My little understanding about the causes & mechanisms that promote thromboinflammation in COVID-19.
Contents:
1. How Covid-19 virus enters the human body?
2. What is the function of ACE2?
3. How SARS-CoV-2 virus lead to thromboinflammation?
3a. Excessive ANG II
3b. Elevated Levels of Tissue Factor (TF)
3c. PAR Signaling
3d. Formation of Neutrophil Extracellular Traps (NETs)
3e. Purinergic signaling
4. Conclusion
5. References
1. How Covid-19 virus enters the human body?
Spike-like protein on the SARS-CoV-2 virus binds to Angiotensin-Converting Enzyme 2 (ACE2). Subsequently, the virus enters and starts replication, causing ACE2 to function abnormally.
 |
| SARS-CoV-2 virus binds to ACE2 |
2. What is the function of ACE2?
Normally, ACE2 protein help to modulate the activities of a protein called angiotensin II (ANG II). ACE2 will be in charge of converting ANG II to other molecules, mostly the ANG 1-7 which can counteract the effects of ANG II.
ANG II will increase blood pressure and inflammation by increasing damage to blood vessel linings and various types of tissue injury. Hence, ACE2 is essential to maintain the normal level of inflammation.
3. How SARS-CoV-2 virus lead to thromboinflammation?
3a. Excessive ANG II
As mentioned earlier, the SARS-CoV-2 virus bind to ACE2, cause ACE2 to function abnormally. Therefore, the ANG II signaling is no longer restricted by ACE2. So the ANG II will increase while the ANG 1-7 will decrease tremendously.
As a result, more ANG II is available to injure tissues and blood vessels that will lead to inflammation.
 |
| Increase of ANG II---increase inflammation |
3b. Elevated Levels of Tissue Factor (TF)
Dysregulation in angiotensin II signaling induces the synthesis & expression of the cell surface glycoprotein tissue factor (TF) in various cell types.
Tissue factor (TF), is also known as platelet tissue factor, or Factor III. It acts as primary initiator of the extrinsic pathway in blood coagulation.
 |
| Coagulation Pathway |
Along the extrinsic pathway, the tissue factor will cause the conversion of factor 7 to become activated factor 7.
Then, the tissue factor combines with the activated factor 7 and calcium ions to convert factor 10 into activated factor 10.
The activated factor 10 will then, in the presence of calcium ions and factor 5, forms prothrombin activator.
And this prothrombin activator will cause the conversion of prothrombin, which is factor 2 into activated factor 2, which is also known as thrombin.
Thrombin is a clotting enzyme. The activated thrombin will act in two ways.
The first one, thrombin further activates factor 1, which is known as fibrinogen. Thrombin link fibrinogen together, become fibrin. A lot of fibrin link together to become fibrin mesh.
 |
| 1. Thrombin further activates fibrinogen |
The second way is thrombin activate factor 13, which is the fibrin stabling effect. Factor 13 will make crosslinking of fibrin. This fibrin mesh has high fiber density and increases resistance to fibrinolysis. Normally it holds the platelet plug in place. In this case, it becomes a thrombus, leading to thrombosis.
 |
| 2. Thrombin activates fibrin stabling effect |
Besides, tissue factor also can enter intrinsic pathway by releasing polyphosphates which are stored in platelet. Polyphosphates active factor 12. Activated factor 12 can contribute to inflammation by its activation of kallikrein, thereby increasing the formation of bradykinin, leading to inflammation reaction.
Besides, kallikrein stimulates the activation of Factor 12, which enters the intrinsic pathway, leading to thrombosis. Thus, activation of coagulation by tissue factor can have multiple thromboinflammatory effects via the diverse effects of activated factor 12
 |
| Activation of coagulation by tissue factor can have multiple thromboinflammatory |
3c. PAR Signaling
Let refers back to the activation of thrombin.
Thrombin (factor 2) is activated by prothrombin, and further convert the soluble fibrinogen into insoluble fibrin at the wound.
On the other hand, the thrombin will also activate the platelet through protease-activated receptor 1 (PAR1) on the platelet surface.
PAR1, which is the short form of protease-activated receptor 1, is actually a G protein-coupled receptor (GPCR).
The activation of PAR1 is accomplished when the thrombin binds to, and cleaves the N-terminal exodomain of PAR1 at a specific site.
This cleavage generates a new receptor N terminus and thereby unmasks a “tethered ligand” that binds to PAR 1 receptor, as shown in the picture on the right. As a result, it causes the activation of platelets.
 |
| Activation of PAR1 |
It is also noteworthy that just one molecule of thrombin can activate multiple PAR 1 receptors.
Therefore, even a small amount of thrombin can activates a great amount of platelets, and further amplifies the coagulation cascade that results in more thrombin, more fibrin and more activated platelets.
As a result, the clot will become larger and larger, until a thrombus occludes the blood flow through the blood vessels.
3d. Formation of Neutrophil Extracellular Traps (NETs)
When there is tissue damage or lung damage in COVID-19 patients, the neutrophils, one of the white blood cell types will release cathelicidins to activate platelets.
And the activated platelet will react in two ways.
Firstly, activated platelet will promote their adhesion to monocytes and neutrophils. This will lead to Neutrophil-platelet aggregation or Neutrophil extracellular traps (NETs).
Secondly, the activated platelet will secrete proinflammatory factors (e.g., IL-1b,RANTES), prothrombotic entities (e.g., TXA2) and platelet-activating factor (PAF).
Both actions, especially the NETS, will further enhance inflammation and platelet activation.
Lastly, this thrombin-mediated activation of platelets will also result in the secretion of ADP, which further initiates purinergic signaling.
3e. Purinergic signaling
Purinergic signaling via ADP is a key mechanism for platelet activation.
ADP can obtain from:
1. Extracellular ADP
2. ADP released by activated platelet (From dense granules)
ADP further bind with purinergic receptor P2Y12 and P2Y1, cause activation of purinergic receptor by exchanging GDP to GTP.
-P2Y12 belong to Gi class of GPCR---Inhibit cAMP pathway
-P2Y1 belong to Gq class of GPCR----IP3 Pathway
*Both Gi and Gq are the subunit of alpha
 |
| P2Y12 and P2Y1 pathway |
After activation, Gi Alpha subunit activated. It inhibits the Adenyl Cyclase which in turn deactivates the cAMP (cyclic Adenosine Monophosphate) pathway. Further inhibit Protein kinase A (PKA), Protein kinase A (PKA) promote the activation of Gp2b 3a complex, which is fibrinogen receptor. Let look at picture. When cell damage, it will secrete von Willebrand factor and cause formation platelet plug. To form a nice platelet plug, Gp2b 3a complex bind the platelet together via fibrinogen.
 |
| Gp2b 3a complex bind the platelet together via fibrinogen |
Next, the mechanism of P2Y1 receptor. activated Gq alpha subunit which drives the Phospholipase C (PLC) activation. Phospholipase C (PLC) break down specific membrane bound structure which called Phosphatidylinositol Biphosphate (PIP2). Phosphatidylinositol Biphosphate (PIP2) further break into two components, diacylglycerol (DAG) and Inositol triphosphate (IP3). diacylglycerol (DAG) activate Protein kinase C (PKC) which further activate Gp2b 3a complex, which is fibrinogen receptor.
Phosphatidylinositol Biphosphate (PIP2) activates Inositol triphosphate (IP3) pathway which promote intracellular release of calcium, leading to platelet activation. Besides, Phospholipase C (PLC) activation also drives the granule secretion from platelets. Among the secretion, TXA2, ADP and PAF are responsible to platelet activation.
Moreover, Gi also can activate Gq, enhance platelet activation and platelet plug
4. Conclusion
The mechanisms that discuss earlier actually are positive feedback loop.
Coronavirus 2 bind with ACE 2, result in decreases ACE 2 activity and ANG2 increase. ANG2 increase cell damage which further cause inflammation and platelet activation, either via PAR or purinergic signaling. Thus, platelet activation leads to coagulation and then certain secretion or formation will further enhance inflammation and platelet activation, such as thrombin, ADP, etc.
Due to this positive loop, platelet plug keeps forming and ultimately cause thrombosis.
 |
| Due to this positive loop, platelet plug keeps forming and ultimately cause thrombosis. |
5. References:
MEDSimplified. (2015, October 22). Coagulation cascade simplest explanation! The extrinsic and
intrinsic pathway of Hemostasis. [Video]. Youtube. https://www.youtube.com/watch?v=LVYmV5mK6QI
Medmovie, (2017). PAR1 Inhibitors (Vorapaxar) Medmovie MOD/MOA Sample Only. [Video].
Youtube. https://www.youtube.com/watch?v=uYpv8T7Qoh0
Medicosis Perfectionalis. (2019). P2Y12 Receptor: Mechanism of Platelet Aggregation. [Video]. Youtube.
https://www.youtube.com/watch?v=PzfirRCNMPU
Medicosis Perfectionalis. (2019). P2Y12 Receptor Inhibitors. [Video]. Youtube.
https://www.youtube.com/watch?v=sw6gI5PqjM4
Medicosis Perfectionalis, (2019). GPIIb/IIIa receptor inhibitors. [Video]. Youtube.
https://www.youtube.com/watch?v=YNxE6jSARog
Medicosis Perfectionalis. (2019, May 27). Protein C and Protein S. [Video].
Youtube. https://www.youtube.com/watch?v=aJ77PhXcVso
Medicosis Perfectionalis. (2020, August 15). Direct Thrombin Inhibitors and Factor Xa
Inhibitors | Pharmacology |Hematology. [Video]. Youtube. https://www.youtube.com/watch?v=xQo7AZ3VQTQ
Ninja nerd lecture. (2017, March 18). Hematology | Hemostasis: Coagulation Cascade. [Video].
YouTube. https://www.youtube.com/watch?v=SGzp9wqeu84&feature=youtu.be%20%E2%80%8B
NCBI. (2010, November 23). What is inflammation?
Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK279298/%E2%80%8B/%E2%80%8B/%E2%80%8B/
NCBI. (n.d.). Thrombosis. Retrieved from
http://www.ncbi.nlm.nih.gov/mesh/68013927%E2%80%8B
Press Release. (2021, May 17). The Noble Assembly At The Karolinska Institute.
Retrieved from https://www.nobelprize.org/prizes/medicine/1982/press-release/
Sriram, K., & Insel, P. A. (2021). Inflammation and thrombosis in COVID-19 pathophysiology:
Proteinase-activated and purinergic receptors as drivers and candidate therapeutic targets. Physiological Reviews, 101(2), 545-567. https://doi.org/10.1152/physrev.00035.2020
The Conversation Media Group Ltd. (2020, May 14). What is the ACE2 receptor, how is it connected
to coronavirus and why might it be key to treating COVID-19? The experts explain. Retrieved from https://theconversation.com/what-is-the-ace2-receptor-how-is-it-connected-to-coronavirus-and-why-might-it-be-key-to-treating-covid-19-the-experts-explain-136928#
NEXT:
PREVIOUS:
Comments
Post a Comment