Michael P. Chapman

Goal-directed Hemostatic Resuscitation of Trauma-induced Coagulopathy: A Pragmatic Randomized Clinical Trial Comparing a Viscoelastic Assay to Conventional Coagulation Assays.

Background:Massive transfusion protocols (MTPs) have become standard of care in the management of bleeding injured patients, yet strategies to guide them vary widely. We conducted a pragmatic, randomized clinical trial (RCT) to test the hypothesis that an MTP goal directed by the viscoelastic assay thrombelastography (TEG) improves survival compared with an MTP guided by conventional coagulation assays (CCA). Methods:This RCT enrolled injured patients from an academic level-1 trauma center meeting criteria for MTP activation. Upon MTP activation, patients were randomized to be managed either by an MTP goal directed by TEG or by CCA (ie, international normalized ratio, fibrinogen, platelet count). Primary outcome was 28-day survival. Results:One hundred eleven patients were included in an intent-to-treat analysis (TEG = 56, CCA = 55). Survival in the TEG group was significantly higher than the CCA group (log-rank P = 0.032, Wilcoxon P = 0.027); 20 deaths in the CCA group (36.4%) compared with 11 in the TEG group (19.6%) (P = 0.049). Most deaths occurred within the first 6 hours from arrival (21.8% CCA group vs 7.1% TEG group) (P = 0.032). CCA patients required similar number of red blood cell units as the TEG patients [CCA: 5.0 (2–11), TEG: 4.5 (2–8)] (P = 0.317), but more plasma units [CCA: 2.0 (0–4), TEG: 0.0 (0–3)] (P = 0.022), and more platelets units [CCA: 0.0 (0–1), TEG: 0.0 (0–0)] (P = 0.041) in the first 2 hours of resuscitation. Conclusions:Utilization of a goal-directed, TEG-guided MTP to resuscitate severely injured patients improves survival compared with an MTP guided by CCA and utilizes less plasma and platelet transfusions during the early phase of resuscitation.

Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spectrum of postinjury fibrinolysis and relevance to antifibrinolytic therapy.

BACKGROUND Fibrinolysis is a physiologic process maintaining patency of the microvasculature. Maladaptive overactivation of this essential function (hyperfibrinolysis) is proposed as a pathologic mechanism of trauma-induced coagulopathy. Conversely, the shutdown of fibrinolysis has also been observed as a pathologic phenomenon. We hypothesize that there is a level of fibrinolysis between these two extremes that have a survival benefit for the severely injured patients. METHODS Thrombelastography and clinical data were prospectively collected on trauma patients admitted to our Level I trauma center from 2010 to 2013. Patients with an Injury Severity Score (ISS) of 15 or greater were evaluated. The percentage of fibrinolysis at 30 minutes by thrombelastography was used to stratify three groups as follows: hyperfibrinolysis (≥3%), physiologic (0.081–2.9%), and shutdown (0–0.08%). The threshold for hyperfibrinolysis was based on existing literature. The remaining groups were established on a cutoff of 0.8%, determined by the highest point of specificity and sensitivity for mortality on a receiver operating characteristic curve. RESULTS One hundred eighty patients were included in the study. The median age was 42 years (interquartile range [IQR], 28–55 years), 70% were male, and 21% had penetrating injuries. The median ISS was 29 (IQR, 22–36), and the median base deficit was 9 mEq/L (IQR, 6–13 mEq/L). Distribution of fibrinolysis was as follows: shutdown, 64% (115 of 180); physiologic, 18% (32 of 180); and hyperfibrinolysis, 18% (33 of 180). Mortality rates were lower for the physiologic group (3%) compared with the hyperfibrinolysis (44%) and shutdown (17%) groups (p = 0.001). CONCLUSION We have identified a U-shaped distribution of death related to the fibrinolysis system in response to major trauma, with a nadir in mortality, with level of fibrinolysis after 30 minutes between 0.81% and 2.9%. Exogenous inhibition of the fibrinolysis system in severely injured patients requires careful selection, as it may have an adverse affect on survival. LEVEL OF EVIDENCE Prognostic study, level III.

Fibrinolysis greater than 3% is the critical value for initiation of antifibrinolytic therapy

BACKGROUND The acute coagulopathy of trauma is present in up to one third of patients by the time of admission, and the recent CRASH-2 and MATTERs trials have focused worldwide attention on hyperfibrinolysis as a component of acute coagulopathy of trauma. Thromboelastography (TEG) is a powerful tool for analyzing fibrinolyis, but a clinically relevant threshold for defining hyperfibrinolysis has yet to be determined. Recent data suggest that the accepted normal upper bound of 7.5% for 30-minute fibrinolysis (LY30) by TEG is inappropriate in severe trauma, as the risk of death rises at much lower levels of clot lysis. We wished to determine the validity of this hypothesis and establish a threshold value to treat fibrinolysis, based on prediction of massive transfusion requirement and risk of mortality. METHODS Patients with uncontrolled hemorrhage, meeting the massive transfusion protocol (MTP) criteria at admission (n = 73), represent the most severely injured trauma population at our center (median Injury Severity Score [ISS], 30; interquartile range, 20–38). Citrated kaolin TEG was performed at admission blood samples from this population, stratified by LY30, and evaluated for transfusion requirement and 28-day mortality. The same analysis was conducted on available field blood samples from all non-MTP trauma patients (n = 216) in the same period. These represent the general trauma population. RESULTS Within the MTP-activating population, the cohort of patients with LY30 of 3% or greater was shown to be at much higher risk for requiring a massive transfusion (90.9% vs. 30.5%, p = 0.0008) and dying of hemorrhage (45.5% vs. 4.8%, p = 0.0014) than those with LY30 less than 3%. Similar trends were seen in the general trauma population. CONCLUSION LY30 of 3% or greater defines clinically relevant hyperfibrinolysis and strongly predicts the requirement for massive transfusion and an increased risk of mortality in trauma patients presenting with uncontrolled hemorrhage. This threshold value for LY30 represents a critical indication for the treatment of fibrinolysis. LEVEL OF EVIDENCE Prognostic study, level III.

Overwhelming tPA release, not PAI-1 degradation, is responsible for hyperfibrinolysis in severely injured trauma patients.

BACKGROUND Trauma-induced coagulopathy (TIC) is associated with a fourfold increased risk of mortality. Hyperfibrinolysis is a component of TIC, but its mechanism is poorly understood. Plasminogen activation inhibitor (PAI-1) degradation by activated protein C has been proposed as a mechanism for deregulation of the plasmin system in hemorrhagic shock, but in other settings of ischemia, tissue plasminogen activator (tPA) has been shown to be elevated. We hypothesized that the hyperfibrinolysis in TIC is not the result of PAI-1 degradation but is driven by an increase in tPA, with resultant loss of PAI-1 activity through complexation with tPA. METHODS Eighty-six consecutive trauma activation patients had blood collected at the earliest time after injury and were screened for hyperfibrinolysis using thrombelastography (TEG). Twenty-five hyperfibrinolytic patients were compared with 14 healthy controls using enzyme-linked immunosorbent assays for active tPA, active PAI-1, and PAI-1/tPA complex. Blood was also subjected to TEG with exogenous tPA challenge as a functional assay for PAI-1 reserve. RESULTS Total levels of PAI-1 (the sum of the active PAI-1 species and its covalent complex with tPA) are not significantly different between hyperfibrinolytic trauma patients and healthy controls: median, 104 pM (interquartile range [IQR], 48–201 pM) versus 115 pM (IQR, 54–202 pM). The ratio of active to complexed PAI-1, however, was two orders of magnitude lower in hyperfibrinolytic patients than in controls. Conversely, total tPA levels (active + complex) were significantly higher in hyperfibrinolytic patients than in controls: 139 pM (IQR, 68–237 pM) versus 32 pM (IQR, 16–37 pM). Hyperfibrinolytic trauma patients displayed increased sensitivity to exogenous challenge with tPA (median LY30 of 66.8% compared with 9.6% for controls). CONCLUSION Depletion of PAI-1 in TIC is driven by an increase in tPA, not PAI-1 degradation. The tPA-challenged TEG, based on this principle, is a functional test for PAI-1 reserves. Exploration of the mechanism of up-regulation of tPA is critical to an understanding of hyperfibrinolysis in trauma. LEVEL OF EVIDENCE Prognostic and epidemiologic study, level II.

TRAUMA-INDUCED COAGULOPATHY: AN INSTITUTION’S 35 YEAR PERSPECTIVE ON PRACTICE AND RESEARCH

Introduction: Injury is the second leading cause of death worldwide, and as much as 40% of injury-related mortality is attributed to uncontrollable hemorrhage. This persists despite establishment of regionalized trauma systems and advances in the management of severely injured patients. Trauma-induced coagulopathy has been identified as the most common preventable cause of postinjury mortality. Methods: A review of the current literature was performed by collecting PUBMED references related to trauma-induced coagulopathy. Data were then critically analyzed and summarized based on the authors’ clinical and research perspective, as well as that reported by other institutions and researchers interested in trauma-induced coagulopathy. A particular focus was placed on those aspects of coagulopathy in which agreement among clinical and basic scientists is currently lacking; these include, pathophysiology, the role of blood components and factor therapy, and goal-directed assessment and management. Results: Trauma-induced coagulopathy has been recognized in approximately one-third of trauma patients. There is a vast range of severity, and the emergence of viscoelastic assays, such as thrombelastography and rotational thromboelastogram, has refined its diagnosis and management, particularly through the establishment of goal-directed massive transfusion protocols. Despite advancements in the diagnosis and management of trauma-induced coagulopathy, much remains to be understood regarding its pathophysiology. The cell-based model of hemostasis has allowed for characterization of endothelial dysfunction, impaired thrombin generation, platelet dysfunction, fibrinolysis, endogenous anticoagulants such as protein-C, and antifibrinolytic proteins. These concepts collectively compose the contemporary, but still partial, understanding of trauma-induced coagulopathy. Conclusion: Trauma-induced coagulopathy is a complex pathophysiological condition, of which some mechanisms have been characterized, but much remains to be understood in order to translate this knowledge into improved outcomes for the injured patient.

Viscoelastic measurements of platelet function, not fibrinogen function, predicts sensitivity to tissue-type plasminogen activator in trauma patients.

Systemic hyperfibrinolysis is a lethal phenotype of trauma‐induced coagulopathy. Its pathogenesis is poorly understood. Recent studies have support a central role of platelets in hemostasis and in fibrinolysis regulation, implying that platelet impairment is integral to the development of postinjury systemic hyperfibrinolysis.

Traumatic brain injury causes platelet adenosine diphosphate and arachidonic acid receptor inhibition independent of hemorrhagic shock in humans and rats

BACKGROUND Coagulopathy in traumatic brain injury (CTBI) is a well-established phenomenon, but its mechanism is poorly understood. Various studies implicate protein C activation related to the global insult of hemorrhagic shock or brain tissue factor release with resultant platelet dysfunction and depletion of coagulation factors. We hypothesized that the platelet dysfunction of CTBI is a distinct phenomenon from the coagulopathy following hemorrhagic shock. METHODS We used thrombelastography with platelet mapping as a measure of platelet function, assessing the degree of inhibition of the adenosine diphosphate (ADP) and arachidonic acid (AA) receptor pathways. First, we studied the early effect of TBI on platelet inhibition by performing thrombelastography with platelet mapping on rats. We then conducted an analysis of admission blood samples from trauma patients with isolated head injury (n = 70). Patients in shock or on clopidogrel or aspirin were excluded. RESULTS In rats, ADP receptor inhibition at 15 minutes after injury was 77.6% ± 6.7% versus 39.0% ± 5.3% for controls (p < 0.0001). Humans with severe TBI (Glasgow Coma Scale [GCS] score ⩽ 8) showed an increase in ADP receptor inhibition at 93.1% (interquartile range [IQR], 44.8–98.3%; n = 29) compared with 56.5% (IQR, 35–79.1%; n = 41) in milder TBI and 15.5% (IQR, 13.2–29.1%) in controls (p = 0.0014 and p < 0.0001, respectively). No patient had significant hypotension or acidosis. Parallel trends were noted in AA receptor inhibition. CONCLUSION Platelet ADP and AA receptor inhibition is a prominent early feature of CTBI in humans and rats and is linked to the severity of brain injury in patients with isolated head trauma. This phenomenon is observed in the absence of hemorrhagic shock or multisystem injury. Thus, TBI alone is shown to be sufficient to induce a profound platelet dysfunction.

Hemolysis exacerbates hyperfibrinolysis, whereas platelolysis shuts down fibrinolysis: evolving concepts of the spectrum of fibrinolysis in response to severe injury.

ABSTRACT Introduction: We have recently identified a spectrum of fibrinolysis in response to injury, in which there is increased mortality in patients who have either excessive fibrinolysis (hyperfibrinolysis [HF]) or impaired fibrinolysis (shutdown). The regulation of the fibrinolytic system after trauma remains poorly understood. Our group’s previous proteomic and metabolomic work identified elevated red blood cell (RBC) degradation products in trauma patients manifesting HF. We therefore hypothesized that hemolysis was contributory to the pathogenesis of HF. Given the central role of platelets in the cell-based model of coagulation, we further investigated the potential role of platelet lysis in mediation of the fibrinolytic system. Methods: Red blood cells from healthy donors were frozen in liquid nitrogen and vortexed to create mechanical membrane disruption. Platelets were prepared in a similar fashion. Assays were performed with citrated whole blood mixed ex vivo with either RBC or platelet lysates. Tissue plasminogen activator (tPA) was then added to promote fibrinolysis, mimicking the tPA release from ischemic endothelium during hemorrhagic shock. The degree of fibrinolysis was evaluated with thromboelastography. To identify the mediators of the fibrinolysis system present in RBC and platelet lysates, these lysates were passed over immobilized tPA and plasminogen affinity columns to capture protein-binding partners from RBC or platelet lysates. Results: The addition of 75 ng/mL of tPA to whole blood increased fibrinolysis from median 30-min lysis of 1.4% (interquartile range [IQR], 0.9%–2.0%) to 8.9% (IQR, 6.5%–11.5%). Red blood cell lysate with tPA increased fibrinolysis to 20.1% (IQR, 12.5%–33.7%), which was nearly three times as much lysis as tPA alone (P < 0.001). Conversely, the addition of platelet lysate decreased tPA-mediated fibrinolysis to 0.35% (IQR, 0.2%–0.8%; P < 0.001). Affinity chromatography coupled with tandem mass spectrometry identified a number of proteins not previously associated with regulation of fibrinolysis and trauma. Conclusion: Red blood cell lysate is a potent enhancer of fibrinolysis, whereas platelet lysate inhibits fibrinolysis. Intracellular proteins from circulating blood cells contain proteins that interact with the two key proteins of tPA-mediated fibrinolysis. Understanding the effect of tissue injury and shock on the lysis of circulating cells may provide insight to comprehending the spectrum of fibrinolysis in response to trauma.

Postinjury fibrinolysis shutdown: Rationale for selective tranexamic acid.

Postinjury systemic fibrinolysis has been recognized as a biologic process for more than 200 years, but the specific mechanisms of regulation and their clinical implications remain to be elucidated. By the 1950s, the plasminogen-plasmin-antiplasmin system was established as critical in preserving microvascular patency during blood clotting to maintain hemostasis. The challenges in modulating systemic fibrinolysis became evident soon thereafter. In the 1960s systemic fibrinolysis was identified by thrombelastography (TEG) during the anhepatic phase of liver transplantation, prompting the recommendation for intraoperative antifibrinolytics. But the administration of antifibrinolytic was associated with fatal postoperative pulmonary emboli. During the same period, there was experimental evidence that antifibrinolytics prevented irreversible hemorrhagic shock. More recently, a randomized trial indicated that plasmin inhibition during coronary artery bypass grafting was associated with increased mortality. The interest in antifibrinolytic therapy for trauma induced coagulopathy (TIC) is a relatively recent event, largely driven by the increasing use of viscoelastic hemostatic assays. The CRASH-2 trial, published in 2010, stimulated worldwide enthusiasm for tranexamic acid (TXA). However, the limitations of this study were soon acknowledged, raising concern for the unbridled use of TXA. Most recently, the documentation of fibrinolysis shutdown soon after injury has highlighted the potential adverse effects due to the untimely administration of TXA. A recent retrospective analysis in severely injured patients supports this hypothesis. But final clarity of this volatile topic awaits the completion of the current ongoing randomized clinical trials throughout the world.

Plasma Is the Physiologic Buffer of Tissue Plasminogen Activator-Mediated Fibrinolysis: Rationale for Plasma-First Resuscitation after Life-Threatening Hemorrhage

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 Spearmans 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.