Abstract 11269: Recombinant Soluble Thrombomodulin in Prolonged Porcine Cardiac Arrest

Introduction: Sudden Cardiac Arrest (CA) affects more than 400,000 people per year in the United States. Although a third of these patients survive to hospital admission, another 60-70% go on to die due to failed recovery of vital organ function. Microvascular thrombosis has been suggested as a potential contributor to prolonged organ dysfunction, but no antithrombotic therapies have been shown to be beneficial and coagulofibrinolytic abnormalities in prolonged CA remain poorly understood. Objectives: To establish key biomarkers of porcine coagulation and fibrinolysis in the setting of prolonged CA and cardiopulmonary resuscitation (CPR) and test the ability of ART-123 (recombinant human thrombomodulin alpha) to reverse these abnormalities. Methods: 15 pigs (n=5 per group) underwent 8 minutes of no-flow CA followed by 50 minutes of mechanical CPR. Animals were randomized to receive saline or ART-123 (~1mg/kg) pre-arrest (5 minutes prior to ventricular fibrillation) or post-arrest (2 minutes after initiation of CPR). Results: Robust and ongoing activation of coagulation and fibrinolysis were detected throughout the resuscitation. After 50 minutes of CPR, plasma tests suggested consumptive coagulopathy, while whole blood testing (thromboelastography) indicated a persistent hypercoagulable state. ART-123 had a clear anticoagulant effect irrespective of timing (TAT complexes 381±25 vs. 238±18 vs. 226±12, p<0.01, and d-dimer 4.86±0.54 vs. 2.39±0.2 vs. 2.46±0.21 for vehicle, pre-arrest, post-arrest, p = 0.05). A pro-fibrinolytic effect was also observed, but only when the drug was given before no-flow, with a significant increase in levels of free endogenous tPA (1.2±0.12 vs. 3.29±0.29 vs. 1.72±0.3, p < 0.001) and corresponding suppression of free PAI-1 (0.59±0.15 vs. 0.14±0.01 vs. 0.41±0.09, p < 0.001). Conclusion: Our porcine CA model provides an excellent platform for evaluating antithrombotic interventions. Plasma testing after prolonged CA/CPR suggests consumptive coagulopathy, although TEG indicates a persistent hypercoagulable state. ART-123 given before no-flow or just after CPR demonstrates antithrombotic effects, although the specific modes of action depending on the timing of administration.

Associations of longitudinal D-Dimer and Factor II on early trauma survival risk

Background Trauma-induced coagulopathy (TIC) is a disorder that occurs in one-third of severely injured trauma patients, manifesting as increased bleeding and a 4X risk of mortality. Understanding the mechanisms driving TIC, clinical risk factors are essential to mitigating this coagulopathic bleeding and is therefore essential for saving lives. In this retrospective, single hospital study of 891 trauma patients, we investigate and quantify how two prominently described phenotypes of TIC, consumptive coagulopathy and hyperfibrinolysis, affect survival odds in the first 25 h, when deaths from TIC are most prevalent. Methods We employ a joint survival model to estimate the longitudinal trajectories of the protein Factor II (% activity) and the log of the protein fragment D-Dimer ($$\upmu$$ μ g/ml), representative biomarkers of consumptive coagulopathy and hyperfibrinolysis respectively, and tie them together with patient outcomes. Joint models have recently gained popularity in medical studies due to the necessity to simultaneously track continuously measured biomarkers as a disease evolves, as well as to associate them with patient outcomes. In this work, we estimate and analyze our joint model using Bayesian methods to obtain uncertainties and distributions over associations and trajectories. Results We find that a unit increase in log D-Dimer increases the risk of mortality by 2.22 [1.57, 3.28] fold while a unit increase in Factor II only marginally decreases the risk of mortality by 0.94 [0.91,0.96] fold. This suggests that, while managing consumptive coagulopathy and hyperfibrinolysis both seem to affect survival odds, the effect of hyperfibrinolysis is much greater and more sensitive. Furthermore, we find that the longitudinal trajectories, controlling for many fixed covariates, trend differently for different patients. Thus, a more personalized approach is necessary when considering treatment and risk prediction under these phenotypes. Conclusion This study reinforces the finding that hyperfibrinolysis is linked with poor patient outcomes regardless of factor consumption levels. Furthermore, it quantifies the degree to which measured D-Dimer levels correlate with increased risk. The single hospital, retrospective nature can be understood to specify the results to this particular hospital’s patients and protocol in treating trauma patients. Expanding to a multi-hospital setting would result in better estimates about the underlying nature of consumptive coagulopathy and hyperfibrinolysis with survival, regardless of protocol. Individual trajectories obtained with these estimates can be used to provide personalized dynamic risk prediction when making decisions regarding management of blood factors.

Severe Consumptive Coagulopathy in an Extremely-Low-Birth-Weight Infant with Intra-Abdominal Umbilical Vein Varix: A Case Report

Recent studies have shown favorable outcomes for intra-abdominal umbilical vein varices (IUVVs) in term neonates who have no other complications. Little is known, however, about the prognosis of IUVVs in preterm neonates. We encountered a case of IUVV in an extremely low-birth-weight infant who developed severe consumptive coagulopathy after birth. The patient's coagulation test normalized as the varix spontaneously obstructed. Although life-threatening hemorrhagic complications were avoided, a cerebellum hemorrhage was found in the brain magnetic resonance imaging at the term-equivalent age. In a literature survey, coagulopathy was reported in 4 out of 15 infants with IUVVs born before 34 weeks of gestation, including our present case. Preterm infants with IUVVs may develop coagulopathy because of the prematurity of their coagulation–fibrinolysis systems. Attention should be given to the coagulation status of preterm neonates with IUVVs.

Kaposiform haemangioendothelioma of duodenum in a neonate

Kaposiform haemangioendothelioma, an endothelial borderline tumour, is typically seen in childhood involving extremities. It has been closely associated with a consumptive coagulopathy state, Kasabach-Merritt phenomenon (KMP). Extracutaneous involvement is uncommon. Intestinal involvement is quite uncommon and can masquerade as an acute abdomen. A 24-day-old neonate presented with bilious vomiting and fever for 5 days. Sections from the resected gangrenous duodenum contained a submucosal tumour composed of infiltrating nodules of slit-like or crescentic CD34-positive spindled-to-flattened endothelial-lined vascular spaces along with zones of fibrosis. No nuclear pleomorphism or necrosis identified. The findings were classic example of kaposiform haemangioendothelioma with an absence of any deranged coagulation profile. The index case raises interest given its congenital incidental presentation at an uncommon site, like duodenum, and absence of coexistent KMP.

Consumptive coagulopathy of severe yellow fever occurs independently of hepatocellular tropism and massive hepatic injury

Yellow fever (YF) is a mosquito-transmitted viral disease that causes tens of thousands of deaths each year despite the long-standing deployment of an effective vaccine. In its most severe form, YF manifests as a hemorrhagic fever that causes severe damage to visceral organs. Although coagulopathy is a defining feature of severe YF in humans, the mechanism by which it develops remains uncertain. Hepatocytes are a major target of yellow fever virus (YFV) infection, and the coagulopathy in severe YF has long been attributed to massive hepatocyte infection and destruction that results in a defect in clotting factor synthesis. However, when we analyzed blood from Brazilian patients with severe YF, we found high concentrations of plasma D-dimer, a fibrin split product, suggestive of a concurrent consumptive process. To define the relationship between coagulopathy and hepatocellular tropism, we compared infection and disease inFah−/−,Rag2−/−, andIl2rɣ−/−mice engrafted with human hepatocytes (hFRG mice) and rhesus macaques using a highly pathogenic African YFV strain. YFV infection of macaques and hFRG mice caused substantial hepatocyte infection, liver damage, and coagulopathy as defined by virological, clinical, and pathological criteria. However, only macaques developed a consumptive coagulopathy whereas YFV-infected hFRG mice did not. Thus, infection of cell types other than hepatocytes likely contributes to the consumptive coagulopathy associated with severe YF in primates and humans. These findings expand our understanding of viral hemorrhagic disease and associated coagulopathy and suggest directions for clinical management of severe YF cases.

Abstract 262: Consumptive Coagulation in a Porcine Model of Prolonged Out-of-hospital Cardiac Arrest Treated with ECPR

Background: Following prolonged cardiac arrest treated with extracorporeal cardiopulmonary resuscitation (ECPR), recovery of organ function and survival are potentially impaired due to a “no reflow” phenomenon associated with microvascular thrombosis. This study evaluated the effects of antithrombotic interventions on coagulation parameters in a in a porcine model of out-of-hospital cardiac arrest (OHCA). Hypothesis: We hypothesized that anticoagulant therapy (argatroban) during CPR and/or thrombolytic (streptokinase) therapy at onset of ECPR would prevent consumptive coagulopathy after prolonged cardiac arrest. Methods: In a blinded and randomized study, 48 swine (40±5kg) were subjected to 8min of ventricular fibrillation cardiac arrest followed by 30min of goal-directed CPR (gdCPR), and 8hr of ECPR (33°C) with heparin anticoagulation during ECPR titrated to ACT values (200-300s). Animals were randomized to one of 4 groups (n=12) with 350mg/kg argatroban (Arg) or placebo (20mL NSS) administered 12min after arrest and 1.5 MU streptokinase (STK) or placebo (50mL NSS) at ECPR initiation: Group 1 (placebo and placebo); Group 2 (Arg and placebo); Group 3 (placebo and STK); and Group 4 (Arg and STK). Blood samples were drawn at baseline and at 8hr of ECPR (or earlier if the experiment ended). Data was analyzed using t-tests and ANOVA (p<0.05 significant). Results: Average platelet count and fibrinogen levels significantly decreased between baseline and at the end of ECPR ( p =<0.0001) without difference between groups ( p =0.6315 and p =0.7692, respectively). D-dimer levels significantly increased across groups from baseline to the end of ECPR ( p =<0.0001) without difference between groups ( p =0.1881). Discussion: These results indicate that this OHCA model induces consumptive coagulopathy and the effects of antithrombotic therapies did not mitigate it in this porcine model.