Landmark cases contributing to the clinical and phenotypic heterogeneity given by ITGA2B and ITGB3 mutations
| Mutation . | Bleeding . | Aggregation . | Clot retraction . | Platelet Fg . | αIIbβ3 expression/activation state . | Comments . |
|---|---|---|---|---|---|---|
| β3 D119Y | Severe | Absent | Absent | None | Normal/NA | Identification of an Fg binding site |
| β3 R214Q or W | Severe | Absent | Absent/low | None/low | Normal/NA | Unstable integrin/altered Ca2+ binding |
| β3 S162L | Severe | Absent | Normal | NS | 16%-27%/NA‡ | Refractory integrin poorly expressed |
| β3 L262P | Moderate | Absent | Substantial | NS | 30%/NA | Unstable integrin poorly expressed |
| β3 S752P* | Mild | Absent | Substantial | Normal | 50%/NA | Signaling role of β3 cytoplasmic tail |
| β3 R724ter* | Severe | Absent | NS | NS | 35%-50%/NA | Signaling role of β3 cytoplasmic tail |
| αIIb Y143H | Mild | Absent | Substantial | NS | 36%-41%/NA | Altered residual β-propeller domain |
| αIIb T176I | Severe | Absent | Much reduced | None | 24%/NA | Altered residual β-propeller domain |
| β3 S527F | Mild | Absent | NS | NS | NR/PAC-1 and Fg§ | αIIbβ3 restrained in active conformation |
| β3 C549R | Severe | Absent | Absent | NS | 1%-14%/PAC-1§ | Partially activated residual integrin |
| β3 C560R | Moderate | Much reduced | Much reduced | Substantial | 20%/PAC-1 and Fg | Fully activated residual integrin |
| αIIb R995Q* or W† | Mild | Reduced | Present | Substantial | 15% and 50%-70%/PAC-1 | Thrombocytopenia and anisocytosis |
| β3 D723H† | None | Normal | NS | NS | Normal/PAC-1 | Thrombocytopenia and anisocytosis |
| β3 L718P | Severe | Much reduced | NS | NS | 47%-78%/PAC-1‖ | Aggregation and secretory defects (P-selectin) + thrombocytopenia |
| β3 c.2134 + 1G > C + 40aa deletion† | Severe | Much reduced | Normal | NS | 32%-66%/NA | Aggregation defect + thrombocytopenia + large platelets |
| Mutation . | Bleeding . | Aggregation . | Clot retraction . | Platelet Fg . | αIIbβ3 expression/activation state . | Comments . |
|---|---|---|---|---|---|---|
| β3 D119Y | Severe | Absent | Absent | None | Normal/NA | Identification of an Fg binding site |
| β3 R214Q or W | Severe | Absent | Absent/low | None/low | Normal/NA | Unstable integrin/altered Ca2+ binding |
| β3 S162L | Severe | Absent | Normal | NS | 16%-27%/NA‡ | Refractory integrin poorly expressed |
| β3 L262P | Moderate | Absent | Substantial | NS | 30%/NA | Unstable integrin poorly expressed |
| β3 S752P* | Mild | Absent | Substantial | Normal | 50%/NA | Signaling role of β3 cytoplasmic tail |
| β3 R724ter* | Severe | Absent | NS | NS | 35%-50%/NA | Signaling role of β3 cytoplasmic tail |
| αIIb Y143H | Mild | Absent | Substantial | NS | 36%-41%/NA | Altered residual β-propeller domain |
| αIIb T176I | Severe | Absent | Much reduced | None | 24%/NA | Altered residual β-propeller domain |
| β3 S527F | Mild | Absent | NS | NS | NR/PAC-1 and Fg§ | αIIbβ3 restrained in active conformation |
| β3 C549R | Severe | Absent | Absent | NS | 1%-14%/PAC-1§ | Partially activated residual integrin |
| β3 C560R | Moderate | Much reduced | Much reduced | Substantial | 20%/PAC-1 and Fg | Fully activated residual integrin |
| αIIb R995Q* or W† | Mild | Reduced | Present | Substantial | 15% and 50%-70%/PAC-1 | Thrombocytopenia and anisocytosis |
| β3 D723H† | None | Normal | NS | NS | Normal/PAC-1 | Thrombocytopenia and anisocytosis |
| β3 L718P | Severe | Much reduced | NS | NS | 47%-78%/PAC-1‖ | Aggregation and secretory defects (P-selectin) + thrombocytopenia |
| β3 c.2134 + 1G > C + 40aa deletion† | Severe | Much reduced | Normal | NS | 32%-66%/NA | Aggregation defect + thrombocytopenia + large platelets |
Variants were included on the basis of their historical importance and of the availability of clinical and biologic data. Mutations are referenced in “Variant-type GT.” Data are included for platelet aggregation, clot retraction, platelet Fg, and platelet surface αIIbβ3 expression and its activation status. When a range of αIIbβ3 expression is given, it corresponds to that given by different monoclonal antibodies. For platelet activation, a positive response for PAC-1 and/or Fg binding is specified. Bleeding severity was noted as described in the original reports or case histories. Mild bleeding basically refers to few spontaneous or trauma-related bleeding manifestations that are easily controlled; moderate bleeding covers frequent epistaxis and/or cutaneous manifestations, infrequent oral cavity and/or gastrointestinal bleeding, menorrhagia controlled by contraceptive pills; severe bleeding includes epistaxis requiring packing, cauterization, and/or blood transfusion and trauma-related bleeding requiring hospitalization and blood transfusion or alternative therapies, spontaneous or trauma-related severe bleeding.
NS indicates not studied; NA, no activation with physiologic agonists; and NR, not reported for platelets.
Heterozygous mutations associated with null alleles.
Only for 3 mutations was transmission recognized as autosomal dominant (AD).
Only the absence of conformational change to RGD peptide binding was studied.
Studied in transfected heterologous cells only.
Decreased in platelets but spontaneously active in transfected cells, effects linked to integrin clustering.