Histone H4 induces platelet ballooning and microparticle release during trauma hemorrhage

Abstract

Trauma hemorrhage is a leading cause of death and disability worldwide. Platelets are fundamental to primary hemostasis, but become profoundly dysfunctional in critically injured patients by an unknown mechanism, contributing to an acute coagulopathy which exacerbates bleeding and increases mortality. The objective of this study was to elucidate the mechanism of platelet dysfunction in critically injured patients. We found that circulating platelets are transformed into procoagulant balloons within minutes of injury, accompanied by the release of large numbers of activated microparticles which coat leukocytes. Ballooning platelets were decorated with histone H4, a damage-associated molecular pattern released in massive quantities after severe injury, and exposure of healthy platelets to histone H4 recapitulated the changes in platelet structure and function observed in trauma patients. This is a report of platelet ballooning in human disease and of a previously unrecognized mechanism by which platelets contribute to the innate response to tissue damage.

Identification of injury and shock driven effects on ex vivo platelet aggregometry: A cautionary tale of phenotyping

“…16,24 However, a recent study of patients with TIC in which platelet function was measured by multiple assays including aggregometry, surface receptor expression, platelet mapping, and platelet function analyzer suggests that, in fact, platelets from patients with TIC retain their secretory function despite evidence of impaired aggregation. 16 Others have identified that inhibitory factors in the plasma of trauma patients may be driving platelet dysfunction 25 or may even lead to changes in platelet morphology and structure leading to subsequent destruction, 26 but the clinical implications of impaired platelet aggregation in the setting of injury remain controversial. While multiple studies have demonstrated strong associations between impaired platelet aggregation and up to 10-fold higher mortality rates, 8,9,21 others have shown that even minor injuries represented by low median ISS scores of 5 can result in platelet inhibition, questioning the clinical relevance of these findings.…”

Procoagulant Phosphatidylserine-Exposing Platelets in vitro and in vivo

“…Platelets from patients with immune thrombocytopenia have increased (apoptosis-induced) PS exposure likely contributing to the decreased platelet counts (128,129). Recently, there has been the report of increased circulating PS-exposing ballooned platelets in trauma hemorrhage in response to the damage-associated molecular pattern histone H4, demonstrating a mechanism by which platelets respond to tissue damage (130).…”

The use of cryopreserved platelets in a trauma‐induced hemorrhage model

“…Trauma-induced coagulopathy is characterized by platelet dysfunction. 1,2 Whereas platelet counts can be preserved during traumatic bleeding, platelet dysfunction occurs in approximately 45% of trauma patients. [1][2][3] In accordance, transfusion of high doses of platelets results in a reduction in early death following trauma compared to lower doses of platelets.…”

“…1,2 Whereas platelet counts can be preserved during traumatic bleeding, platelet dysfunction occurs in approximately 45% of trauma patients. [1][2][3] In accordance, transfusion of high doses of platelets results in a reduction in early death following trauma compared to lower doses of platelets. 4,5 Liquid stored platelet products however, have a limited shelf-life (5-7 days at room temperature).…”