Prevention Of Thromboembolic Disease Research Articles

The prevention and treatment of venous thromboembolic disease in pregnancy

The prevention and treatment of venous thromboembolic disease in pregnancy

Patients with stable, therapeutic INR values should remain on warfarin

The second decade of the 21st century will be remembered as a significant milestone in the treatment and prevention of thromboembolic diseases. The approval of target-specific oral anticoagulants (TSOACs) means that patients with atrial fibrillation (AF) have, for the first time ever, multiple treatment options for the prevention of embolic stroke. Evidence from the landmark registration trials convincingly shows that the TSOACs are at least as safe and effective as warfarin in this setting. Because the new agents do not require routine coagulation monitoring and have very few drug or dietary interactions, they offer both convenience and, possibly, a public health benefit if they are used by patients who otherwise would have declined to take warfarin. However, patients on a highly stable, therapeutic dose of warfarin should not expect better health outcomes if switching to a TSOAC.

Effect of different genetics variants: CYP2C9*2, CYP2C9*3 of cytochrome P-450 CYP2C9 and 1639G>A of the VKORC1 gene; On acenocoumarol requirement in Moroccan patients

Coumarin derivatives such as acenocoumarol represent the therapy of choice for the long-term treatment and prevention of thromboembolic diseases. Many genetics determinants involved in the metabolism of acenocoumarol have been shown to influence the anticoagulant dosage. The aim of this work was to evaluate, for the first time in Maghreb, the allelic frequencies of CYP2C9*2, CYP2C9*3 and VKORC1 -1639G>A mutations, and to establish the role of this polymorphisms in modulating the acenocoumarol requirement in Moroccan patients receiving anticoagulation treatment. Three groups of patients, with low, medium, or high acenocoumarol dose requirements were studied. Genetic analyses of VKORC1 -1639G>A, CYP2C9*2, and CYP2C9*3, were performed in 114 Moroccan patients with stable acenocoumarol dose. The results showed that the allelic frequencies of the three mutations studied was varies, most of patients having CYP2C9*2 and CYP2C9*3 mutations belong to a group with low dose of acenocoumarol, with P-value of 0.0082 and the single patient with CYP2C9*3 on homozygous form belongs to the same group and carried the A allele for VKORC1 gene. In conclusion, the present study confirmed the large interindividual variability in acenocoumarol maintenance dose due to CYP2C9*2, CYP2C9*3 and VKORC1 -1639G>A polymorphisms, and demonstrated that these alleles modulates sensitivity to acenocoumarol, a finding indicating that a reduced initial loading dose of acenocoumarol should be used in carriers of this allele, also, she indicates the usefulness of predictive testing concerning these mutations when an hypocoagulability is installed and not explained by the dose of VKA.

Is Venous Foot Pump Effective In Prevention of Thromboembolic Disease After Joint Arthroplasty: A Meta-Analysis

The goal of this meta-analysis was to evaluate the efficacy of venous foot pumps in prevention of venous thromboembolism following joint arthroplasty. Using different databases, we found 13 prospective clinical trials published meeting our inclusion criteria. In total, 1514 patients were included in the final analysis. Venous foot pump devices are effective in prevention of venous thromboembolic disease after total hip and knee arthroplasty compared to chemoprophylaxis. This was especially significant in prevention of major deep vein thrombosis and pulmonary emboli rate. The use of mechanical devices like venous calf or foot pump, either alone or in combination with less potent chemical prophylaxis, on the other hand can reduce the rate of venous thromboembolism and complications of potent chemoprophylaxis like wound hematoma.

Prevention of thrombosis in pregnancy: How practical are consensus derived clinical practice guidelines?

Thromboembolic disease (TED) has, for many years, consistently been identified as one of the leading causes of direct maternal mortality. In November 2009, the RCOG published a guideline on the prevention of TED that has been rapidly adopted by hospital trusts in the UK. The aim of our study was to determine the number and profile of women in our population that would require treatment with low molecular weight heparin (LMWH) and the cost implications of such treatment if these guidelines were implemented. A retrospective review of the first 100 women who delivered at the Coombe Women & Infants University Hospital (CWIUH) in 2010 was conducted and risk stratification applied at the relevant time points. A total of 51% were deemed to be at intermediate or high risk of TED at some point during pregnancy. In 35 of the 51 women (70%), this risk was attributable to factors such as age > 35 years, parity ≥ 3, BMI > 30 kg/m2 or cigarette smoking. In our obstetric population, the percentage of women with these risk factors was: 25.5%, 8.5%, 19% and 16.7%, respectively. Implementation of this guideline would increase the hospital annual expenditure on LMWH by a factor of 17. The strategy of attributing risk by accumulating factors that individually have a low risk of TED and are prevalent in the population needs to be re-visited. The cost of implementation of these guidelines is not inconsiderable in the absence of data to indicate that clinical outcome is improved with their implementation.

Vitamin K antagonists: from discovery to pharmacogenetics

VitaminK antagonists (VKA) are used for 60 years in the treatment and prevention of thromboembolic disease. VKA were first used as rodenticides. There was a growing use of VKA in humans after President Eisenhower received them after a heart attack in 1955. However, the use of VKA is still challenging because they are characterized by a narrow therapeutic index and a great inter-individual variability in the dose response to the drug. This variability can partly be explained by demographic, clinical and therapeutic factors, but also by genetic variations. The main enzyme responsible for VKA metabolism is the hepatic cytochrome P450 2C9 (CYP2C9). VitaminK epoxide reductase complex subunit I (VKORC1) is a key enzyme in the vitaminK cycle and was identified as the pharmacological target of VKA. Genetic variations affecting both CYP2C9 and VKORC1 are associated with a significant decrease in the VKA dose requirements and an increased risk of bleeding. Genotyping both CYP2C9 and VKORC1 before the initiation of VKA allows to identify a subgroup of patients with an early response to VKA therapy, that expose them to overdosage and a higher bleeding risk. More recently, a polymorphism in the gene encoding CYP4F2 has been identified and may partly explain the variability in warfarin maintenance dose by altering the metabolism of vitaminK. In addition, rare mutations have been found in VKORC1 that could explain very high VKA dose requirements and pharmacodynamic resistance.

Influence of genetics and non-genetic factors on acenocoumarol maintenance dose requirement in Moroccan patients

Coumarin derivatives such as acenocoumarol represent the therapy of choice for the long-term treatment and prevention of thromboembolic diseases. Many genetic, clinical and demographic factors have been shown to influence the anticoagulant dosage. Our aim was to investigate the contribution of genetic and non-genetic factors to variability in response to acenocoumarol in Moroccan patients. Our study included 114 adult Moroccan patients, receiving long-term acenocoumarol therapy for various indications. Tests for VKORC1 -1639G>A promoter polymorphism (rs9923231), CYP2C9*2 rs1799853, CYP2C9*3 rs1057910, and CYP4F2 rs2108622 alleles were undertaken using Taq Man(®) Pre-Developed Assay Reagents for allelic discrimination. The statistical analysis was performed using the SAS V9 statistical package. Genotyping showed that the allele frequencies for the SNPs studied were no different to those found in Caucasians population. A significant association was observed between the weekly maintenance dose and the VKORC1 (P = 0·0027) and CYP2C9 variant genotypes (P = 0·0082). A final multivariate regression model that included the target International Normalized Ratio, VKORC1 and CYP2C9 genotypes explained 36·2% of the overall interindividual variability in acenocoumarol dose requirement. Our study shows large interindividual variability in acenocoumarol maintenance dose requirement in our population. VKORC1 and CYP2C9 variants significantly affected acenocoumarol dose, in-line with results in other populations. For the Moroccan population, the SNPs that have the largest effect on acecoumarol dose are CYP2C9 rs1799853, CYP2C9 rs1057910 and VKORC1 rs9923231.

Pathologies respiratoires liées à l’obésité

SUMMARY Obesity is a chronic disease responsible for an high morbidity and mortality. This is both an organ pathology due to the alteration of the structure of adipose tissue, and systemic disease due to these effects at a distance. Obesity is associated with a many complications, the most frequent are cardiovascular and respiratory diseases, diabetes type 2 and osteoarthritis. The respiratory consequences of obesity are generally underestimated and play a major role in morbidity and mortality associated with obesity. Being overweight impairs lung function. Respiratory complications of obesity are the restrictive syndrome, obesity-hypoventilation syndrome, obstructive sleep apnea syndrome (OSAS), bronchial asthma and pulmonary hypertension. These consequences justify a precise clinical examination of respiratory function and guidance in a specialized unit for suspected OSAS or in the presence of hypoxe- mia with or without hypercapnia. The treatment of respiratory complications is dominated by the prevention of thrombo-embolic disease and the management of sleep apnea and alveolar hypoventilation.

Percutaneous Closure of the Left Atrial Appendage in Atrial Fibrillation, Second Thoughts?

Life expectancy of the population is steadily increasing world wide. Consequently, the incidence and ultimately the prevalence of atrial fibrillation (AF) and it’s sequelae will be rising proportionately. It is estimated that 3-5% of persons above 65 years of age have chronic AF, 30% of which will suffer at least one stroke. On the other hand, chronic AF is responsible for about 20% of all cerebrovascular accidents. Predictors of stroke in AF have been defined by the CHADS2 score, and in these patients, oral anticoagulation has been the cornerstone of thromboembolic disease prevention. Because elderly patients have an increased risk of bleeding complications even under the newer antagonists of Factor Xa and direct Thrombin inhibitors, percutaneous occlusion of the left atrial appendage (LAA) as the main thrombogenic source offers an attractive alternative to permanent anticoagulation. This promising new therapeutic approach is put into clinical real world perspective.

AAOS Guidelines on Prevention of Thromboembolic Disease: New Update

AAOS Guidelines on Prevention of Thromboembolic Disease: New Update

Thrombolytic along with anti-platelet activity of crinumin, a protein constituent of Crinum asiaticum

Several anticoagulants, anti-platelet and thrombolytic medications are used for the treatment of thrombotic disorders. Anti-coagulants and anti-platelet agents prevent the formation of blood clots but do not dissolve existing clots, whereas thrombolytic agents are able to dissolve a clot but emboli can form even after successful treatment. Thus, none of them provide a permanent and complete solution. In this regard a single molecule that could both dissolve the clot and prevent the formation of new clots would be useful in the treatment of thrombotic diseases. Crinumin, a stable and active (in many adverse conditions) serine protease, shows plasmin-like fibrinolytic activity and inhibits platelet aggregation and P-selectin exposure, as established by photography, phase contrast microscopy, whole blood optical Lumi-aggregometry and flow cytometry. Crinumin could be an efficient and inexpensive therapeutic agent for the treatment and prevention of thromboembolic diseases.

Response to “Role of Orally Available Antagonists of Factor Xa in the Treatment and Prevention of Thromboembolic Disease: Focus on Rivaroxaban”

Response to “Role of Orally Available Antagonists of Factor Xa in the Treatment and Prevention of Thromboembolic Disease: Focus on Rivaroxaban”

Novel oral anticoagulants: focus on stroke prevention and treatment of venous thrombo-embolism

Anticoagulation for the long-term treatment and prevention of thrombo-embolic diseases as well as for stroke prevention in atrial fibrillation (AF) has been accomplished by vitamin K antagonists for the last half century. Although effective under optimal conditions, the imminent risk of a recurrent event vs. the risk of bleeding due to the narrow therapeutic window, numerous food- and drug interactions, and the need for regular monitoring complicate the long-term use of these drugs and render treatment with these agents complicated. As a result, novel anticoagulants which selectively block key factors in the coagulation cascade are being developed. The efficacy and safety of the direct thrombin inhibitor dabigatran etexilate, as well as of the selective factor Xa inhibitors rivaroxaban and apixaban, have been demonstrated in Phase III trials for stroke prevention in AF and the treatment and secondary prophylaxis of venous thrombo-embolism. This review summarizes the results from recently published pivotal clinical trials and discusses the opportunities as well as uncertainties in the clinical applications of these novel agents.

Thrombotic disease in critically ill children

To summarize a) epidemiology of arterial and venous thromboembolism, pulmonary embolism, and deep venous thrombosis in children; b) the risk factors for thrombosis in the pediatric intensive care unit; c) diagnostic techniques for arterial/venous thromboembolism; and d) the current recommendations for management and prevention of thromboembolic disease in critically ill children. Literature review, using National Library of Medicine PubMed and the following terms: arterial, venous thromboembolism; deep venous thrombosis; pulmonary embolism; thrombosis; as well as citations of interest from these articles. Both pediatric and adult literature addressing thrombotic disease were reviewed. Articles were chosen for more extensive discussion when containing prospective studies, guidelines for practice, or data in critically ill patients. When data in children were unavailable, applicable data in adults were referenced. Due to the paucity of data in critically ill children, available adult and pediatric data were combined with institutional experience to provide suggestions for current practice and future inquiry. Increasing awareness regarding the recognition and current approaches to management and prevention of thromboembolic disease in children is needed among pediatric intensivists, so outcome of these life-threatening processes might be improved.

New Anticoagulants for Thrombo-embolic Disease: Clinical Implications

The medical community and patients have long awaited new oral anticoagulants, a substitute for warfarin. Finally, 2 drugs have received limited approval and many more are in various developmental stage. Recently, as a result of the RE-LY study, a phase 3 clinical trial, the FDA approved an oral anticoagulant Dabigatran (Pradaxa), a direct thrombin inhibitor, for prevention of stroke in patients with non-valvular atrial fibrillation. A major advantage is that there is no need for frequent monitoring of coagulation or dose adjustment. Results of the RE-LY study (NEJM) showed that dabigatran 150 mg twice a day has decreased incidence of systemic embolization and stroke but similar rates of major hemorrhage when compared to warfarin. This drug can be used in both outpatient and inpatient settings and has already been approved in 75 countries including many European countries. It is being investigated for many clinical conditions, including prevention and treatment of DVT and pulmonary embolism. The European Medicines Agency approved dabigatran in 2008 for the prevention of thrombo-embolic disease and expanded the indication in 2011. Additional oral Xa inhibitors; apixaban, edoxaban, betrixaban are in different stages of development and likely to get approval for different indications in the near future. Although the market for oral anticoagulants is billions of dollars, safety, clinical, and economic issues will influence the acceptance and use of these drugs. The costs of these drugs is likely to be higher than warfarin, however, elimination of frequent coagulation tests will help reduce overall costs. Important limitations for these new classes of drugs, is the absence of simple, easily available, cost effective reversal agents. This article reviews the clinical trials, pharmacokinetics, side effects and potential clinical applications of these new oral thrombin inhibitors.

Bemiparin in Oncology

An association between cancer and thrombosis has been recognized since 1865. It is considered to be a two-way association; cancer is associated with an increased risk of venous thromboembolism (VTE), whereas activation of the coagulation cascade enhances the proliferation, angiogenesis potential and metastasis of tumour cells. A sizeable proportion of VTE events in cancer patients undergoing major surgery occur after discharge from hospital, suggesting that extended thromboprophylaxis beyond the normal 7-10 days is warranted in these patients. Studies have demonstrated reduced incidences of VTE with extended thromboprophylaxis using low molecular weight heparins (LMWH) and guidelines recommend continuing thromboprophylaxis after discharge in patients who have undergone major cancer surgery, but the evidence is still considered limited and of low quality, and the recommendations have not been widely implemented in clinical practice. Extended prophylaxis with bemiparin was shown to reduce significantly the incidence of major VTE in patients undergoing major cancer surgery in the Cancer, Bemiparin and Surgery Evaluation study, providing further support for the routine use of extended thromboprophylaxis with LMWH in cancer patients. Heparins, particularly LMWH, in addition to preventing VTE in cancer patients, can block tumour cell growth, invasion, metastasis and angiogenesis. As with other LMWH, bemiparin and its ultra-low molecular weight derivative, RO-14, appear to be effective in preventing angiogenesis in in-vitro models. Recent clinical studies have demonstrated significant survival advantages when LMWH have been added to chemotherapy in cancer patients. This could be partly due, not only to the prevention of thromboembolic diseases in these patients, but also to 'direct' antineoplastic properties of LMWH. The survival benefits appeared greater in patients with limited cancer, especially limited small cell lung cancer. The Adjuvant Bemiparin in Small Cell Lung Cancer study is assessing the effect of bemiparin on survival in patients with limited small cell lung cancer, and although results are not yet available, preliminary data appear very promising.

Prevention of Thromboembolic Disease in Minimally Invasive Total Hip Arthroplasty With Acetylsalicylic Acid Is Safe, Cost-efficient, and Effective

Prevention of Thromboembolic Disease in Minimally Invasive Total Hip Arthroplasty With Acetylsalicylic Acid Is Safe, Cost-efficient, and Effective

Role of Orally Available Antagonists of Factor Xa in the Treatment and Prevention of Thromboembolic Disease: Focus on Rivaroxaban

Interpatient variability in the safety and efficacy of oral anticoagulation with warfarin presents several challenges to clinicians, thus underscoring the emergent need for new orally available anticoagulants with predictable pharmacokinetic and pharmacodynamic profiles and ability to target circulating clotting factors. Seven compounds including rivaroxaban, apixaban, betrixaban, and eribaxaban are orally available direct inhibitors of activated factor X currently in development for the prevention and treatment of venous thromboembolism and for thromboprophylaxis in patients with atrial fibrillation or following an acute coronary syndrome. At doses used in phase 2 and 3 clinical trials, rivaroxaban and apixaban demonstrated a predictable onset of effect, maximal plasma concentration, and half-life that was unaffected by age, renal, or hepatic disease. In clinical trials for the treatment and prevention of venous thromboembolism, rivaroxaban and apixaban produced equivalent or superior reductions in the development or progression of venous thromboembolism compared with either low molecular weight heparin or warfarin. Trials comparing the efficacy of rivaroxaban or apixaban to standard therapy for stroke prophylaxis in patients with atrial fibrillation are in process. Rivaroxaban, the sentinel compound in this class, is already approved in the European Union and Canada. It is likely to be approved for use in the United States in 2010.

Combined oral anticoagulant and antiplatelet treatment: need for an evidence-based approach

Oral anticoagulants and antiplatelets are used in the longterm treatment and prevention of thromboembolic diseases. For more than 50 years, vitamin K antagonists (VKA), i.e. warfarin, acenocoumarol, and phenprocoumon, have been the only available oral anticoagulants. New oral anticoagulant drugs will soon be available: those at a more advanced stage of development are a direct thrombin inhibitor (dabigatran etexilate) and two direct factor Xa inhibitors (rivaroxaban and apixaban). Antiplatelet drugs interfere with some steps in the activation process, including adhesion, release, and/or aggregation. Aspirin and thienopyridines (ticlopidine and clopidogrel) are the currently used drugs, but new molecules are coming. VKA are used in the primary and secondary prevention of venous thromboembolism, in the prophylaxis of cardioembolic events in patients with mechanical or biological prosthetic heart valves, in patients with atrial fibrillation, and in some other ischemic myocardial diseases; antiplatelets are used mainly to prevent and/or to treat myocardial infarction, stroke, and peripheral arterial diseases. Combined anticoagulant‐antiplatelet treatment has been attempted in order to increase the efficacy of the antithrombotic treatment in some clinical conditions. Moreover, one patient already on anticoagulant treatment may develop also the indication for antiplatelet treatment, or vice versa. For both anticoagulants and antiplatelets, the efficacy in treating and preventing thromboembolic diseases cannot be dissociated from an increased risk of bleeding; therefore, the combination of these drugs can be not only more effective, but also more dangerous, and should be considered with caution. Overall, the evidence of benefit of combined treatment is limited, and the increased risk of bleeding is proven. However, combined anticoagulant and antiplatelet treatment is frequently prescribed in clinical practice: an aggressive therapeutic approach seems currently to be more attractive and popular than an evidence-based one. Sometimes it may be difficult to assess

Circulación pulmonar: aportaciones del año 2009

A significant number of studies on pulmonary circulation diseases have been published in 2009 that are likely to have a notable clinical impact. Anticoagulant treatment is on the verge of a significant change with the arrival of new oral drugs that have an inhibitory effect over factor X (rivaroxaban, apixaban) or thrombin (dabigatran). New studies have shown an efficacy comparable to enoxaparin in the prevention of thromboembolic disease and in some cases a lower risk of haemorrhage. Also interesting is a study on the incidence of pulmonary thromboembolism in patients with chronic obstructive pulmonary disease, a little known aspect. A study that demonstrates some efficacy of rosuvastatin in the prevention of thromboembolic disease, something that could change our current practices. Pulmonary hypertension (PH) continues to produce numerous publications. One French study has shown a relatively low risk of developing PH in patients with systemic sclerosis over a period of 3 years. As regards treatment, ambrisentan seems to confirm it lower risk of hepatoxicity compared to other endothelin antagonists. A new phosphodiesterase-5 inhibitor, tadalafil, has made a strong impact on the PH scene during this year. Its results are similar to other oral drugs with a convenient posology. The surgical treatment of PH due to chronic thromboembolism in one of the hospitals of our country has been present with results that, particularly in the past few years, are perfectly comparable to other centres of excellence. To summarise, 2009 has continued to provide important news in the area of pulmonary circulation.