Coagulation (secondary hemostasis)

Definitions & Key takeaways

Coagulation is the process of formation of a blood clot. It is secondary hemostasis that occurs after vascular damage has occurred and platelets have been activated. Its purpose is to form the fibrin mesh necessary to stabilize the platelet plug to stop bleeding. Coagulation happens in a series of steps called the coagulation cascade, which is a series of enzymatic reactions that leads to the conversion of fibrinogen to fibrin. The final product is a stable plug that stops the bleeding. Factors XII, XI, IX, VIII, VII, V, and IV are essential for the initiation of coagulation. Proteins C and S inhibit the coagulation cascade by inactivating factors Va and VIIIa, respectively.

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Introduction0:00–1:04

Hemostasis can be broken down into hemo referring to blood or bleeding and stasis meaning to stop - so together it means stopping bleeding.
Hemostasis has two phases: primary and secondary hemostasis. In primary hemostasis, platelets aggregate to form a plug at the site of an injured blood vessel.
While these platelets are aggregating, coagulation, or secondary hemostasis starts. This is where numerous enzymes that are always floating around in the blood called clotting factors get proteolytically activated, meaning that activation happens when a small piece is chopped off - a bit like pulling the pin out of a grenade.
These factors activate one another, eventually leading to the activation of fibrin or factor Ia. That results in a fibrin mesh which forms around the platelet plug to reinforce it and hold it together.
Without primary and secondary hemostasis, our body would suffer massive blood loss from even the most minor injuries--imagine losing all of your blood volume from something as simple as a pinprick!

Secondary hemostasis1:04–1:44

So let’s get into the details of secondary hemostasis. The process of forming the fibrin mesh begins via two pathways --the extrinsic and intrinsic pathways.
The intrinsic pathway is called intrinsic because all of the factors required to activate it are intrinsic, or found within the blood.
Conversely, the extrinsic pathway is called extrinsic because it’s activated by tissue factor found extrinsically, or outside of the blood.
Both pathways can become activated independently and ultimately culminate in the activation of factor X, which then proceeds to activate the rest of the coagulation cascade via the common pathway.

Extrinsic pathway1:44–2:42

Let's start with the extrinsic pathway. It starts when trauma damages the blood vessel, and exposes the cells under the endothelial layer, like smooth muscle cells, which have tissue factor or factor III in their membrane.
Now, it turns out that there’s an enzyme called factor VII floating around in the blood, and some of it is active, meaning that it’s already set to proteolytically cleave other proteins.
When it’s in that state, it’s called active factor VII or VIIa. “a '' for active.
Factor VIIa binds to a tissue factor and a calcium ion -which get released by nearby activated platelets--and it forms a VIIa-TF complex on the surface of the smooth muscle cell.
Both the calcium ions and tissue factors are co-factors, meaning that they need to bind to the enzyme factor VIIa to allow it to really get going.
This complex then cleaves clotting factor X yielding the active form called factor Xa. Once factor Xa is generated via the extrinsic pathway, it cleaves factor V into Va and then it uses factor Va and a calcium ion as the cofactors to form the prothrombinase complex which activates prothrombin or factor II, into thrombin or factor IIa.

Common pathway2:42–4:15

In fact, each prothrombinase complex can activate thousands of thrombin, so there’s enormous amplification that occurs at this step.
Thrombin uses calcium ion as a cofactor and it has a number of pro-coagulative effects. First, thrombin binds to receptors on platelets causing them to activate.
Activated platelets change their shape to form tentacle-like arms that allow them to stick to other platelets. Second, thrombin activates three cofactors; factor V, which is used in the common pathway; factor VIII; and fabin, which proteolytically cleaves fibrinogen or factor I, into factor Ia or fibrin.
Third, the effect of thrombin on fibrinogen plays a big role. Fibrinogen is soluble in blood, but fibrin isn’t, so fibrin precipitates out of the plasma and forms long protein chains that are like ropes.
The fibrin tether platelets to one another, holding the platelet plug together. And fourth, thrombin proteolytically cleaves stabilizing factor or factor XIII into factor XIIIa.
Factor XIIIa combines with a calcium ion cofactor to form cross links between the fibrin chains, further reinforcing the fibrin mesh.
This is where the intrinsic pathway comes into play. The intrinsic pathway starts when a circulating factor XII comes into contact with negatively charged phosphates on the membrane of activated platelets or subendothelial collagen exposed by trauma, then it undergoes conformational change to get activated into factor XIIa.

Intrinsic pathway4:15–5:10

Factor XIIa proteolytically cleaves factor XI into factor XIa, which combines with a calcium ion to proteolytically cleave factor IX into IXa.
Finally, IXa forms a complex with a calcium ion and factor VIIIa, and this complex proteolytically cleaves factor X into Xa.
It is important to note that factor VIII degrades rapidly in the blood if it is not bound to a protein called Von Willebrand's Factor, which is released by activated platelets and endothelial cells during primary hemostasis.
Now there are two blood tests to test coagulation. The prothrombin time, or PT, tests whether the extrinsic pathway is working.

PT/PTT5:10–5:36

You can think “Playing Tennis” which is done outdoors. Then there’s the activated partial thromboplastin time, or aPTT or just PTT, which tests whether the intrinsic pathway is working.
You can think “Playing Table Tennis” which is done indoors. Now to remember the various factors in both pathways, let’s use a mnemonic.

Mnemonic5:36–6:56

Let’s start with agent 007 representing factor VII, who’s sneezing into a tissue (tissue factor) because he’s been playing tennis (PT) outside (extrinsic pathway).
Agent 007 simply hops on the common train (common pathway). Meanwhile, we have a farmer carrying 12 eggs (factor XII) on his way back from playing table tennis (PTT) indoors (intrinsic pathway).
He clumsily drops an egg, so now there’s only 11 eggs (factor XI). Suddenly a mean alleycat with 9 lives (factor IX) jumps in his way.
The farmer chucks his boot at the cat, which dies - so that it only has 8 lives (factor VIII). The farmer hops on the common train as well.
The train carriage has 10 seats available (factor X), but 5 of them are occupied (factor V). Some more people sit down, and soon there are only 2 seats left (factor 2), and then just 1 (factor 1).
Agent 007 and the farmer look at each other, and scramble over to grab it - who do you think got the seat?Alright, as a quick recap, secondary hemostasis involves the formation of a fibrin mesh via the coagulation cascade.
Coagulation starts when collagen and activated platelets activate the intrinsic pathway by activating factor XII, which activates factor XI, which activates factor IX which activates factor X.

Review6:56–8:01

Factor X starts the common pathway where it activates factor II, which activates factor I that builds the fibrin mesh. When factor II gets activated it also activates 4 other factors: V, VIII, XI, and XIII.
Factor V gets activated and acts as a cofactor for X, factor VIII acts as a cofactor for factor IX, and factor XIII helps factor I, or fibrin, form crosslinks.
In the extrinsic pathway, exposed tissue factor activates factor VII, which activates factor X and starts the common pathway.
Factors II, VII, VIII, IX, X, XI, and XIII needs calcium as a cofactor in order to function. 10, 11 and 13 need calcium