Why does clotting have to happen?

Clotting appears to be becoming a big issue in the world. We now know excess deaths are a global phenomenon. To what degree clotting contributes to this excess death, if any, is still a mystery to us. But we do know clotting can be a contributing factor to long COVID-19 thus it could have a contribution to excess deaths currently experienced.

Merogenomics is studying the information behind the clotting associated with this pandemic but to fully understood that process, it is necessary to understand background information on clotting itself. Therefore, this blog post is dedicated to summarizing two publications dedicated to the background in clotting conditions afflicting humans and clotting in animals.

Clotting, officially known as thrombus formation (thrombosis), is designed to stop bleeding from damaged blood vessels. The process of arresting bleeding is also referred to as hemostasis. Another scientific term we are going to throw in here is that blood vessels are made of endothelial cells. When we are talking about damage to blood vessels, we are talking about the endothelial cells making up the blood vessel walls being damaged and allowing blood to seep out.

Clotting and stopping blood loss is a very finely regulated process, and if dysregulated, can be seriously problematic, even deadly. If clotting is not efficient, a hemorrhage can occur, and if it happens too much, it can result in clogged vessels. Clogged vessels will disrupt blood flow and this can result in heart attack, stroke, venous thromboembolism (clots in the veins). If vein clots travel to the lung, they can also cause a pulmonary embolism (blocking blood flow to part of the lung).

In a nutshell, clotting is a specific interaction between endothelium (blood vessel walls), platelets, and coagulation factors to plug up a hole at the site of vascular injury. The process can be roughly divided into four phases:

• Temporary vasoconstriction (narrowing of the blood vessel at the site of injury)
• Coagulation to form a meshwork of proteins and platelets that plug up the hole in blood vesselThe star of this show is fibrin
• Fibrinolysis to remove the platelet/fibrin plug (clot removal)
• Tissue repair at the site of injury

Let’s introduce the players one by one now.

The “How to make a clot” recipe

Platelets are cell fragments from cells called megakaryocytes that circulate in the blood. As a consequence, platelets do not have a nucleus and everything needed for the functioning of the platelet has to be packaged inside them. They do not have an opportunity to create new proteins without having genetic materials to guide the production of proteins. Overall, platelets are important in coagulation, and are also involved immune and inflammatory reactions.

After a blood vessel injury, the vessel constricts to narrow the passage of blood, and as a consequence, concentrate the platelets flowing over the site of the injury. This helps platelets aggregate and start forming a plug at the damaged spot by binding to sites exposed by the wall’s damage. These “injury attached” platelets react to this process and promote further aggregation of platelets and coagulation factors (either by sporting specific receptors on the cell surface or by releasing special chemicals). This also involves inflammation, as inflammatory molecules can enhance this process.

For example, an inflammatory molecule called von Willebrand factor can be released by surrounding endothelium cells, and it can start binding to the scaffolding proteins outside blood vessels to help bring platelets to the site of injury.

Coagulation factors, on the other hand, are blood proteins produced mainly by the liver that are involved in complex chain reactions where one factor activates another which then activates another and another, and so on, to finally get to the processing of our main protein of interest, fibrin.

Before fibrin, platelets mix with fibrinogen (where fibrinogen binds to a type of receptor on the surface of platelets) and form a loose aggregate plug. If damage is minimal, this may be sufficient to patch the site of injury and prevent the loss of blood.

However, fibrinogen itself is cut by a protein called thrombin into fibrinopeptides A and B that form fibrin. Fibrin can spontaneously interact with itself and assemble into soluble fibrin chains or strings referred to as polymers. Another coagulation factor can cross-link independent fibrin polymers to make the polymer insoluble and the entire fibrin-platelet aggregate more compact and denser while allowing for full coverage of the damaged area when more serious blood vessel injuries occur.

How to break a clot?

To dissolve a clot while the injured blood vessel is healed, it is the fibrin-platelet aggregate that is dissolved. This is referred to as thrombolysis or fibrinolysis and primarily involves a blood protein called plasminogen. Plasminogen binds to fibrin in the clot. Plasminogen itself is then cut into fragments called plasmin, for it to be converted to a fibrinolytic protein that will dissolve the fibrin polymers by breaking down the cross-linking bonds between the insoluble fibrin strands. These insoluble fibrin fragments now in turn can have clot preventing measures. For example, they can inhibit thrombin, interfere with fibrin polymerization, or coat platelets to prevent their aggregation. Soluble fibrin does not achieve that and rather is involved in the exact opposite processes described above.

As you can imagine, the rate of thrombolysis also has to be carefully controlled so it does not happen too quickly to allow bleeding to persist and as not to be too slow to unnecessarily block the blood flow.

In other words, thrombosis, or clot formation, involves aggregation of platelets and fibrinogen which is converted to fibrin to create a dense plug aggregate. Then to dissolve the plug, fibrinolysis has to take place which primarily involves plasminogen that needs to be converted to plasmin by tissue-type plasminogen activator (tPA) for the fibrin aggregate to be broken down.

Whew, and that was just a basics explanation!

Of course, clots are more complex than just that and can also entrap other types of cells besides platelets; they often entrap many additional proteins. For example, red blood cells and immune cells can also be entangled. Immune cells also can contribute towards clot formation through providing further attachments or releasing molecules that promote clot formation. (We mentioned already that inflammation factors are also involved.)

Depending on where a clot is formed, the components of the clot can somewhat vary. In other words, clots from a heart attack can have slightly different percentages of involved players than clots from stroke and so on. For example, in early studies of isolated clots from patients with different coronary disorders showed two main types of clots: white clots and red clots. White clots were mainly composed of fibrin, whereas red clots were mainly composed of red blood cells entrapped in the clots. As you can imagine, the white clots were much more resistant to breakage and fibrinolysis, also have higher levels of platelets and the von Willebrand inflammatory factor.

This helps us understand some of the assertions previously made by some authors on the make up of strange clots that at times are apparently being isolated from people, and what got us going into studying fibrin in the first place.

Thus, the take home message is, the more fibrin that is involved in the clot, the more resistant the clot will be.

How are clots treated?

We recently did a video on this topic when introducing nattokinase which is the most effective natural anti-clotting agent.

Plasminogen activator inhibitor-1 inhibits tPA that is responsible for converting plasminogen to plasmin. As a consequence, plasminogen activator inhibitor-1 is a major inhibitor of fibrinolysis and thus promotes fibrin stabilization. Plasminogen activator inhibitor-1 also inactivates activated plasmin.

However, most official thrombosis treatments include the use of antiplatelets, anticoagulants, and fibrinolytic agents as the treatments might depend on where the clots are formed. Antiplatelets are generally used to prevent and treat arterial clots (which can lead to heart attacks or strokes) as they are caused by a rupture of atherosclerotic plaques which results in blood vessel damage and exposure to scaffolding proteins underneath the blood vessels which attracts platelet aggregation. Venous clots (which are abundant in fibrin) are largely driven by imbalance in coagulation and are treated with anticoagulants. Finally, fibrinolytic agents may be used to treat both arterial and venous clots, and which are centered around helping convert plasminogen into plasmin. Thus, tPA is used or tPA that has been modified to be even more effective.

Visualization of atherosclerotic plaque formation leading to rupture, clotting cascade & platelet aggregation, resulting in total thrombus occlusion of an artery. #MedEd #MedTwitterpic.twitter.com/CBwJpxvkx4

— The Innovation | Medicine (@Innov_Medicine) December 21, 2022

In the end, clotting is a very important biological process but can become dangerous and deadly if dysregulated or if the vascular system is facing too many injuries. But now, there is an emerging theory that clotting is a major issue associated with COVID-19 (the actual disease, and not just a PCR test result) and this form of clotting may be induced by the spike protein itself (more on this in a future post, hence this backgrounder article). If this theory (of spike protein formed clots) holds true, we might be very interested in learning more about clotting treatments in order to minimize risks associated with SARS-CoV-2 infection (which would result in significant spike protein exposure) or as a treatment for long COVID-19. It is for these important reasons why Merogenomics wanted to focus on clotting basics before we take a deep dive this new form of clotting.

But as always, we will remind you that your best defense should always include healthy living. We all know what that means: healthy diet, regular exercise, good quality sleep, a positive attitude and no smoking. With these basics and the reviewed information about clotting, get ready to tune in to our follow-up posts featuring fibrin and the spike protein endothelial damage!

This article has been produced by Merogenomics Inc. and edited by Jason Chouinard, B.Sc. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.

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