Risk Factor For Arterial Thrombosis Research Articles

Myeloproliferative Neoplasms Are Associated with Increased Risk of Major Adverse Limb Events Among Patients Hospitalized for Peripheral Arterial Disease

Background: Myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are at high risk of cardiovascular (CV) disease, including atherosclerosis and peripheral arterial disease (PAD). Major adverse limb events (MALE), including major amputation, are dreaded complications of PAD that portend poor prognosis. Among patients with MPN, arterial thrombotic events are common and prior studies suggest that PAD is a risk factor for arterial thrombosis in this patient population. However, there are limited data on outcomes of patients with MPN and PAD. Therefore, the effect of MPN status on MALE, in-hospital death and unplanned readmissions among patients hospitalized for PAD. Methods: This was a retrospective cohort analysis of the National Readmission Database (NRD) of adult patients with a primary diagnosis of PAD from 2017 and 2018 with or without a history of MPN, as identified by ICD-10 codes. Primary outcome was MALE which was a composite of index hospitalization death, major amputation, 30-day readmission for PAD, lower extremity ulceration, gangrene, rest pain, major amputation or arterial thromboembolism. Secondary outcomes were bleeding complications at index hospitalization (including gastrointestinal, intracranial, post-procedure, and retroperitoneal bleeding), 90-day readmissions for any-cause, PAD, CV reason (including PAD, myocardial infarction, stroke, or heart failure), and bleeding. Propensity scores (PS) for estimating probability of MPN were calculated using non-parsimonious multivariable logistic regression that included all baseline patient characteristics examined. PS matching (PSM) 1 MPN case to 5 non-MPN controls was performed. Patients between groups were compared and standardized mean difference (SMD) was calculated for variables before and after PSM. Imbalances between groups were insignificant if SMD for a given co-variable was < 0.10. Odds ratio (OR) for MALE and in-hospital outcomes were calculated using logistic regression. For 90-day readmission analyses, patients who died during index hospitalization were excluded and hazard ratios (HR) were estimated using Cox proportional hazards regression. Risk factors for MALE among patients with MPN were assessed using backward stepwise logistic regression. Results: After PSM, 1702 patients with MPN (1338 ET, 273 PV, 91 PMF) were matched with 8510 non-MPN patients. After PSM, variables were well-balanced between patients with and without MPN, Table. MPN was associated with increased risk of MALE (40.3% vs 27.9%, OR 1.75, 95% CI 1.57 - 1.95) and major amputation at index hospitalization (34.6% vs 23.5%, OR 1.72, 95% CI 1.54 - 1.92) but not in-hospital death (1.8% vs 2.0%, OR 0.92, 95% CI 0.63 - 1.36) or bleeding (17.5% vs 19.5%, OR 0.90, 95% CI 0.79 - 1.03). MPN was associated with increased risk of 90-day readmission for any-cause (HR 1.21, 95% CI 1.10 - 1.33), PAD (HR 1.22, 95% CI 1.11 - 1.35), and CV reason (HR 1.32, 95% CI 1.17 - 1.49) but not for bleeding (HR 1.33, 95% CI 0.90 - 1.97), Figure. Among patients with MPN, ET (OR 2.08, 95% CI 1.44 - 3.01), end-stage renal disease (OR 1.59, 95% CI 1.12 - 3.11), anemia (OR 1.75, 95% CI 1.39 - 2.21), gangrene (HR 1.95, 95% CI 1.38 - 2.75), and sepsis (OR 1.90, 95% CI 1.36 - 2.66) were associated with increased risk of MALE while compared surgical bypass (OR 0.46, 95% CI 0.31 - 0.68) and endovascular revascularization (OR 0.71, 95% CI 0.54 - 0.94) during index hospitalization were associated with decreased risk of MALE. Conclusions: Among patients hospitalized for PAD, MPN was associated with increased risk of MALE and 90-day readmission for any-cause, PAD, and CV reasons. Among patients with MPN, ET was associated with increased risk of MALE while revascularization during index hospitalization was associated with decreased risk. Further studies are needed to further elucidate risk of MALE and adverse CV events among patients with MPN in order to improve clinical outcomes in this high-risk patient population.

MAGT1 Deficiency Dysregulates Platelet Cation Homeostasis and Accelerates Arterial Thrombosis and Ischemic Stroke in Mice.

MAGT1 (magnesium transporter 1) is a subunit of the oligosaccharide protein complex with thiol-disulfide oxidoreductase activity, supporting the process of N-glycosylation. MAGT1 deficiency was detected in human patients with X-linked immunodeficiency with magnesium defect syndrome and congenital disorders of glycosylation, resulting in decreased cation responses in lymphocytes, thereby inhibiting the immune response against viral infections. Curative hematopoietic stem cell transplantation of patients with X-linked immunodeficiency with magnesium defect causes fatal bleeding and thrombotic complications. We studied the role of MAGT1 deficiency in platelet function in relation to arterial thrombosis and hemostasis using several in vitro experimental settings and in vivo models of arterial thrombosis and transient middle cerebral artery occlusion model of ischemic stroke. MAGT1-deficient mice (Magt1-/y) displayed accelerated occlusive arterial thrombus formation in vivo, a shortened bleeding time, and profound brain damage upon focal cerebral ischemia. These defects resulted in increased calcium influx and enhanced second wave mediator release, which further reinforced platelet reactivity and aggregation responses. Supplementation of MgCl2 or pharmacological blockade of TRPC6 (transient receptor potential cation channel, subfamily C, member 6) channels, but not inhibition of store-operated calcium entry, normalized the aggregation responses of Magt1-/y platelets to the control level. GP (glycoprotein) VI activation of Magt1-/y platelets resulted in hyperphosphorylation of Syk (spleen tyrosine kinase), LAT (linker for activation of T cells), and PLC (phospholipase C) γ2, whereas the inhibitory loop regulated by PKC (protein kinase C) was impaired. A hyperaggregation response to the GP VI agonist was confirmed in human platelets isolated from a MAGT1-deficient (X-linked immunodeficiency with magnesium defect) patient. Haploinsufficiency of TRPC6 in Magt1-/y mice could normalize GP VI signaling, platelet aggregation, and thrombus formation in vivo. These results suggest that MAGT1 and TRPC6 are functionally linked. Therefore, deficiency or impaired functionality of MAGT1 could be a potential risk factor for arterial thrombosis and stroke.

Outcomes of patients with a myeloproliferative neoplasm and atrial fibrillation.

7070 Background: Patients with myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are associated with increased risk of cardiovascular (CV) disease including arterial thrombosis (AT). Atrial fibrillation (AF) is also associated with increased risk of AT and often co-exists with MPN. However, thrombotic and bleeding outcomes in patients with MPN compared with those without have not been thoroughly investigated. Methods: Patients aged ≥ 18 years with a hospital admission for AF with and without a history of MPN in 2017 and 2018 were identified using the National Readmission Database. Primary outcomes were 30-day (D) and 90-D any-cause, AT-related (including stroke, myocardial infarction, arterial thromboembolism), and bleeding-related readmissions. Propensity score weighting (PSW) was performed in order to adjust for imbalances between MPN and non-MPN patients. PSW Cox proportional hazards was performed to estimate risk of 90-D readmission in patients with MPN compared with patients without. Results: A total of 468,094 patients with AF were identified with 1,617 patients having a history of MPN. CHA2DS2-VASC (mean 3.8 vs 3.7) and HAS-BLED scores (mean 2.4 vs 2.3), risk scores for AT and bleeding in AF, were similar between MPN and non-MPN patients. After PSW Cox proportional hazards, patients with MPN had an increased risk of 30-D all-cause (HR 1.72, 95% CI 1.70 – 1.74), AT (HR 1.45, 95% CI 1.38 – 1.53), and bleeding (HR 2.21, 95% CI 2.01 – 2.44) re-admissions. MPN patients had an increased risk of 90-day any cause (HR 1.38, 95% CI 1.37 – 1.40) and bleeding (HR 1.76, 95% CI 1.65 – 1.88) but not AT (HR 1.03, 95% CI 0.99 – 1.08) readmissions. Conclusions: Among patients admitted for AF, MPN is associated with increased risk of 30-D and 90-D any-cause and bleeding readmissions and 30-D AT readmissions despite similar CHA2DS2-VASC and HAS-BLED risk scores. Further studies are needed to identify risk factors for bleeding and AT in patients with MPN and AF and improve on current risk scores, which do not include MPN status. [Table: see text]

Genome-wide meta-analysis identifies 93 risk loci and enables risk prediction equivalent to monogenic forms of venous thromboembolism.

We report a genome-wide association study of venous thromboembolism (VTE) incorporating 81,190 cases and 1,419,671 controls sampled from six cohorts. We identify 93 risk loci, of which 62 are previously unreported. Many of the identified risk loci are at genes encoding proteins with functions converging on the coagulation cascade or platelet function. A VTE polygenic risk score (PRS) enabled effective identification of both high- and low-risk individuals. Individuals within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of the variants G20210A (c.*97 G > A) in F2 and p.R534Q in F5. We also document that F2 and F5 mutation carriers in the bottom 10% of the PRS distribution had a risk similar to that of the general population. We further show that PRS improved individual risk prediction beyond that of genetic and clinical risk factors. We investigated the extent to which venous and arterial thrombosis share clinical risk factors using Mendelian randomization, finding that some risk factors for arterial thrombosis were directionally concordant with VTE risk (for example, body mass index and smoking) whereas others were discordant (for example, systolic blood pressure and triglyceride levels).

Methylenetetrahydrofolate Reductase 677T Allele Is a Risk Factor for Arterial Thrombosis in Chinese Han Patients with Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies (aPL) and thrombotic or obstetric events. Given the heterogeneity of the clinical manifestations, it is likely that genetic and acquired factors are involved in the pathogenesis of APS. The inherited polymorphisms of the thrombophilic gene, including methylenetetrahydrofolate reductase (MTHFR) C677T, type 1 plasminogen activator inhibitor (PAI-1) 4G/5G, factor V Leiden (FVL) G1691A, prothrombin (PT) G20210A, antithrombin (AT), and fibrinogen (Fg) polymorphisms, were analyzed in 67 aPL(+) patients from the Chinese Han population, including 41 APS patients and 26 persistent aPL carriers. The MTHFR C677T genotypes of 105 healthy controls, and the PAI-1 4G/5G polymorphism of 120 healthy controls, from the Chinese Han population were acquired for this study. Both the MTHFR C677T genotype (χ2 = 10.67, p = 0.004) and C/T allele distribution (χ2 = 5.92, p = 0.019) between the aPL(+) patients and healthy controls were found to be significantly different. Furthermore, we observed that the patients with at least one T allele had a higher risk of arterial thrombosis (CT vs. CC, OR 11.00, p= 0.025; CT + TT vs. CC, OR 10.27, p = 0.018). The C677T mutation of MTHFR is a risk factor for arterial thrombosis in Chinese Han patients with APS.

Post-Covid-19 Recurrent Lower Limb Ischemia in Healty Young Patient

Background: Although SARS-CoV-2 infection is primarily a respiratory illness, complications such as arterial and venous thromboembolism have been reported during acute infection and in the period after its resolution.Methods: We report the case of a 33-year-old male, previously healthy patient with acute recurrent unilateral arterial thrombosis of the leg occurring one month after a mild Covid-19 infection.Results: The patient has recently been diagnosed with essential hypertension and did not have other known risk factors for arterial thrombosis. He presented to the Emergency Department with a pale left foot and absent dorsal pedal pulse and after confirmed arterial occlusion by Doppler ultrasound, he underwent urgent thromboembolectomy. The following day a computed tomography angiogram showed recurrent thrombosis of the superficial femoral artery which was then resolved in an Angio-suite by balloon dilatation. Three months later he experienced another occlusion of the left superficial femoral artery based on pronounced neointimal hyperplasia and again underwent endarterectomy with patch plastic.Conclusion: SARS-Cov-2 infection should be considered a risk factor in the development of both arterial and venous thrombo-sis during the acute phase and in the post-infective period

Prevalence of the JAK2V617F Mutation in Patients with Ischemic Stroke

Introduction: Patients with the Philadelphia negative myeloproliferative neoplasms (MPN) have an increased risk of thromboembolic events, ischemic cerebrovascular events in particular. The somatic mutation JAK2V617F is associated with MPN with a prevalence of 96% in polycythemia vera (PV), 55% in essential thrombocythemia (ET), and 65% in primary myelofibrosis (PMF). The JAK2V617F mutation is found to be an independent risk factor for thrombosis in patients with MPN. However, whether the JAK2V617F mutation is a risk factor for arterial thrombosis in the absence of an MPN diagnosis is still uncertain. The sensitivity of the assay used for detection is crucial when assessing the presence of the JAK2V617F mutation. A higher sensitivity enables detection of lower allele burdens. This is illustrated by the varying prevalences (0.1-3.1%) in background population studies. In the Danish population study GESUS of approximately 20.000 individuals, the JAK2V617F mutation was detected by droplet digital PCR (ddPCR) with an assay sensitivity of 0.009%. The GESUS study found a JAK2V617F prevalence of 3.1%. Similarly, prevalence studies of JAK2V617F mutation in stroke have varying detection limits from 0.01-5% mutant alleles. The vast majority of these studies are retrospective studies in younger subpopulations of stroke patients. We aimed to investigate the prevalence of the JAK2V617F mutation in a prospective design of consecutively enrolled unselected patients with ischemic stroke or transient ischemic attack by the highly sensitive ddPCR. Method: We recruited 90 consecutive patients with ischemic stroke or transient ischemic attack during admission at the Department of Neurology, Zealand University Hospital, Denmark. A blood sample was taken within 7 days of the onset of symptoms and screened for the JAK2V617F mutation by ddPCR. Patients unable to give informed consent were excluded from the study. Results: Out of 90 patients (mean age 71, range 46-92; female 37%) with ischemic stroke or transient ischemic attack, the JAK2V617F mutation was found in 11 patients (12.2%). Allele burdens ranged from 0.0021 to 24. All 11 patients suffered an ischemic stroke. Six out of 11 patients with the JAK2V617F mutation had elevated blood cell levels i.e. erythrocytosis, thrombocytosis, and/or leukocytosis at the time of recruitment. Only three patients had continuously elevated blood cell levels after 1 month. Patient no. 6 with a JAK2V617F mutation allele burden of 34% had blood cell levels meeting the diagnostic criteria for MPN and was diagnosed with ET. Patient no. 2 had a JAK2V617F allele burden of 14% and increased levels of hemoglobin and platelet count, which both normalized spontaneously after 1 month. The patient was referred for a hematological workup and was found to have mild splenomegaly and a bone marrow biopsy showing myeloproliferative features. In light of the normal blood cell parameters, patient no. 2 was diagnosed with MPN-U. The patients with a JAK2V617F mutation are presented in table 1. Additional data will be presented at ASH. Conclusion and implications: The present study reveals a JAK2V617F mutation prevalence (12.2%) in a stroke population that is substantially higher compared to the background population (GESUS) in the same region of Denmark, using the same assay. The GESUS study showed a JAK2V617F mutationprevalence of 3.1% and for individuals above age 60 a prevalence of 4.1%. Given the fact that the JAK2V617F mutation is present in patients with and without cytosis, our results highly suggest that the JAK2V617F mutation per se is a thrombogenic factor in ischemic stroke. This calls for an exploration of the pathophysiological mechanisms and potential treatments to prevent future thrombotic events in individuals with and without cytosis. Table legend: Clinical and paraclinical characteristics of ischemic stroke patients with the JAK2V617F mutation. IS, ischemic stroke; TIA, transient ischemic attack; HTN, hypertension; HLP, hyperlipidemia; AF, atrial fibrillation; IHD, ischemic heart disease; DM2, diabetes mellitus type 2; Hb, hemoglobin; PLT, platelet count; WBC, white blood cells. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P1682: MTHFR C677T GENOTYPE IN CORRELATION WITH THROMBOSIS AND ASSOCIATION WITH FVIII COAGULANT ACTIVITY IN GREEK PAEDIATRIC POPULATION

Background: The polymorphism C>T substitution in position 677 (C677T) of the encoding gene of methylenetetrahydrofolate reductase (MTHFR), creates a thermolabile enzyme with reduced activity that may predispose to hyperhomocysteinemia, an established risk factor for arterial thrombosis and premature atherosclerosis and a probable risk factor for venous thromboembolic disease and its recurrence in the general population. There are conflicting results as to the role of the MTHFR C677T polymorphism as a risk factor for thrombosis. Although the homozygous substitution is often associated with hyperhomocysteinemia, mainly in folate deficiency, a clear association between this genetic marker and thrombosis has not yet been established. Aims: Primary aim was to evaluate the prevalence of mutant C677T MTHFR and its association with thrombosis in the Greek paediatric population. Secondary aim was to evaluate whether different MTHFR genotype is associated with evidence of activation of coagulation cascade through increased factor VIII activity. Methods: Data were retrospectively collected from children referred to our Haemostasis and Thrombosis Centre for laboratory screening of thrombophilia between 2018 and 2020. Some of them were checked due to history of thrombosis. Children were categorized according to MTHFR C677T genotype. FVIII Coagulant activity (%) was measured by One Stage Assay, away from acute thrombosis. The identification of mutations was based on polymerase chain reaction (PCR) and reverse- hybridization. Statistical analysis was performed with t-test and ANOVA. Results: A total of 688 children (boys: 49 %) of mean age 8.9± 8 years (0-18) were investigated. Twelve percent (81/688) of them had history of thrombosis, mainly venous thromboembolic disease. Children were categorized as follows: homozygous MTHFR C677T (15%), heterozygous (47%) and normal (38%). There was thrombosis history in 12% of homozygous MTHFR C677T, 11% heterozygous and 12 % of normal, fact showing that there is no association between MTHFR C677T genotype with thrombosis. Children with homozygosity MTHFR C677T, compared to children with heterozygosity and normal MTHFR C677T showed increased factor VIII values (132.8 vs 126.4 and 131.6, %, respectively), but without statistically significant difference. However, independently of MTHFR C677T genotype, mean factor VIII values were significantly increased in all children, with thrombosis history when they were compared to children without thrombosis history (161.3 vs 125.1, %, p<0.001). Interestingly, in children with thrombosis, mean factor VIII level was statistically increased in heterozygous and normal MTHFR C677T in contrast to children with MTHFR C677T homozygosity, in whom no statistically significant increase was found (166.9 vs 121.4, %-p<0.05, 160.2 vs 127.6, %-p<0.05 and 148.3 vs 130.6, %-p>0.05, respectively). Finally, it should be noticed that during the year 2020 mean factor VIII values were much increased in all children in comparison to the years 2018, 2019 and 2021 (137 vs 129, 123 and 127, %, respectively), probably reflecting the effects of unknown pandemic COVID-19 which initiated in 2020, and showing that factor VIII could be an evidence of stress condition. Summary/Conclusion: There is no probably association between MTHFR C677T genotype and thrombosis in our paediatric population. Moreover, it was not proved that different MTHFR genotypes affect factor VIII activity.

JAK2V617F Is a Risk Factor for TIA/Stroke in Young Patients.

The objective of this study was to assess the risk of arterial thrombosis in patients who harbor the JAK2V617F allele burden ≥1% detected during workup for myeloproliferative neoplasms (MPNs). We conducted a large cross-sectional analysis consisted of 5,220 patients who were tested for JAK2V617F and 1,047,258 people matched in age from health care insurance provider, taking into account age, sex, hypertension, diabetes, atrial fibrillation. Compared with noncarriers, mutation carriers were older, less likely to be current or past smokers and had lower body mass index. There was no significant difference between the groups regarding myocardial infarction and peripheral vascular disease. However, JAK2V617F ≥1% at age 34 to 54 years was associated with eightfold more likely to have transient ischemic attack (TIA)/stroke history unrelated to hypertension, diabetes, or atrial fibrillation. Association of JAK2V617F with TIA/stroke was also observed in the older age group, albeit a weaker association and not statistically significant. Prevalence of TIA/stroke was higher in patients with JAK2V617F negative, with odds ratio of 3.93 when compared with the general population after confounder adjustments. Further research is warranted to verify the relation between allele burden of JAK2V617F mutation and TIA/stroke and the role of JAK2V617F per se as a risk factor for arterial thrombosis in the absence of overt MPN. Also, consideration should be paid to the screened group with JAK2V617F negative due to the high incidence of TIA/stroke among them in comparison to the general population.

Characteristics and risk factors for thrombosis in POEMS syndrome: A retrospective evaluation of 230 patients.

Thromboses are prevalent in POEMS syndrome, but few risk factors for POEMS-associated thrombosis have been identified. The objective of this study is to identify novel risk factors for POEMS-associated thrombosis. In this retrospective cohort of 230 POEMS patients, 27% developed thrombosis. Arterial events were slightly more common than venous. Stroke accounted for 26% of all thromboses and 53% of arterial events. There were differences in baseline features between the thrombosis group and the no thrombosis group, and these were driven by patients with arterial thrombosis. Risk factors for arterial thrombosis included thrombocytosis, elevated hemoglobin/hematocrit, extravascular volume overload, and splenomegaly. Hyperprolactinemia appeared to be a risk factor for venous thrombosis. The risk of thrombosis was most striking among men with elevated hemoglobin (32% vs. 5%, p< .001) and hematocrit (42% vs. 5%, p< .001) compared to men without. Most thromboses occurred prior to POEMS directed therapy, and most that occurred during therapy happened within 3months of diagnosis. Twenty-one percent of patients with thrombosis had recurrence. In recognition of high overall rates of thrombosis in this population, all patients with POEMS syndrome should receive prophylactic antiplatelet therapy, and clinicians should consider anticoagulation in patients with risk factors for POEMS-associated thrombosis.

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.

A case-control study on factor V Leiden: an independent, gender-dependent risk factor for venous thromboembolism

BackgroundActivated protein C resistance (APCR) due to factor V Leiden (FVL) mutation (R506Q) is a major risk factor in patients with venous thromboembolism (VTE). The present study investigated the clinical manifestations and the risk of venous thromboembolism regarding multiple clinical, laboratory, and demographic properties in FVL patients.Material and methodsA retrospective cross-sectional analysis was conducted on a total of 288 FVL patients with VTE according to APCR. In addition, 288 VET control samples, without FVL mutation, were also randomly selected. Demographic information, clinical manifestations, family and treatment history were recorded, and specific tests including t-test, chi-square and uni- and multi-variable regression tests applied.ResultsAPCR was found to be 2.3 times significantly more likely in men (OR: 2.1, p < 0.05) than women. The risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in APCR patients was 4.5 and 3.2 times more than the control group, respectively (p < 0.05). However, APCR could not be an independent risk factor for arterial thrombosis (AT) and pregnancy complications. Moreover, patients were evaluated for thrombophilia panel tests and showed significantly lower protein C and S than the control group and patients without DVT (p < 0.0001).ConclusionFVL mutation and APCR abnormality are noticeable risk factors for VTE. Screening strategies for FVL mutation in patients undergoing surgery, oral contraceptive medication, and pregnancy cannot be recommended, but a phenotypic test for activated protein C resistance should be endorsed in patients with VTE.

Acute progressive arterial thrombosis after coronary artery bypass graft in a COVID-19 patient

The longer the SARS-CoV-2 pandemic takes, the greater the prothrombotic effects of the disease, which varies from venous thromboembolic events to limb arterial thrombosis and stroke. How we deal with the effects of the COVID-19 disease, is still unclear. In this study, researchers will report the clinical presentation, outcome and management of the patient with COVID-19 after coronary artery bypass graft (CABG) surgery, which led to rapid progression of arterial thrombosis. The COVID-19 positive patient underwent emergency CABG, due to developed coronary artery disease. Despite receiving high-dose preoperative Plavix and heparin and also postoperative aspirin, the patient developed progressive thrombosis in both lower extremities 4 days after surgery. It then spread to bilateral iliac arteries, aorta, abdominal and renal artery. Femoral endarterectomy was performed two times for atheromatous plaque removal which was unsuccessful and the patient died few days later due to multi-organ failure. COVID-19 is a risk factor for arterial thrombosis with high mortality and morbidity rate. If thrombosis happens, the prognosis will be poor. Comprehensive treatments have to be started immediately after diagnosis. In patients undergoing surgery for extensive arterial thrombosis due to poor prognosis, not only surgical revascularization is needed but also thrombolysis treatments may be considered as off-label use. As the pandemic continues, new approaches and interventions may be applied.

Prognostic Factors for Developing Thrombosis in Polycytemia Vera: A Retrospective Analysis of 331 Patients with Long-Term Follow-up Highlights the Importance of White Blood Cells Levels

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis, constitutively active mutations in JAK2 and an increased susceptibility to thrombotic events (TEs). There is still controversy about the role of increased hematocrit and of other variables including elevated white blood cell count as risk factors for the occurrence of TEs. A better definition of the relative prognostic importance of hematologic parameters would help us to better tailor the therapeutic approach to PV patients (pts), which is currently mainly based on the use of acetilsalycilic acid (ASA), venesection and hydroxyurea . The aim of our study was to analyze if any clinical or laboratory variables were significantly associated to the occurrence of TEs both at PV diagnosis and during the course of the disease in a large series of PV pts uniformly followed at a single Center over a period of 29.5 years from January 1986 to June 2019. Clinical and laboratory data were obtained from the time of diagnosis until death, progression to acute leukemia or last follow-up. Hematocrit (Hct), hemoglobin (Hb), white blood cell (WBC) and platelet (PLT) levels were recorded for each patient at least every 6 months. Among a total of 331 pts, the median age was 65 years (range 30-92 years), and 56% were male. "High risk" features (age ≥ 60 years and/or history of prior thrombosis) were present in 221 pts (66.7%). The incidence of cardiovascular risk factors was: hypertension 64%, diabetes 15%, hyperlipidemia 28%, history of active or remote smoking 41%. Patients on ASA were 279 (84%), 19 (6%) were on oral anticoagulation, while 27 (8%) were on ASA+oral anticoagulant. At PV diagnosis 54 pts (16%) presented with thrombosis, arterial in 32 (59%) and venous in 22 (41%). A previous TE was recorded in 57 pts (17%): in 43 (75%) arterial, in 12 (22%) venous and in 2 (3%) mixed (arterial+venous). Previous thrombosis was the only variable significantly associated with the presence of a TE at PV diagnosis (P=0.02). After PV diagnosis, with a median follow-up of 81 months (range 1-374 months), 63 pts (19%) experienced a TE and 11 of them a further episode, for a total of 74 TEs. The incidence rate (pts/year) of TEs was 2.7%. Forty-two events were arterial (57%), 31 were venous (42%) and 1 (1%) was mixed. It was the first TE for 37 pts. Cerebrovascular accidents and deep-venous thrombosis were the most frequent arterial and venous TEs both at PV diagnosis and throughout the disease course, with a relative incidence of 50% and 32% respectively. The table compares the characteristics of patients who did or did not develop a TE after PV diagnosis. At univariate analysis, PV high risk status, a previous TE and hyperlipidemia at PV diagnosis were significantly associated with a subsequent TE. Among hematologic variables an elevated WBC count at the time of thrombosis, but not Hct or PLT levels, was highly significantly associated with the development of a TE. At multivariate analysis, WBC count ≥10.4 x 10^9/L and hyperlipidemia maintained their independent prognostic value, while high risk status and a previous TE lost their prognostic significance. Both at univariate and multivariate analysis, hyperlipidemia at diagnosis (P=0.009 and P=0.002) and high WBC count at thrombosis (P=0.001 and P=&amp;lt;0.0001) predicted for arterial thromboses, while only a history of prior thrombosis (P=0.03) predicted for venous ones. In conclusion, our analysis confirms that elevated WBC count at the moment of the event more than increased hematocrit is associated to the development of thrombosis in PV pts. We also found that hyperlipidemia was an independent risk factor for arterial thrombosis, calling for an accurate management of increased lipid levels. Whether a reduction of the WBC count during the course of PV may reduce the frequency of TE remains to be demonstrated by prospective studies. Table Disclosures D'Adda: Novartis: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Other: Advisory board. Rossi:Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Epidemiology of polycythemia vera in a Mexican population

Epidemiology of polycythemia vera (PV) is derived from cohort studies in Western populations. PV studies in the Latin population are limited and have described a lower prevalence of JAK2 mutation. A retrospective cohort of 90 Mexican patients from a single center with PV according to the 2016 World Health Organization diagnostic criteria was studied to establish clinical presentation in Mexicans and evaluate risk factors for mortality and vascular events. At diagnosis, the median age was 59 years; half were females, 90.7% harbored the JAK2 V617F mutation, and 7.1% had an exon 12 mutation. Arterial and venous thromboses were observed in 13.3 and 27.8% of patients, respectively. Seventy-one patients received hydroxyurea and one interferon alpha-2a, of which 51.5% achieved a complete response and 25.0% a partial response. The incidence rate for postdiagnosis arterial thrombosis was 2.68 cases per 100 person–years, for venous thrombosis 2.84, for major hemorrhage 2.57, for progression to myelofibrosis 1.14, and for leukemic transformation 0.44. The mortality rate was 3.54 cases per 100 person–years, and median of survival was 150 months. In multivariable analysis, survival was adversely affected by leukocytosis ≥12 × 109/L (p = 0.013); thrombocytosis ≥450 × 109/L was a risk factor for arterial thrombosis (p = 0.023), and anticoagulation at diagnosis for major hemorrhage (p = 0.049). In conclusion, epidemiology of PV in Mexican population is similar to that reported in Western studies, but with more venous thrombosis at diagnosis and a higher incidence of vascular complications postdiagnosis.

PF683 ARTERIAL THROMBOSIS IN YOUNG PV PATIENTS

Background:Polycythemia Vera (PV) is a myeloproliferative neoplasm mainly affecting median advanced age while rarely occurs in young patients. PV natural history is marked by vascular complications and studies exploring the thrombotic events and their management in young PV patient are lacking.Aims:The purpose of the present study is to evaluate the natural history and in particular arterial thrombotic complications in young patients with PV.Methods:We selected from our database 203 consecutive patients (103 males, 100 females; mean age at diagnosis 60 ± 15.6 y; median follow‐up 7.48 y – range 0.02 – 43.5) diagnosed with PV between 1969 and 2018. All diagnoses were performed or revised according to WHO 2016 criteria. Patients have been stratified according to age at diagnosis in “Youngs”, with an age at diagnosis ≤ 45 y (n = 41, 20.2%) and “Old”, with an age at diagnosis &gt; 45 y (n = 162, 79.8%). For all patients the presence of at least one cardiovascular risk factor (CVRF) (smoking habit, hypertension, diabetes and dyslipidemia) and all thrombotic events were recorded. All patients were treated with low dose aspirin, phlebotomies to maintain hematocrit below 45% and cytoreduction when indicated. Statistical analysis was performed using the χ2 test or Fisher's exact, Kaplan Meyer (KM) method for survival curves and the Cox regression model for multivariate analysis.Results:CVRF are more frequent in Old (68 % vs 49% in Youngs; p = 0,027). Follow‐up was significantly longer (13.6 y range 0.7–43.5 vs 6.5 y range 0.02–29.2, p &lt;0.001) in Youngs that display also a better overall survival (p &lt; 0.001). 7 out of 41 (17%) Youngs and 34 out of 162 Old (21%) suffered for an arterial thrombotic event (p = NS). In 5 (12%) and 14 (8%) respectively, arterial thrombosis occurred at diagnosis, therefore being the patients not treated. In contrast, respectively in 2 (5%) and 20 (12%) patients arterial thrombosis occurred during follow up (p = NS). Youngs display a significant longer arterial thrombosis free survival (p = 0.015) compared to old patients. Old age at diagnosis is confirmed as an independent risk factor for arterial thrombosis during follow‐up also in Cox regression model adjusted for CVRF (Figure 1; p = 0,04; HR 7,93; CI95% 1,05–59,76).Summary/Conclusion:The young patients here evaluated are one fifth of all PV patients, in agreement with other few available data of the literature. Not surprisingly, the CVRF were more common in old than in young patients and Youngs have a longer overall survival. We failed to recognize a significant difference in the incidence of arterial thrombosis in different ages and we think that this is due to the small number of young patients. However, it seems that old age per se represents a risk factor for arterial thrombotic risk, meaning that a patient diagnosed before the age of 45, treated appropriately since youth and strictly managed, has less endothelial damage compared to an older patient.imageStrengths of this study are the diagnosis obtained in agreement with WHO 2016 criteria in all PV patients, the long duration of follow‐up in a single center that allowed the estimation of the risk of thrombosis, and the management in all cases in agreement with best clinical practice guidelines. Among the limitations, there is the retrospective design of the study that impose caution on the interpretation of results. Larger and prospective studies are needed to confirm and clarify our findings.

Impact of risk factors on the occurrence of arterial thrombosis and venous thromboembolism in adults with primary immune thrombocytopenia – Results from two nationwide cohorts

BackgroundPrevious studies have found that patients with Immune thrombocytopenia (ITP) have an increased risk of arterial thrombosis (AT) and venous thromboembolism (VTE). However, risk factors for thrombosis in adults with primary ITP remain unassessed in large cohorts.AimTo assess the occurrence and impact of risk factors for AT and VTE in patients with primary ITP in France and Sweden. MethodsBoth countries have national health databases, including hospital diagnoses and drug dispensing data. Adults with incident primary ITP identified using algorithms between the years 2009–2015 in France, and 2009–2016 in Sweden were included. Cumulative incidence rates (IR) of AT and VTE were calculated by risk factors and multivariable Cox models were used to estimate associations. ResultsThe study included 7225 patients from France and 2490 from Sweden. The IR of AT were 15.0 (95% CI: 13.4–16.7) and 14.7 (95% CI: 12.4–17.5) per 1000 person-years, respectively. The incidences of VTE were 6.9 (95% CI: 5.9–8.1) and 6.5 (95% CI: 5.1–8.4), respectively. Increasing age, male sex and a previous AT were associated with AT in both countries and so were exposure to antiplatelet drugs in France and a history of VTE and chronic kidney disease in Sweden. Increasing age and a history of VTE were associated with VTE in both countries, in France also cancer. ConclusionThe IR of AT and VTE were similar in France. Age and male sex remained the most important risk factors for AT, age for VTE.

SUN-LB025 Superior Mesenteric Artery Thrombosis: An Uncommon Complication of Diabetic Ketoacidosis

Introduction: Diabetic Ketoacidosis (DKA) has been shown to promote a prothrombotic state. Mortality rate in DKA can be as high as 20% due to thromboembolic complications. Acute mesenteric ischemia has mortality rates of 60-80% due to late and difficult diagnosis. Very few cases of superior mesenteric artery (SMA) thrombosis associated with DKA have been described in literature. The presentation of acute SMA thrombosis can be masked by concurrent DKA due to its non-specific signs and symptoms and laboratory markers leading to delay in diagnosis and treatment. Case: A 68-year-old female with Type 2 diabetes since 25 years was hospitalized with nausea, vomiting and abdominal pain of 3 days duration. Initial lab work showed: Serum glucose 631 mg/dl (n 70-140 mg/dl), bicarbonate 11 mmol/L (n 22-28 mmol/L), anion gap 32(n 12-16), lactic acid 3.0 mmol/L (n 0.5-2.2 mmol/L), HbA1c 14.1 % (n 4.6-6.5%) and serum osmolarity of 310 mOsm/kg (n 275-295 mOsm/kg). CECT abdomen on admission was unremarkable. She was adequately managed for DKA with intravenous fluids and insulin. Lactic acid normalized with fluids and anion-gap closed within 24 hours of admission. However, she kept complaining of diffuse abdominal pain described as sharp and deep inside the abdomen. D-dimer and repeat lactic acid were elevated at 1,155 ng/ml (n 150-234 ng/ml) and 2.4 mmol/L (n 0.5-2.2 mmol/L) respectively. CT angiography obtained at 48 hours from the time of admission showed occlusion of SMA at its mid-portion, approximately 7 cm distally from origin with abrupt loss of contrast signal at branch point of the ileocolic artery after several jejunal branches. She underwent urgent SMA thrombectomy, exploratory laparotomy and small bowel resection. Echocardiogram didn’t reveal any cardiac source of embolism or septal defects. EKG showed sinus rhythm and patient didn't have any prior history of thromboembolism or cardiac arrhythmias. Laboratory panel for thrombophilia and screening for auto-immune disorders was negative. Patient recovered well post surgery and was started on anti-coagulation. Discussion: We didn't find any other risk factor for arterial thrombosis in our case other than diabetic ketoacidosis and uncontrolled diabetes. Studies have shown that Free Protein S and Protein C activity levels decrease and von Willebrand factor levels increase during DKA. Platelet hyperreactivity, coagulation activation, hyperosmolarity, endothelial damage and impaired fibrinolysis- all contribute to hypercoagulability during DKA. Routine use of prophylactic anticoagulation in DKA is controversial. Clinicians should maintain a high index of suspicion of thrombosis in DKA. Pain out of proportion to the physical exam findings and persistent abdominal pain and lactic acidosis despite treatment should point towards mesenteric ischemia. Early diagnosis and treatment of mesenteric ischemia in critical in influencing the survival. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Atteinte coronarienne et syndrome néphrotique au cours du lupus systémique : à propos d’une observation

IntroductionHeart failure during systemic lupus erythematosus has various causes. Case reportA 29-year-old female presented with a systemic lupus flare and a nephrotic syndrome, followed by cardiogenic shock requiring extra-corporeal membranous oxygenation. Ventricular dysfunction was related to massive myocardial infarction due to an anterior interventricular artery thrombosis and an underlying atheroma. The young age and the absence of chest pain were not suggestive of coronary artery disease initially. Coronary thrombosis was probably favored by the nephrotic syndrome, in which the arterial thrombotic risk is increased. ConclusionCoronary artery disease should be systematically evoked in the presence of ventricular dysfunction in patients with systemic lupus, including when they are young and in the absence of chest pain. Nephrotic syndrome should be identified as a risk factor for arterial thrombosis.

Methylenetetrahydrofolate Reductase Gene Polymorphism (C677T) as a Risk Factor for Arterial Thrombosis in Georgian Patients.

Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (C677T)] is a well-recognized genetic risk factor for venous thrombosis; however, its association with arterial thrombosis is still under debate. Herein, we evaluated the prevalence of MTHFR C677T polymorphism in Georgian patients in comparison with healthy individuals and its association with arterial thrombosis. We enrolled 214 participants: 101 with arterial thrombosis (71.3% males; mean age: 66.3 ± 12.1 years) and 113 controls (67.3% males; mean age: 56.6 ± 11.3 years). Genomic DNA was extracted from dry blood spot on Whatman filter paper. Polymerase chain reaction was performed to determine MTHFR C677T polymorphism. Frequency of C677T allele polymorphism in controls was 21.2%, which corresponded to heterozygous and homozygous stage frequencies of 35.4% and 3.5%, respectively. In patient group, an allelic frequency of 33.2% was found, which corresponded to the presence of 48.5% of heterozygous and 8.9% of homozygous individuals. Comparing the frequency of mutated alleles between the 2 groups, a significantly high frequency of mutated alleles was found in patient group (P < .05). In conclusion, high frequency of MTHFR C677T polymorphism found in arterial thrombosis patient group suggests that this polymorphism might increase the risk of arterial thrombosis in Georgian patients.