Elevated serum amyloid A levels in cases of aborted equine fetuses due to fetal and placental infections.

Determination of fetal serum amyloid A (SAA) concentrations in aborted fetuses can provide valuable information regarding the infectious and/or inflammatory process of abortion in horses. To investigate the relationship between fetal SAA levels and the infectious/inflammatory disease process in feto-placental tissues, a SAA ELISA was used to test heart serum samples of 89 equine fetuses that were necropsied and diagnosed in the following groups: a multiorgan disease process diagnosed with an identified microorganism (14 cases, group 1); only placentitis diagnosed with an identified microorganism (nine cases, group 2); only placentitis diagnosed with no microorganism identified (six cases, group 3); and no infectious or inflammatory disease process diagnosed (60 cases, group 4). Serum amyloid A concentrations in equine fetuses were elevated from 10.5 to ≥40 mg/L in 10 of 14 cases in group 1; and from less than 2.5 mg/L to greater than 40 mg/L in seven of nine cases in group 2. In group 3, SAA concentrations were found to be less than 2.5 mg/L in five of six cases. In group 4, SAA concentrations were less than 2.5 mg/L in 55 cases, whereas in five cases SAA concentrations were elevated. Statistical significant differences were found between the concentrations of SAA in fetal horse blood and the presence of infectious and/or inflammatory disease process in the feto-placental tissues when a causative microorganism was identified. These results suggest that testing SAA concentrations in fetal heart blood may aid in further understanding the causes of abortions in horses.

Discrimination of healthy versus sick steers by means of continuous remote monitoring of animal activity.

OBJECTIVE: To test a unique electronic ear tag designed to collect movement data to determine whether physical activity of sick steers differed from that of healthy steers. ANIMALS: 206 steers. PROCEDURES: Physical activity in 2 groups of steers during November and December of 2010 (101 steers; the tag of 1 steer failed, and thus that steer was removed from the study, which resulted in data for 100 steers) and 2011 (105 steers) was monitored with an electronic ear tag device with an on-board triple-axis accelerometer. The accelerometer recorded motion in all 3 axes in the form of counts per minute. A radio-frequency transmitter on the ear tag delivered serial packets of motion data to a local server. An algorithm was developed to analyze the activity data to determine whether this technique could be used to assess health status with high accuracy. RESULTS: Steers that became sick had significantly fewer activity counts (approx 25% fewer), compared with the activity counts of steers that remained healthy the entire time. CONCLUSIONS AND CLINICAL RELEVANCE: In this study, automated detection of health status in growing cattle was feasible through remote monitoring of animal activity. Early identification of sick animals should lead to improved health outcomes, increased marketability, and improved animal well-being and help to minimize the use of antimicrobials that could contribute to resistant bacteria.

Bartonella bovis isolated from a cow with endocarditis.

A 7-year-old pregnant Angus cow was found dead in the field. At necropsy, the aortic valve was expanded by moderate fibrous connective tissue and acidophilic coagulum containing multifocal marked bacteria, mineral, neutrophils, and red blood cells. Numerous tiny grayish, opaque bacterial colonies were detected on blood agar plates at 7 days after inoculation with a swab of the heart valve of the cow. The bacterium was a Gram-negative, very small coccobacillus that was catalase, oxidase, and urease negative, and did not change litmus milk, triple sugar iron agar, and sulfide-indole-motility medium. The bacterium was negative for esculin hydrolysis, phenylalanine deaminase, nitrate reduction, and gelatin hydrolysis. The isolate did not produce acid from glycerol, inulin, lactose, maltose, mannose, raffinose, salicin, sorbitol, sucrose, trehalose, glycogen, ribose, or starch. Polymerase chain reaction tests for the gltA, ssrA, ftsZ, ribC, rpoB, and 16S ribosomal RNA genes of Bartonella species were positive for the isolate. Amplicons were sequenced, and the gltA, ribC, ssrA, and 16S ribosomal RNA gene sequences were found to have 100% homology to the type strain of Bartonella bovis, whereas the fts and rpoB sequences showed 99.9% and 99.6% homology, respectively, to the type strain of Bartonella bovis. Diagnosticians should be aware of slow-growing microorganisms, and culture media should be incubated beyond the standard period to enhance the recovery of Bartonella species.

Evaluation of gadobutrol, a macrocyclic, nonionic gadolinium chelate in a brain glioma model: comparison with gadoterate meglumine and gadopentetate dimeglumine at 1.5 T, combined with an assessment of field strength dependence, specifically 1.5 versus 3 T.

PURPOSE: To evaluate in a rat brain glioma model intraindividual tumor enhancement at 1.5 T using gadobutrol (Gadovist), a nonionic, macrocyclic chelate currently in clinical trials in the United States, in comparison with both an ionic macrocyclic chelate, gadoterate meglumine (Dotarem), and an ionic linear chelate, gadopentetate dimeglumine (Magnevist), and to compare the degree of tumor enhancement with gadobutrol at 1.5 and 3 T. MATERIALS AND METHODS: A total of 24 rats, divided into three groups with n = 8 animals per group, were evaluated. Animals in group 1 received injections of gadobutrol and gadopentetate dimeglumine, whereas those in group 2 received gadobutrol and gadoterate meglumine. Injections were performed in random order and separated by 24 hours. Magnetic resonance imaging (MRI) examinations were performed immediately following each contrast injection with a 1.5 T MR system. Animals in group 3 received gadobutrol injections using the same protocol but with scans performed at 1.5 and 3 T. In all examinations, T1-weighted images were acquired precontrast, 1 minute postcontrast, and at 4 consecutive 2-minute intervals thereafter. A contrast dose of 0.1 mmol/kg was used in all instances. RESULTS: In groups 1 and 2, tumor signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were higher for gadobutrol compared to both other agents at each timepoint postcontrast injection. The improvement in tumor CNR with gadobutrol, depending on time, was between 12% and 40% versus gadopentetate dimeglumine, with the difference achieving statistical significance at 7 minutes. The improvement in tumor CNR with gadobutrol, depending on time, was between 15% and 27% versus gadoterate meglumine, with the difference statistically significant at 5 and 9 minutes. In group 3 the improvement in tumor SNR and CNR seen with the increase in field strength from 1.5 to 3 T for gadobutrol was statistically significant at all acquired timepoints (P < 0.002). CNR mean values ranged from 10.4 +/- 2.9 to 24.6 +/- 5.0 at 1.5 T and from 20.5 +/- 5.9 to 47.8 +/- 15.7 at 3 T depending on the timepoint postcontrast. CONCLUSION: Consistently greater tumor enhancement was noted at all measured timepoints following contrast injection with gadobutrol compared to both gadopentetate dimeglumine and gadoterate meglumine at 1.5 T. A substantial further improvement in tumor enhancement was noted using gadobutrol at 3 T.

Comparative evaluation of lesion enhancement using 1 M gadobutrol vs. 2 conventional gadolinium chelates, all at a dose of 0.1 mmol/kg, in a rat brain tumor model at 3 T.

PURPOSE: The purpose of this study is to compare the differences in contrast enhancement using 0.1 mmol/kg body weight 1 M gadobutrol versus 2 standard gadolinium chelates, both formulated at 0.5 M, (gadopentetate dimeglumine and gadoterate meglumine) in a standardized rat brain glioma model at 3 T. MATERIALS AND METHODS: A total of 19 rats were evaluated, divided into 2 groups. Group 1 (n = 10) was examined using gadobutrol and gadopentetate dimeglumine and group 2 (n = 9) was examined using gadobutrol and gadoterate meglumine. The time between the intraindividual injections was at least 24 hours and contrast agent injections were performed in a randomized order. All agents were applied at a dose of 0.1 mmol/kg body weight.Image acquisition was performed using a T1-weighted 2D TSE technique (repetition time/echo time (TE) 500/16, FA 180 degrees) with an acquisition time of 1:47 minutes:seconds. At a field-of-view of 75 x 75 mm2 and a matrix size of 320 x 320, a voxel size of 0.2 x 0.2 x 2.0 mm3 was achieved. Data acquisition was performed before and at 5 consecutive time points every 2 minutes after contrast agent injection. Signal-to-noise ratios (SNRs) of tumor and normal contralateral brain as well as contrast-to-noise ratio (CNR) measurements were performed using region of interest analysis. RESULTS: The increase in tumor contrast enhancement, ranged between 19.6% and 35.9% for gadobutrol versus gadopentetate dimeglumine (group 1) and between 23.2% and 27.8% for gadobutrol versus gadoterate meglumine (group 2). Overall, CNR was statistically significantly higher for gadobutrol in both groups (P < 0.0001). CNR values for gadobutrol were 25.5 +/- 8.2 in group 1 and 27.1 +/- 8.3 in group 2 with respective CNR values for gadopentetate dimeglumine of 18.6 +/- 5.6 and gadoterate meglumine of 19.2 +/- 5.3. At each acquired time point mean values of tumor SNR were higher for gadobutrol (group 1: SNR(mean) range from 78.7-89.1 vs. 74.3-80.8; group 2: SNR(mean) range from 79.9-88.9 vs. 74.2-80.8). Tumor SNR was statistically significant different at all measured time points in group 2 (P < 0.05). In group 1, the difference of tumor SNR was also statistically significant for the gadobutrol/gadopentetate dimeglumine comparison (P < 0.05) with exception of time point at 9 minutes postcontrast (P = 0.07). CONCLUSION: The results of this study show significantly higher brain tumor SNR and CNR postcontrast for gadobutrol compared with gadopentetate dimeglumine and gadoterate meglumine at 3 T. Injecting the same gadolinium chelate dose on a weight basis, tumor mean SNR gains were superior for gadobutrol at all acquired postcontrast time points. This result with gadobutrol may facilitate better brain tumor detection in the presence of blood-brain barrier disruption.

Brain tumor enhancement in magnetic resonance imaging at 3 tesla: intraindividual comparison of two high relaxivity macromolecular contrast media with a standard extracellular gd-chelate in a rat brain tumor model.

OBJECTIVES: The aim of this study was to evaluate lesion enhancement (LE) and contrast-to-noise ratio (CNR) properties of P846, a new intermediate sized, high relaxivity Gd-based contrast agent at 3 Tesla in a rat brain glioma model, and to compare this contrast agent with a high relaxivity, macromolecular compound (P792), and a standard extracellular Gd-chelate (Gd-DOTA). MATERIALS AND METHODS: Seven rats with experimental induced brain glioma were evaluated using 3 different contrast agents, with each MR examination separated by at least 24 hours. The time between injections assured sufficient clearance of the agent from the tumor, before the next examination. P792 (Gadomelitol, Guerbet, France) and P846 (a new compound from Guerbet Research) are macromolecular and high relaxivity contrast agents with no protein binding, and were compared with the extracellular agent Gd-DOTA (Dotarem, Guerbet, France). T1w gradient echo sequences (TR/TE 200 milliseconds/7.38 milliseconds, flip angle = 90 degrees , acquisition time: 1:42 minutes:sec, voxel size: 0.2 x 0.2 x 2.0 mm, FOV = 40 mm, acquisition matrix: 256 x 256) were acquired before and at 5 consecutive time points after each intravenous contrast injection in the identical slice orientation, using a dedicated 4-channel head array animal coil. The order of contrast media injection was randomized, with however Gd-DOTA used either as the first or second contrast agent. Contrast agent dose was adjusted to compensate for the different T1 relaxivities of the 3 agents. Signal-to-noise ratio, CNR, and LE were evaluated using region-of-interest analysis. A veterinary histopathologist confirmed the presence of a glioma in each subject, after completion of the imaging study. RESULTS: P792 showed significantly less LE as compared with Gd-DOTA within the first 7 minutes after contrast agent injection (P < 0.05) with, however, reaching comparable LE values at 9 minutes after injection (P = 0.07). However, P792 provided significantly less CNR as compared with Gd-DOTA (P < 0.05) for all examination time points. P846 provided comparable but persistent LE as compared with Gd-DOTA (P < 0.05) and demonstrated significantly greater LE and CNR when compared with P792 (P < 0.05). No statistically significant differences between CNR values for Gd-DOTA and P846 were noted for all examination time points (P < 0.05), with P846 administered at one-fourth the dose as compared with Gd-DOTA. CONCLUSION: The intravascular contrast medium P792 showed significantly less LE and CNR in comparison to Gd-DOTA and P846, suggesting that it does not show marked extravasation from tumor neocapillaries and does not significantly cross the disrupted blood brain-barrier in this rat glioma model. In distinction, P846 provides comparable enhancement properties at a field strength of 3 Tesla to the extracellular contrast agent Gd-DOTA, using the adjusted dose, suggesting that it crosses the disrupted blood-brain-barrier and tumor capillaries, most likely based on the decreased molecular weight as compared with P792. At the same time, the high relaxivity of this compound allows for decreasing the injected gadolinium dose by a factor of 4 whereas providing comparable enhancement properties when compared with a standard extracellular Gd-chelate (Gd-DOTA) at a dose of 0.1 mmol/kg body weight.

Naturally occurring sheep-associated malignant catarrhal fever in North American pigs.

Two cases of sheep-associated malignant catarrhal fever (MCF) in pigs were diagnosed on a small farm in New York, and in Kentucky. In both cases, the initial diagnosis was based on histopathological changes representing typical lymphoproliferative vasculitis in multiple tissues of the affected pigs. Ovine herpesvirus 2 (OvHV-2) DNA was detected by polymerase chain reaction in the tissues of affected pigs in both cases. The amplified sequences were identical between the clinically affected pigs and the OvHV-2-infected sheep. Additional virological and bacteriological examination showed that the affected pigs were negative for agents that cause Aujeszky's disease, classical swine fever, porcine enterovirus, and rabies. An antibody against a conserved epitope among MCF viruses was detected in 1 clinically affected pig and 2 unaffected cohort pigs, as well as in all the associated sheep. To the authors' knowledge, this is the first report of porcine MCF in North America, and suggests that OvHV-2 is associated with clinical MCF in pigs.

Brain tumor enhancement in magnetic resonance imaging: dependency on the level of protein binding of applied contrast agents.

PURPOSE: To evaluate the dependency of tumor contrast enhancement (CE) in regard to protein-binding properties of contrast agents, using 4 different agents with a wide range of protein-binding capacities in a standardized rat brain glioma model. MATERIAL AND METHODS: Sixteen rats with implanted brain gliomas were evaluated at 1.5 T with a multielement wrist coil in 2 different comparative settings. In both groups, a non-protein-binding agent (gadopentetate dimeglumine, Bayer Healthcare Inc.) and a weak protein-binding agent (gadobenate dimeglumine, Bracco Diagnostics Inc.) were applied and compared with either a approximately 90% protein-binding agent (group A; B22956/1, Bracco Research USA) or a approximately 50% protein-binding agent (group B; BRU 52, Bracco Research USA). All agents were applied at a dose of 0.1 mmol/kg and a single data acquisition with standard T1-weighted turbo spin-echo sequence (TR/TE = 480/15 ms) was initiated 10 seconds after injection. Evaluation of tumor CE and contrast-to-noise ratio (CNR) was based on region of interest measurements within the tumor and remote normal brain. RESULTS: With B22956/1 (group A), CE increased by 93% in comparison with gadobenate dimeglumine (15.0 +/- 5.3 vs. 7.8 +/- 2.7; P = 0.010) and by 136% in comparison with gadopentetate dimeglumine (15.0 +/- 5.3 vs. 6.4 +/- 1.9; P = 0.013). CNR using B22956/1 increased by 116% in comparison with gadobenate dimeglumine (14.0 +/- 5.9 vs. 6.5 +/- 2.6; P = 0.015) and increased by 138% in comparison with gadopentetate dimeglumine (14.0 +/- 5.9 vs. 5.9 +/- 1.7; P = 0.034). Using BRU 52 (group B), CE increased by 60% in comparison with gadobenate dimeglumine (21.7 +/- 1.4 vs. 13.6 +/- 2.5; P = 0.013) and by 94% in comparison with gadopentetate dimeglumine (21.7 +/- 1.4 vs. 11.2 +/- 0.5; P < 0.0001). CNR using BRU 52 increased by 72% in comparison with gadobenate dimeglumine (21.2 +/- 1.3 vs. 12.3 +/- 3.1; P = 0.0002) and by 122% in comparison with gadopentetate dimeglumine (21.3 +/- 1.3 vs. 9.6 +/- 0.8; P < 0.0001). CONCLUSION: The protein-binding capacity of gadolinium chelates shows a significant impact on CE and CNR in brain tumors with disrupted blood-brain barrier. In comparison with currently approved agents, high albumin-binding agents show further improved brain tumor CE. However, the time course of enhancement and optimal time frame for scanning after injection of agents with higher protein-binding capacities (approximately 50%-90%) has yet to be evaluated.

Anthrax toxin-induced shock in rats is associated with pulmonary edema and hemorrhage.

Bacillus anthracis infections are frequently associated with severe and often irreversible hypotensive shock despite appropriate antibiotics and aggressive hemodynamic and pulmonary support. Based on the observations that the anthrax secreted proteins-protective antigen (PA), lethal factor (LF), and edema factor (EF) also produce shock and mortality in animal models, we chose to characterize further the clinical chemistries and microscopic pathology of toxin treated rats. Groups of three male Sprague Dawley rats received bolus intravenous infusions of PA/LF, PA/EF, LF, or EF alone and blood samples and tissues were collected and assayed for chemistries and tissue pathology. In PA/LF and PA/EF treated animals but not other groups, chemistries showed transaminasemia and elevated lactate dehydrogenase. PA/LF treated animals alone showed elevated hemoglobin and hematocrits; PA/EF treated animals alone showed lymphopenia. Pathology was remarkable for pulmonary edema in PA/LF treated rat lungs and pulmonary hemorrhage in PA/EF treated rat lungs. These results are consistent with our and others' previous findings that the morbidity and mortality associated with anthrax are not cytokine-mediated but due to a direct effect of the toxins on the cardiovascular system along with toxin-specific alterations in blood counts. PA/LF pathology matches that seen with acute cardiac failure, and PA/EF pathology coincides with direct vascular endothelial injury. These observations provide a rational basis for drug interventions to reduce the effect of these toxins on the heart and blood vessels.

Complete diphallia, imperforate ani (type 2 atresia ani), and an accessory scrotum in a 5-day-old calf.

A 5-day-old Angus calf was submitted to the necropsy service at the University of Kentucky Livestock Disease Diagnostic Center. At birth, the calf was noted to have 2 scrota. Five days post-calving the calf developed severe tenesmus and an umbilical infection. Clinical examination revealed atresia ani. At necropsy, complete diphallus, imperforate ani (type 2 atresia ani), and remnants of 2 scrota were identified. This report describes the gross pathologic appearance of a rare case of complete diphallia, imperforate ani (type 2 atresia ani), and an accessory scrotum in a 5-day-old calf.

Congenital diaphragmatic eventration in a stillborn foal.

A stillborn full term foal was presented at necropsy. The dilated duodenum and the dorsal and ventral left colon and cecum extended into the thoracic cavity and were encased by a thin transparent membrane originating from the diaphragm. The congenital condition was diagnosed as a developmental anomaly with diaphragmatic eventration. To the authors' knowledge, this is the first report of diaphragmatic eventration in a Thoroughbred stillborn foal.

Clinicopathologic aspects of animal and zoonotic diseases of bioterrorism.

We live in an era of emerging infectious diseases and the threat of bioterrorism. Most of the infectious agents of modern concern, from plague to avian influenza H5N1, are zoonotic diseases: infectious agents that reside in quiet animal reservoir cycles that are transmitted occasionally to humans. The public health, health care, and veterinary communities have an enormous challenge in the early recognition, reporting, treatment, and prevention of zoonotic diseases. An intimate understanding of the natural ecology, geographic distribution, clinical signs, lesions, and diagnosis of these diseases is essential for the early recognition and control of these diseases.

Fatal cytauxzoonosis in a Kentucky cat (Felis domesticus).

A male domestic shorthair cat was presented with lethargy, anorexia, pyrexia and respiratory harshness. Diagnostic clinical chemistries, viral identification and tissue fluorescent antibody testing were negative or revealed no underlying system failure. Histopathology examination revealed multifocal, variable sized and shaped protozoal life forms in the brain, heart, lung, intestine, spleen, lymph node and kidney consistent with the intraleukocytic schizonts of Cytauxzoon felis.

The efficacy of gadobenate dimeglumine (Gd-BOPTA) at 3 Tesla in brain magnetic resonance imaging: comparison to 1.5 Tesla and a standard gadolinium chelate using a rat brain tumor model.

OBJECTIVES: The objectives of this study were to analyze the differences in contrast enhancement using gadobenate dimeglumine (Gd-BOPTA or MultiHance) at 3 T versus 1.5 T and to compare Gd-BOPTA with a standard gadolinium chelate, gadopentetate dimeglumine (Gd-DTPA or Magnevist), at 3 T in a rat glioma model. MATERIALS AND METHODS: Twelve rats with surgically implanted gliomas were randomized to either comparing Gd-BOPTA at 1.5 T versus 3 T (n=7) or comparing Gd-BOPTA and Gd-DTPA at 3 T (n=5). Matched T1-weighted spin-echo techniques were used for both comparisons and the order of examinations was randomized. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and lesion enhancement (LE) were evaluated using a region-of-interest analysis. A veterinary histopathologist evaluated all brain specimens. RESULTS: In the evaluation of Gd-BOPTA at 3 T and 1.5 T, there were significant increases in SNR, LE, and CNR at 3 T. Average increases in brain and tumor SNR were 93% (P<0.0001) and 92% (P<0.0001), respectively. CNR increased by 121% (P<0.0001). Comparison of Gd-BOPTA and Gd-DTPA at 3 T demonstrated significantly higher CNR and LE with Gd-BOPTA. CNR increased by 35% (P=0.002). LE increased by 44% (P=0.03). CONCLUSIONS: Gd-BOPTA provides significantly higher CNR at 3 T compared with 1.5 T and also demonstrates significantly higher CNR when compared with a standard Gd-chelate at 3 T. As a result of transient protein binding, Gd-BOPTA may be superior to standard gadolinium chelates in neurologic imaging at 3 T.

Brain tumor enhancement in magnetic resonance imaging: comparison of signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) at 1.5 versus 3 tesla.

OBJECTIVE: The objective of this study was to compare the difference in lesion enhancement between 1.5 and 3 T using an extracellular gadolinium chelate in a rat brain glioma model. METHODS: Five rats (CDF Fischer 344) with implanted C6/LacZ brain gliomas were evaluated using matched T1-weighted spin echo techniques and hardware configurations at 1.5 and 3 T. Serial imaging over 10 minutes after gadoteridol (ProHance) administration was performed. Contrast enhancement (CE), signal-to-noise ratios (SNR) for brain and tumor, as well as contrast-to-noise ratios (CNR) were evaluated using region-of-interest (ROI) analysis at both field strengths. All gliomas were also evaluated by histopathology. RESULTS: CE at 3 T increased by 106% to 137% (all P<0.05) with maximum CE occurring at 5 minutes for both 1.5 and 3 T (9.8+/-2.2 vs 21.1+/-3.5; P=0.0004). At 3 T, SNR increased for normal brain by 66% to 76% (P<0.01) and SNR for tumor increased by 70% to 89% (P<0.01). CNR increased by 101% to 137% (P<0.05) depending on the time postcontrast. The highest CNR for both 1.5 T and 3 T occurred 5 minutes after contrast (1.5 T: 9.4+/-1.1 vs 3 T: 20.3+/-2.4; P<0.0004). CONCLUSION: Using a standardized animal model and matched scan techniques, this study shows a significant benefit of 3 T compared with 1.5 T in contrast-enhanced brain tumor magnetic resonance imaging.

Equine abortion and premature birth associated with Cellulosimicrobium cellulans infection.

During the 2002 and 2003 foaling seasons, Cellulosimicrobium (Cellumonas) cellulans (formerly Oerskovia xanthineolytica) was the principal microorganism isolated from fetal tissues or placentas from cases of equine abortion, premature birth, and term pregnancies. Significant pathologic findings included chronic placentitis and pyogranulomatous pneumonia. In addition, microscopic and macroscopic alterations in the allantochorion from 4 of 7 cases of placentitis were similar to those caused by Crossiella equi and other nocardioform bacteria. This report confirms a causative role of C. cellulans infection in equine abortion.

A 24-hour continuous infusion study of bivalirudin in the rat.

The potential toxic effects of bivalirudin (an anticoagulant) were evaluated in this intravenous infusion study in Sprague-Dawley rats. Bivalirudin was administered over a 24-hour period by continuous intravenous infusion to six groups of rats. Dose levels of 100, 500, and 2000 mg/kg/24 h were selected for the low-, mid-, and high-dose groups. Three bivalirudin-treated groups of 12 males and 12 females each were designated for toxicology assessment. Six animals/sex/group were euthanized at the completion of 24-hour infusion, and the remaining animals were assigned to a 14-day recovery period. Three additional groups of 10 rats/sex/group were designated for toxicokinetic assessment. This study included a saline control group and a vehicle control group. No bivalirudin-related toxicity was noted. There were no treatment-related effects on clinical pathology parameters. No definitive test article-related macroscopic, organ weight, or microscopic changes were identified. Three animals in the 500-mg/kg/24 h group, and 7 animals in the 2000-mg/kg/24 h group in the toxicokinetic assessment phase of the study were found dead or euthanized in extremis (following blood sampling). The concurrent clinical signs suggest that the animals hemorrhaged, which is consistent with the pharmacological action of bivalirudin. The extent of systemic exposure was similar in male and female rats, indicating a lack of a sex-related difference. Plasma concentrations of bivalirudin appeared to be linear and dose independent. Based on the results of this study, the no-observed-adverse-effect level (NOAEL) for bivalirudin, administered to rats via intravenous infusion over a 24-hour period, was 2000 mg/kg/24 h. However, the known pharmacological properties of bivalirudin could result in hemorrhage in the presence of an appropriate challenge (e.g., blood collection).