Microvascular Thrombosis as a Critical Factor in Severe COVID-19.

Platelet-endothelial interactions have a critical role in microcirculatory function, which maintains tissue homeostasis. The subtle equilibrium between platelets and the vessel wall is disturbed by the coronavirus disease 2019 (COVID-19), which affects all three components of Virchow's triad (endothelial injury, stasis and a hypercoagulable state). Endotheliitis, vasculitis, glycocalyx degradation, alterations in blood flow and viscosity, neutrophil extracellular trap formation and microparticle shedding are only few pathomechanisms contributing to endothelial damage and microthrombosis resulting in capillary plugging and tissue ischemia. In the following opinion paper, we discuss major pathological processes leading to microvascular endothelial activation and thrombosis formation as a possible major adverse factor driving the deterioration of patient disease course in severe COVID-19.

Protease-activated receptor-mediated platelet aggregation in patients with type 2 diabetes on potent P2Y12 inhibitors.

BACKGROUND: Antiplatelet therapy is a cornerstone in the secondary prevention of ischemic events following percutaneous coronary intervention (PCI). The new P2Y12 receptor inhibitors prasugrel and ticagrelor have been shown to improve patients' outcomes. Whether or not these drugs have equal efficacy in individuals with or without diabetes is disputed. Furthermore, platelets can be activated by thrombin, which is, at least in part, independent of P2Y12 -mediated platelet activation. Protease-activated receptor (PAR)-1 and -4 are thrombin receptors on human platelets. We sought to compare the in vitro efficacy of prasugrel (n = 121) and ticagrelor (n = 99) to inhibit PAR-mediated platelet aggregation in individuals with type 2 diabetes (prasugrel n = 26, ticagrelor n = 29). MATERIALS AND METHODS: We compared P2Y12 -, PAR-1- and PAR-4-mediated platelet aggregation as assessed by multiple electrode platelet aggregometry between prasugrel- and ticagrelor-treated patients without and with type 2 diabetes who underwent acute PCI. RESULTS: Overall, there were no differences of P2Y12 -, PAR-1- and PAR-4-mediated platelet aggregation between prasugrel- and ticagrelor-treated patients. However, both drugs inhibited P2Y12 -mediated platelet aggregation stronger, and thereby to a similar extent in patients with type 2 diabetes than in those without diabetes. There was no correlation between either P2Y12 -, or PAR-1- or PAR-4-mediated platelet aggregation and levels of HbA1c or the body mass index (BMI). However, we observed patients with high residual platelet reactivity in response to PAR-1 and PAR-4 stimulation in all cohorts. CONCLUSION: Prasugrel and ticagrelor inhibit P2Y12 - and PAR-mediated platelet aggregation in individuals with diabetes to a similar extent, irrespective of HbA1c levels and BMI.

Toll-like Receptors as Pro-Thrombotic Drivers in Viral Infections: A Narrative Review.

Toll-like receptors (TLRs) have a critical role in the pathogenesis and disease course of viral infections. The induced pro-inflammatory responses result in the disturbance of the endovascular surface layer and impair vascular homeostasis. The injury of the vessel wall further promotes pro-thrombotic and pro-coagulatory processes, eventually leading to micro-vessel plugging and tissue necrosis. Moreover, TLRs have a direct role in the sensing of viruses and platelet activation. TLR-mediated upregulation of von Willebrand factor release and neutrophil, as well as macrophage extra-cellular trap formation, further contribute to (micro-) thrombotic processes during inflammation. The following review focuses on TLR signaling pathways of TLRs expressed in humans provoking pro-thrombotic responses, which determine patient outcome during viral infections, especially in those with cardiovascular diseases.

Low-density lipoprotein cholesterol reduction with immediate combination therapy of statin and ezetimibe compared to statin monotherapy after percutaneous coronary intervention.

BACKGROUND: Current guidelines recommend a stepwise initiation of lipid-lowering therapy after percutaneous coronary interventions (PCI) in treatment-naïve individuals. Patients might benefit from an earlier and stronger low-density lipoprotein-cholesterol (LDL-C) reduction through upfront combination therapies. METHODS: This retrospective study included patients without previous lipid-lowering therapy undergoing acute or elective PCI with stent implantation between January 2016 and December 2019. Patients initiated on statin monotherapy vs. a combination of statin and ezetimibe were compared. The primary endpoint was an LDL­C reduction into the target range of < 55 mg/dL at 3 months. The secondary endpoint was the occurrence of major cardiovascular events (MACE). RESULTS: A total of 204 lipid-lowering therapy naive patients were included, of whom 157 (77.0%) received statin monotherapy and 47 (23.0%) combination therapy. Median LDL­C levels were higher in patients initiated on combination therapy vs. monotherapy (140 mg/dL, interquartile range, IQR, 123-167 mg/dL vs. 102 mg/dL, IQR 80-136 mg/dL, p < 0.001). The LDL­C reduction was greater in patients treated with combination therapy vs. statin monotherapy (-73 mg/dL, -52.1% vs. -43 mg/dL, -42.2%, p < 0.001). While the primary endpoint was similar between groups (44.7% vs. 36.1%, p = 0.275), combination therapy significantly increased the proportion of patients achieving the treatment target in the presence of an admission LDL-C > 120 mg/dL (46.2% vs. 26.2%, p = 0.031). The rates of MACE were similar between the two groups (10.6% vs. 17.8%, p = 0.237) at a median follow-up of 2.2 years, IQR 1.46-3.10 years. CONCLUSION: Immediate initiation of high-intensity statin and ezetimibe treatment might be considered as the default strategy in treatment-naïve patients with high admission LDL­C undergoing PCI.

Impact of body size on platelet function in patients with acute coronary syndrome on dual antiplatelet therapy.

INTRODUCTION: Patients undergoing acute percutaneous coronary intervention receive dual antiplatelet therapy for secondary prevention. Recurrent myocardial infarction or bleedings are possibly due to under- or overdosing of antiplatelet therapy in relation to body size. METHODS: We correlated residual platelet aggregation with body mass index, body surface area, lean body mass and blood volume in 220 patients on prasugrel (n = 121) or ticagrelor (n = 99). RESULTS: Platelet aggregation outside the recommended window was recorded in 85 patients, but not correlated with any of the body indices. CONCLUSION: Body size does not affect platelet response to prasugrel or ticagrelor at the guideline-recommended fixed dosages.

Short dual antiplatelet therapy and dual antiplatelet therapy de-escalation after primary percutaneous intervention: For whom and how.

Dual antiplatelet therapy (DAPT) for 6-12 months, followed by lifelong aspirin monotherapy is considered an effective standard therapy for the prevention of thrombo-ischemic events in patients with acute and chronic coronary syndrome (ACS, CCS) undergoing percutaneous coronary intervention (PCI) or after a primarily conservative treatment decision. In ACS patients, the stronger P2Y12-inhibitors ticagrelor or prasugrel are recommended in combination with aspirin unless the individual bleeding risk is high and shortening of DAPT is warranted or clopidogrel is preferred. However, also in patients at low individual bleeding risk, DAPT is associated with a higher risk of bleeding. In recent years, new antithrombotic treatment strategies, such as shortening DAPT followed by early P2Y12-inhibitor monotherapy and de-escalating DAPT from potent P2Y12-inhibitors to clopidogrel by maintaining DAPT duration time, have been investigated in clinical trials and shown to reduce bleeding complications in cardiovascular high-risk patients without negative effects on ischemic events. In this review, we summarize the current knowledge and discuss its implication on future antithrombotic strategies in terms of a personalized medicine.

Protease-activated receptor-mediated platelet aggregation in acute coronary syndrome patients on potent P2Y12 inhibitors.

BACKGROUND: Despite the increasing use of potent P2Y12 inhibitors, further atherothrombotic events still impair the prognosis of many acute coronary syndrome (ACS) patients. This may in part be attributable to intact platelet aggregation via the human thrombin receptors protease-activated receptor (PAR)-1 and PAR-4. OBJECTIVE: We studied PAR mediated platelet aggregation in ACS patients following percutaneous coronary intervention (PCI) with stent implantation in a cross-sectional study. METHODS: Platelet aggregation to ADP as well as to the PAR-1 agonist SFLLRN and the PAR-4 agonist AYPGKF was assessed by multiple electrode aggregometry in 194 ACS patients on dual antiplatelet therapy with aspirin and either prasugrel (n = 114) or ticagrelor (n = 80) 3 days after PCI. RESULTS: Based on the consensus cutoff value, high on-treatment residual platelet reactivity to ADP (HRPR ADP) was observed in only 2 prasugrel-treated patients. Both patients with HRPR ADP had also a normal response to SFLLRN and AYPGKF. Among the 112 prasugrel-treated patients with adequate P2Y12 inhibition, 50 patients (45%) still had a normal response to SFLLRN, and 70 patients (63%) still had a normal response to AYPGKF. Among the 80 ticagrelor-treated patients with adequate P2Y12 inhibition, 25 patients (31%) still had a normal response to SFLLRN, and 50 (63%) still had a normal response to AYPGKF. CONCLUSION: Normal platelet aggregation via PAR-1 and PAR-4 is preserved in many patients with adequate P2Y12 inhibition by prasugrel and ticagrelor. The present findings may at least in part explain adverse ischemic events despite potent P2Y12 inhibition.