Table 1

Novel antiplatelet agents targeting GPIb, GPIIb/IIIa and GPVI mechanosensing axes

Axis	Target	Agent	Description	Antithrombotic effect	Phase of development	Clinical trials gov identifier	References
GPIb	VWF	Lp (Q1238-E1260)	The N-terminal polypeptide sequence of VWF-A1 that autoinhibits VWF-A1 binding to platelet GPIb.	Inhibits platelet attachment on VWF in whole blood perfusion in vitro.	Preclinical		57
	14-3-3ζ	MPαC	Designed based on the 14-3-3ζ-binding sequence in GPIbα. Blocks 14-3-3ζ binding to GPIbα.	Weakens GPIbα-VWF interaction and inhibits GPIbα mechanosignalling.	Preclinical		92 93
	VWF	BAX 930	Recombinant ADAMTS13; cleaves VWF at A2 domain to weaken its activity.	Inhibits arterial thrombosis.	III	NCT03393975	88 89
	VWF	NMC4	A monoclonal antibody against VWF-A1.	Inhibits arterial thrombosis.	Preclinical		73
	VWF	Caplacizumab	A nanobody against VWF-A1.	Showed inhibitory effects on thrombosis in primate models without causing adverse side effects.	FDA approved		71 72
	VWF	ARC1779	An anti-VWF aptamer.	Showed encouraging results in inhibiting thrombosis.	II (terminated)	NCT00742612	75 85
	GPIbα	p0p/B	An antibody against GPIbα.	Dramatically reduces infarct volumes in cerebral ischaemia model.	Preclinical		77
	GPIbα	H6B4	An antibody against GPIbα.	Inhibits high-shear arterial thrombosis in baboons without causing adverse side effects.	Preclinical		76
	GPIbα	GPG-290	A recombinant human GPIbα chimeric protein which blocks GPIbα binding to VWF.	Inhibits coronary artery thrombosis in a canine model.	Preclinical		74
	GPIbα	agkistin	Blocks GPIbα binding to VWF.	Reduces thrombus formation under arterial shear conditions.	Preclinical		78
	GPIbα	Anfibatide	Inhibits both VWF and α-thrombin binding to GPIbα.	In experimental models, inhibits platelet adhesion, aggregation and thrombus formation without increasing bleeding time.	I, II	NCT01585259	79
GPIIb/IIIa	PI3Kβ	AZD6482	Inhibits PI3Kβ downstream GPIIb/IIIa mechanosignaling and shear-induced platelet activation.	Inhibits thrombus formation in vivo in preclinical models with minimal effects on bleeding.	I	NCT00853450	138
	Gα₁₃	mP₆	A myristoylated peptide (Myr-FEEERA) that inhibits association of Gα₁₃ with integrin β₃ cytoplasmic tail and suppresses the early phase of GPIIb/IIIa outside-in signalling.	Inhibits platelet spreading and thrombus formation in preclinical models with no effects on bleeding time.	Preclinical		104
	PDI	Isoquercetin	Inhibits PDI activity in plasma and decreases platelet-dependent thrombin generation; also reduces levels of coagulation markers at higher doses.	Inhibits platelet thrombus formation and fibrin formation in preclinical models. Partial inhibition does not cause serious bleeding.	II–III	NCT02195232	141
	Active GPIIb/IIIa	scFv SCE5	Single-chain antibody that specifically inhibits the active conformation of GPIIb/IIIa; can also be used to deliver clot-directed thrombolytic, antiplatelet and anticoagulant agents.	Inhibits platelet aggregation and thrombus formation in preclinical models without major increase in bleeding time.	Preclinical		145
	GPIIb/IIIa	RUC-4	A small molecule that binds to the metal ion-binding site on the GPIIIa without causing major conformational changes; specific to GPIIb/IIIa (α_IIbβ₃) over α_Vβ₃ integrins.	Inhibits platelet aggregation and thrombus formation in preclinical models; effects on bleeding not yet evaluated.	I	NCT03844191	150
	GPIIb/IIIa	PSI A1, PSI B1, PSI C1, PSI E1	Antibodies against GPIIIa PSI domain, inhibiting its thiol isomerase function.	Inhibits platelet aggregation and thrombus formation in preclinical models.	Preclinical		128
GPVI	GPVI	9O12	A monoclonal antibody Fab that blocks the collagen/fibrin-binding site of GPVI with high affinity. The recombinant scFv version is also available.	Inhibits thrombosis and appears to maintain haemostasis in preclinical models.	Preclinical		163
	Collagen	Revacept	Dimeric GPVI-Fc that blocks vascular collagen at sites of plaque or vascular erosion and collagen-induced platelet activation	Inhibits platelet thrombus formation at sites of vascular injury in preclinical models; no effect on bleeding time.	I, II	NCT01645306	165
	GPVI	Losartan (DuP-753)	An angiotensin II (Ang II) type I receptor (AT1R) antagonist that has been reported to exert an anti-platelet activity besides its antihypertensive effect.	Inhibits platelet adhesion to collagen and subsequent collagen induced platelet activation and aggregation via GPVI.	IV	NCT00805311	169

PDI, protein disulfide isomerase; scFv, single-chain variable fragment.