Three family members from three successive generations presented with a moderate
bleeding tendency and a functional platelet defect. They had absent aggregation with
arachidonic acid (0.6--3 microM), reversible aggregation with
ADP (4 microgram) and cyclic endoperoxide analogues, single wave aggregation only with
adrenaline (5.4 microgram) and a prolonged template bleeding time (> min).
Malondialdehyde formation was reduced after
N-ethylmaleimide stimulation (2--6 nmol/10(9) 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 was decreased whereas
prostaglandin F2a, and E2 and probably D2 were increased. Evidence for enhanced production of
prostaglandin D2 was also provided by the rise in the patient's platelet
cyclic AMP levels following stimulation with
arachidonic acid. The patient's washed platelets stimulated the production of 6-keto
PGF 1a by
aspirin-pretreated cultured bovine endothelial cells. The plasma levels of 6-keto PGF1a (439--703 pg/ml; normal 181 +/- 46 pg/ml) were raised. The decreased production of
thromboxane B2, HHT and
malondialdehyde and increased formation of
prostaglandin F2a, E2, D2 and of 6-keto PGF1a 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.