Hemostasis

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.

     2. Aggregated platelets release Platelet Thromboplastin (Factor III) which activates the clotting     process.

     3. Clumped platelets provide a surface essential for the clotting process.Along with ADP, the     clumped platelets secrete thromboxane, a powerful vasoconstrictor.

III. Coagulation Phase - Begins 30 seconds to several minutes after phases I and II have commenced.

      A.  The overall process involves the formation of the insoluble protein Fibrin from the plasma      protein Fibrinogen through the action of the enzyme Thrombin.  Fibrin forms a network of fibers      which traps blood cells and platelets forming a thrombus or clot.

      B.  This 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

      Activator (Factor X). Depending on the initial trigger for the clotting reactions, there are two      pathways leading to the formation of the thrombus; the Extrinsic Pathway and the Intrinsic      Pathway.

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.

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).

FACTOR   NAME         SOURCE     PATHWAY

I     Fibrinogen      Liver     Common

II        Prothrombin (enzyme)   Liver *        Common

III Thromboplastin Released by damaged cells

Extrinsic

III      Thromboplastin Released by platelets Intrinsic

IV    Calcium ions          Bone and gut Entire process

V          Proaccererin    (heat labile cofactor)

Liver and Platelets    Extrinsic and Intrinsic

VII       Proconvertin (enzyme)   Liver *       Extrinsic

VIII   Anti-hemolytic factor(cofactor) 

Platelets and endothelium

Intrinsic

IX Christmas factor(plasma thromboplastin component)

Liver * Intrinsic

X   Stuart Prower factor (enzyme)  

Liver *         Extrinsic and Intrinsic

XI    Plasma thromboplastin antecedent (enzyme)

Liver      Intrinsic

XII              Hageman factor Liver    Intrinsic; also activates plasmin

XIII          Fibrin stabilizing factor Liver         Retards fibrinolysis*vitamin K dependent

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, inhibitsthe aggregation of platelets and produces vasodilation.

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:

a. In breast-fed newborns, the gut hasn't built up a vigorous bacterial flora.

b. Obstruction of the biliary system will lead to poor fat digestion.  As a result, fat-soluble vitamins like K will be lost with the feces.  Vitamin K is routinely injected into a patient with liver disease or obstructed bile ducts before any surgical procedure.

c. Long term antibiotic therapy can eliminate the bacterial flora of the gut.

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:

a.  Autoimmune destruction of thrombocytes - This condition may be relieved with cortisone.

b.  Damage to red marrow as a result of exposure to radiation or toxic chemicals.

c.  Long term use of sulfa antibiotics, e.g., Bactrim.

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.