Familial Bleeding Tendency with Partial Platelet Thromboxane Synthetase Deficiency: Reorientation of Cyclic Endoperoxide Metabolism

Abstract

Three family members from 3 successive generations presented with a moderate bleeding tendency and a functional platelet defect. They had absent aggregation with arachidonic acid (0.6-3 mM), reversible aggregation with ADP (4 .mu.M) and cyclic endoperoxide analogs, single wave aggregation only with adrenaline [epinephrine] (5.4 .mu.M) and a prolonged template bleeding time (> 30 min). Malondialdehyde formation was reduced after N-ethylmaleimide stimulation (2-6 nmol/109 platelets; control values 8-12 nmol) and serum thromboxane B2 values were reduced (33-101 ng/ml; control values 200-700 ng/ml). When the platelets were incubated with [3H]arachidonic acid the final metabolite of the lipoxygenase pathway (HETE) was produced in normal amounts but the production of thromboxane B2 and HHT [12-L-hydroxyheptadecatrienoic acid] was decreased; prostaglandin [PG]F2.alpha., PGE2 and probably PGD2 were increased. Evidence for enhanced production of PGD2 was also provided by the rise in the patient''s platelet cAMP levels following stimulation with arachidonic acid. The patient''s washed platelets stimulated the production of 6-keto PGF1.alpha. by aspirin-pretreated cultured bovine endothelial cells. The plasma levels of 6-keto PGF1.alpha. (439-703 pg/ml; normal 181 .+-. 46 pg/ml) were raised. The decreased production of thromboxane B2, HHT and malondialdehyde and increased formation of PGF2.alpha., PGE2, PGD2 and of 6-keto PGF1.alpha. are compatible with a partial platelet thromboxane synthetase deficiency and reorientation of cyclic endoperoxide metabolism. The markedly prolonged bleeding time would result not only from reduced formation of thromboxane A2 but also from increased production of the aggregation inhibiting prostaglandins PGI2 and PGD2.