Summary 1. Three cationic proteins–fibrinogen, Hageman factor, and gamma globulin‐are all capable of restoring aggregation capability of washed human platelets. 2. The aggregation‐restoring effect of gamma globulin is inhibited by acetic proteins in subfractions of Cohn fraction IV and fractions V and VI. 3. Artificial enhancement of the net negative charge of plasma proteins through acylation produces derivatives capable of inhibiting platelet aggregation in platelet‐rich plasma. 4. It is proposed that the rate of platelet aggregation is regulated in part by the equilibrium between cationic and anionic proteins in plasma and on the platelet membrane surface. This concept finds support in the following clinical observations. 5. Platelets of Glanzmann's thrombasthenia incapable of aggregation fail to adsorb cationic proteins to their surface. 6. Purified myeloma proteins from patients with platelet dysfunction do not restore aggregation of normal washed platelets and inhibit the aggregation‐restoring effect of normal IgG. 7. Enhanced platelet aggregation demonstrable in chronic, active glomerular disease may result from the loss in the urine of plasma proteins normally inhibiting platelet aggregation.
Platelet (P) levels of cyclic AMP (cAMP) and thromboxane (TX) synthesis have been identified as major regulators of P aggregation and release. We have utilized as probes drugs which either decrease TX synthesis by cyclooxygenase inhibition (aspirin and indomethacin) or which increase P cAMP (adenosine; PGE1; theophylline; isobutyl methyl xanthine; and SH-869, a dipyridamole analog) to evaluate relative contributions of cAMP and TX and their possible interreactions in mediating P function. Cyclooxygenase inhibitors at concentrations 8-16 fold lower than those inhibiting P aggregation and release caused almost complete inhibition of TXB2 synthesis from exogenous 14C-arachidonic acid (aa) and malonyldialdehyde (MDA) production in P stimulated by thrombin (T) or N-ethylmaleimide (NEM). Drugs elevating P cAMP at concentrations equal to or greater than those causing complete inhibition of P aggregation and release did not inhibit TXB2 synthesis from exogenous 14C-aa, nor did they inhibit MDA production in P stimulated by NEM or by concentrations of T sufficient to produce maximal TX synthesis.However, these drugs variably inhibited MDA production when P were stimulated at lower T concentrations causing only minor TX synthesis.Thus, elevated P cAMP did not inhibit TX synthesis from aa but appeared to weakly inhibit aa phospholipase. We conclude that TX synthesis cannot be the sole, final mediator of P aggregation and release but that these events result from as yet unidentified mechanisms modulated largely independently by TX synthesis and intra-P cAMP levels.
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