A haemorrhagic platelet disorder associated with altered stimulus-response coupling and abnormal membrane...

Haemorrhagic diatheses due to platelet function defects are a heterogenous and poorly understood group of conditions. We report the investigation of a female with a lifelong history of epistaxes, haemarthroses, menorrhagia and persistent iron-deficiency anaemia. Although platelet numbers and morphology were normal, platelet function was abnormal both in vivo and in vitro. Skin bleeding time was prolonged and aggregation thresholds in platelet-rich plasma to a variety of weak and strong agonists were increased. Platelet granule contents were normal and membrane glycoproteins GpIb and GpIIIa were present in normal amounts. Polyphosphoinositide metabolism and phosphatidic acid generation were diminished in thrombin-stimulated platelets, as was phosphorylation of the 47 kD substrate for protein kinase C and the 20 kD protein myosin light chain kinase, indicating impaired generation of the intracellular second messengers diacylglycerol and inositol trisphosphate due to diminished stimulated phospholipase C activity. Although intracellular free calcium, calmodulin activity and basal cAMP concentrations were normal, washed platelets showed increased cAMP accumulation following stimulation with prostaglandin E1 and forskolin. Platelet membrane lipid analysis revealed a reduction in plasmalogen phosphatidylethanolamine content. It is suggested that the membrane phospholipid abnormalities cause the abnormal platelet reactivity by interfering with signal transduction from platelet receptor, via intermediary G proteins, to phospholipase C and adenylate cylase. The bleeding tendency is likely to be a consequence of the altered stimulus-response coupling.