Publications by authors named "Donald F Brophy"

Article Synopsis
  • A Phase II clinical trial examined the effects of intravenous vitamin C on patients receiving hematopoietic stem cell transplants to reduce nonrelapse mortality (NRM).
  • Patients (55 total) were given IV vitamin C for 14 days, which corrected their initial vitamin C deficiency and showed a trend towards lower NRM (11%) compared to historical controls (25%).
  • The study suggests that vitamin C repletion is safe and may improve survival rates (82% vs. 62%), but further randomized trials are necessary to validate these findings.
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Unlabelled: Intravenous (IV) vitamin C improves organ function and reduces inflammation in sepsis, an inflammatory state like the post-hematopoietic stem cell transplant (SCT) milieu. The safety and efficacy of parenteral vitamin C after allogeneic hematopoietic stem cell transplant (HSCT) were evaluated in a phase I/II trial and clinical outcomes compared with a propensity score - matched historical control.

Methods: Patients with advanced hematologic malignancies were enrolled in a phase 2 clinical trial, receiving IV vitamin C, 50mg/kg/d, divided into 3 doses given on days 1-14 after HSCT, followed by 500 mg bid oral from day 15 until 6 months post-SCT.

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Background: Perfluorocarbon emulsions (PFCs) are intravenous artificial oxygen carriers with enhanced gas solubility. As lipid micelle nanoparticle emulsions, PFCs may have a class effect that causes degrees of thrombocytopenia. Understanding the extent of the platelet effects, including mechanism and potential inflammation after PFC infusion, is important for safe human trials.

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Introduction: Tissue factor pathway inhibitor (TFPI) is an endogenous protein that inhibits the extrinsic (tissue factor) pathway and negatively regulates thrombin production during coagulation. Inhibiting TFPI may become a useful target for haemophilia drug development to allow greater thrombin generation without use of the intrinsic (contact) pathway.

Aims: The in vitro effects of befovacimab, a humanized TFPI neutralizing antibody, were studied in whole blood and plasma samples from patients with severe FVIII deficiency.

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Diet is major modifiable risk factor for cardiovascular disease that can influence the immune status of the individual and contribute to persistent low-grade inflammation. In recent years, there has been an increased appreciation of the role of polyunsaturated fatty acids (PUFA) in improving immune function and reduction of systemic inflammation via the modulation of pattern recognition receptors (PRR) on immune cells. Extensive research on the use of bioactive lipids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and their metabolites have illustrated the importance of these pro-resolving lipid mediators in modulating signaling through PRRs.

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Importance: Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS).

Objective: To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS.

Design, Setting, And Participants: The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours.

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Background: Recombinant factor VIIa (rFVIIa) enhances thrombin generation in a platelet-dependent manner; however, rFVIIa binds activated platelets with relatively low affinity. Triggering receptor expressed on myeloid cells (TREM)-like transcript (TLT)-1 is expressed exclusively on activated platelets.

Objective: To enhance the potency of rFVIIa via binding TLT-1.

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Background: Human factor XIa (FXIa) is an actively pursued target for development of safer anticoagulants. Our long-standing hypothesis has been that allosterism originating from heparin-binding site(s) on coagulation enzymes is a promising approach to yield safer agents.

Objectives: To develop a synthetic heparin mimetic as an inhibitor of FXIa so as to reduce clot formation in vivo but not carry high bleeding risk.

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Introduction: Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of the extrinsic pathway that negatively regulates thrombin production during coagulation. Under haemophilic conditions, where the intrinsic coagulation pathway is impaired, inhibition of TFPI may improve clotting.

Aim: We investigated the ex vivo effects of a human TFPI neutralizing antibody, marstacimab (previously PF-06741086), in coagulation assays including rotational thromboelastometry (ROTEM), thrombin generation assay (TGA) and the dilute prothrombin time (dPT) assay, performed in haemophilic whole blood and plasmas.

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Background: Fluid resuscitation plays a prominent role in stabilizing trauma patients with hemorrhagic shock yet there remains uncertainty with regard to optimal administration time, volume, and fluid composition (e.g., whole blood, component, colloids) leading to complications such as trauma-induced coagulopathies (TIC), acidosis, and poor oxygen transport.

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Background: Novel crystalloid solutions containing polyethylene glycol polymers (PEG-20k) produce dramatic resuscitation effects but dose-dependently produce a hypocoagulative state. The objective of this study was to examine possible mechanisms of this effect. Based on previous thromboelastography data, we hypothesize the effect is largely due to platelet interactions with the polymers.

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Essentials Platelets in trauma-induced coagulopathy (TIC) are impaired, but the mechanism is not known. We performed comprehensive longitudinal platelet function testing in trauma patient samples. Platelets in TIC are widely impaired early after injury, but platelet activatability is intact.

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Background: Low volume resuscitation (LVR) in shock prevents deleterious effects of crystalloid loading in pre-hospital settings. Polyethylene glycol 20,000 (PEG-20k) based LVR solutions are 20-fold more effective at maintaining perfusion and survival in shock compared to conventional crystalloids. The aim of this study was to determine coagulation and platelet function of whole blood treated with 10% PEG-20k.

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Targeting of cancer stem cells (CSC) is expected to be a paradigm-shifting approach for the treatment of cancers. Cell surface proteoglycans bearing sulfated glycosaminoglycan (GAG) chains are known to play a critical role in the regulation of stem cell fate. Here, we show for the first time that G2.

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Continuous-flow (CF) left ventricular assist devices (LVADs) are a safe and durable therapeutic option for patients with advanced heart failure as a bridge to transplant or as destination therapy. Despite the remarkable technological advances in device design and increasing familiarity with the physiologic effects of CF, major complications such as gastrointestinal bleeding (GIB) continue to cause significant morbidity. The causes underlying CF-LVAD-related GIB are multifactorial.

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Poor quality data in preclinical trials can result from inconsistent and unstandardized experimental processes. Unpredictable pre-intervention variability generates unreliable data, biases outcomes and results in needless waste of animals and resources. We applied Define-Measure-Analyse-Improve-Control (DMAIC) quality improvement processes to pilot development of a swine model of trauma, haemorrhagic shock and coagulopathy.

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Introduction: The thrombin generation assay (TGA) can be used to monitor factor replacement therapy in patients with haemophilia. The TGA assay is typically performed using tissue factor as the reaction activator; however, activating with FIXa or FXIa can enhance assay sensitivity when FVIII < 1%.

Aims: To evaluate the sensitivity of the TGA when FIXa (5 nmol/L) and FXIa (0.

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Background: Coagulopathy and inflammation induced by hemorrhagic shock and traumatic injury are associated with increased mortality and morbidity. Vitamin C (VitC) is an antioxidant with potential protective effects on the proinflammatory and procoagulant pathways. We hypothesized that high-dose VitC administered as a supplement to fluid resuscitation would attenuate inflammation, coagulation dysfunction, and end-organ tissue damage in a swine model of multiple injuries and hemorrhage.

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Trauma is a major problem in the United States. Mortality from trauma is the number one cause of death under the age of 45 in the United States and is the third leading cause of death for all age groups. There are approximately 200,000 deaths per year due to trauma in the United States at a cost of over $671 billion in combined healthcare costs and lost productivity.

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Background: Gastrointestinal (GI) bleeding is one of the most common complications after continuous-flow left ventricular assist device implantation. More than one third of patients with incident bleed go on to develop recurrent GI bleeding. Octreotide, a somatostatin analog, is proposed to reduce the risk of recurrent GI bleeding in this population.

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Aim: To examine the effect of high doses of vitamin C (VitC) on human platelets (PLTs).

Methods: Platelet concentrates collected for therapeutic or prophylactic transfusions were exposed to: (1) normal saline (control); (2) 0.3 mmol/L VitC (Lo VitC); or (3) 3 mmol/L VitC (Hi VitC, final concentrations) and stored appropriately.

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