Prasugrel or double-dose clopidogrel to overcome clopidogrel low-response--the TAILOR (Thrombocytes And IndividuaLization of ORal antiplatelet therapy in percutaneous coronary intervention) randomized trial.

High on-treatment platelet reactivity (HTPR) is associated with poor prognosis in patients undergoing percutaneous coronary intervention (PCI). The antiplatelet effect and safety of prasugrel was compared to that of double-dose clopidogrel in patients with stable coronary artery disease or acute coronary syndrome (ACS) exhibiting HTPR on clopidogrel and treated with PCI, using multiple electrode aggregometry (MEA) to assess platelet reactivity. Of 923 patients screened, 237 (25.7%) exhibited HTPR. Of these, 106 were eligible for participation in a randomized trial comparing two intensified antiplatelet regimen: 52 were assigned to double maintenance-dose clopidogrel and 54 to standard-dose prasugrel. At 1 month, tailoring antiplatelet therapy improved platelet inhibition to a level considered as therapeutic in 73.1% of patients. Prasugrel entailed greater platelet inhibition (p = 0.02) and a lower rate of persisting HTPR at follow-up compared to double-dose clopidogrel (HTPR persisted in 20.4% and 42% respectively, p = 0.02). Within the 30-day follow-up, no major bleeds were observed and the incidence of major adverse cardiovascular events (MACE) was similar in the two treatment arms. Prasugrel demonstrated superiority to double-dose clopidogrel in overcoming HTPR and reducing platelet activity. Intensifying antiplatelet therapy in both ACS and stable angina pectoris (SAP) patients exhibiting HTPR prior to PCI was well tolerated.

Pressure-aided transfusion of platelets: does it affect the platelets?

BACKGROUND: In massively bleeding patients, pressure infusers are used for transfusion of red blood cells and plasma but not for platelets (PLTs) due to an assumed negative effect on the PLTs. This study examined whether pressure-aided in vitro transfusion affected the number, activation state, and/or function of the PLTs as measured by flow cytometry and thrombelastography (TEG). STUDY DESIGN AND METHODS: PLT concentrates stored for 1 (n = 8) or 8 (n = 7) days were transfused in vitro by means of a pressure inducer (300 mmHg). Samples before and after transfusion were measured for PLT concentration and expression of CD62P, CD63, and PAC-1. These activation markers were measured by flow cytometry on resting PLTs as well as PLTs stimulated with thrombin receptor-activating peptide. Clot generation and strength was examined by TEG by measuring the angle (degree) and maximum amplitude (mm), values that are highly dependent on the PLT function. RESULTS: PLT concentrations were unchanged after pressure-aided transfusion reflecting no destruction. With respect to activation state and in vitro functional capacity either no or only minor differences (<7%) were detected. CONCLUSION: In this study, use of a pressure inducer decreased the transfusion time of in vitro PLT transfusion by approximately 50%. No or only minor and inconsistent changes of the PLT number and function were observed. Consequently, this study indicates that pressure infusers could be used for transfusion of PLTs if clinically indicated, that is, in massively bleeding patients. However, in vivo studies to assess the safety and utility of pressure-aided PLT transfusion are warranted.

Studies of variations of the cyclin-dependent kinase inhibitor 1C and the cyclin-dependent kinase 4 genes in relation to type 2 diabetes mellitus and related quantitative traits.

CDK4 is involved in the regulation of body weight, pancreatic beta-cell proliferation, insulin responsiveness, and diabetes pathogenesis. CDK4 activity is inhibited by CDKN1C, which is regulated by insulin. In addition, CDKN1C plays an important role in beta-cell proliferation and is involved in the pathogenesis of the Beckwith-Wiedemann syndrome, a disorder characterized by neonatal hyperinsulinaemic hypoglycaemia and pre- and post-natal overgrowth. The aim of this study was to investigate if variations in the proximal promoter and the coding region of the CDKN1C and CDK4 genes are associated with type 2 diabetes or changes in related quantitative phenotypes among glucose-tolerant subjects. Mutation analyses of the two genes in 62 type 2 diabetic patients resulted in the discovery of seven variants of CDKN1C and two variants of CDK4. In a case-control study comprising 717 type 2 diabetic patients and 518 glucose-tolerant subjects the most frequent variants did not show any difference in allele frequencies between the type 2 diabetic patients and the control subjects. However, in two genotype-quantitative trait correlation studies involving 206 glucose-tolerant offspring of type 2 diabetic patients and 359 young, healthy subjects the CDKN1C del171APVA variant associated with increased birth weight (P=0.05 and P=0.05). Furthermore, the same variant tended to be associated with decreased basal glucose oxidation among 16 genotypically discordant dizygotic twins (P=0.03). In a genotype-quantitative trait study involving 500 middle-aged glucose-tolerant subjects the CDK4 IVS2-31G-->A variant was associated with an increased waist circumference (P=0.03) and waist-to-hip ratio (P=0.02) and altered fasting plasma glucose (P=0.03). However, these later findings could not be replicated in additional studies. In conclusion, variants in CDKN1C may contribute to the inter-individual variation in birth weight.

Hypoglycemia Event Rates: A Comparison Between Real-World Data and Randomized Controlled Trial Populations in Insulin-Treated Diabetes.

INTRODUCTION: Hypoglycemia is the most common adverse effect of diabetes therapy, particularly insulin treatment. Hypoglycemia is associated with considerable clinical and economic burden, and may be under-reported. The aim of this study was to com pare the frequency of hypoglycemic events reported in real-world settings with those reported in clinical trials. METHODS: We conducted a structured literature review in PubMed to identify hypoglycemic event rates in patients with type 1 diabetes mellitus (T1DM) and insulin-treated type 2 diabetes mellitus (T2DM) from real-world data (RWD) and randomized controlled trials (RCTs). The search was restricted to English language, full-text publications from 2010 onwards, reporting on treatment of T1DM or T2DM with basal only, basal-bolus, or premix insulin. RESULTS: The final dataset included 30 studies (11 RWD studies and 19 RCTs). Six studies (RWD, n = 2; RCT, n = 4) reported hypoglycemia event rates in people with T1DM. For all reported categories of hypoglycemia (severe, non-severe, and nocturnal), rates were consistently higher in RWD studies compared with RCTs. Twenty-five studies (RWD, n = 10; RCT, n = 15) reported hypoglycemia event rates in people with insulin-treated T2DM. For T2DM basal-oral therapy; the highest rates were observed in RWD studies, although there was an overlap with RCT rates. For basal-bolus therapy, there was considerable between-study variability but higher rates of severe and non-severe hypoglycemia were generally observed in RWD studies. For T2DM premix insulin, reported rates of hypoglycemia in RWD studies and RCTs were similar. CONCLUSION: We found that higher rates of hypoglycemia are observed in real-world settings compared with clinical trial settings, although there is a large degree of overlap. Due to the inherent constraints of RCTs, they are likely to underestimate the burden of hypoglycemia in clinical practice. Further, high-quality RWD are needed to determine a more accurate incidence of hypoglycemia in clinical practice.

[Liberal red blood cell transfusion may increase mortality].

In addition to the known adverse effects of red blood cell transfusion, evidence suggests that transfusion with allogeneic red blood cells in itself may increase mortality, risk of infection and even cancer recurrence rates. Among possible mechanisms to explain this effect are transfusion-related immune modulation and storage lesions. However, anaemia may also increase mortality and the risk of anaemia should be balanced against the risks of transfusion. Further properly designed and powered studies are needed to clarify the beneficial and harmful effects of red blood cell transfusion in well-defined patient categories.

Hypercoagulability in patients undergoing coronary artery bypass grafting: prevalence, patient characteristics and postoperative outcome.

OBJECTIVES: To investigate the prevalence of preoperative hypercoagulability assessed by thromboelastography (TEG), to identify patient characteristics associated with hypercoagulability and to explore whether hypercoagulability is associated with a greater risk for myocardial infarction (MI), stroke and mortality 30 days after coronary artery bypass grafting (CABG) surgery. METHODS: This is a prospective, observational study of 200 consecutive CABG surgery patients. Hypercoagulability was defined as TEG maximum amplitude >69 mm. RESULTS: Eighty-seven out of 200 (43.5%) CABG patients were TEG-hypercoagulable. In univariate regression analysis, age, female gender, hypertension, severe chronic obstructive pulmonary disease, platelet count and fibrinogen level were significantly associated with TEG-hypercoagulability. Multivariate regression analysis revealed higher age, platelet count and fibrinogen levels as variables independently associated with TEG-hypercoagulability. Thirty-day outcome data: MI (TEG-hypercoagulable 6.9% vs. TEG-normocoagulable 3.7%, NS), stroke (8.0 vs. 2.8%, NS) and mortality (4.6 vs. 0.9%, NS). There was a significant difference in 30-day combined event rate of MI, stroke and mortality (17.2 vs. 6.6%, P = 0.019). In univariate analysis, only female gender and TEG-hypercoagulability were significantly associated with 30-day combined event rate. In multivariate analysis, only female gender was significantly associated with 30-day outcome (P = 0.014), whereas TEG-hypercoagulability demonstrated a trend (P = 0.065). CONCLUSIONS: Hypercoagulability identified by TEG was preoperatively found in 43.5% of CABG patients, and the findings of this study support the notion that TEG-hypercoagulable patients have a higher risk for a combination of thromboembolic complications and death after surgery.

Thrombelastographic haemostatic status and antiplatelet therapy after coronary artery bypass surgery (TEG-CABG trial): assessing and monitoring the antithrombotic effect of clopidogrel and aspirin versus aspirin alone in hypercoagulable patients: study protocol for a randomized controlled trial.

BACKGROUND: Hypercoagulability, assessed by the thrombelastography (TEG) assay, has in several observational studies been associated with an increased risk of post-procedural thromboembolic complications. We hypothesize that intensified antiplatelet therapy with clopidogrel and aspirin, as compared to aspirin alone, will improve saphenous vein graft patency in preoperatively TEG-Hypercoagulable coronary artery bypass surgery (CABG) patients and reduce their risk for thromboembolic complications and death postoperatively. METHODS/DESIGN: This is a prospective randomized clinical trial, with an open-label design with blinded evaluation of graft patency. TEG-Hypercoagulability is defined as a TEG maximum amplitude above 69 mm. Two hundred and fifty TEG-Hypercoagulable patients will be randomized to either an interventional group receiving clopidogrel 75 mg daily for three months (after initial oral bolus of 300 mg) together with aspirin 75 mg or a control group receiving aspirin 75 mg daily alone. Monitoring of antiplatelet efficacy and on-treatment platelet reactivity to clopidogrel and aspirin will be conducted with Multiplate aggregometry. Graft patency will be assessed with Multislice computed tomography (MSCT) at three months after surgery. CONCLUSIONS: The present trial is the first randomized clinical trial to evaluate whether TEG-Hypercoagulable CABG patients will benefit from intensified antiplatelet therapy after surgery. Monitoring of platelet inhibition from instituted antithrombotic therapy will elucidate platelet resistance patterns after CABG surgery. The results could be helpful in redefining how clinicians can evaluate patients preoperatively for their postoperative thromboembolic risk and tailor individualized postoperative antiplatelet therapy. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT01046942.

The influence of low platelet count on whole blood aggregometry assessed by Multiplate.

The Multiplate, a whole blood (WB) platelet function test, has shown promising results identifying patients on antiplatelet therapy at increased risk of rethrombosis. In the present study, the influence of low platelet count on platelet aggregation was analyzed and compared with aggregation results in an artificial matrix, platelet-rich plasma (PRP). Heparinized and citrated blood was diluted with autologous plasma to platelet concentrations 200 to 25 × 10(9)/L in WB samples (n = 10) and 200 to 100 × 10(9)/L in PRP samples (n = 7). The platelet aggregation was investigated by the ADP-, ASPI-, COL-, and TRAP-test. The WB responses decreased at platelet concentration of ≤100 × 10(9)/L (all P < .03), except for heparin-TRAP (50 × 10(9)/L, P = .008) and citrate-ASPI (150 × 10(9)/L, P = .03). In general, WB samples demonstrated higher aggregation than PRP samples at platelet concentrations 200 to 100 × 10(9)/L (P < .05). In conclusion, platelet concentration of <150 × 10(9)/L may influence Multiplate which should be considered in clinical settings. Furthermore, the findings emphasize the importance of evaluating haemostasis in its natural matrix, WB.

Thrombelastography and tromboelastometry in assessing coagulopathy in trauma.

Death due to trauma is the leading cause of lost life years worldwide, with haemorrhage being responsible for 30-40% of trauma mortality and accounting for almost 50% of the deaths the initial 24 h. On admission, 25-35% of trauma patients present with coagulopathy, which is associated with a several-fold increase in morbidity and mortality. The recent introduction of haemostatic control resuscitation along with emerging understanding of acute post-traumatic coagulability, are important means to improve therapy and outcome in exsanguinating trauma patients. This change in therapy has emphasized the urgent need for adequate haemostatic assays to monitor traumatic coagulopathy and guide therapy. Based on the cell-based model of haemostasis, there is emerging consensus that plasma-based routine coagulation tests (RCoT), like prothrombin time (PT) and activated partial thromboplastin time (APTT), are inappropriate for monitoring coagulopathy and guide therapy in trauma. The necessity to analyze whole blood to accurately identify relevant coagulopathies, has led to a revival of the interest in viscoelastic haemostatic assays (VHA) such as Thromboelastography (TEG) and Rotation Thromboelastometry (ROTEM). Clinical studies including about 5000 surgical and/or trauma patients have reported on the benefit of using the VHA as compared to plasma-based assays, to identify coagulopathy and guide therapy. This article reviews the basic principles of VHA, the correlation between the VHA whole blood clot formation in accordance with the cell-based model of haemostasis, the current use of VHA-guided therapy in trauma and massive transfusion (haemostatic control resuscitation), limitations of VHA and future perspectives of this assay in trauma.