Haemostasis

Hello, in this post we'll be taking a look at how the body prevents blood from escaping its vessels - a process called haemostasis. We'll take a look at how haemostasis works and how it is regulated which will include an explanation of the coagulation cascade. 

Haemostasis

Haemostasis is the arrest of the escape of blood from a blood vessel. This is achieved through the formation of a thrombus: a compact mass of aggregated platelets and fibrin that build up in a blood vessel of an animal. It is formed by the interaction between platelets, blood vessel walls and clotting factors and is the end-product of coagulation. After a vessel ruptures, the thrombus slows down the blood flow which initiates healing.


When the coagulation system is functioning properly this is referred to as haemostasis. When there is "too much" haemostasis or the mechanism isn't activated properly, it is referred to as thrombosis. "Too little" haemostasis leads to haemorrhage.

How does Haemostasis Work? 

Haemostasis occurs as a result of interactions between blood vessel walls, platelets and soluble clotting factors.


Blood Vessel Walls


Blood vessels leading to and from capillary beds contain a layer of smooth muscle in their walls. This smooth muscle promotes laminar flow. If there are irregularities on the lining of the vessel, turbulent flow occurs and this may lead to blood clotting and the formation of thrombi. Endothelial cells release a variety of substances which have opposing effects to try and counterbalance haemorrhage and thrombosis.

The mechanisms used by the endothelial cells to prevent clotting include antiplatelet factors, anticoagulant factors, and fibrinolytic factors. Antiplatelet factors include:

• A physical barrier: the endothelial cells separate the platelets and subendothelial collagen.
• Vasodilators: these include prostacyclin and nitric oxide
• Adenosine diphosphatase: this degrades ADP and inhibits platelet aggregation.

The endothelial cells also secrete substances that prevent coagulation from occurring. These include:

• Heparin-like molecules: these bind to AT-III (Antithrombin 3) and increases its ability to inactivate thrombin.
• Thrombomodulin: this binds to thrombin and converts it to an anticoagulant which activates Protein C. Protein C inhibits coagulation.

Fibrinolytic factors, such as t-PA, are also secreted. t-PA promotes fibrinolytic activity to clear fibrin deposits from endothelial cells.

Endothelial cells have products with prothrombotic properties. These are:

• Von Willebrand Factor: this is a cofactor of Factor VIII and helps platelets stick to collagen
• Tissue Factor: this is also known as Factor III and activates the extrinsic clotting cascade. 
• Inhibitors of plasminogen activators: these prevent plasminogen from being converted to plasmin and so fibrin remains intact. 
• Endothelins: these are potent vasoconstrictors.   

Platelets and Soluble Clotting Factors

The following diagram provides an overview of haemostasis and shows how the platelets and soluble clotting factors (which make up the coagulation cascade) work together. 

Overview of Haemostasis

The job of the platelets in haemostasis is to form the primary haemostatic plug which works to prevent blood from escaping the vessel. This plug works well in the short term but it isn't quite stable as the process is reversible. The formation of the primary haemostatic plug occurs in three stages: platelet adhesion, platelet secretion and platelet aggregation.

• Platelet Adhesion: when the wall of the blood vessel is damaged, the platelets become exposed to the subendothelial collagen. Prostacyclin (a substance that prevents platelet activation and causes vasodilation) production decreases and this encourages platelets to adhere to the irregularity in the vessel wall. 
• Platelet Secretion: platelet adhesion cause the synthesis and secretion of substances that will augment platelet adhesion and encourage platelet aggregation. These include:
• ADP which attracts more platelets to the area which results in more ADP release and a positive feedback loop.
• Thromboxane A2 which causes vasoconstriction and platelet aggregation. 
• Serotonin, this also causes vasoconstriction
• Von Willebrand Factor, this helps the platelets stick to the collagen. 
• Platelet factor 3 which participates in the formation of thrombin and factor VIII
• Platelet factor 4. This inhibits the action of heparin (heparin prevents clotting) and Fibrin Degradation Products (FDPs)
• Fibrinogen. This is used in the formation of the secondary haemostatic plug
• Tissue Factor: this triggers the coagulation cascade.
• Platelet Aggregation: when the platelets have stuck to the exposed collagen and have secreted their prothrombotic substances they also change shape which encourages more aggregation. This causes the primary haemostatic plug to form. 

The tissue damage also directly activates coagulation and causes the vascular endothelium to become prothrombotic. Since the coagulation cascade was triggered by the release of Tissue Factor by the platelets, thrombin is formed and this promotes further platelet aggregation. Thrombin also causes the conversion of fibrinogen to fibrin and this firmly "glues" the primary haemostatic plug in place, forming the secondary haemostatic plug which is irreversible. 

The diagram above also explains how the process is regulated (the red, purple and navy writing). We'll explore that part when we take a closer look at the coagulation cascade and how it is regulated and that should help you to make sense of that part of the diagram.

The Coagulation Cascade

Okay, so here's where it gets a bit complicated. I've drawn a diagram (below) to try and simplify the process. I would definitely sit down and take some time to try and fully understand the process :) I'll be referring to this diagram during my explanation.

The coagulation cascade can be broken down into three pathways: the intrinsic, extrinsic and common pathways.

The Extrinsic Pathway

This is the simplest of the three. Tissue damage causes the release of Tissue Factor (TF - also known as Factor III). Tissue factor causes factor VII to be activated (VIIa). Factor VII and Ca ions work together to activate factor X and initiate the common pathway. 

 The Intrinsic Pathway
 
Tissue damage triggers the intrinsic pathway by causing the activation of Factor XII which in turn activates Factor XI (XIa). Factor XIa then forms a complex with Factor VIIIa and Ca ions which goes on to activate Factor X (triggering the common pathway).

The Common Pathway

Activated Factor X along with activated factor V and Calcium ions cause the conversion of Factor II to Factor IIa (Thrombin). Thrombin causes the conversion of fibrinogen to fibrin and Factor XIIIa catalyses the formation of covalent bonds which cross link adjacent fibrin molecules, making them insoluble.This fixes the thrombus in place.

Regulation of the Coagulation Cascade

There are three main groups of substances which are used to regulate the coagulation cascade:

• Fibrinolytic agents: they promote the breakdown of fibrin and try to reduce the size of the thrombus and prevent additional fibrin from forming. This group includes:
• Plasmin which causes fibrinolysis. Plasmin is converted from plasminogen when tissue damage occurs
• Protein C: this inhibits alpha 2 - antiplasmin (which antagonises plasmin), thus promoting fibrinolysis. 
• Coagulation Inhibitors: These work to prevent coagulation from occurring. They include:
• Atithrombin III (AT-III): which inhibits thrombin and IXa and Xa. The inhibition of thrombin causes factors V, VIII, XI and XIII to be deactivated.
• Protein S: this degrades factors V, VIIIa and Xa.
• Fibrin Degradation Products (FDPs): which inhibit thrombin. 
• Fibrinolytic Inhibitors: these try to prevent the fibrinolytic agents from working so that the thrombus can dissolve at a slow and appropriate rate. They include alpha 2-antiplasmin and PAI (Plasmin Activator Inhibitor). 

That's all for now, in the next post we'll take a look at what happens when haemostasis doesn't work properly. I hope this post will help you understand the process, if you have any questions please feel free to ask in the comments section below :)