Friday Hope: Aspirin II: Blocking Activation of αIIbβ3

We continue to learn how key safe, accessible and inexpensive OTC medicines and supplements effectively counteract the Spike Protein.

Inhibiting platelet thromboxane (TX)A2 synthesis with low-dose aspirin or blocking the P2Y12 receptor for adenosine diphosphate (ADP) with ticagrelor or clopidogrel has similar effects on cardiovascular and bleeding outcomes. (A) The activation of platelets is induced by the interaction of several agonists with receptors expressed on the platelet membrane and depicts outside-in signalling mediated by TXA2, ADP, and thrombin. The TXA2-evoked increase in intracellular Ca2+ and ADP-induced decrease in cAMP levels independently lead to platelet aggregation through a change in the ligand-binding properties of the glycoprotein IIb/IIIa (αIIbβ3), which acquires the ability to bind soluble adhesive proteins such as circulating fibrinogen. The secondary release of ADP and TXA2 induces further platelet activation and aggregation, thereby amplifying the initial activation signal(s).8 (B) The main efficacy (left graph) and safety (right graph) results of the GLOBAL LEADERS trial,11 a randomized comparison of ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs. aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months. (C) Time-to-event curves of the co-primary cardiovascular (left graph) and bleeding (right graph) endpoints for the overall 1-year analysis of the intention-to-treat population of the STOPDAPT-3 trial.10 (A) Redrawn from Davì and Patrono;8 (B) taken from the GLOBAL LEADERS presentation at the 2018 ESC Congress through the courtesy of Professor Marco Valgimigli; (C) reproduced from Watanabe et al.10 in the current issue of the European Heart Journal

Monday, we reviewed how the Spike Protein binds to the integrin αIIbβ3, potentiating the all-too-well known clots. In August, we reviewed how Aspirin can be used to treat Spike-induced inflammation by inhibiting the NLRP3 inflammasome. However, I have now discovered another mechanism by which Aspirin blunts the Spike Protein. Aspirin blocks the activation of αIIbβ3.

Our recent observations in a mouse model of TTP documented that adhesion of platelet GPIbα to VWF caused activation of the platelet fibrinogen receptor, αIIbβ3, allowing fibrinogen binding and initiation of platelet aggregation. Thrombus size was decreased by pre-treatment of mice with aspirin, which blocks the activation of αIIbβ3, or eptifibatide, which blocks binding of fibrinogen to αIIbβ3.

ASPIRIN PROPHYLAXIS FOR HEREDITARY AND ACQUIRED THROMBOTIC THROMBOCYTOPENIC PURPURA?
https://pmc.ncbi.nlm.nih.gov/articles/PMC9262856/

As such, Aspirin reduces the stimulatory effects of αIIbβ3 activation, reducing the adhesive processes that occur during thrombus formation.

We conclude that erythrocytes up-regulate the agonistic effects of platelet releasates on αIIbβ3 activation and secretion by recruited platelets. This effect contributes to platelet-platelet and platelet-leukocyte adhesive processes and recruitment that occur during thrombus formation. Reduction of the stimulatory capacity of combined cellular releasates by aspirin contributes to the clinical benefits of this compound as an antithrombotic modality because recruitment is the actual limiting step for formation of an occlusive thrombus.

Platelet-erythrocyte interactions enhance αIIbβ3 integrin receptor activation and P-selectin expression during platelet recruitment: down-regulation by aspirin ex vivo
https://ashpublications.org/blood/article/99/11/3978/106869/Platelet-erythrocyte-interactions-enhance-IIb-3

Interestingly, when looking at blood clot stiffness in those who had coronary bypass surgery, Aspirin reduced the stiffness of transfusion-related clotting induced by αIIbβ3.

Blood clot stiffness with and without abciximab, was compared in a ratio test (S/Sabciximab) named the Platelet Function Index (PFI). PFI was hypothesized to be positively correlated with platelet contributions through integrin αIIbβ3 to clot stiffness. PFI for CPB subjects was lower for those receiving transfusions than those not receiving transfusions (p<0.006). A receiver-operator characteristics (ROC) analysis correlating the PFI with the blinded surgical team's decision on transfusions that included platelet concentrates generated an area under the curve (AUC) of 0.79 (p<0.001). Additionally, the mean value of PFI for subjects on aspirin therapy was lower than for those not on aspirin therapy (p<0.02) and correlated with a 1.73-fold enhanced risk of receiving a peri-operative transfusion.

Sonorheometry assessment of platelet function in cardiopulmonary bypass patients: Correlation of blood clot stiffness with platelet integrin αIIbβ3 activity, aspirin usage, and transfusion risk
https://pubmed.ncbi.nlm.nih.gov/26688324/

There is evidence that Aspirin may help those suffering from Long COVID, which is almost certainly driven by microthrombi induced by the Spike.

In a study of 845 South African people with long COVID, 70 were identified as having laboratory markers consistent with microthrombi (105). A subset of patients (n=24) were treated with one month of dual antiplatelet therapy (clopidogrel 75mg/aspirin 75mg) once a day, as well as a direct oral anticoagulant (apixiban 5 mg) twice a day. The participants in this small case series (not yet peer-reviewed) reported relief of symptoms, primarily fatigue, and biomarker measurements improved including fibrin amyloid microclots and platelet pathology scores.

Therapeutic trials for long COVID-19: A call to action from the interventions taskforce of the RECOVER initiative
https://pmc.ncbi.nlm.nih.gov/articles/PMC10034329/

I am fascinated by the findings we have made. Certain key medicines and supplements provide multiple therapeutic benefits in ameliorating damage and disease caused by the Spike Protein. Vitamin D, Vitamin C, now Aspirin. And they are all safe, effective, inexpensive and everywhere. Of course, this is a work of medical research and not medical advice. Always check with your Primary Care Provider before using any medication or supplement.

Thank you, as always, for your support, dialog and readership. After a brutally cold Winter, we had the first inklings of Spring this week here in northern Vermont – and it was invigorating! Blessings and a joyous weekend to all.