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Introduction: Oral anticoagulant drugs reduce the risk of stroke associated with atrial fibrillation. Vitamin K antagonists, gold standard therapy for decades, have been deposed by the direct oral anticoagulants that exhibit superior safety profiles. However, hemorrhagic complications remain a major concern to anticoagulation., Areas Covered: We searched available data in the literature to review the current knowledge on the safety profiles of available anticoagulants., Expert Opinion: Despite a relevant leap forward with the introduction of DOACs, safety concerns persist in some fields of the current pharmacotherapy for stroke prevention in atrial fibrillation. In-depth knowledge of the safety profile of available anticoagulants and dealing with safety issues in patient subgroups is of utmost importance. Bleeding risk scores should not be dichotomously used to decide anticoagulation treatment but rather to promote shared decision, identify and correct modifiable risk factors, and set monitoring frequency. Additional issues that wait to be investigated in order to improve the safety of therapy include circulating levels of direct oral anticoagulants and anticoagulation in patient sub-groups: very elderly, frail, those with advanced kidney or liver disease, and so on. Safety may be improved from the in-depth knowledge of safety concerns and therapeutic options.

Aim: To clarify whether the activities of multiple CYPs associated with warfarin metabolism would be correlated with each other., Methods: Oral clearances (CLpo) of warfarin enantiomers were estimated in 378 Chinese, Caucasians and African-Americans. The partial metabolic clearances (CLm) for 7-hydroxywarfarin enantiomers were also measured. In addition, CLpo and CLm were determined in a patient on warfarin and rifampicin., Results: Correlations between CLpo for warfarin enantiomers existed across the three populations. In addition, there was a significant correlation between the CLm for 7-hydroxylation of warfarin enantiomers. Under induced conditions by rifampicin, there were significant correlations between the enantio- and regio-selective metabolisms of warfarin., Conclusion: Metabolic activities of CYP2C9, CYP1A2 and CYP3A4 may be regulated by common transcriptional mechanism(s).

The term "lupus anticoagulant" (LA) refers to a heterogeneous group of immunoglobulins behaving as acquired in vitro inhibitors of coagulation. These antibodies, namely anti-β2GPI and anti-prothrombin antibodies, induce the in vitro elongation of clotting time interfering with phospholipid-dependent coagulation cofactors. Positive LA is associated with thrombosis and pregnancy complications, providing one of the three laboratory criteria for the classification of the anti-phospholipid syndrome. LA is the strongest predictor of clinical events, especially when associated with other anti-phospholipid antibodies. Much more controversial is the risk conveyed by isolated and weak LA. LA detection is technically laborious, envisaging screening, mixing and confirming tests. Hopefully critical issues in LA detection, such as the interference of anticoagulants, will be overcome, in the next future.

Introduction: Oral anticoagulation (OAC) is given for ischemic stroke prevention in patients with nonvalvular atrial fibrillation. OAC's most serious complications are major bleeding and, in particular, hemorrhagic stroke. Together with vitamin K antagonists (VKAs), direct oral anticoagulants (DOAC) are now available which have a more rapid onset/offset of action and more predictable anticoagulant effect. The advent of DOAC has given to the clinician an opportunity to tailor OAC therapy in order to maximize advantages and minimize complications., Areas Covered: This review covers data published in literature regarding the risk of hemorrhagic stroke in patients taking OAC. Bleeding risk assessment is discussed and different bleeding risk factors are presented. The paper will also review clinical studies comparing DOAC against standard anticoagulation, in regard to the risk of hemorrhagic stroke., Expert Opinion: Bleeding assessment is mandatory in order to select patients at high hemorrhagic risk who will benefit the most from close monitoring. Blood pressure, alcohol intake, concomitant medication and comorbidities should be constantly evaluated and treated accordingly. During VKA therapy, adherence and intensity of anticoagulation must be strictly monitored. DOAC are associated with lower risk of hemorrhagic stroke than VKA. However, periodic hepatic and renal checks as well as careful evaluation of time adherence are necessary to reduce the risk of bleeding.

Introduction: The introduction of novel anticoagulants has had contrasting effects on the agents in the pipeline, fueling the development of some and sinking the others. The complexity of the coagulation cascade offers interesting inhibition choices that might become valid treatment options., Areas Covered: This review will highlight some of the anticoagulants in the pipeline. Following the success of the direct thrombin and FXa inhibitors already in the market, new agents are being tested. These include AZD0837, betrixaban, letaxaban, darexaban, and LY517717. Targeting other components of the hemostatic pathway might lead to better safety profiles without influencing efficacy. Inhibitors to FVIIa-tissue factor (FVIIa/TF) complex, FIX, FXI, and FXII are being assessed. New inspiring inhibitors are antisense oligonucleotides (ASOs) and aptamers. These are highly specific agents with readily reversible effect and might be engineered to inhibit any coagulation factor. Currently tested ASOs and aptamers are inhibitors of FXI, FXII, thrombin, FIXa, and platelet GPIV., Expert Opinion: Some of the agents in the pipeline offer valid treatment option for long-term therapy, overcoming some of the drawbacks of the novel anticoagulants. Research is being driven by an expanding market in the anticoagulation field that has been unexploited for a long time.

Introduction: Currently used anticoagulants such as unfractionated heparin, low-molecular-weight heparin and vitamin K antagonists, have several drawbacks, mostly related to safety. In this review, we will briefly discuss and compare the safety of anticoagulation therapy with 'old' and new agents., Areas Covered: Safety issues with anticoagulation therapy are mostly related to bleeding. The intensity of anticoagulation is related to the risk of bleeding and thus, for the efficacy not to be affected, must be maintained at the lower effective intensity. Several improvements have been made in the management of anticoagulation therapy; these include monitoring, pathology-based treatment schemes taking into account patient characteristics, patient education and the introduction of anticoagulation centers. Safety of novel anticoagulants is encouraging., Expert Opinion: Novel agents have the potential to compete with existing therapy for thromboprophylaxis, treatment and stroke prevention in atrial fibrillation. Promising results have emerged from trials comparing them with existing treatment. Not long from now we will see these new agents in the armamentarium of antithrombotic drugs.

Introduction: Thromboembolic disease encompasses a spectrum of conditions extending from deep vein thrombosis to stroke and myocardial infarction. The current anticoagulation therapy is cumbersome and characterized by several important drawbacks., Areas Covered: Existing treatments and latest breakthroughs on emerging anticoagulants are presented. Oral and parenteral novel anticoagulants are being developed and tested for efficacy and safety and results are being published regularly. The introduction of novel anticoagulants marks a new era in the management of anticoagulated patients. It is important for the healthcare provider to understand the benefits and risks of the armamentarium of anticoagulants that will be available in the very near future. The critical conclusions drawn will help the reader look past what is the most highlighted feature of the new anticoagulantion era: the non-necessity for monitoring., Expert Opinion: Currently, novel anticoagulants seem to lack the indefinable 'charm' of weakness. However, important questions remain unanswered and will require in-depth evaluations.

Aim: A total of 371 patients under stable warfarin therapy were retrospectively selected to develop a pharmacogenetic algorithm to identify the individual maintenance dose., Materials & Methods: The variables that were entered into the algorithm were: VKORC1, CYP2C9 and CYP4F2 polymorphisms, body surface area and age., Results: The percentage of cases whose predicted mean weekly warfarin dose was within 20% of the actual maintenance dose was 51.8% considering patients overall, and were 36.2, 66.2 and 55.4%, respectively, taking into account patients requiring low (≤25 mg/week), intermediate (25-45 mg/week) and high (≥45 mg/week) doses. The algorithm could correctly assign 73.8 and 63.2% of patients to the low- and high-dose regimens, respectively. We developed and validated a pharmacogenetic algorithm in a series of Italian patients, we then tested, in the same series of italian patients, the formulas of three published algorithms. These three algorithms were developed and validated by their authors in a series of patients different from our own. The performance of our algorithm in our patients series was slightly higher than that achieved when using the three other algorithms in our patients series., Conclusion: The high predictive accuracy of low and high warfarin requirements of our algorithm warrants its application in prospective studies for clinical validation.

Anti-beta2-Glycoprotein I (beta2GPI) autoantibodies are the prominent laboratory feature of Hughes syndrome. By prolonging some coagulation tests in the presence of exogenous phospholipids (PL), they behave as classical Lupus Anticoagulants (LA). We investigated the effect of 3 affinity-purified anti-beta2GPI IgG preparations from patients with Hughes syndrome on fibrin polymerization and fibrinolysis of normal plasma, measured by comparing the optical densities of assay mixtures in the presence of the autoantibodies or normal IgG. The presence of anti-beta2GPI IgG in diluted Russell Viper Venom Time (dRVVT) assays, carried out using a PL dilution of 1:8 or 1:64, resulted in a delay in the onset of polymerization by 30-40 and 60-70s, respectively. Fibrin polymerization was complete after 250s for both anti-beta2GPI IgG and normal IgG. The inhibitory effect of the anti-beta2GPI antibodies was not observed in the presence of excess PL, as expected for LA. Anti-beta2GPI IgG increased the plateau level of polymerization when dRVVT was performed in the presence of 1.5 nM recombinant tissue plasminogen activator, but did not impair the fibrinolytic process, which was almost complete after 250 min. The autoantibodies did not delay the onset of fibrin polymerization in tests carried out using recombinant tissue factor. On the contrary, the autoantibodies enhanced polymerization in prothrombin time assays, and accelerated it in tissue thromboplastin inhibition tests, with no effect on fibrinolysis. These data provide evidence that anti-beta2GPI LA may act as either anticoagulants or procoagulants in different in vitro coagulation tests.