title: Abnormal whole blood thrombi in humans with inherited platelet receptor defects.
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.
authors.affiliation: W. M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, United States of America. fcastell@nd.edu
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Castellino
authors.forename: Zhong
authors.initials: Z
authors.lastname: Liang
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Davis
authors.forename: Rashna D
authors.initials: RD
authors.lastname: Balsara
authors.forename: Harsha
authors.initials: H
authors.lastname: Musunuru
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Donahue
authors.forename: Denise L
authors.initials: DL
authors.lastname: Smith
authors.forename: Mayra J
authors.initials: MJ
authors.lastname: Sandoval-Cooper
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Ploplis
authors.forename: Mark
authors.initials: M
authors.lastname: Walsh
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology / Q000502:physiology; D000293:Adolescent; D016718:Arachidonic Acid / Q000494:pharmacology / Q000502:physiology; D001483:Base Sequence; D001606:Bernard-Soulier Syndrome / Q000097:blood* / Q000235:genetics; D001777:Blood Coagulation; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D003029:Coagulants / Q000494:pharmacology; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D015539:Platelet Activation; D010974:Platelet Aggregation; D019038:Platelet Glycoprotein GPIb-IX Complex; D044463:Receptor, PAR-1 / Q000502:physiology; D012310:Ristocetin / Q000494:pharmacology; D017384:Sequence Deletion; D013915:Thrombasthenia / Q000097:blood* / Q000235:genetics; D013916:Thrombelastography; D013917:Thrombin / Q000494:pharmacology / Q000502:physiology; D055682:Viscoelastic Substances; D055815:Young Adult
chemical_list: D003029:Coagulants; D008562:Membrane Glycoproteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D044463:Receptor, PAR-1; D055682:Viscoelastic Substances; C094990:adhesion receptor; D012310:Ristocetin; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate; D013917:Thrombin