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.
Highlights
An initial step in thrombus formation in the injured vascular endothelium is the adhesion of platelets to exposed subendothelial components, e.g., von Willebrand Factor, under high rates of shear, via the interaction of the platelet glycoprotein (GP) 1b/ V/IX receptor complex with subendothelial vWF [1]
Other signaling events occur as a result of agonist-platelet receptor interactions, one example being ADP interactions with its platelet receptor, P2Y12 [6], which results in activation of the integrin complex, aIIb/b3, the major fibrinogen receptor on platelets [7]
We propose that additional significant advances can be made by employing the critical end-point of whole blood thrombus-based examination of platelet function, in combination with platelet aggregation studies, which would expand knowledge on relationships between the receptor interactions leading to platelet aggregation and stable thrombus formation
Summary
An initial step in thrombus formation in the injured vascular endothelium is the adhesion of platelets to exposed subendothelial components, e.g., von Willebrand Factor (vWF), under high rates of shear, via the interaction of the platelet glycoprotein (GP) 1b/ V/IX receptor complex with subendothelial vWF [1]. This tethering of platelets promotes their firmer binding to subendothelial collagen (COL) fibers via platelet receptors, e.g., GPVI [2,3] and integrin aIIb1 [4]. This step promotes platelet aggregation via fibrinogen bridging and thrombus growth
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