Prinicples of coag

Question 1

Describe the 1st phase of coagulation.

Answer 1

Phase 1: The first phase consists of localized vasoconstriction which occurs near the

site of vessel injury and is initiated by reflex neurogenic mechanisms as well as by

the release of vasoconstrictor substances such as endothelin which are derived from

endothelial cells. The function of localized vasoconstriction is to reduce the

magnitude of blood loss by decreasing blood flow to the injured area. In addition, the

narrowing of the blood vessel leads to a redistribution of the flowing elements in

blood such that the red blood cells and white cells are carried into the center of the

flowing stream and the platelets and coagulation proteins are moved to the outer

edge which enhances their interaction with the vessel wall

Question 2

Describe phase 2 of coagulation

Answer 2

Phase 2: The second phase is called primary hemostasis which refers to the

interactions that occur between blood platelets and exposed subendothelial collagen.

Platelets adhere to collagen by an interaction involving a protein called von

Willebrand Factor and specific surface membrane glycoprotein receptors on the

platelet. Following adhesion, platelets undergo a shape change in which the

individual platelets begin to spread out over the exposed collagen surface.

Following shape change, the adherent platelets are stimulated to release substances

contained within specific granules inside of the platelet. These substances lead to

activation of additional platelets in the area which then can bind to other regions of

exposed collagen or to other platelets in a process referred to as platelet recruitment.

Platelet-platelet interaction leads to further stimulation and granule release by a process

called platelet aggregation. Eventually, enough platelets accumulate at the site to

form a primary hemostatic plug that stops further blood loss (see Figure 3).

Question 3

Describe phase 3 of coagulation.

Answer 3

Phase 3: The third phase of hemostasis is referred to as secondary hemostasis and

consists of a complex series of reactions referred to as the coagulation cascade. The

coagulation cascade is activated when circulating plasma proteins encounter

endothelial cells which have expressed tissue factor, a membrane bound procoagulant

protein synthesized by endothelial cells which is exposed at the site of vascular injury.

Exposure of plasma proteins to tissue factor leads to formation of a protease

called thrombin by a sequential series of calcium and phospholipid- activated

reactions that are localized to the membrane surface of platelets present in the

primary hemostatic plug. Once formed, thrombin cleaves another soluble circulating

plasma protein called fibrinogen to form an insoluble fibrin polymer. The fibrin

polymer forms a matrix that surrounds and traps the platelets and essentially cements

them together stabilizing the primary hemostatic plug. As the fibrin polymer forms,

circulating white blood cells and red blood cells also may become trapped within the

growing thrombus (see Figure 4).

Question 4

Describe phase 4 of coagulation.

Answer 4

Phase 4: The final phase of hemostasis consists of a series of events in which: 1) the

thrombotic process is terminated by counter-regulatory mechanisms (such as

thrombomodulin produced by endothelial cells) and 2) the fibrin polymer which is

formed at the site, undergoes remodeling by a process referred to as fibrinolysis

(initiated by two endothelial cell proteins referred to as tissue type plasminogen

activator or TPA and urokinase plasminogen activator or UPA).

Fibrinolytic remodeling of the thrombus begins at the outer surface of the clot and

proceeds relatively slowly. When the thrombus is shrinks sufficiently, endothelial cells

will proliferate and restore a contiguous endothelial surface. The function of this

process is to eventually allow for restoration of blood flow to the tissue distal to the site

of injury in order to maintain the viability of the cells in that region (see Figure 5 and

Figure 6).

Question 5

Describe various regulatory mechanisms that keep coagulation localized and rapid.

Answer 5

To function effectively, the hemostatic process must be rapid and localized to the site

of vascular injury. Primary hemostasis is localized by specific interactions of platelets

with subendothelial matrix components that are only exposed at the site of vessel

injury. Secondary hemostasis is in part localized by virtue of the fact that certain

critical reactions in the coagulation cascade are dependent on the presence of specific

anionic phospholipids which are exposed on the membrane surface of platelets

which accumulate at the site. Other important factors which control the hemostatic

process include blood flow itself which reduces the chance of a localized concentration

of precursors building up and removes activated materials by dilution into a larger

volume of flowing blood. Plasma also contains a number of inhibitors which

inactivate proteases generated by the coagulation cascade. Endothelial cells also play

a vitally important role in regulating normal hemostasis. Endothelial cells possess a

number of clot-promoting or procoagulant activities as well as a number of clot-
inhibiting or anti-coagulant activities. The critical role of these regulatory mechanisms

will be discussed in more detail in future lectures.