Platelet Hyperactivation is caused by the Covid Spike Protein
...and contributes to the microclots that drive Long Covid.
In my last post, I talked about platelet activation as part of the natural process of blood clotting and the fact that platelet hyperactivation occurs with microclotting in Long Covid.
In this post, I want to go into more detail about the mechanism of platelet hyperactivation that accompanies microclotting, including reviewing the data that shows that platelet hyperactivation is caused by the spike protein and that platelet hyperactivation does occur in Long Covid patients.
Covid Spike Protein Causes Platelet Hyperactivation
Covid Spike Protein has been shown to directly cause platelet hyperactivation, as seen by Fluorescence Microscopy and Scanning Electron Microscopy (SEM).
Fluorescence Microscopy
Platelet hyperactivation induced by the Spike protein was observed by fluorescence microscopy. (Ref 1) In this experiment, a sample of healthy hematocrit containing unactivated platelets was treated with purified recombinant Spike protein (1 ng/mL), followed by a fluorescent marker for platelet activation called CD62P-PE. CD62P-PE is a purple fluorescent marker that detects P-selectin, which is located inside unactivated platelets but translocates to the platelet surface upon platelet activation. As a control, healthy hematocrit was treated with the CD62P-PE fluorescent marker alone. In the control, very little membrane-bound P-selectin is detected on the unactivated platelets, as reflected by only a small amount of purple fluorescence (panel A below). When the platelet is hyperactivated by treatment with Spike protein, large amounts of P-selectin are detected as purple fluorescence (panel B below).
Scanning Electron Microscopy (SEM)
Platelet hyperactivation induced by the Spike protein was also observed by scanning electron microscopy. (Ref 1) A healthy whole blood (WB) sample was treated with purified recombinant Spike protein (1 ng/mL) and pipetted onto a slide for visualization by SEM. An untreated sample of healthy whole blood (WB) was used as a control. In the control, “slight platelet activation is seen due to contact activation” with the slide (panel B, below). When the platelet is hyperactivated by treatment with Spike protein, the platelet membrane spreads, takes on a granular appearance on the platelet surface, and microparticle formation begins (panel D, below). The hyperactivated platelet in this form releases the contents of its granules into the extracellular matrix and begins expressing multiple cell surface receptors that contribute to coagulation, inflammation, and immune response.
Platelet Hyperactivation Occurs in Long Covid Patients
Now that we know that the Covid spike protein causes hyperactivation of platelets, next we want to examine whether platelet hyperactivation is observed in blood samples from Long Covid patients. (Spoiler: It is…)
Here’s the data:
Pretorius, Kell, and co-workers examined samples of blood from healthy individuals (control), acute Covid-19 patients, and Long Covid Patients. (Ref 2) Each sample was treated with both the CD62P-PE purple fluorescent marker (that detects activated P-selectin) and the PAC-1 green fluorescent marker (that detects activated GP IIb/IIIa). In control samples (panels A & B, below), very little purple or green fluorescence, and therefore very little platelet hyperactivation, is detected. In the acute Covid-19 patient samples, a moderate amount of platelet hyperactivation is detected, as seen by the purple and green platelets (panels C & D, below). In the Long Covid patient samples (panels E-H, below), a large and strong fluorescence signal is detected, indicating a large amount of platelet hyperactivation.
Additional blood samples from Long Covid patients show that when severe platelet hyperactivation occurs, platelets both spread (panel A) and clump (panel B). (Refs 3 & 4) Importantly, in these studies, platelet hyperactivation was observed in ALL patients with Long Covid (80 out of 80 patients). (Ref 4)
HOW does Spike Protein cause Platelets Hyperactivation?
As a medicinal chemist, I always want to know the mechanism, at a chemical level, for how biological events occur. So the next question I want to answer is: HOW does the spike protein from Covid actually bind to and activate platelets.
When I went into the literature, I found an answer that was both surprising and at the same time unsurprising.
Covid spike protein binds to platelets through Angiotensin Converting Enzyme 2 (ACE2) receptors expressed on the cell surface of the platelet. (Ref 4) It turns out that platelets have a high expression of ACE2 receptor on their cell surface and the Covid spike protein can bind readily to it. Just like Covid spike protein readily binds to ACE2 receptor expressed by epithelial cells in the lining of the lungs upon initial infection.
So Covid spike protein directly binds to ACE2 receptors on the cell surface of the platelet, thereby directly triggering platelet hyperactivation, and initiating the downstream effects of coagulation, inflammation, and immune response.
To underscore this point, these investigators (Ref 4) actually captured SEM images of Covid virus particles bound to human platelets (platelets 2 & 3, below).
What’s Next?
The next question that come to mind for me are:
Can platelet activation inhibitors, like aspirin, be used to suppress platelet hyperactivation in Long Covid that is caused by spike protein?
Does inhibiting platelet hyperactivation have any effect on the formation and treatment of microclots?
Stay tuned for answers to these questions and more.
Leave me a comment below and let me know what you think of this post.
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References:
SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19. Bioscience Reports 2021, 41, BSR20210611.
Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovasc. Diabetol. 2021, 20, 172.
TEG®, Microclot and Platelet Mapping for Guiding Early Management of Severe COVID-19 Coagulopathy. J. Clin. Med. 2021, 10, 5381.
Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/Post-Acute Sequelae of COVID-19 (PASC). Cardiovasc. Diabetol. 2022, 21, 148.
SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. Journal of Hematology & Oncology 2020, 13, 120.