What are the underlying pathophysiological mechanisms in TTP?
vWF is a large glycoprotein present in the plasma whose functions include binding factor VIII, and activating and binding platelets in response to endothelial injury.
It is produced in the endothelium as ultra-large multimers that are inactivated when cleaved by Von-Willebrand factor-cleaving protease (vWF-CP), also known as ADAMTS13 (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13
The pathological hallmark in TTP is a deficiency of von Willebrand factor-cleaving protease (vWF-CP) or ADAMTS13. This may be genetic (absence of enzyme) or acquired (presence of autoantibody to vWF-CP).
In TTP, these multimers are not cleaved resulting in ultra-large multimers
The VWF multimers bind to platelets and result in uncontrolled platelet activation. Fibrin is deposited and thrombus propagated
The end result is ischaemia distally, and red cells are shredded as they pass the fibrin/platelet mesh (microangiopathic haemolytic anaemia, MAHA).