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Objectives: The purpose was to describe the frequency of orthopaedic trauma and postsurgical complications associated with psychiatric diagnoses., Design: Query of TriNetx Analytics Network., Setting: Participating hospitals., Patient Selection Criteria: Those ≥18 years old with psychiatric illness and orthopaedic trauma., Outcome Measures and Comparisons: Fractures and postoperative complications were described. A 1:1 propensity score matching function was used. Odds ratios compared intercohort complications., Results: A total of 11,266,415 patients were identified with a psychiatric diagnosis, including bipolar disorder (8.9%), schizophrenia (3.3%), major depression (12.4%), stress-related disorder (9.6%), anxiety disorder (64.5%), borderline personality disorder (1.1%), or antisocial personality (0.2%). Prevalence of 30.2% was found for a fracture and at least 1 psychiatric diagnosis. Antisocial personality disorder had the highest risk ratio relative to people without that mental disorder (relative risk [RR] = 5.09) of having 1 or more associated fracture, followed by depression (RR = 3.03), stress-related disorders (RR = 3.00), anxiety disorders (RR = 2.97), borderline personality disorder (RR = 2.92), bipolar disorder (RR = 2.80), and schizophrenia (RR = 2.69). Patients with at least 1 psychiatric comorbidity had greater risk of pulmonary embolism, superficial and deep surgical site infections, pneumonia, urinary tract infection, deep venous thrombosis, osteonecrosis, and complex regional pain syndrome by 1 month after fixation, when compared with patients without psychiatric disorder. By 1 year, they were also at an increased risk for stroke and myocardial infarction., Conclusions: All psychiatric comorbidities were associated with increased RR of fracture and higher odds of complications compared with patients without psychiatric comorbidities. Providers should be aware of preexisting psychiatric diagnoses during treatment of acute injuries because of these risks., Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Recidivism is common following injury. Interventions to enhance patient engagement may reduce trauma recidivism. Education, counseling, peer mentorship, and other resources are known as Trauma Recovery Services (TRS). The authors hypothesized that TRS use would reduce trauma recidivism., Methods: Over five years at a level 1 trauma center, 954 adults treated operatively for pelvic, spine, and femoral fractures were reviewed. Recidivism was defined as return to trauma center for new injury within 30-months. All patients were offered TRS. Multivariate logistic regression statistical analysis was used to identify predictors of recidivism., Results: Three hundred and ninety-seven of all patients (42 %) utilized TRS, including educational materials (n = 293), peer visits (n = 360), coaching (n = 284), posttraumatic stress disorder (PTSD) screening (n = 74), and other services. Within the entire sample, 136 patients (14 %) returned to the emergency department for an unrelated trauma event after mean 21 months. 13 % of TRS users became recidivists. Overall, 49 % of recidivists had history of pre-existing mental illness. High rates of TRS engagement between recidivists and non-recidivists were seen (75 %); however, non-recidivists were more likely to use multiple types of recovery services (49 % vs 34 %, p = 0.002), and were more likely to engage with trauma peer mentors (former trauma survivors) more than once (91 % vs 81 %, p = 0.03). After multivariable analysis, patients using multiple different recovery services had a lower risk of recidivism (p = 0.04, OR 0.42, 95 % CI [0.19-0.96])., Conclusions: Multifaceted engagement with recovery programming is associated with less recidivism following trauma. Future study of resultant reductions in healthcare costs are warranted., Level of Evidence: Level II; Prognostic., Competing Interests: Declaration of Competing Interest The authors have no financial or other conflicts of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: Post Traumatic Stress Disorder (PTSD) commonly occurs following acute trauma. Post-injury outcomes are negatively impacted by PTSD. Trauma Recovery Services (TRS) programming was developed at our institution in 2013 to provide psychosocial programming that increases patient satisfaction with care and ability to return to work and decreases PTSD symptoms. We sought to identify factors that influence patients' decision to participate in programming., Methods: Over a 3-year period at a single, urban level 1 trauma center, 172 patients over the age of 18 screened positive for PTSD on the validated PTSD checklist for DSM-5 (PCL-5) screening tool. Demographic, socioeconomic, injury, and medical comorbidity information was collected. Variables were initially compared in a univariate manner via Chi-squared, Fisher exact, t-test, or Mann-Whitney U, as appropriate. Variables that had a p-value <0.2 on univariate analysis were entered into a backward stepwise logistic regression model to identify independent predictors of participation in TRS programming., Results: Mean age was 37.8 years. 70.1% of patients were male. The most common mechanisms of injury were gunshot wound (33.7%), motor vehicle crash (19.0%), and burn. 33.5% of patients participated in TRS programming. Nine predictors had p<.2 on univariate analysis and were entered into the stepwise regression model. Four predictors remained in the final model. Patients with private insurance (RR=2.2, p=.038), high school diploma or greater (RR=1.53, p=.002; Table 1), and PCL-5 score greater than 50 were more likely to participate in TRS programming (RR=1.42, p=.046). Patients who live 20 or more minutes away by car from TRS were less likely to participate in programming (RR=0.47, p=.065)., Discussion: Patients with more severe PTSD, higher levels of education, and private insurance were more likely to participate in TRS programming. Participation in TRS and similar psychosocial programs may be improved by minimizing the participant's potential commute to the program location., Competing Interests: Declaration of Competing Interest The authors have no financial or other conflicts of interest to report., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Survivors of physical trauma, their home caregivers, and their medical providers all have an increased risk of developing psychological distress and trauma-related psychiatric disease. The purpose of this study was to describe the frequency and change over time of trauma society research presentations regarding mental health to identify opportunities for growth., Methods: Archives from 2018 to 2020 from the American Association for the Surgery of Trauma, the Eastern Association for the Surgery of Trauma, and the Western Trauma Association were reviewed. The studies that measured mental illness, psychosocial distress, and other psychosocial factors were assessed: for (1) the use of patient-reported outcome measures ; (2) the association of psychosocial variables with outcomes; and (3) the interventions investigated. Change over time was assessed using χ 2 analysis., Results: Of 1,239 abstracts, 57 (4.6%) addressed at least 1 mental health-related factor. Mental health was more frequently studied over time (2018 [3.2%]; 2019 [3.5%]; 2020 [7.7%]; P = .003). The most frequently measured factors were post-traumatic stress disorder, quality of life, general mental health, and depression. Seventeen (29.8%) abstracts addressed substance abuse, most commonly opioid abuse. Seven (12.3%) abstracts measured mental health in caregivers or medical providers. Patient-reported outcome measures were used in 32 studies (56.1%). Two-thirds of studies reported findings suggesting that mental illness impairs trauma-related outcomes. Only 5 (8.8%) investigated interventions designed to reduce adverse outcomes., Conclusion: Although academic discussion of mental health after trauma increased from 2018 to 2020, the topic remains a limited component of annual programs, patient-reported outcome measures remain underutilized, and intervention studies are rare., (Copyright © 2022. Published by Elsevier Inc.)

Summary: Trauma is a major public health issue. Orthopaedic trauma surgeons are skilled in the acute management of musculoskeletal injury; however, formal training and resources have not been devoted to optimizing recovery after trauma. Recovery entails addressing the biomedical aspects of injury, as well as the psychological and social factors. The purposes of this study were to describe existing programs and resources within trauma centers, developed to promote psychosocial recovery. Supporting research data will be referenced, and potential barriers to program implementation will be discussed. The American College of Surgeons has mandated screening and treatment for mental illness after trauma, which will raise the bar to highlight the importance of these social issues, likely enabling providers to develop new programs and other resources within their systems. Provider education will promote the informing of patients and families, with the intent of enhancing the efficiency and scope of recovery., Competing Interests: The authors report no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Patient-specific factors may influence posttraumatic stress disorder (PTSD) development and warrant further examination. This study investigates potential association between patient-reported fear of death at the time of injury and development of PTSD., Methods: Over 35 months, 250 patients were screened for PTSD at their first posthospitalization clinic visit and were asked "Did you think you were going to die from this injury?" (yes or no). PTSD screening was conducted using the PTSD checklist for DSM-5 questionnaire. A score ≥33 was considered positive for PTSD, and patients were offered ancillary psychiatric services. Retrospectively, medical records were reviewed for baseline demographics and injury information., Results: Forty-three patients (17%) indicated a fear of death. The mean age was 46 years, with patients who feared death being younger (36 versus 48, P < 0.001), and 62% were male. The most common mechanisms of injury were motor vehicle or motorcycle collisions (30%) and ground-level falls (21%). Gunshot wounds were more common among patients who feared death from trauma (44% versus 7%, P < 0.001). PTSD questionnaires were completed a median of 26 days after injury, with an average score of 12.6. PTSD scores were higher for patients with fear of death (32.7 versus 8.5), and these patients required more acute interventions (47% versus 7%), both P < 0.001. After multivariable logistic regression, patients who thought that they would die from their trauma had >13 times higher odds of developing PTSD (odds ratios: 13.42, P < 0.0001). Apart from positive psychiatric history (OR: 5.46, P = 0.001), no factors (ie, age, sex, mechanism, or any injury or treatment characteristic) were predictive of positive PTSD scores on regression., Dicussion: Patients who reported fear of death at the time of injury were 13 times more likely to develop PTSD. Simply asking patients whether they thought that they would die at the time of injury may prospectively identify PTSD risk., Level of Evidence: Prognostic Level II., (Copyright © 2021 by the American Academy of Orthopaedic Surgeons.)

Background: Prior investigation of violence intervention programs has been limited. This study will describe resources offered by Victims of Crime Advocacy and Recovery Program (VOCARP), their utilization, and effect on recidivism., Methods: VOCARP was established in 2017 at our center, and all patients who engaged with programming (n=1019) were prospectively recorded. Patients are offered services in the emergency department, on inpatient floors and at outpatient clinic visits. Two control groups (patients sustaining violent injuries without VOCARP use (n=212) and patients with non-violent trauma (n=201)) were similarly aggregated., Results: During 22 months, 96% of patients accepted education materials, 31% received financial compensation, 27% requested referrals, and 22% had crisis interventions. All other resources were used by <20% of patients. Patients who used VOCARP resources were substantially different from those who declined services; they were less often male (56% vs. 71%), more often single (79% vs. 51%), had greater unemployment (63% vs. 51%) and were less frequently shot (gunshot wound: 26% vs. 37%), all p<0.05. Overall recidivism rate was 9.4%, with no difference between groups. Use of mental health services was linked to lower recidivism rates (4.4% vs. 11.7%, p=0.016). While sexual assault survivors who used VOCARP resources had lower associated recidivism (2.4% vs. 12%, p=0.14), this was not statistically significant., Discussion: This represents the largest violence intervention cohort reported to date to our knowledge. Despite substantial engagement, efficacy in terms of lower recidivism appears limited to specific subgroups or resource utilization., Level of Evidence: Level II. Therapeutic., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Attending clinic appointments after injury is crucial for orthopaedic trauma patients to evaluate healing and to update recommendations. However, attendance at these appointments is inconsistent. The purpose of this study was to assess the effect of a personalized phone call placed 3 to 5 days after hospital discharge on attendance at the first postdischarge outpatient clinic visit., Methods: This prospective study was done at an urban level 1 trauma center. One hundred fifty-nine patients were exposed to a reminder phone call, with 33% of patients being reached for a conversation and 28% receiving a voicemail reminder. Phone calls were made by a trained trauma recovery coach, and the main outcome measure was attendance at the first postdischarge clinic visit., Results: Eighty-six patients (54%) attended their scheduled appointments. Appointment adherence was more common among the group reached for a conversation (70% versus 51% for voicemail cohort and 34% for no contact group). Patients exposed to the Trauma Recovery Services (TRS) during their hospital stay attended appointments more often (91% versus 61%, P = 0.026). Age, sex, mechanism of injury, and distance from the hospital were not associated with specific follow-up appointment adherence. Insured status was associated with higher attendance rates (71% versus 46%, P = 0.0036). Other economic factors such as employment were also indicative of attendance (64% versus 48%, P = 0.05). Current tobacco use was associated with poor appointment attendance (30%) versus 56% for nonsmokers (P = 0.001)., Discussion: Patients reached by telephone after discharge had better rates of subsequent clinic attendance. Economic factors and substance use appear vital to postoperative clinic visit compliance. Patients with met psychosocial needs, as identified by individuals with satisfactory emotional support, and exposure to TRS had the highest rates of postdischarge appointment attendance.

Introduction: The purpose of this study is to assess the impact of Trauma Recovery Services (TRS), a program facilitating engagement and recovery on satisfaction after orthopaedic trauma., Methods: Two hundred ninety-four patients with surgically managed extremity fractures were prospectively surveyed. Satisfaction was assessed after 12 months using a 13-question telephone survey, rated on a Likert scale from 1 to 5 (with five being excellent). TRS resource utilization during and after hospitalization was recorded. Eighty-eight patients (30%) used TRS., Results: Overall satisfaction was high with a mean score of 4.32. Although no differences were observed between the control group and patients with TRS utilization in age, sex, race, insurance, smoking history, or employment status, TRS patients sustained more high-energy mechanisms (81% versus 56%) and had more associated psychiatric illness (33% versus 17%), both P < 0.01. Multivariable regression indicated general exposure to TRS to be an independent predictor of higher overall care ratings (B = 1.31; P = 0.03)., Discussion: Utilization of TRS was the greatest predictor of better overall care ratings. This study builds on existing evidence demonstrating the positive impact of Trauma Survivor Network programming. We conclude that a hospital-wide program supporting patient education and engagement can effectively increase patient satisfaction after traumatic injury., Level of Evidence: Prognostic Level II.

Objectives: To observe the availability of information about social, emotional, and psychological factors in abstracts presented at the Orthopaedic Trauma Association (OTA) annual meeting., Data Source: OTA website (https://ota.org/education/meetings-and-courses/meeting-archive/)., Study Selection: All abstracts selected for paper or poster presentation at the 2016 through 2018 OTA annual meetings, as published in the final program. Studies were included if they sought to measure mental illness, substance use or abuse, pain, or other psychosocial issues. If studies utilized 1 or more patient-reported outcome measures (PROMs), they were also included., Data Extraction: For each abstract meeting inclusion criterion, studies were assessed for interventions intended to improve outcomes in any of the listed psychosocial domains., Data Synthesis/results: Nine hundred forty-two abstracts were evaluated over a 3-year period. Of these, 294 (31.2%) met inclusion criteria. Twenty-five abstracts (8.5% of 294) reported mental illness, with depression (n = 14), anxiety (n = 9), and posttraumatic stress disorder (n = 5) being the most common. Eighty-eight abstracts (29.9% of 294) reported substance-use of tobacco, alcohol, narcotics, and/or recreational drugs. Tobacco-use was most prevalent (n = 59), followed by opioid-use (n = 31). Ten abstracts reported substance abuse. Pain was measured in 95 abstracts, and 203 abstracts utilized PROMs. Thirty-five abstracts found that these psychosocial elements significantly impacted outcomes or complications. Many abstracts did not assess the influence of these factors on clinical outcomes (n = 99). Sixteen studies described an intervention aimed at mitigating these features., Conclusions: This study illustrates limited attention to the impact of psychological, social, and environmental factors on outcomes after orthopaedic trauma. Substance-abuse problems and mental health concerns are not only predictors of poor clinical and PROMs of pain and quality of life after injury, but have also been implicated in subsequent recidivism. Only 3% of 942 abstracts observed mental health and 1% reported substance-abuse. Moving forward, greater understanding of psychosocial issues may enhance interventions to impact long-term outcomes., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Orthopaedic Trauma Association.)

The purpose was to determine the utility of an open access mobile device application (App: http://bit.ly/traumaapp) to improve patient education and engagement., Methods: A patient education app was developed with information regarding injury, treatment, and recovery for orthopaedic and other injuries. Data regarding usage, satisfaction, and desired improvements were gathered., Results: The app was downloaded 725 times, and the pages in the app were viewed 9,043 times in 34 months. User sessions >2 minutes accounted for 34%. Participation was less in those older than 55 years (12% versus 68% P < 0.001). Sixteen percent of patients did not have a device to use the app. Most (55%) rated it as helpful or extremely helpful; 78% of users were likely to recommend it. Patients most frequently suggested more information on other injuries and simpler language., Discussion: There was strong interest in this simple, free patient education app. Despite an urban, trauma population, five of six patients had access to a device that could load the app. Nearly half of the patients downloaded an orthopaedic patient education app when offered. Those who did not use the app were more likely to be older than 55 years. This represents an innovative opportunity for education and engagement of our patients and their families., Competing Interests: None of the following authors or any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Childs, Ms. Breslin, Mr. Andres, Ms. Swetz, Ms. Hendrickson, Dr. Moore, Dr. Ho, and Dr. Vallier., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Objective: To determine the prevalence of positive screening for posttraumatic stress disorder (PTSD) amongst trauma patients., Design: Prospective, longitudinal study., Setting: Single urban US level 1 trauma center., Patients and Methods: Four hundred fifty-two adult trauma patients were administered the PTSD checklist for DSM-V (PCL-5) survey upon posthospital outpatient clinic visit. This included 300 men (66%) and 152 women with mean age 43.8 years and mean Injury Severity Score (ISS) 11.3, with 83% having fractures of the pelvis and/or extremities. Medical and injury related variables were recorded. Multivariate logistic regression analysis was performed to identify factors predictive of screening positive for PTSD., Main Outcome Measurement: Prevalence and risk factors for screening positive for PTSD amongst the trauma patient population., Results: Twenty-six percent of trauma patients screened positive for PTSD after mean 86 days following injury. These patients were younger (35 vs 46 years old, P  < 0.001) and more commonly African American (56% vs 43% Caucasian, P  < 0.001). Pedestrians struck by motor vehicles (OR 4.70, P  = 0.040) and victims of crime (OR 4.12, P  = 0.013) were more likely to screen positive. Psychiatric history, injury severity (ISS), and injury type did not predict positive screening., Conclusion: One-in-four patients suffering traumatic injuries screened positive for PTSD suggesting the prevalence of PTSD among trauma patients far exceeds that of the general population. Predictive factors included victims of crime and pedestrians struck by motor vehicles. Screening measures are needed in orthopaedic trauma surgery clinics to refer these at-risk patients for proper evaluation and treatment., Level of Evidence: Prognostic; Level II., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Orthopaedic Trauma Association.)

Background: The primary goal of the present study is to describe the psychosocial support services provided at our institution and the evolution of such programming through time. This study will also report the demographics and injury patterns of patients using available resources., Methods: Trauma Recovery Services (TRS) is a social and psychological support program that provides services and resources to patients and families admitted to our hospital. It includes a number of different services such as emotional coaching from licensed counselors, educational materials, peer mentorship from trauma survivors, monthly support groups, post-traumatic stress disorder (PTSD) screening and programming for victims of crime. Patients using services were prospectively recorded by hired staff, volunteers and students who engaged in distributing programming. Demographics and injury characteristics were retrospectively gathered from patient's medical records., Results: From May of 2013 through December 2018, a total of 4977 discrete patients used TRS at an urban level 1 trauma center. During the study period, 31.4% of the 15 640 admitted adult trauma patients were exposed to TRS and this increased from 7.2% in 2013 to 60.1% in 2018. During the period of 5.5 years, 3317 patients had 'direct contact' (coaching and/or educational materials) and 1827 patients had at least one peer visit. The average number of peer visits was 2.7 per patient (range: 2-15). Of the 114 patients who attended support groups over 4 years, 55 (48%) attended more than one session, with an average of 3.9 visits (range: 2-10) per patient. After the establishment of PTSD screening and Victims of Crime Advocacy and Recovery Program (VOCARP) services in 2017, a total of 482 patients were screened for PTSD and 974 patients used VOCARP resources during the period of 2 years, with substantial growth from 2017 to 2018., Conclusions: Hospital-provided resources aimed at educating patients, expanding support networks and bolstering resiliency were popular at our institution, with nearly 5000 discrete patients accessing services during a period of 5.5 years. Moving forward, greater investigation of program usage, development, and efficacy is necessary., Level of Evidence: Level II therapeutic., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To identify resources that patients perceive as helpful to their recovery and to characterize the impact of the Trauma Survivor Network (TSN), a program committed to enhancing recovery through education and engagement., Design: Prospective cohort study., Setting: Level 1 trauma center., Patients/participants: Four hundred eighty-five patients with musculoskeletal injuries. Two hundred eleven were exposed to TSN resources (Group 1). One hundred thirty-five patients were treated during the same period with no exposure (Group 2, control). One hundred thirty-nine patients were treated 1 to 3 months prior to TSN implementation (Group 3, control)., Intervention: TSN resources including educational materials, family classes, peer survivor visits, coaching, online services, and support groups., Main Outcome Measure: A survey to assess hospital experience and perceptions about recovery., Results: On a Likert scale from 0 to 5, patients were highly satisfied (mean 4.24), with no differences based on TSN exposure. Patients exposed to TSN programming reported greater perceived likelihood of recovery: mean 3.73 vs 3.41 vs 3.38, Group 1 vs Group 2 vs Group 3 ( P  = .05) and regarding return to daily activities: 3.69 vs 3.49 vs 3.10, P  = .003. Fifty-three percent of Group 1 patients exposed to TSN programming utilized peer relationships and 42% read the educational materials provided. Support groups were also popular, with 26% of patients attending at least 1 session. Patients who recalled utilization of TSN services were overall highly satisfied with these services, mean 4.42., Conclusion: Patients were overall highly satisfied with their hospital stay, with those exposed to TSN services reporting greater perceived likelihood of recovery and return to daily activities. Development of nontraditional services, including peer visitation and support groups, appears to enhance expectations about recovery., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Orthopaedic Trauma Association.)

Elevated plasma levels of fibrinogen are associated with the presence of cardiovascular disease, but it is controversial whether elevated fibrinogen causally imparts an increased risk, and as such is a true modifier of cardiovascular disease, or is merely associated with disease. By investigating a transgenic mouse model of hyperfibrinogenemia, we show that elevated plasma fibrinogen concentration (1) elicits augmented fibrin deposition in specific organs, (2) interacts with an independent modifier of hemostatic activity to regulate fibrin turnover/deposition, (3) exacerbates neointimal hyperplasia in an experimental model of stasis-induced vascular remodeling, yet (4) may suppress thrombin generation in response to a procoagulant challenge. These findings provide direct experimental evidence that hyperfibrinogenemia is more than a by-product of cardiovascular disease and may function independently or interactively to modulate the severity and/or progression of vascular disease.

Mutations in the gene encoding thrombomodulin (TM), a thrombin regulator, are suspected risk factors for venous and arterial thrombotic disease. We have previously described the generation of TM(Pro/Pro) mice carrying a TM gene mutation that disrupts the TM-dependent activation of protein C. Here, it is shown that inbred C57BL/6J TM(Pro/Pro) mice exhibit a hypercoagulable state and an increased susceptibility to thrombosis and sepsis. Platelet thrombus growth after FeCl(3)-induced acute endothelial injury was accelerated in mutant mice. Vascular stasis after permanent ligation of the carotid artery precipitated thrombosis in mutant but not in normal mice. Mutant mice showed increased mortality after exposure to high doses of endotoxin and demonstrated altered cytokine production in response to low-dose endotoxin. The severity of the hypercoagulable state and chronic microvascular thrombosis caused by the TM(Pro) mutation is profoundly influenced by mouse strain-specific genetic differences between C57BL/6 and 129SvPas mice. These data demonstrate that in mice, TM is a physiologically relevant regulator of platelet- and coagulation-driven large-vessel thrombosis and modifies the response to endotoxin-induced inflammation. The phenotypic penetrance of the TM(Pro) mutation is determined by as-yet-uncharacterized genetic modifiers of thrombosis other than TM.

The thrombomodulin (TM) gene was ablated in mice in a cell type-restricted manner from vascular endothelium by Cre-recombinase-mediated excision controlled by the endothelial cell lineage-specific Tie2 promoter. Forty percent of mutant (TMLox-) mice display a distinct lethal embryonic phenotype not observed in completely TM-deficient embryos. The remaining 60% of TMLox mice survive beyond birth, but invariably succumb to a severe hypercoagulable state and massive thrombosis after 3 weeks, terminating in a lethal consumptive coagulopathy. The progression of thrombosis was age- and sex-dependent. Disruption of the TM/protein C pathway was not associated with a latent proinflammatory state. Disease onset and progression could be prevented by warfarin anticoagulation. These results show that in mice, loss of endothelial cell TM function causes spontaneous and fatal thrombosis in the arterial and venous circulation, resulting from unfettered activation of the coagulation system. The combination of complete disease penetrance, uniform disease onset at young age, large vessel thrombosis of the extremities and multiple organ systems, and consumptive coagulopathy as the disease end-point provides a unique mouse model of human thrombotic disease.

The endothelial cell surface receptor thrombomodulin (TM) inhibits blood coagulation by forming a complex with thrombin, which then converts protein C into the natural anticoagulant, activated protein C. In mice, a loss of TM function causes embryonic lethality at day 8.5 p.c. (post coitum) before establishment of a functional cardiovascular system. At this developmental stage, TM is expressed in the developing vasculature of the embryo proper, as well as in non-endothelial cells of the early placenta, giant trophoblast and parietal endoderm. Here, we show that reconstitution of TM expression in extraembryonic tissue by aggregation of tetraploid wild-type embryos with TM-null embryonic stem cells rescues TM-null embryos from early lethality. TM-null tetraploid embryos develop normally during midgestation, but encounter a secondary developmental block between days 12.5 and 16.5 p.c. Embryos lacking TM develop lethal consumptive coagulopathy during this period, and no live embryos are retrieved at term. Morphogenesis of embryonic blood vessels and other organs appears normal before E15. These findings demonstrate a dual role of TM in development, and that a loss of TM function disrupts mouse embryogenesis at two different stages. These two functions of TM are exerted in two distinct tissues: expression of TM in non-endothelial extraembryonic tissues is required for proper function of the early placenta, while the absence of TM from embryonic blood vessel endothelium causes lethal consumptive coagulopathy.

Murine gammaherpesvirus 68 (MHV68) is a gammaherpesvirus that was first isolated from murid rodents. MHV68 establishes a latent infection in the spleen and other lymphoid organs. Several gammaherpesviruses, including herpesvirus saimiri, human herpesvirus 8, and MHV68, encode proteins with extensive homology to the D-type cyclins. To study the function of the cyclin homologue, a recombinant MHV68 has been constructed that lacks the cyclin homologue and expresses beta-galactosidase as a marker (MHV68(cy-)). MHV68(cy-) grows in vitro with kinetics and to titers similar to those of the wild type. BALB/c mice infected with mixtures of equivalent amounts of the wild type and MHV68(cy-) show deficient growth of the MHV68(cy-) in an acute infection. Infection of SCID mice with virus mixtures also showed decreased MHV68(cy-) virus growth, indicating that the deficiency is not mediated by T or B cells. Although mice infected with mixtures containing 100 times as much MHV68(cy-) had greater splenic titers of the mutant virus than wild-type virus in acute infection, at 28 days postinfection splenocytes from these mice reactivated primarily wild-type virus. Quantitative PCR data indicate that equivalent genomes were present in the latent state. Reinsertion of the cyclin homologue into the cyclin-deleted virus restored the wild-type phenotype. These results indicate that the MHV68 cyclin D homologue mediates important functions in the acute infection and is required for efficient reactivation from latency.

Human herpesvirus-8 (HHV-8) has been detected in Kaposi's sarcoma (KS) lesions of all types (AIDS-related, classical and endemic), in body-cavity-based B-cell lymphomas (BCBLs) and in lesions of multicentric Castleman's disease (MCD). We have identified a major gamma-herpesvirus-divergent locus (DL-B) in HHV-8 DNA encoding several HHV-8 unique open reading frames (ORFs), including a homologue of interleukin-6 (IL-6) and two homologues of macrophage inflammatory protein MIP-1. We show that the HHV-8-encoded IL-6 homologue (vIL-6) shares functional properties with endogenous IL-6 proteins and that both vIL-6 and vMIP-1 transcripts are present at high levels following butyrate induction of an HHV-8' BCBL cell line. Low amounts of constitutive vIL-6, but not vMIP-1, mRNA were also detected. The presence of a functional IL-6 homologue encoded by HHV-8 may provide a mechanistic model for the hypothesized role of HHV-8 in KS, MCD and BCBL that involves the mitogenic effects of vIL-6 on surrounding cells. MIP-1 proteins may enhance these effects through the chemotactic recruitment of endogenous cytokine-producing cells into affected tissues and could potentially influence HIV disease progression in coinfected individuals through interactions with the HIV co-receptor CCR-5.