A comparison of direct thrombin inhibitors in the treatment of heparin-induced thrombocytopenia: a single institution experience

Background and objective Heparin-Induced Thrombocytopenia (HIT), if left untreated, can lead to thrombocytopenia, thromboembolic complications and even death. Two thrombin inhibitors, lepirudin and argatroban, have been shown to improve clinical outcomes compared to historical controls in the management of HIT. The purpose of this retrospective study was to compare the effects of lepirudin and argatroban in the management of HIT. Methods Adult subjects with a positive anti-heparin platelet factor 4 (PF4) antibody test and >50% decrease in platelet count during the first 30 days of admission over a period of 2 years were included in the study. Patient demographics, platelet counts, choice of antithrombin therapy, occurrence of thrombosis, length of hospital stay, and date and cause of death, if applicable, were collected for each patient. Results Eighty-two patients met inclusion criteria: 41 patients did not receive any thrombin inhibitors after the diagnosis of HIT, 24 patients received lepirudin and 17 patients received argatroban. Subjects treated with a thrombin inhibitor were more likely to experience platelet count recovery (87.5% for the lepirudin group and 82.4% for the argatroban group) compared to those who did not receive antithrombin therapy (51.2%) after the diagnosis of HIT was made (P < 0.001). The thrombosis rate for subjects who did not receive antithrombin therapy after the diagnosis of HIT was 26.8%, compared to 8.3% for the lepirudin group and 5.9% for the argatroban group (P < 0.01). The incidence of death was also higher in the group of subjects that did not receive antithrombin therapy (48.8%) compared with the lepirudin group (16.7%) or the argatroban group (23.5%), P < 0.01. Conclusion Our findings suggest that thrombin inhibitors can improve the outcomes of patients with HIT by decreasing the incidence of morbidity and mortality relating to HIT. No significant difference could be determined in outcomes between argatroban and lepirudin therapy.     

Effectiveness and safety of a management protocol to correct over-anticoagulation with oral vitamin K: a retrospective study of 1,043 cases

Background Timely reversal of excessive anticoagulation is important in preventing bleeding complications. The use of vitamin K in correcting over-anticoagulation is widely accepted to be superior to discontinuation of therapy but its effectiveness and safety in large scale cohort studies has not been assessed. Methods According to our protocol, 2 mg of oral vitamin K in addition to omitting the day’s dose of warfarin, were administered to all patients presenting INR levels ≥5.0 and below 10.0; the INR values were checked 20 h after vitamin K administration. The rate of decay of INR, bleeding and thromboembolic complications at presentation and the following 30 days, as well as resistance to warfarin were assessed. Results Of the 1,611 events, 1,043 (878 patients) met the selection criteria. The median (interquartile range) INR was 6.64 (6.12–7.52) at presentation (day zero) and fell to a median (interquartile range) INR of 2.72 (2.18–3.52, P < 0.0001) after the vitamin K administration (day one) and 90.6% of the INRs were below 4.5. In 98 (9.4%) instances the INR values did not fall below the safe limit of 4.5 and in 173 (17%) instances the INR values were overcorrected to below 2.0. Median INR value on day zero in these two groups was higher (7.3 vs. 6.6, P < 0.0001) and lower (6.5 vs. 6.7, P = 0.049) than that of the remaining cases, respectively. Overcorrection occurred more frequently in women (P = 0.0002). Female gender was an independent factor associated with INR overcorrection (P = 0.001; OR = 1.7, 95% CI 1.3–2.3). The INRs on day one were inside, above and below the therapeutic range in 44%, 36% and 20% respectively. Warfarin resistance was observed in six cases (0.6%). Major bleeding was reported in one case (1.1 per 100 patient-years), minor bleeding in 14 cases (16.1 per 100 patient-years) and thromboembolic events in six high risk patients (6.9 per 100 patient-years) during the one month period following vitamin K administration. Conclusions This adopted protocol for the reversal of excessive anticoagulation in asymptomatic or minor symptom presenting patients is easily applied, effective in lowering the INR and preventing complications. Its use in high risk thromboembolic patients warrants caution.     

A comparison of the efficacy and rate of response to oral and intravenous Vitamin K in reversal of over-anticoagulation with warfarin

The role of oral Vitamin K administration in the reversal of anticoagulation is not yet clear because of a paucity of data on the early effects of treatment, apparent differences in efficacy between preparations and a lack of data comparing oral with intravenous administration. We have compared the effects on the International Normalized Ratio (INR) and activities of the Vitamin K-dependent clotting factors II, VII, IX and X at 4 h and 24 h after administration of three oral Vitamin K preparations and of intravenous Vitamin K in 64 anticoagulated patients who required non-urgent partial correction of anticoagulation. Our data confirm that correction of anticoagulation is more rapid after intravenous administration of Vitamin K than after oral administration of similar or larger doses. At 24 h, satisfactory correction of INR can be achieved using low-dose Vitamin K given by either the intravenous or oral route. Our data, and that from previous studies, suggest that there may be differences in efficacy between orally administered products. Administration of Vitamin K by either route was accompanied by changes in the activities of the Vitamin K-dependent clotting factors that reflected their respective biological half-lives. In the 24 h after treatment, the relationship between the INR and the individual Vitamin K-dependent clotting factors was similar to that described previously in stable anticoagulated patients. We conclude that the reversal of anticoagulation with warfarin is achieved more rapidly by intravenous administration of Vitamin K. Satisfactory, but slower, reversal of anticoagulation can be effected using oral Vitamin K, but there may be differences in efficacy between the products tested in our study.     

Use of thromboelastography and thrombin generation assay to predict clinical phenotype in patients with severe FVII deficiency

Bleeding tendency is weakly correlated with the activity of factor VII (FVII) in the plasma of patients with FVII deficiency. A laboratory method for predicting bleeding risk in patients with this coagulation disorder is lacking. We investigated whether global coagulation assays, specifically thromboelastography (TEG) and thrombin generation assay (TGA), could be used to predict bleeding risk. We also sought to identify factors that may explain the differences in bleeding phenotype observed among individuals with severe FVII deficiency. The study comprised 12 patients with severe FVII deficiency (FVII activity <1%). Eleven patients were homozygous for the Gln100Arg mutation and one patient was compound heterozygous. Clinically, 10 patients had increased haemorrhagic diathesis, whereas two patients were asymptomatic. Blood sampling was performed at baseline for TEG and TGA analyses. The platelet aggregation assay was performed and the plasma level of anticoagulation inhibitors and thrombophilic risk factors assessed. No difference in the TEG and TGA results was observed in all FVII‐deficient individuals. The level of free tissue factor pathway inhibitor was within the normal range and similar in symptomatic and asymptomatic subjects. None of the participants had the FV Leiden mutation, prothrombin gene mutation, or abnormal anticoagulant inhibitor levels. Asymptomatic subjects showed normal platelet aggregation. These data suggested that TEG and TGA were not suitable methods for predicting the clinical phenotype in FVII‐deficient subjects.     

Comparison of the anticoagulant effect of a direct thrombin inhibitor and a low molecular weight heparin in an acquired antithrombin deficiency in children with acute lymphoblastic leukaemia treated with L-asparaginase: an in vitro study

Thrombosis occurs in 37% of children with acute lymphoblastic leukaemia (ALL) and is related to an L-asparaginase-induced acquired antithrombin (AT) deficiency. The incidence dictates the need for anticoagulant prophylaxis. Direct thrombin inhibitors (DTI) are independent of AT for effect and may thus have advantages in this population. The objective of this study was to determine the interaction of an AT deficiency with the anticoagulant effects of a DTI and a low molecular weight heparin (LMWH). Plasma samples from children with ALL were pooled (mean AT 0.53 U/ml). LMWH 0.3 and 0.7 U/ml or melagatran 0.3 and 0.5 micromol/l were added to the pools, then divided and AT was added back to one aliquot. In additional experiments, AT was added to AT immuno-depleted plasma. Endogenous thrombin generation capacity (ETGC) was assessed by the continuous method. In plasma with LMWH, there was a 66-88% decrease in ETGC in AT-normalised samples compared with neat. Conversely, no significant difference in ETGC with or without AT added for melagatran was seen. Experiments with AT-depleted plasma showed no effect of AT level on anticoagulant activity of DTI, but a significant relationship for LMWH. By contrast to LMWH, DTI provides a consistent anticoagulant response independent of AT levels in children with AT deficiency.     

Uninterrupted administration of edoxaban vs vitamin K antagonists in patients undergoing atrial fibrillation catheter ablation: Rationale and design of the ELIMINATE‐AF study.

Patients with atrial fibrillation (AF) are at an approximately 0.5% to 3% increased risk of thromboembolism during and immediately after catheter ablation. Treatment guidelines recommend periprocedural oral anticoagulation plus unfractionated heparin during ablation. Rivaroxaban and dabigatran are the only non–vitamin K oral anticoagulants for which there are randomized controlled trials assessing uninterrupted anticoagulation in patients undergoing catheter ablation of AF. Edoxaban, a direct factor Xa inhibitor, is noninferior vs warfarin for the prevention of stroke or systemic embolism with less major bleeding in patients with nonvalvular AF. The ELIMINATE‐AF (Evaluation of Edoxaban Compared With VKA in Subjects Undergoing Catheter Ablation of Nonvalvular Atrial Fibrillation) trial is a multinational, multicenter, prospective, randomized, open‐label, parallel‐group, blinded‐endpoint evaluation (PROBE) study to assess the safety and efficacy of once‐daily edoxaban 60 mg (30 mg in patients indicated for a dose reduction) vs vitamin K antagonists (VKA) in patients with nonvalvular AF undergoing catheter ablation ( http://www.ClinicalTrials.gov : NCT02942576). A total of 560 patients are planned for randomization to edoxaban or VKA (2:1 ratio) to obtain 450 patients fully compliant with the protocol. Patients will complete 21 to 28 days of anticoagulation prior to the ablation and a 90‐day post‐ablation period. The primary efficacy endpoint is the composite of all‐cause death, stroke, and major bleeding. The primary safety endpoint is major bleeding. A magnetic resonance imaging substudy will assess the incidence of silent cerebral lesions post‐ablation. ELIMINATE‐AF will define the efficacy and safety of edoxaban for uninterrupted oral anticoagulation during catheter ablation of AF.     

Dueling for dual inhibition: Means to enhance effectiveness of PI3K/Akt/mTOR inhibitors in AML

The phosphatidylinositol 3-kinase/protein kinase B (Akt)/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathway is amplified in 60–80% of patients with acute myelogenous leukemia (AML). Since this complex pathway is crucial to cell functions such as growth, proliferation, and survival, inhibition of this pathway would be postulated to inhibit leukemia initiation and propagation. Inhibition of the mTORC1 pathway has met with limited success in AML due to multiple resistance mechanisms including direct insensitivity of the mTORC1 complex, feedback activation of the PI3k/Akt signaling network, insulin growth factor-1 (IGF-1) activation of PI3K, and others. This review explores the role of mTOR inhibition in AML, mechanisms of resistance, and means to improve outcomes through use of dual mTORC1/2 inhibitors or dual TORC/PI3K inhibitors. How these inhibitors interface with currently available therapies in AML will require additional preclinical experiments and conduct of well-designed clinical trials.     

Vitamin D deficiency and clinical outcome in patients with chronic heart failure: A review

Aim

The aim of this review was to summarize evidence on the role of Vitamin D deficiency in heart failure (HF), from pathophysiological mechanisms to clinical effects of Vitamin D supplementation.

Vitamin D supplementation in pregnancy and early infancy in relation to gut microbiota composition and C. difficile colonization: implications for viral respiratory infections

ABSTRACT

In Canada and the US, the infant diet is supplemented with vitamin D via supplement drops or formula. Pregnant and nursing mothers often take vitamin D supplements. Since little is known about the impact of this supplementation on infant gut microbiota, we undertook a study to determine the association between maternal and infant vitamin D supplementation, infant gut microbiota composition and Clostridioides difficile colonization in 1,157 mother-infant pairs of the CHILD (Canadian Healthy Infant Longitudinal Development) Cohort Study over 2009–2012. Logistic and MaAsLin regression were employed to assess associations between vitamin D supplementation, and C. difficile colonization, or other gut microbiota, respectively. Sixty-five percent of infants received a vitamin D supplement. Among all infants, infant vitamin D supplementation was associated with a lower abundance of genus Megamonas (q = 0.01) in gut microbiota. Among those exclusively breastfed, maternal prenatal supplementation was associated with lower abundance of Bilophila (q = 0.01) and of Lachnospiraceae (q = 0.02) but higher abundance of Haemophilus (q = 0.02). There were no differences in microbiota composition with vitamin D supplementation among partially and not breastfed infants. Neither infant nor maternal vitamin D supplementation were associated with C. difficile colonization, after adjusting for breastfeeding status and other factors. However, maternal consumption of vitamin-D fortified milk reduced the likelihood of C. difficile colonization in infants (adjustedOR: 0.40, 95% CI: 0.19–0.82). The impact of this compositional difference on later childhood health, especially defense against viral respiratory infection, may go beyond the expected effects of vitamin D supplements and remains to be ascertained.     

Timely reperfusion for ST-segment elevation myocardial infarction:Effect of direct transfer to primary angioplasty on time delays and clinical outcomes

Primary percutaneous coronary intervention(PPCI) is the preferred reperfusion therapy for patients presenting with ST-segment elevation myocardial infarction(STEMI) when it can be performed expeditiously and by experienced operators. In spite of excellent clinical results this technique is associated with longer delays than thrombolysis and this fact may nullify the benefit of selecting this therapeutic option. Several strategies have been proposed to decrease the temporal delays to deliver PPCI. Among them,prehospital diagnosis and direct transfer to the cath lab,by-passing the emergency department of hospitals,has emerged as anattractive way of diminishing delays. The purpose of this review is to address the effect of direct transfer on time delays and clinical events of patients with STEMI treated by PPCI.     

Targeting the PI3K/Akt signaling pathway in pancreatic β‐cells to enhance their survival and function: An emerging therapeutic strategy for type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of the insulin‐producing β‐cells within the pancreas. Islet transplantation represents one cure; however, during islet preparation and post transplantation significant amounts of β‐cell death occur. Therefore, prevention and cure of T1D is dependent upon the preservation of β‐cell function and the prevention of β‐cell death. Phosphoinositide 3‐kinase (PI3K)/Akt signaling represents a promising therapeutic target for T1D due to its pronounced effects on cellular survival, proliferation, and metabolism. A growing amount of evidence indicates that PI3K/Akt signaling is a critical determinant of β‐cell mass and function. Modulation of the PI3K/Akt pathway, directly (via the use of highly specific protein and peptide‐based biologics, excretory/secretory products of parasitic worms, and complex constituents of plant extracts) or indirectly (through microRNA interactions) can regulate the β‐cell processes to ultimately determine the fate of β‐cell mass. An important consideration is the identification of the specific PI3K/Akt pathway modulators that enhance β‐cell function and prevent β‐cell death without inducing excessive β‐cell proliferation, which may carry carcinogenic side effects. Among potential PI3K/Akt pathway agonists, we have identified a novel parasite‐derived protein, termed FhHDM‐1 (Fasciola hepatica helminth defense molecule 1), which efficiently stimulates the PI3K/Akt pathway in β‐cells to enhance function and prevent death without concomitantly inducing proliferation unlike several other identified stimulators of PI3K/Akt signaling . As such, FhHDM‐1 will inform the design of biologics aimed at targeting the PI3K/Akt pathway to prevent/ameliorate not only T1D but also T2D, which is now widely recognized as an inflammatory disease characterized by β‐cell dysfunction and death. This review will explore the modulation of the PI3K/Akt signaling pathway as a novel strategy to enhance β‐cell function and survival.