Loss of GPVI and GPIbα contributes to trauma-induced platelet dysfunction in severely injured patients

Trauma-induced coagulopathy (TIC) is a complex, multifactorial failure of hemostasis that occurs in 25% of severely injured patients and results in a fourfold higher mortality. However, the role of platelets in this state remains poorly understood. We set out to identify molecular changes that may underpin platelet dysfunction after major injury and to determine how they relate to coagulopathy and outcome. We performed a range of hemostatic and platelet-specific studies in blood samples obtained from critically injured patients within 2 hours of injury and collected prospective data on patient characteristics and clinical outcomes. We observed that, although platelet counts were preserved above critical levels, circulating platelets sampled from trauma patients exhibited a profoundly reduced response to both collagen and the selective glycoprotein VI (GPVI) agonist collagen-related peptide, compared with those from healthy volunteers. These responses correlated closely with overall clot strength and mortality. Surface expression of the collagen receptors GPIbα and GPVI was reduced on circulating platelets in trauma patients, with increased levels of the shed ectodomain fragment of GPVI detectable in plasma. Levels of shed GPVI were highest in patients with more severe injuries and TIC. Collectively, these observations demonstrate that platelets experience a loss of GPVI and GPIbα after severe injury and translate into a reduction in the responsiveness of platelets during active hemorrhage. In turn, they are associated with reduced hemostatic competence and increased mortality. Targeting proteolytic shedding of platelet receptors is a potential therapeutic strategy for maintaining hemostatic competence in bleeding and improving the efficacy of platelet transfusions

Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: Case Report and systematic literature review

<p>Abstract</p> <p>Background</p> <p>Dyskeratosis congenita (DC) is a progressive, multi-system, inherited disorder of telomere biology with high risks of morbidity and mortality from bone marrow failure, hematologic malignancy, solid tumors and pulmonary fibrosis. Hematopoietic stem cell transplantation (HSCT) can cure the bone marrow failure, but it does not eliminate the risks of other complications, for which life-long surveillance is required. Pulmonary fibrosis is a progressive and lethal complication of DC.</p> <p>Case presentation</p> <p>In this report, we describe a patient with DC who developed pulmonary fibrosis seven years after HSCT for severe aplastic anemia, and was successfully treated with bilateral lung transplantation. We also performed a systematic literature review to understand the burden of pulmonary disease in patients with DC who did or did not receive an HSCT. Including our patient, we identified 49 DC patients with pulmonary disease (12 after HSCT and 37 without HSCT), and 509 with no reported pulmonary complications.</p> <p>Conclusion</p> <p>Our current case and literature review indicate that pulmonary morbidity is one of the major contributors to poor quality of life and reduced long-term survival in DC. We suggest that lung transplantation be considered for patients with DC who develop pulmonary fibrosis with no concurrent evidence of multi-organ failure.</p

Early changes within the lymphocyte population are associated with the development of multiple organ dysfunction syndrome in trauma patients

2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.JM was funded, in part, by the Royal College of Surgeons of England, The Phillip King Charitable Trust Research Fellowship and The National Institute of Health Research (NIHR)

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Alterations in platelet behavior after major trauma: adaptive or maladaptive?

Platelets are damage sentinels of the intravascular compartment, initiating and coordinating the primary response to tissue injury. Severe trauma and hemorrhage induce profound alterations in platelet behavior. During the acute post-injury phase, platelets develop a state of impaired ex vivo agonist responsiveness independent of platelet count, associated with systemic coagulopathy and mortality risk. In patients surviving the initial insult, platelets become hyper-responsive, associated with increased risk of thrombotic events. Beyond coagulation, platelets constitute part of a sterile inflammatory response to injury: both directly through release of immunomodulatory molecules, and indirectly through modifying behavior of innate leukocytes. Both procoagulant and proinflammatory aspects have implications for secondary organ injury and multiple-organ dysfunction syndromes. This review details our current understanding of adaptive and maladaptive alterations in platelet biology induced by severe trauma, mechanisms underlying these alterations, potential platelet-focused therapies, and existing knowledge gaps and their research implications

Alterations in platelet behavior after major trauma: adaptive or maladaptive?

Platelets are damage sentinels of the intravascular compartment, initiating and coordinating the primary response to tissue injury. Severe trauma and hemorrhage induce profound alterations in platelet behavior. During the acute post-injury phase, platelets develop a state of impaired ex vivo agonist responsiveness independent of platelet count, associated with systemic coagulopathy and mortality risk. In patients surviving the initial insult, platelets become hyper-responsive, associated with increased risk of thrombotic events. Beyond coagulation, platelets constitute part of a sterile inflammatory response to injury: both directly through release of immunomodulatory molecules, and indirectly through modifying behavior of innate leukocytes. Both procoagulant and proinflammatory aspects have implications for secondary organ injury and multiple-organ dysfunction syndromes. This review details our current understanding of adaptive and maladaptive alterations in platelet biology induced by severe trauma, mechanisms underlying these alterations, potential platelet-focused therapies, and existing knowledge gaps and their research implications