Traumatic-Induced Coagulopathy as a Systems Failure: A New Window into Hemostasis

Abstract

Traumatic-induced coagulopathy (TIC) is often associated with significant bleeding, transfusion requirements, inflammation, morbidity, and mortality. This review considers TIC as a systems failure, not as a single-event manifestation of trauma. After briefly reviewing the meaning of TIC and the bewildering array of fibrinolysis phenotypes, we will discuss the role of platelets and fibrinogen in coagulopathy. Next, we will review the different TIC hypotheses and drill down to a single mechanistic domain comprising (1) thrombin's differential binding to thrombomodulin, (2) the expression of annexin II-S100A10 complex, and (3) the functional integrity of the endothelial glycocalyx. This triad forms the basis of the “switch” hypothesis of TIC. We will next address the potential limitations of current practice in treating a coagulation or fibrinolytic defect, and the next defect, and so on down the line, which often leads to what U.S. surgeon William C. Shoemaker considered “an uncoordinated and sometimes contradictory therapeutic outcome.” The treat-as-you-go approach using sequential, single-target treatments appears to be a by-product of decades of highly reductionist thinking and research. Lastly, we will present a unified systems hypothesis of TIC involving three pillars of physiology: the central nervous system (CNS)–cardiovascular system, the endothelial glycocalyx, and mitochondrial integrity. If CNS control of ventriculoarterial coupling is maintained close to unity following trauma, we hypothesize that the endothelium will be protected, mitochondrial energetics will be maintained, and TIC (and inflammation) will be minimized. The Systems Hypothesis of Trauma (SHOT) also helps to answer why certain groups of severely bleeding trauma patients are still dying despite receiving the best care. Currently, no drug therapy exists that targets the whole system.

Trauma of major surgery: A global problem that is not going away

“…Surgical stress can be defined as an acute response to one or more breaches of the body's barrier functions from sterile injury (incision, excision, manipulation and pain), pathogen invasion (gut bacterial translocation or postoperative wound infection) and/or anesthesia. After induction of anesthesia and the first incision, the stress response begins with an increase in sympathetic discharge [ [20] , [21] , [22] , [23] ] which, if not contained, has multiple effects on whole body homeostasis; it increases inflammation [ [24] , [25] , [26] , [27] ], alters coagulation [ [28] , [29] , [30] ], modifies immune competency and T cell mobilization through a β2-adrenergically-mediated process [ 24 , [31] , [32] , [33] ], increases susceptibility to infection [ 31 , 34 ], and reduces tissue oxygenation [ 23 , [35] , [36] , [37] , [38] ]. This wave of secondary injury increases the probability of multiple organ dysfunction by altering multiple homeostatic circuits linking brain, heart, lung, kidney, liver, gut and muscle functions [ 39 ] (see Fig.…”

“…In formulating a working hypothesis to reduce surgical morbidity and mortality, Cannon's insight into traumatic injury being a system's perturbation beginning with the CNS cannot be overstated [ 29 , 42 ]. New ways are required to prevent the CNS from entering into ‘overdrive’ after receiving damage signals from the surgical incision, excision, cauterizing, manipulation, suturing and anesthesia.…”

“…Shifting the autonomic balance by inhibiting sympathetic and upregulating parasympathetic outflows is a key component to the hypothesis because activation of parasympathetic pathways exerts anti-inflammatory actions [ 78 ] and reduces the potential for ‘downstream’ secondary injury progression. We have proposed how this might work in a Systems Hypothesis of Trauma (SHOT) which has three pillars of protection [ 29 ] and apply it to surgical stress ( Fig. 2 ).…”

“…The endothelial-glycocalyx forms a nexus between the blood circulation and tissues and covers an enormous surface area (up to 50,000 m 2 ). By maintaining different cell morphologies over this vast surface area the endothelial-glycocalyx plays a key integrator role in coupling CNS-Cardiovascular function to oxygen transport and energy production [ 29 ]. Impaired VA coupling can lead to hypoperfusion and activate the endothelium.…”

The Complexity of Trauma-Induced Coagulopathy

“…Dobson et al therefore give their view on the systems failure in the early stages of trauma. 10 Treatment of TIC also remains controversial. The current management is institution-dependent and often not initiated based on the patient's coagulation status.…”