Targeting shear gradient activated von Willebrand factor by the novel single-chain antibody A1 reduces occlusive thrombus formation in vitro
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Intraluminal thrombus formation precipitates situations similar to acute myocardial infarction and disturbs native blood move leading to areas of quickly altering blood move velocities and steep gradients of blood shear fee. Shear fee gradients are identified to be pro-thrombotic with an vital position for the shear-sensitive plasma protein von Willebrand issue (VWF).
Right here, we developed a single-chain antibody (scFv) that targets a shear gradient particular conformation of VWF to particularly inhibit platelet adhesion at websites of SRGs however not in areas of fixed shear. Microfluidic move channels with stenotic segments had been used to create shear fee gradients throughout blood perfusion. VWF-GPIbα interactions had been elevated at websites of shear fee gradients in comparison with fixed shear fee of matched magnitude.
The scFv-A1 particularly diminished VWF-GPIbα binding and thrombus formation at websites of SRGs however didn’t block platelet deposition and aggregation underneath fixed shear fee in upstream sections of the channels. Considerably, the scFv A1 attenuated platelet aggregation solely within the later levels of thrombus formation. Within the absence of shear, direct binding of scFv-A1 to VWF couldn’t be detected and scFV-A1 didn’t inhibit ristocetin induced platelet agglutination.
We’ve got exploited the pro-aggregatory results of SRGs on VWF dependent platelet aggregation and developed the shear-gradient delicate scFv-A1 antibody that inhibits platelet aggregation solely at websites of shear fee gradients. The shortage of VWF inhibition in non-stenosed vessel segments locations scFV-A1 in a wholly new class of anti-platelet remedy for selective blockade of pathological thrombus formation whereas sustaining regular haemostasis.