Q. We learnt about a pretty rare disorder called thrombotic thrombocytopenic purpura (TTP) in which super-huge von Willebrand Factor (vWF) multimers are made which lead to occlusion of microcirculation. It was explained that this is often due to deficiency of the ADAMTS13 enzyme, which normally inhibits vWF multimers from getting too large. My question is about the normal state of play between vWF and ADAMTS 13. From what I can infer: when no clotting is needed, the ADAMTS13 successfully stops the vWF forming multimers etc. But what happens when we need to clot? What inhibits the ADAMTS 13 protease? What’s that mechanism?
A. First, a little background about von Willebrand factor (VWF). VWF is constitutively released into the blood by endothelial cells as multimers of varying size. A significant amount of VWF is stored in Weibel-Palade bodies, mostly as super-big multimers (called ultra-large VWF, or UL-VWF); this pool is released upon endothelial cell activation. Larger VWF multimers bind circulating platelets more readily than smaller forms. These big multimers also change shape as blood flows faster (normally they circulate in globular forms, but when they are exposed to increased shear forces – like in the microcirculation, or in areas of endothelial injury – they unravel into “stringlike” shapes, which expose more platelet-binding sites on the VWF molecule).  So at sites of endothelial disruption, VWF binds to collagen and unfolds in response to shear forces. This facilitates platelet tethering (adhesion) to the subendothelium, which is necessary for the formation of a good platelet plug.
If we didn’t have a way to keep these large VWF multimers under control, there would be a ton of thrombus formation going on! In fact, that is exactly what happens in the disease you mention, thrombotic thrombocytopenic purpura (we’ve talked about TTP before here and here). Patients have tons of UL-VWF floating around, and they make lots of little thrombi, especially in the microcirculation.
It turns out we do have a way to keep these large VWF from running rampant: it’s an enzyme called ADAMTS13. This enzyme cleaves the UL-VWF, inactivating it.  But if you think about it, you’d need a way to regulate the ADAMTS13 too – which is exactly what you’re asking. If you didn’t have some way to regulate ADAMTS 13 activity, you’d never make good platelet plugs when you needed to! The ADAMTS 13 would just cleave the VWF as soon as it unraveled, and you’d get no platelet tethering and no thrombus.
The answer to that conundrum is that thrombin, plasmin, and factor XA all cleave ADAMTS 13 and inactivate it. Thrombin, in particular, seems to do a really good job. That’s cool: thrombin actually inactivates an enzyme (ADAMTS 13) in order to promote growth of the thrombus! And on the surface of adjacent uninjured endothelium, any thrombin hanging around would preferentially bind to thrombomodulin (and so be unable to interact with – and inhibit – ADAMTS 13). So in this region of normal endothelium, ADAMTS 13 would be able to act like it normally does, cleaving vWF and preventing thrombus formation.
Whew. The more people find out about coagulation and thrombus formation, the more I think you can just take whatever little coagulation cascade diagram you have and draw arrows from everything to everything else.
Image of Adam (looking fairly inactive at the moment): Michelangelo, Sistine Chapel.
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