Blood Clotting
(Transcribed
from Dr. Laville’s lecture on Wed, 16 February 2000 by Brian Buschman)
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In platelets to aggregate two factors are vitally important in regulation of the pathway:
1) The platelets released Thromboxane A2 (TxA2).
2) The capillary endothelial cells produce and release Prostaglandin I2 (PgI2).
These factors (as well as all prostaglandins) are derived from arachidonic acid through the common intermediate, PgH2, to be discussed in a future lecture.
To prevent coagulation when the blood vessels have not been damaged the capillary endothelial cells produce and release PgI2. When the capillary endothelial cells are injured then quit releasing PgI2 and the TxA2 made and released from platelets is able to induce platelet aggregation.
When the damage occurs and platelets begin to aggregate then require the presence of von Willibrand’s factor to mediate the binding of platelets to the collagen in the capillary walls. Binding sites for von Willibrand’s factor exist on the platelets and the binding of the von Willibrand’s factor/platelet complex to collagen stimulates the platelets to produce and release TxA2 which, as already discussed, causes platelets to aggregate.
During clotting fibrinogen molecules are activated to fibrin molecules that form disulfide bridges between each other to form a “soft fibrin clot.”
Most enzymes in the body, including all clotting factors, are initially released as zymogens that are inactive forms of the enzyme and are activated as needed. Zymogens are identified as their names either begin with pro- (procollagen) or end in –ogen (fibrinogen).
There are two clotting cascades:
1) The Intrinsic Pathway that is so called because all of the factors are located in the blood. It is called the “simple pathway” and is the pathway used to clot when the capillary endothelium has been damaged (this is both when just the endothelium is damaged and also when the extrinsic pathway has also been activated).
2) The Extrinsic Pathway named because one Tissue Factor (factor III) that is essential in this pathway is not found in the blood but is in most tissues. It’s also called the “complex pathway” and in induced then there is trauma breaking through both the endothelium and tissues outside of that.
3) The Common Pathway is the final steps in both pathways.
It is easiest to understand this when you diagram them but I don’t have to software to do that for you. Take what I say here and make a chart illustrating it.
The Common Pathway begins form either pathway with the activation of factor X to Xa (all clotting factors are labeled with an “a” when activated). Factor Xa and Va induce the conversion of prothrombin (II) to thrombin (IIa) that in turn cleaves fibrinogen (I) to make a fibrin aggregate (Ia). Factor XIIIa then will convert the fibrin aggregate to a cross-linked fibrin clot.
The Extrinsic Pathway begins with the conversion of VII to factor VIIa but the pathway is not activated until trauma induces the release of Tissue Factor (III) that induces the activation of factor X to Xa. The rest follows the common pathway.
The Intrinsic Pathway begins with the release of Kininogen that is released when the blood comes into contact with the tunica media (to be discussed in histology of blood vessels). Kininogen activated XII to XIIa that activates XI to XIa that activates IX to IXa. Factor IXa in combination with factor VIIIa will then activate X to Xa to begin the common pathway.
After the tissue has healed it is time for the clot to be broken down. Urokinase is released and activates plasminogen to plasmin that cleaves the fibrin clot.
Vitamin K is essential for the production of usable thrombin (II), VII, IX, and X that are not active unless they are bound to the endothelium. Ca2+ mediates their binding but the factors must be modified to interact with Ca2+. To interact with the Ca2+ they must have a chain of 10 glutamate residues at the end of their chain that have been converted to g-carboxyglutamate. The pathway to make the conversion is done through a reduced form of vitamin K. With a lack of vitamin K usable versions of the above factors cannot be synthesized.
Dicumarol (warfarin) is an anticoagulant that is a vitamin K analog that functions to block the reduction of vitamin K preventing proper formation of these factors. Poisoning by OD of warfarin is treated by administration of menadione that is another vitamin K analog that blocks the effects of dicumarol.
Vitamin K deficiency will lead to clotting problems and can come about through three common sources:
1) Steatorrhoea that is a shortage of bile salts that inhibits the uptake of fatty acids in the gut therefore preventing the uptake of the fat-soluble vitamin.
2) Long-term use of broad-spectrum antibiotics. Intestinal bacteria produce Vitamin K so killing the normal flora is not desired.
3) Cholestasis that is a problem with fat uptake that will also prevent the uptake of vitamin K.
Two tests are used to determine if there is a sufficient level of clotting factors in the blood stream and to determine if a patient has a clotting disorder.
Prothrombin Time Test (PT test) that tests for the factors of the extrinsic and common pathways (VII, X, V, prothrombin and fibrinogen).
Activated Partial Thromboplastin Time Test (PTT test) that tests for the factors of the intrinsic and common pathways (XII, XI, IX, VIII, X, V, prothrombin and fibrinogen).
(To help you remember, the one with the longer name tests for more factors and vice versa.)
The PTT test will test for the two types of hemophilia:
1) Hemophilia A that represents a shortage of factor VIII.
2) Hemophilia B that represents a shortage of factor IX.
Thrombocytopenia is a deficiency of platelets due to a lack of formation from any of a number of problems
Storage Pool Disease is an inherited lack of granules containing necessary factors.
Congenital Afibrinogenaemia is an inherited failure to produce fibrin.
Von Willibrand’s Disease is a lack of von Willibrand’s factor, the protein that mediates the binding of platelets to collagen.
Aspirin Toxicity is a disorder where regulation of the production of TxA2 has been removed excess is produced.
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