Although Btk plays an important role in platelet signalling, increased bleeding tendency in patients on ibrutinib is more complex than Btk inhibition alone and is because of several antiplatelet mechanisms, namely inhibition of Btk and Tec kinases, which play a key role in platelet activation downstream of the collagen GPVI and Glycoprotein Ib.
Collagen III has two major hemostasis domains, with binding motifs for von Willebrand factor, α2β1 integrin, platelet binding octapeptide and glycoprotein VI, consistent with the bleeding tendency observed with COL3A1 disease-causing sequence variants.
Individuals with low VWF due to blood group 0 and low platelet collagen receptor density often exhibit a bleeding tendency, e.g. bleedings from mucosal membranes or menorrhagia in females.
Human patients with defects associated with the platelet collagen receptor, glycoprotein (GP)VI, are rare and usually described as having a mild bleeding disorder.