Key questions resulting from the JUPITER trial assessing cardiovascular disease intervention with rosuvastatin.

THIS PAPER PRESENTS AN ANALYSIS OF THE RECENTLY PUBLISHED JUSTIFICATION FOR THE USE OF STATINS IN PREVENTION (JUPITER: an intervention trial evaluating rosuvastatin) trial, which tested the statin rosuvastatin in apparently healthy individuals with no prior cardiovascular (CVD) disease and with normal plasma low density lipoprotein (LDL) cholesterol concentrations but with raised plasma high sensitivity C-reactive protein (hsCRP) levels. The rate of the combined primary CVD endpoint was significantly reduced in the treatment arm after a median of under 2 years. The JUPITER trial is distinct from previous studies examining statin use in primary prevention groups because the target group for drug therapy was apparently healthy men and women at low or intermediate risk for developing CVD.

Potential of new anticoagulants in patients with cancer.

Cancer-associated thrombosis is a major cause of morbidity and mortality. Although anticoagulation remains the mainstay for prevention and treatment of thrombosis, current anticoagulants are problematic in cancer patients. Parenteral anticoagulants, such as heparin or low-molecular heparin, require daily subcutaneous injection, whereas warfarin requires coagulation monitoring and frequent dose adjustments.

New oral anticoagulants in development.

Although currently available anticoagulants are effective for the prevention and treatment of thromboembolic disorders, they have several drawbacks. Low-molecular-weight heparins and fondaparinux produce a predictable level of anticoagulation that obviates the need for coagulation monitoring, but they must be given parenterally, which renders them inconvenient for long-term use. Vitamin K antagonists, such as warfarin, are administered orally, but produce a variable anticoagulant response because genetic polymorphisms, dietary vitamin K intake and multiple drug-drug interactions affect their metabolism.

HD1, a thrombin- and prothrombin-binding DNA aptamer, inhibits thrombin generation by attenuating prothrombin activation and thrombin feedback reactions.

HD1, a DNA aptamer, binds exosite 1 on thrombin and blocks its clotting activity. Because HD1 also binds prothrombin and inhibits its activation by prothrombinase, we hypothesised that HD1 would be a more potent inhibitor of coagulation than other exosite 1-directed ligands, such as Hir(54-65)(SO(3)(-)). Supporting this concept, the effect of HD1 on the prothrombin time and activated partial thromboplastin time was two-fold greater than that of Hir(54-65)(SO(3)(-)) even though both agents inhibited thrombin-mediated factor (F) V and FVIII activation to a similar extent.

Leukocyte urokinase plasminogen activator receptor and PSGL1 play a role in endogenous arterial fibrinolysis.

Fibrin is an integral component of arterial thrombi. Using a mouse model of arteriolar thrombosis, high-speed fluorescence microscopy reveals that, within minutes, the fibrin content of thrombi rapidly increases and then decreases. The decrease in fibrin coincides with leukocyte binding to the thrombi, a process mediated by the interaction of leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) with P-selectin on the surface of activated platelets.

Dabigatran versus warfarin in the treatment of acute venous thromboembolism.

Background: The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy to warfarin for patients who have acute venous thromboembolism.

Methods: In a randomized, double-blind, noninferiority trial involving patients with acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days (interquartile range, 8 to 11), we compared oral dabigatran, administered at a dose of 150 mg twice daily, with warfarin that was dose-adjusted to achieve an international normalized ratio of 2.0 to 3.

Update on heparin: what do we need to know?

Over the last 15 years, there has been a shift from unfractionated heparin to low-molecular-weight heparin or fondaparinux for many indications. Nonetheless, heparin continues to be used and it remains the drug of choice for selected indications and patients. This paper reviews when and how to use heparin and when low-molecular-weight heparin or fondaparinux may be a better choice.

Comparison of recombinant and plasma-derived antithrombin biodistribution in a rabbit model.

Antithrombin (AT) is a native plasma protein that acts as the main inhibitor of enzymes generated by the coagulation cascade. In extreme thrombotic conditions, consumption of plasma AT can make treatment with AT-associated heparin therapies less effective. Supplementation with recombinant human AT (rhAT) has shown promise but altered pharmacokinetics were observed when comparing stable heparin complexes of the plasma-derived AT (pAT) and rhAT proteins.

Factors that predict risk of thrombosis in relatives of patients with unprovoked venous thromboembolism.

Background: Factors that predict the risk of venous thromboembolism in the first-degree relatives of patients with unprovoked venous thromboembolism are uncertain but important for counseling. We aimed to identify risk factors for, and quantify the risk of, venous thromboembolism in first-degree relatives of patients (index case patients) with a first episode of unprovoked venous thromboembolism.

Methods: In a cross-sectional study, using a standardized method and without knowledge of whether patients or their relatives had thrombophilia, we assessed the prevalence of previous venous thromboembolism in 1,916 first-degree relatives of 378 unselected patients with a first episode of unprovoked venous thromboembolism.

Anticoagulant mechanisms of covalent antithrombin-heparin investigated by thrombelastography. Comparison with unfractionated heparin and low-molecular-weight heparin.

We have developed an antithrombin-heparin covalent complex (ATH) which inhibits coagulation enzymes by two mechanisms: directly, or by catalytic activation of plasma antithrombin (AT). Anticoagulation by ATH was compared to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) using a blood-based, tissue factor (TF)-activated thrombelastography (TEG) assay. Simplified TEG assays with plasma or purified plasma components were used to determine the contribution of the direct and catalytic mechanisms to ATH efficacy.

New antithrombotic drugs.

Thrombosis, both venous and arterial, is a major cause of morbidity and mortality worldwide. Consequently, there is an ongoing search for new antithrombotic drugs, particularly novel antiplatelet agents and anticoagulants. A better understanding of the biochemical pathways involved in platelet activation and coagulation and of the links between these systems and the impact of thrombosis on inflammation has led to the identification of new targets for antithrombotic drugs.

Identification of a novel human cellular HDL biosynthesis defect.

Aims: Severe high-density lipoprotein cholesterol (HDL-C) deficiency is attributed to mutations in several genes and may contribute to the genetic basis of coronary artery disease. To identify the cellular basis of a novel HDL-deficiency phenotype, we screened 54 subjects of French Canadian ancestry with severe HDL deficiency.

Methods And Results: We excluded individuals with mutations in genes currently associated with low HDL (ABCA1, LCAT, APOA-I, and SMPD1).

Evidence supporting a role for endoplasmic reticulum stress in the development of atherosclerosis in a hyperglycaemic mouse model.

We previously observed a correlation between elevated levels of vascular endoplasmic reticulum (ER) stress and accelerated atherosclerotic plaque development in chronically hyperglycemic apolipoprotein-deficient (ApoE(-/-)) mice. We hypothesize that ER stress plays a causative role in diabetic atherogenesis. Here we examine the temporal relation between the onset of hyperglycemia, glucosamine accumulation in the vessel wall, ER stress, and the development of atherosclerosis.

Unanswered questions in venous thromboembolism.

We have made great strides in the diagnosis, treatment and prevention of venous thromboembolism (VTE). Despite these advances, however, questions remain. Perhaps the most important unmet need is the development and implementation of strategies to increase the uptake of guidelines for thromboprophylaxis.

The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response.

Recent studies have shown a link between obesity and endoplasmic reticulum (ER) stress. Perturbations in ER homeostasis cause ER stress and activation of the unfolded protein response (UPR). Adipocyte differentiation contributes to weight gain, and we have shown that markers of ER stress/UPR activation, including GRP78, phospho-eIF2, and spliced XBP1, are upregulated during adipogenesis.

Should D-dimer testing be used to predict the risk of recurrence after discontinuation of anticoagulant therapy for a first unprovoked episode of venous thromboembolism?

Recurrent venous thromboembolism carries significant risks of morbidity and mortality. Although recurrence can be prevented by ongoing anticoagulant therapy, treatment is inconvenient and associated with risks of major bleeding. As a consequence, the decision as to whether or not to continue anticoagulants after the first three months of treatment must take into account both potential benefits and potential risks.

Tissue factor and cancer.

Tissue factor (TF), the key regulator of haemostasis and angiogenesis, is also involved in the pathology of several diseases, including cardiovascular, inflammatory and neoplastic conditions. In the latter, TF is upregulated by cancer cells, as well as by certain host cells, and it is the interactions between these distinct pools of TF-expressing cells that likely influence tumour progression in several ways. Furthermore, the release of TF microparticles into the circulation is thought to contribute to the systemic coagulopathies commonly observed in cancer patients.

ER stress and lipogenesis: a slippery slope toward hepatic steatosis.

Endoplasmic reticulum (ER) stress and activation of the unfolded protein response have been linked to many human disorders, including obesity, type 2 diabetes, and cancer. In this issue of Developmental Cell,Rutkowski et al. (2008) show that unresolved ER stress contributes to metabolic dysfunction and hepatic steatosis.

Tissue factor regulation by epidermal growth factor receptor and epithelial-to-mesenchymal transitions: effect on tumor initiation and angiogenesis.

ErbB oncogenes drive the progression of several human cancers. Our study shows that in human carcinoma (A431) and glioma (U373) cells, the oncogenic forms of epidermal growth factor receptor (EGFR; including EGFRvIII) trigger the up-regulation of tissue factor (TF), the transmembrane protein responsible for initiating blood coagulation and signaling through interaction with coagulation factor VIIa. We show that A431 cancer cells in culture exhibit a uniform TF expression profile; however, these same cells in vivo exhibit a heterogeneous TF expression and show signs of E-cadherin inactivation, which is coupled with multilineage (epithelial and mesenchymal) differentiation.

Protective effects of activated protein C in sepsis.

Sepsis remains a complex syndrome associated with significant morbidity and mortality. It is now widely accepted that the pathways of inflammation, coagulation, apoptosis, and endothelial permeability are intimately linked in sepsis pathophysiology. The clinical success of activated protein C (APC), a natural anticoagulant, in reducing mortality in patients with severe sepsis has fuelled basic and preclinical research on the protective effects of this molecule.

Contribution of host-derived tissue factor to tumor neovascularization.

Objective: The role of host-derived tissue factor (TF) in tumor growth, angiogenesis, and metastasis has hitherto been unclear and was investigated in this study.

Methods And Results: We compared tumor growth, vascularity, and responses to cyclophosphamide (CTX) of tumors in wild-type (wt) mice, or in animals with TF levels reduced by 99% (low-TF mice). Global growth rate of 3 different types of transplantable tumors (LLC, B16F1, and ES teratoma) or metastasis were unchanged in low-TF mice.

Gastrointestinal bleeding after acute ischemic stroke.

Objective: Recent studies report that major bleeding is associated with a significant increase in mortality after acute coronary syndrome. Major bleeding has also been reported to be common after ischemic stroke, most often gastrointestinal, but its association with clinical outcome is less certain. We sought to describe the incidence, risk factors, and association with clinical outcomes of gastrointestinal bleeding following acute ischemic stroke.