In APS the auto-antibodies are directed against ß2-glycoprotein I. ß2-Glycoprotein I is a plasma protein without a known function. The auto-antibodies dimerise ß2-glycoprotein I, thereby inducing a conformational change and consequently new functions in this protein. We have constructed dimeric ß2-glycoproteine I by extending ß2-glycoproteine I with apple 4 of factor XI (the dimerization domain of factor XI). With this model system we have studied the effects of ß2-glycoproteine I on platelet and endothelial cell function in vitro and in vivo. We have identified LRP8 as receptor on platelets, monocytes and endothelial cells as mediator in the activation of cells by anti-ß2-glycoprotein I antibodies and we have developed protein inhibitors for LRP8, which can completely prevent thrombus formation in an animal model with APS.
In TTP, the auto-antibodies are directed against ADAMTS-13, a protease involved in the processing of vWF. Absence of ADAMTS-13 activity results in a very high multimers of vWF that are in a GPIb binding conformation. As a consequence platelets clump, resulting in thrombotic microangiopathy. We have shown that absence of ADAMTS13 is not enough to explain the presence of vWF in a GPIb-binding conformation.
Specific aims
To understand why antibodies directed against ß2Glycoprotein can cause thrombosis in every vessel within the human body.
To understand the role of LRP8 plays in haemostasis.
To understand the consequences that conformational changes within vWF and GPIb have for the development of thrombotic microangiopathies (but sometimes also haemorrhages).
Project leader: Prof.dr. Ph.G. de Groot