Sudden and severe loss of blood can lead to shock and death. When blood vessels are damaged, Hemostasis (clot formation) will arrest bleeding. This process is divided into three phases.
I. Vascular phase - Cutting or damaging blood vessels leads to vascular spasm of the smooth muscle in the vessel wall. This produces a vasoconstriction which will slow or even stop blood flow. This response will last up to 30 minutes and is localized to the damaged area.
II. Platelet phase - Damaged endothelial cells lining the blood vessel release von Willebrand's Factor. This substance makes the surfaces of the endothelial cells "sticky". This condition may, by itself, be enough to close small blood vessels. In larger blood vessels, platelets begin to stick to the surfaces of endothelial cells. This effect is called Platelet Adhesion.
The platelets that adhere to the vessel walls now begin to secrete Adenosine diphosphate (ADP) which is released from "stuck" platelets. This material causes the aggregation of nearby free platelets which attach to the fixed platelets and each other. This
aggregation of platelets leads to the formation of a platelet plug.
This clumping of platelets serves a number of functions:
1. It can plug the break in a small blood vessel.
platelets release Platelet Thromboplastin (Factor III) which activates the clotting
platelets provide a surface essential for the clotting process.Along with ADP, the
III. Coagulation Phase - Begins 30 seconds to several minutes after phases I and II have commenced.
overall process involves the formation of the insoluble protein Fibrin from the plasma
process depends on the presence in the blood of 11 different clotting factors (proteins)
and calcium (Factor IV). Ultimately,
these factors will generate the production of Prothrombin
Extrinsic Pathway - Is initiated with material outside of or "extrinsic" to the blood. This material, Tissue Thromboplastin (Factor III), is released by damaged tissue cells. Factor III permits the clotting process to take a chemical shortcut. As a result, the extrinsic pathway is a very rapid process, i.e., within 12 to 15 seconds. However, the production of Thrombin is low and the resulting clot is small. This pathway is most effective as a "quick patch" process.
1. Damaged tissue releases Tissue Thromboplastin (Factor III).
2. Tissue Thromboplastin activates Factor VII (Calcium dependent step).
3. Factor VII activates Factor X - Prothrombin Activator (Calcium dependent step).
Intrinsic Pathway - Is initiated by the blood coming in contact with exposed collagen in the blood vessel wall, i.e., material within the blood or blood vessel wall. This process is considerably slower (5 to 10 minutes) but results in the formation of larger amounts of thrombin. This allows the formation of larger clots.
1. Factor XII is activated by making contact with exposed collagen underlying the endothelium in the blood vessel wall.
2. Factor XII activates Factor XI.
3. Factors XII and XI (contact activation product) jointly activate Factor IX.
4. Factor IX activates Factor VIII.
5. Factor VIII together with Calcium ions and Factor III from platelets (Platelet Thromboplastin) activate Factor X - Prothrombin Activator. Since Factor III is released from activated platelets, the completion of the Intrinsic Pathway depends on there being an adequate number of platelets in circulation.
It should be noted that both pathways lead to the same reaction, namely, the activation of Factor X - Prothrombin Activator. From this point on, both pathways follow the same course to Fibrin formation. For this reason the steps from Factor X activation to Fibrin formation are referred to as the Common Pathway.
1. Factor X (active) engages in a series of reactions with Factor V, Calcium ions and phospholipids derived from platelets. This composite of clotting factors and their reactions is referred to as the Factor V Complex or Prothrombin Activator.
2. Factor V Complex initiates the conversion of Prothrombin to active form of the enzyme Thrombin.
3. Thrombin accelerates the formation of
Fibrin threads from Fibrinogen (Factor I).
IV. Clot Retraction - After 2 or 3 days, the clot begins to contract. Platelets in the clot contain contractile proteins. These proteins pull the edges of the wound together and reduces the chance of further hemorrhage. This activity also assists the repair processes.
V. Fibrinolysis - Dissolution of the clot. The breakdown of the clot is due to the production of a powerful proteolytic enzyme Plasmin. Plasmin is formed through the same chemical pathway that produces thrombin. These reactions demonstrate that materials which induce clot formation (Thrombin and Factor XII) will eventually assist in the breakup of the clot.
Other Anti-Hemostatic Activities
1. An intact endothelium separates platelets and clotting factors from the thrombogenic collagen.
2. Activated platelets release Thrombin which stimulates the production of prostacyclin, a protaglandin, by the endothelium. Prostacyclin inhibits the adherence of platelets to the surrounding uninjured endothelium, inhibits aggregation of platelets and is a potent vasodilator. The increased flow of blood past a non- occlusive clot helps to control the spread of the clotting process by diluting the activating factors (IX, X, XI for example) at the site. The circulation will carry these factors to the liver where they are degraded.
3. Endothelial cells inhibit platelet aggregation by breaking down ADP.
4. Surface molecules on the endothelial cells interact with plasma components to produce anticoagulant activity.
ANTICOAGULANT COMPONENTS OF HEMOSTASIS
1. Smooth, intact endothelium - an undamaged endothelial lining prevents the initiation of hemostasis.
2. Thrombin adsorption to fibrin - 9O% of thrombin formed during hemostasis is adsorbed to fibrin preventing the diffusion of thrombin to surrounding areas.
3. Heparin - released from mast cells (tissue basophils) inactivates thrombin.
4. Activated thrombin - stimulates
endothelial cells to release a prostaglandin, prostacyclin. Prostacyclin prevents
adherence of platelets to surrounding, uninjured endothelial cells, inhibits
5. Fibrinolytic system - is turned on as a direct outcome of the clotting process. Hageman factor (XII) activates plasminogen forming the fibrin digesting enzyme plasmin.
ACQUIRED CLOTTING DISORDERS - CAUSES
1. Liver Damage - Various diseases, e.g., Cirrhosis, Hepatitis and Liver cancer, depress the production of all liver-dependent clotting factors. This may lead to severe bleeding.
2. Vitamin K Deficiency - This essential component of hemostasis is normally produced by bacteria of the gut. Certain conditions will lead to a severe deficiency of this vitamin:
3. Thrombocytopenia - Reduced numbers of circulating thrombocytes (less than 7O,OOO/mm3 of whole blood) will lead to a severely reduced clotting capacity of the blood. Conditions leading to this disorder include:
Inherited Clotting Disorders
1. Hemophilia A (classic hemophilia) - leads to the production of a defective Factor VIII. This is the most common form of hemophilia and is due to a X chromosome-linked recessive gene. It is most common in males.
2. Hemophilia B (Christmas disease) - leads to the production of a defective Factor IX. Hemophilia B is due to a defective gene linked to the X chromosome and is most commonly found in males.
3. Von Willebrand's Disease - the result of a lack of effective von Willebrand's Factor. It is due to an autosomal dominant gene and occurs equally in males and females.