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Learning Center
Coagulation Corner
Monday, August 4, 2008
HISTORY OF BLOOD COAGULATION
The study of blood coagulation can be traced back to about 400BC and the father of medicine, Hippocrates. He observed that the blood of a wounded soldier congealed as it cooled, as well as bleeding from a small wound stopped as skin covered the blood. If the skin was removed bleeding started again. Aristotle noted that blood cooled when removed from the body which initiated decay resulting in the congealing of the blood. If fibers were removed, there was no clotting. It wasn't until 1627 that Mercurialis observed clots in veins that were at body temperature. In 1770 William Hewson challenged the cooling theory and believed that air and lack of motion were important in the initiation of clotting. Hewson described the clotting process demonstrating that the clot comes from the liquid portion of blood, the coagulable lymph, and not from the cells, disproving the cooling theory. It was Paul Morawitz in 1905 that assembled coagulation factors into the scheme of coagulation which demonstrated that in the presence of calcium and thromboplastin, prothrombin (II) was converted to thrombin which in turn converted fibrinogen (I) into a fibrin clot. This theory persisted for 40 years until Paul Owren, in 1944, discovered a bleeding patient that a four factor concept of clotting could not apply, thus factor V was discovered. Owren also observed a cofactor that was involved in the conversion of prothrombin to thrombin. In 1952 Loeliger named this factor VII. Factor VIII was identified as classic hemophilia prior to the identification of VII in 1936-1937) In 1947 Pavlovsky reported that the blood from some hemophiliac patients corrected the abnormal clotting time in others. In 1952 this was called Christmas disease, after the family in which it was discovered, or Factor IX. Factor X deficiency was described in 1957 in a woman named Prower and a man Stuart, where there blood clotting when mixed with factor VII deficient plasma; hence a new factor was defined. Factor XI was described in 1953 as a milder bleeding tendency. In 1955 Ratnoff and Colopy identified a patient John Hageman with a Factor XII deficiency that died from a thrombotic event not a bleeding disorder. In 1960 Ducker described patients that had a bleeding diathesis and characteristic delayed wound healing. This fibrin stabilizing factor was called Factor XIII. Prekallikrein (1965) discovered from four siblings in the Fletcher family demonstrated no bleeding tendencies, as well as High-Molecular-Weight Kininogen (1975). These were both identified as contact activation cofactors that participated in the activation of factor XI by factor XII. (1) In 1882 platelets were recognized as being different than white and red blood cells by Bizzozero, but its relationship in coagulation didn't become important until 1970. Each platelet makes 14,00 trips through the bloodstream in its life span of 7-10 days.
Testing of blood plasma factors and platelets depended on seeing the clotting process directly or microscopically. The first whole blood clotting time was done in 1780 by William Hewson who noted that blood taken from healthy people clotted in 7 minutes while some disease stated took from 15-20 minutes up to 1 ½ hours.
In 1897 Brodie and Russel begin observing the process on a glass slide. A drop of blood was placed on a glass cone, in a temperature controlled glass chamber agitated by an air jet. Blood no longer moved microscopically but clotted in 3 minutes and was completed at 8 minutes. In 1905 Golhorm used a wire loop attached to a glass tube. In 1910 Kottman observed an increased viscosity in clotting blood in a Koaguloviskosimeter. Blood was rotated at 20 degrees 12-15 time/minute. In 1936 Baldes and Nygaard added photoelectric tracings called a coagelgram depicting shape change by light transmittance.
In the 1960's BBL introduced the Fibrometer. This instrument provided mechanical registration of clots that allowed more reproducible timing and an expression of the clotting process. (2)
1. Owen, Charles, A., "A History of Blood Coagulation", Mayo Foundation for Medical Education and Research, Rochester, Minnesota, 2001.
2. Hougie, Cecil, "Fundamentals of Blood Coagulation in Clinical Medicine", McGraw-Hill Book Company, New York 1963.
So what do you know?
We know that coagulation is a system of checks and balances that relies on a series of enzymatic reactions, naturally occurring anticoagulants and inhibitors. This waterfall theory is based on activation of factors and the initiation of coagulation. This occurred through two pathways, the extrinsic and the intrinsic pathway. The extrinsic pathway relied on the interaction of tissue factor and factor VII, while the intrinsic pathway utilized factor XII and the contact factor. These meet at the common pathway where they generate factor X to Xa and the conversion of prothrombin to its active form thrombin which then allows the conversion of fibrinogen to fibrin. This process follows laboratory based testing hence we have the in-vitro process. It allows us to follow the logic (not that you usually see the word logic and coagulation in the same sentence) of our testing- so what do we know? From this we can report the following:
1. Patient with just an abnormal PT, no meds, factor VII deficiency
2. With just an abnormal APTT, no meds, bleeding VIII, IX and XI, no bleeding XII
3. Both PT and APTT, look at the common pathway for factors I, II, V and X.
This schematic has served the laboratory well in testing and diagnosing disorders. But like all of the history before us, there have always been questions. For example:
1. Why is Factor IX a vitamin K dependent factor?
2. How come some factor XI patients bleed, while others don't?
3. Why don't people with a XII deficiency bleed?
4. Why can't one pathway take over when there is a deficiency in the other?
5. What is the relationship of platelets in this process? They aren't measured in the process.
6. How does this testing account for the variation in hemophilia, and how does recombinant VIIa work?
7. Just how important is thrombin?
This cascade, while is very important in laboratory based coagulation testing,, does not reflect what happens physiologically.
The in vivo model is a cell-based model of coagulation. This relies on 3 stages of coagulation and how they work.
INITIATION - Tissue Factor (TF) activates VII to VIIa which in turn activates FX to FXa and also activates FIX to FIXa
AMPLIFICATION: FXa starte to generate thrombin, which binds to platelets and begins the feedback mechanism of thrombin.
Thrombin is the most powerful coagulant. It activates V and VIII, but as thrombin increases it also destroys V and VIII by proteolysis. Factor Xa enhances fVII, but through a reaction with tissue factor pathway inhibitor, it prevents further activate. Thrombin feedback activation of IX can help to explain whay the intrisinc pathey can occur in the absence of contact factors. Since TF is expressed following an injury, we know it forma a complex with VIIa, then activaes X and IX, it is further amplified by V, VII and XI leading to intrinsic pathway activation. This feedback theory can help explain why patient with fador XII deficiencies don't bleed.
PROPAGATION: activated platelet and thrombin formation continue to make large amount of thrombin and allows for fibrin formation.
The extrinsic pathway is based on tissue bearing cells to initiate and amplify coagulation
The Intrinsic pathway operates on an activated platelet surface to produce the burst of thrombin to stabilize the clot.
So now what do we know - using the cell based model of coagulation:
1. The APTT reflects factors in the intrinsic platelet surface pathway
2. Hemophilia is a failure of platelet surface thrombin generation
3. Factor Xa can't tell the difference between a tissue factor bearing call and platelet surface
4. As a result one pathway can't make up for deficiencies in the other- because they produce complexes on different cell surfaces
5. Using rVIIa in hemophiliacs with inhibitors was though to boost tissue factor pathways, but to work in hemophilia you need to generate Xa to thrombin on platelet surfaces. The way rVIIa works is that is binds to activated platelets and activates X on platelet surfaces, high doses are neede because rVIIa binds to platelets with a low affinity.
It seems as though coagulation has just touched the tip of the understanding and holds keys to the many mysteries of the working and disease process in man.
So what do we know, is that we have a lot more to learn!
Donna Castellone
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About the Author
Donna Castellone,
MS, MT(ASCP)SH
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