Daniel N. Darlington

United States Army Institute of Surgical Research

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P. Andrew

Family Health International 360

Xiaowu Wu

United States Army Institute of Surgical Research

James A. Bynum

The University of Texas Health Science Center at Houston

Michael A. Dubick

United States Army Institute of Surgical Research

Donald S. Gann

University of Maryland, Baltimore

Mary F. Dallman

University of California, San Francisco

Richard E. Mains

UConn Health

Jeffrey D. Keesee

United States Army Institute of Surgical Research

Betty Eipper

UConn Health

Michael A. Meledeo

United States Army Institute of Surgical Research

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United States Army Institute of Surgical Research

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The University of Texas Health Science Center at San Antonio

Joint Base San Antonio

The University of Texas Health Science Center at Houston

The University of Texas at San Antonio

Uniformed Services University of the Health Sciences

Weatherford College

Centre National de la Recherche Scientifique

University of Michigan–Ann Arbor

Inserm

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Effect of tranexamic acid administration on acute traumatic coagulopathy in rats with polytrauma and hemorrhage

PLoS ONE (2019)

Xiaowu Wu Avi Benov Daniel N. Darlington Jeffrey D. Keesee Bin Liu

Trauma and hemorrhagic shock can lead to acute traumatic coagulopathy (ATC) that is not fully reversed by prehospital resuscitation as simulated with a limited volume of fresh whole blood (FWB) in a rat model. Tranexamic Acid (TXA) is used as an anti-fibrinolytic agent to reduce surgical bleeding if administered prior to or during surgery, and to improve survival in trauma if given early after trauma. It is not clear from the existing clinical literature whether TXA has the same mechanism of action in both settings. This study sought to explore the molecular mechanisms of TXA activity in trauma and determine whether administration of TXA as a supplement to FWB resuscitation could attenuate the established ATC in a rat model simulating prehospital resuscitation of polytrauma and hemorrhagic shock. In a parallel in-vitro study, the effects on clotting assays of adding plasmin at varying doses along with either simultaneous addition of TXA or pre-incubation with TXA were measured, and the results suggested that maximum anti-fibrinolytic effect of TXA on plasmin-induced fibrinolysis required pre-incubation of TXA and plasmin prior to clot initiation. In the rat model, ATC was induced by polytrauma followed by 40% hemorrhage. One hour after trauma, the rats were resuscitated with FWB collected from donor rats. Vehicle or TXA (10mg/kg) was given as bolus either before trauma (TXA-BT), or 45min after trauma prior to resuscitation (TXA-AT). The TXA-BT group was included to contrast the coagulation effects of TXA when used as it is in elective surgery vs. what is actually feasible in real trauma patients (TXA-AT group). A single dose of TXA prior to trauma significantly delayed the onset of ATC from 30min to 120min after trauma as measured by a rise in prothrombin time (PT). The plasma d-dimer as well as plasminogen/fibrinogen ratio in traumatized liver of TXA-BT were significantly lower as compared to vehicle and TXA-AT. Wet/dry weight ratio and leukocytes infiltration of lungs were significantly decreased only if TXA was administrated later, prior to resuscitation (TXA-AT). In conclusion: Limited prehospital trauma resuscitation that includes FWB and TXA may not correct established systemic ATC, but rather may improve overall outcomes of resuscitation by attenuation of acute lung injury. By contrast, TXA given prior to trauma reduced levels of fibrinolysis at the site of tissue injury and circulatory d-dimer, and delayed development of coagulopathy independent of reduction of fibrinogen levels following trauma. These findings highlight the importance of early administration of TXA in trauma, and suggest that further optimization of dosing protocols in trauma to exploit TXA’s various sites and modes of action may further improve patient outcomes.

Polytrauma

Damage Control Surgery

10.1371/journal.pone.0223406

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Citations (16)

Platelets derived from fresh and cold‐stored whole blood participate in clot formation in rats with acute traumatic coagulopathy

British Journal of Haematology (2017)

Xiaowu Wu Daniel N. Darlington Robbie K. Montgomery Bin Liu Jeffrey D. Keesee

The in vitro haemostatic functions of fresh whole blood (FWB) are well preserved after cold storage. This study aimed to determine whether platelets derived from FWB and stored whole blood (SWB) contribute to clot formation in tissue injury after transfusion into coagulopathic rats with polytrauma/haemorrhage (T/H). The rats were resuscitated 1 h after trauma with FWB or SWB collected from green fluorescence protein (GFP) transgenic rats. After transfusion, a liver incision was made and the tissue was collected 10 min after injury to identify GFP+ platelets by immunohistochemistry. In comparison to FWB, platelet aggregation to adenosine diphosphate and protease-activated receptor-4 was reduced by 35% and 20%, and clotting time was shortened by 25% in SWB. After transfusion, SWB led to a significant increase in platelet activation as measured by an elevation of CD62P and phosphatidylserine expression. The platelets from SWB were in a higher activation state, and showed higher clearance rate and formation of platelet-leucocyte aggregates than those from FWB after transfusion. Platelets from both FWB and SWB were equivalently incorporated into the clot at the incisional site, as determined by co-localization of CD61 and GFP. This study suggests that SWB contributes to haemostatic function and is an effective alternative resource to treat trauma patients.

Thromboelastometry

Platelet Transfusion

Thromboelastography

Clotting time

10.1111/bjh.14999

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High-dose radiation exposure of cold-stored whole blood does not affect hemostatic function

Journal of Trauma and Acute Care Surgery (2022)

Sandra C. Becerra Daniel N. Darlington I. Abaasah Maryanne C. Herzig James A. Bynum

BACKGROUND Whole blood (WB) transfusion is routinely used to resuscitate severely injured military trauma patients. Blood can be stored refrigerated while still maintaining reasonable function but is susceptible to environmental influences, including radiation exposure. Immune-compromised patients are transfused with irradiated blood to inactivate donor lymphocyte function (25 Gy per Association for the Advancement of Blood and Biotherapies [AARB] standard 5.7.3.2). However, there is limited information on function of WB exposed to high radiation doses. OBJECTIVE This study aimed to determine if stored irradiated WB still retains function. This will be important if the stored blood supply is exposed to radiation in a combat situation or mass casualty incident when the need for blood will be high. METHODS Whole blood collected from healthy donors was irradiated at 0, 25, or 75 Gy and stored at 4°C. Blood cell count, blood gas chemistry, thromboelastometry, platelet aggregation, and reactive oxygen species were measured before irradiation and at 1, 7, and 14 days of storage. Irradiated WB was compared with nonirradiated WB controls. RESULTS Irradiated WB stored for up to 14 days was not significantly different than nonirradiated WB in most of the parameters measured. Stored blood showed expected changes associated with functional decline at longer storage times, but irradiation did not hasten the decline. There was a significant change in potassium and sodium ion concentrations after irradiation, but the functional relevance is not clear. CONCLUSION High-dose irradiation had little effect on stored WB. Although there were changes in plasma sodium and potassium levels, there was little to no effect on hemostasis and blood cell viability. This suggests that stored blood subjected to a radiation event generating at least a dose of 75 Gy is still suitable for transfusion, which could be particularly important in the event of a mass casualty event where a large amount of blood is needed.

Blood irradiation therapy

Thromboelastometry

10.1097/ta.0000000000003750

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Outcomes of Patients Who Have Incidental Non-Sustained Ventricular Tachycardia Identified on Cardiac Implantable Electronic Device Interrogation

Hearts (2021)

Aditya Narain Chun Shing Kwok Caterina Liggett-Wright Joseph Mayer Daniel N. Darlington

Background: Non-sustained ventricular tachycardia (NSVT) is an arrhythmia prevalent in both structurally normal and abnormal hearts. Methods: We conducted a single-center retrospective clinical audit of patients followed-up in a device clinic with one or more incidental NSVT episodes recorded on their device between November 2017 and August 2018 and followed up patients for outcomes until January 2019. Results: A total of 83 patients were included in the analysis with one or more episodes of NSVT on device interrogation. Those identified to have NSVT were more likely to be male (74.7%) and there was a mean of 14.2 beats per episode and a mean of 3.7 episodes for each patient. Only 24.7% of patients had electrolytes checked within 4 weeks of episode detection and 18.3% had an echocardiogram post-episode. The majority of patients (73.5%) were followed up again in the pacing clinic but had no changes in medication, or other management implemented. In terms of outcomes, 81.7% of patients had no admission to hospital, mortality, or shock during the follow-up period. Conclusions: Most patients who developed NSVT did not have an extra follow-up, medication review, or investigation. Despite this, outcomes such as admission, shock, or death were uncommon.

Single Center

10.3390/hearts2030024

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Rostral pontine and caudal mesencephalic control of arterial Pressure and Iliac, celiac and renal vascular resistance. II. Separate control and topographic organization

Brain Research (1985)

Daniel N. Darlington David G. Ward

Pons

10.1016/0006-8993(85)91301-0

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Citations (19)

Purine Nucleosides Stimulate Na/K ATPase, and Prolong Survival in Hemorrhagic Shock

Journal of Trauma and Acute Care Surgery (2005)

Daniel N. Darlington Donald S. Gann

Background: Hemorrhagic shock leads to the appearance of substances in plasma that depress Na/K ATPase activity leading to a rise in plasma potassium. Recently, we reported that adenosine can stimulate Na/K ATPase activity, lower the plasma potassium back to control and prolong survival in shocked rats. However, adenosine also caused bradycardia. We therefore searched for adenosine analogs that stimulate Na/K ATPase without the side effects of bradycardia. Methods: Na/K ATPase activity was assessed using 86Rb uptake in erythrocytes. Pentobarbital anesthetized rats had their femoral artery and vein cannulated, bled to 35 mm Hg for 1 hour and resuscitated. Results: We found that the purine nucleosides, inosine, guanosine, adenosine, deoxyadenosine and deoxyguanosine, stimulated Na/K ATPase in a dose-dependent manner and overcame partial inhibition by ouabain. However, the de-ribosylated bases, the nucleotides and the pyrimidines had little or no effect on Na/K ATPase activity. Purine nucleosides did not stimulate Na/K ATPase activity through adenosine receptors, as caffeine(1 mmol/L) or aminophylline (1 mmol/L) did not block stimulation. However, stimulation was blocked by inhibitors of the equilibrative nucleoside transporter (dipyridamole, 1 mmol/L, or S-(4-nitrobenzyl)-6-thioinosine, 10 μmol/L), suggesting that the mechanism of action is intracellular. Inosine, guanosine and adenosine (2.5 mmol/L) significantly increased survival of rats in hemorrhagic shock as compared with saline and cytidine controls, and lowered the shock-elevated plasma K+. Conclusions: Purine nucleosides stimulate Na/K ATPase and prolong survival in hemorrhagic shock in rats, probably through an intracellular mechanism.

Inosine

10.1097/01.ta.0000169801.08019.b9

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Citations (16)

A re-examination of the effect of vitamin B₁₂ concentrate on the hepatic injury produced by carbon tetrachloride

British Journal Of Nutrition (1959)

K. Aterman Daniel N. Darlington

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CARBON TETRACHLORIDE POISONING

Tetrachloride

10.1079/bjn19590024

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Citations (2)

Prolyl hydroxylase domain inhibitor is an effective pre-hospital pharmaceutical intervention for trauma and hemorrhagic shock

Scientific Reports (2024)

Xiaowu Wu P. Andrew James A. Bynum Tiffani C. Chance Daniel N. Darlington

Abstract Pre-hospital potentially preventable trauma related deaths are mainly due to hypoperfusion-induced tissue hypoxia leading to irreversible organ dysfunction at or near the point of injury or during transportation prior to receiving definitive therapy. The prolyl hydroxylase domain (PHD) is an oxygen sensor that regulates tissue adaptation to hypoxia by stabilizing hypoxia inducible factor (HIF). The benefit of PHD inhibitors (PHDi) in the treatment of anemia and lactatemia arises from HIF stabilization, which stimulates endogenous production of erythropoietin and activates lactate recycling through gluconeogenesis. The results of this study provide insight into the therapeutic roles of MK-8617, a pan-inhibitor of PHD-1, 2, and 3, in the mitigation of lactatemia in anesthetized rats with polytrauma and hemorrhagic shock. Additionally, in an anesthetized rat model of lethal decompensated hemorrhagic shock, acute administration of MK-8617 significantly improves one-hour survival and maintains survival at least until 4 h following limited resuscitation with whole blood (20% EBV) at one hour after hemorrhage. This study suggests that pharmaceutical interventions to inhibit prolyl hydroxylase activity can be used as a potential pre-hospital countermeasure for trauma and hemorrhage at or near the point of injury.

Hemorrhagic shock

Hypoxia

Polytrauma

10.1038/s41598-024-53945-w

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Citations (1)

Use of Specialized Pro‐Resolving Mediators to Alleviate Cold Platelet Storage Lesion

Transfusion (2020)

Kristin M. Reddoch‐Cardenas Umang Sharma Christi Salgado Carolina Cantu Daniel N. Darlington

BACKGROUND Cold‐stored platelets are an attractive option for treatment of actively bleeding patients due to a reduced risk of septic complications and preserved hemostatic function compared to conventional room temperature–stored platelets. However, refrigeration causes increased platelet activation and aggregate formation. Specialized pro‐resolving mediators (SPMs), cell signaling mediators biosynthesized from essential fatty acids, have been shown to modulate platelet function and activation. In this study, we sought to determine if SPMs could be used to inhibit cold‐stored platelet activation. METHODS Platelets were collected from healthy donors (n = 4‐7) and treated with SPMs (resolvin E1 [RvE1], maresin 1 [MaR1], and resolvin D2 [RvD2]) or vehicle (VEH; 0.1% EtOH). Platelets were stored without agitation in the cold and assayed on Days 0 and 7 of storage for platelet activation levels using flow cytometry, platelet count, aggregation response using impedance aggregometry, and nucleotide content using mass spectrometry. RESULTS Compared to VEH, SPM treatment inhibited GPIb shedding (all compounds), significantly reduced both PS exposure and activation of GPIIb/IIIa receptor (RvD2, MaR1), and preserved aggregation response to TRAP (RvD2, MaR1) after 7 days of storage. Similar to untreated cold‐stored platelets, SPM‐treated samples did not preserve platelet counts or block the release of P‐Selectin. Nucleotide content was unaffected by SPM treatment in cold‐stored platelets. CONCLUSIONS SPM treatment, particularly Mar1 and RvD2, led to reduced platelet activation and preserved platelet function after 7 days of storage in the cold. Future work is warranted to better elucidate the mechanism of action of SPMs on cold platelet function and activation.

P-selectin

10.1111/trf.15750

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Citations (9)

Measuring plasminogen activator inhibitor activity in plasma by two enzymatic assays

Journal of Biochemical and Biophysical Methods (2000)

William C. Chiu Donald S. Gann Daniel N. Darlington

Plasminogen activator inhibitor-1

Blood plasma

10.1016/s0165-022x(00)00103-2

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Citations (4)