Wednesday, December 9, 2009
DECEMBER COAGULATION CORNER
You know fibrin, and factors and inhibitors and platelets
Protein C, Protein S, APCR and activators
But do you recall, the most powerful coagulant of all-
Thrombin the strongest clotter,
Has a very important role
And for you to understand this
You would have to know where thrombin works
All of the other factors
Thought thrombin was just needed for a final clot
They never realized poor thrombin
Worked throughout the cascade and really did a lot!
Then one time when someone said
It seems things are confused
If we have 2 pathways,
Why doesn't one takeover when the other can't work?
Then all the factors realized,
As they shouted out with glee
Thrombin the strongest clotter
Works through initiation, amplification and propagation, all three!
So I hope Rudolph doesn't get insulted that I borrowed his tune to tout the role of thrombin. Like Rudolph thrombin has been very misunderstood and underappreciated!
The primary role of thrombin in the basic in-vitro coagulation cascade is in the conversion of fibrinogen to fibrin. Additional responsibilities of thrombin includes the activation of Factor XIII ïƒ XIIIa, resulting in crosslinked fibrin and the activation of platelets and its feedback mechanism within this cycle to activate additional factors. However, coagulation does not occur as was previously thought of through a "cascade" or "waterfall" series of interactions. In reality, coagulation is a network of simultaneous interactions with regulation and modulation of these interactions during thrombin generation. Generation of thrombin is in reality the pivotal step of hemostasis.
CELL BASED MODEL OF COAGULATION:
The cell-based model of coagulation suggests that there are "intrinsic" and "extrinsic" pathways in the coagulation process, but it has been discovered that these pathways occur on different surfaces.. The "extrinsic" or tissue factor (TF) pathway consists of the FVIIa/TF complex and the FXa/Va complex. It operates on the TF-bearing cell to initiate the coagulation process. While the intrinsic pathway consists of FXI(a), the FIXa/VIIIa complex,and the FXa/Va complex, which operates on the surface of the platelet and generates of burst of thrombin during propagation. Both pathways are needed and operate on different surfaces.
Step one is INITIATION:
In this phase, the combination of tissue factor (TF) and Factor VII (FVII) leads to the direct activation of FX to Factor Xa (FXa). The reaction, however, is not robust and can be effectively inhibited by Tissue factor pathway inhibitor. (TFPI). The combination of TF and FVII also is capable of activating Factor IX (FIX) to Factor IXa (FIXa), which may help to explain why IX is the only intrinsic factor affected by Vitamin K.
Step Two is AMPLIFICATION:
In this phase, the small amount of FXa produced by TF-rFVIIa interaction leads to a limited amount of thrombin generation. The amount of thrombin produced is inadequate to support normal fibrin generation and in fact can be significantly inhibited by antithrombin. The signal becomes amplified when thrombin binds to platelets and initiates several positive feedback loops. This demonstrates the continuing role of platelets in this process, as well as the beginning of the feedback mechanism of thrombin.
What is the role of thrombin:
- Thrombin (IIa) activates FV->Va as the prothrombin complex which assembles on platelet membranes
- Thrombin releases VIII->VIIIa as a component of a tenase complex which assembles on platelet surfaces
- Thrombin (IIa) activates XI->XIa and IX->IXa
- IIa then leads to platelet activation to set the stage for tenase & prothrombin complex
At the end of the amplification phase, the stage is set for the large burst of thrombin generation that is essential to stable clot formation.
Step three is PROPAGATION:
Then propagation of coagulation occurs including activation of platelets, factors V and VIII. Activated factors VIII and IX combine on the surface of these activated platelets activating factor X, resulting in the generation of large amounts of thrombin fibrin formation and the ultimate process of clot formation.
Thrombin not only plays a crucial role in hemostasis it is also a regulator of many pro-inflammatory processes. Some of these include:
- Leukocyte adhesion molecule expression on endothelium
- Platelet activation
- Leukocyte chemotasis
- Endothelial cell production of prothrombotic factors
Thrombin also is a potent growth factor which can initiate endothelial, fibroblast and smooth muscle cell proliferation as well as up regulating other growth factors.
It has also been found that thrombin plays a central role in atherosclerotic lesion formation.
Thrombin's role truly is the center of coagulation. Identifying many of its processes, better explains many unanswered questions in coagulation
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