Blood is one of the most amazing substances in existence. It flows around your body in a liquid form, and yet whenever there is a hole somewhere in your circulatory system, it solidifies to plug the hole. It is like those tires that instantly fix a puncture, except that nature did it better and much more eloquently millions of years earlier.
Before we get down to business, there are a few simple terms that we should be aware of and understand.
-Platelet Adhesion: Process by which platelets stick to non-platelet surfaces.
-Platelet Aggregation: Process by which platelets stick to one another.
-Primary Hemostatic (Platelet) Plug: Initial aggregation or clump of platelets before fibrin strands attach.
-Coagulation: Process by which soluble fibrinogen converts to insoluble fibrin strands.
-Secondary Hemostatic (Platelet) Plug: Platelets with overlying layer of fibrin strands.
Before we get down to how the clots form, it may be a good idea to go over why our blood doesn't just solidify.
As you know blood is contained within blood vessels. Now the walls of your blood vessels are exactly like the walls in your house, or would be, if the walls in your house repainted themselves, fixed holes and cracks on their own, and kept themselves in extremely good all around working order, which also means not letting new walls form in the middle (ie. thrombus). The endothelial cells that form the walls of your blood vessels are living, breathing, biologically active cells and as such preform very important functions. One such function is to form a barrier to prevent platelets from binding to collagen which will activate the platelets. They also release Nitric Oxide (NO), Prostocyclin (PGI2) and Endothelial-ADPase, all of which are antiplatelet factors to prevent the platelets from activating and becoming sticky. The endothelial cells also help express heparin sulfate. Heparin sulfate then combines with Antithrombin 3 (which is released from the liver and circulates in the blood). Activated Antithrombin 3 destroys clotting factors Xa and IXa (we will get to those clotting factors a little later) and if attached to a properly sized heparin molecule, it can destroy thrombin. Healthy epithelial cells also express Thrombomodulin which is a devious little protein which takes active thrombin and twists it to its nefarious purpose. Once thrombin is under the control of thrombomodulin it can express protein C and with the help of Vitamin K, it destroys clotting factors Va and VIIIa (I should make a note, though I think that it is fairly obvious by this point, that the clotting factors are expressed as Roman numerals). Healthy epithelium also produces Tissue Plasminogen Activator (t.P.A.) which converts plasminogen to plasmin which then breaks down fibrin into fibrin degradation products (FDP), natural fibrinolysis to prevent clot from floating around your body. As you can see, a healthy epithelium is very much like a disapproving father sitting on the porch, cleaning his shotgun and generally discouraging any funny business.
Things change however when there is a hole in a blood vessel. The first thing to happen, and it happens faster than a greyhound on cocaine (I bet someone has actually tried that, though I do not condone it), is vasoconstriction. There are different processes by which this occurs. Nervous reflex constriction occurs when damaged nerve endings in the area release tell the smooth muscle to contract. There is myogenic constriction is which damaged smooth muscle contracts. And, then damaged endothelial cell release vasoconstrictors such as Endothelin also causing constriction. All have the same goal however, limit blood loss.
Now when the endothelial cells are injured and interesting thing occurs. Platelets attach to the now exposed collagen and are activated. Von Willebrand Factor (vWF), also attaches to now exposed collagen and helps to grab platelets and stick them to that spot (sort of like Velcro), the fact that these areas are often high shear areas (I can explain it at a later time if you really want to listen to me talk about fluid dynamics) makes the vWF work that much better (remember how clots can often form in turbulent areas like the bifurcation (splitting) of major arteries). This is that platelet adhesion thing from way earlier.
Once platelets are stuck by either collagen or vWF they become activated and change their shape from somewhat disc-like to spiny balls. Activated platelets begin releasing granules. Alpha granules have things like more vWF, enzymes and proteins, and certain clotting factors (particularly V and VIII). Dense (delta) granules contain serotonin, calcium (extremely important in the actual clotting cascade), and ADP. ADP is very important as it helps to activate platelets continuing platelet aggregation and making the plug bigger. Once the platelet is activated, the membrane enzyme phospholipase A2 is also activated which helps release arachidonic acid from phospholipids. Some of the arachidonic acid (I always remember it as spider acid) is converted by cyclooxygenase (COX) into Thromboxin A2 (TxA2) which is another important platelet aggregator as well as a vasoconstrictor.
Now that we have the whole platelet plug thing out of the way. We can actually get to the actual clotting cascade. There are two different pathways: the contact activation (intrinsic) pathway and the tissue factor (extrinsic) pathway. We will start with the intrinsic pathway.
Intrinsic Pathway:
-Clotting factor XII comes into contact with a negatively charged surface and is activated becoming XIIa.
-Factor XIIa reacts with factor XI creating XIa.
-Factor XIa activates factor IX to IXa.
-Factor IXa, with the help of phospholipids, calcium and factor VIIIa, change factor X to Xa.
-Factor Xa, with the help of phopholipids, calcium and factor Va convert Prothrombin to Thrombin.
-Thrombin converts fibrinogen to fibrin which stabilizes the clot.
*It is important to note that thrombin also acts to convert factors V to Va, VII to VIIa, and XI to XIa. It also converts factor XIII to XIIIa which basically causes the cross hatching of fibrin strands, strengthening the clot. Its like you just piled a bunch of empty beer cans in the back of a pick-up truck and are trying to get to the recycling depot. What is going to hold them better? Some rope running back and forth across them or a net?
Fortunately for you the more common pathway is also quite a bit more simple. The extrinsic pathway goes something like this:
-A tissue factor released by injured epithelial cells interacts with factor VII creating VIIa.
-Tissue factor and VIIa then convert factor X to Xa and the rest is the same as the intrinsic pathway.
*Please note that the extrinsic pathway is generally the pathway used in the human body.
There are some important cofactors that were very briefly talked about. The phospholipids provide a place for some of the clotting factors to come together. Calcium is sort of like the seat belt that holds them in place so the reaction can occur. Vitamin K is also extremely important in allowing certain clotting factors to mature (shouldn't be any offspring if they haven't matured). Without enough vitamin K the whole clotting cascade falls apart which is the basis behind how Warfarin and related Coumarins work.
Once the fibrin strands are holding tight to the platelets (and trapping a few red blood cells as well then you have a successful stop to the bleeding, unless you pick at it.
Anyway, I will leave it there because I have already put down much, much more than I originally intended and anyone who has read this far probably hates me for it. I may write some more in the future though on fibrinolysis and also some pharmacology affecting the clotting cascade such as Heparin, Aspirin, Warfarin, etc.
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