Journal Article

Abnormal Whole Blood Thrombi in Humans with Inherited Platelet Receptor Defects

Davis, Patrick K., Liang, Zhong, Donahue, Deborah L., Castellino, Francis J., Balsara, Rashna D., Smith, Denise L., Ploplis, Victoria A., Musunuru, Harsha, Sandoval-Cooper, Mayra J., Walsh, Mark

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenosine diphosphate / Adenosine Diphosphate - pharmacology / Adenosine Diphosphate - physiology / Adolescent / Agglomeration / Arachidonic acid / Arachidonic Acid - pharmacology / Arachidonic Acid - physiology / Base Sequence / Bernard-Soulier syndrome / Bernard-Soulier Syndrome - blood / Bernard-Soulier Syndrome - genetics / Biology / Blood / Blood clots / Blood Coagulation / Blood platelets / Blood Platelets - drug effects / Blood Platelets - physiology / Coagulants - pharmacology / Collagen / Coronary vessels / Defects / DNA Mutational Analysis / Emergency medical care / Female / Females / Genetic aspects / Glycoproteins / Humans / Joint surgery / Male / Medicine / Membrane Glycoproteins - genetics / Middle Aged / Molecular Sequence Data / Mutation / Patients / Platelet Activation / Platelet Aggregation / Platelet Glycoprotein GPIb-IX Complex / Platelets / Receptor, PAR-1 - physiology / Ristocetin / Ristocetin - pharmacology / Sequence Deletion / Stains & staining / Surgery / Thrombasthenia - blood / Thrombasthenia - genetics / Thrombelastography / Thrombin / Thrombin - pharmacology / Thrombin - physiology / Thrombosis / Trauma / Viscoelastic Substances / Viscoelasticity / Young Adult