TGFBIp: more than meets the eye?

After damage to the endothelium, platelets prevent excessive bleeding by adhering to the exposed ECM. In this issue of Blood, Kim and colleagues¹  describe a novel function of TGFBIp that potentiates platelet adhesion and activation, a protein with a previously established role in corneal dystrophies.² 

When platelets adhere, spread, and become activated, they form a procoagulant surface that stabilizes the wounded area. Platelets adhere to several extracellular matrix (ECM) proteins including collagen, von Willebrand factor (VWF), and fibrinogen.³  However, multiple interactions are necessary to secure platelet adhesion; mice deficient in fibrinogen and VWF still form occlusive thrombi.⁴  This suggests that other ECM or platelet-derived proteins contribute to adhesive events at the vascular wall. One of these proteins appears to be transforming growth factor beta–induced protein (TGFBIp). Interestingly, TGFBIp has been shown to affect sight. Abnormal deposition of TGFBIp mutants has been linked to blurred vision.²  In the current study, Kim et al go “outside the eye” to discover that platelets store TGFBIp and release it upon thrombin activation. Although future studies are necessary to resolve how TGFBIp accumulates inside platelets, the authors show that TGFBIp facilitates platelet adhesion and spreading and that soluble TGFBIp induces the expression of surface P-selectin and phosphatidylserine. Taken together, these data indicate that activated platelets may release TGFBIp, which, in turn, recruits additional platelets to the site of injury (see figure).

The mechanism behind TGFBIp-induced platelet activation requires further insight. The FAS1 domain of TGFBIp regulates platelet adhesion, in part through interactions with integrin α₅β₁. However, other partners likely participate since interruption of TGFBIp binding to α₅β₁ partially interferes with, but does not completely abrogate, platelet adhesion. Once adhesion has occurred, TGFBIp promotes platelet spreading through its RGD domain, most likely through interactions that involve integrin α_IIbβ₃. In this regard, the authors demonstrate that TGFBIp induces conformational activation of α_IIbβ₃. These intriguing observations indicate new roles for TGFBIp in platelet activation and provide an impetus for identifying the cognate TGFBIp receptor so that more in-depth mechanistic studies can be pursued.

Interestingly, too much TGFBIp may induce thrombosis. By simulating arterial shear rates, the authors demonstrate that platelets more readily adhere to collagen and form thrombi in the presence of TGFBIp. Furthermore, injections of epinephrine in mice in conjunction with increased levels of TGFBIp (through either coadministration of the recombinant protein or transgenic overexpression of TGFBIp) results in increased pulmonary emboli compared with mice receiving epinephrine alone.

So is TGFBIp an important player in arterial thrombosis? The pulmonary embolism model used by the authors provide evidence in favor of TGFBIp promoting increased platelet aggregation in the vasculature.⁵  Nevertheless, questions still remain about the in vivo relevance of TGFBIp in thrombus formation. Exploiting different thrombosis models, such as ferric chloride or laser-induced injury, may supply further support that elevated levels of TGFBIp foster thrombosis. The crux of its role, however, will need to be elucidated by other approaches that may include studies in murine platelets lacking TGFBIp or possibly in humans that possess mutations in the TGFBIp gene. These investigative avenues will help us visualize the exact function of TGFBIp in platelet biology and discern whether inhibitors that target TGFBIp may dampen a person's risk for thrombosis.