PCSK9 as a Positive Modulator of Platelet Activation

Camera, Marina; Rossetti, Laura; Barbieri, Silvia Stella; Zanotti, Ilaria; Canciani, Barbara; Trabattoni, Daniela; Ruscica, Massimiliano; Tremoli, Elena; Ferri, Nicola

doi:10.1016/j.jacc.2017.11.069

Cited by 70 publications

(84 citation statements)

References 4 publications

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“…The relative risk of major vascular events was similar for all drug classes (statins, bile acid sequestrants, ezetimibe, and fibrates), and the lower achieved LDL C levels (not percentage reductions) were associated with a reduced incidence of major CV events (8). As recently reported in a meta-analysis and meta-regression analysis of 34 primary and secondary prevention trials of intensive (136,299 patients) vs less intensive (133,989 patients) LDL lowering therapy (statins, ezetimibe and PCSK9 inhibitors) clear differences were detected in patients who benefitted most from LDL lowering. In terms of risk reduction of total and CV mortality, myocardial infarction (MI), revascularization, and major adverse cardiac events (MACE), patients with baseline LDL-C  100mg/dL and receiving the more intensive treatment had the greatest benefit (9,10).…”

Section: Low-density Lipoproteinsmentioning

confidence: 52%

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Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

et al. 2018

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Inflammatory changes are responsible for maintenance of the atherosclerotic process and may underlie some of the most feared vascular complications. Among the multiple mechanisms of inflammation, the arterial deposition of lipids and particularly of cholesterol crystals is the one responsible for the activation of inflammasome NLRP3, followed by the rise of circulating markers, mainly C-reactive protein (CRP). Elevation of lipoproteins, LDL but also VLDL and remnants, associates with increased inflammatory changes and coronary risk. Lipid lowering medications can reduce cholesterolemia and CRP: patients with elevations of both are at greatest cardiovascular (CV) risk and receive maximum benefit from therapy. Evaluation of the major drug series indicates that statins exert the largest LDL and CRP reduction, accompanied by reduced CV events. Other drugs, mainly active on the triglyceride/HDL axis, for example, PPAR agonists, may improve CRP and the lipid pattern, especially in patients with metabolic syndrome. PCSK9 antagonists, the newest most potent medications, do not induce significant changes in inflammatory markers, but patients with the highest baseline CRP levels show the best CV risk reduction. Parallel evaluation of lipids and inflammatory changes clearly indicates a significant link, both guiding to patients at highest risk, and to the best pharmacological approach. Key messages Lipid lowering agents with "pleiotropic" effects provide a more effective approach to CV prevention In CANTOS study, patients achieving on-treatment hsCRP concentrations ≤2 mg/L had a higher benefit in terms of reduction in major CV events The anti-inflammatory activity of PCSK9 antagonists appears to be of a minimal extent.

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Section: Low-density Lipoproteinsmentioning

confidence: 52%

“…PCSK9 circulating levels have been related to a large number of CVD risk factors, i.e. LDLcholesterolemia (128), TGs (129), Lp(a) (130), atherogenic lipoproteins(131), arterial stiffness(132), and platelet activation(133). Moreover, a significant proportion of plasma PCSK9 (20-40%) circulates bound to lipoproteins, i.e.…”

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confidence: 99%

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

et al. 2018

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“…It has been recently shown that in primary hypercholesterolemia the in vivo treatment with PCSK9 inhibitors, beyond their lipid-lowering action, had important inhibitory effects on platelet aggregation and activation [129]. Given the activating direct effect of PCSK9 on platelets [195] and the relationship between PCSK9 and higher platelet reactivity [196][197][198], it is plausible that PCSK9 can directly influence platelet reactivity, thus PCSK9 inhibitors also would reduce the direct PCSK9 stimulatory effects on platelets.…”

Section: Role Of Dyslipidemia In the Impaired Platelet Reactivitymentioning

confidence: 99%

Influence of Cardiometabolic Risk Factors on Platelet Function

Barale

Russo

2020

IJMS

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Platelets are key players in the thrombotic processes. The alterations of platelet function due to the occurrence of metabolic disorders contribute to an increased trend to thrombus formation and arterial occlusion, thus playing a major role in the increased risk of atherothrombotic events in patients with cardiometabolic risk factors. Several lines of evidence strongly correlate metabolic disorders such as obesity, a classical condition of insulin resistance, dyslipidemia, and impaired glucose homeostasis with cardiovascular diseases. The presence of these clinical features together with hypertension and disturbed microhemorrheology are responsible for the prothrombotic tendency due, at least partially, to platelet hyperaggregability and hyperactivation. A number of clinical platelet markers are elevated in obese and type 2 diabetes (T2DM) patients, including the mean platelet volume, circulating levels of platelet microparticles, oxidation products, platelet-derived soluble P-selectin and CD40L, thus contributing to an intersection between obesity, inflammation, and thrombosis. In subjects with insulin resistance and T2DM some defects depend on a reduced sensitivity to mediators-such as nitric oxide and prostacyclin-playing a physiological role in the control of platelet aggregability. Furthermore, other alterations occur only in relation to hyperglycemia. In this review, the main cardiometabolic risk factors, all components of metabolic syndrome involved in the prothrombotic tendency, will be taken into account considering some of the mechanisms involved in the alterations of platelet function resulting in platelet hyperactivation.

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“…It may be hypothesized that alirocumab could negatively affect blood clotting after trauma, as PSCK9 positively affects platelets' activation and thrombosis. 8 In our case, hemorrhage developed in the masticatory mucosa of the gingiva and the palate, a commonly traumatized site of the oral mucosa, 3 days after the injection of the drug, when alirocumab reaches its maximum concentration and free PCSK9 its minimum level, 9 while the patient was synchronously medicated with two antiplatelet drugs, clopidogrel and aspirin. This hypothesis cannot explain the lack of hemorrhage in other commonly traumatized intraoral sites, such as the buccal mucosa and the tongue, or ischemia.…”

Section: Discussionmentioning

confidence: 71%

“…The site of contusion was not specified, while there are no theories on its possible pathogenesis. It may be hypothesized that alirocumab could negatively affect blood clotting after trauma, as PSCK9 positively affects platelets’ activation and thrombosis . In our case, hemorrhage developed in the masticatory mucosa of the gingiva and the palate, a commonly traumatized site of the oral mucosa, 3 days after the injection of the drug, when alirocumab reaches its maximum concentration and free PCSK9 its minimum level, while the patient was synchronously medicated with two antiplatelet drugs, clopidogrel and aspirin.…”

Section: Discussionmentioning

confidence: 77%

Gingival Ischemia and Petechiae in a Patient Medicated With PCSK9 Inhibitor for Hypercholesterolemia: An Adverse Drug Event?

Thermos

Tosios

2018

Clin Adv Periodontics

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Introduction Monoclonal antibodies against proprotein‐convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a newly‐introduced therapeutic approach against hypercholesterolemia. Clinical trials have reported few adverse effects of PCSK9 inhibitors and there are no reports of oral adverse effects. We present the case of a patient that showed gingival discomfort on eating and toothbrushing, coupled with the presence of gingival ischemia and petechiae, 3 days after a subcutaneous abdominal injection of 75‐mg alirocumab for hypercholesterolemia, and contemplate on their possible pathogenesis. Case Presentation Αn 81‐year‐old male presented with gingival discomfort during eating and toothbrushing, 3 days after receiving a subcutaneous abdominal injection of alirocumab. Intraoral examination revealed that the anterior free and attached gingiva of both jaws appeared pale and the surrounding mucosa showed confluent petechiae that were more evident on the anterior palatal gingiva. The patient was asked to brush his teeth with a soft toothbrush and use a mouthwash containing hydrogen peroxide three times daily. At the 8‐day re‐examination he was symptom‐free, and the mucosa appeared totally normal. At the 5‐month follow‐up visit he reported having the same symptoms after each one of the 12 doses of alirocumab he received. Conclusions Adverse dugs effects associated with subcutaneous injection of alirocumab may manifest in the gingiva. Therefore, oral and periodontal examination should be included in the regular follow‐up of patients medicated with this drug.

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PCSK9 as a Positive Modulator of Platelet Activation

Cited by 70 publications

References 4 publications

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

Influence of Cardiometabolic Risk Factors on Platelet Function

Gingival Ischemia and Petechiae in a Patient Medicated With PCSK9 Inhibitor for Hypercholesterolemia: An Adverse Drug Event?

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