thromboxane-a2 and Duodenal-Ulcer

Arachidonic acid (AA), when cleaved from phospholipids by cytosolic phospholipase A2 alpha (cPLA2a), generates eicosanoids, with pro-hemostatic, pro-inflammatory, vasoactive and gastro-protective functions. We describe a patient (27-year-old man) and his twin-sister with early-onset bleeding diathesis and recurrent gastro-intestinal (GI) ulcers. Platelet aggregation/δ-granules secretion by collagen was impaired, but normal by AA; serum levels of thromboxane (Tx) B2 and 12-hydroxyeicosatetraenoic acid, and urinary levels of 11-dehydro-TxB2 were extremely low. Patients were homozygous for 1723G>C transition in PLA2G4A gene, which changed the codon for Asp575 to His. GI ulcers affected 5/14 heterozygous (< 40 years) and 1/16 wild-type homozygous (> 60 years) family members; none had bleeding diathesis. The proband, his sister and mother also had mildly reduced factor XI levels. Platelet messenger RNA expression did not differ among subjects with different PLA2G4A genotypes. Conversely, platelet cPLA2a was undetectable by Western Blotting in the proband and his sister, and decreased in 1723G>C heterozygous subjects, suggesting that the variant is transcribed, but not translated or translated into an unstable protein. We described a syndromic form of deficiency of cPLA2a , characterised by recurrent GI ulcers and bleeding diathesis, associated with mild inherited deficiency of factor XI. Unlike other reported patients with cPLA2a deficiency, these patients had extremely low levels of platelet TxA2 biosynthesis.

Topics: Adult; Blood Coagulation Disorders, Inherited; Blood Platelets; DNA Mutational Analysis; Duodenal Ulcer; Factor XI; Female; Genetic Predisposition to Disease; Group IV Phospholipases A2; Hemostasis; Heredity; Heterozygote; Homozygote; Humans; Male; Middle Aged; Pedigree; Phenotype; Platelet Aggregation; Platelet Function Tests; Recurrence; Stomach Ulcer; Thromboxane A2; Twins

Synthesis of prostaglandins (PGE2, PGI2 and PGF2 alpha) and thromboxane A2 was investigated in short term incubates of duodenal mucosa biopsies. Mucosa close to the ulcer site synthesised significantly less PGF2 alpha (p less than 0.001) and PGI2 (p less than 0.002) measured as its stable metabolite 6-oxo-PGF1 alpha than healthy mucosa from non-ulcer patients. In paired biopsies taken from the ulcer site and opposite the ulcer in the same patient PGF2 alpha and PGI2 syntheses were both significantly and similarly depressed when compared with normal mucosa. Synthesis of PGE2 and TxA2 (as its stable metabolite TxB2) was not different in any tissue. There is a defect in the ability of the human duodenal mucosa in duodenal ulcer disease to synthesise PGF2 alpha and PGI2; the defect is not limited to the ulcer site.

Topics: Dinoprost; Dinoprostone; Duodenal Ulcer; Duodenum; Epoprostenol; Humans; Intestinal Mucosa; Prostaglandins; Prostaglandins E; Prostaglandins F; Thromboxane A2