Table 1.

Summary of the main genetic mutations, modes of inheritance, functional defects, and related clinical manifestations in 18 patients with impaired platelet response to adenosine diphosphate (ADP) reported in the literature to date (1992–2022).

1st Author, Year	Genetic Abnormality	Domain	Mode of Inheritance	Functional Defect	Clinical Manifestations
Cattaneo et al., 1992 [9]	p.Gln98fs	Not identified	Likely autosomal recessive	Defective aggregation induced using ADP, epinephrine, PAF-acether, U46619, collagen, and arachidonic acid Impaired release of 14C-serotonin Partial inhibition of aggregation by ADP scavengers Defective fibrinogen and vWF binding induced using exogenous ADP ADP does not accelerate Anti-GPIIb/IIIa mAbs binding to platelets ADP prevented PGE1-induced increase in platelet cAMP	Mucosal bleeding Easy bruising Need for transfusion after accidents Nonsteroidal anti-inflammatory drugs worsened the bleeding diathesis
Nurden et al., 1995 [10]	p.Phe240fs. No mutation was identified in one of the two alleles	Not identified	Not specified	Limited and always reversible ADP-mediated platelet aggregation Failure in PGE1-induced cAMP decrease in response to ADP Markedly reduced platelet binding of [3H]2-MeS-ADP Impaired binding of fibrinogen to ADP-stimulated platelets Aggregates comprising a small number of loosely bound platelets with few contact points Weak response to Anti-GPIIb/IIIa mAbs	Brief episodes of excessive bleeding Excessive post-surgical bleeding
Cattaneo et al., 2000 [11]	378delC; p.Thr126fs	TM3	Likely autosomal recessive	Small and reversible wave of platelet aggregation in PRP induced using ADP or PAF-acether Impaired platelet secretion induced using agonists Failure in PGE1-induced cAMP decrease in response to ADP Severely decreased number of binding sites in platelets for [33P]2 MeS-ADP	Easy bruising Menorrhagia Severe bleeding complications after dental extractions or major surgery
					Easy bruising Epistaxis Menorrhagia Moderate bleeding complications after dental extractions
Cattaneo et al., 2003 [12]	p.Arg256Gln; p.Arg265Trp	TM6 and EL3	Compound heterozygous	Markedly lower and rapidly reversible ADP-induced platelet aggregation P2Y12 antagonist ARC69931MX is ineffective on platelets Weak or absent ATP secretion from platelets stimulated with ADP and other agonists Failure in PGE1-induced cAMP decrease in response to ADP	Easy bruising Excessive post-traumatic and post-surgical blood loss
Shiraga et al., 2005 [13]	ATG > AGG	translation initiation codon	Homozygous	Transient platelet aggregation induced using ADP, collagen, U46619, or PAR1 TRAP P2Y12 antagonist ARC69931MX is ineffective on platelets Abnormal inhibitory effect of ADP on PGE1-stimulated cAMP accumulation in platelets Impaired spreading on immobilized fibrinogen Formation of unstable thrombi on type 1 collagen	Easy bruising Mild bleeding tendency Massive bleeding during delivery
Remijn et al., 2007 [14]	p.Pro258Thr	EL3	Heterozygous	Impaired or absent platelet aggregation induced using ADP and collagen Small thrombi consisting of a spread and incomplete layer of platelets on top after perfusion of blood	Severe epistaxis Easy bruising Excessive post-traumatic blood loss
Daly et al., 2009 [15]	p.Lys174Glu	EL2	Heterozygous	Reduced and transient platelet aggregation to ADP Reduction in the maximal level of dense granule secretion induced using ADP and PAR-4 peptide in platelets Reduction in ADP and PAR-4-induced ATP secretion Reduced P2Y12 binding to [3H]2-MeS-ADP	Mild bleeding
Fontana et al., 2009 [16]	Haploinsufficiency of P2Y12 gene (single allele encodes a normal P2Y12)	Not identified	Not specified	Abnormal aggregation and ATP secretion induced using ADP, U46619, PAF-acether, or collagen Moderate deficiency of platelet-binding sites for [33P]2MeS-ADP Partial impairment of inhibition of adenylate cyclase by ADP	Mildly prolonged bleeding time
Nisar et al., 2011 [17]	p.Pro341Ala	PDZ-binding motif	Heterozygous	Pronounced reduction in P2Y12 surface binding sites in platelets Impaired inhibition of PGE2-stimulated adenylyl cyclase Sustained aggregation and dense granule secretion P2Y12 antagonist ARC69931MX is effective on platelets Impaired correct receptor recycling back to the membrane in human platelets	Mild bleeding tendency
Patel et al., 2014 [18]	p.Arg122Cys	DRY motif	Homozygous	Reduced platelet aggregation in response to ADP, PAR-1 peptide, or collagen Abrogated inhibition of pVASP phosphorylation Reduced cell surface P2Y12 expression T allele-associated decreased expression of PAR-1 on platelets, lower secretion responses to the PAR-1-activating peptide, and decreased procoagulant activity	Spontaneous bleeding Post-surgery hemorrhage
Lecchi et al., 2014 [19]	p.His187Gln	TM5	Homozygous	Normal expression of the receptor but decreased affinity for its ligand Completely suppressed function of the mutant receptor Straight and tilted TM5 Decreased affinity for [3H]PSB-0413 antagonist Normal number of platelet binding sites Reduced affinity for the P2Y12 receptor antagonist radioligand [3H]PSB-0413, ADP and 2MeSADP	Epistaxis Post-operative bleeding after tooth extraction
					Severe bleeding history
Dangelmaier et al., 2022 [20]	p.Asp121Asn	DRY motif	Heterozygous	Strongly inhibited response to 2-MeS-ADP Mild Akt phosphorylation at Ser473 Defects in both aggregation and secretion at low doses of AYPGKF Defective VASP phosphorylation and GTP-Rap1b formation Inhibited signaling downstream of Gi-coupled P2Y12 Reduced thrombus formation in whole blood	No bleeding diathesis

Gln: glutamine; fs: frameshift; ADP: adenosine diphosphate; PAF: platelet-activating factor; vWF: von Willebrand factor; GP: glycoprotein; mAbs: monoclonal antibodies; PGE₁: prostaglandin E₁; cAMP: cyclic adenosine monophosphate; Phe: phenylalanine; [³H]2-MeS-ADP: [³H]2-methylthio-adenosine diphosphate; del: deletion; Thr: threonine; TM: transmembrane domain; PRP: platelet-rich plasma; Arg: arginine; Trp: tryptophan; EL: extracellular loop; ATP: adenosine triphosphate; PAR: protease-activated receptor; TRAP: thrombin receptor-activating peptide; Pro: proline; Lys: lysine; Glu: glutamate; Ala: alanine; PDZ: post-synaptic density 95/disc large/zonula occludens-1; PGE₂: prostaglandin E₂; Cys: cysteine; pVASP: platelet vasodilator-stimulated phosphoprotein; His: histidine; [³H]PSB-0413: [³H]2-Propylthioadenosine-59-adenylic acid (1,1-chloro-1-phosphonomethyl-1-phosphonyl) anhydride; Asp: aspartate; Asn: asparagine; Akt: protein kinase B; Ser: serine; AYPGKF: PAR-4 agonist peptide.