Plasma is the physiologic buffer of tissue plasminogen activator-mediated fibrinolysis: rationale for plasma-first resuscitation after life-threatening hemorrhage

J Am Coll Surg. 2015 May;220(5):872-9. doi: 10.1016/j.jamcollsurg.2015.01.026. Epub 2015 Mar 31.

Abstract

Background: Prehospital resuscitation with crystalloid exacerbates fibrinolysis, which is associated with high mortality. We hypothesized that plasma compared with crystalloid resuscitation prevents hyperfibrinolysis in a tissue plasminogen activator (tPA)-rich environment via preservation of proteins essential for regulation of fibrinolysis.

Study design: Healthy individuals donated blood, which was assayed using a native (nonactivated) thrombelastography (TEG). Whole-blood was mixed with normal saline (NS) or platelet poor plasma (PPP) at progressive dilutions. Tissue plasminogen activator was added to promote a fibrinolytic environment. In a separate experiment, PPP was run through a 100 kDa filter and liquid remaining on top of the filter (TFP) and below the filter (BFP) was obtained. Whole blood was diluted by 50% with TFP, BFP, and NS and assayed with a tPA TEG challenge. The TFP and BFP were assayed for protein concentration and protein composition.

Results: Normal saline and PPP dilution of whole blood without tPA did not affect clot lysis at 30 minutes (LY30) (NS Spearman's rho 0.300, p = 0.186 and PPP 0.294, p = 0.288). When tPA was added, NS dilution of whole blood increased LY30 in a percentage-dependent manner (0.844, p < 0.001), but did not significantly increase with PPP dilution (0.270, p = 0.202). The difference in LY30 from whole blood to diluted whole blood with PPP (mean change, -1.05, 95% CI, -9.42 to 7.33) was similar with TFP (1.23, 95% CI, -5.20 to 7.66, p = 0.992). However, both BFP (37.65, 95% CI 24.47 to 50.82, p = 0.001) and NS (47.36, 95% CI 34.3 to 60.45, p < 0.001) showed large increases in fibrinolysis compared with PPP.

Conclusions: Crystalloid and plasma dilution of whole blood does not increase fibrinolysis. However, NS dilution of whole blood increases susceptibility to tPA-mediated fibrinolysis. Plasma resuscitation, simulated by plasma dilution of whole blood, attenuates increased susceptibility to tPA-mediated fibrinolysis. The benefits of plasma resuscitation are mediated through preservation of plasma proteins.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Blood Component Transfusion*
  • Crystalloid Solutions
  • Female
  • Fibrinolysis / drug effects*
  • Fibrinolytic Agents / administration & dosage
  • Fibrinolytic Agents / pharmacology*
  • Hemorrhage / therapy*
  • Humans
  • In Vitro Techniques
  • Isotonic Solutions / administration & dosage
  • Isotonic Solutions / pharmacology
  • Male
  • Middle Aged
  • Plasma*
  • Resuscitation / methods*
  • Sodium Chloride / administration & dosage
  • Sodium Chloride / pharmacology
  • Tissue Plasminogen Activator / administration & dosage
  • Tissue Plasminogen Activator / pharmacology*

Substances

  • Crystalloid Solutions
  • Fibrinolytic Agents
  • Isotonic Solutions
  • Sodium Chloride
  • Tissue Plasminogen Activator