Venous thromboembolism risk in ischemic stroke patients receiving extended-duration enoxaparin prophylaxis: results from the EXCLAIM study.

BACKGROUND AND PURPOSE: The optimal duration of venous thromboembolism prophylaxis in acute stroke patients is unknown. This subanalysis of the Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization (EXCLAIM) study investigated extended-duration thromboprophylaxis with enoxaparin, compared with placebo following standard-duration enoxaparin, in ischemic stroke patients. METHODS: Acutely ill medical patients with recently reduced mobility received open-label enoxaparin 40 mg for 10±4 days, and they were then randomized to double-blind enoxaparin 40 mg daily or placebo for further 28±4 days. Venous thromboembolism incidence (symptomatic/asymptomatic deep-vein thrombosis, symptomatic/fatal pulmonary embolism) up to day 28 after randomization and major bleeding rates up to 48 h after the last dose of study treatment were reported. RESULTS: In total, 389 of 5963 (6.5%) randomized patients had ischemic stroke: 198 received extended-duration prophylaxis and 191 placebo. Extended-duration prophylaxis reduced venous thromboembolism incidence versus placebo (2.4% versus 8.0%; absolute risk difference, -5.6%; 95% CI, -10.5% to -0.7%), but it was associated with an increase in major bleeding (1.5% versus 0% in enoxaparin and placebo groups; absolute risk difference, +1.5%; 95% CI, -0.2% to 3.2%). CONCLUSIONS: Extended-duration thromboprophylaxis with enoxaparin was associated with reduced venous thromboembolism risk and increased major bleeding in the subgroup of patients with ischemic stroke in the EXCLAIM study.

Laboratory assessment of rivaroxaban: a review.

Research into new anticoagulants for preventing and treating thromboembolic disorders has focused on targeting single enzymes in the coagulation cascade, particularly Factor Xa and thrombin, inhibition of which greatly decreases thrombin generation. Based on the results of phase III clinical trials, rivaroxaban, a direct Factor Xa inhibitor, has been approved in many countries for the management of several thromboembolic disorders. Owing to its predictable pharmacokinetic and pharmacodynamic characteristics, fixed-dose regimens are used without the need for routine coagulation monitoring. In situations where assessment of rivaroxaban exposure may be helpful, anti-Factor Xa chromogenic assays (in tandem with standard calibration curves generated with the use of rivaroxaban calibrators and controls) could be used. It is important to note that test results will be affected by the timing of blood sampling after rivaroxaban intake. In addition, the anti-Factor Xa method measures the drug concentration and not the intensity of the drug's anticoagulant activity, and a higher than expected rivaroxaban plasma level does not necessarily indicate an increased risk of bleeding complications. Therefore, clinicians need to consider test results in relation to the pharmacokinetics of rivaroxaban and other patient risk factors associated with bleeding.

Measurement of dabigatran and rivaroxaban in primary prevention of venous thromboembolism in 106 patients, who have undergone major orthopedic surgery: an observational study.

No routine coagulation laboratory test is recommended during rivaroxaban or dabigatran treatment. However measuring drug concentration and/or anticoagulant activity can be desirable in some special clinical settings, such as bleeding, thrombosis recurrence or emergency surgery. The effects of dabigatran etexilate and rivaroxaban on various coagulation assays have been previously studied in normal plasma spiked with increasing concentrations of the drug. In contrast, few data are available in routinely treated patients. In order to perform and to interpret the results of these tests, it is necessary to determine the usual responses of patient's plasma. We have used several coagulation tests in a prospective study including 106 patients receiving thromboprophylactic treatment with dabigatran 150 or 220 mg od and rivaroxaban 10 mg od for major orthopaedic surgery. The most common tests--prothrombin time (PT) and activated partial thromboplastin time (aPTT)--give results, which vary according to the reagent used. To overcome this limitation, we advocate the use of plasma calibrators, which decreases the inter-laboratory heterogeneity of results. Anti-Xa measurement and Hemoclot, a thrombin diluted clotting assay, are specific assays which have been proposed for rivaroxaban and dabigatran respectively. These tests, conventional PT, aPTT and thrombin generation (TG) have been performed. We demonstrated that measurements of both drugs can determine reliably the drug concentration in patients' plasmas. PT is more prolonged with rivaroxaban than with dabigatran. Interestingly, the pattern of TG was clearly different in relation to the difference in the mechanism of action of the two new anticoagulants. A significant inter-individual variability of response is detected. Rivaroxaban--mean Cmax 140 ng/mL (extremes 0-412) induces a greater increase of PT than dabigatran. aPTT is sensitive to dabigatran. Rivaroxaban concentrations were in good agreement with two other studies while unexplained lower than expected concentrations were found in dabigatran patients receiving 220 mg once a day [mean Cmax 60 ng/mL (extremes 0-320)]. An interference by pantoprazole, a drug which reduces dabigatran absorption, could explain the observed lower than expected results.

Massive transfusion: an overview of the main characteristics and potential risks associated with substances used for correction of a coagulopathy.

Massive transfusion (MT) is an empiric mode of treatment advocated for uncontrolled bleeding and massive haemorrhage, aiming at optimal resuscitation and aggressive correction of coagulopathy. Conventional guidelines recommend early administration of crystalloids and colloids in conjunction with red cells, where the red cell also plays a critical haemostatic function. Plasma and platelets are only used in patients with microvascular bleeding with PT/APTT values >1.5 times the normal values and if PLT counts are below 50×10(9)/L. Massive transfusion carries a significant mortality rate (40%), which increases with the number of volume expanders and blood components transfused. Controversies still exist over the optimal ratio of blood components with respect to overall clinical outcomes and collateral damage. While inadequate transfusion is believed to be associated with poor outcomes but empirical over transfusion results in unnecessary donor exposure with an increased rate of sepsis, transfusion overload and infusion of variable amounts of some biological response modifiers (BRMs), which have the potential to cause additional harm. Alternative strategies, such as early use of tranexamic acid are helpful. However in trauma settings the use of warm fresh whole blood (WFWB) instead of reconstituted components with a different ratio of stored components might be the most cost effective and safer option to improve the patient's survival rate and minimise collateral damage. This manuscript, after a brief summary of standard medical intervention in massive transfusion focuses on the main characteristics of various substances currently available to overcome massive transfusion coagulopathy. The relative levels of some BRMs in fresh and aged blood components of the same origin are highlighted and some myths and unresolved issues related to massive transfusion practice are discussed. In brief, the coagulopathy in MT is a complex phenomenon, often complicated by chronic activation of coagulation, platelets, complement and vascular endothelial cells, where haemolysis, microvesiculation, exposure of phosphatidyl serine positive cells, altered red cells with reduced adhesive proteins and the presence of some BRM, could play a pivotal role in the coagulopathy and untoward effects. The challenges of improving the safety of massive transfusion remain as numerous and as varied as ever. The answer may reside in appropriate studies on designer whole blood, combined with new innovative tools to diagnosis a coagulopathy and an evidence based mode of therapy to establish the optimal survival benefit of patients, always taking into account the concept of harm reduction and reduction of collateral damage.

Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial.

BACKGROUND: Extended-duration low-molecular-weight heparin has been shown to prevent venous thromboembolism (VTE) in high-risk surgical patients. OBJECTIVE: To evaluate the efficacy and safety of extended-duration enoxaparin thromboprophylaxis in acutely ill medical patients. DESIGN: Randomized, parallel, placebo-controlled trial. Randomization was computer-generated. Allocation was centralized. Patients, caregivers, and outcome assessors were blinded to group assignment. (ClinicalTrials.gov registration number: NCT00077753) SETTING: 370 sites in 20 countries across North and South America, Europe, and Asia. PATIENTS: Acutely ill medical patients 40 years or older with recently reduced mobility (bed rest or sedentary without [level 1] or with [level 2] bathroom privileges). Eligibility criteria for patients with level 2 immobility were amended to include only those who had additional VTE risk factors (age >75 years, history of VTE, or active or previous cancer) after interim analyses suggested lower-than-expected VTE rates. INTERVENTION: Enoxaparin, 40 mg/d subcutaneously (2975 patients), or placebo (2988 patients), for 28 +/- 4 days after receiving open-label enoxaparin for an initial 10 +/- 4 days. MEASUREMENTS: Incidence of VTE up to day 28 and of major bleeding events up to 48 hours after the last study treatment dose. RESULTS: Extended-duration enoxaparin reduced VTE incidence compared with placebo (2.5% vs. 4%; absolute risk difference favoring enoxaparin, -1.53% [95.8% CI, -2.54% to -0.52%]). Enoxaparin increased major bleeding events (0.8% vs. 0.3%; absolute risk difference favoring placebo, 0.51% [95% CI, 0.12% to 0.89%]). The benefits of extended-duration enoxaparin seemed to be restricted to women, patients older than 75 years, and those with level 1 immobility. LIMITATION: Estimates of efficacy and safety for the overall trial population are difficult to interpret because of the change in eligibility criteria during the trial. CONCLUSION: Use of extended-duration enoxaparin reduces VTE more than it increases major bleeding events in acutely ill medical patients with level 1 immobility, those older than 75 years, and women. PRIMARY FUNDING SOURCE: Sanofi-aventis.

The significance of endothelial heterogeneity in thrombosis and hemostasis.

The endothelium is recognized today as a functional and dynamic component of the body that plays an important part in health and disease. This article briefly reviews the role of endothelium in thrombosis and hemostasis. There is a paradigm shift from one that regards the endothelium as one single entity to the concept that the endothelium is heterogeneous. Thrombotic complications in many disorders show a predilection to specific locations, despite the fact that a hypercoagulable state affects the entire body. Likewise, bleeding is more commonly encountered in certain anatomical locations than in others. Recent observations of the heterogeneous distribution of coagulation and fibrinolytic factors in the endothelium and the adaptation of the endothelium to various stimuli may provide an explanation for the diverse phenotypes. Recognition of this changing paradigm is helpful to for the diagnosis and management of bleeding and thrombotic complications. It also helps in the understanding of the pathogenesis of many bleeding and thrombotic disorders, and in the development of new drug designs for site-specific therapy.

Assays for measuring rivaroxaban: their suitability and limitations.

Several new oral anticoagulants such as rivaroxaban (which targets Factor Xa) and dabigatran etexilate (which targets thrombin) are in advanced stages of clinical development and are already available for clinical use in some countries. Although these agents do not require routine coagulation monitoring, assays to assess the level of anticoagulation may be of assistance in certain circumstances such as in case of overdose, in patients with a hemorrhagic or thromboembolic event during treatment, or to assess compliance. Moreover, the influence of the new oral anticoagulants on routine coagulation tests must be recognized. The prothrombin time is not suitable for rivaroxaban measurement for several reasons, and the routinely used international normalized ratio for monitoring the vitamin K antagonists cannot be applied to rivaroxaban. Development of universal assays is challenging because the new oral anticoagulants have different targets, and even those with the same target have variable effects on routine coagulation assays. Focusing on rivaroxaban, there is emerging evidence that an anti-Factor Xa assay that uses rivaroxaban-containing plasma calibrators may provide the optimal method for determining plasma rivaroxaban concentrations.

Newer anticoagulants in 2009.

Several newer anticoagulants are under clinical development. Recently two of them, Dabigatran etexilate/Pradaxa. and Rivaroxaban/Xarelto obtained marketing authorization in Europe and Canada for the prevention of thromboembolic events following major orthopedic surgery such as total hip and knee replacement. The results of Phase III clinical studies in thromboprophylaxis in major orthopedic surgery are highlighted and discussed in detail. Ongoing Phase II and III clinical trials assess their efficacy in the secondary prevention and treatment of deep vein thrombosis and pulmonary embolism, and in the long-term prevention of stroke in patients with non-valvular atrial fibrillation and in combination with aspirin and clopidogrel in patients with acute coronary syndromes. Many other small antithrombotic molecules including a new generation of low molecular weight heparins, are currently in different stages of clinical development. In addition to being administered orally, the newer anticoagulant agents have a more balanced benefit/risk ratio and wider therapeutic window. They have a rapid onset of action, a predictable anticoagulant effect that does not require routine laboratory monitoring. They have minor food and drug interactions, including those with cytochrome P450 and P.gp. They are highly specific and targeted to a single coagulation factor, and could carry similar or less hemorrhagic risks compared to the older anticoagulant agents. Finally, they may be used in a broader variety of patients, especially the medically ill patients with advanced cancer, and the elderly without any dosage adjustment, regardless of the patient age, gender, body weight, or in patients with mild renal impairment. Their use in the general world will hopefully confirm the promising results of clinical trials.

Clinical studies with anticoagulants to improve survival in cancer patients.

Cancer is linked with hypercoagulability and risk of thrombosis and this close association was recognized by Armand Trousseau in 1865. The relation between cancer and blood coagulation is reciprocal: cancer induces a hypercoagulable state and predisposes to thrombosis and activation of platelets, blood coagulation and fibrinolysis interfere with tumor cell biology, tumor growth, angiogenesis and metastatic process. In the present article, we analyze the clinical trials which assessed the influence of anticoagulant treatment on the survival of patients with cancer. The available data show that low-molecular-weight heparins (LMWHs) tend to be more effective and safer than vitamin K antagonists (VKA) in improving survival in patients with cancer. The beneficial effect of anticoagulation with either LMWHs or VKA is not universal for all patients with cancer. There are some histological types of cancers which, at early stages, appear to be more sensitive than others to the effect of anticoagulant treatment. The available clinical trials, although limited, are encouraging for the beneficial effect of anticoagulant treatment on the survival of cancer patients. More clinical trials are needed, targeting groups of patients homogenous regarding the type of cancer, the stage of the disease and life expectancy. The forthcoming clinical trials have to address some issues regarding the optimal dose, the timing and the duration of treatment with LMWH in relation to chemotherapy or other anticancer therapies.

Afibrinogenemia resulting from homozygous nonsense mutation in A alpha chain gene associated with multiple thrombotic episodes.

Congenital afibrinogenemia is a rare disorder characterized by the absence in circulating fibrinogen, a hexamer composed of two sets of three polypeptides (Aalpha, Bbeta and gamma). Although predisposition to thrombosis is a well known feature of dysfibrinogenemia, the relatively frequent thrombotic manifestations seen in congenital afibrinogenemia are puzzling. We herein report a mutational analysis of a young afibrinogenemic man from Turkey with multiple thrombo-embolic events involving both arteries and veins. Purified DNAs of the propositus was used for amplification by polymerase chain reaction of all the exons of the A subunit gene with primers allowing the analysis of the intron-exon boundaries. Analysis of the genes coding for the three fibrinogen chains of the propositus found a homozygous G to A transition in the exon 5 of the A alpha chain gene (g.g4277a; access number gi458553). The TGG to TGA codon change predicts a homozygous W315X in the A alpha chain (p.W334X when referring to the translation initiation codon). Both parents and his brother were found to carry this heterozygous mutation. This is the first report of a patient homozygous for this rare mutation associated with afibrinogenemia. Our patient was free of known risk factors as well as diseases associated with thrombosis including atherosclerosis, vasculitis, Buerger's disease, and it seems therefore probable that afibrinogenemia itself might have contributed to both arterial and venous thrombosis.

Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality.

Venous thromboembolism (VTE) is often asymptomatic, mis-diagnosed, and unrecognized at death, and there is a lack of routine postmortem examinations. These factors are thought to result in marked underestimates ofVTE incidence. The objective of our study was to estimate the total burden of VTE within the European Union (EU) per annum. An epidemiological model was constructed to estimate the number of community- and hospital-acquired incidents and recurrent cases (attack rate) of nonfatal VTE and VTE-related deaths, as well as incident and prevalent cases of post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (PH) occurring in the EU per annum. Individual models were developed for six EU countries. The models were populated with data from published literature and, where necessary, expert opinions. The findings were tested using probabilistic sensitivity analyses. The estimated total number of symptomaticVTE events (range based on probabilistic sensitivity analysis) per annum within the six EU countries was 465,715 (404,664-538,189) cases of deep-vein thrombosis, 295,982 (242,450-360,363) cases of pulmonary embolism (PE), and 370,012 (300,193-483,108) VTE-related deaths. Of these deaths, an estimated 27,473 (7%) were diagnosed as being antemortem; 126,145 (34%) were sudden fatal PE, and 217,394 (59%) followed undiagnosed PE. Almost three-quarters of all VTE-related deaths were from hospital-acquired VTE. VTE is a major health problem in the EU, with over one million VTE events or deaths per annum in the six countries examined. Given the availability of effective VTE prophylaxis, many of these events and deaths could have been prevented. These results have important implications for the allocation of healthcare resources.

An electronic tool for venous thromboembolism prevention in medical and surgical patients.

BACKGROUND AND OBJECTIVES: Venous thromboembolism (VTE) is a complex disorder influenced by numerous risk factors, and occurs frequently in at-risk hospitalized patients. Because appropriate prevention with thromboprophylaxis is underused, we wanted to create an electronic tool to provide a simple risk assessment and suggest appropriate prophylaxis. DESIGN AND METHODS: To develop the risk matrix, iterative rating of odds ratios was performed for 60 predisposing VTE risk factors, using analytical methods that account for multiple risk factors in a single patient and their non-independence. For exposing risk factors, a single score was assigned to each set of factors, both medical (25 items) and surgical conditions (144 items). A CART regression model was used to integrate the risk scales into a 4-level measure of overall risk. The validity of the level of risk and the appropriateness of 11 different prophylactic approaches was assessed using the RAND/UCLA appropriateness method and validated by expert opinion ratings (n=1998) on sample case scenarios (n=108). RESULTS: Correlation between the level of risk calculated by the risk matrix and that offered by expert opinion for individual surgical and medical clinical cases was high (65% and 70%, respectively). The matrix over-estimated the level of risk, compared with that offered by expert opinion, in 28% and 20% of surgical and medical cases, respectively, but the appropriate prophylaxis suggested was no different. Between-expert agreement on the appropriateness of the prophylaxis recommendations was high (90-94% of indications). INTERPRETATION AND CONCLUSIONS: This computer-based electronic tool for individualized assessment of venous thromboembolic risk successfully identified both the perceived risk of thrombosis and the appropriate prophylactic approach for medical and surgical patients.

An update on prevention of venous thromboembolism in hospitalized acutely ill medical patients.

Both the recently updated consensus guidelines published by the American College of Chest Physicians, and the International Union of Angiology recommend thromboprophylaxis with either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) in medical patients at risk of VTE. However, no guidance is given regarding the appropriate dosing regimens that should be used for thromboprophylaxis in this patient group. LMWH (enoxaparin and dalteparin) and UFH have been shown to be effective for thromboprophylaxis in at-risk hospitalized medical patients. Although LMWH once daily (o.d.) has been shown to be as effective as UFH three times daily (t.i.d.) for thromboprophylaxis in at-risk medical patients, there are no data to show that UFH twice daily (b.i.d) is as effective as either LMWH o.d. or UFH t.i.d. On the basis of currently available evidence, the LMWHs enoxaparin and dalteparin are more attractive alternatives to UFH for the prevention of VTE in hospitalized medical patients because of their convenient once-daily administration and better safety profile, demonstrated in terms of reduced bleeding, HIT, and other adverse events.

The influence of methylene blue light treatment and methylene blue removal filter on fibrinogen activity states and fibrin polymerisation indices.

BACKGROUND/OBJECTIVE: Methylene blue light treatment (MBLT) is efficient in inactivating viruses in plasma. However, it may cause alterations in clotting factors, especially fibrinogen (Fg). The true mechanism of such a selective alteration is poorly understood, The effects of MBLT and MB removal filters (MBRF) on Fg concentration, functional activity and fibrin polymerisation were studied. DESIGN: Apheresis plasma collected by Haemonetic MCS Plus (n=10) was split into two equal aliquots. Both were leukofiltered and virally inactivated in a standardized fashion, using Theraflex MB-Plasma Photodynamic viral inactivation Macopharma method. One of the pair was subsequently processed, using Blueflex MBRF to remove residual MB and its by-products. Control plasma samples were obtained after filtration but before MBLT. Samples were also obtained after MBLT and MBRF. All samples were analyzed for the Fg activity, Fg antigen, thrombin clotting time (TT), and alterations fibrin polymerisation indices. RESULTS: After MBLT, mean Fg concentration increased slightly (2%) whereas functional activity decreased by 31%, as compared to control samples. Mean TT prolonged by 6s after MBLT, with no further changes after MBRF. A similar trend was observed using RT. Both thrombin and reptilase triggered fibrin polymerisation were delayed and the polymerisation curves slopes were decreased slightly, with concomitant changes in fibrin opacity in samples from MBLT and MBRF as compared to control. Comparison is made for the first time with a similar changes observed in dysfibrinogenemia. CONCLUSION: MBLT resulted in about 30% decrease in Fg activity but a slight modification in fibrin polymerisation indices, with no additional alteration subsequent to MBRF. These in vitro changes are similar to those seen in plasma from patients with dysfibrinogenemia, which are usually without clinical significance.

[Non-VKA oral anticoagulants: an update for the clinical biologists]. / Anticoagulants directs oraux : actualités pour les biologistes.

Non-VKA oral anticoagulants (NOACs), thanks to their ease of use and their similar or superior safety/efficacy profiles versus warfarin, have now widely reached the lucrative market of anticoagulation. However, while the marketing authorization holders always claim, in a quite unclear way that no monitoring is required, accumulative evidence and cases of major bleeding have been described in the literature and reported by spontaneous reporting systems at the regulator's level. These compounds are usually given at fixed doses without routine coagulation monitoring. However, new data suggests that an assessment of the response at the individual level could improve the benefit-risk ratio of, at least dabigatran. Therefore, in certain patient populations, i.e. acute or chronic renal impairment or multiple drug interactions, measurement of drug exposure may be useful to ensure an optimal treatment response. More specific circumstances such as patients experiencing a haemorrhagic or thromboembolic event during the treatment duration, patients who require urgent surgery or an invasive procedure, or patient with a suspected overdose could benefit from such a measurement. This article aims at providing guidance on how to best estimate the intensity of anticoagulation using laboratory assays in daily practice.

Quantification of risk factors for venous thromboembolism: a preliminary study for the development of a risk assessment tool.

BACKGROUND AND OBJECTIVES: Venous thromboembolism is a frequent and serious disorder influenced by numerous factors. As the first step in creating a tool to assess an individual patient's risk of venous thromboembolism, we carried out a literature review in order to quantify risk factors for venous thromboembolism. EVIDENCE AND INFORMATION SOURCES: Risk factors were identified as being either predisposing, that is, those risks presented by a patient prior to hospital admission, or exposing, that is, those risks occurring when a patient is hospitalized for a certain medical condition or surgical procedure. Predisposing risk factors were classified with regard to the patients' characteristics (including general characteristics and inherent risk factors), and recent and chronic clinical conditions. RESULTS: The major predisposing factors among the patients' characteristics were age, hormonal therapy and personal history of venous thromboembolism, along with inherited coagulation factor abnormalities. Clinical situations associated with the highest risk of venous thromboembolism were recent surgery, hospitalization for medical conditions and immobilization, moderate to severe congestive heart failure, and malignancy. CONCLUSIONS: This literature review will assist in the development of a suitable risk assessment tool for aiding healthcare professionals to decide whether to employ thromboprophylaxis, and, if so, to select the appropriate type and duration of prophylaxis.

Evaluation of the pharmacological properties and clinical results of the synthetic pentasaccharide (fondaparinux).

Fondaparinux (Arixtra) is the first of a new class of selective indirect antithrombin-dependent factor Xa inhibitors, which inhibits thrombin generation. Fondaparinux is a completely synthetic pentasaccharide. It is a single molecular entity with a well-defined pharmacological target. Fondaparinux has nearly complete bioavailability after subcutaneous injection. The pharmacokinetics of fondaparinux appears predictable and consistent. The peak plasma level is obtained about 2 h after the subcutaneous injection, indicating that a rapid onset of antithrombotic activity is obtained on initiation of treatment. The elimination half-life is about 17 h and it is dose-independent, which allows a convenient once-daily dosing regimen. Fondaparinux is eliminated exclusively by the kidneys. Thus, the estimation of the renal function especially in elderly patients is important for the treatment with fondaparinux, whereas it is contraindicated in patients with severe renal insufficiency. Phase II clinical studies have identified a subcutaneous dose of 2.5 mg once daily for prophylaxis of venous thromboembolism in patients undergoing major orthopaedic surgery. Four phase-III clinical trials using bilateral phlebography for the diagnosis of DVT, demonstrated a combined 50% relative risk reduction of asymptomatic venous thromboembolic events in orthopaedic surgery patients in comparison to the low-molecular-weight heparin (LMWH) enoxaparin. Hemorrhagic complications for fondaparinux were either comparable or higher than those for LMWH but the authors did not judge that the increased bleeding was clinically relevant. A dose ranging study led to the selection of the dose of 7.5 mg at a single daily subcutaneous injection as optimal for the treatment of VTE. In two phase III clinical trials, the dose of 7.5 mg/day is expected to be as efficacious and safe as heparin for the treatment of DVT or PE, respectively. Phase II studies show that the efficacy-to-safety ratio of fondaparinux in the treatment of unstable angina or as an adjunct to thrombolysis in acute myocardial infarction is promising. These results demonstrated that a single anti-Xa agent devoid of antithrombin activity is a potent antithrombotic drug. Fondaparinux has obtained FDA and European health authorities approval. Its use on a large scale will allow the evaluation of its efficacy and tolerance in the daily clinical practice. Chemical modifications of the original synthetic pentasaccharide increase the affinity to AT resulting in a more potent inhibition of FXa and longer half-life. Idraparinux is the first of these new oligosaccharides that we named "meta-pentasaccharides." After subcutaneous injection the half-life of idraparinux is about 80 h allowing a single injection per week. A dose-finding study has established the optimal dose given once a week to be compared with warfarin for the treatment of DVT.

Standard measurement of clot-bound thrombin by using a chromogenic substrate for thrombin.

We have developed an in vitro protocol for the measurement of clot-bound thrombin. This protocol uses a chromogenic substrate for thrombin and a microtiter plate reader and is suitable for screening inhibitors for thrombin that are directed to clot-bound thrombin. Clots were obtained after recalcification of human plasma. For the measurement of clot-bound thrombin, we read the optical density (OD) at 405 nm on a spectrophotometer and compared the results to that obtained with a standard curve of human alpha thrombin. We stopped the amidolytic reaction at 10 min because the optical density was linear until 20 min under our experimental conditions. We suggest that clot-bound thrombin can be measured using a chromogenic substrate specific for thrombin under our experimental condition.

[Pregnancy-associated venous thrombosis in women with hereditary heterozygous factor V Leiden and/or factor II gene mutations]. / Risque de thrombose lié à la grossesse chez les femmes porteuses d'une mutation hétérozygote du facteur V Leiden, du facteur II ou de leur association.

The risk of venous thromboembolism (VTE) in pregnant women with heterozygous factor V Leiden and/or heterozygous factor II 20210A gene mutations is poorly documented, and the need for prophylaxis is therefore controversial. We retrospectively studied 208 women with hereditary thrombophilia (heterozygous FV Leiden and/or factor II gene mutations), who had a total of 406 full-term pregnancies, including 10 with thromboprophylaxis. The ante- and post-partum incidence of VTE was significantly higher in women with both mutations (17.8 %) than in women with FII gene mutation alone (6.2%) p = 0.003. In contrast, there was no significant difference between women with FV+FII mutation and those with FV mutations alone (10%). Thus, the two most common hereditary risk factors for thrombophilia seem to have an additive rather than a synergistic effect on the antepartum/post-partum risk of VTE. In contrast, a previous history of VTE before pregnancy in women with both the FV and the FII gene mutations was associated with a very high risk of VTE (50%). The incidence of VTE was higher during the post-partum period than the ante-partum period. There was no significant difference in the incidence of fetal loss in the three groups, but this was not a primary endpoint. These results, obtained in a single center, have implications for VTE prophylaxis. Routine use of LMWH is not indicated during pregnancy in asymptomatic women with a single mutation. In contrast, it is justified throughout pregnancy in women with both mutations and a history of venous thrombosis. Regarding asymptomatic women with both mutations, the need for prophylaxis during part or all of the pregnancy should be weighed up on an individual basis. In the post-partum period, there is a consensus on the use of LMWH for 6 weeks in women with single or dual mutations associated with thrombophilia.

Pharmacology and laboratory testing of the oral Xa inhibitors.

New oral factor Xa inhibitors are intended to progressively substitute the oral vitamin K antagonists and parenteral indirect inhibitors of factor Xa in the prevention and treatment of venous and arterial thromboembolic episodes. This article focuses on the main clinical studies and on biological measurements of new oral factor Xa inhibitors, and addresses several safety issues. These newer agents do not require any routine laboratory monitoring of blood coagulation; however, biological tests have been developed in order to assess the plasma concentration of these drugs in several clinical settings. This article reviews these 4 oral direct factor Xa inhibitors.