Prevalence of FACTOR IX-R338L (FACTOR IX PADUA) IN A COHORT of PATIENTS with Venous Thromboembolism and Mild Elevation of FACTOR IX LEVELS.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 5057-5057
Author(s):  
Bruna de Moraes Mazetto ◽  
Fernanda A. Orsi ◽  
Lúcia Helena Siqueira ◽  
Erich Vinicius de Paula ◽  
Tayana B Mello ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Recombinant Expression ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Control Group ◽  
Increased Risk ◽  
Pcr Rflp

Abstract Abstract 5057 Introduction Elevated plasma levels of blood coagulation factor IX (FIX) have been associated with increased risk of venous thromboembolism (VTE) in humans. However, the molecular mechanisms underlying elevated FIX have not been elucidated. Recently, a mutation in the FIX gene resulting in a FIX molecule with Arginine Leucine substitution at position 338 (FIX-R338L or Factor IX Padua) has been associated with very high levels of FIX (776%) in a patient with spontaneous VTE. Recombinant expression of FIX-R338L confirmed the gain-of-function mutation. Objective Here we evaluated the levels of FIX and the prevalence of Factor IX Padua in a cohort of patients with VTE followed at our center. The prevalence of FIX Padua was evaluated by using a PCR-RFLP strategy by which PCR with specific primers was followed by digestion with the enzyme TaqI. Results The prevalence of FIX Padua was evaluated in a population of 192 patients with spontaneous VTE (69 males and 123 females; median age 36-yo). A population of 192 healthy individuals matched for age, sex and ethnicity was used as a control group for the determination of FIX levels. Median FIX levels was 128.0% (61.0-207.0%) in patients with VTE. Twenty-nine patients presented FIX levels above the 90th percentile (160.2%). Factor IX Padua was not identified in any patients or controls, even in those with elevated FIX levels. Conclusion in the present study FIX Padua was not identified in any of our patients, indicating that this mutation is not associated with mild elevations of FIX levels frequently observed in patients with VTE. Disclosures No relevant conflicts of interest to declare.

Circulating Microparticles and Risk of Venous Thromboembolism.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3987-3987
Author(s):  
Paolo Bucciarelli ◽  
Emanuele Previtali ◽  
Ida Martinelli ◽  
Andrea Artoni ◽  
Serena M Passamonti ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Venous Thromboembolism ◽  
Body Mass ◽  
Plasma Levels ◽  
Conflicts Of Interest ◽  
Factor V Leiden ◽  
Control Group ◽  
Dependent Manner ◽  
Healthy Controls ◽  
Increased Risk

Abstract Abstract 3987 Poster Board III-923 Background Microparticles (MPs) are circulating, submicroscopic fragments (<1 μm of diameter) of membrane-bound cytoplasm that shed from the surface of an activated or apoptotic cell and play a role in coagulation, inflammation, cell remodelling and proliferation. There is increasing evidence that MPs are involved in thrombosis, but whether or not they are an independent risk factor for venous thromboembolism (VTE) is not established. Aim of the study To investigate the association between high plasma levels of MPs and risk of VTE Patients and Methods In a case-control study, 186 patients with a first episode of VTE (deep venous thrombosis and/or pulmonary embolism) and 418 healthy controls were included. MPs were analyzed by flow cytometry with a gate defined by a 1 μm beads and using APC-Annexin V together with FITC anti-CD41 or FITC anti-CD142 antibodies in order to identify platelet MPs (MP-Plts) and MPs exposing tissue factor (MP-TF), respectively. MPs levels were expressed as number/μL. Results Patients had significantly higher median plasma levels of both MPs-Plts and MPs-TF than controls [1942 vs 1519 (p<0.0001) and 579 vs 454 (p<0.0001)]. Higher median levels of MP-Plts and MP-TF were found in 41 patients who underwent blood sampling within 6 months from VTE than in those sampled later [2114 vs 1694 (p=0.086) and 652 vs 543 (p=0.120)]. Sex, age, body mass index and factor VIII plasma levels had no influence on MPs levels, as well as the use of oral contraceptives (this latter evaluated only in controls). In the whole study population, carriership of thrombophilia (antithrombin, protein C or protein S deficiency, factor V Leiden, prothrombin G20210A, antiphospholipid antibodies, hyperhomocysteinemia or combined abnormalities) had higher levels of MP-Plts and MP-TF than non-carriers [1907 vs 1565 (p=0.002) and 532 vs 468 (p=0.011)]. The odds ratio (OR) for VTE, adjusted for sex, age, body mass index and thrombophilia was 2.5-fold higher in individuals with MPs plasma levels >95th percentile of the control group (3633/μL for MPs-Plts and 1113/μL for MPs-TF) than in those with MPs levels ≤95th percentile [for MPs-Plts: OR=2.59 (95%CI 1.23 – 5.45); for MPs-TF: OR=2.38 (1.15 – 4.92)]. The risk increased in a dose-dependent manner for both MPs-Plts and MPs-TF, particularly above the 75th percentile of the distribution in controls. The exclusion of patients whose MPs levels were measured within 6 months from VTE (in order to avoid the possible effect of the acute phase on MPs measurements), did not change the results [adjusted OR: 2.63 (1.18 – 5.89) for MPs-Plts and 2.36 (1.10 – 5.19) for MPs-TF]. The Table shows the relative risks of VTE associated with the presence or absence of high MPs levels and thrombophilia. Individuals with MPs >95th percentile or thrombophilia alone had a 2 to 3-fold increased risk of VTE, whereas those with both MPs-Plts >95th percentile and thrombophilia had a 9-fold increased risk of VTE. This synergistic effect was confirmed also for MPs-TF and remained after the exclusion of patients whose blood sample was collected within 6 months from VTE [OR 7.72 (1.68-35.4) for MP-Plts and 8.14 (2.08-31.8) for MP-TF]. Conclusions Plasma levels of MPs are significantly higher in patients with VTE than in healthy controls. MPs levels >95th percentile are associated with a 2.5-fold increased risk of VTE. There is a synergistic interaction between high levels of MPs and thrombophilia on VTE risk. Disclosures: No relevant conflicts of interest to declare.

Prospective Evaluation of plasma Levels of FVIII in Patients with venous Thromboembolism,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3348-3348
Author(s):  
Luis Fernando Bittar ◽  
Bruna Mazetto Fonseca ◽  
Silmara Lima Montalvão ◽  
Fernanda Loureiro de Andrade Orsi ◽  
Erich V de Paula ◽  
...  
Keyword(s):  
Risk Factor ◽  
Venous Thromboembolism ◽  
Plasma Levels ◽  
Conflicts Of Interest ◽  
Coagulation Factor ◽  
Geographic Area ◽  
First Episode ◽  
Control Group ◽  
Post Thrombotic Syndrome

Abstract Abstract 3348 Introduction: Venous thromboembolism (VTE) is a multifactorial disease, and increased levels of coagulation factor VIII (FVIII) has been demonstrated as risk factor for first and recurrent episodes of VTE. Some authors reported that these high levels of FVIII were still persistent after 4 years of the episode, but median follow-up in these studies are relatively short. The aim of the study was investigate if after a long-term follow-up of 4–15 years (median of 10 years), patients with high levels of FVIII after anticoagulant treatment still showed this alteration. Design and Methods: Previously, we selected 174 adult patients with a first episode of acute VTE between January 1990 and September 2004. One hundred seventy four healthy adult individuals selected from blood donors were chosen as controls, from the same geographic area of origin. Of this group of VTE patients, 68 patients with plasma FVIII: C levels above the 90th percentile were selected. FVIII levels (FVIII:C) were measured by a one-stage clotting assay with FVIII-deficient plasma in duplicate in an automated coagulometer. Levels were measured twice, in 2004 and then in 2011. C-reactive protein (CRP) levels were determined in the same samples by a nephelometric method to evaluate the influence of inflammation on FVIII levels. For individuals with CRP values higher than 1mg/dL, an additional blood sample was analyzed. High FVIII levels were only considered for further analysis when in the presence of normal CRP levels. The presence of post-thrombotic syndrome (PTS) was evaluated and classified clinically by the Clinical-Etiologic-Anatomic-Pathophysiologic (CEAP) classification System. Results: 68 patients with VTE and high levels of FVIII (19M:49F) with a median age of 47 years (range 20–70) were included in the study. The control group consisted of 59 subjects (42M:17F) with a median age of 35 years (range 21–56 years). VTE was spontaneous in 26 (38.2%) patients and secondary to an acquired risk factor in 61.8%. In the 1st evaluation, in 2004, patients with VTE had higher plasma levels of FVIII:C (median 235.8 IU/dL vs. 127.0 IU/dL; p<0.001) compared to controls. In 2011, seven years after the first evaluation and after a median follow-up of 10 years after the first VTE episode, this difference was still present (median 144.6 IU/dL vs. 96.4 IU/dL; p<0.001). Patients with severe PTS (167 IU/dL) showed higher plasma levels of FVIII when compared with patients without PTS (median 141.4 IU/dL), mild PTS patients (median 142.8 IU/dL), and moderate PTS patients (median 143.2); p=0.04. Conclusions: Our results show that even after a median of 10 years of VTE, patients still have increased levels of FVIII. Moreover, there seems to be a relationship between severe post-thrombotic syndrome and increased plasma levels of FVIII. Disclosures: No relevant conflicts of interest to declare.

Elevated Levels of IL-6 and IL-8 Are Associated with An Increased Risk of Venous Thromboembolism – a Case Control Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2975-2975
Author(s):  
Marinez F Matos ◽  
Dayse M Lourenço ◽  
Cristina M Orikaza ◽  
Maria A E Noguti ◽  
Vânia M Morelli
Keyword(s):  
Venous Thromboembolism ◽  
Prospective Studies ◽  
Plasma Levels ◽  
Conflicts Of Interest ◽  
Limit Of Detection ◽  
Case Control ◽  
Control Group ◽  
Case Control Studies ◽  
Increased Risk ◽  
The Impact

Abstract Abstract 2975 Poster Board II-953 Background: high levels of some cytokines have been associated with an increased risk of venous thromboembolism (VTE) in some case-control studies, but not in prospective studies. However, data regarding the impact of cytokines levels on the risk of VTE are still limited. The aim of this study was to investigate the association between the risk of VTE and plasma levels of interleukin (IL)-1β, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-αa and monocyte chemotactic protein (MCP)-1. Materials and Methods: we studied 122 patients (96 women, 79%), with a first objectively confirmed episode of VTE and with a median age of 39.5 years (range: 21-60). Exclusion criteria were malignancy, autoimmune diseases, antiphospholipid syndrome, chronic renal or liver disease and arterial thrombosis. Patients were seen at least 1 month after the discontinuation of the anticoagulant treatment and > 7 months after the event of VTE. Control group was comprised of 131 healthy subjects (105 women, 80%), with median age of 38 years (range: 18-66), recruited via the patients from the same geographic region and ethnic background. Controls were matched for age and sex. Plasma levels of cytokines were measured by commercial ELISA and a highly sensitive assay was used to measure IL-1β, IL-6 and IL-10 levels. Since a high percentage of samples of IL-1β (73%), IL-10 (62%) and TNF-αa (97%) was below the lower limit of detection (LLD) of the assay, levels of these cytokines were categorized as detectable (> LLD) and not detectable (< LLD). Elevated levels of IL-6 (> 2.15pg/mL), IL-8 (> 10.11pg/mL) and MCP-1 (> 84.11pg/mL) were defined by plasma concentration of these cytokines exceeding the 90th percentile of the distribution of the control population. Results: elevated levels of IL-6 were detected in 27% of the patients with VTE in comparison with 10% (by definition) of the controls [odds ratios (OR) = 3.4, 95% Confidence Interval (CI) 1.6 - 7.6]. Elevated levels of IL-8 were detected in 21% of the patients in comparison with 10% of the controls (OR = 2.5, 95%CI 1.1 - 5.6). The risk remained significant for IL-6 (OR = 2.8, 95%CI 1.2 - 6.5) and IL-8 (OR = 2.6, 95%CI 1.1 - 6.7) after adjustment for putative confounders (sex, age, body mass index, smoking and high levels of homocysteine and C-reactive protein). On the other hand, we found no significant association between VTE and elevated levels of MCP-1 (OR = 0.8, 95%CI 0.3 - 1.9) as well as detectable levels of IL-1β (OR = 0.9, 95%CI 0.5-1.6), IL-10 (OR = 1.3, 95%CI 0.8 - 2.2) and TNF-αa (OR = 6.7, 95%CI 0.8 - 56.7). In our study, patients were included at different time intervals after the VTE episode [median: 36 months (range: 7-87)]. No correlation was found between the time since the event of VTE and levels of IL-6 (rs = 0.06, P = 0.54) and IL-8 (rs= 0.07; P = 0.48). Conclusion: this study shows a significant impact of elevated levels of IL-6 and IL-8 on the risk of VTE in a relatively young population of patients. Interestingly, no association was found between the time since the event and the level of these cytokines. Taking into account the importance of the relationship between inflammation and VTE, more epidemiological data including prospective studies are required to elucidate the role of inflammation on the risk of VTE. This study was supported by FAPESP (2005/56799-0). Disclosures: No relevant conflicts of interest to declare.

Thrombotic Variables and Risk of Idiopathic Venous Thromboembolism in Women Aged 45-64 Years

2000 ◽  
Vol 83 (04) ◽  
pp. 530-535 ◽  
Author(s):  
Mark Woodward ◽  
Martin Vessey ◽  
Ann Rumley ◽  
Parimala Gough ◽  
Edel Daly ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Relative Risk ◽  
Protein C ◽  
Controlled Trial ◽  
Hormone Replacement ◽  
Activated Protein C ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Apc Resistance ◽  
Increased Risk

SummaryHormone replacement therapy (HRT) has been shown to increase the relative risk of idiopathic venous thromboembolism (VTE) about threefold in several observational studies and one randomised controlled trial. Whether or not this relative risk is higher in women with underlying thrombophilia phenotypes, such as activated protein C (APC) resistance, is unknown. We therefore restudied the participants in a case-control study of the relationship between the use of HRT and the occurrence of idiopathic VTE in women aged 45-64 years. After protocol exclusions, 66 of the cases in the original study and 163 of the controls were studied. Twenty haematological variables relevant to risk of VTE were analysed, including thrombotic states defined from the literature. The relative risk of VTE showed significant associations with APC resistance (OR 4.06; 95% CI 1.62, 10.21); low antithrombin (3.33; 1.15, 9.65) or protein C (2.93; 1.06, 8.14); and high coagulation factor IX (2.34; 1.26, 4.35), or fibrin D-dimer (3.84; 1.99, 7.42). HRT use increased the risk of VTE in women without any of these thrombotic states (OR 4.09; 95% CI 1.26, 13.30). A similar effect of HRT use on the relative risk of VTE was also found in women with prothrombotic states. Thus for example, the combination of HRT use and APC resistance increased the risk of VTE about 13-fold compared with women of similar age without either APC resistance or HRT use (OR 13.27; 95% CI 4.30, 40.97).We conclude that the combination of HRT use and thrombophilias (especially if multiple) increases the relative risk of VTE substantially; hence women known to have thrombophilias (especially if multiple) should be counselled about this increased risk prior to prescription of HRT. However, HRT increases the risk of VTE about fourfold even in women without any thrombotic abnormalities: possible causes are discussed.

scholarly journals Inpatient Outcomes and Rates of Venous Thromboembolism and Gastrointestinal Bleeding in Patients with Hepatocellular Carcinoma: Results from Nationwide Inpatient Sample Database 2007-2016

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2162-2162
Author(s):  
Kamelah Abushalha ◽  
Sawsan Abulaimoun ◽  
Ryan Walters ◽  
Sara Albagoush ◽  
Hussain I Rangoonwala ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Venous Thromboembolism ◽  
Gastrointestinal Bleeding ◽  
Hospital Mortality ◽  
Hospital Cost ◽  
Clinical Decision Making ◽  
Conflicts Of Interest ◽  
Increased Risk ◽  
Increasing Trend ◽  
Increasing Trends

Background: Patients with hepatocellular carcinoma (HCC) are at an increased risk for developing venous thromboembolism (VTE)- mainly portal venous thrombosis (PVT). Malignancy and liver cirrhosis ( 80%-90% of HCC cases are related to cirrhosis) are conditions that can perturb the hemostatic balance towards a prothrombotic state. Also, these patients with HCC are at high risk for gastrointestinal bleeding (GIB), making thromboprophylaxis and anticoagulation a treatment challenge. Additional information regarding the outcomes and severity of both VTE and GIB in patients with HCC would be useful to guide clinical decision-making Aim: To determine the rates, inpatient mortality, length of stay (LOS) and hospital cost of VTE and GIB-related admissions in patients with hepatocellular carcinoma. Method: We used ICD-9-CM and ICD-10-CM codes to identify hospitalizations from 2007 to 2016 that included HCC with primary discharge diagnoses of GIB or VTE. Linear trends in the rate of GIB and VTE, as well as in-hospital mortality, LOS, and inflation-adjusted hospital cost (in 2016 US dollars), were evaluated using Daniel's test; piecewise slopes were used as needed. All analyses accounted for the NIS sampling design with updated hospital trend weights used as appropriate. SAS v. 9.4 was used for all analyses. Results: Between 2007 and 2016, we identified 6,527,871 hospitalizations with HCC and a primary discharge diagnosis of GIB (3,517,059; 53.9%) or VTE (3,010,812; 46.1%). From 2007 to 2010, a decreasing trend was observed in the rate of GIB diagnoses (55.5% to 51.6%, ptrend < .001), whereas an increasing trend was observed for VTE diagnoses (44.5% to 48.4%, ptrend < .001). By contrast, from 2010 to 2016, an increasing trend was observed in GIB (51.6% to 55.2%, ptrend < .001), whereas a decreasing trend was observed in VTE (48.4% to 44.8%, ptrend < .001). For in-hospital mortality, a decreasing trend was observed for GIB (2.3% to 1.9%, ptrend < .001), whereas a decreasing trend was observed in VTE until 2012 (1.8% to 1.5%, ptrend < .001), after which no trend was indicated (1.5% to 1.6%, ptrend = .337). Although decreasing trends in LOS were observed for GIB (3.4 days to 3.2 days, ptrend < .001) and VTE (4.3 days to 3.3 days, ptrend < .001), increasing trends were observed for inflation-adjusted hospital cost for both GIB ($6,996 to $7,707, ptrend < .001) and VTE ($7,283 to $7,584, ptrend = .048). Conclusion: In this NIS cohort of hospitalized patients with HCC, GIB was more frequently observed than VTE. Trends observed in the rates of GIB and VTE went in opposite directions. In general decreasing trends were observed in in-hospital mortality and LOS for both VTE and GIB. By contrast, increasing trends were observed in the hospital cost for both diagnoses. Clinicians should balance benefits against risks when deciding VTE prophylaxis and treatment in patients with HCC. Future studies are needed to determine the ideal agent and specific dosages to treat HCC-associated VTE. Disclosures No relevant conflicts of interest to declare.

Elevated venous thromboembolism risk in preeclampsia: molecular mechanisms and clinical impact

2015 ◽  
Vol 43 (4) ◽  
pp. 696-701 ◽  
Author(s):  
Karl Egan ◽  
Barry Kevane ◽  
Fionnuala Ní Áinle
Keyword(s):  
Venous Thromboembolism ◽  
Molecular Mechanisms ◽  
Endothelial Activation ◽  
Extracellular Traps ◽  
Increased Risk ◽  
Consensus Statements ◽  
Maternal Hypertension ◽  
The Subject ◽  
Developed World

Venous thromboembolism (VTE) remains a leading cause of maternal death and morbidity in the developed world. Strategies for prevention of VTE in pregnancy have been the subject of recent guidelines and consensus statements. These guidelines recommend thrombosis prevention in women who have risk factors associated with an elevated VTE risk. Preeclampsia is characterized by maternal hypertension and proteinuria developing after 20 weeks gestation, complicating up to 7% of pregnancies and is associated with a massive annual morbidity and mortality burden. Women with preeclampsia have been shown to be at increased risk of VTE with studies to date suggesting that this risk may be up to 5-fold greater than the risk of pregnancy-associated VTE in the general population. Despite the fact that preeclampsia is so common and potentially devastating, our understanding of its pathogenesis and potential therapeutic strategies remain poor. In addition, the mechanisms underlying the prothrombotic phenotype in preeclampsia are also poorly characterized although a number of potential mechanisms have been postulated. Derangements of platelet and endothelial activation and impairment of endogenous anti-coagulant pathways have been reported and may contribute to the observed VTE risk. Recently, evidence for the role of neutrophil extracellular traps (NETs) and cell-free DNA in the pathogenesis of VTE has emerged and some evidence exists to suggest that this may be of relevance in preeclampsia. Future studies aimed at understanding the diagnostic and potential therapeutic relevance of this procoagulant state are likely to be of enormous clinical benefit for pregnant women affected with this potentially devastating condition.

Endogenous Thrombin Potential (ETP) for Assessing the Risk of Recurrent Venous Thromboembolism.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1622-1622 ◽  
Author(s):  
Sabine Eichinger ◽  
Gregor Hron ◽  
Ansgar Weltermann ◽  
Marietta Kollars ◽  
Paul A. Kyrle
Keyword(s):  
Venous Thromboembolism ◽  
Factor V Leiden ◽  
Factor Ix ◽  
Clotting Factor ◽  
Study Endpoint ◽  
Cumulative Probability ◽  
Computer Assisted ◽  
Risk Of Recurrence ◽  
Increased Risk ◽  
Factor Ii

Abstract Venous thromboembolism (VTE) is a multifactorial chronic disease. The number and severity of risk factors determine the risk of recurrence. A laboratory method that measures the overall thrombophilia is required. In a prospective cohort study, we measured ETP in 778 patients with a first unprovoked VTE. Patients were followed after discontinuation of anticoagulants for an average of 49 months. The study endpoint was recurrent symptomatic VTE. ETP was determined by a commercially available (research use only) assay (Dade Behring, Marburg, Germany) in platelet poor plasma by use of a chromogenic substrate and automatic registration as well as computer assisted calculation of thrombin generation over time. Patients with recurrence had higher ETP than those without recurrence (104.2% ± 15.4% vs. 101.4% ±14.2%. Patients with ETP ≥ 100% had an almost two-fold higher relative risk (RR) of recurrence than patients with lower levels (RR 1.6, 95% CI 1.0 – 2.5). At 4 years, the cumulative probability of recurrence was 14.4% in patients with ETP ≥ 100% and 6.1% in those with lower levels (p = 0.05). Patients with ETP ≥ 100% had higher clotting factor levels (Table). ETP was significantly increased in heterozygous carriers of factor II G20210A as compared with patients with wild type factor II (128% ± 18% vs. 100 ± 12%, p &lt; 0.001). Patients with a first unprovoked VTE and an ETP ≥ 100% have an increased risk of recurrence. Table Characteristics of 778 Patients with VTE ETP &lt; 100% ETP ≥ 100% p-value Men, no. (%) 160 (42%) 174 (44%) n.s. Age at first VTE (yrs) 46 ± 17 47 ± 14 n.s. Factor V Leiden, no. (%) 124 (32%) 108 (28%) n.s. Factor II G20210A, no. (%) 4 (1%) 49 (13%) &lt; 0.001 Factor VIII (IU/dL) 162 ± 46 168 ± 45 0.09 Factor IX (IU/dL) 113 ± 24 123 ± 27 &lt; 0.001 Factor XI (IU/dL) 102 ± 21 110 ± 24 &lt; 0.001

Statins and Venous Thromboembolism In Lung Cancer

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5122-5122
Author(s):  
Moh'd Khushman ◽  
Abdel-ghanie Abu-samra ◽  
Shatha Farhan ◽  
Gordon Jacobsen ◽  
Amr Hanbali ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Venous Thromboembolism ◽  
Cancer Patients ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Lipid Lowering ◽  
Coagulation Cascade ◽  
Controlled Study ◽  
Increased Risk ◽  
Statin Use

Abstract Abstract 5122 Background: Dyslipidemia plays a major role in the pathophysiology of atherosclerosis which may also contributed to an increased risk of and thromboembolism from the injury of the vascular endothelium and its activation of platelets, thereafter, the coagulation cascade. It has been well-established that the use of statins in patients with dyslipidemia reduces cardiovascular events and mortality, therefore, improves survival. In addition to a cholesterol-lowering effect, statins exhibit antithrombotic and anti-inflammatory properties that may confer a protective benefit to an increased risk of thromboembolism in cancer patients. Several case-controlled studies reported that cancer patients receiving long-term statins, but not other non-statin lipid lowering treatment, had a lower incidence of venous thromboembolism. Methods: To investigate any protective benefit from statin use in lung cancer patients, we have conducted this retrospective, case-controlled study. Total of 1548 patients with lung cancer were included from the tumor registery at Henry Ford Health System, Detroit, Michigan, between January 1999 and December 2004. The data were extracted from available electronic medical records of these patients. Statistical analyses were performed and stratified for statin users versus non statin users. Results: Out of 1,548 patients, 315 patients (average age was 68, range 46–90) were statin users at the time of their lung cancer diagnosis. The remaining 1233 patients (average age was 65.9, range 29–94) were non- statin users. After stratifying for statin use, 25 of the 315 statin users developed DVT/PE (7.9%), while 100 of the 1233 non-statin users developed DVT/PE (8.1%). This potential benefit from statin use can also be better visualized from comparing the development of DVT/PE between the statin and non-statin groups in a Kaplan-Meier curve for the probability of freedom from DVT/PE across time. Though statistical significance was not reached (log-rank p-value = 0.377), a trend towards a slightly decreased incidence of DVT/PE onset in the patients who receiving statin as the lipid-lowering agent has been observed. Conclusion: Based on our preliminary data, statin use in patients with lung cancer has demonstrated a weak but favorable protective effect on the development of a venous thromboembolism. The nature as a retrospective study and not well-balanced two group of patients (e.g., the average age of statin users were 2 years older than the non-statin users) may limit our results from reaching statistical significance. In addition, some of the patients who had no clear documentation of their home medications had also been categorized as non-statin users in our study. The results from our final data analysis will be presented. Disclosures: No relevant conflicts of interest to declare.

Intracellular Retention, Enhanced Clearance, and Defective FVIII Binding Are Common Features of Von Willebrand Factor D'-D3 Domain Mutations in Patients with Von Willebrand Disease Type 1 From the European Mcmdm-1VWD Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 99-99 ◽  
Author(s):  
Reinhard Schneppenheim ◽  
Ulrich Budde ◽  
Javier Batlle ◽  
Giancarlo Castaman ◽  
Jeroen C. J. Eikenboom ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Recombinant Expression ◽  
Von Willebrand Disease ◽  
Phenotypic Characterization ◽  
Clinical Markers ◽  
In Trans ◽  
Von Willebrand ◽  
In Cis

Abstract Abstract 99 Background: Von Willebrand disease (VWD) type 1 is characterized by a partial reduction of structurally and functionally normal VWF with normal VWF multimers. As part of a large European study (Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD) patients previously diagnosed with VWD type 1 were studied systematically to assess the phenotypic and genotypic spectrum. Objective: To confirm the pathogenicity of VWF gene mutations and to elucidate the molecular mechanisms of VWD type 1. Patients and methods: VWD type 1 patients were recruited by twelve expert centers in nine European countries. VWF genotyping was performed in all index cases (IC). The eight mutations studied here are located in the VWF D'-D3 domain and corresponded to 57 patients from 19 families. They were reproduced by recombinant expression with subsequent phenotypic characterization, two of them in cis and one in trans with a second mutation. Results and Discussion: Intracellular VWF:Ag of all mutants was normal or near normal suggesting normal expression levels. However, seven mutations (p.M771I, p.I1094T, p.C1130R, p.C1130G, p.C1130F, p.W1144G and p.Y1146C) caused intracellular retention and impaired VWF secretion. In addition, we observed a major loss of high molecular weight multimers as in type 2A and a novel finding of a severe VWF:FVIII binding defect in most of the homozygously expressed mutants. Additional mutations either in cis or in trans had no modifying effect. The recombinant VWD type 1 Vicenza mutation p.R1205H with or without the allelic variant p.M740I seen in three Italian IC was secreted normally and had normal function leaving enhanced clearance of mutant VWF as the only pathomechanism. In conclusion, the majority of mutations in the D3 domain impair VWF multimerization, cause intracellular retention and correlate with defective FVIII binding. An elevated ratio of VWF propeptide to VWF:Ag suggests enhanced VWF clearance as an important pathomechanism of most mutations and particularly of p.R1205H. Disclosures: No relevant conflicts of interest to declare.

Molecular Diagnosis Of One Chinese Patient With Hemophilia B

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4790-4790
Author(s):  
Rong-Fu Zhou ◽  
Bo Gao ◽  
Jian Ou-yang
Keyword(s):  
De Novo ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Coagulation Factor ◽  
Chinese Patient ◽  
Factor Ix ◽  
Hemophilia B ◽  
Coagulation Tests ◽  
Prolonged Aptt ◽  
Pcr Products

FTo investigate the molecular mutation leading to Hemophilia B in one patient. Methods FOne-stage method was used to detect APTT, PT, TT, Fibrinogen and FVIII:C, FIX:C. The genomic DNA was extracted from the peripheral blood of proband. All exons and their flanks of Factor IX gene were amplified by polymerase chain reaction (PCR). The PCR products were sequenced directly. Results FThe proband was a 20-month boy presenting with scalp hematoma after trauma. Regular coagulation tests showed that his APTT was 135.1s, PT 11.9s, TT 15.6s and Fibrinogen 2g/l. Normal mixed plasma could correct the prolonged APTT to 35s. His FIX:C was 6.4% and FVIII:C was normal. Direct sequencing of PCR products suggested that there was a 5085T>C mutation (NG_007994.1) in Exon1, and a 36060G>C mutation in Exon8 of F9 gene. The former mutation caused the substitution of Leu19 by Pro, which lies in -28th in signal peptide. The later mutation lead to the substituion of Gln370 by His. Conclusion FMutations of 5085T>C in Exon1 and 36060G>C in Exon8 might be the causes of coagulation factor IX defiency for the patient. These mutations are de novo ones according to the database presenting in http://www.factorix.org/. Disclosures: No relevant conflicts of interest to declare.

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