Hi George,
Thank you, thank you, thank You for your educational materials. I have been a tech for 20-some years but this is my first year in special coag and your lectures have helped me tremendously.
From the cell-based coagulation lectures, I am having trouble understanding why the TF/VIIa route does not compensate for a lack of IX or VIII. I understand that the Xa is “on the wrong cell” but after injury to the vessel and exposure of the cell to the platelet, why doesn’t the direct hand-off of Xa and the small amount of thrombin that gets “directly handed to the platelet” create amplification through that part of the “new extrinsic pathway?” Is it simply that there is not enough of the Xa/Va complex generated to cause the formation of enough thrombin to create enough fibrin? Or does it not get handed off to the platelet after exposure because there is no IXa? Please clear away the fog!
Thank you, Anne
From: [email protected]
Anne, I’ve been avoiding your question since Tuesday because it drove me back to the books. Here’s the best answer, which I take from Monroe DM, Hoffman M. What does it take to make the perfect clot? Arteroscler Thromb Vasc Biol 2006;26:41-8.
“The model makes it clear what goes wrong in hemophilia. Platelet adhesion at a site of injury occurs normally, as does production of FXa and small amounts of thrombin on TF-bearing cells during the initiation stage of coagulation. However, platelet surface FX activation by FIXa/FVIIIa is abolished, therefore platelet surface thrombin generation fails. The FVIIa/TF complex cannot effectively substitute for the FIXa/VIIIa complex bcause it produces FXa on the wrong surface. Although it is possible for some FXa to diffuse from its site of production on TF-bearing cells through the fluid phase to the platelet surface, the presence of AT and TFPI is a significant barrier to this process. In addition, the amount of FXa produced by the FVIIa/TF complex may be limited by TFPI.”
I hope this answers the question. To me this means the amplification phase on platelets requires both the Xa/Va and the IXa/VIIIa complexes. At the same time, the amplification effect of XIa seems variable, and for many patients, nearly negligible.
If others are reading this and wondering what this is all about, please go to Educational Modules and take a look at the Cell-based Hemostasis lectures. Geo.
A question from Vilas Hiremath on hemophilia and the thrombo
A question from Vilas Hiremath on hemophilia and the thromboelastograph (follow-up to a February, 2008 post).
Dear George,
A thromboelastograph (TEG) tracing in hemophilia shows low angle (fibrinogen activity) and low MA (platelet aggregation) in spite of normal fibrinogen and normal platelet count. Is it because of low thrombin generation? What is the relation between factor VIII and platelets in hemophilia patients? please comment.
Dear Vilas Hiremath,
On a TEG tracing, the angle is a measure of the rate of clot formation and the maximum amplitude (MA) reflects the “strength” of the fibrin clot. Although strength of clot is ascribed to platelet function, in this instance it is probably a reflection of reduced plasma factor VIII activity, as is the reduced rate of clot formation. There is probably no direct relationship between platelet function and factor VIII activity in hemophilia unless the condition is complicated by a secondary platelet disorder or low von Willebrand factor activity. Geo.