Abstract
LAIR-1 (Leukocyte Associated Ig-like Receptor -1) is a collagen receptor that functions as an inhibitory receptor on immune cells. It has a soluble family member, LAIR-2, that also binds collagen and can interfere with LAIR-1/collagen interactions. Collagen is a main initiator for platelet adhesion and aggregation. Here, we explored the potential of soluble LAIR proteins to inhibit thrombus formation in vitro. LAIR-2/Fc but not LAIR-1/Fc inhibited collagen-induced platelet aggregation. In addition, LAIR-2/Fc also interfered with platelet adhesion to collagen at low shear rate (300 s−1; IC50 = 18 µg/ml) and high shear rate (1500 s−1; IC50 = 30 µg/ml). Additional experiments revealed that LAIR-2/Fc leaves interactions between collagen and α2β1 unaffected, but efficiently prevents binding of collagen to Glycoprotein VI and von Willebrand factor. Thus, LAIR-2/Fc has the capacity to interfere with platelet-collagen interactions mediated by Glycoprotein VI and the VWF/Glycoprotein Ib axis.
Highlights
The formation of platelet-rich thrombi is a multistep process involving several components [1]
Since binding of platelets to the collagen-matrix is an important event in the haemostatic process, we tested if platelets express LAIR-1 and/or LAIR-2
Since we previously observed that unstimulated platelets do not have surface expression of LAIR-1 ([16] and Steevels et al, Manuscript submitted for publication), we tested whether upon activation platelets LAIR-1 expression was induced
Summary
The formation of platelet-rich thrombi is a multistep process involving several components [1]. The initial step of thrombus formation requires the capturing of platelets from flowing blood to the exposed subendothelial matrix of an injured vessel wall. Once bound to this matrix, platelets become activated, allowing the formation of platelet-platelet interactions which is needed for thrombus growth. Platelet activation is enhanced via thrombin, a product of the coagulation cascade or via stimulatory agents (such as ADP, epinephrine and thromboxane A2) that are released from platelet storage granules This primary activation and aggregation step is followed by a second wave of signals that lead to stabilization of the platelet aggregate [2]. Studies using VWF-deficient mice have shown that the absence of VWF is associated with delayed platelet adhesion and defective thrombus formation in vessels with high and low shear rates [3,4]
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