The α-globin Chain of Hemoglobin Potentiates Tissue Plasminogen Activator Induced Hyperfibrinolysis in vitro

J Trauma Acute Care Surg. 2021 Sep 16. doi: 10.1097/TA.0000000000003410. Online ahead of print.


Background: Severe injury predisposes patients to trauma-induced coagulopathy (TIC), which may be subdivided by the state of fibrinolysis. Systemic hyperfibrinolysis (HF) occurs in ~25% of these patients with mortality as high as 70%. Severe injury also causes the release of numerous intracellular proteins which may affect coagulation, one of which is hemoglobin, and hemoglobin substitutes induce HF in vitro. We hypothesize that the α-globin chain of hemoglobin potentiates HF in vitro by augmenting plasmin activity.

Methods: Proteomic analysis was completed on a pilot study of 30 injured patients prior to blood component resuscitation, stratified by their state of fibrinolysis, plus 10 healthy controls. Different concentrations of intact hemoglobin (HbA), the α- and β-globin chains, or normal saline (NS, controls) were added to whole blood and tPA-challenge thrombelastography (TEG) was used to assess the degree of fibrinolysis. Interactions with plasminogen (PLG) were evaluated using surface plasmon resonance (SPR). TPA-induced plasmin activity was evaluated in the presence of the α-globin chain.

Results: Only the α- and β-globin chains increased in HF patients (p < .01). The α-globin chain but not HbA or the β-globin chain decreased the R-time and significantly increased Ly30 on CN-TEGs (p < 0.05). The PLG and α-globin chain had interaction kinetics similar to tPA:PLG, and the α-globin chain increased tPA-induced plasmin activity.

Conclusions: the α-globin chain caused HF in vitro by binding to PLG and augmenting plasmin activity and may represent a circulating "moonlighting" mediator released by the tissue damage and hemorrhagic shock inherent to severe injury.

Level of evidence: III prognostic.