Platelet function in diabetes mellitus : studies on postprandial platelet activation and aspirin treatment

Diabetes mellitus (DM) is a prothrombotic disease which is associated with a high risk for cardiovascular events, especially in type 2 DM (T2DM). The aim of this work is to contribute to the improvement of cardiovascular risk in DM. Patients with DM have reduced responses to antiplatelet treatment with aspirin, perhaps due to an increased platelet turnover, and this is associated with a poor outcome. Postprandial hyperglycemia is an independent risk factor for cardiovascular complications. We compared the laboratory responses to twice daily dosing of aspirin 75 mg, the regular once daily dose of 75 mg or a higher once daily dose of 320 mg in an open cross-over study in 25 patients with T2DM and micro/macrovascular complications, We found an improved response to 75 mg twice daily as compared to both once daily doses using two whole blood methods; impedance platelet aggregometry and the IMPACT-R cone and platelet analyzer. Both patients with a high and low platelet turnover could benefit from twice daily dose of aspirin. The role of postprandial hyperglycemia in postprandial platelet activation was examined in a randomized cross-over study comparing premeal insulin (0.1 and 0.2 U/kg insulin aspart) and placebo in 18 patients with T2DM. Platelet activation was studied in the fasting state, before and after normalizing glucose levels, and 90 min after a carbohydrate rich meal. Although postprandial glucose levels decreased after insulin injection, platelet activation increased. Glucose normalization with IV insulin aspart before the meal also resulted in platelet activation mainly via the thromboxane pathway as studied with the thromboxane analogue U46619 using flow cytometry. The postprandial platelet activation was correlated directly to insulin levels and inversely to glucose levels. We therefore concluded that postprandial platelet activation in T2DM is related to insulin rather than to glucose levels. The role of insulin in postprandial platelet activation was further investigated by comparing T1DM (n=11) and T2DM (n=9), without premeal insulin before and after a carbohydrate rich meal. T1DM patients, who had very high postprandial glucose levels due to inability to secrete insulin, had no platelet activation after the meal. These findings further support the role of insulin in postprandial platelet activation. Microparticles derived from platelets, monocytes and endothelial cells were formed after a carbohydrate meal in both patients with T1DM and T2DM in the above study. The microparticles had a prothrombotic potential (thrombin generation assay) which was related to phosphatidylserine and not to tissue factor expression. As opposed to the importance of insulin in postprandial platelet activation seen in T2DM, the procoagulant microparticles increased similarly or even more in T1DM. Therefore microparticle release may be related to hyperglycemia rather than hyperinsulinemia. This work suggests that twice daily dosing can improve the response to low-dose aspirin treatment in T2DM which might improve cardiovascular prognosis, and that liberal usage of premeal insulin may not benefit patients with T2DM as it contributes to postprandial platelet activation, and insulin treatment has been related to increased cardiovascular risk in DM. Postprandial platelet activation does not occur without premeal insulin in T1DM but should also be studied after insulin. Prothrombotic microparticle release however occurs in both T1DM and T2DM after the meal

Exacerbation of immune thrombocytopenia following initial and booster vaccination with Pfizer-BioNTech COVID-19 vaccine

As the immune thrombocytopenia exacerbation rate after booster COVID-19 vaccines is unknown, we explore the rates after first, second and booster Pfizer-BioNTech COVID-19 vaccines. A retrospective study of adult ITP patients, receiving 1–3 vaccines was performed. The primary outcome was clinical ITP exacerbation defined as platelet count decrease requiring initiation/escalation of ITP treatment and/or new medical attention due to bleeding, within 3 months. Secondary outcome was any clinically relevant platelet decrease during the 3 months post-vaccination. The study included 93 ITP patients receiving 1 (n = 2), 2 (n = 22) or 3 (n = 69) vaccines. ITP exacerbation occurred in 2/93 (2.2%) patients following initial vaccination and in 3/69 (4.3%) following booster dose. Clinically relevant platelet decreases after initial doses occurred in 8/72 (11.1%) patients and in 8/39 (20.5%) after the booster. Clinical ITP exacerbation after booster doses did not follow clinical exacerbation after initial doses. Half of patients with clinically relevant platelet decreases after booster dose also had clinically relevant decreases following initial vaccination. We concluded that clinical ITP exacerbation is infrequent following Pfizer-BioNTech COVID-19 vaccine. Clinical exacerbation after booster doses was not preceded by clinical exacerbation after initial doses. Clinically relevant platelet decreases after booster doses occur frequently in patients with clinically relevant decreases after initial doses

Meal intake increases circulating procoagulant microparticles in patients with type 1 and type 2 diabetes mellitus

Diabetes mellitus (DM) is associated with prothrombotic alterations, and postprandial hyperglycemia is an independent risk factor for cardiovascular complications. We therefore investigated whether a standardized mixed meal alters circulating microparticles (MPs) and their procoagulant activity in DM patients. Patients with DM type 1 (T1DM, n = 11) and type 2 (T2DM; n = 9) were studied before and 90 min after a standardized meal (without premeal insulin). MPs in plasma derived from platelets (PMPs), endothelial cells (EMPs), or monocytes (MMPs) were measured by flow cytometry. MP-induced thrombin generation in plasma was assessed by a calibrated automated thrombogram. In the fasting state, MPs did not differ significantly between T1DM and T2DM. Meal intake increased the following microparticles: PMPs expressing phosphatidylserine (by 55%, on average), P-selectin (by 86%), and tissue factor (TF; by 112%); EMPs expressing E-selectin (by 96%) and MMPs expressing TF (by 164%), with no significant group differences between T1DM and T2DM. There were no increments in EMPs expressing phosphatidylserine or TF. Meal intake increased MP-induced thrombin generation similarly in T1DM and T2DM with increased endogenous thrombin potential (p = 0.02) and peak thrombin (p = 0.03) and shortened time to peak (p = 0.02). Phosphatidylserine inhibition by lactadherin completely abolished MP-induced thrombin generation, while an anti-TF antibody had no effect. In conclusion, meal intake increased several types of circulating MPs in patients with diabetes mellitus. These MPs have a procoagulant potential, which is related to phosphatidylserine expression and negatively charged MP surfaces rather than to TF

Cancer‐associated venous thromboembolism in Israel: Incidence, risk factors, treatment, and health care utilization in a population based cohort study

Abstract Background Recent international guidelines recommend thromboprophylaxis in patients with cancer at intermediate‐high venous thromboembolism (VTE) risk. Objectives We aimed to assess the current incidence, risk factors and management of cancer‐associated VTE and associated health care resource utilization in a 2.5‐million‐member state‐mandated health service in Israel. Methods Patients aged ≥18 years with newly diagnosed cancer, initiating systemic anticancer treatment from 2010 through 2018 were identified from the Israel National Cancer Registry. The index date was fixed as the first day of systemic anticancer treatment. The cumulative VTE incidence from the first day of systemic anticancer treatment and the respective hazard ratios for VTE risk factors were calculated at 12 months of follow‐up. Health care resource utilization (primary care physician, emergency room, and hospital visits) during the study period was compared between patients with and without VTE. Results A total of 15 388 patients were included, and 338 had VTE with a 12‐month cumulative incidence of 2.2% (95% confidence interval, 1.96%‐2.43%). In a multivariable model, older age, higher comorbidity index, intermediate‐high‐risk Khorana score, certain malignancy types, and chemotherapy were significantly associated with an increased VTE risk in the year after initiating anticancer treatment. Compared with matched controls, the VTE subcohort were more likely to be hospitalized (81.4% vs 35.2%), have longer hospital stays (20.1 days vs 13.1 days), have an emergency room visit (41.5% vs 19.3%), and have a larger number of primary care physician visits (17.6 vs 12.5). Conclusion Several risk factors, including the Khorana score, were associated with VTE incidence. VTE was associated with long‐term use of anticoagulation. Health care utilization was higher in patients with VTE

Outcome of Elderly Patients with Venous Thromboembolism Treated with Direct Oral Anticoagulants—A Retrospective Cohort Study

Introduction: Randomized controlled trials that compared direct oral anticoagulants (DOACs) to vitamin K antagonists (VKA) for the treatment of venous thromboembolism (VTE), demonstrated both efficacy and safety of DOACs. The aim of the current study was to compare DOACs to VKA for the treatment of VTE in the elderly, in a real-life setting. Methods: A retrospective cohort study was performed in Rabin Medical Center encompassing a 7-year period. Hospitalized patients >65 years, with a diagnosis of VTE discharged with DOACs or VKA were included. The primary outcome was a composite of all-cause mortality, major bleeding, recurrent VTEs and hospitalizations throughout the follow-up period of one year. Results: A total of 603 patients were included in the final analysis. The mean age was 79.6 ± 8.5 years. The primary composite outcome occurred in 74.6% and 56.7% of the patients in the VKA group and DOACs group, respectively, hazard ratio 0.59, 95% confidence interval 0.46 to 0.76, in favor of the DOACs group. In a matched cohort analysis, the results were the same as the original analysis. Conclusion: In the elderly population, treatment of VTE with DOACs was associated with a lower rate of the composite outcome. DOACs are safe and effective for elderly patients with VTE