Abnormal Whole Blood Thrombi in Humans with Inherited Platelet Receptor Defects |
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Authors: | Francis J. Castellino Zhong Liang Patrick K. Davis Rashna D. Balsara Harsha Musunuru Deborah L. Donahue Denise L. Smith Mayra J. Sandoval-Cooper Victoria A. Ploplis Mark Walsh |
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Affiliation: | 1. W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, United States of America.; 2. Department of Emergency Medicine, Memorial Hospital of South Bend, South Bend, Indiana, United States of America.; University of Leuven, Belgium, |
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Abstract: | To delineate the critical features of platelets required for formation and stability of thrombi, thromboelastography and platelet aggregation measurements were employed on whole blood of normal patients and of those with Bernard-Soulier Syndrome (BSS) and Glanzmann’s Thrombasthenia (GT). We found that separation of platelet activation, as assessed by platelet aggregation, from that needed to form viscoelastic stable whole blood thrombi, occurred. In normal human blood, ristocetin and collagen aggregated platelets, but did not induce strong viscoelastic thrombi. However, ADP, arachidonic acid, thrombin, and protease-activated-receptor-1 and -4 agonists, stimulated both processes. During this study, we identified the genetic basis of a very rare double heterozygous GP1b deficiency in a BSS patient, along with a new homozygous GP1b inactivating mutation in another BSS patient. In BSS whole blood, ADP responsiveness, as measured by thrombus strength, was diminished, while ADP-induced platelet aggregation was normal. Further, the platelets of 3 additional GT patients showed very weak whole blood platelet aggregation toward the above agonists and provided whole blood thrombi of very low viscoelastic strength. These results indicate that measurements of platelet counts and platelet aggregability do not necessarily correlate with generation of stable thrombi, a potentially significant feature in patient clinical outcomes. |
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