Rate Of Thrombosis In Patients Research Articles

401 Detecting Hypofibrinolysis in Clinical Coagulation Testing

OBJECTIVES/GOALS: The goal of this study is twofold: To develop a method for an ex vivo hypofibrinolytic control and second to analyze patterns in standard and recently developed clinical coagulation assays for the detection of hypofibrinolytic states. METHODS/STUDY POPULATION: We analyzed blood samples from healthy patients first under normal conditions and then laced with human recombinant PAI-1 under three different concentrations. We then analyzed both samples using standard clinical assays (PT, aPTT, D-dimer, Fibrinogen), thromboelastography point-of-care tests (Hemosoncs- Quantra system), and with research assays of clot size and aggregation. Our previous research of diagnostic errors showed the patient group with the highest overall risk of these non-identifiable thrombotic complications was post-menopausal women with chronic diseases. We therefore focused our patient population to healthy post-menopausal women who were not using hormone replacement therapy. RESULTS/ANTICIPATED RESULTS: Research assays showed PAI-1 significantly increased clot size and aggregation. Preliminary results of clinical assays showed no detectable difference in hypofibrinolytic samples at any concentration. We anticipate ongoing testing will show similar results. Results on Quantra tests showed much larger differences between control and hypofibrinolysis samples, and we anticipate ongoing testing will achieving statistical significance. It is still unknown whether the mean value for hypofibrinolysis samples on the Quantra Clot Stability assay will be outside of the “normal” reference range. We theorize that this may be due to hypofibrinolytic changes in the overall structure and core density of the clots. DISCUSSION/SIGNIFICANCE: Cellular stress stimulates a concomitant activation of inflammation and coagulation, including decreased fibrinolysis. Unfortunately, current clinical assays do not assess clot breakdown. This connection would account for the increased rate of thrombosis in patients with chronic inflammation without detectable results on clinical tests.

Clinical evaluation of the safety and efficacy of enoxaparin in patients with COVID-19.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), increases thrombotic risk in hospitalised patients. The rate of thrombosis in patients with COVID-19 is unclear. The role of heparin, frequently used in the management of hospitalised patients, also needs to be clarified. In this study, we investigated the efficacy and safety of enoxaparin given at prophylactic or therapeutic dose in hospitalised patients with COVID-19, and evaluated its role in the development of disease in terms of mortality, and incidence of thrombotic and bleeding events. We included 141 patients with SARS-CoV-2 infection, admitted to five different wards (one intensive care unit, 2 sub-intensive care units, and 2 general infectious disease units) of Cotugno Hospital, a tertiary care hospital in Naples, Italy, between March and May 2020. Over a median time of 17 days (IQR 11-25), enoxaparin was given to 90/141 patients (63.8%) of whom 65 took a prophylactic and 25 a therapeutic dose. We documented 14 episodes of thrombosis (9.9%); almost all were cases of pulmonary embolism. No significant difference in terms of thromboembolic prevention was found between those patients not receiving anticoagulants and those on prophylactic or therapeutic dose of enoxaparin. Five episodes of major bleeding occurred (3.5%); therapeutic dose of enoxaparin was associated with a greater bleeding risk than prophylactic dose (p=0.002). During follow-up, 31 patients (22%) died; these were mostly elderly men with two or more comorbidities at admission. No advantages of enoxaparin, either as prophylaxis or at high doses, in terms of mortality were observed. At multivariate analysis, low estimated glomerular filtration rate, and high total bilirubin and fasting hyperglycemia were independently associated with a higher mortality. We did not observe advantages in terms of either thromboembolic prevention or mortality of enoxaparin, which however was more frequently used in patients with more severe disease. Prophylactic enoxaparin was not seen to be associated with bleeding risk.

Screening for occult cancer after unprovoked venous thromboembolism: Assessing the current literature and future directions.

While significant evidence has established an increased rate of thrombosis in patients with cancer, the risk of occult malignancy in the setting of an unprovoked thrombosis is less clear. Despite continued interest in developing an effective screening system for occult malignancy following unprovoked venous thromboembolism (VTE), discrepancies in the literature and guideline recommendations leave providers uncertain whether to screen or perform further diagnostics for this patient population. Evidence suggests that screening for malignancy can detect cancer sooner in patients with unprovoked VTE, but there is a lack of high-quality evidence demonstrating improvements in survival who receive early detection. In the following manuscript, we summarize VTE in relation to cancer epidemiology and pathophysiology. Our literature review summarizes the spectrum of testing strategies for occult malignancy following unprovoked VTE, including biomarker detection methods and various imaging approaches. We evaluate the benefit of additional diagnostic strategies, review current guidelines on the issue, and provide guidance to the reader on the best practice for investigating undiagnosed malignancy in patients with unprovoked VTE.

Clinical evaluation of the safety and efficacy of enoxaparin in patients with COVID-19.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), increases thrombotic risk in hospitalised patients. The rate of thrombosis in patients with COVID-19 is unclear. The role of heparin, frequently used in the management of hospitalised patients, also needs to be clarified. In this study, we investigated the efficacy and safety of enoxaparin given at prophylactic or therapeutic dose in hospitalised patients with COVID-19, and evaluated its role in the development of disease in terms of mortality, and incidence of thrombotic and bleeding events. We included 141 patients with SARS-CoV-2 infection, admitted to five different wards (one intensive care unit, 2 sub-intensive care units, and 2 general infectious disease units) of Cotugno Hospital, a tertiary care hospital in Naples, Italy, between March and May 2020. Over a median time of 17 days (IQR 11-25), enoxaparin was given to 90/141 patients (63.8%) of whom 65 took a prophylactic and 25 a therapeutic dose. We documented 14 episodes of thrombosis (9.9%); almost all were cases of pulmonary embolism. No significant difference in terms of thromboembolic prevention was found between those patients not receiving anticoagulants and those on prophylactic or therapeutic dose of enoxaparin. Five episodes of major bleeding occurred (3.5%); therapeutic dose of enoxaparin was associated with a greater bleeding risk than prophylactic dose (p=0.002). During follow-up, 31 patients (22%) died; these were mostly elderly men with two or more comorbidities at admission. No advantages of enoxaparin, either as prophylaxis or at high doses, in terms of mortality were observed. At multivariate analysis, low estimated glomerular filtration rate, and high total bilirubin and fasting hyperglycaemia were independently associated with a higher mortality. We did not observe advantages in terms of either thromboembolic prevention or mortality of enoxaparin, which however was more frequently used in patients with more severe disease. Prophylactic enoxaparin was not seen to be associated with bleeding risk.

Familial thrombocythaemia - a distinct entity from essential thrombocythaemia.

Familial thrombocythaemia (FT) includes a group of predominantly autosomal dominant conditions due to various mutations in the thrombopoietin (THPO), myeloproliferative leukaemia virus oncogene (MPL), or Janus kinase 2 (JAK2) genes.1 These disorders differ from essential thrombocythaemia (ET), one of the classical, Philadelphia chromosome breakpoint cluster region-Abelson tyrosine-protein kinase 1 (BCR-ABL1)-negative myeloproliferative neoplasms (which are a group of diseases characterised by vascular and bleeding complications and risk of fibrotic or leukaemic transformation.) Of the three common drivers responsible for ET [JAK2, calreticulin (CALR) and MPL), MPL is responsible for <5% of ET cases.2, 3 In this issue, Al-Harbi et al.4 describe a cohort of 64 patients with familial thrombocythaemia due to four different MPL mutations. The cohort described in this paper is young, with a median age of 20 years (Table I) and approximately ˜40% of subjects being aged ≤14 years.4 While ET is the most common classical myeloproliferative neoplasm in young patients,5 it is classically a disease of older patients, with a median age in the 50’s.2 The median platelet count in this cohort was 707·5 × 109/l; two older cohorts of MPL-mutated ET patients had higher median counts (749 and 949 × 109/l).2, 3 The majority of patients in this cohort had the c.317C>T (Pro106Leu) mutation, which has previously been reported in patients with familial thrombocythaemia.2-4 Only one patient in this cohort had a thrombotic event, and this occurred after organ transplant. Thrombotic events have been reported in patients with familial thrombocythaemia harbouring the MPL Ser505Asn mutation.6 While there is a clear association between JAK2V617F mutation and thrombosis,7 the relationship between MPL mutations and thrombotic events is less well defined. Various series report rates of thrombosis in patients with MPL-mutated ET ranging from 0% to 40%.8 A portion of the patients in this cohort (11%) were treated with cytoreductive therapy with hydroxyurea, yet there are no clear guidelines for management of familial thrombocythaemia nor any data suggesting platelet count is associated with thrombotic risk. Management of ET is dependent on risk stratification, and cytoreductive therapy is generally not recommended in younger patients without JAK2V617F mutation and no other indications for cytoreduction (such as acquired von Willebrand disease or thrombosis).9 Alternatively, aspirin is often used for patients with ET with vascular symptoms, and 32% of this cohort received aspirin. While this paper was a retrospective analysis, it is reassuring that no patients were identified to have myelofibrotic or leukaemic progression. Development of marrow fibrosis and decreased survival has been reported in patients with familial thrombocythaemia and MPL Ser505Asn mutation.10 Progression to post-ET myelofibrosis or acute leukaemia has been reported in patients with MPL-mutated ET, and some series report poorer outcomes with MPL-mutated ET, which may be due to mischaracterisation of pre-myelofibrosis as ET.3 Given the difference in prognosis, it is important to distinguish between ET and FT. Obtaining a detailed family history and characterising the specific MPL mutation involved can help with this distinction, and when haematological complications or uncertainty are present, a bone marrow evaluation can help aid in the diagnosis of ET. One of the most interesting aspects of this cohort is the role of the tribal system and its relevance for genetic disease. There are numerous tribes in Saudi Arabia and tribal affiliation is often maintained through intra-tribal and intra-familial pairing.11 All of the patients in this cohort were members of only 26 tribes, and 48% of patients belonged to two tribes. While many forms of familial thrombocythaemia have autosomal dominant transmission, the authors suggest autosomal recessive transmission plays a role in this setting. More than half of the patients with MPL Pro106Leu were homozygous for the mutation, and autosomal recessive transmission has been previously suggested with this mutation.12 This is a large series of patients with familial thrombocythaemia and supports previous reports that for disease associated with many of the known MPL mutations there is a benign clinical course. Treatment with cytoreductive therapies involves potential risks and side-effects, and further insight into the clinical course of familial thrombocythaemia is important for physicians treating patients with these conditions. While management of vascular symptoms with aspirin when present is reasonable, reacting to the mere presence of thrombocythaemia with cytoreductive therapies does not seem appropriate or necessary. Nicole Kucine received support from a grant from the National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) K23HL127223.

Thrombosis in Non-Hemolytic Paroxysmal Nocturnal Haemogloinuria

▪Paroxysmal Nocturnal Hemoglobinuria (PNH), a rare hematological condition, presents in patients with a variety of symptoms. The risk of thrombosis is high, with a cumulative thrombosis incidence over an eight to ten year period of between 23% and 30% (in the pre-eculizumab era). 20% of patients have multi-site thrombosis and 10% of patients present with thrombosis. Thrombosis in PNH is a clinical emergency, due to risk of death, thrombosis extension and long term morbidity.The complement and coagulation systems are intimately linked, and explain some of the mechanisms for thrombosis in PNH. Intravascular haemolysis is associated with thrombosis risk however, thrombosis has been observed in patients without hemolysis, most likely related to white cell and platelet factors.The proportion of granulocyte PNH cells correlates with thrombosis risk; those with cell proportions over 50% have a cumulative ten-year incidence of thrombosis of 34.5% compared to 5.3-7% in those with a clone of <50%. Thus in the UK, those with PNH cellular proportions over 50% commence prophylactic anticoagulation.The Leeds (UK) PNH service manages 394 patients with PNH, and has observed PNH patients with minimal hemolysis suffer thrombosis. Predicting those at highest risk is difficult. A retrospective review to identify rates of thrombosis in patients with no/minimal hemolysis was undertakenMethodsThe Leeds PNH database was interrogated, and identified patients with a PNH granulocyte or monocyte clone of over 10% and an LDH less than twice the upper limit of normal for the laboratory in which the sample was tested. Anonymised clinical data was then analysed to determine risk factors for thrombosis. Comparisons between those with and without thrombosis were assessed.All patients who fulfilled the above requirements were then subdivided into groups as below:Group 1: White cell clone >30%, red cell clone <10%, LDH <2xULNGroup 2: White cell clone >30%, red cell clone >10% with higher proportion of type II red cells than type III red cells, LDH <2xULNGroup 3: White cell clone: 10-30%, red cell clone <10%, LDH <2xULNResults29 patients were identified who fit the criteria. Median age of the patient cohort was 62 years (range 22-80 years). 12 patients fit the criteria for group 1, of whom 6 (50%) had thrombosis, 12 patients fit the criteria for group 2 of whom 2 (16.6%) had thrombosis and 5 patients fit the criteria for group 3, with no thrombosis. All 8 patients with thrombosis are detailed in the Table7 patients were not on anticoagulation at the time of the thrombosis, with on patient extending their thrombosis whilst on warfarin (patient 1).Discussion and conclusionsWe report the first case series of patients with non-hemolytic PNH who experience thrombosis. Patients at higher risk of thrombosis in this cohort were those with non-hemolytic PNH, high white cell clones and low red cell clones (group I). However those with a greater proportion of type II red cell clones compared to type III red cells and LDH <2x ULN were also at risk of thrombosis. This is an under-recognised risk for patients with PNH cells.Whilst the risk of arterial thrombosis is around 20%, interestingly and surprisingly, arterial thrombosis in this patient cohort was disproportionately high, with 62.5% of patients with either arterial or mixed venous and arterial thrombosis. It should also be noted that only one patient was anticoagulated at the time of their CVA extension. This was due to a combination of patients not being diagnosed with PNH at the time of thrombosis, or thought to be unsuitable for anticoagulation due to thrombocytopenia.This study supports the theory that while hemolysis may be associated with a thrombotic event, white cell and platelet factors have a more pivotal role than previously thought in the mechanisms of thrombosis in PNH. As per the National recommendations in England, thrombosis thought to be due to PNH regardless of LDH level, is an indication to commence treatment [Display omitted] DisclosuresGriffin:Alexion Pharmaceuticals, Inc.: Honoraria. Munir:Gilled: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria; Janssen: Honoraria; Roche: Honoraria; AbbVie: Honoraria. Hillmen:Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Celgene: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Arnold:Alexion Pharmaceuticals, Inc.: Honoraria. Richards:Alexion Pharmaceuticals, Inc.: Honoraria. Hill:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Efficacy and Thrombotic Adverse Events of Romiplostim Use in Patients with Thrombocytopenia Related to Underlying Malignancies

Background: Chemotherapy-Induced Thrombocytopenia (CIT) often results in treatment delay, dose reduction, or need for alternate cancer therapy. There is no validated or approved treatment of CIT. At our institution, the thrombopoietin-receptor agonist romiplostim, is being tested in a phase II clinical trial to treat CIT (being reported separately). Further, since there is no alternative, some oncologists have been using romiplostim off-label/off study to treat CIT and prevent recurrence of CIT when chemotherapy is resumed. Raising the platelet count could potentially increase the risk of thrombosis. Therefore, as a Quality Assessment initiative, we conducted a retrospective analysis of all use of romiplostim in cancer patients at MSKCC to determine the efficacy for treatment of CIT, as well as rates of thrombosis.Methods: We performed a retrospective review of all romiplostim use in cancer patients at MSKCC from 1/1/2010 to 4/14/2017. Patients without cancer or patients whose thrombocytopenia was due to an unrelated indication, such as ITP, Evans syndrome, underlying cirrhosis, or hereditary thrombocytopenia syndromes, were not included in this analysis. All medical records, radiology reports, and romiplostim administration records were reviewed by one or more study investigator. The study was approved by the IRB.Results: From 1/1/2010 through 4/14/2017, romiplostim use was documented in 292 patients. We derived 239 patients with cancer-associated indications. 185 (77.4%) of patients had thrombocytopenia related to chemotherapy and/or radiation therapy. Other causes of thrombocytopenia included primary or metastatic cancer of the liver (n=21, 8.8%), bone metastases (n=16, 6.7%), immune thrombocytopenia related to lymphoma (n=11, 4.6%), or other (n=6, 2.5%). 184 patients had solid tumors (77%) and 55 had hematologic malignancy (23%).We performed an analysis of efficacy response to romiplostim in the cohort of solid tumor patients and lymphoid malignancies (lymphoma/myeloma), the two groups with the most patients (Table 1A). The analysis of lymphoma/myeloma below does not include stem cell transplant patients. One solid tumor patient died before any followup labs were available and is not included in the analysis.For both solid tumor and lymphoid malignancies, the mean platelet counts at least doubled by day 14. Resumption of chemotherapy was at the discretion of the treating oncologist, and beyond Day 14 the platelet counts reflected the competing effects of maintenance romiplostim support of the platelet counts and platelet suppression by chemotherapy. The majority of patients tolerated resumption of chemotherapy without reoccurrence of CIT (Data not shown).We analyzed the rates of thrombosis, adjusted for time of exposure to romiplostim (Table 1B). The cumulative romiplostim use in the 239 patients was 129 years. There were a total of 15 venous thromboembolic events (DVT and/or PE). This calculated to 11.6% VTE events per patient-year, well within the historical rate of thrombosis in patients with metastatic cancer or lymphoma on chemotherapy (i.e. Khorana AA et al, Cancer 2013;119:648-55). In addition, no episodes of ischemic stroke or myocardial infarction were identified in the cancer patients while on romiplostim.Discussion: In this retrospective analysis of romiplostim use in cancer patients, we found evidence of efficacy in patients with solid tumors and lymphoid malignancies. Platelet counts increased over two-fold within 14 days of initiation of romiplostim. And importantly, we did not find evidence of increased thrombotic rates compared with historical experience. How to optimally utilize romiplostim in cancer patients with thrombocytopenia is the focus of ongoing clinical research. [Display omitted] DisclosuresSoff:Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.

Effect of occult malignancy on femoropopliteal bypass graft thrombosis

ObjectiveThe presence of cancer increases arterial thromboembolic events, specifically myocardial infarction and stroke, before a formal diagnosis of cancer. To the best of our knowledge, this increase in thrombotic risk has not been studied in patients with lower extremity bypass grafts. In the present study, we aimed to determine the effect of occult cancer on femoropopliteal bypass patency. MethodsA retrospective review of femoropopliteal bypass procedures completed from 2001 to 2018 was performed. International Classification of Diseases, 9th and 10th revision, codes corresponding to breast, lung, prostate, colorectal, skin, brain, and hematologic cancer were used to identify patients who had had occult cancer. Occult cancer was defined as cancer diagnosed within ≤1 year after the bypass procedure. The demographics, comorbidities, bypass configuration and conduit, 1-month, 3-month, 6-month, and 1-year occlusion rates, major adverse limb events, and mortality rates were analyzed. Statistical analysis included t tests, χ2 tests, and Cox regression analysis. ResultsA total of 621 procedures in 517 patients met the inclusion criteria. Of the 621 procedures, 36 (5.8%) were classified as procedures in patients with occult cancer. The patients with occult cancer had had higher occlusion rates at 3 months (27.8% vs 8.0%; P < .001), 6 months (30.5% vs 15.1%; P < .01), and 1 year (44.4% vs 19.8%; P < .001). In Cox regression analysis for bypass thrombosis at 1 year, the only significant predictors were occult cancer (hazard ratio [HR], 2.03; P = .01), below-the-knee distal target (HR, 1.88; P < .01), and a compromised conduit (HR, 2.14; P < .001). ConclusionsWe found an increase in bypass graft thrombosis rates in patients who had undergone femoropopliteal bypass who had had occult cancer. Thrombosis of the graft within 1 year postoperatively might be a sign of occult cancer.

Characterization of the Rate, Predictors, and Thrombotic Complications of Thrombocytosis in Iron Deficiency Anemia

Introduction: Iron deficiency anemia (IDA) is the most common cause of anemia worldwide and is frequently untreated or undertreated (Kesselbaum et al. 2014). The association of thrombocytosis with IDA is well-recognized, with recent work elucidating its underlying physiology (Xavier-Ferrucio et al. 2018). Thrombocytosis in IDA may predispose to thrombotic complications, as described in many case reports. Given that IDA is ubiquitous, even minor increases in thrombotic risk due to thrombocytosis have dramatic public health implications. Data describing the rate, predictors, and risk of thrombotic complications are limited. This study characterizes these features of thrombocytosis in IDA. Methods: We queried a large institutional patient data repository containing comprehensive chart data for over 5.8 million patients to identify patients with IDA with and without thrombocytosis and thrombotic events over a 40-year time period (1979 to 2019). Demographic information, hematological parameters, thrombosis history, and other medical history were collected at time of peak thrombocytosis, time of IDA diagnosis, and clinical baseline (before IDA diagnosis or after resolution). The fidelity of query data was assessed by performing detailed manual chart review of 700 total patients. Clinical diagnoses of IDA were verified by confirming ferritin values &amp;lt;30 ng/ml and consistent CBC parameters. Temporal association of thrombocytosis with IDA was confirmed and patients with other causes of thrombocytosis (including active malignancy, infection, inflammatory bowel disease, recent surgery/trauma, inflammatory arthritis, and myeloproliferative neoplasms) were excluded. Only arterial and venous thrombotic events occurring concurrently with IDA or IDA with thrombocytosis were included. Data were analyzed using t-tests, chi-square tests, Pearson correlations, and multivariate regression. Results: Our queries identified 36,327 IDA cases and 15,022 IDA with thrombocytosis cases. Query fidelity rates were 95% and 75%, respectively, yielding a true thrombocytosis rate of 32.6% in patients with IDA. After excluding cases with other causes of thrombocytosis, we calculated a 7.8% rate of thrombosis in patients with IDA and a 15.8% rate of thrombosis in patients with reactive thrombocytosis secondary to IDA (Table 1, Figure). The odds ratio for thrombosis in IDA with thrombocytosis vs IDA alone was 2.23 (2.09-2.38, p&amp;lt;0.0001). Both venous and arterial thrombotic events were more likely in patients with IDA and thrombocytosis (Table 1). Risk factors for thrombotic events were slightly more common in patients with IDA and thrombosis (OR 1.28, Table 1). Mean duration of IDA episode (from IDA diagnosis to normalization of hemoglobin and platelet count) was 2.03 years. Among patients with IDA and thrombocytosis, ferritin and hemoglobin (Hgb) were both moderately negatively correlated with platelet count (Plt) (Table 2). Platelet mass index (Plt x MPV) at time of IDA diagnosis and peak thrombocytosis was significantly higher than baseline. Platelet mass index and Hgb were strongly negatively correlated at peak thrombocytosis. Multivariate regression including age, sex, WBC count, Hgb, Plt, and MCV demonstrated a significant predictive relation between decreasing Hgb and increasing Plt at peak thrombocytosis. Conclusions: In this large retrospective analysis, we describe the rate and predictors of thrombocytosis in IDA in addition to rates of thrombosis in IDA patients with and without reactive thrombocytosis. Combining queries of a massive clinical database with manual chart review to ensure data validity, we found a 32.6% rate of thrombocytosis in IDA, negative correlations between both Hgb/ferritin and Plt, and a 2-fold increased thrombotic risk in patients with thrombocytosis reactive to IDA relative to IDA alone. We also found increased total body platelet mass in IDA patients with thrombocytosis, which may contribute to this increased thrombotic risk. Thrombosis rates overall were high, possibly due to database inclusion of more morbid inpatients in addition to outpatients. Given the global burden of untreated and undertreated IDA, our findings suggest that adequate IDA treatment may reduce thrombotic complications and associated morbidity and mortality. Acknowledgements: A. Song is the recipient of the American Society of Hematology HONORS Award (provides research support). Disclosures Kuter: Daiichi Sankyo: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents &amp; Royalties: 3 Up-to-Date chapters; Caremark: Consultancy, Honoraria; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Platelet Disorder Support Association: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Zafgen: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Kezar: Research Funding; Principia: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Kyowa-Kirin: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Protalix: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Shinogi: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding. Al-Samkari:Agios: Consultancy, Research Funding; Dova: Consultancy, Research Funding; Moderna: Consultancy.

Low-Dose Aspirin Reduces the Rate of Renal Allograft Thrombosis in Pediatric Renal Transplant Recipients.

Renal allograft thrombosis is an important cause of early renal allograft loss. A previous study from our unit showed thrombosis rates in patients who received heparin that were similar to those who did not receive any thromboprophylaxis. This study evaluated the impact of aspirin prophylaxis on renal allograft thrombosis rates in pediatric renal transplant recipients. We conducted a retrospective study of 456 consecutive pediatric allografts from deceased and living related donors over age 22 years in a single center. Routine perioperative heparin was introduced in 1994 and was subsequently changed to aspirin prophylaxis in 2000. Group 1 comprised 126 patients who did not receive any thromboprophylaxis, group 2 comprised 128 patients who received heparin, and group 3 comprised 202 patients who received aspirin therapy. Variables associated with increased risk of renal allograft loss were examined using multivariable logistic regression. Thrombosis occurred in 11% (14/126) of grafts in group 1, 9% (11/128) of grafts in group 2, and 1% (2/202) of grafts in group 3 (odds ratio for aspirin group = 0.38, 95% confidence interval, 0.22-0.64; P = .02). In patients who received aspirin (group 3), there was only one renal allograft loss secondary to hemorrhage, and no grafts were lost in patients younger than 5 years of age. After our center introduced a change from heparin to aspirin prophylaxis, the thrombosis rate in pediatric renal allografts fell from 9% to 1%. Although there are a number of possible confounding variables, the introduction of aspirin has led to a reduced rate of renal allograft thrombosis.

Venous thrombosis in children, adolescents and young adults with acute lymphoblastic leukemia receiving chemotherapy in the Republic of Belarus

Objective: to clarify the conditions for the occurrence of thrombosis and assess the effect of anticoagulant therapy on the survival and outcome of thrombosis in children, adolescents and young adults with acute lymphoblastic leukemia (ALL) receiving program chemotherapy.Materials and methods. The study included 592 patients with ALL received program chemotherapy from 2008 to 2017 in the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (Minsk, Belarus). Of them, in 42 patients various localization venous thrombosis was detected at different therapy phase.Results.The cumulative detection rate of thrombosis was 7.5 ± 1.1 %. The use of pegelated asparaginase (PEG-asp) at a dose of 1000 IU/m2 in induction therapy increased the relative risk of thrombosis in the first 5 weeks of treatment by 3 times (relative risk 3.4; 95 % confidence interval 0.98–11.9), compared to patients not receiving PEG-asp. The cumulative detection rate of thrombosis in patients with the post-induction L-asparaginase (L-asp) 25,000 IU/m2 regimen was 14.7 ± 2.6 %, which was higher (p = 0.0536) than when using L-asp in other dosing regimens. In addition to ALL as the main disease, taking chemotherapy drugs, other risk factors for thrombosis (thrombophilia, the presence of antiphospholipid antibodies, a decrease of natural anticoagulants activity) in various combinations were in half (23 of 42) patients with venous thrombosis. Therapeutic dose of low molecular weight heparins (LMWH) 150–200 IU/kg received 30 patients. Reduced for the period of thrombocytopenia from 100 to 35 × 109/L for up to 4 weeks, a daily dose of LMWH was received by 12 patients. The dose of LMWH was reduced in proportion to the blood platelets count. After the recovery of the platelet count of more than 100 × 109/L, patients continued treatment of LMWH in a daily dose of 150–200 anti-Xa IU/kg. Reducing of LMWH dose during thrombocytopenia period did not affect the outcome of thrombosis (χ2 = 0.494; p = 0.78). Among 42 patients with thrombosis, 38 completed maintenance therapy, eventfree survival was 83.0 ± 8.0%, which did not differ (p = 0.654) from that (81.0 ± 2.0 %) in patients without thrombosis. Conclusion. The presence of venous thrombosis with the use of LMWH as antithrombotic therapy did not lead to a decrease in the event-free survival of ALL patients, compared with those without thrombosis. Reducing the therapeutic dose of LMWH did not affect the outcome of thrombosis in the analyzed groups.

Abstract TP355: Rate of Deep Vein Thrombosis in Patients When Pharmacological DVT Prophylaxis is Delayed Due to IV tPA Use

Introduction: Deep vein thrombosis (DVT) is associated with pulmonary embolism and reduced post stroke recovery. After thrombolysis, current US guidelines recommend a delay of 24 hours before initiation of pharmacological DVT prophylaxis. We sought to determine the rate of DVT in post-tPA patients with delayed pharmacological prophylaxis. Methods: Using GWTG stroke registry data from three large comprehensive stroke centers in the Northeast, South and West, we analyzed 13,420 consecutive stroke admissions from 02/2002 - 06/2018. Rates of DVT were compared between those with delayed prophylaxis due to post-tPA vs. all others. Chi-square was used for categorial data, T-Test for parametric continuous and Wilcoxon for non-parametric continuous variables. Multiple regression analysis (MV) was used to identify associations. Results: Of the 13,420 patients, 2974 (22.2%) received IV-tPA, 772 (5.8%) underwent EVT, 252 (1.9%) only EVT and 3279 (24.4%) received IV-tPA and/or EVT. There was a total of 536 (4.0%) patients with a documented DVT during the in-hospital stay. The rate of DVT in patients who received IV-tPA was significantly higher than in those who did not (4.6% vs 3.8%, p=0.036). Rates of DVT were 3.8% in patients not receiving tPA or EVT, 4.6% in IV tPA only group, 4.0% in EVT only group and 4.4% in IV tPA and/or EVT group. On univariate analysis Caucasian race, atrial fibrillation, smoking, weakness on presentation and use of IV tPA was significantly associated with DVT. On MV, only age, Caucasian race and a history of smoking was remained significantly associated with DVT. Conclusion: Although the NINDS tPA trial delayed DVT ppx initiation to 24 hrs, ECASS 3 allowed DVT ppx in post tPA patients without delay. Our analysis shows that post-thrombolysis patients with delayed DVT ppx had higher rates of DVT, although this effect did not remain significant on MV analysis. Larger studies to assess the safety of delaying DVT ppx in post tPA patients are warranted.

Venous Thromboembolism in Patients with B-Cell Non-Hodgkin Lymphoma (NHL) Treated with Lenalidomide

Background: Lenalidomide is an immunomodulatory agent FDA approved for the treatment of multiple myeloma (MM) and relapsed/refractory mantle cell lymphoma (MCL). More recently, lenalidomide has been shown to enhance the activity of rituximab and has shown activity in first-line and refractory MCL, diffuse large B-Cell lymphoma (DLBCL), and indolent NHL, both as a single agent and in combination with rituximab. In patients with MM treated with lenalidomide, there is a well-documented risk of venous thromboembolism (VTE), cited as 0.7-0.8 events per 100 patient-cycles. However, this risk has never been well-defined in patients with B-cell NHL treated with lenalidomide and remains an important clinical question. We present preliminary findings of a systematic review and meta-analysis determining rates of venous thrombosis in patients with B-cell NHL treated with lenalidomide. We also present subgroup analyses comparing those patients treated with single-agent lenalidomide and those treated with lenalidomide in combination with chemotherapy or biologic agents.Aims: Study aims were to assess rates of VTE in B-cell NHL patients treated with lenalidomideMethods: We conducted a systematic literature search to identify studies in the MEDLINE (1946 to January 2017), EMBASE (1980 to January 2017), and Web of Science Core Collection using the OVID engine, and reviewed the footnotes of all included studies for additional potential studies. We reviewed all abstracts using a structured format and reviewed candidate articles to ensure that they included prospective enrollment of patients with newly diagnosed or relapsed/refractory B-cell NHL, treatment with lenalidomide, and that the number of cycles of lenalidomide given, as well as safety data including rates of VTE, were reported. Two reviewers independently assessed articles for eligibility and extracted data. A VTE event was prospectively defined as Grade II or greater venous thrombosis, and primary outcome defined as VTE events per patient cycle. This was subsequently converted to VTE events per 100 patient cycles for ease of use. The authors were contacted directly if the study would otherwise have met eligibility criteria but did not report all outcomes.Results: 1719 citations were identified in our initial literature search. Of these, 24 articles were deemed eligible. In total, our review identified 8270 cycles of lenalidomide received by patients with B-cell NHL with 65 VTE events, with an event rate of 0.78 per 100 patient-cycles, a rate very consistent with that of lenalidomide in the treatment of MM.In subgroup analyses, the rate of VTE in patients treated with single-agent lenalidomide was 1.56 per 100 patient/cycles versus 0.41 in patients treated with lenalidomide + biologics with a relative risk (RR) of 3.78 (95% CI: 2.04-7.02, p<0.001). The rate of VTE in patients treated with single-agent lenalidomide was 1.56 per 100 patient/cycles versus 0.66 in patients treated with lenalidomide + chemotherapy with a RR of 2.35 (95% CI: 1.31-4.24, p=0.004). See Tables 1 and 2.There was no significant difference in rates of VTE between patients treated with lenalidomide + chemotherapy or lenalidomide + biologics. In addition, there was no statistically significant difference between patients treated for DLBCL, MCL, or indolent lymphoma, although our analysis was inadequately powered to detect such a difference. Further risk stratification by disease and patient characteristics, as well as pooled estimates and forest plot creation, is ongoing and will be included in our final report.Conclusion: Rates of thrombosis in patients with B-cell lymphoma treated with lenalidomide are significantly greater in patients treated with single-agent lenalidomide vs those treated with lenalidomide in combination with either chemotherapy or biologic agents. This is consistent with the findings of a phase II trial by Leonard et al. comparing single-agent lenalidomide and lenalidomide + rituximab in follicular lymphoma that showed a differential risk of thrombosis, although statistical significance was not reached in that study. Rates of thrombosis in patients treated with lenalidomide for B-cell NHL are comparable to rates of VTE in MM. These data inform the consideration of strategies for monitoring and prophylaxis in specific clinical settings. [Display omitted] DisclosuresLeonard:Celgene: Consultancy, Research Funding; Roche: Consultancy. Ruan:Cell Medica: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

CANCER AND ARTERIAL THROMBOSIS RISK: INSIGHTS FROM THE 2012 NATIONAL INPATIENT SAMPLE

Background: Patients with cancer have increased risk for venous thromboembolism (VTE). However, the risk of arterial thrombosis in patients with types of cancer at high risk for VTE has not been described. The goal of this study is to determine the rate of arterial thrombosis in patients with

Clinical evaluation of the revised International Prognostic Score of Thrombosis for essential thrombocythemia (IPSET-thrombosis) in a cohort of 746 Chinese adult patients

目的评估修订版国际血栓预测模型（IPSET）在中国原发性血小板增多症（ET）患者中的应用价值，探索适用于中国ET患者的血栓预测模型。方法对1982年3月1日至2012年4月30日期间诊治的746例成人ET患者的病历资料进行回顾性分析。结果全部746例患者中，男305例，女441例，诊断时中位年龄52（18~87）岁。采用修订版IPSET将患者分组，其中极低危组271例（36.3%）、低危组223例（29.9%）、中危组63例（8.4%）、高危组189例（25.3%），四组的无血栓生存差异有统计学意义（χ2=72.301，P<0.001）。修订版IPSET在原版IPSET低危组中区分出36例中危患者，在原版IPSET中危组中区分出19例高危患者，在原版IPSET高危组中区分出51例低危患者，避免了部分患者的治疗不足或过度。修订版IPSET低危组中有心血管危险因素（CVF）者的血栓发生率显著高于无CVF者[16.3%（8/49）对5.2%（9/174），χ2=5.264，P=0.022]，而与中危组相当[16.3%（8/49）对14.3%（9/63），χ2=0.089，P=0.765]。因此，在修订版IPSET的基础上，低危组中伴CVF者被划分至中危组，即为适于中国ET患者的修订版IPSET，此模型能区分出更多的血栓患者。结论修订版IPSET在血栓预测方面优于原版IPSET，将修订版IPSET优化后得到了更适于中国ET患者的修订版IPSET，为中国ET患者的分层治疗提供了依据。

The Incidence of Peripheral Catheter-Related Thrombosis in Surgical Patients.

Background. Central venous catheters and peripherally inserted central catheters are well established risk factors for upper limb deep vein thrombosis. There is limited literature on the thrombosis rates in patients with peripheral catheters. A prospective observational study was conducted to determine the incidence of peripheral catheter-related thrombosis in surgical patients. Methods. Patients deemed high risk for venous thrombosis with a peripheral catheter were considered eligible for the study. An ultrasound was performed on enrolment into the study and at discharge from hospital. Participants were reviewed twice a day for clinical features of upper limb deep vein thrombosis during their admission and followed up at 30 days. Results. 54 patients were included in the study. The incidence of deep vein thrombosis and superficial venous thrombosis was 1.8% and 9.2%, respectively. All cases of venous thrombosis were asymptomatic. Risk factor analysis was limited by the low incidence of thrombosis. Conclusion. This study revealed a low incidence of deep vein thrombosis in surgical patients with peripheral catheters (1.8%). The study was underpowered; therefore the association between peripheral catheters and thrombosis is unable to be established. Future studies with larger sample sizes are required to determine the association between peripheral catheters and thrombosis.

Thromboembolic events in patients with severe inherited fibrinogen deficiency

Inherited afibrinogenemia and hypofibrinogenemia are rare bleeding disorders characterized by markedly reduced levels of fibrinogen in blood. Thrombotic complications in these disorders have been rarely described. We performed a multicenter retrospective study and reviewed the occurrence of thrombotic complications among patients with inherited fibrinogen deficiency. Cases were identified during a review of medical records of all patients with inherited fibrinogen deficiency followed at three different university hospitals in Israel. Nine patients were included in this study: five were afibrinogenemic and four hypofibrinogenemic. There were seven thrombotic events, mostly venous, that occurred in four out of nine patients (44%). All thrombotic events occurred in afibrinogenemic patients. Mean age at the time of thrombosis was 45 (range 28-61) years. Thrombophilic evaluation performed was negative in all cases. At the time of thrombosis in five out of seven (71.4%) events, fibrinogen replacement therapy was concurrently given. Therapeutic approach was different among patients ranging from supportive therapy alone, antiplatelet agents and anticoagulant therapy with the concurrent administration of fibrinogen replacement therapy. This study discloses a high rate of thrombosis in patients with afibrinogenemia. Events were both venous and arterial and may be recurrent. Management is highly problematic due to the precarious balance between bleeding and thrombotic risk in these patients. Fibrinogen replacement therapy should be cautiously used in these patients as most thrombotic events followed the administration of fibrinogen replacement therapy. Larger cohorts are warranted to better characterize the best management strategy in these paradoxical events.

Thromboelastography to Detect Hypercoagulability in Patients with Newly Diagnosed Acute Lymphoblastic Leukemia

Background: Patients with newly diagnosed acute lymphoblastic leukemia (ALL) are known to be hypercoagulable due to their disease and from side effects of chemotherapy. Studies have shown rates of venous thromboembolism (VTE) between 5-70% in patients with ALL (depending on various definitions and modalities of investigation) (Caruso et al, 2006, Mitchell et al, 2003). Established methods to monitor hypercoagulability or predict VTE do not exist. We have previously described methods using thromboelastography (TEG) to detect hypercoagulability (Ko et al., 2013). We believe that a global assay of hemostasis such as TEG holds promise to monitor hypercoagulability in patients with newly diagnosed ALL.Methods: This was a prospective study of newly diagnosed ALL patients between 1-21 years in whom a central venous catheter (either a peripherally inserted central catheter [PICC] or a subcutaneously implanted port) was placed at diagnosis. Patients were enrolled at Children's Hospital Los Angeles from September 2012 until July 2015. None of the patients had a known past medical or family history of thrombosis or bleeding or clotting disorders and none were taking any medications (other than induction chemotherapy) that could affect coagulation (e.g. NSAIDs). Patients had complete blood counts (CBC), TEG, and markers of thrombin generation (quantitative D-dimers, thrombin:antithrombin complexes, and prothrombin fragment 1.2) performed before initiation of treatment and then once weekly during induction until they either presented with a symptomatic VTE or completed Induction therapy. All patients had a Doppler ultrasound of the extremity in which their central venous catheter was placed at the end of induction or at presentation with symptoms suggesting thrombosis.Results: Eighty patients have been enrolled (see Table 1 for demographics) with 72 being fully evaluable currently. Three (4.3%) patients developed symptomatic VTE and 7 (15%) patients had an asymptomatic VTE for an overall incidence of VTE of 21.7%. We demonstrate that R time gradually increases over time from baseline during induction therapy. Additionally, maximum amplitude (MA) is initially diminished, but then increases with time. There were no statistically significant differences in VTE incidence between males and females, different age groups (though there was a trend towards increased incidence for older children), or CVC type (none of the patients with an implanted port had a VTE). Interestingly, MA did not seem to be associated with platelet count.Conclusion: Patients in this prospective study of patients with newly diagnosed ALL during induction at a single institution show rates of thrombosis in patients with ALL similar to that in the literature. Furthermore, TEG results demonstrated a shortening of the clotting time (R) and an increase in the clot rigidity (MA) during induction. Though not statistically significant, older children and patients with HR-ALL were more likely to have a VTE. Additional analyses will be performed to investigate the ability of the TEG, as well as the CBC and markers of thrombin generation, in predicting the development of VTE in these patients.Table 1Patient DemographicsPatient DemographicsGenderFemale33 (46%)Male38 (54%)Age< 5 years28 (39%)9-12 years26 (37%)10+ years17 (24%)Patient VTE classificationSymptomatic VTE3 (4%)Asymptomatic VTE12 (17%)No VTE56 (79%)Demographics by CVC TypeType of CVCPICCPort-a-CathTotalGenderFemale35 (45%)3 (100%)38 (48%)Male42 (55%)0 (0%)42 (53%)Age< 5 years29 (38%)2 (67%)31 (39%)9-12 years30 (39%)0 (0%)30 (38%)10+ years18 (23%)1 (33%)19 (24%)Type of ALLSR-ALL54 (70%)0 (0%)54 (68%)HR-ALL23 (30%)2 (67%)25 (31%)T-ALL0 (0%)1 (33%)1 (1%)Patient VTE classificationSymptomatic VTE3 (4%)0 (0%)3 (4%)Asymptomatic VTE12 (17%)0 (0%)12 (17%)No VTE54 (78%)2 (100%)56 (79%)Patient VTE classificationDemographics by VTESymptomatic VTEAsymptomatic VTENo VTETotalGenderFemale1 (33%)7 (58%)25 (45%)33 (46%)Male2 (67%)5 (42%)31 (55%)38 (54%)Age categories< 5 years1 (33%)4 (33%)23 (41%)28 (39%)9-12 years0 (0%)3 (25%)23 (41%)26 (37%)10+ years2 (67%)5 (42%)10 (18%)17 (24%)Type of ALLSR-ALL1 (33%)7 (58%)39 (70%)47 (66%)HR-ALL2 (67%)5 (42%)16 (29%)23 (32%)T-ALL0 (0%)0 (0%)1 (2%)1 (1%) [Display omitted] [Display omitted] DisclosuresKo:Alexion: Honoraria; NovoNordisk: Consultancy. Young:Bayer: Consultancy; Kedrion: Consultancy; Novo Nordisk: Consultancy, Honoraria; Baxter: Consultancy; Biogen Idec: Consultancy, Honoraria.

The Influence of Hemostasis Genetic Features on Thrombosis Rates in Patients with Polycythemia Vera

Background. Thrombotic complications are the main cause of disability and mortality in Polycythemia Vera (PV) patients. Thrombosis in PV is a result of both inherited (genetic) and acquired predisposition under the external factors influence. Effective personalized prophylactic antithrombotic therapy is a key factor to save quantity and quality of life in PV patients.Objective. The objective of study was to assess the prevalence of hereditary thrombophilia genetic markers in PV patients in overall and groups with or without thrombotic complications.Materials and methods. 104 PV patients (60 females, 44 males, median age 58 years, range 31-82) were researched. Blood probes were examined by PCR for the presence of nucleotide polymorphisms in the following genes: FV (Leiden mutation), FII (prothrombin), methylenetetrahydrofolate reductase (MTHFR), fibrinogen (FI), plasminogen activator inhibitor (PAI-1), and platelet fibrinogen receptor type IIIA (GPIIIA). We studed the overall hereditary thrombophilia markers rate and the statistical significance between PV patients groups with (Thr+) or without thrombosis (Thr+). We used the next statistical methods: descriptive statistics, the significances of differences by gender and genes frequencies in the groups were evaluates with Fisher exact test, differences in age at the time of diagnosis were assessed with Mann-Whitney U test.Results. Thrombotic complications occurred in 20 (19.2%) of patients (16 arterial and 5 venous thrombotic episodes, 1 patient had both arterial and venous thrombotic episodes). Myocardial infarction was found in 7 (6.7%), cerebrovascular accident in 9 (8.7%) patients. The general PV population thrombophilia markers frequencies were: heterozygous (G/A) Leiden mutation in 4 (3,8%) patients; heterozygous mutation in prothrombin gene (G20210-A) in 4 (3,8%) patients; homozygous (T/T) mutation in MTHFR in 8 (7,7%) patients, heterozygous (C/T) mutation in 43 (41,3%) patients; homozygous (A/A) mutation in FI gene in 4 (3,8%) patients, heterozygous (G/A) mutation in FI gene in 43 (41,3%) patients; combination of mutations in FI and MTHFR was registered in 23 (22,1%) patients; homozygous (4G/4G) mutation in PAI-1 gene was revealed in 35 (33,7%) patients, heterozygous (4G/5G) mutation in 49 (47,1%) patients; mutation frequencies in GPIIIA gene were as follows: homozygous (A2/A2) in 5 (4,8%) patients, heterozygous (A1/A2) in 26 (25%) patients. The markers of hereditary thrombophilia was not identified only in one patient (1%).Characteristics and difference significances in the frequency of detection of thrombophilia genes between groups of patients with thrombosis (Thr+) and without their presence in history (Thr-) are shown in table 1.Table 1Characteristics of PV patients with (Thr+) or without (Thr-) thrombotic complications.Thr+ (n=20)Thr- (n=84)pAge, median (range)63 (36-73)58 (32-82)0.75Gender, male/female9/1135/490.81Factor V Leiden mutation, GA/GG2/182/820.17Prothrombin gene (G20210A) mutation, GA/GG1/193/810.58MTHFR mutation, (TT+CT)/CC14/637/470.05FI mutation, (AA+GA)/GG6/1441/430.14PAI-1 mutation, (4G/4G+4G/5G)/(5G/5G)17/367/170.76GPIIIA mutation, (A2A2+A1A2)/A1A11/1930/540.01Conclusions. Various hereditary thrombophilia gene mutations were present in almost all PV patients. PV patients with and without thrombotic complications were significantly (p≤0.05) differed in frequencies of mutations in methylenetetrahydrofolate reductase gene (MTHR) and platelet fibrinogen receptor type IIIA (GPIIIA). We also observed statistical trends (p≤0.30) in differences of mutations frequencies in fibrinogen (FI) gene and Factor V Leiden mutation, for the confirmation of which the further research is required. DisclosuresNo relevant conflicts of interest to declare.

The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia.

Patients with CKD suffer high rates of thrombosis, particularly after endovascular interventions, yet few options are available to improve management and reduce thrombotic risk. We recently demonstrated that indoxyl sulfate (IS) is a potent CKD-specific prothrombotic metabolite that induces tissue factor (TF) in vascular smooth muscle cells (vSMCs), although the precise mechanism and treatment implications remain unclear. Because IS is an agonist of the aryl hydrocarbon receptor (AHR), we first examined the relationship between IS levels and AHR-inducing activity in sera of patients with ESRD. IS levels correlated significantly with both vSMC AHR activity and TF activity. Mechanistically, we demonstrated that IS activates the AHR pathway in primary human aortic vSMCs, and further, that AHR interacts directly with and stabilizes functional TF. Antagonists directly targeting AHR enhanced TF ubiquitination and degradation and suppressed thrombosis in a postinterventional model of CKD and endovascular injury. Furthermore, AHR antagonists inhibited TF in a manner dependent on circulating IS levels. In conclusion, we demonstrated that IS regulates TF stability through AHR signaling and uncovered AHR as an antithrombotic target and AHR antagonists as a novel class of antithrombotics. Together, IS and AHR have potential as uremia-specific biomarkers and targets that may be leveraged as a promising theranostic platform to better manage the elevated thrombosis rates in patients with CKD.