The α-globin chain of hemoglobin potentiates tissue plasminogen activator induced hyperfibrinolysis in vitro

J Trauma Acute Care Surg. 2022 Jan 1;92(1):159-166. doi: 10.1097/TA.0000000000003410.


Background: Severe injury predisposes patients to trauma-induced coagulopathy, which may be subdivided by the state of fibrinolysis. Systemic hyperfibrinolysis (HF) occurs in approximately 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 before blood component resuscitation, stratified by their state of fibrinolysis, plus 10 healthy controls. Different concentrations of intact hemoglobin A, the α- and β-globin chains, or normal saline (controls) were added to whole blood, and tissue plasminogen activator (tPA)-challenged thrombelastography was used to assess the degree of fibrinolysis. Interactions with plasminogen (PLG) were evaluated using surface plasmon resonance. Tissue plasminogen activator-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 < 0.01). The α-globin chain but not hemoglobin A or the β-globin chain decreased the reaction time and significantly increased lysis time 30 on citrated native thrombelastographies (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: Prognostic, level III.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Blood Coagulation Disorders* / blood
  • Blood Coagulation Disorders* / diagnosis
  • Blood Coagulation Disorders* / etiology
  • Female
  • Fibrinolysin / metabolism*
  • Fibrinolysis* / drug effects
  • Fibrinolysis* / physiology
  • Fibrinolytic Agents / pharmacology
  • Hemoglobins / metabolism
  • Humans
  • Male
  • Metabolic Networks and Pathways
  • Prognosis
  • Proteomics / methods
  • Thrombelastography / methods
  • Tissue Plasminogen Activator / pharmacology*
  • Wounds and Injuries* / blood
  • Wounds and Injuries* / complications
  • alpha-Globins / metabolism
  • beta-Globins / metabolism*


  • Fibrinolytic Agents
  • Hemoglobins
  • alpha-Globins
  • beta-Globins
  • Tissue Plasminogen Activator
  • Fibrinolysin