Susceptibility to platelet-type bleeding disorder-13 is due to a defective thromboxane A2 receptor on platelets. The susceptibility is inherited in an autosomal dominant pattern, but clinical features, including mild mucocutaneous bleeding, occur only in the presence of a ... Susceptibility to platelet-type bleeding disorder-13 is due to a defective thromboxane A2 receptor on platelets. The susceptibility is inherited in an autosomal dominant pattern, but clinical features, including mild mucocutaneous bleeding, occur only in the presence of a 'second hit' affecting platelet function; this second hit may be either in the TBXA2R gene or in another gene affecting the coagulation cascade (summary by Mumford et al., 2010).
Weiss and Lages (1977) reported a 10-year-old boy with easy bruising and excessive bleeding after a tooth extraction at age 2 years. Laboratory studies showed normal platelet counts, but defective second phase platelet aggregation in response to epinephrine ... Weiss and Lages (1977) reported a 10-year-old boy with easy bruising and excessive bleeding after a tooth extraction at age 2 years. Laboratory studies showed normal platelet counts, but defective second phase platelet aggregation in response to epinephrine or ADP. Addition of platelet-rich plasma from a normal person who had ingested aspirin resulted in platelet aggregation, indicating that the defect was not in cyclooxygenase (PTGS1; 176805). Addition of prostaglandin G2 did not result in patient platelet aggregation, suggesting a defect in the production of or response to thromboxane A2. Weiss and Lages (1977) postulated a defect in thromboxane synthesis (TBXAS1; 274180). However, in a follow-up study, Lages et al. (1981) found that the patient's platelets did not aggregate in response to TBXAS1 generated from arachidonic acid in normal platelets, but were capable of synthesizing thromboxane from both arachidonic acid and prostaglandin G2. Patient platelets also showed a defect in mobilization of intracellular calcium. Overall, the findings indicated that the defect in this patient did not result from a thromboxane synthetase deficiency, but may be due to impaired platelet response to thromboxane A2 and impaired mobilization of platelet calcium, consistent with the possibility that thromboxane A2 may act as a calcium ionophore. Ushikubi et al. (1987) and Fuse et al. (1993) reported 2 unrelated patients with a mild bleeding disorder caused by impaired platelet aggregation responses to TBXA2 and its analogs, despite a normal response to thrombin. Although the patients' platelets exhibited normal binding activities to TXA2 analogs, they showed decreased GTPase activity and second messenger formation when stimulated by a stable TXA2 agonist. Platelets also showed defective intracellular calcium mobilization in response to these stimuli. This led to the proposal that the defect in the patients was due to impaired coupling of TBXA2R to the G protein. Hirata et al. (1994) provided follow-up of the patient reported by Ushikubi et al. (1987). The patient's son, daughter, and brother had a similar, but milder, defect in platelet aggregation in response to a TXA2 agonist. Mumford et al. (2010) reported a 14-year-old white boy with a history of easy bruising and prolonged epistaxis since infancy. Laboratory studies showed lack of platelet aggregation in response to low doses of arachidonic acid and impaired aggregation in response to a TBXA2 agonist. Platelets from the father showed a similar pattern, although he had no bleeding symptoms.
In affected members of 2 unrelated families with a bleeding disorder (Ushikubi et al., 1987 and Fuse et al., 1993), Hirata et al. (1994) identified a heterozygous mutation in the TBXA2 gene (R60L; 188070.0001). The mutant receptor expressed ... In affected members of 2 unrelated families with a bleeding disorder (Ushikubi et al., 1987 and Fuse et al., 1993), Hirata et al. (1994) identified a heterozygous mutation in the TBXA2 gene (R60L; 188070.0001). The mutant receptor expressed in Chinese hamster ovary cells showed normal ligand binding affinities, but decreased agonist-induced second messenger formation. Dominant inheritance of the disorder suggested that the mutation produces a dominant-negative effect. In a 14-year-old white boy with a mild mucocutaneous bleeding disorder characterized by defective platelet response to TBXA2, Mumford et al. (2010) identified a heterozygous mutation in the TBXA2R gene (D304N; 188070.0002). The patient's father, who also carried the mutation, had no bleeding symptoms. In vitro studies of platelets from both the boy and his father showed impaired aggregation and ATP secretion responses to arachidonic acid and a TBXA2R agonist. In vitro functional expression studies in CHO cells showed normal surface membrane expression of the mutant protein, but there was significantly decreased binding and a significant reduction (more than 85%) in intracellular calcium levels in response to a TBXA2R agonist compared to wildtype, consistent with a loss of function. Noting the phenotypic differences between the boy and his father, Mumford et al. (2010) speculated that the clinical bleeding phenotype demonstrated by the boy represented the effect of the heterozygous D304N mutation combined with an additional unidentified hemostatic defect. Mumford et al. (2010) concluded that heterozygosity for mutations in the TBXA2R gene is sufficient to cause abnormal platelet functional responses in vitro, but is insufficient to cause clinically significant dysfunction in vivo. In an individual whose platelets showed defective response to TBXA2 in vitro, Flamm et al. (2012) identified a heterozygous mutation in the TBXA2R gene (V241G; 188070.0003). In vitro functional expression studies showed normal expression of the mutant receptor, but impaired calcium mobilization and aggregation in response to a TBXA2 agonist. Because G protein signaling through ADP was normal, Flamm et al. (2012) concluded that the mutation caused abnormal coupling of TBXA2R to Gq, resulting in impaired calcium mobilization. The individual's platelets also showed impaired response to the anticoagulants aspirin and indomethacin, which inhibit the production of thromboxane A2. The individual had no self-reported bleeding tendencies.