Platelet prostaglandin-endoperoxidase synthase-1 deficiency is a hematologic disorder characterized by mildly increased bleeding due to a platelet defect. The PTGS1 gene (176805) encodes prostaglandin-endoperoxidase synthase-1, also known as COX1 or PGHS1, which catalyzes the formation of prostaglandin G2 ... Platelet prostaglandin-endoperoxidase synthase-1 deficiency is a hematologic disorder characterized by mildly increased bleeding due to a platelet defect. The PTGS1 gene (176805) encodes prostaglandin-endoperoxidase synthase-1, also known as COX1 or PGHS1, which catalyzes the formation of prostaglandin G2 (PGG2) and prostaglandin H2 from arachidonic acid, and the downstream formation of thromboxane A2 (TXA2) and prostacyclin. Thromboxane A2 is important for platelet aggregation (summary by Matijevic-Aleksic et al., 1996).
Malmsten et al. (1975) studied a 30-year-old man with a tendency to easy bruising and retinal bleeding at age 19. An uncle had excessive bleeding twice during surgery. Laboratory studies showed impaired platelet aggregation due to a deficiency ... Malmsten et al. (1975) studied a 30-year-old man with a tendency to easy bruising and retinal bleeding at age 19. An uncle had excessive bleeding twice during surgery. Laboratory studies showed impaired platelet aggregation due to a deficiency of platelet cyclooxygenase that catalyzes formation of PGG2. Normal platelet aggregation and release reaction were restored with added PGG2. In a study on the Aland Islands, Nyman et al. (1979) identified a family with mild bleeding due to defective platelet function in 7 members of 3 generations, suggesting autosomal dominant inheritance. Only platelet aggregation with arachidonate was deficient; response to other inducers of platelet aggregation was normal. Cyclooxygenase deficiency was suggested. Lagarde et al. (1978) studied 2 patients with impaired TXA2 synthesis from arachidonic acid. Pareti et al. (1980) reported a woman with a bleeding disorder characterized by a mildly prolonged bleeding time and defective platelet-release reaction due to congenital deficiency of cyclooxgenase. Horellou et al. (1983) reported a mother and her 2 children with a bleeding disorder due to platelet cyclooxygenase deficiency. Clinical features included spontaneous hematomas, menorrhagia, epistaxis, and hemarthroses. Biochemical studies showed impaired platelet aggregation and lack of TXA2 formation. Matijevic-Aleksic et al. (1996) reported 3 unrelated adult women with a history of a bleeding disorder, including recurrent spontaneous bruising, epistaxis, postsurgical bleeding, recurrent gastrointestinal bleeding, and menorrhagia. Laboratory studies showed that all had a functional platelet defect, with defective second-wave aggregation and defective TXA2 synthesis. Further biochemical studies indicated normal TXAS1 (TBXAS1; 274180) activity, but decreased PGHS1 activity. Treatment of patient platelets with prostaglandin H2 resulted in normal thromboxane levels. One patient had a normal amount of platelet PGHS1 protein, but the other 2 patients had undetectable protein levels. Matijevic-Aleksic et al. (1996) concluded that the 3 patients represented 2 types of PGHS1 deficiency. Type 1 manifested as complete loss of platelet PGHS1 protein and was postulated to result from a transcriptional defect or posttranslational modification resulting in rapid protein degradation. Type 2 manifested as normal levels of a dysfunctional protein that was postulated to result from inhibitory extrinsic factors or a mutation in the active site of the enzyme. Matijevic-Aleksic et al. (1996) noted that the deficiency appeared to be restricted to platelets, although PGHS1 is constitutively expressed in most cells. Fuse et al. (1996) reported a 41-year-old Japanese woman with a lifelong history of mild bleeding. Laboratory studies showed prolonged bleeding time and inability of the patient's platelets to transform arachidonic acid to prostaglandin G2, indicating a deficiency in PGHS1. However, the PGHS1 defect was not observed in vascular endothelial cells or bone marrow fibroblasts. Oral administration of aspirin, which inhibits PGHS1, resulted in a marked prolongation of the bleeding time. These findings suggested that TXA2 released from vessel walls plays an important role in maintaining hemostasis. Dube et al. (2001) studied an 18-year-old woman with a lifelong bleeding disorder, moderate thrombocytopenia, and a prolonged bleeding time. Her platelets aggregated in the presence of both prostaglandin H2 (PGH2) and a stable TXA2 analog, but did not aggregate in the presence of arachidonic acid. The activity of PGHS1 in platelets was reduced to 13% of the activity measured in control subjects. The PGHS1 protein level was reduced in B lymphocytes. However, PGHS1 mRNA was detected as a 2.8-kb band in both the patient and control, with similar intensity of the band; this suggested a normal transcriptional rate of PGHS1. Dube et al. (2001) concluded that the defect responsible for the reduced levels of PGHS1 protein was probably posttranscriptional, and not due to a mutation in the PGHS1 gene.