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Factor XII Deficiency and the Intrinsic Pathway

Ellie Coggins, MLS(ASCP)CM, MSHA, writes, I have a coagulation question I’m hoping you can help me with. I am wondering why factor VII deficiency causes significant bleeding problems but factor XII deficiency does not. One source I found stated that this is because the extrinsic pathway is the primary pathway in vivo and that the intrinsic pathway is of lesser importance, which seems to answer the question. However, the more I thought about it, Iwondered why hemophilia A and hemophilia B are so severe since they are involved in the intrinsic pathway. Why doesn’t the extrinsic pathway just “pick up the slack” and allow the patient to remain asymptomatic as it seems to with Factor XII deficiency? Thank you in advance for any clarification you can provide!

Hello, Ms. Coggins, and thank you for your excellent question. I’ll take the factor XII question first. Factor XII, along with its cofactors high molecular weight kininogen (HMWK, Fitzgerald factor), and prekallikrein (PK, Fletcher factor) are contact factors that become activated by in vitro negatively charged surfaces and particles. The contact factors have no part in in vivo coagulation, though they may become activated by prostheses such as stents or artificial valves.

To continue, though factor VIII and IX are part of the intrinsic pathway, factor VIII and IX deficiencies are associated with significant bleeding, whereas factor XI deficiency, also part of the intrinsic mechanism, causes variable mild to moderate bleeding. Because the exposure of subendothelial tissue factor and its activation of factor VII, part of the extrinsic pathway, constitute the key coagulation mechanism trigger, why can’t the extrinsic pathway bypass the intrinsic pathway, and make up for factor VIII, IX, or XI deficiency?

The answer is that we portray coagulation incompletely with our plasma-based coagulation mechanism. Hoffman and Monroe revised the coagulation model based on laboratory experiments and reported their results beginning with  publications in 2002, calling the updated mechanism the cell-based coagulation mechanism. Rather than writing a lengthy explanation here, I recommend you see my audio PowerPoints, Cell-based Coagulation 1 and Cell-based Coagulation 2, which explain the new mechanism in detail. Don’t despair, we still use the plasma-based mechanism for all our clinical decision-making, though the cell-based approach will lead to know laboratory and therapeutic approaches in the future. I hope this answers your question. Geo.

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