Introduction
Blood transfusions are commonly used to treat life-threatening anemia in critically ill veterinary patients. Approximately 3% to 28% of veterinary patients that receive blood products develop transfusion reactions.1,2,3 In human medicine, important predisposing factors for transfusion reactions include the accumulation of histamine, proinflammatory cytokines, or eicosanoids in stored blood products.4,5,6
The synthesis and release of histamine contributes to allergic responses and anaphylaxis. Histamine concentration is greatest within mast cells, but other types of cells, such as platelets, leukocytes, and enterochromaffin cells, can also synthesize and release histamine.7,89,10 Once released, histamine mediates several physiologic responses, including type I hypersensitivity reactions, gastric acid production, smooth muscle motility, inflammation mediation, and vascular permeability.7,8 Once synthesized, histamine has a short half-life; therefore, N-methylhistamine (NMH), a stable histamine metabolite, is commonly used to assess systemic histamine concentrations.11,12
The histamine concentration within stored human blood products increases over time, especially when those products are stored for > 14 days.13,14,15 Human patients who develop anaphylactoid reactions following transfusion of stored blood products have a significantly greater plasma histamine concentration than patients who develop other types of transfusion reactions; however, it is unknown whether the increase in plasma histamine concentration is the result of increased histamine synthesis by the patient in response to the transfused product or the histamine present within the transfused product.16 Currently, it is unknown whether histamine accumulates during storage in units of blood collected from veterinary species.
Most canine blood products do not routinely undergo prestorage leukoreduction and platelet depletion procedures. Consequently, most stored canine blood products contain cells capable of histamine synthesis. In human medicine, leukoreduction filters are used to remove most leukocytes and platelets from stored units of blood, significantly decreasing the histamine concentration in those units.14,17
The objective of the study reported here was to determine the effects of leukoreduction on NMH concentration (a marker of histamine load) in units of canine whole blood following storage and incubation at room temperature (approx 22 °C) to simulate temperature conditions during transfusion. We hypothesized that the histamine load would be elevated in units of whole blood that were stored and warmed to transfusion temperature and that the histamine load in stored blood units could be mitigated if the blood underwent leukoreduction prior to storage.
Materials and Methods
Animals
All animal procedures were reviewed and approved by the Mississippi State University Institutional Animal Care and Use Committee and were performed in compliance with requirements for a facility accredited by the American Association for Accreditation of Laboratory Animal Care. An a priori sample size calculation was performed, for which it was assumed that the difference in NMH concentration between canine whole blood units that did and did not undergo leukoreduction would be similar to that observed in units of human packed RBCs during the first 28 days of storage13 (mean ± SD NMH concentration during the first 3 days of storage, 0.69 ± 0.15 ng/mL vs 20.46 ± .038 ng/mL on day 28 of storage). The power was set at 0.95, and the α was set a 0.05. Results of that calculation indicated that at least 8 dogs/treatment group would be necessary.
Eight university-owned adult Walker Hounds (5 sexually intact females and 3 neutered males) were used for the study. The dogs had a median age of 5.3 years (range, 3.0 to 5.7 years) and body weight of 54.8 kg (range, 49.0 to 67.2 kg). All dogs were determined to be healthy on the basis of results of a physical examination, CBC, serum biochemical profile, and urinalysis and had negative results on a Dirofilaria immitis antigen test. The dogs did not receive any medications or vaccines for at least 2 weeks before study initiation.
Blood collection and processing
Each dog was randomly assigned by means of a random number sequence generator18 to 1 of 2 groups (A or B; 4 dogs/group). All dogs underwent a standard blood donation procedure twice. Briefly, each dog was sedated with butorphanol tartrate (Torbutrol; 0.4 mg/kg, IV) and midazolam (Midazolam; 0.5 mg/kg, IV) and positioned in either right or left lateral recumbency. The hair over the nondependent jugular vein was clipped, and the underlying skin was aseptically prepared in routine manner. A 16-gauge needle was inserted into the jugular vein, and approximately 450 mL of blood was aseptically collected with the aid of negative pressure. Blood from each dog in group A was collected directly into a standard triple blood banking bag system (Teruflex Optisol; Terumo Corp), whereas blood from each dog in group B was collected directly into a quadruple blood banking bag system (Imuflex-WB-RP blood bag with integral whole blood leukocyte reduction filter; Terumo Corp) that contained a leukoreduction filter. Both blood banking bag systems contained citrate-phosphate-dextrose solution as an anticoagulant. This procedure was repeated for each dog at least 28 days later, except blood from dogs in group A was collected into a quadruple blood banking bag system and blood from dogs in group B was collected into a standard triple blood banking bag system. No adverse events were observed for any of the dogs during or after blood collection.
All primary units of blood were thoroughly mixed, and external pressure was applied to the bag to force blood into the in-line tubing. A 10-mL sample of blood was collected from the in-line tubing and centrifuged at 2,000 × g for 10 minutes. The resulting plasma was harvested from the sample, placed in a cryovial, and stored frozen at –80 °C until analysis for NMH concentration.
All blood units were stored at room temperature for 30 minutes. For the units collected into the triple blood banking bag system, a 1-mL blood sample was collected from the in-line tubing for determination of the total leukocyte and platelet counts by use of an automated hematologic analyzer (Cell-Dyn 3700; Abbott Laboratories). For the units collected into the quadruple blood banking bag system, blood was passed through the leukoreduction filter associated with the blood collection system to remove leukocytes and platelets. A 1-mL blood sample was collected from the in-line tubing before and after the leukoreduction filter for determination of the total leukocyte and platelet counts by use of an automated hematologic analyzer. An additional 10-mL blood sample was collected from the in-line tubing after the leukoreduction filter, processed, and stored as previously described for determination of NMH concentration.
Each unit of blood was divided into 2 half units by the application of external pressure to the bag containing the blood to force half of the blood into an attached empty bag. All half units of blood were stored vertically at 4 °C in a dedicated refrigerator for 14 or 28 days.
On day 14 of storage, 1 half unit of blood from each dog that did and did not undergo leukoreduction was removed from the refrigerator and inverted repeatedly until thoroughly mixed. A blood spike was inserted into each half unit, and 10 mL of blood was removed, processed, and stored as previously described for determination of NMH concentration. To mimic transfusion conditions, the remainder of each half unit was maintained at room temperature for 5 hours, after which another 10-mL blood sample was collected, processed, and stored for determination of NMH concentration. On day 28 of storage, the remaining half units of blood were removed from the refrigerator, and blood samples were collected from those units and processed as described for those obtained on day 14 of storage.
Determination of NMH concentration
The plasma NMH concentration was determined at 5 different times for units of blood that did not undergo leukoreduction (on the day of donation and before and after 5 hours of incubation at room temperature on days 14 and 28 of storage) and at 6 different times for units of blood that underwent leukoreduction (on the day of donation before and after the blood was passed through the leukoreduction filter and before and after 5 hours of incubation at room temperature on days 14 and 28 of storage). All frozen plasma samples were shipped overnight on dry ice to the Gastrointestinal Laboratory at the Texas A&M University College of Veterinary Medicine and Biomedical Sciences for determination of NMH concentration.
Prior to analysis of all samples, a pilot study was conducted to determine whether in vitro enzymatic degradation of histamine to NMH was necessary to assess the entire histamine load within plasma samples. Ten plasma samples obtained from units of blood that did and did not undergo leukoreduction were incubated with and without rat histamine-N-methyltransferase (HNMT; Creative BioMart) and S-adenosyl methionine (SAME; Sigma-Aldrich) for 90 minutes before sample extraction and NMH quantification. Results of the pilot study indicated that enzymatic degradation of histamine to NMH optimized estimation of the histamine load. The sample results from the pilot study were not included in the final analysis. The plasma samples assessed in the pilot study were reassessed with the rest of the study samples by use of the same NMH quantification protocol.
All study plasma samples were thawed and incubated with rat HNMT and SAME for 90 minutes at room temperature prior to quantification of NMH concentration by use of a gas chromatography–mass spectrometry assay as described13,14 and validated19 for use with canine samples. Briefly, following the addition of trideuterated NMH standards to the plasma sample, NMH was extracted by use of a solid-phase method.11 The final extract was resuspended in ethyl acetate and injected into the gas chromatography–mass spectrometer for analysis.19 The NMH concentration was determined by comparison of the area under each chromatographic peak for a given plasma sample with the area under the chromatographic peak for the internal standard.
Statistical analysis
For the pilot study, the NMH concentration between samples incubated with and without HNMT and SAME was compared by means of the Wilcoxon signed rank test. For the primary study, linear mixed models were used to assess the effect of leukoreduction and sample time on plasma NMH concentration. The model included fixed effects for leukoreduction status (treatment [yes or no]), combination of storage time and sample temperature (sample time), and the interaction between treatment and sample time and a random effect to account for the fact that 2 units of blood (1 leukoreduced and 1 nonleukoreduced) were analyzed from each dog. A spatial power covariance structure was used to account for correlation owing to analysis of multiple plasma samples from the same unit of blood. Additional mixed linear models were created to compare the NMH concentration between samples that were obtained before (prefiltered samples) and after (postfiltered samples) the leukoreduction filter from the units of blood that underwent leukoreduction on the day of donation and between samples that were obtained from nonleukoreduced units and postfiltered samples obtained from leukoreduced units on the day of donation. For each model, all fixed effects were initially included in the model, then nonsignificant effects were removed from the model one by one and the model was refit until only variables with values of P < 0.05 remained. Residual plots for each model were visually assessed to ensure that the assumptions of normality and homoscedasticity were not violated. We also attempted to use linear mixed models to compare the leukocyte and platelet counts between nonleukoreduced units and postfiltered samples obtained from leukoreduced units on the day of donation; however, the assumptions of normality and homoscedasticity were not met for those models. Consequently, those comparisons were performed by use of Wilcoxon signed rank tests. All analyses were performed with a statistical software program (SAS version 9.4; SAS Institute Inc), and values of P < 0.05 were considered significant.
Results
Leukoreduction and platelet depletion
On the day of donation (day 0), the median leukocyte count for nonleukoreduced units was 4,020 WBCs/µL (range, 3,040 to 5,830 WBCs/µL). For leukoreduced units, the median leukocyte count was 4,110 WBCs/µL (range, 3,430 to 7,860 WBCs/µL) for prefiltered samples and 20 WBCs/µL (10 to 30 WBCs/µL) for postfiltered samples.
The median platelet count was 175,500 platelets/µL (range, 104,000 to 203,000 platelets/µL) in nonleukoreduced units. For leukoreduced units, the median platelet count was 167,500 platelets/µL (range, 102,000 to 226,000 platelets/µL) for prefiltered samples and 0 platelets/µL (range, 0 to 3 platelets/µL) for postfiltered samples.
NMH concentration
In the initial pilot study, the mean ± SD NMH concentration for plasma samples that were incubated with HNMT and SAME (27.53 ± 15.6 pg/µL) was significantly (P = 0.002) greater than that for the same plasma samples that were not incubated with HNMT and SAME (7.15 ± 4.6 pg/µL). This suggested that enzymatic degradation of histamine to NMH was necessary to achieve a better estimation of the histamine load in plasma samples. Thus, all subsequent results presented in this report are for plasma samples that were incubated with HNMT and SAME prior to gas chromatography–mass spectrometry analysis.
The plasma NMH concentrations in all samples were summarized (Figure 1). Plasma NMH concentration was not significantly affected by leukoreduction status (P = 0.997), sample time (P = 0.513), or the interaction between leukoreduction status and sample time (P = 0.103). On the day of donation, the mean ± SD plasma NMH concentration for nonleukoreduced units (20.4 ± 7.2 pg/µL) was significantly (P = 0.014) greater than that for prefiltered samples of leukoreduced units (16.1 ± 5 pg/µL). Additionally, for leukoreduced units on the day of donation, the mean ± SD plasma NMH concentration for prefiltered samples was significantly (P = 0.022) lower than that for postfiltered samples (26.2 ± 12.2 pg/µL).
Box-and-whisker plots of the plasma NMH concentration in units of canine whole blood that did not undergo leukoreduction (nonLR; gray bars) and before (prefilter) and after (postfilter) leukoreduction (LR; white bars) on the day of donation prior to storage at 4 °C and before (preinc) and after (postinc) incubation at room temperature (approx 22 °C) for 5 hours on days 14 and 28 of storage. For each plot, the × denotes the mean, the horizontal line within the box represents the median, the lower and upper borders of the box denote the interquartile (25th to 75th percentile) range, and the whiskers denote the range. Brackets indicate that the mean NMH concentration differed significantly (P < 0.05) between the connected units.
Citation: American Journal of Veterinary Research 82, 11; 10.2460/ajvr.82.11.890
Box-and-whisker plots of the plasma NMH concentration in units of canine whole blood that did not undergo leukoreduction (nonLR; gray bars) and before (prefilter) and after (postfilter) leukoreduction (LR; white bars) on the day of donation prior to storage at 4 °C and before (preinc) and after (postinc) incubation at room temperature (approx 22 °C) for 5 hours on days 14 and 28 of storage. For each plot, the × denotes the mean, the horizontal line within the box represents the median, the lower and upper borders of the box denote the interquartile (25th to 75th percentile) range, and the whiskers denote the range. Brackets indicate that the mean NMH concentration differed significantly (P < 0.05) between the connected units.
Citation: American Journal of Veterinary Research 82, 11; 10.2460/ajvr.82.11.890
Box-and-whisker plots of the plasma NMH concentration in units of canine whole blood that did not undergo leukoreduction (nonLR; gray bars) and before (prefilter) and after (postfilter) leukoreduction (LR; white bars) on the day of donation prior to storage at 4 °C and before (preinc) and after (postinc) incubation at room temperature (approx 22 °C) for 5 hours on days 14 and 28 of storage. For each plot, the × denotes the mean, the horizontal line within the box represents the median, the lower and upper borders of the box denote the interquartile (25th to 75th percentile) range, and the whiskers denote the range. Brackets indicate that the mean NMH concentration differed significantly (P < 0.05) between the connected units.
Citation: American Journal of Veterinary Research 82, 11; 10.2460/ajvr.82.11.890
On day 14 of storage, the mean ± SD plasma NMH concentrations for nonleukoreduced units before (24.1 ± 10.9 pg/µL) and after (23.5 ± 7.5 pg/µL) incubation at room temperature for 5 hours did not differ significantly. The mean ± SD plasma NMH concentrations for leukoreduced units before (32.6 ± 22.6 pg/µL) and after (24.9 ± 13.2 pg/µL) incubation at room temperature for 5 hours also did not differ significantly.
On day 28 of storage, the mean ± SD plasma NMH concentration for nonleukoreduced units before (36.9 ± 13.8 pg/µL) and after (24.9 ± 8.8 pg/µL) incubation at room temperature for 5 hours did not differ significantly. The mean ± SD plasma NMH concentrations for leukoreduced units before (26.6 ± 12.1 pg/µL) and after (26.8 ± 12.2 pg/µL) incubation at room temperature for 5 hours did not differ significantly.
The mean ± SD plasma NMH concentration did not differ significantly between leukoreduced and nonleukoreduced units on day 14 or 28 of storage or between units before and after incubation at room temperature for 5 hours.
Discussion
In human blood products, histamine concentrations increase during storage,13,14,15 and that accumulation can be greatly reduced by leukoreduction and platelet depletion before storage.14,17 Results of the present study suggested that, unlike in human blood products, the histamine concentration in units of canine whole blood does not increase during storage and leukoreduction and platelet depletion have only a minimal effect on histamine load as evidenced by NMH concentrations.
Histamine is primarily synthesized by basophils and mast cells, and, when activated, those cells degranulate and release substantial amounts of histamine into the extracellular matrix. Histamine has an important role in allergic and anaphylactoid responses in human patients, and patients that receive blood product transfusions and subsequently develop an anaphylactoid reaction have a significantly greater plasma concentration, compared with transfusion recipients that develop other types of transfusion reactions.16 Patient factors, such as the ability to remove histamine from plasma and histamine receptor sensitivity, might contribute to clinical manifestations of histamine-associated transfusion reactions.13 In dogs, histamine concentrations during transfusion reactions, including anaphylaxis, have not been reported.
The exponential increase in the histamine concentration in units of human blood products during storage might be associated with an autocatalytic process that occurs when released histamine causes an increase in cell permeability and lysis of basophils and other leukocytes with histamine-containing granules.13,14 Once released, histamine can activate additional cells within the unit, resulting in a progressive increase in histamine concentration. The use of leukoreduction filters to remove cells with histamine-containing granules decreases the histamine load within stored units of human blood.14,17 However, in the present study, passage of canine blood through a leukoreduction filter to deplete leukocytes and platelets prior to storage did not significantly decrease the NMH concentration relative to that in units of canine blood that did not undergo leukoreduction prior to storage. This finding suggested that an alternate source of histamine, such as erythrocytes, might contribute to the overall histamine load in stored units of canine blood.
The histamine load (as assessed by NMH concentration) within a unit of human blood can also increase during transfusion.13 A potential explanation for that phenomenon is that the temperature of the blood within the unit increases when exposed to room temperature during transfusion, which may cause blood cell lysis and the release of histamine.13 Another possible explanation for the increase in histamine concentration during transfusion is cell lysis caused by handling of the blood as it passes through IV lines, a fluid or syringe pump, and microaggregate filters.13 In the present study, units of canine blood were removed from a refrigerator after 14 or 28 days of storage and maintained at room temperature for 5 hours to simulate temperature conditions during transfusion. Additionally, all units were handled minimally and as carefully as possible, and the blood was not passed through IV lines and pumps or microaggregate filters. Interestingly, the mean plasma NMH concentration did not change from before to after 5 hours of incubation at room temperature for either the leukoreduced or nonleukoreduced units.
In the present study, passing blood through a leukoreduction filter to remove leukocytes and platelets resulted in an immediate increase in plasma NMH concentration. Additionally, the mean plasma NMH concentration for nonleukoreduced units on the day of donation was significantly greater than that for the prefiltered samples, but did not differ significantly from postfiltered samples, obtained from the leukoreduced units. The reason for those differences remains unknown because the process for obtaining samples following collection of the 450 mL of blood, including the duration from collection to freezing of plasma samples, was the same for both leukoreduced and nonleukoreduced units.
Results of another study20 in which canine blood was passed through the same type of leukoreduction filter used in the present study indicate that blood filtration led to an increase in the concentrations of prostanoids such as thromboxane B2 and prostaglandin F2α. However, the concentrations of thromboxane B2 and prostaglandin F2α in leukoreduced units decreased during storage and became comparable to the concentrations of thromboxane B2 and prostaglandin F2α in nonleukoreduced units.20 Because leukoreduction results in the immediate release of reactive molecules such as prostanoids, it is recommended that blood products are stored following leukoreduction and not immediately transfused into a patient.21 In the present study, the NMH concentration for leukoreduced units did not decrease during the first 28 days of storage; therefore, the duration of storage required for canine blood products following leukoreduction to reduce the risk of histamine-associated complications is unknown.
The plasma NMH concentration was measured in the present study and used as a proxy for histamine load in blood units. N-methylhistamine is a stable metabolite of histamine. Histamine is rapidly metabolized following release from cells; therefore, it is difficult to accurately measure histamine concentrations.11,22 One mechanism by which histamine is metabolized is enzymatic conversion to NMH by HNMT. Histamine-N-methyltransferase is an intracellular cytosolic enzyme that is expressed in numerous tissues including the kidney, liver, and gastrointestinal tract as well as human and canine erythrocytes.22,23 Studies13,14,16,17 that have documented an increase in histamine concentration in human blood products during storage measured the stable metabolite NMH rather than the less-stable histamine. Although HNMT is present in human erythrocytes, those studies13,14,16,17 incubated plasma from units of blood with additional HNMT and a methionine donor in vitro prior to extraction of NMH to ensure complete conversion of histamine to NMH. Results of the pilot study conducted for the present study likewise indicated that incubation of canine plasma samples with HNMT and SAME was necessary to ensure complete conversion of histamine to NMH for measurement.
The present study had several limitations. The sample size was small. Although the results of the sample size calculation suggested that collection of blood from 8 dogs would provide ample power for the study, assessment of blood collected from more than 8 dogs or dogs of various breeds might have yielded different results. Another limitation was the assessment of NMH concentration in units of blood after only 14 and 28 days of storage. In a study14 involving stored units of human blood, the histamine concentration continued to increase beyond 28 days of storage. In the present study, on day 28 of storage, the mean NMH concentration in nonleukoreduced units of blood was approximately 81% greater than that on the day of donation, whereas the mean NMH concentration in leukoreduced units of blood remained essentially unchanged from that on the day of donation. Although the mean NMH concentration did not differ significantly between nonleukoreduced and leukoreduced units on day 28 of storage, it is possible that the difference in NMH concentration between nonleukoreduced and leukoreduced units would have increased in magnitude had it been monitored over a longer storage period or for a greater number of dogs. In units of human blood, there is an exponential increase in the histamine load (as assessed by NMH concentration) following storage for 14,13 21,14 and 4217 days. In the present study, units of canine blood were stored for only 28 days, which is the standard storage period for blood products at our hospital. It is possible we would have documented a significant increase in the NMH concentration in stored canine blood units had we assessed it over a longer period (eg, 35 to 42 days of storage).
Another limitation of the present study was that only 1 type of leukoreduction filter was used for leukocyte and platelet depletion of blood in the leukoreduced units. Although the leukoreduction filter used in this study effectively removed leukocytes and platelets from the blood, it is not the only type of leukoreduction filter available, and other filter types might have yielded different results. Additionally, the blood units in this study were stored as whole blood rather than as packed RBCs to ensure that sufficient plasma would be available for quantification of NMH concentration at 14 and 28 days of storage. To maximize the range of products obtained from each blood donation, whole blood is commonly separated and stored as plasma and packed RBCs. Our results may have differed had we monitored changes in NMH concentration during storage of packed RBCs. Also, we only measured the histamine load in units of stored whole blood and not in transfusion recipients. Further investigation is necessary to determine whether administration of blood products increases the plasma histamine concentration in dogs during and after transfusion and whether the histamine load in stored units of blood contributes to transfusion reactions in recipients of that blood. Finally, the units of blood in the present study were maintained at room temperature for 5 hours on days 14 and 28 of storage to simulate temperature conditions during transfusion. Other transfusion-associated effects, such as passage of blood through an IV line or a microaggregate or macroaggregate filter were not assessed. Although canine RBCs are not adversely affected by passage through a microaggregate filter,24 it is possible that other transfusion-associated effects might affect the NMH concentration in blood during transfusion.
Results of the present study suggested that the histamine load (as assessed by plasma NMH concentration) in units of canine whole blood did not increase significantly during the first 28 days of storage, even after units were maintained at room temperature for 5 hours to simulate temperature conditions during transfusion. Additionally, although passing blood through a leukoreduction filter 30 minutes after collection resulted in a significant increase in the plasma NMH concentration, that concentration did not change significantly during the subsequent 28 days of storage, nor did the plasma NMH concentration differ significantly between units of blood that did and did not undergo leukoreduction. Further research is necessary to determine whether histamine contributes to the development and severity of blood transfusion reactions in dogs.
Acknowledgments
Sample collection was performed at the College of Veterinary Medicine, Mississippi State University, and analysis was performed at the Gastrointestinal Laboratory at the Texas A&M College of Veterinary Medicine.
Funded by the Atlantic Veterinary Internal Medicine and Oncology Hospital and the Mississippi State University College of Veterinary Medicine Office of Research and Graduate Studies. Funding sources did not have any involvement in study design, data analysis and interpretation, or writing and publication of the manuscript.
The authors declare that there were no conflicts of interest.
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