Once activated, platelets can accumulate and clump, but to get them to stay put and really form a plug that stops blood fluids from leaking out, requires another process called coagulation. As stated earlier this process will activate fibrinogen, a very important protein used to link all of the platelets together. To activate fibrinogen, coagulation requires an array of proteins known as coagulation factors or clotting factors which are found circulating within the plasma in an inactive state. These factors are typically represented by Roman numerals which indicate the order in which they were identified, but offer no explanation as to their function (yes, sort of annoying but at least they have numbers!). Upon encountering vessel damage, certain of these factors become activated and initiate complex chemical cascades which ultimately lead to the formation of a blood clot. This activation may occur through either an intrinsic pathway (within the bloodstream) or an extrinsic pathway (outside of the blood stream). Both pathways ultimately lead to a common pathway through which a blood clot forms.

The chart above shows the cascade of clotting factor activation. The pathway has two entry points to begin the cascade, the "intrinsic" and "extrinsic" pathways. The common pathway begins with the activation of clotting factor X, which is also called "Stuart Factor". The image below is just another artist rendition of the same thing (showing the intrinsic and extrinsic pathways of the clotting cascade).

Intrinsic Pathway

When blood vessels incur damage, collagen within the vessel walls is exposed to the circulating bloodstream. Contact with collagen reacts with factor XII which in turn activates factor XI which sequentially initiates factor IX. Factor IX recruits factor VIII, platelet phospholipids, and Ca²⁺ ion cofactors to form a complex that activates factor X, thereby initiating the common pathway.

Extrinsic Pathway

Unlike the intrinsic pathway which is activated by exposed collagen, the extrinsic pathway is activated by chemical signals released by damaged tissues external to the bloodstream. Damage to these tissues destroys cellular plasma membranes yielding a collection of phospholipids and an integral receptor protein known as tissue thromboplastin (alternatively known as factor III or tissue factor). As blood rushes into these damaged tissues, circulating molecules of factor VII associate with the released combination of factor III molecules and phospholipids to form an enzymatic complex. Ca²⁺serves as a required cofactor for the formation of this complex. This complicated enzymatic complex reacts with and activates factor X and the common pathway is again initiated. This factor III, VII, phospholipid and calcium complex are also capable of activating factor IX within the intrinsic pathway, indicating a one-way connection between the two pathways.

Common Pathway

Upon activation, factor X joins with factor V, Ca²⁺, and platelet surface phospholipids to form a prothrombin activating complex. This complex targets prothrombin (factor II) and converts it to a molecule known as thrombin. Thrombin is an important enzyme which converts a protein known as fibrinogen into a fibrous clot forming protein known as fibrin.

Fibrin plays a critical role in the formation of a clot by forming a dense, fibrous weave against which blood "congeals" into a thicker, gel-like clot capable of clogging damaged areas of vessels.

The activation of thrombin initiates a positive feedback mechanism, as thrombin is capable of activating numerous factors within the coagulation pathways. Consequently, thrombin exerts a stimulatory effect on its own production. Furthermore, thrombin also activates factor XIII which stabilizes the clot by catalyzing the formation of covalent bonds between fibrin strands. Finally, thrombin initiates additional platelet activation. Thus, the thrombin positive feedback mechanism stimulates further platelet plug proliferation in addition to its coagulation effects.

Thrombus vs Embolus

A blood clot, which will include platelets and fibrin, is also called a thrombus if it is anchored to the vessel wall where it was created. If this thrombus breaks away from the vessel wall and begins to circulate in the vascular system, it is called an Embolus or an Embolism. An embolus can be very dangerous because it may get stuck in a small blood vessel and block blood flow from reaching cells further downstream. Cells die without constant blood flow reaching them. If an Embolus blocks enough blood flow to cells in the heart or the brain, it can quickly become lethal.