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.
The existence of different domains within the nucleus has been clear from the time, in the late 1920s, that heterochromatin and euchromatin were discovered. The observation that heterochromatin is less transcribed than euchromatin suggested that microscopically identifiable structures might correspond to functionally different domains of the nucleus. Until 15 years ago, studies linking gene expression and subnuclear localization were limited to a few genes. As we discuss in this Review, new genome-wide techniques have now radically changed the way nuclear organization is analyzed. These have provided a much more detailed view of functional nuclear architecture, leading to the emergence of a number of new paradigms of chromatin folding and how this folding evolves during development.
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