Sex dimorphisms in coagulation: Implications in trauma-induced coagulopathy and trauma resuscitation.

Trauma-induced coagulopathy (TIC) is one of the leading causes of preventable death in injured patients. Consequently, it is imperative to understand the mechanisms underlying TIC and how to mitigate this mortality. An opportunity for advancement stems from the awareness that coagulation demonstrates a strong sex-dependent effect. Females exhibit a relative hypercoagulability compared to males, which persists after injury and confers improved outcomes. The mechanisms underlying sex dimorphisms in coagulation and its protective effect after injury have yet to be elucidated. This review explores sex dimorphisms in enzymatic hemostasis, fibrinogen, platelets, and fibrinolysis, with implications for resuscitation of patients with TIC.

Hormones, age, and sex affect platelet responsiveness in vitro.

BACKGROUND: Female sex confers a survival advantage following severe injury in the setting of trauma-induced coagulopathy, with female platelets having heightened responsiveness likely due to estrogen. The effects of testosterone on platelet biology are unknown, and platelets express both estradiol and androgen receptors on the plasma membrane. We hypothesize testosterone decreases platelet responses in vitro, and there are baseline differences in platelet function and metabolism stratified by sex/age. STUDY DESIGN AND METHODS: Apheresis platelets were collected from: older males (OM) ≥45 years, younger males (YM) <45 years, older females (OF) ≥54 years, and younger females (YF) <54 years, and testosterone and estradiol were measured. Platelets were incubated with testosterone (5.31 ng/ml), estradiol (105 pg/ml) or vehicle and stimulated with buffer, adenosine diphosphate (20 µM), platelet activating factor (2 µM), or thrombin (0.3 U/ml). Aggregation, CD62P surface expression, fibrinogen receptor surface expression, and platelet mitochondrial metabolism were measured. RESULTS: Testosterone significantly inhibited aggregation in OF and OM (p < .05), inhibited CD41a expression in YF, YM, and OM (p < .05), and affected a few of the baseline amounts of CD62P surface expression but not platelet activation to platelet-activating factor and adenosine diphosphate, and variably changed platelet metabolism. DISCUSSION: Platelets have sex- and age-specific aggregation, receptor expression, and metabolism. Testosterone decreases platelet function dependent on the stimulus, age, and sex. Similarly, platelet metabolism has varying responses to sex hormones with baseline metabolic differences dependent upon sex and age.

Apolipoprotein A-I, elevated in trauma patients, inhibits platelet activation and decreases clot strength.

Apolipoprotein A-I (ApoA-I) is elevated in the plasma of a subgroup of trauma patients with systemic hyperfibrinolysis. We hypothesize that apoA-I inhibits platelet activation and clot formation. The effects of apoA-I on human platelet activation and clot formation were assessed by whole blood thrombelastography (TEG), platelet aggregometry, P-selectin surface expression, microfluidic adhesion, and Akt phosphorylation. Mouse models of carotid artery thrombosis and pulmonary embolism were used to assess the effects of apoA-I in vivo. The ApoA-1 receptor was investigated with transgenic mice knockouts (KO) for the scavenger receptor class B member 1 (SR-BI). Compared to controls, exogenous human apoA-I inhibited arachidonic acid and collagen-mediated human and mouse platelet aggregation, decreased P-selectin surface expression and Akt activation, resulting in diminished clot strength and increased clot lysis by TEG. ApoA-I also decreased platelet aggregate size formed on a collagen surface under flow. In vivo, apoA-I delayed vessel occlusion in an arterial thrombosis model and conferred a survival advantage in a pulmonary embolism model. SR-BI KO mice significantly reduced apoA-I inhibition of platelet aggregation versus wild-type platelets. Exogenous human apoA-I inhibits platelet activation, decreases clot strength and stability, and protects mice from arterial and venous thrombosis via the SR-BI receptor.

Current Surgical Trainee Perceptions and Experiences in Telehealth.

Introduction:Broad expansion of telehealth technologies has been implemented during the coronavirus disease 2019 (COVID-19) pandemic to allow for physical distancing and limitation of viral transmission within health care facilities. Although telehealth has been studied for its impact on patients, payors, and practitioners, its educational impact is largely unstudied. To better understand the trainee experience and perception of telehealth during the COVID-19 pandemic, we conducted a survey of the membership of the American College of Surgeons Resident and Associate Society (RAS).Methods:An anonymous survey was sent to members of RAS. Descriptive analysis was used to report experiences and perceptions. Chi-square analysis was used to compare cohorts with and without exposure to telehealth.Results:Of the 465 RAS respondents, 292 (62.8%) reported knowledge of telehealth technologies at their institutions. The majority of these respondents experienced a decrease in in-person clinic volume (94.4%) and an associated increase in virtual clinic volume (95.7%) related to the COVID-19 pandemic. Trainee integration into telehealth workflows increased drastically from prepandemic levels (11% vs. 54.5%, p < 0.001). Likelihood of trainee exposure to telehealth was associated with university-based training programs or larger program size. Trainees demonstrated a desire for more integration and development of curricula.Conclusions:These data serve as the first description of surgical trainee experience with, and opinion of, telehealth. Trainees recognize the importance of their integration and training in telehealth. These results should be used to guide the development of workflows and curricula that integrate trainees into telemedicine clinics.

28-day thawed plasma maintains α2 -antiplasmin levels and inhibits tPA-induced fibrinolysis.

INTRODUCTION: Evidence supports the use of plasma-first resuscitation in the treatment of trauma-induced coagulopathy (TIC). While thawed plasma (TP) has logistical benefits, the ability of plasma proteins to attenuate fibrinolysis and correct TIC remain unknown. We hypothesize that TP retains the ability to inhibit tissue plasminogen activator(tPA)-induced fibrinolysis at 28-day storage. METHODS: Healthy volunteers underwent blood draws followed by 50% dilution of whole blood (WB) with TP at 28-, 21-, 14-, 7-, 5-, and, 0-day storage, normal saline (NS), and WB control. Samples underwent citrated tPA-challenge (75 ng/ml) thromboelastography (TEG). Plasminogen activator inhibitor-1 (PAI-1) and α2 -antiplasmin (α2 -AP) concentrations in thawed or stored plasma were determined. RESULTS: In the presence of tPA, 28-day TP inhibited tPA-induced coagulopathy as effectively as WB. 28-day TP had a similar R-time, MA, and fibrinolysis (P > 0·05 for all) compared to WB, while angle was enhanced (P = 0·02) compared to WB. Significant correlations were present between storage time and clot strength (P = 0·04) and storage time and fibrinolysis (P = 0·0029). Active PAI-1 levels in thawed plasma were 1·10 ± 0·54 ng/mL while total PAI-1 levels were 4·79 ± 1·41 ng/mL. There was no difference of α2 -AP levels in FFP (40·45 ± 3·5 µg/mL) compared to plasma thawed for 14 (36·78 ± 5·39 µg/mL, P = 0·65) or 28 days (45·16 ± 5·61 µg/mL, P = 0·51). DISCUSSION: Thawed plasma retained the ability to inhibit tPA-induced fibrinolysis over 28-day storage at 1-4°C. α2 -AP levels were maintained in plasma thawed for 28 days and FFP. These in vitro results suggest consideration should be made to increasing the storage life of TP.

A Stitch in Time Saves Clots: Venous Thromboembolism Chemoprophylaxis in Traumatic Brain Injury.

BACKGROUND: Venous thromboembolism chemoprophylaxis (VTE-CHEMO) is often delayed in patients with traumatic brain injury because of the concern for intracranial hemorrhage (ICH) progression. We hypothesize that (1) late time to VTE-CHEMO (≥48 h) is associated with higher incidence of VTE, and (2) VTE-CHEMO use does not correlate with ICH progression. MATERIALS AND METHODS: This is a multiinstitutional retrospective study of patients with traumatic brain injury admitted between 2014 and 2016. Inclusion criteria were head Abbreviated Injury Code ≥2, ICH present on initial head computed tomography, and two or more head computed tomography scans after admission. The primary outcome was VTE, and the secondary outcome was ICH progression. Patients were classified as receiving VTE-CHEMO early (<48 h) or late (≥48 h). Multivariable analysis with Cox proportional hazards regression was performed. RESULTS: Overall, 1803 patients were included. Patients with VTE (n = 137) were more likely to have spinal cord injury, blunt cerebrovascular injury, pelvic or femur fractures, and missed VTE-CHEMO doses. After multivariable regression, body mass index >30 (hazard ratio [HR], 1.05; P = 0.002), Injury Severity Score (HR, 1.004; P < 0.001), pelvic or femur fractures (HR, 1.05; P < 0.0001), spinal cord injury (HR, 1.28; P = 0.02), and missed VTE-CHEMO doses (HR, 1.08; P = 0.01) were significant predictors of VTE. In those who required neurosurgery, late VTE-CHEMO predicted VTE (HR, 1.21; P = 0.0001). Overall, 32% patients experienced ICH progression, which did not correlate with VTE-CHEMO use or timing. CONCLUSIONS: This multicenter study highlights benefits from early VTE-CHEMO and identifies high-risk groups who may benefit from more aggressive prophylaxis. These data also emphasize risk to patients by withholding VTE-CHEMO.

"Bedside Anatomy": A Tool to Contextualize Learning and Introduce Surgical Careers.

BACKGROUND: Many medical students cite an unwelcoming culture in surgery and perceive surgeons as arrogant or unfriendly. These perceptions have been reported as factors discouraging medical students from applying to surgical residency programs. This highlights an opportunity early in medical education to address these negative stereotypes and create opportunities for positive interactions with surgeons. We hypothesize that positive experiences with surgical residents and introduction to representative surgical cases early in the medical school curriculum can provide a real-world context for learning anatomy and encourage students to consider a surgical career. METHODS: We developed and implemented a series of structured, one-hour, cadaver-based sessions cofacilitated by anatomists and surgical residents for medical students during their anatomy didactics. Sessions included common surgical cases and focused on critical thinking and problem-solving skills, while offering opportunities to review cadaver anatomy. Students completed a postcourse survey. RESULTS: Nine sessions were implemented with involvement of eight surgical residents and 185 students; 83 students completed a postcourse survey (response rate of 45%). A majority of students rated the sessions "very helpful" in terms of highlighting the importance of anatomy in medical education (n = 52, 63%) and providing clinical context (n = 59, 71%). 54% (n = 45) indicated interest in a surgical career and 64% (n = 53) agreed that session participation had increased their interest in surgery. CONCLUSIONS: Overall, students agreed that sessions provided clinical context for their learning and increased interest in a surgical career. Surgical faculty and residents should engage in preclinical medical education to bridge the basic science and clinical years and introduce positive surgical role models early during medical training.

High Rate of Fibrinolytic Shutdown and Venous Thromboembolism in Patients With Severe Pelvic Fracture.

BACKGROUND: Trauma patients with pelvic fractures have a high rate of venous thromboembolism (VTEs). The reason for this high rate is unknown. We hypothesize that fibrinolysis shutdown (SD) predicts VTE in patients with severe pelvic fracture. METHODS: Retrospective chart review of trauma patients who presented with pelvic fracture from 2007 to 2017 was performed. Inclusion criteria were injury severity score > 15, abdomen/pelvis abbreviated injury scale >/= 3, blunt mechanism, admission citrated rapid thrombelastography (TEG). Fibrinolytic phenotypes were defined by fibrinolysis on citrated rapid TEG as hyperfibrinolysis, physiologic lysis, and SD. Univariate analysis of TEG measurements and clinical outcomes, followed by multivariable logistic regression (MV) with stepwise selection, was performed. RESULTS: Overall, 210 patients were included. Most patients (59%) presented in fibrinolytic shutdown. VTE incidence was 11%. There were no significant differences in fibrinolytic phenotypes or other TEG measurements between those who developed VTE and those who did not. There was a higher rate of VTE in patients who underwent pelvic external fixation or resuscitative thoracotomy. On MV, pelvic fixation and resuscitative thoracotomy were independent predictors of VTE. CONCLUSIONS: In severely injured patients with pelvic fractures, there was a high rate of VTE and the majority presented in SD. However, we were unable to correlate initial SD with VTE. Ultimately, the high rate of VTE in this patient population supports the concept of implementing VTE chemoprophylaxis measures as soon as hemostasis is achieved.

A Cadaver-Based Course for Humanitarian Surgery Improves Manual Skill in Powerless External Fixation.

BACKGROUND: General surgery residents interested in humanitarian careers may benefit from supplemental training beyond modern residency. The Colorado Humanitarian Surgical Skills Workshop is a 2-d cadaver-based course for senior surgical residents, teaching low-resource skills across multiple specialties, including orthopedics. We assessed the course's ability to transmit manual competence in a critical humanitarian surgical skill, powerless lower extremity external fixation. MATERIALS AND METHODS: We created a novel standardized manual skills test of powerless lower extremity external fixation. Course participants had no prior experience with this technique. At course initiation, paired participants attempted to stabilize a proximal tibia-fibula fracture in a cadaver. Subsequently, participants received didactics from orthopedic surgeons followed by hands-on practice. At course completion, paired participants repeated the exercise. Fixator constructs were scored using standardized criteria. Precourse and postcourse surveys measured participants' level of confidence in performing external fixation. RESULTS: Twelve senior surgical residents were included. Average scores of external fixator constructs improved significantly (23% pre versus 75% post, P < 0.01). On pretesting, none of the participants completed the exercise within 15 min. Only one of six constructs was marginally stable, and none were aligned. On post-testing, five of six teams completed the exercise in an average of 12.4 min. Four of six constructs were stable and two of six were also well aligned. Confidence with external fixation also improved significantly. CONCLUSIONS: Participants in a short cadaver-based workshop demonstrated significant improvements in manual skill and confidence related to powerless external fixation. However, additional training is likely required to achieve clinical competence.

Surgical Apgar scores predict complications after emergency general surgery laparotomy.

BACKGROUND: The Surgical Apgar Score (SAS) is a 10-point validated score comprised of three intraoperative variables (blood loss, lowest heart rate, and lowest mean arterial pressure). Lower scores are worse and predict major postoperative complications. The SAS has not been applied in emergency general surgery (EGS) but may help guide postoperative disposition. We hypothesize that SAS can predict complications in EGS patients undergoing a laparotomy. METHODS: We performed a retrospective review of adult patients at a single, quaternary care center who underwent an exploratory laparotomy for EGS conditions within 6 hours of surgical consultation from 2015 to 2019. Patients were grouped by whether they experienced a postoperative complication (systemic, surgical, and/or death). Multivariable regression was performed to predict complications, accounting for SAS and other statistically significant variables between groups. Using this model, predicted probabilities of a complication were generated for each SAS. RESULTS: The cohort comprised 482 patients: 32.8% (n = 158) experienced a complication, while 67.2% (n = 324) did not. Patients with complications were older, frailer, more often male, had worse SAS (6 vs. 7, p < 0.0001) and American Society of Anesthesiologists scores, and higher rates of perforated hollow viscus ( p = 0.0003) and open abdomens ( p < 0.0001). On multivariable regression, an increasing SAS independently predicted less complications (adjusted odds ratio, 0.85; 95% confidence interval, 0.75-0.96; p = 0.009). An SAS ≤4 was associated with a 49.2% predicted chance of complications, greater rates of septic shock (9.7% vs. 3%, p = 0.01), respiratory failure (20.5% vs. 10.8%, p = 0.02), and death (24.1% vs. 7.5%, p < 0.0001). An SAS ≤ 4 did not correlate with surgical complications ( p = 0.1). CONCLUSION: The SAS accurately predicts postoperative complications in EGS patients undergoing urgent laparotomy, with an SAS ≤ 4 identifying patients at risk for septic shock, respiratory failure, and mortality. This tool can aid in rapidly determining postoperative disposition and resource allocation. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Using chest X-ray to predict tube thoracostomy in traumatic pneumothorax: A single-institution retrospective review.

BACKGROUND: Traumatic pneumothorax (PTX) is a common occurrence in thoracic trauma patients, with a majority requiring tube thoracostomy (TT) for management. Recently, the "35-mm" rule has advocated for observation of patients with PTX less than 35 mm on chest computed tomography (CT) scan. This rule has not been examined in chest x-ray (CXR). We hypothesize that a similar size cutoff can be determined in CXR predictive of need for tube thoracostomy. METHODS: We performed a single-institution retrospective review of patients with traumatic PTX from 2018 to 2022, excluding those who underwent TT prior to CXR. Primary outcomes were size of pneumothorax on CXR and need for TT; secondary outcome was failed observation, defined as TT more than 4 hours after presentation. To determine the size cutoff on CXR to predict TT need, area under the receiver operating curve (AUROC) analyses were performed and Youden's index calculated (significance at p < 0.05). Predictors of failure were calculated using logistic regression. RESULTS: There were 341 pneumothoraces in 304 patients (94.4% blunt trauma, median injury severity score 14). Of these, 82 (24.0%) had a TT placed within the first 4 hours. Fifty-five of observed patients (21.2%) failed, and these patients had a larger PTX on CXR (8.6 mm [5.0-18.0 mm] vs. 0.0 mm [0.0-2.3 mm] ( p < 0.001)). Chest x-ray PTX size correlated moderately with CT size (r = 0.31, p < 0.001) and was highly predictive of need for TT insertion (AUC 0.75, p < 0.0001), with an optimal size cutoff predicting TT need of 38 mm. CONCLUSION: Chest x-ray imaging size was predictive of need for TT, with an optimal size cutoff on CXR of 38 mm, approaching the "35-mm rule." In addition to size, failed observation was predicted by presenting lactic acidosis and need for supplemental oxygen. This demonstrates this cutoff should be considered for prospective study in CXR. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

The Trauma Fellow's Perspective on Grit and Resilience and Its Role in Wellness.

Purpose of Review: To describe the unique stressors of surgical training and fellowship and how grit and resilience influence trainee wellness. Recent Findings: Surgical training is an intense, high-stress experience. For fellows-in-training, unique stressors are associated with this chapter of training, from financial pressors to the stress of job acquisition. Wellness is essential for surgical fellows, not just for the critical need for quality mental health of providers, but also for the patients who are also affected by provider burnout. There are various wellness programs that can be instituted nationally and institutionally to optimize fellow wellness, but one of the most high-yield foci for fellow wellness is focused mentorship, the key to assuring wellness and harnessing grit. Summary: Surgical residency and fellowship are prodigiously demanding experiences, which mandate grit and resilience. It is imperative that widespread cultural and institutional changes take place to best support surgical trainees.

Elucidating the molecular mechanisms of fibrinolytic shutdown after severe injury: The role of thrombin-activatable fibrinolysis inhibitor.

BACKGROUND: The mechanisms underlying trauma-induced coagulopathy remain elusive. Hyperfibrinolysis has been linked to increased plasminogen activation and antiprotease consumption; however, the mechanistic players in its counterpart, fibrinolysis shutdown, remain unclear. We hypothesize that thrombin-activatable fibrinolysis inhibitor (TAFI) plays a major role in fibrinolytic shutdown after injury. METHODS: As part of this observational cohort study, whole blood was collected from trauma activation patients at a single, level 1 trauma center. Citrated rapid thrombelastography and the following enzyme-linked immunosorbent assays were conducted: thrombin, antithrombin, thrombin-antithrombin complex, TAFI, plasminogen, antiplasmin, plasmin-antiplasmin (PAP), tissue plasminogen activator, plasminogen activator inhibitor 1, and tissue plasminogen activator-plasminogen activator inhibitor 1 complex. Univariate and cluster analysis were performed. RESULTS: Overall, 56 patients (median age, 33.5 years; 70% male) were included. The majority (57%) presented after blunt mechanism and with severe injury (median New Injury Severity Score, 27). Two clusters of patients were identified: Group 1 (normal fibrinolysis, n = 21) and Group 2 (fibrinolysis shutdown, n = 35). Group 2 had significantly lower fibrinolysis with a median LY30 of 1.1% (interquartile range [IQR], 0.1-1.9%) versus 2.1% (IQR, 0.5-2.8%) in Group 1; while the median LY30 was within physiologic range, 45% of patients in Group 2 were in shutdown (vs. 24% in Group 1, p = 0.09). Compared with Group 1, Group 2 had significantly higher PAP (median, 4.7 [IQR, 1.7-9.3] vs. 1.4 [1.0-2.1] µg/mL in Group 1; p = 0.002) and higher TAFI (median, 152.5% [IQR, 110.3-190.7%] vs. 121.9% [IQR, 93.2-155.6%]; p = 0.04). There was a strong correlation between PAP and TAFI ( R2 = 0.5, p = 0.0002). CONCLUSION: The presented data characterize fibrinolytic shutdown, indicating an initial plasmin burst followed by diminished fibrinolysis, which is distinct from hypofibrinolysis (inadequate plasmin burst and fibrinolysis). After an initial thrombin and plasmin burst (increased PAP), fibrinolysis is inhibited, mediated in part by increased TAFI.

A metabolomic and proteomic analysis of pathologic hypercoagulability in traumatic brain injury patients after dura violation.

BACKGROUND: The coagulopathy of traumatic brain injury (TBI) remains poorly understood. Contradictory descriptions highlight the distinction between systemic and local coagulation, with descriptions of systemic hypercoagulability despite intracranial hypocoagulopathy. This perplexing coagulation profile has been hypothesized to be due to tissue factor release. The objective of this study was to assess the coagulation profile of TBI patients undergoing neurosurgical procedures. We hypothesize that dura violation is associated with higher tissue factor and conversion to a hypercoagulable profile and unique metabolomic and proteomic phenotype. METHODS: This is a prospective, observational cohort study of all adult TBI patients at an urban, Level I trauma center who underwent a neurosurgical procedure from 2019 to 2021. Whole blood samples were collected before and then 1 hour following dura violation. Citrated rapid and tissue plasminogen activator (tPA) thrombelastography (TEG) were performed, in addition to measurement of tissue factory activity, metabolomics, and proteomics. RESULTS: Overall, 57 patients were included. The majority (61%) were male, the median age was 52 years, 70% presented after blunt trauma, and the median Glasgow Coma Score was 7. Compared with pre-dura violation, post-dura violation blood demonstrated systemic hypercoagulability, with a significant increase in clot strength (maximum amplitude of 74.4 mm vs. 63.5 mm; p < 0.0001) and a significant decrease in fibrinolysis (LY30 on tPAchallenged TEG of 1.4% vs. 2.6%; p = 0.04). There were no statistically significant differences in tissue factor. Metabolomics revealed notable increases in metabolites involved in late glycolysis, cysteine, and one-carbon metabolites, and metabolites involved in endothelial dysfunction/arginine metabolism/responses to hypoxia. Proteomics revealed notable increase in proteins related to platelet activation and fibrinolysis inhibition. CONCLUSION: A systemic hypercoagulability is observed in TBI patients, characterized by increased clot strength and decreased fibrinolysis and a unique metabolomic and proteomics phenotype independent of tissue factor levels.

Estradiol provokes hypercoagulability and affects fibrin biology: A mechanistic exploration of sex dimorphisms in coagulation.

BACKGROUND: Sex dimorphisms in coagulation are well established, with female-specific hypercoagulability conferring a survival benefit in the setting of trauma-induced coagulopathy (TIC). The mechanism behind these phenomena remains to be elucidated. We hypothesize that estradiol provokes a hypercoagulable profile and alters clot proteomics and fibrin crosslinking. METHODS: Whole blood was collected from healthy adult volunteers (n = 30). A battery of thrombelastography (TEG) assays (native, kaolin, platelet-mapping, functional fibrinogen), whole blood thrombin generation, proteomics, and clot structure architecture (via analysis of fibrin crosslinks and fluorescent fibrinogen-visualized clots) were performed after pre-treatment of the blood with physiologic concentrations of beta-estradiol. In addition, a prospective study of coagulation through the menstrual cycle was conducted by collecting blood from women on peak and nadir estrogen days in the standard 28-day menstrual cycle. RESULTS: On TEG, in females, estradiol provoked a hypercoagulable phenotype, specifically a shorter time to clot formation and greater thrombin generation, greater rate of clot propagation and functional fibrinogen, higher clot strength, and diminished clot fibrinolysis. In both males and females, estradiol increased platelet hyperactivity. Similar changes were seen in time to clot formation and clot strength in vivo during peak estrus of the menstrual cycle. On proteomic analysis, in both males and females, estradiol was associated with increases in abundance of several procoagulant and antifibrinolytic proteins. Crosslinking mass spectrometry analysis showed addition of estradiol increased the abundance of several FXIII crosslinks within the FIBA alpha chain in both sexes. Fluorescent fibrinogen analysis revealed a trend toward increased fiber resolvability index after addition of estradiol. CONCLUSION: Estradiol provokes a hypercoagulable phenotype, affecting time to clot formation, clot propagation, clot strength, clot fibrinolysis, and clot structure. In sum, these data highlight the role of estradiol is driving female-specific hypercoagulability and highlights its potential role as a therapeutic adjunct in resuscitation of TIC.

Beyond uterine atony: characterizing postpartum hemorrhage coagulopathy.

BACKGROUND: Postpartum hemorrhage is a leading cause of morbidity and mortality worldwide, yet the associated early coagulopathy is not well defined. OBJECTIVE: We hypothesized that women who develop postpartum hemorrhage have a distinct derangement of thrombin generation and coagulation factors compared with postpartum women without postpartum hemorrhage. STUDY DESIGN: This prospective study of pregnant patients with postpartum hemorrhage was completed at a single urban hospital. Blood was drawn on postpartum hemorrhage diagnosis and 2 and 4 hours later. Assays of patients with postpartum hemorrhage included thrombelastography, whole blood thrombin generation, coagulation factor activity, tissue factor levels and activity, and tissue factor pathway inhibitor levels, which were compared with that of patients without postpartum hemorrhage. RESULTS: A total of 81 patients were included in this study. Of those patients, 66 had postpartum hemorrhage, and 15 served as controls. Compared with patients without PPH, patients with postpartum hemorrhage had lower fibrinogen levels (469.0 mg/dL vs 411.0 mg/dL; P=.02), increased tissue plasminogen activator resistance (fibrinolysis 30 minutes after maximal clot strength: 8.7% vs 4.2%; P=.02), decreased peak thrombin concentration (150.2 nM vs 40.7 nM; P=.01), and decreased maximal rate of thrombin generation (60.1 nM/minute vs 2.8 nM/minute; P=.02). Furthermore, compared with patients without postpartum hemorrhage, patients with postpartum hemorrhage had decreased tissue factor levels (444.3 pg/mL vs 267.1 pg/mL; P=.02) and increased tissue factor pathway inhibitor levels (0.6 U/mL vs 0.8 U/mL; P=.04), with decreased tissue factor pathway inhibitor ratios (624 vs 299; P=.01). CONCLUSION: PPH is not only an issue of uterine tone and mechanical bleeding but also a distinct coagulopathy that is characterized by decreased fibrinogen level, clot breakdown resistance, and markedly low thrombin generation. This pathology seemed to be driven by low tissue factor and high tissue factor pathway inhibitor levels.

Hemorrhagic shock and tissue injury provoke distinct components of trauma-induced coagulopathy in a swine model.

INTRODUCTION: Tissue injury (TI) and hemorrhagic shock (HS) are the major contributors to trauma-induced coagulopathy (TIC). However, the individual contributions of these insults are difficult to discern clinically because they typically coexist. TI has been reported to release procoagulants, while HS has been associated with bleeding. We developed a large animal model to isolate TI and HS and characterize their individual mechanistic pathways. We hypothesized that while TI and HS are both drivers of TIC, they provoke different pathways; specifically, TI reduces time to clotting, whereas, HS decreases clot strength stimulates hyperfibrinolysis. METHODS: After induction of general anesthesia, 50 kg male, Yorkshire swine underwent isolated TI (bilateral muscle cutdown of quadriceps, bilateral femur fractures) or isolated HS (controlled bleeding to a base excess target of - 5 mmol/l) and observed for 240 min. Thrombelastography (TEG), calcium levels, thrombin activatable fibrinolysis inhibitor (TAFI), protein C, plasminogen activator inhibitor 1 (PAI-1), and plasminogen activator inhibitor 1/tissue-type plasminogen activator complex (PAI-1-tPA) were analyzed at pre-selected timepoints. Linear mixed models for repeated measures were used to compare results throughout the model. RESULTS: TI resulted in elevated histone release which peaked at 120 min (p = 0.02), and this was associated with reduced time to clot formation (R time) by 240 min (p = 0.006). HS decreased clot strength at time 30 min (p = 0.003), with a significant decline in calcium (p = 0.001). At study completion, HS animals had elevated PAI-1 (p = 0.01) and PAI-1-tPA (p = 0.04), showing a trend toward hyperfibrinolysis, while TI animals had suppressed fibrinolysis. Protein C, TAFI and skeletal myosin were not different among the groups. CONCLUSION: Isolated injury in animal models can help elucidate the mechanistic pathways leading to TIC. Our results suggest that isolated TI leads to early histone release and a hypercoagulable state, with suppressed fibrinolysis. In contrast, HS promotes poor clot strength and hyperfibrinolysis resulting in hypocoagulability.