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Thromboembolic Disease (thromboembolic + disease)

Distribution by Scientific Domains

Medical Sciences	91%
2 Other Domains	9%

Distribution within Medical Sciences

General & Introductory Veterinary Medicine	17%
General & Internal Medicine	8%

Kinds of Thromboembolic Disease

venous thromboembolic disease

Selected Abstracts

Laboratory findings associated with thrombophilia are not more common in inflammatory bowel disease

INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 4 2000
K. K. Sundaram
Summary Thromboembolic disease (TED) has been recognized as a complication of inflammatory bowel disease (IBD) since the 1930s ( Bargen & Barker 1936). The relative contributions of inherited or acquired thrombophilia and the inflammatory response to the mechanism of this tendency is unclear. Thrombotic events are more common in active disease although significant numbers also occur spontaneously, when the disease is in clinical remission ( Talbot et al. 1986 ; Jackson et al. 1997 ). Studies looking at the prevalence of specific thrombophilic states such as Antithrombin III deficiency ( Jackson et al. 1997 ; Lake, Stauffer & Stuart 1978; Cianco et al. 1996 ; Ghosh et al. 1983 ), Factor V Leiden mutation (APC Resistance) ( Jackson et al. 1997 ; Probert et al. 1997 ; Ardizzone et al. 1998 ; Liebman et al. 1998 ), anticardiolipin antibodies ( Ciancio et al. 1996 ), Protein C ( Wyshock, Caldwell & Crowley 1988; Korsten & Reis 1992) and Protein S deficiencies ( Jorens et al. 1990 ; Aadland et al. 1992 ) in IBD have been contradictory or equivocal. We had previously found that IBD patients with a history of TED are not more likely to have a laboratory thrombophilic abnormality than those with uncomplicated disease. We also demonstrated that the prevalence of heterogenous laboratory thrombophilic abnormalities (usually minor) in all IBD patients may be as high as 60%, much higher than the recognized prevalence of TED ( Lim, Jones & Gould 1996). We wondered how this would compare with the healthy non-IBD population. We have therefore explored the prevalence of such thrombophilic abnormalities in a group of IBD patients who had no history of TED and compared them with healthy age and sex matched controls. [source]

Canine leishmaniasis with nephrotic syndrome and aortic and caudal vena cava thromboembolism

JOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE, Issue 5 2008
Nuno Félix DVM
Abstract Objective , To describe a case of leishmaniasis associated with nephrotic syndrome and aortic and caudal vena cava thrombosis in a dog. Case Summary , A 3-year-old male Boxer was referred to the Faculty of Veterinary Medicine, Lisbon, with vomiting, polyuria, polydipsia, lethargy, anorexia, and weight loss. On admission, the dog was thin, quiet, and dehydrated. Initial laboratory abnormalities were compatible with a diagnosis of leishmaniasis (confirmed by serology and bone marrow aspirate), and nephrotic syndrome. Three days later, the animal developed lumbar pain, paraparesis, and absent femoral pulses. Coagulation tests showed a marked reduction in antithrombin (AT) and a mild increase in serum fibrinogen concentration. A diagnosis of thromboembolism was made. In spite of treatment aimed at controlling the primary condition and decreasing further thrombus formation, necrosis developed in the distal right pelvic limb and the nail beds of the left pelvic limb. Against medical advice, medication was stopped and, 15 days later, the dog returned to the hospital, showing extensive necrosis of both pelvic limb extremities. Euthanasia was performed at the owner's request. Necropsy showed a thrombus localized at the distal aorta and extending into the right iliac artery, and an additional thrombus extending from both femoral veins onto the caudal vena cava. New or Unique Information Provided , Thromboembolic disease is rare in dogs with leishmaniasis with nephrotic syndrome. This case suggests that a marked decrease in AT and a mild increase in serum fibrinogen may elicit a hypercoagulable state in these patients. [source]

Routine Transesophageal Echocardiography for the Evaluation of Cerebral Emboli in Elderly Patients

ECHOCARDIOGRAPHY, Issue 9 2005
Sergey Vitebskiy M.D.
Background: Approximately 20% of cerebral infarctions are cardioembolic in nature. Transesophageal echocardiography (TEE) is widely regarded as the initial study of choice for evaluating cardiac source of embolism. Although the majority of cerebrovascular accidents occur in elderly patients, the value of TEE in this population is poorly defined. Methods: We compared 491 patients older than 65 years with suspected embolic stroke or transient ischemic attack (TIA) who had undergone TEE evaluation between April 2000 and February 2004 to an age-, sex-, and time-matched control group that consisted of 252 patients. Studies were reviewed for abnormalities associated with thromboembolic disease. Results: The overall incidence of stroke risk factors was significantly higher in the study than in the control group. However, the four patients with left atrial thrombi had a history of atrial fibrillation. Although ascending and aortic arch sessile atheromata were observed more frequently in the study than control group, there were no significant differences in the incidence of either complex or mobile aortic atheromata. The incidence of atrial septal aneurysm was higher in the stroke/TIA group, but not in association with patent foramen ovale. Finally, there were also no differences in the incidence of spontaneous echocontrast, and/or patent foramen ovale between study and control groups. Conclusions: We conclude: (1) There is a higher incidence of abnormalities implicated as sources of thromboembolic disease on TEE in elderly patients with cerebral infarctions, but (2) this incidence is driven by the presence of sessile aortic atheroma and atrial septal aneurysm. Until the benefits of specific therapies for these conditions are known, routine TEE in elderly patients with suspected embolic neurological events appears to be unwarranted. [source]

From heparins to factor Xa inhibitors and beyond

EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2005
S. Alban
Abstract Despite some disadvantages, unfractionated heparin (UFH) and oral anticoagulants have been the only anticoagulants for prophylaxis and therapy of thromboembolic disorders for several decades. Based on the increasing knowledge of the structure and pharmacology of heparin, low molecular weight heparins (LMWH) have been developed in the 1980s. Compared to UFH, their advantages are mainly based on their reduced nonspecific binding to proteins and cells resulting in improved pharmacokinetics. In 1991, LMWH were declared as the most efficient prophylaxis in high-risk patients. Although the use of LMWH is increasing and they are today also applied for therapy and in other indications like acute coronary syndrome, they are considered not optimal concerning efficacy and safety. With the approval of fondaparinux for the prevention of venous thromboembolic disease in high-risk orthopedic patients, there might be a paradigm shift in the field of anticoagulants. Fondaparinux, a synthetic, chemically defined pentasaccharide, is the first selective inhibitor of factor Xa. By its highly specific binding to antithrombin, it selectively inhibits factor Xa and consequently prevents thrombin generation. In contrast to UFH and LMWH, it does not bind to any other cells and other proteins than antithrombin. This leads to a favourable linear pharmacokinetic profile, allowing once-daily subcutaneous application of a fixed dose without monitoring in thromboembolism prophylaxis. In addition to the evaluation of fondaparinux for further indications, chemical modifications of this pentasaccharide such as the long-acting idraparinux are currently under investigation. [source]

Haemophilia and thrombophilia: an unexpected association!

HAEMOPHILIA, Issue 4 2004
Y. Dargaud
Summary., In patients with haemophilia, a close correlation is usually observed between the clinical expression of the disease and plasmatic factor VIII/factor IX clotting activity. However, some patients experience milder bleeding phenotypes than others, although they exhibit a similar biological profile. The high prevalence of some inherited thrombophilia risk factors offers the possibility of a co-inheritance in haemophilic patients which could influence the phenotypic expression of the disease. Rare thrombotic complications occurring in haemophiliacs could also be facilitated by the co-inheritance of modifier genes. The majority of thrombotic events occurring in haemophiliacs are in relation to clotting factor infusions or central venous catheters. Concerning surgical situations, in the absence of therapeutic recommendations, postoperative thromboprophylaxis is not systematically performed in haemophiliacs. However, substitutive treatment more or less completely corrects the coagulation defect and makes the venous thrombosis risk closer to the control population. It should be emphasized that haemophilia does not fully protect against venous thromboembolic disease. Patients with haemophilia very infrequently experience thrombotic events. Thus, the management of thrombotic complications occurring in haemophilic patients should be discussed in each case according to the precipitating risk factors, the clinical context and the thrombo-haemorrhagic balance of the patient with respect to a particular clinical situation. [source]

Audit of community-based anticoagulant monitoring in patients with thromboembolic disease: is frequent testing necessary?

INTERNAL MEDICINE JOURNAL, Issue 11 2004
L. Young
Abstract Oral anticoagulant monitoring is managed by general practitioners in Auckland. An audit of this service in 452 patients demonstrated that anticoagulant control was in line with recommended international guidelines, with 58.3% of international normalized ratio (INR) measurements in the therapeutic range. However, the frequency of testing was high, with the majority of patients (68%), including those on long-term treatment, having INR measurements at weekly intervals. We question the need for such frequent INR testing. (Intern Med J 2004; 34: 639,641) [source]

Hereditary angioedema: an update on available therapeutic options

JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, Issue 9 2010
Marcus Maurer
Summary There is no cure for hereditary angioedema (HAE). Therapeutic approaches consist of symptomatic therapy for acute attacks, short-term prophylaxis before surgery, and long-term prophylaxis for those with frequent and severe attacks. In Germany, C1-INH concentrate and icatibant are licensed for acute therapy. C1-INH concentrate, which is obtained from human plasma, is administered intravenously to restore the deficient C1-INH activity. This therapy, which has been available for decades, is effective and well-tolerated. Batch documentation is required by German law. The synthetic decapeptide icatibant is administered subcutaneously. It competes with bradykinin, the responsible inducer of edema formation, for binding to the bradykinin B2 receptor. Icatibant is also effective and well-tolerated, even on repeated administration. An additional human C1-inhibitor, a recombinant human C1-inhibitor and the recombinant inhibitor of kallikrein ecallantide are currently under development. There are no licensed treatment options available in Germany for long- and short-term prophylaxis. Androgen derivatives are established in long-term prophylaxis. However, they are associated with many adverse effects, some of which are severe. Many drug interactions also limit their use. They are contraindicated in pregnancy, lactation, for children and in cases of prostate cancer. Antifibrinolytics have fewer adverse effects but are also less effective than androgens. They are contraindicated in thromboembolic disease and impaired vision. If androgen therapy has too negative an effect on quality of life, it may be worth reducing the dose or discontinuing therapy entirely and treating attacks with acute therapy. [source]

Venous thromboembolic disease: A single-centre case series study

JOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 12 2006
Fiona Newall
Aim: The epidemiology of venous thromboembolism in children has likely changed since first being described a decade ago because of evolving management strategies and a greater awareness of predisposing factors for thrombosis in children. The Royal Children's Hospital commenced a 4-year prospective registry of venous thrombosis in 1999 to determine the current Australian epidemiology of venous thrombosis in infants and children. Methods: A prospective, single-centre registry was established to determine the prevalence, aetiology, diagnostic criteria, management and outcome of venous thromboembolism in an Australian tertiary paediatric centre. Results: The incidence of venous thrombosis was 8.0/10 000 hospital admissions. Fifty-eight per cent of infants and 49% of children were male. Seventy-seven per cent of venous thromboses in infants were associated with central venous cannulation compared with 47% in children. Doppler ultrasonography was the most frequently used diagnostic tool. Treatment strategies varied between age groups. The all-cause mortality rate for infants and children in this study was 8.4% (direct thrombus-related mortality 0%). Fifteen per cent of all patients demonstrated complete resolution of their venous thrombosis at discharge, with 48% demonstrating complete resolution at follow-up assessment. Fifteen per cent of patients experienced significant thrombosis-related morbidity at follow-up assessment. Conclusion: In this single-centre registry, venous thrombosis in infants and children occurred with greater frequency than has previously been reported and its epidemiology varied. Central venous catheterisation continues to be a common precipitant to venous thrombosis. Optimal diagnostic and treatment interventions for venous thromboembolism have not yet been determined for infants and children, despite the significant incidence of long-term sequelae. [source]

Air pollution and hospitalization for venous thromboembolic disease in Chile

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2010
R. E. DALES
See also Mannucci PM. Fine particulate: it matters. This issue, pp 659,61; Bonzini M, Tripodi A, Artoni A, Tarantini L, Marinelli B, Bertazzi PA, Apostoli P, Baccarelli A. Effects of inhalable particulate matter on blood coagulation. This issue, pp 662,8. Summary.,Background:,Ambient air pollution is a risk factor for stroke and myocardial infarction, possibly because of alterations in coagulation that influence the arterial circulation. Whether air pollution influences diseases associated with peripheral venous thrombogenesis remains largely unknown. Objectives: To determine the association between air pollution and venous thromboembolic disease (VTE) in a sample of the general population. Methods: A time-series analysis was used to test the association between daily air pollution and VTE hospitalizations in Santiago between 2001 and 2005. Results were adjusted for long-term trends, day of the week and average daily humidex. Results: From a population of 5.4 million, there were, on average, 2.3 admissions for VTE per day. Pooled estimates of relative risk (RR) [95% confidence interval (CI)] of hospitalization for venous disease were: 1.07 (1.05, 1.09) for a 58.4 p.p.b. increase in ozone (O3); 1.06 (1.02, 1.09) for a 5.85 p.p.b. increase in sulphur dioxide (SO2); 1.08 (1.03, 1.12) for a 29.25 ,g/m3 increase in nitrogen dioxide (NO2); and 1.05 (1.03, 1.06) for a 20.02 ,g/m3 increase in particulate matter , 2.5 ,m in mean aerodynamic diameter (PM2.5). For pulmonary embolism (PE) results were: 1.10 (1.07, 1.13) for O3; 1.05 (1.02, 1.08) for SO2; 1.07 (1.04, 1.09) for NO2; and 1.05(1.03, 1.06) for PM2.5, respectively. Conclusion: Air pollution appears to be a risk factor for venous thrombosis and PE, a disease with a significant fatality rate. [source]

Site and clinical outcome of deep vein thrombosis of the lower limbs: an epidemiological study

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 7 2005
C. SEINTURIER
Summary., Clinical outcomes of patients diagnosed with venous thromboembolic disease (VTED) have rarely been assessed on large series of patients from single institutions. This was work based on our practice to routinely screen all suspected pulmonary embolism (PE) and deep venous thrombosis (DVT) patients with bilateral proximal and distal venous US was designed to evaluate survival, recurrence and cancer occurrence in patients diagnosed with symptomatic or asymptomatic DVT and to assess their relationship with the site of the DVT (proximal vs. distal, bilateral vs. unilateral). Our study is based on the cross-matching of the VTED register of the Grenoble University Hospital with the local Cancer Register and community mortality data. Survival analyses were performed with the Kaplan,Meier method; prognostic variables were tested using the log,rank test. A total of 1913 patients with a DVT of the lower limbs from 1993 to 1998 were included (57% women; mean age, 69 years). Of these, 1018 patients were diagnosed with proximal DVT (156 bilateral) and 895 distal DVT (112 bilateral). PE was associated in 760 patients. Patients with PE and no detected DVT were not included. At 2 years, adjusted survival rates were 80% in patients with unilateral-distal DVT, 67% in bilateral-distal, 72% in unilateral-proximal and 65% in bilateral-proximal DVT patients. The cumulated VTED recurrence rates were 7.7% in unilateral-distal DVT, 13.3% when DVT was bilateral-distal, 14% when unilateral-proximal and 13.2% when bilateral-proximal. The rate of new cancer was 6.4% in unilateral-distal DVT, 10.8% when it was bilateral-distal, 6.5% when unilateral-proximal and 6.1% when bilateral-proximal. Based on a large series of unselected patients, our results show that the site of the DVT and principally the bilaterality provides important prognostic information that may be used in the setting up of medical strategies. [source]

Inhibition of factor VIII with a partially inhibitory human recombinant monoclonal antibody prevents thrombotic events in a transgenic model of type II HBS antithrombin deficiency in mice

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2004
M. Dewerchin
Summary., Venous thromboembolic disease is a major cause of morbidity and mortality, necessitating antithrombotic therapy. A human monoclonal anti-factor (F)VIII antibody, LCL-mAb-LE2E9, produced by a lymphoblastoid cell line derived from a hemophilia A patient with inhibitor to wild-type but not mutant self FVIII, was previously reported to achieve efficient inhibition of thrombosis in an experimental vena cava thrombosis model in mice. Here, the antithrombotic efficacy of a recombinant DNA-derived version of this anti-FVIII antibody (rec-mAb-LE2E9) was tested in mice which carry a type II heparin binding site antithrombin deficiency mutation and display spontaneous chronic thrombosis in several sites including the penile vein of sexually active males. The recombinant anti-FVIII antibody (100 µg, repeated after 3 days) prevented thrombotic priapism in all treated males, whereas all control animals treated with saline (group of four animals) developed priapism within 6 days after mating (P < 0.05 for treated vs. saline). The rec-mAb-LE2E9 and the original LCL-mAb-LE2E9 were equally effective (five and seven males/group, respectively). These results confirm that FVIII inhibition represents a potent antithrombotic strategy, and show that both LCL-mAb-LE2E9 and rec-mAb-LE2E9 efficiently prevent thrombosis in a physiological model representative of thrombosis in patients with a severe prothrombotic risk. [source]

Pediatric venous thromboembolic disease in one single center: congenital prothrombotic disorders and the clinical outcome

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2003
C. H. Van Ommen
Summary., To learn more about the frequencies of congenital prothrombotic disorders in pediatric venous thromboembolism (VTE) and the outcome of this disease, we evaluated consecutive patients from 0 to 18 years with objectively diagnosed VTE at a single tertiary center over a 12-year period. We included 100 patients, with a median age at diagnosis of 1.0 year (range 2 days to 17 years). At least one underlying clinical condition was present in 96% of the patients. Factor (F)V G1691A mutation was present in 13%, FII G20210A mutation in 3%, antithrombin deficiency in 1%, protein C deficiency in 1% and protein S deficiency in 1% of the tested patients. Combined defects were present in 2.6% of the 77 patients with a complete work-up. Positive family history appeared to be the only predictor for positive testing for congenital disorders (OR 14.9, 95% CI 1.9,113). The overall mortality rate was 20%. The cumulative recurrence-free survival was 92% after 1 year of follow-up, and 82% after 7 years. The incidence and severity of the post-thrombotic syndrome was analyzed in a subgroup of 33 patients with VTE of the lower extremities. Twenty-three (70%) patients developed PTS: moderate in three and mild in 20 patients. In conclusion, congenital prothrombotic disorders seem to play a role in the development of pediatric VTE, and the risk of complications of this disease is high. [source]

Use of Rheolytic Thrombectomy in the Treatment of Feline Distal Aortic Thromboembolism

JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 2 2006
S. Brent Reimer
The purpose of this prospective clinical trial was to evaluate the safety and efficacy of a commercially available rheolytic thrombectomy system in the treatment of naturally occurring feline aortic thromboembolic disease. All 6 cats enrolled in the investigation were affected at the level of the distal aorta and had signs of the disease affecting both pelvic limbs. Cats were anesthetized and an arteriotomy was performed on 1 carotid artery to gain access to the arterial system. Selective arterial angiography was used to confirm the presence of thromboembolic disease. The thrombectomy system was advanced to the level of the thrombus using fluoroscopic guidance. Repeat angiography was used intermittently to assess progress of thromboembolus dissolution throughout the procedure. The use of the rheolytic thrombectomy system resulted in successful thrombus dissolution in 5 of 6 cats. Three of 6 cats survived to discharge. Both of these results compare favorably with conventional therapies used in the treatment of this disease. Feline distal aortic thromboembolism is a frustrating disease that warrants a guarded to poor prognosis. Rheolytic thrombectomy may provide veterinarians with an alternative therapy in the treatment of thromboembolic diseases, including feline distal aortic thromboembolism. [source]

The role of antiphospholipid antibodies toward the protein C/protein S system in venous thromboembolic disease,

AMERICAN JOURNAL OF HEMATOLOGY, Issue 9 2009
Valeria Rossetto
No abstract is available for this article. [source]

SHORT COMMUNICATION: Comparison of Serum Markers for Thrombophilia and Autoimmune Disease in Reproductive Age Women with and without False Positive Rapid Plasma Reagin Tests

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2009
Yael Swica
Problem, The rapid plasma reagin test (RPR) is performed frequently in clinical practice, particularly among reproductive age women. The phenomenon of the biologic false positive RPR is well-recognized, but its clinical significance is poorly characterized. Our objective was to assess the relationship between the false positive RPR and several established clinical and biological markers for thrombophilia and/or autoimmune disease. Method of study, We conducted a clinic-based, case,control study of 41 healthy, reproductive age women with history of a biologic false positive RPR and 30 control women with a negative RPR to assess the relationship between the false positive RPR and several established clinical and biological markers for thrombophilia and/or autoimmune disease. We used t -tests and constructed frequency tables for case,control comparisons. Results, Cases were significantly more likely than controls to have lupus anticoagulant present in serum, have a positive ANA, and a positive ANA with a titer of 1:320 or greater. Cases were also more likely to be positive for anticardiolipin antibodies and have a prolonged activated partial thromboplastin time, but the CIs for those point estimates included the null value. Eight participants tested positive for both lupus anticoagulant and ANA. All eight were in the case group. Conclusion, These results suggest that the RPR test might be used to identify a subset of women who warrant further testing for autoimmune and/or thromboembolic disease. [source]

Antenatal pulmonary embolism: risk factors, management and outcomes

BJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 4 2008
M Knight
Objectives, To estimate the incidence of antenatal pulmonary embolism and describe the risk factors, management and outcomes. Design, A national matched case,control study using the UK Obstetric Surveillance System (UKOSS). Setting, All hospitals with consultant-led maternity units in the UK. Participants, A total of 143 women who had an antenatal pulmonary embolism between February 2005 and August 2006. Two hundred and fifty nine matched control women. Methods, Prospective case and control identification through the UKOSS monthly mailing. Main outcome measures, Incidence and case fatality rates with 95% CIs. Adjusted odds ratio estimates. Results, One hundred per cent of UK consultant-led obstetric units contributed data to UKOSS. A total of 143 antenatal pulmonary embolisms were reported, representing an estimated incidence of 1.3 per 10 000 maternities (95% CI 1.1,1.5). Seventy per cent of women had identifiable classical risk factors for thromboembolic disease. The main risk factors for pulmonary embolism were multiparity (adjusted odds ratio [aOR] 4.03, 95% CI 1.60,9.84) and body mass index , 30 kg/m2 (aOR 2.65, 95% CI 1.09,6.45). Nine women who had a pulmonary embolism should have received antenatal thromboprophylaxis with low-molecular-weight heparin (LMWH) according to national guidelines; only three (33%) of them did. Six women (4%) had a pulmonary embolism following antenatal prophylaxis with LMWH; three of these women (50%) were receiving lower than recommended doses. Two women had recurrent pulmonary emboli (1.4%, 95% CI 0.2,5.1%). Five women died (case fatality 3.5%, 95% CI 1.1,8.0%). Conclusions, Significant severe morbidity from thromboembolic disease underlies the maternal deaths from pulmonary embolism in the UK. This study has shown some cases where thromboprophylaxis was not provided according to national guidelines, and there may be scope for further work on guideline implementation. [source]

Recent concerns surrounding HRT

CLINICAL ENDOCRINOLOGY, Issue 2 2003
Mary Armitage
Summary Millions of women are treated with hormone replacement therapy (HRT) for relief of menopausal symptoms, including vasomotor flushes and sweats for which oestrogen is uniquely and highly effective. Others may continue longer-term treatment in the hope that HRT will help to prevent chronic disease. The preservation of bone mass with continuing oestrogen therapy and reduction of subsequent risk of fracture is well established. Observational studies of the metabolic and vascular effects of oestrogens have suggested a potential benefit in reducing the risk of vascular disease, but recently published randomized controlled trials demonstrate no evidence of benefit in women with established vascular disease or in apparently healthy women. The increased risks of breast cancer and thromboembolic disease have been confirmed in these trials, with evidence of increased risk of stroke. Observational data suggest there may be a small increased risk of ovarian cancer associated with longer-term use of HRT. The premature termination of one arm of the Women's Health Initiative randomized controlled trial caused concern among patients, doctors and pharmaceutical companies. There are difficulties in extrapolating the results from trials using a specific HRT product to advise women on the wide range of other hormone products, doses, combinations and routes of administration. However, in the absence of evidence that other products are safer, the data suggest that for many women the risks associated with long-term use of HRT outweigh the benefits. There are nonhormonal strategies for the prevention and treatment of osteoporosis. HRT is not, and has never been, licensed in the UK for the prevention or treatment of vascular disease, and the data suggesting potential benefit should now be regarded as biased. The absolute incidence of an adverse event is low, and the risk in an individual woman in a single year is very small, but the risks are cumulative over time with long-term use. The risk,benefit balance of each woman needs regular reappraisal with continued use. [source]

Functional profiling of uncommon VCAM1 promoter polymorphisms prevalent in African American populations,,

HUMAN MUTATION, Issue 8 2007
Gila Idelman
Abstract Multiple variants of the vascular adhesion molecule-1 (VCAM1) promoter show increased nucleotide heterozygosity in the African American population. Using a novel transfection-based transcriptional pathway profiling method, we show that select uncommon variants are functionally hyperactive. Eight candidate VCAM1 promoter haplotypes comprising 13 previously identified SNPs were assessed for response to known mitogens. Activity was correlated with bioinformatic analysis of hyper- and hyporesponsive variants to identify the gain or loss of haplotype-specific transcription factor binding site (TFBS). Using this approach, a low frequency regulatory allele (c.,540A>G; dbSNP rs3783605:A>G), found in a hyperactive VCAM1 promoter haplotype, was shown to create a candidate binding site for ETS2 that was confirmed in vivo by chromatin immunoprecipitation. This report provides the first functional evaluation of VCAM1 promoter polymorphisms and establishes a hypothetical foundation for investigation of their role in the pathogenesis of VCAM1 -associated diseases that disproportionately afflict African Americans, including thromboembolic diseases, asthma, and multiple myeloma. Hum Mutat 28(8), 824,829, 2007. Published 2007, Wiley-Liss, Inc. [source]

Syntheses of [14C]BAY 59-7939 and its radiolabeled metabolite M-4

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 11 2006
U. Pleiss
Abstract BAY 59-7939 is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic diseases. Radiolabeled BAY 59-7939 was required for drug absorption, distribution, metabolism and excretion (ADME studies). The BAY 59-7939 was labeled with carbon-14 in the carboxamide group in one step in an overall radiochemical yield of 85% starting from 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}mor-pholin-3-one and 5-chlorothiophene-2-[14C]carboxylic acid. The radiolabeled metabolite M-4 was prepared in 77% yield starting from [1- 14C]glycine and 5-chlorothiophene-5-carboxylic acid. Copyright © 2006 John Wiley & Sons, Ltd. [source]

Study of bioaccumulation of dalteparin at a prophylactic dose in patients with various degrees of impaired renal function

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2009
P. SCHMID
Summary.,Background: Low-molecular-weight heparins (LMWH) have been shown to be effective and safe for prophylaxis of thromboembolic diseases. However, issues regarding safety and optimal use of LMWH arise in patients with renal insufficiency (RI). Objectives: To compare pharmacokinetic data of dalteparin for up to 3 weeks in patients with various degrees of RI. Patients and methods: Patients from general medical and surgical wards were included in this prospective cohort study and divided into three groups according to renal function: A = normal (GFR , 60 mL min,11.73 m,2), B = mild RI (GFR 30,59 mL min,11.73 m,2), C = severe RI (GFR < 30 mL min,11.73 m,2). Dalteparin was injected s.c. once daily at a prophylactic dose. Peak anti-Xa activity levels (anti-Xa) were measured 4 ± 1 h after injection on day 1 and every third day up to 3 weeks. Primary objectives were peak anti-Xa levels and adjusted anti-Xa levels, adjustment being carried out for dose and body weight. Results: A total of 42 patients could be analyzed during a median of 10 days (interquartile range IQR 4,13, range 1,20). In all groups, adjusted peak anti-Xa levels were not different on day 10 compared with day 1. No bioaccumulation >30% could be found up to day 10 even in patients with severe RI. Conclusion: The use of dalteparin at a prophylactic dose was not associated with a bioaccumulation >30% even in patients with severe renal insufficiency during a median follow-up of 10 days (IQR 4,13, range 1,20). [source]

Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2008
P. C. WONG
Summary.,Background:,Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. Objective:,We evaluated the in vitro properties of apixaban and its in vivo activities in rabbit models of thrombosis and hemostasis. Methods:,Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrically mediated carotid arterial thrombosis (ECAT) and cuticle bleeding time (BT) models. Results:,In vitro, apixaban is potent and selective, with a Ki of 0.08 nm for human FXa. It exhibited species difference in FXa inhibition [FXa Ki (nm): 0.16, rabbit; 1.3, rat; 1.7, dog] and anticoagulation [EC2× (,m, concentration required to double the prothrombin time): 3.6, human; 2.3, rabbit; 7.9, rat; 6.7, dog]. Apixaban at 10 ,m did not alter human and rabbit platelet aggregation to ADP, ,-thrombin, and collagen. In vivo, the values for antithrombotic ED50 (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT and the values for BT ED3× (dose that increased BT by 3-fold) were 0.27 ± 0.03, 0.11 ± 0.03, 0.07 ± 0.02 and > 3 mg kg,1 h,1 i.v. for apixaban, 0.05 ± 0.01, 0.05 ± 0.01, 0.27 ± 0.08 and > 3 mg kg,1 h,1 i.v. for the indirect FXa inhibitor fondaparinux, and 0.53 ± 0.04, 0.27 ± 0.01, 0.08 ± 0.01 and 0.70 ± 0.07 mg kg,1 day,1 p.o. for the oral anticoagulant warfarin, respectively. Conclusions:,In summary, apixaban was effective in the prevention of experimental thrombosis at doses that preserve hemostasis in rabbits. [source]