HEMOSTASIS: HEMOSTATIC PROCESS, PRIMARY AND SECONDARY - MEDICINE - 2025

The hemostasis is a set of physiological processes which aims to stop the bleeding when a blood vessel injury occurs a. This mechanism includes the formation of a plug or clot that stops the bleeding and then all the mechanisms for the repair of the damage.

The goal of hemostasis is to keep the cardiovascular system, which is a closed circulation system, intact. The hemostatic system, therefore, works like a plumber in a water pipe system, plugging leaks or leaks and then repairing them to restore the damaged structure.

General diagram of the coagulation process (Source: Joe D via Wikimedia Commons)

As the hemostatic process is quite complex and involves the participation of many different physiological mechanisms, it has been divided into two processes to facilitate its study. Thus, we speak of primary hemostasis and secondary hemostasis.

Primary hemostasis deals with the initial study of the hemostatic process, that is, the formation of the platelet plug. Secondary hemostasis takes care of the coagulation process itself.

Two thousand years ago, the Greek philosopher Plato described that "the blood when it left the body formed fibers." Plato was the first to use the term "Fibrin" referring to blood.

This description was later accepted by many other philosophers, but it was not until the late 1800s and early 1900s that platelets were discovered and the first model of the coagulation mechanism was made.

Hemostatic process

When damage occurs to a blood vessel, three processes are activated sequentially. First, local vasoconstriction occurs, that is, the smooth muscle of the vascular wall contracts, reducing the diameter of the vessel to reduce blood loss.

Sometimes, when the vessels are very small, the constriction is so effective that it occludes the lumen of the tube and by itself stops the bleeding.

Injury to the vascular endothelium promotes platelet adhesion to the injury site and this platelet adhesion promotes the aggregation of more platelets that either end up occluding the injury site or, in small vessels, can obstruct the vessel and stop blood flow in the vessel. affected vessel.

This process is self-limiting, so that the platelet plug does not spread throughout the vessel, and constitutes the second process.

The blood clot is then formed by the sequential activation of a series of enzymes of the coagulation system that are circulating in the blood in their inactive form. These processes stop the bleeding, but circulation must be restored (third process).

Therefore, once the initial objective has been achieved, which is to prevent leakage, the walls of the vessel are repaired and now the clot formed is smoothed or destroyed (fibrinolysis) and the blood returns to flow normally through the entire and perfectly reconstituted vessel.

This entire complex hemostatic process is rigorously regulated, so that its effects are limited to the injured area and damage can be quickly contained. Alterations in the physiological balance or regulation of hemostasis lead to pathological states that present with thrombosis or bleeding.

Primary hemostasis

Primary hemostasis refers to all the processes that allow the platelet plug to form. This involves platelet adhesion, activation, secretion, and aggregation.

Platelets are small coreless cell fragments 1 to 4 microns in diameter. These are formed by fractionation of cells produced by the bone marrow called megakaryocytes. Platelets have a half-life of 8 to 12 days and are very active structures.

Origin of platelets (Source: パ タ ゴ ニ ア via Wikimedia Commons)

Vasoconstriction

In the hemostasis process, the first thing that occurs is a vasoconstriction due to contraction of the smooth muscle of the vascular wall in the area of ​​injury. This contraction is produced by direct mechanical effect of the element that injured the vessel and / or by activation of the perivascular nerve fibers.

Platelet plug formation

When a blood vessel is injured, the collagen just below the endothelium is exposed, and platelets adhere to it and become activated. When activated, attached platelets release adenosine diphosphate (AD P) and thromboxane A 2. These substances in turn induce the adhesion and activation of more platelets.

Adhesion and aggregation may continue until one of the small-caliber injured vessels is completely obstructed. Initially, the platelet plug is loose, then during the next clotting process, the fibrin strands will turn it into a rigid plug.

In areas adjacent to the vascular lesion, endothelial cells begin to secrete prostafilin, which is a substance with antiplatelet effects, that is, it prevents platelets from adhering.

The secretion of prostafillin by the vascular endothelium in the healthy areas peripheral to the lesion limits the extension, along the vessel, of the platelet plug and confines it to the area of ​​injury.

Activated platelets also secrete serotonin, a substance that is capable of enhancing vasoconstriction. In addition, they secrete thromboplastin, which is a substance that activates part of the coagulation cascade, as will be described later.

Coagulation cascade as it works in vivo.

By Dr Graham Beards (and), via Wikimedia Commons

Other substances secreted by platelets are proteins called "fibrin stabilizing factor" and a "growth factor". The growth factor induces the growth of endothelial cells, fibroblasts, and smooth muscle cells in the injured vessel.

The final effect of the growth of vascular wall structures induced by growth factors released by platelets is to initiate repair of the vascular injury.

Secondary hemostasis

Secondary hemostasis refers to the coagulation process itself. It is an enzymatic process that involves a cascade of reactions by which soluble fibrinogen is converted to fibrin, an insoluble substance that polymerizes and crosslinks to form a stable clot.

In extensive vascular lesions the clot begins to appear about 15 to 20 seconds after the injury. On the other hand, in minor injuries this appears 1 to 2 minutes later.

Three types of substances are responsible for starting this enzymatic cascade.

1- Activating substances from the injured vascular wall.

2- Substances produced by platelets.

3- Blood proteins that adhere to the injured vascular wall.

More than 50 substances related to blood clotting processes have been found. These can be classified into those that promote coagulation, which are called procoagulants, and those that inhibit coagulation, which are called anticoagulants.

The balance between the activity of these two groups of substances will be responsible for whether the blood clots or not. Anticoagulants normally predominate, except in the area where some trauma to a vessel occurs in which the activity of procoagulant substances will predominate.

Clot formation

The enzymatic activation cascade ends by activating a group of substances that are collectively called prothrombin activator. These prothrombin activators catalyze the transformation of prothrombin to thrombin, and the latter acts as an enzyme that converts fibrinogen to fibrin.

Fibrin is a fibrous protein that polymerizes and forms a network in which it traps platelets, blood cells, and plasma. These fibrin fibers additionally adhere to the injured surface of the vessel. This is how the clot forms.

Clot retraction

Once formed, the clot begins to retract and squeezes out all the serum that was inside. The squeezed fluid is serum and not plasma, as it does not contain coagulation factors or fibrinogen.

Platelets are essential for clot retraction to occur. These produce the stabilizing factor fibrin, which is a procoagulant substance. Furthermore, they contribute directly to the retraction process by activating their own contractile proteins (myosin).

Clot lysis

A plasma protein called plasminogen, which is also called profibrinolysin, is retained in the clot along with other plasma proteins. The injured tissues and vascular endothelium release a potent plasminogen activator called tissue plasminogen activator (t-PA).

The release of t-PA is slow and is complete within a few days after the clot has formed and bleeding stops. T-PA activates plasminogen and converts it to plasmin, a proteolytic enzyme that digests fibrin fibers and much of the clotting factors confined to the clot.

Thus, plasmin removes the clot once the vessel is repaired. If the clot was in a small vessel obstructing blood flow, the effect of plasmin rechannels the vessel and flow is restored. Thus ends the hemostatic process.

References

1. Best and Taylor's Physiological Basis of Medical Practice, 12th ed, (1998) William and Wilkins.
2. Ganong, WF, & Barrett, KE (2012). Ganong's review of medical physiology. McGraw-Hill Medical.
3. Guyton AC, Hall JE: The Body Fluid Compartments: Extracellular and intracellular fluids; Edema, in Textbook of Medical Physiology, 13th ed, AC Guyton, JE Hall (eds). Philadelphia, Elsevier Inc., 2016.
4. Smyth, SS, McEver, RP, Weyrich, AS, Morrell, CN, Hoffman, MR, Arepally, GM,… & 2009 Platelet Colloquium Participants. (2009). Platelet functions beyond hemostasis. Journal of Thrombosis and Haemostasis, 7 (11), 1759-1766.
5. Versteeg, HH, Heemskerk, JW, Levi, M., & Reitsma, PH (2013). New fundamentals in hemostasis. Physiological reviews, 93 (1), 327-358.