis (HR 0.5; 0.2-0.9), and also of arterial thrombosis, in univariate analysis (HR 0.6; 0.3-0.9), without being associated with an increased risk of major hemorrhage (p=0.64); by contrast, beneficial effect from cytoreductive therapy was not evident for either arterial (p=0.37) or venous (p=0.77) thrombosis. In low-risk patients with Ext ≥1500 x 10 9/L, both aspirin and cytoreductive therapy were protective of venous events (Figure 1), without affecting hemorrhage-free survival.ConclusionExT ≥1500 x 10 9/L in ET was associated with major hemorrhage at diagnosis but did not affect thrombosis-free or hemorrhage-free survival. Initial therapy with aspirin and/or cytoreductive therapy was protective of venous events in ET patients with ExT ≥1500 x 10 9/L, including those with low-risk disease, without enhancing the risk of hemorrhage. The limited number of informative cases with ExT in the validation cohort, underscore the foreseeable challenges associated with controlled studies. [Display omitted] DisclosuresSzuber: Novartis: Honoraria. Vannucchi: AbbVie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barbui: AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Cytogenetics in Essential Thrombocythemia: Phenotype and Molecular Correlates and Prognostic Relevance in 818 Informative Cases

▪BackgroundCytogenetic abnormalities at diagnosis are relatively uncommon in essential thrombocythemia (ET). In the current study of 818 consecutive patients with ET who were fully annotated for karyotype, we describe the spectrum and prevalence of cytogenetic abnormalities at diagnosis, followed by a comprehensive assessment of phenotypic and molecular correlates and prognostic relevance.MethodsThe study cohort consisted of 818 consecutive patients with ET that were diagnosed according to the World health Organization 2016 criteria and underwent evaluation between 1967-2021. In order to minimize the inadvertent inclusion of patients with masked polycythemia vera, JAK2 mutated cases with hemoglobin (Hb) level >16 g/dL in women and 16.5 g/dL in men were excluded; similarly, cases with anemia defined by sex adjusted Hb level of <11 g/dL in women and <12.5 g/dL in men were also excluded, in order to avoid inadvertent inclusion of patients with prefibrotic myelofibrosis. Cytogenetic studies were performed either at or within one year of diagnosis and reported according to the International System for Human Cytogenetic Nomenclature. Disease status and survival information was updated in May 2021. JMP Pro 16.0.0 software package, SAS Institute, Cary, NC was utilized for all analyses.Results •Prevalence and spectrum of cytogenetic abnormalitiesKaryotype was normal in 755 patients (92%), showed loss of Y chromosome (-Y) in 16 (2%), and showed abnormalities other than -Y in 47 (5.7%); most common abnormalities included del(20q) (n=10, 21%), trisomy 9 (n=8, 17%), trisomy 8 (n=2, 4%), del(5q) (n=2, 4%), and del(3p) (n=2, 4%). Other sole cytogenetic abnormalities were identified in 18 (38%) patients. •Phenotypic and molecular correlatesAbnormal karyotype, other than -Y, in comparison with normal karyotype was associated with older age (median age; 63 vs 58 years, p=0.02), lower hemoglobin level (p=0.003), and a higher incidence of arterial thrombosis prior to/at diagnosis (25% vs 13%; p=0.03). 603 patients were annotated for driver mutations; abnormal/normal/-Y frequencies were 78%/60%/71% for JAK2, 22%/26%/14% CALR, 0%/3%/0% MPL and 0%/10% /14% triple negative (p=0.31). NGS information was available in 226 patients and showed absence of ASXL1 mutation in all patients with abnormal karyotype vs 8/211 (4%) with normal karyotype vs 2/4 (50%) with -Y (p<0.0001). •Disease transformation and overall-survival.At a median follow-up of 9.6 years (range; 0.01-49.4 years), a total of 96 patients (12%) underwent fibrotic transformation: 6 (13%) with abnormal karyotype, 89 (12%) with normal karyotype and 1 (6%) with -Y (p=0.77). Leukemic transformation rates were also similar with respective frequencies of 4%, 3% and 0% (p=0.71). Abnormal karyotype and -Y were associated with inferior survival with median of 12 years (range; 0.1-34) and 9 years (range; 0.01- 19.9), respectively, compared to 21 years (range; 0.01-49.4) for normal karyotype (p<0.0001) (Figure). In univariate analysis, risk factors for overall survival included abnormal karyotype (p=0.001), - Y (p=0.004), age >60 years (p<0.0001), leukocytosis >11 x10 9/L (p<0.0001), male gender (p=0.0003), and history of thrombosis (p=0.001). During multivariable analysis, abnormal karyotype other than -Y (p=0.003), age >60 years (p<0.0001), leukocytosis >11 x10 9/L (p=0.001), and male gender (p=0.01) remained significant. Additional analysis suggested individual prognostic impact for del(20q) (p=0.04) and also for trisomy 9 (p=0.09) and other abnormalities (p=0.07), with borderline significance.ConclusionThe current study confirms the association of abnormal karyotype in ET with older age, lower hemoglobin level, and history of arterial thrombosis, and its mutual exclusivity with ASXL1 mutations. Our observation regarding the independent adverse impact of abnormal karyotype other than -Y, on overall survival, in the absence of association with fibrotic or leukemic transformation, requires clarification from additional studies, which should also investigate the effect of specific abnormalities. [Display omitted] DisclosuresSzuber: Novartis: Honoraria.

O25 Catastrophic antiphospholipid crisis triggered by anticoagulant switch

O25 Catastrophic antiphospholipid crisis triggered by anticoagulant switch

Characteristics of 809 Patients with Essential Thrombocythemia in Real-World Clinical Practice: A Chart Review Study in the United States

Background: Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by elevated platelet counts and proliferation of mature megakaryocytes in the bone marrow. The quantitative and qualitative platelet alterations in ET may lead to increased risks of thrombosis and bleeding. Risk factors for thrombotic complications include age >60 years, prior history of venous or arterial thrombosis, JAK2 V617F mutation, and cardiovascular risk factors. The current management of ET with cytoreductive therapy is largely directed at lowering the risk of thrombotic complications. This study aimed to characterize patients with ET treated with cytoreductive therapy in real-world clinical practice.Methods: Data were extracted from medical charts of patients with ET who were managed with cytoreductive therapy between June 1, 2011, and September 15, 2016, at participating community oncology/hematology clinics. Physician and patient characteristics, medical history, diagnostic tests and results, and signs and symptoms at ET diagnosis were reported descriptively.Results: 50 hematologists and oncologists participated in the study. The participating physicians had a mean (SD) of 17.5 (7.3) years of practice, and treated a mean (SD) of 31.6 (22.4) patients with ET in the past 5 years. A total of 809 patients with ET who received cytoreductive therapy from the 50 hematologists and oncologists were included. Patients were predominantly white (75.4%) with a mean (SD) age of 68.7 (11.5) years, and 48.9% were male. The majority (81.1%) of patients were referred to the participating physicians. Physicians reported that 64.5% of patients were diagnosed using World Health Organization criteria. However, less than half (48.8%) of patients had undergone a bone marrow biopsy at the time of diagnosis. Overall, 708 (87.5%) patients underwent JAK2 mutation testing; among these patients, 512 (72.3%) were positive. Physicians also noted JAK2 exon 12 mutation testing in 24 (3.0%) patients, however, none were positive. Reflex CALR and MPL molecular testing was conducted in 26.3% of patients, with 7.0% and 4.6% positive, respectively. Per physician assessment, 41.7%, and 42.5% were low and high risk, respectively; risk category was unknown in 15.8% of patients. At diagnosis, 11.4% and 19.5% of patients had a history of arterial thrombosis and venous thrombosis, respectively, and 64.4% of patients had ≥1 cardiovascular risk factor (arterial hypertension, 28.2%; smoking, 26.9%; hypercholesterolemia, 26.5%; overweight, 23.6%; diabetes, 15.3%). The most common ET signs and symptoms were fatigue (53.2%), headache (20.4%), and splenomegaly (15.1%); 90.3% of patients had platelet counts ≥600 × 109/L and 55.9% had white blood cell counts ≥10 × 109/L. For their first-line cytoreductive therapy, 755 patients (93.3%) received hydroxyurea (HU), 30 (3.7%) anagrelide, 10 (1.2%) ruxolitinib, 10 (1.2%) pegylated interferon or interferon alfa, and 4 (0.5%) other.Conclusions: Patients with ET receiving cytoreductive therapy had substantial clinical burden of disease (eg, symptoms, elevated blood counts) at the time of diagnosis. Furthermore, a large proportion of these patients were at high risk of a thrombotic event because of age ≥60 years, prior thrombosis, ≥1 risk factor for cardiovascular event, or having a JAK2 mutation. DisclosuresYu:Incyte Corporation: Employment, Equity Ownership. Colucci:Incyte Corporation: Employment, Equity Ownership. Paranagama:Incyte Corporation: Employment, Equity Ownership. Sivaraman:Incyte Corporation: Employment, Equity Ownership. Atanasov:Incyte Corporation: Consultancy. Hanna:Incyte Corporation: Consultancy. Tang:Incyte Corporation: Consultancy. Parasuraman:Incyte Corporation: Employment, Equity Ownership.

The Anatomy of Recurrent Thrombosis and Its Risk Factors in Myeloproliferative Neoplasms

Background:The main objective of current treatment in both essential thrombocythemia (ET) and polycythemia vera (PV) is to prevent thrombotic complications, specifically in high-risk patients. The most reliable predictor for such complications is a similar previous event. The current study considered the central importance of thrombosis history in predicting future events in ET and PV and, therefore, focused only on patients presenting with a history of thrombosis; the objective was to identify additional risk factors and assess the impact of anti-thrombosis treatment documented at the time of diagnosis.Methods:Study patients were selected from our institutional database of MPN, based on documentation of thrombosis history at or before the time of diagnosis, made according to WHO criteria (Arber et al. Blood 2016;127:2391). Statistical analyses considered clinical and laboratory data collected at the time of diagnosis. Thrombosis-free survival (TFS) was calculated both by considering all vascular events (arterial + venous) as well as by separately analyzing arterial vs venous TFS.Results:i) Presenting features:A total of 290 patients with ET (n=175) or PV (n=115) presented with history of thrombosis, either “at” (n=146; 50%) or “before” (n=194; 67%) the time of diagnosis. The respective arterial vs venous distribution of events was 35% vs 15% “at” and 49% vs 21% “before” the time of diagnosis. When ET and PV were analyzed separately, the respective incidences of thrombosis history (arterial + venous) were 19% vs. 25% (p=0.02) “at” and 64% vs 71% (p=0.19) “before” the time of diagnosis; the respective figures for arterial thrombosis were 44% vs 21% (p=0.0002) “at” and 50% vs 44% (p=0.75) “before” time of diagnosis and for venous thrombosis 12% vs 18% (p=0.13) “at” and 18% vs 23% (p=0.12) “before” time of diagnosis.ii) Treatment documented at time of diagnosis:Treatment at time of diagnosis was documented in 95% of the patients and included cytoreductive therapy in 82%, anti-platelet therapy in 61% and systemic anticoagulation in 26%, with no significant difference between ET and PV; the most frequent combination therapies were cytoreductive + anti-platelet therapy (42%), cytoreductive therapy alone (19%) and cytoreductive + systemic anticoagulation (13%); 9% of the patients received combination of all three treatment modalities.iii) Post-diagnosis events:Median follow-up was 9 years and was longer for ET (10 years) compared to PV (7 years; p=0.002); during this period, 146 (50%) deaths, 10 (3%) leukemic transformations, 17 (6%) fibrotic progressions, and 86 (30%) thrombotic events were recorded. Among the latter, 72 (25%) were arterial and 22 (8%) were venous. The incidence of post-diagnosis arterial (p=0.2) or venous (p=0.9) events was not significantly different between ET and PV.iv) Risk factors for thrombosis-free survival (including both arterial and venous):In univariate analysis, significant risk factors for arterial + venous TFS included male sex (HR 1.9; 95% CI 1.3-3.0), diabetes history (HR 1.8, 95% CI 1.01-3.2) and use of coumarins (HR 1.7, 95% CI 1.1-2.7). During multivariable analysis, male sex and use of coumarins remained significant.v) Risk factors for arterial vs venous thrombosis-free survival:In univariate analysis, significant risk factors for arterial TFS included older age, male sex and history of arterial thrombosis; male sex (HR 1.7, 95% CI 1.1-2.7) and arterial thrombosis history (HR 2.6, 95% CI 1.3-5.3) remained significant during multivariable analysis. Significant risk factors for venous TFS included history of venous thrombosis (HR 4.9, 95% CI 1.9-12.3) and use of coumarins (HR 5.3, 95% CI 2.2-12.9); both remained significant during multivariable analysis.Conclusions:The significant association between thrombosis history and future vascular events in patients with ET or PV is major vessel-specific in its distribution (i.e. arterial vs venous) and the current study identifies male sex and use of coumarins as additional independent risk factors for arterial and venous events, respectively. The unexpected association between coumarin use and recurrent venous thrombosis might be related to a higher underlying risk in the patients chosen to receive such therapy or detrimental drug effect; prospective studies are needed for further clarification. DisclosuresNo relevant conflicts of interest to declare.

Phenotypic and Prognostic Relevance of the Who Diagnostic Distinction between Polycythemia Vera and JAK2 -Mutated Essential Thrombocythemia: Combined Analysis of 785 Informative Cases

Background:The 2016 World Health Organization (WHO) classification system (Arber et al. Blood 2016;127:2391) distinguishes essential thrombocythemia (ET) from polycythemia vera (PV), based primarily on hemoglobin/hematocrit level. However, there is significant overlap between the two in terms of other clinical and laboratory parameters and the majority of patients with both ET and PV share the JAK2 V617F mutation. These observations have suggested the possibility that JAK2 -mutated ET and PV represent a clinic-pathologic disease continuum with similar phenotype and prognosis; we explored this possibility by a combined analysis of 785 consecutive cases of WHO-defined PV or JAK2 -mutated ET.Methods:Study patients were selected from our institutional database of myeloproliferative neoplasms (MPN). Diagnoses of ET, PV, blast phase disease, and post-ET/PV myelofibrosis (MF) were according to WHO (Arber et al. Blood 2016;127:2391) and international working group for MPN research and treatment (IWG-MRT; Barosi et al. Leukemia 2008;22:437) criteria. Statistical analyses considered clinical and laboratory data collected at the time of diagnosis. Overall (OS), leukemia-free (LFS), myelofibrosis-free (MFFS) and thrombosis-free (TFS) survivals were calculated from the date of diagnosis to the date of death, event or last contact.Results:The study population (n=785) was selected from a larger cohort of 1383 consecutive cases of PV and ET and included 456 cases with PV and 329 with JAK2 -mutated ET. 1.Phenotypic comparisons at diagnosis between PV and JAK2-mutated ETOutside of the expected differences in hemoglobin level and platelet count, the 329 patients with JAK2 -mutated ET, compared to the 456 with PV, displayed a preponderance of female gender (63% vs 48%; p<0.0001) and lower incidences of leukocytosis (28% vs 55%; p<0.0001), microcirculatory symptoms (20% vs 34%; p=0.0005) and palpable splenomegaly (20% vs 29%; p=0.005). On the other hand, notable similarities included the incidences of age ≥60 years (51% vs 53%; p=0.6), thrombosis history (24% vs 25%; p=0.70), arterial thrombosis history (18% vs 16%; p=0.66) and abnormal karyotype (14% vs 19%; p=0.1). Of note, when PV was compared to all ET cases regardless of JAK2 mutational status (n=927), significant differences were also noted for age, abnormal karyotype and venous thrombosis. 1.Rates of complications post-diagnosis in PV vs JAK2-mutated ETAt a median follow-up of 9 years, 323 (41%) deaths, 26 (3%) leukemic transformations, 89 (11%) fibrotic progressions, and 161 (20%) thrombotic complications, including 115 (15%) arterial events were recorded. Compared to that of JAK2 -mutated ET, mortality (44% vs 36%; p<0.0001) and fibrotic progression (14% vs 8%; p=0.02) rates were higher in PV; there was no significant difference in blast transformation (4% vs 3%; p=0.44) or post-diagnosis thrombotic events (21% vs 20%; p=0.8). 1.Combined analysis of OS, LFS, MFFS and TFS:When all 785 study patients were analyzed together, multivariable analysis identified diagnosis of “PV” vs “ JAK2 -mutated ET” (HR 1.5, 95% CI 1.03-2.1), age ≥60 years (HR 4.3, 95% CI 3.0-6.2), leukocyte count ≥11 x 10(9)/L (HR 1.4, 95% CI 1.03-2.0) and abnormal karyotype (HR 1.9, 95% CI 1.3-2.8) as significant risk factors for OS; figure 1 depicts survival comparisons of PV vs JAK2 -mutated ET vs JAK2- unmutated ET; the apparent difference in survival between the latter two was accounted for by the significant difference in age distribution. A similar analysis for TFS identified history of diabetes (HR 2.0, 95% CI 1.3-3.2) and thrombosis (HR 1.9, 95% CI 1.4-2.7), but not the specific diagnosis of PV vs ET (p=0.7) as significant risk factors. The number of events was too small to determine the relevance of PV vs ET diagnosis for LFS or MFFS.Conclusions:The current study validates the phenotypic and prognostic relevance of the current WHO-defined diagnostic distinction between JAK2 -mutated ET and PV; phenotypically, the two were primarily different in their gender distribution and leukocyte count while survival was worse in PV; thrombotic complication rates between the two were similar, implicating the JAK2 mutation as the common offender. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Direct oral anticoagulants in antiphospholipid syndrome: Meta-analysis of randomized controlled trials.

The gold standard for secondary thromboprophylaxis in APS is long term anticoagulation with vitamin K antagonists (VKAs). Because of their widespread use and potential advantages of directs oral anticoagulants (DOACs) over VKAs, they have been prescribed in APS without definitive evidence of their safety and efficacy in this context. Recent specific randomized controlled trials (RCT) in APS and results from pivotal RCTs comparing DOACs vs VKAs are now available. Their results are conflicting but these studies have been conducted in different APS populations. To summarize available data from RCT and determine risks of recurrent thrombosis and bleeding. Four studies were included and 23 and 10 thrombotic events were recorded among 282 and 294 APS patients treated with DOACs and warfarin respectively. Overall recurrent thrombotic events were not significantly increased during DOACs treatment (OR=2.22 [95% CI, 0.58-8.43]) compared to VKAs. However, when different types of thrombosis were analyzed separately, there was an increased risk of recurrent arterial thrombosis (5.17 [95% CI, 1.57-17.04]) with DOACs compared to warfarin but no significant higher risk of venous thrombosis (OR 0.69 [95% CI, 0.23-2.06). No increased risk of bleeding was found. In APS patients treated with DOACs compared to those treated with warfarin, no evidence of a higher risk of recurrent venous thromboembolism was found however there was a significantly increased risk of recurrent arterial thrombosis. Moreover risk of recurrent arterial thrombosis tended to be more frequent in patients with a history of arterial thrombosis. These results are in line with international guidelines which recommend not to use DOACs in APS patients with a history of arterial thrombosis but raise the question of the efficacy of DOACs to prevent venous thrombosis in a subset of APS patients without a history of arterial thrombosis.

SAT0194 LACK OF EFFICACY OF RIVAROXABAN IN THE TREATMENT OF ANTIPHOSPHOLIPID SYNDROME AND CLINICAL SIGNIFICANCE OF ANTIPHOSPHOLIPID ANTIBODIES

Background:Chronic anticoagulation with vitamin K antagonists (VKA) is the standard treatment to prevent thrombotic events in antiphospholipid syndrome (APS). But in recent years treatment schemes began to include rivaroxaban. Use of direct oral anticoagulants (DOAC) is an attractive and often preferred alternative to VKAs in other medical settings owing to greater ease of use, fewer food and drug interactions, and lower bleeding risks [1].However, according to last guidelines, rivaroxaban should not be used in patients with triple aPL positivity due to the high risk of recurrent events [2].Objectives:1.To determine the risk of recurrent thrombosis in single or double positive APS patients treated with rivaroxaban.2.Find out possible association between presence of particular antiphospholipid antibodies or high level of lupus anticoagulant (LA) and type of vascular events.Methods:33 patients with confirmed APS (25 female (75.8%), 8 male (24.2%), mean age 43.2±11.6 years) were included in the study. 17 (51.5%) of investigated patients had primary APS, in remaining 16 (48.5%) APS was included in the framework of SLE. 18 (54.5%) patients were treated with warfarin 2.5-7.5 mg/daily, 15 (45.5%) patients - with rivaroxaban 20mg/daily for a follow-up period of 12 months. The data is introduced as odds ratios (OR) with 95% confidence interval (CI). The results were considered significant when p &lt;0.05.Results:At baseline 21 (63.6%) patients had history of arterial thrombosis, 10 (30.3%) - venous thrombosis, 17 (51.5%) - pregnancy loss. According to results of serum immunology check, 29 (87.9%) patients were anticardiolipin antibody (ACA) positive, 9 (27.3%) - LA positive, 19 (57.6%) - anti-ß2-glycoprotein antibodies (anti-ß2-gp) positive; 20 (60.6%) patients were double positive (12 (36.4%) of them had positive ACA and anti-ß2-gp, 6 (18.2%) - ACA and LA, and 2 (6.1%) - anti-ß2-gp and LA), 4 (12.1%) patients were triple positive.No association between vascular event and/or pregnancy loss in patients with single positive ACA was found. We have found positive association between arterial thrombosis and single positive anti-ß2-gp (OR /CI 95%/ = 5.0 /2.08 – 23.06/, p&lt; 0.05), positive association between positive LA and venous thrombosis (OR /CI 95%/ = 10 /1.7-57.7/, p&lt; 0.05), strong positive association between positive LA and thromboembolism of pulmonary artery (OR /CI 95%/ = 46.0 /4.0-525.1/, p&lt; 0.001), negative association between positive LA and pregnancy loss (OR /CI 95%/ =0.06 /0.03 – 0.1/, p&lt; 0.01).Risk of thrombosis and/or pregnancy loss was not significantly increased in double positive patients, but triple positive patients had increased risk of venous thrombosis (OR /CI 95%/ =9.4 /3.2 – 105.8/, p&lt;0.04).Recurrent thrombosis was detected in 16 patients: 2 patients (12.5%) were on warfarin, 14 (87.5%) - on rivaroxaban (10 (71.4%) arterial thrombosis, 4 (28.6%) venous thrombosis).No association between warfarin 2.5-7.5 mg/daily and occurrence of recurrent thrombosis was detected. An association between use of warfarin and increased risk of bleeding was found, but the risk was not significant (OR /CI 95%/ = 7.0 /0.7 – 66/, p= 0.09). Rivaroxaban 20 mg/daily was associated with recurrent thrombosis not only for triple positive patients (p&lt; 0.02), but also in double positive patients (OR /CI 95%/ = 21.3 /1.8 – 251/, p&lt; 0.04).Conclusion:Rivaroxaban does not prevent recurrent thrombosis not only in triple positive patients, but also in single and double positive APS patients. Type of antiphospholipid antibodies can be predictive for the type of further vascular event.

New Insights into the Use of Direct Oral Anticoagulants in Non-high Risk Thrombotic APS Patients: Literature Review and Subgroup Analysis from a Meta-analysis.

The efficacy of direct oral anticoagulants (DOACs) in antiphospholipid syndrome (APS) is discussed. Results from randomized controlled trials are available. It has been stated that a history of arterial thrombosis and triple positivity was associated with a higher risk of thrombosis in APS patients treated with DOACs. However, their efficacy in non-high-risk APS patients with isolated venous manifestations is unsolved. Therefore, we performed a sub-group analysis of a previously published meta-analysis after the exclusion of patients with triple positivity and those with history of arterial or small vessel thrombosis. We identified 290 APS patients with previous isolated venous event treated with DOACs; among them, 25 (8.6%) patients experienced a recurrent thrombosis in comparison to 16% in the original cohort. We found that the rate of recurrent thrombosis is lower in APS patients with isolated venous manifestations than in overall APS patients including high-risk patients. Research about DOAC use in non-high-risk APS patients needs to be continued.

Health-Related Quality of Life in Antiphospholipid Syndrome: Current Knowledge and Future Perspectives.

Antiphospholipid syndrome (APS) is a chronic autoimmune disease that can be seen as a burden, with consequences on patients' daily life. Health has traditionally been measured using measures of morbidity or mortality. Health-related quality of life (HRQoL) is a concept that includes quality of life through physical, mental, and social domains. As in other autoimmune diseases, HRQoL has been investigated in patients with APS. Here, we provide a comprehensive review of the current knowledge of the assessment of HRQoL in APS. APS patients have an impaired HRQoL compared with the general population. The presence of systemic lupus erythematosus (SLE) in APS patients is associated with a worse HRQoL than in patients without SLE. Several determinants of HRQoL impairment in APS have been identified: age, gender, history of arterial thrombosis, organ damage, lack of social support and treatments. This review highlights the negative impact of thrombosis on APS patients' HRQoL that should not be neglected. Besides, there is a need for a better strategy of communication and information, in order to improve HRQoL in APS.

Antiphospholipid syndrome and direct oral anticoagulants: to the future and back again?

Antiphospholipid syndrome and direct oral anticoagulants: to the future and back again?

Determinants of Long-Term Outcome in Type 1/like Calreticulin-Mutated Myelofibrosis

Background:Type 1 calreticulin (CALR) variants comprise ~70% of all CALR mutations in primary myelofibrosis (PMF) and form a distinct phenotypic and prognostic disease subset (Leukemia. 2014;28:1568). Determinants of long-term outcome have not, however, been systematically appraised in this population. The current study documents the natural history, molecular correlates, and independent predictors of overall (OS), leukemia-free (LFS), and thrombosis-free (TFS) survival in CALR type 1/like-mutated myelofibrosis.Methods:Patients were recruited from the Mayo Clinic, Rochester, MN, USA. Diagnoses were consistent with World Health Organization (PMF, fibrotic/leukemic transformations) (Blood. 2016;127:2391) and International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria (post-essential thrombocythemia (ET) MF) (Leukemia. 2008;22:437). Laboratory and clinical data were retrospectively abstracted corresponding to time of referral (PMF) or myelofibrotic transformation (post-ET MF). Conventional prognostic scoring was as previously outlined (Blood. 2010;115:1703; J Clin Oncol. 2018;36:1769). Recipients of allogeneic stem cell transplant were censored at the time of transplant. Standard statistical methods were used for all analyses using the JMP® Pro 13.0.0 software package (SAS Institute, Cary, NC, USA).Results:A total of 162 consecutive patients with CALR type 1/like-mutated myelofibrosis were identified: 139 (86%) with PMF and 23 (14%) with post-ET MF with median age 55 years (range 23-85), 62% male. The PMF and post-ET MF cohorts displayed similar phenotypic features with the exception of higher platelet counts (median 443 vs 340 x 109/l; P=0.02) in post-ET MF (Table 1). The most frequent co-existing mutations were ASXL1 (n=47; 37%) and SRSF2 (n=4; 3%), with ASXL1 seen more frequently in PMF (39% vs 11% post-ET MF; P=0.07). Over a median follow-up of 6 years (range 0-25 years), a total of 20 (12%) leukemic transformations and 66 (41%) deaths were recorded, with no significant differences between the PMF and post-ET MF cohorts (P=0.16 and 0.11, respectively). Kaplan-Meier survival estimates revealed comparably favorable median OS in both CALR type 1/like-mutated variants: not yet reached and 13 years in post-ET MF vs PMF, respectively (P=0.7) (Figure 1A).Multivariable analysis disclosed moderate to severe sex-adjusted anemia (P<0.001), ≥2% circulating blasts (P<0.001), very high risk (VHR) karyotype (P<0.001), age >70 years (P=0.006), and constitutional symptoms (P=0.008) to be independent predictors of inferior OS in CALR type 1/like-mutated PMF (Table 2). LFS was significantly shortened in the presence of IDH1 mutations (P=0.01) and platelets <100 x 109/l (P=0.02) while IDH2 mutations (P=0.02), leukocytosis ≥11 x 109/l (P=0.03) and history of arterial thrombosis (P=0.04) were independent predictors of shortened TFS. Importantly, myelofibrosis variant (primary vs post-ET) did not influence survival (P=0.7) or complication rates (P=0.8 for LFS, P=0.09 for TFS) (Table 2).The karyotype- and mutation-enhanced international prognostic scoring system (MIPSS70+ version 2.0), was effective in risk stratifying type 1/like CALR-mutated PMF (P-values 0.01 to <0.0001), with the exception of low vs intermediate (P=0.22) and intermediate vs high risk (P=0.49) (Figure 1C). The detrimental influences of unfavorable/VHR karyotype and ASXL1 mutations were confirmed (Figure 2A-B) while borderline adverse and prognostically neutral effects were seen on OS for U2AF1 (n=116; P=0.05) and SRSF2 (n=120; P=0.98) respectively (Figure 2C-D).Conclusions:The current study documents analogous disease patterns in primary and post-ET CALR type 1/like-mutated MF and provides information on determinants of long-term survival. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Increased risk of thrombosis in antiphospholipid syndrome patients treated with direct oral anticoagulants. Results from an international patient-level data meta-analysis.

Direct oral anticoagulants (DOACs) are widely used for secondary prevention of venous thromboembolism (VTE) but their clinical efficacy and safety are not established in Antiphospholipid Syndrome (APS) patients. There is only one randomized controlled trial published while others are still ongoing. Many non-randomized studies have been published in this field with conflicting opinions. We conducted a systematic review using MEDLINE, EMBASE and Cochrane databases from 2000 until March 2018 regarding APS patients treated with DOACs. We performed a patient-level data meta-analysis to a) estimate the prevalence of recurrent thrombosis in APS patients treated with DOACs in the literature, and b) identify variables associated with recurrent thrombosis. We identified 47 studies corresponding to 447 APS patients treated with DOACs. Three commercially available DOACs were analyzed: rivaroxaban (n = 290), dabigatran etexilate (n = 144) and apixaban (n = 13). A total of 73 out of 447 patients (16%) experienced a recurrent thrombosis while on DOACs with a mean duration until thrombosis of 12.5 months. Rates of recurrent thromboses were 16.9% and 15% in APS patients receiving either anti-Xa inhibitors or dabigatran respectively. Triple positivity (positivity for all three antiphospholipid antibodies) was associated with a four-fold increased risk of recurrent thrombosis (56% vs 23%; OR = 4.3 [95%CI; 2.3-7.7], p < 0.0001) as well as a higher number of clinical criteria for APS classification. In patients treated with anti-Xa inhibitors, history of arterial thrombosis was associated with a higher risk of recurrent thrombosis (32% vs 14%; OR = 2.8 [95%CI; 1.4-5.7], p = 0.006). In conclusion, DOACs are not effective in all APS patients and should not be used routinely in these patients. Randomized controlled trials assessing clinical efficacy and safety as primary endpoints are underway. In the meantime, a registry of APS patients on DOACs could be proposed to establish in which APS subgroups DOACs would be a safe alternative to warfarin.

Factors associated with the 6-minute walk distance in patients with systemic sclerosis

BackgroundThere is an ongoing debate regarding the relevance of the 6-minute walking distance (6MWD) in systemic sclerosis (SSc) assessment, widely used as a usual test in these patients as well as an outcome measure in clinical trials. In this work, we aimed to assess the associations between the 6MWD and various disease parameters in patients with SSc.MethodsConsecutive patients followed in our SSc National Reference Centre were included in this cross-sectional study if they fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism criteria for SSc. Data were systematically collected during a comprehensive standardized evaluation that included a 6-minute walk test, clinical assessment, biological results, pulmonary function tests, transthoracic echocardiography, composite scores (European Scleroderma Study Group Activity Index, Medsger severity score, Health Assessment Questionnaire–Disability Index (HAQ-DI)) and treatments.Associations of the 6MWD with various disease parameters were assessed by linear regression in univariate and multivariate analyses.ResultsThe study population comprised 298 patients (females 81%; mean age 58.2 ± 13.3 years; limited cutaneous SSc 82%; interstitial lung disease (ILD) 42%; pulmonary arterial hypertension (PAH) 6%). The 6MWD was significantly and independently associated with gender, age, body mass index, baseline heart rate (HR), HR variation during the test, PAH, history of arterial thrombosis and C-reactive protein levels, as well as with the HAQ-DI score in a sensitivity analysis. Muscle involvement, joint involvement and ILD were not independently associated with the 6MWD.ConclusionsDuring SSc, the 6MWD is independently associated with initial HR and HR variation; with PAH but not ILD, suggesting that pulmonary vasculopathy may have a greater impact than parenchymal involvement on functional limitation; and with global markers of disease activity and patient disability. These results give clinicians further insight into how to interpret the 6MWD in the context of SSc.

Identification of Serum Lactate Dehydrogenase (LDH) As an Independent Prognostic Biomarker in Polycythemia Vera

BackgroundThe International Working Group for Myeloproliferative Neoplasms (MPN) Research and Treatment (IWG-MRT) has previously identified older age, leukocytosis, venous thrombosis and abnormal karyotype as risk factors for overall survival (OS) in polycythemia vera (PV), and older age, abnormal karyotype and leukocytes ≥15 × 109/l as risk factors for leukemia-free survival (LFS) (Leukemia2013;27:1874). Serum lactate dehydrogenase (LDH) is a surrogate quantitative measure of cell turnover and tumor burden. We hypothesized that, compared to leukocyte count, serum LDH might be a biologically more accurate indicator of tumor aggression and sought to examine its potential utility as a prognostic biomarker in PV.MethodsStudy patients were selected from our institutional database of MPN based on their meeting the 2008 or 2016 World Health Organization criteria for diagnosis of PV (Blood. 2009;114:937; Blood 2016 127:2391) and availability of serum LDH level, obtained within six months of diagnosis. Information on karyotype and targeted next-generation sequencing was available in a subset of the patients (Blood 2015 126:354). Statistical analyses considered clinical and laboratory parameters obtained at time of diagnosis. Age and leukocyte count prognostic categories were based on previously published IWG-MRT study (Leukemia2013;27:1874).ResultsPatient characteristics:A total of 216 patients (50% females) met the above-outlined criteria: median (10th-90th percentile) levels were for age 63 years (38-81), hemoglobin 18 g/dL (16.6-20.7), platelets 467 x 10(9)/L (237-833), leukocyte count 11.7 x 10(9)/L (7.2-20.3) and spleen size 0 cm (0-2). Pruritus was documented in 28%, microcirculatory symptoms in 31%, erythromelalgia in 6%, hypertension in 45%, diabetes in 7%, active tobacco use in 13%, hyperlipidemia in 25%, palpable spleen in 26% and abnormal karyotype in 15% of informative cases. Grading for bone marrow reticulin fibrosis was documented for 144 patients: 50% grade "0", 42% grade "1", 7% grade "2" and 1 grade "3". Thrombosis history at diagnosis was documented in 26% of patients and occurred after diagnosis in 19%. Mutation analysis was available in 72 patients and revealed TET2 mutations in 18 (25%), ASXL1 in 5 (7%), SRSF2 in 2 (3%) and IDH2 in one (1.4%).Serum LDH levels and correlates:Median serum LDH level was 226 U/L (range 71-1008); the upper normal limit (UNL) for Mayo Clinic was 222 U/L. Increased serum LDH was recorded in 110 (51%) patients that included 26 (12%) patients with LDH ≥1.5 x UNL. A significant correlation was demonstrated between increased serum LDH and older age (p=0.007), female sex (p=0.04), leukocytosis (p=0.01), venous thrombosis history (p=0.005) and, interestingly, absence of active tobacco use (p=0.003); no correlation was noted for bone marrow reticulin fibrosis, presence of palpable splenomegaly, abnormal karyotype or ASXL1 mutation.Survival analysis:After a median follow-up of 77 months, 82 (38%) deaths, 8 (3.7%) leukemic transformations, 13 (6%) fibrotic progressions and 41 (19%) thrombotic events were documented. In univariate analysis, the following adversely affected OS: advanced age (P<0.0001), increased LDH as a continuous variable (p=0.0006), LDH ≥1.5 x UNL (p<0.0001), leukocyte count ≥15 x 10(9)/L (p=0.02) and arterial thrombosis history (p=0.001). In multivariable analysis, only age and LDH remained significant; multivariable HR (95% CI) were 5.4 (2.8-10.4) for age ≥67 years, 3.2 (1.8-6.0) for LDH ≥1.5 x UNL and 2.4 (1.2-4.7) for age 57 to 66 years. In the subset of patients with available information on karyotype and non-JAK2 mutations (n=72), advanced age, LDH ≥1.5 x UNL and ASXL1 mutations remained significantly associated with inferior survival.Serum LDH also predicted leukemic transformation (HR 17.8, 95% CI 4.1-78) and fibrotic progression (HR 11.6, 95% CI 25-53.7); in multivariable analysis, only serum LDH ≥1.5 x UNL (HR 22.3, 95% CI 2.1-234.6) and abnormal karyotype (HR 9.5, 95% CI 1.2-74.7) predicted leukemic transformation and only the former predicted fibrotic progression.ConclusionsSerum LDH is a simple and inexpensive biomarker that might supersede leukocyte count as an independent predictor of overall, leukemia-free and myelofibrosis-free survival in PV; advanced age and ASXL1 mutations also retained significance for OS and abnormal karyotype for LFS. DisclosuresNo relevant conflicts of interest to declare.