Tissue injury suppresses fibrinolysis after hemorrhagic shock in nonhuman primates (rhesus macaque)

Abstract

BACKGROUND Hypoperfusion is associated with hyperfibrinolysis and early death from exsanguination, whereas tissue trauma is associated with hypofibrinolysis and delayed death from organ failure. We sought to elucidate the effects of injury patterns on fibrinolysis phenotypes using a nonhuman primate (NHP) model. METHODS NHPs were randomized to three injury groups (n = 8/group): 60 minutes severe pressure-targeted controlled hemorrhagic shock (HS); HS + soft tissue injury (HS+); or HS + soft tissue injury + femur fracture (HS++). Animals were resuscitated and monitored for 360 minutes. Blood samples were collected at baseline, end-of-shock, end-of-resuscitation (EOR), and T = 360 minutes for assessments of: severity of shock (lactate) and coagulation via prothrombin time, partial thromboplastin time, D-dimer, fibrinogen, antithrombin-III, von Willebrand factor, and viscoelastic testing (ROTEM). Results are reported as mean ± SEM; statistics: two-way analysis of variance and t-tests (significance: p < 0.05). RESULTS Blood loss, prothrombin time, partial thromboplastin time, antithrombin-III, fibrinogen, and von Willebrand factor were equivalent among groups and viscoelastic testing revealed few differences throughout the study. D-dimer increased approximately threefold, at EOR in the HS group, and at T = 360 minutes in the HS+ and HS++ groups (p < 0.05). At EOR, in the HS group compared with the HS+ and HS++ groups; the D-dimer-lactate ratio was twofold greater (2.2 ± 0.3 vs. 1.1 ± 0.3 and 1.1 ± 0.2, respectively; p < 0.05) and tissue factor-activated fibrin clot 30-minute lysis index was lower (98 ± 1% vs. 100 ± 0% and 100 ± 0%, respectively; p < 0.05). CONCLUSION NHPs in HS exhibit acute suppression of fibrinolysis in the presence of tissue injury. Additional assessments to more comprehensively evaluate the mechanisms linking tissue injury with the observed fibrinolysis shutdown response are warranted.

Targeting resuscitation to normalization of coagulating status: Hyper and hypocoagulability after severe injury are both associated with increased mortality

“…Furthermore, the duration that a patients remains in a hypercoagulable state, the higher risk of mortality (23). Animal work has demonstrated that tissue injury causes fibrinolysis shutdown, while hemorrhagic shock increases fibrinolysis(12, 24). These early changes in may represent a response to injury in attempt to attain hemostasis but retain blood flow to organs, but prolongation of deranged coagulation may be pathologic.…”

Thrombelastography indicates limitations of animal models of trauma-induced coagulopathy

“…Perhaps gene modification of the coagulation proteins may provide an opportunity in the future. Nonhuman primates represent the best approximation at this time , but are logistically prohibitive [18, 19]. Although rats are widely used in coagulation studies, they represent a limited animal model to study TIC [5].…”

Defining trauma‐induced coagulopathy with respect to future implications for patient management: Communication from the SSC of the ISTH

“…In primary coagulopathy, trauma and traumatic shock give rise to systemic and persistent thrombin generation associated with platelet dysfunction from the early to late phases of trauma. Fibrinolytic systems bring about dynamic two‐phase changes: increased fibrinolysis due to shock‐induced t‐PA release at an early stage, and the inhibition of fibrinolysis due to persistent expression of PAI‐1 at a later stage of trauma . These imbalances are predictors of mortality in observational studies, and importantly, those patients with physiologic levels of fibrinolysis on admission have been shown to have the lowest mortality .…”

“…Fibrinolytic systems bring about dynamic two-phase changes: increased fibrinolysis due to shock-induced t-PA release at an early stage, 50,70 and the inhibition of fibrinolysis due to persistent expression of PAI-1 at a later stage of trauma. 51,71,72 These imbalances are predictors of mortality in observational studies, and importantly, those patients with physiologic levels of fibrinolysis on admission have been shown to have the lowest mortality. [8][9][10][11] However, depending on the mechanism of injury, and the type and speed of resuscitative measures imparted, the evolution from hyperfibrinolytic-type to hypofibrinolytic-type can occur in minutes to hours.…”