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

Fibrinogen

Liver

Common

II

Prothrombin (enzyme)

Liver *

Common

III

Thromboplastin

Released by damaged
Extrinsic
cells

III

Thromboplastin

Released by platelets

Intrinsic

IV

Calcium ions

Bone and gut

Entire process

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

Stuart Prower factor

(enzyme)

Liver *

Extrinsic and Intrinsic

XI

Plasma thromboplastin
antecedent (enzyme)

Liver

Intrinsic

Liver

Intrinsic; also
activates plasmin

Liver

Retards fibrinolysis

XII
XIII

Hageman factor
Fibrin stabilizing factor

*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, inhibits
the 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.