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The interaction of fibrinogen with monocytes was studied. After stimulation with ADP (10 jiM) or thrombin (1 U/ml), plateletfree suspensions of human monocytes bind 1251-fibrinogen with two different affinities in a specific and Ca2+-dependent reaction with saturation at 5.80-7.35 X 1o-7 M of added protein. The binding of fibrinogen to specific receptors on monocytes induces the procoagulant activity of these cells. Thrombasthenic cells or normal monocytes preincubated with a monoclonal antibody to the platelet glycoprotein IUb/IlIa complex (1OE5) do not bind fibrinogen and have no procoagulant activity. Metabolic studies with I35Slmethionine revealed that cultured monocytes actually synthesize a surface antigen precipitated by lOE5 antibody as a major band with 92,000 relative molecular weight. Our data indicate that monocytes express receptors for fibrinogen only in part related to the platelet glycoprotein IIb/Illa complex. Furthermore, the binding of fibrinogen to monocytes enhances the cooperation of these cells in hemostasis.

Impaired platelet aggregation, normal shape change, and agglutination and normal ATP secretion and thromboxane synthesis in response to high concentrations of thrombin or arachidonic acid were found in a patient with multiple myeloma and hemorrhagic tendency. The purified IgG1 kappa or its F(ab'}2 fragments induced similar changes when added in vitro to plateletrich plasma from normal subjects. In addition, the paraprotein inhibited adhesion to glass microbeads, fibrin clot retraction, and binding of radiolabeled fibrinogen or von Willebrand factor to platelets exposed to thrombin or arachidonic acid without affecting intraplatelet levels of cAMP. The radiolabeled paraprotein bound to an average of 35,000 sites on normal platelets but it bound to <2,000 sites on the platelets from a patient with Glanzmann's thrombasthenia. Immunoprecipitation studies showed that the platelet antigen identified by the paraprotein was the glycoprotein IlIa. Furthermore, binding of radiolabeled prostaglandin El (PGEI) to resting platelets as well as binding of von Willebrand factor to platelets stimulated with ristocetin were entirely normal in the presence of patient's inhibitor. These studies indicate that bleeding occurring in dysproteinemia may be the result of a specific interaction of monoclonal paraproteins with platelets. In addition, our data support the concept that the interaction of fibrinogen and/or von Willebrand factor with the platelet glycoprotein Ilb-IIla complex is essential for effective hemostasis.

SummaryPlatelet aggregation and fibrinogen binding were studied in 15 individuals before and 7 days after the oral administration of ticlopidine (250 mg b.i.d.). Ticlopidine significantly inhibited platelet aggregation induced by adenosine diphosphate (ADP), the endoperoxide analogue U46619, collagen or low concentrations of thrombin, but did not inhibit platelet aggregation induced by epinephrine or high concentrations of thrombin. Ticlopidine inhibited 125I-fibrinogen binding induced by ADP, U46619 or thrombin (1 U/ml). The ADP scavengers apyrase or CP/CPK, added in vitro to platelet suspensions obtained before ticlopidine, caused the same pattern of aggregation and 125I-fibrihogen binding inhibition as did ticlopidine. Ticlopidine did not inhibit further platelet aggregation and 125I-fibrinogen binding induced in the presence of ADP scavengers. After ticlopidine administration, thrombin or U46619, but not ADP, increased the binding rate of the anti-GPIIb/IIIa monoclonal antibody 7E3 to platelets. Ticlopidine inhibited clot retraction induced by reptilase plus ADP, but not that induced by thrombin or by reptilase plus epinephrine, and prevented the inhibitory effect of ADP, but not that of epinephrine, on the PGE1-induced increase in platelet cyclic AMP. The number of high- and low-affinity binding sites for 3H-ADP on formalin-fixed platelets and their K d were not modified by ticlopidine. These findings indicate that ticlopidine selectively inhibits platelet responses to ADP.