Finding a common definition of heparin resistance in adult cardiac surgery: communication from the ISTH SSC subcommittee on perioperative and critical care thrombosis and hemostasis.

Ensuring adequate anticoagulation for patients requiring cardiac surgery and cardiopulmonary bypass (CPB) is important due to the adverse consequences of inadequate anticoagulation with respect to bleeding and thrombosis. When target anticoagulation is not achieved with typical doses, the term heparin resistance is routinely used despite the lack of uniform diagnostic criteria. Prior reports and guidance documents that define heparin resistance in patients requiring CPB and guidance documents remain variable based on the lack of standardized criteria. As a result, we conducted a review of clinical trials and reports to evaluate the various heparin resistance definitions employed in this clinical setting and to identify potential standards for future clinical trials and clinical management. In addition, we also aimed to characterize the differences in the reported incidence of heparin resistance in the adult cardiac surgical literature based on the variability of both target-activated clotting (ACT) values and unfractionated heparin doses. Our findings suggest that the most extensively reported ACT target for CPB is 480 seconds or higher. Although most publications define heparin resistance as a failure to achieve this target after a weight-based dose of either 400 U/kg or 500 U/kg of heparin, a standardized definition would be useful to guide future clinical trials and help improve clinical management. We propose the inability to obtain an ACT target for CPB of 480 seconds or more after 500 U/kg as a standardized definition for heparin resistance in this setting.

Evaluation of the efficacy and safety of amustaline/glutathione pathogen-reduced RBCs in complex cardiac surgery: the Red Cell Pathogen Inactivation (ReCePI) study-protocol for a phase 3, randomized, controlled trial.

BACKGROUND: Red blood cell (RBC) transfusion is a critical supportive therapy in cardiovascular surgery (CVS). Donor selection and testing have reduced the risk of transfusion-transmitted infections; however, risks remain from bacteria, emerging viruses, pathogens for which testing is not performed and from residual donor leukocytes. Amustaline (S-303)/glutathione (GSH) treatment pathogen reduction technology is designed to inactivate a broad spectrum of infectious agents and leukocytes in RBC concentrates. The ReCePI study is a Phase 3 clinical trial designed to evaluate the efficacy and safety of pathogen-reduced RBCs transfused for acute anemia in CVS compared to conventional RBCs, and to assess the clinical significance of treatment-emergent RBC antibodies. METHODS: ReCePI is a prospective, multicenter, randomized, double-blinded, active-controlled, parallel-design, non-inferiority study. Eligible subjects will be randomized up to 7 days before surgery to receive either leukoreduced Test (pathogen reduced) or Control (conventional) RBCs from surgery up to day 7 post-surgery. The primary efficacy endpoint is the proportion of patients transfused with at least one study transfusion with an acute kidney injury (AKI) diagnosis defined as any increased serum creatinine (sCr) level ≥ 0.3 mg/dL (or 26.5 µmol/L) from pre-surgery baseline within 48 ± 4 h of the end of surgery. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to pathogen-reduced RBCs through 75 days after the last study transfusion. With ≥ 292 evaluable, transfused patients (> 146 per arm), the study has 80% power to demonstrate non-inferiority, defined as a Test group AKI incidence increase of no more than 50% of the Control group rate, assuming a Control incidence of 30%. DISCUSSION: RBCs are transfused to prevent tissue hypoxia caused by surgery-induced bleeding and anemia. AKI is a sensitive indicator of renal hypoxia and a novel endpoint for assessing RBC efficacy. The ReCePI study is intended to demonstrate the non-inferiority of pathogen-reduced RBCs to conventional RBCs in the support of renal tissue oxygenation due to acute anemia and to characterize the incidence of treatment-related antibodies to RBCs.

Identification of coagulation factor IX variants with enhanced activity through ancestral sequence reconstruction.

Orthologous proteins contain sequence disparity guided by natural selection. In certain cases, species-specific protein functionality predicts pharmacological enhancement, such as greater specific activity or stability. However, immunological barriers generally preclude use of nonhuman proteins as therapeutics, and difficulty exists in the identification of individual sequence determinants among the overall sequence disparity. Ancestral sequence reconstruction (ASR) represents a platform for the prediction and resurrection of ancient gene and protein sequences. Recently, we demonstrated that ASR can be used as a platform to facilitate the identification of therapeutic protein variants with enhanced properties. Specifically, we identified coagulation factor VIII (FVIII) variants with improved specific activity, biosynthesis, stability, and resistance to anti-human FVIII antibody-based inhibition. In the current study, we resurrected a panel of ancient mammalian coagulation factor IX (FIX) variants with the goal of identifying improved pharmaceutical candidates. One variant (An96) demonstrated 12-fold greater FIX activity production than human FIX. Addition of the R338L Padua substitution further increased An96 activity, suggesting independent but additive mechanisms. after adeno-associated virus 2 (AAV2)/8-FIX gene therapy, 10-fold greater plasma FIX activity was observed in hemophilia B mice administered AAV2/8-An96-Padua as compared with AAV2/8-human FIX-Padua. Furthermore, phenotypic correction conferred by the ancestral variant was confirmed using a saphenous vein bleeding challenge and thromboelastography. Collectively, these findings validate the ASR drug discovery platform as well as identify an ancient FIX candidate for pharmaceutical development.

Controlled Multifactorial Coagulopathy: Effects of Dilution, Hypothermia, and Acidosis on Thrombin Generation In Vitro.

BACKGROUND: Coagulopathy and hemostatic abnormalities remain a challenge in patients following trauma and major surgery. Coagulopathy in this setting has a multifactorial nature due to tissue injury, hemodilution, hypothermia, and acidosis, the severity of which may vary. In this study, we combined computational kinetic modeling and in vitro experimentation to investigate the effects of multifactorial coagulopathy on thrombin, the central enzyme in the coagulation system. METHODS: We measured thrombin generation in platelet-poor plasma from 10 healthy volunteers using the calibrated automated thrombogram assay (CAT). We considered 3 temperature levels (31°C, 34°C, and 37°C), 3 pH levels (6.9, 7.1, and 7.4), and 3 degrees of dilution with normal saline (no dilution, 3-fold dilution, and 5-fold dilution). We measured thrombin-generation time courses for all possible combinations of these conditions. For each combination, we analyzed 2 scenarios: without and with (15 nM) supplementation of thrombomodulin, a key natural regulator of thrombin generation. For each measured thrombin time course, we recorded 5 quantitative parameters and analyzed them using multivariable regression. Moreover, for multiple combinations of coagulopathic conditions, we performed routine coagulation tests: prothrombin time (PT) and activated partial thromboplastin time (aPTT). We compared the experimental results with simulations using a newly developed version of our computational kinetic model of blood coagulation. RESULTS: Regression analysis allowed us to identify trends in our data (P < 10). In both model simulations and experiments, dilution progressively reduced the peak of thrombin generation. However, we did not experimentally detect the model-predicted delay in the onset of thrombin generation. In accord with the model predictions, hypothermia delayed the onset of thrombin generation; it also increased the thrombin peak time (up to 1.30-fold). Moreover, as predicted by the kinetic model, the experiments showed that hypothermia increased the area under the thrombin curve (up to 1.97-fold); it also increased the height of the thrombin peak (up to 1.48-fold). Progressive acidosis reduced the velocity index by up to 24%; acidosis-induced changes in other thrombin generation parameters were much smaller or none. Acidosis increased PT by 14% but did not influence aPTT. In contrast, dilution markedly prolonged both PT and aPTT. In our experiments, thrombomodulin affected thrombin-generation parameters mainly in undiluted plasma. CONCLUSIONS: Dilution with normal saline reduced the amount of generated thrombin, whereas hypothermia increased it and delayed the time of thrombin accumulation. In contrast, acidosis in vitro had little effect on thrombin generation.

Catastrophic Intracardiac Thrombosis During Emergency Repair of an Expanding Aortic Pseudoaneurysm: A Case Report.

Catastrophic thrombosis is a rare but frequently fatal event following complex cardiac surgery. It is most often encountered following separation from cardiopulmonary bypass (CPB) and reversal of heparin anticoagulation, and somewhat paradoxically, at the time when bleeding from post-CPB coagulopathy is being treated. We report the case of a 41-year-old female taken to the operating room for repair of an expanding ascending aortic pseudoaneurysm. Following a prolonged operation, she developed intracardiac thrombus during transfusion of hemostatic blood products and procoagulant agents. Potential contributing factors are discussed.

Non-Antithrombin-Mediated Heparin Resistance During Cardiac Surgery: Two Case Reports.

It is well known that antithrombin (AT) deficiency results in decreased heparin sensitivity, also known as "heparin resistance." However, non-AT-mediated causes of heparin resistance are generally poorly characterized and less prevalent in the literature. We present 2 case reports of non-AT-mediated heparin resistance during cardiac surgery due to paraproteinemia and hyperfibrinogenemia. These cases highlight the challenges posed by unusual conditions in achieving adequate anticoagulation for cardiopulmonary bypass (CPB). The pros and cons of the treatment selections for these cases are discussed, and the potential complications of large doses of unfractionated heparin are considered.

Safety of Intranasal Ketamine for Reducing Uncontrolled Cancer-Related Pain: Protocol of a Phase I/II Clinical Trial.

BACKGROUND: Approximately 12 million Americans are affected with cancer. Of these, 53% experience pain at all stages of cancer. Pain may remain uncontrolled despite high-dose opioid therapy, and opioids have many well-documented harmful side effects. Intranasal ketamine has been shown to be effective in controlling breakthrough noncancer pain in a double-blind randomized control trial (DBRCT) by Carr et al in 2003 as well as to help with depression in a DBRCT by Lapidus et al in 2014. We seek to obtain preliminary data on the safety, feasibility, and utility of this novel technique for the treatment of uncontrolled cancer pain. OBJECTIVE: This study aimed to obtain preliminary data via a clinical trial addressing the safety, feasibility, pharmacokinetics, and pharmacodynamics of intranasal ketamine. These initial findings will be applied to a subsequent trial to determine the effectiveness and associated toxicities of ketamine in a larger sample of cancer patients and to address the compelling need to identify new, successful management therapies for cancer pain. METHODS: This is an institutional review board- and investigational new drug-approved, prospective phase I/II trial to investigate the safety and use of intranasal ketamine in patients with uncontrolled pain related to cancer or cancer treatment. Informed consent will be obtained prior to all study procedures. All patients will be assigned to the same investigational treatment arm. After patient selection via inclusion/exclusion criteria, patients will be seen over 5 visits, with each visit conducted 2-7 days apart. Patients will be administered ketamine on visits 1-4 and monitored for 240 minutes with continuous pulse oximetry and regular blood pressure checks. Blood samples as well as patient-reported outcomes will be collected at set time points at baseline and after drug delivery. Patients will receive 10 mg intranasal ketamine on visit 1, 10 mg intravenous ketamine on visit 2, 30 mg intranasal ketamine on visit 3, and 50 mg intranasal ketamine on visit 4. On visit 5, an addition blood sample will be drawn. RESULTS: As of March 2019, enrollment is in progress, and a total of 7 subjects have completed the study. Enrollment is expected to be completed by April 2019. Final data analysis will commence soon after, and the results are expected to be submitted for publication in 2019. CONCLUSIONS: If intranasal ketamine can be utilized for pain control in cancer patients, it could provide superior analgesia and better quality of life, without the risk of significant respiratory depression and constipation associated with opioid medications. These findings will be an important initial step toward testing the effectiveness of intranasal ketamine as a nonopioid medication for cancer pain and as potential maintenance outpatient therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT03146806; https://clinicaltrials.gov/ct2/show/NCT03146806. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/12125.

Platelet function, but not thrombin generation, is impaired in acute normovolemic hemodilution (ANH) blood.

STUDY OBJECTIVE: We investigated the coagulation changes that might occur in acute normovolemic hemodilution (ANH) blood over several hours during cardiac surgery requiring cardiopulmonary bypass. DESIGN: This study was a prospective observational study. SETTING: This study took place at a university teaching hospital. PATIENTS: This study included 26 patients, either ASA 3 or 4 and without known coagulation disorders, undergoing cardiac surgery. Patients were included if the use of cardiopulmonary bypass was expected to reach 2.5 h. INTERVENTIONS: ANH blood was collected into CPDA-1 collection bags before systemic heparinization. Samples were taken directly from the bags at time of collection and reinfusion to assess changes in platelet and thrombin generation parameters. MEASUREMENTS: Whole blood from citrated tubes was used immediately for rotational thromboelastometry and platelet aggregometry analyses. Thrombin generation was assessed using calibrated automated thrombography with platelet poor plasma. MAIN RESULTS: Despite no significant change in platelet count over the ANH storage period, there was significant degradation in platelet function as measured by thrombin receptor activating peptide stimulation on Mulltiplate™ analysis and maximum clot formation on ROTEM™ EXTEM. Notably, there was no change in the ability to generate thrombin. CONCLUSIONS: Little data exists regarding the quality of coagulation factors in autologous blood. Our study confirms ANH collection results in decreased platelet aggregation with TRAP stimulation; however, this is not appreciated with ADP stimulation. Thrombin generation capacity remains preserved.

Effects of blood storage age on immune, coagulation, and nitric oxide parameters in transfused patients undergoing cardiac surgery.

BACKGROUND: Retrospective studies suggested that storage age of RBCs is associated with inflammation and thromboembolism. The Red Cell Storage Duration Study (RECESS) trial randomized subjects undergoing complex cardiac surgery to receive RBCs stored for shorter versus longer periods, and no difference was seen in the primary outcome of change in multiple organ dysfunction score. STUDY DESIGN AND METHODS: In the current study, 90 subjects from the RECESS trial were studied intensively using a range of hemostasis, immunologic, and nitric oxide parameters. Samples were collected before transfusion and on Days 2, 6, 28, and 180 after transfusion. RESULTS: Of 71 parameters tested, only 4 showed a significant difference after transfusion between study arms: CD8+ T-cell interferon-γ secretion and the concentration of extracellular vesicles bearing the B-cell marker CD19 were higher, and plasma endothelial growth factor levels were lower in recipients of fresh versus aged RBCs. Plasma interleukin-6 was higher at Day 2 and lower at Days 6 and 28 in recipients of fresh versus aged RBCs. Multiple parameters showed significant modulation after surgery and transfusion. Most analytes that changed after surgery did not differ based on transfusion status. Several extracellular vesicle markers, including two associated with platelets (CD41a and CD62P), decreased in transfused patients more than in those who underwent surgery without transfusion. CONCLUSIONS: Transfusion of fresh versus aged RBCs does not result in substantial changes in hemostasis, immune, or nitric oxide parameters. It is possible that transfusion modulates the level of platelet-derived extracellular vesicles, which will require study of patients randomly assigned to receipt of transfusion to define.

A Step Toward Balance: Thrombin Generation Improvement via Procoagulant Factor and Antithrombin Supplementation.

BACKGROUND: The use of prothrombin complex concentrates in trauma- and surgery-induced coagulopathy is complicated by the possibility of thromboembolic events. To explore the effects of these agents on thrombin generation (TG), we investigated combinations of coagulation factors equivalent to 3- and 4-factor prothrombin complex concentrates with and without added antithrombin (AT), as well as recombinant factor VIIa (rFVIIa), in a dilutional model. These data were then used to develop a computational model to test whether such a model could predict the TG profiles of these agents used to treat dilutional coagulopathy. METHODS: We measured TG in plasma collected from 10 healthy volunteers using Calibrated Automated Thrombogram. TG measurements were performed in undiluted plasma, 3-fold saline-diluted plasma, and diluted plasma supplemented with the following factors: rFVIIa (group rFVIIa); factors (F)II, FIX, FX, and AT (group "combination of coagulation factors" [CCF]-AT); or FII, FVII, FIX, and FX (group CCF-FVII). We extended an existing computational model of TG to include additional reactions that impact the Calibrated Automated Thrombogram readout. We developed and applied a computational strategy to train the model using only a subset of the obtained TG data and used the remaining data for model validation. RESULTS: rFVIIa decreased lag time and the time to thrombin peak generation beyond their predilution levels (P < 0.001) but did not restore normal thrombin peak height (P < 0.001). CCF-FVII supplementation decreased lag time (P = 0.034) and thrombin peak time (P < 0.001) and increased both peak height (P < 0.001) and endogenous thrombin potential (P = 0.055) beyond their predilution levels. CCF-AT supplementation in diluted plasma resulted in an improvement in TG without causing the exaggerated effects of rFVIIa and CCF-FVII supplementation. The differences between the effects of CCF-AT and supplementation with rFVIIa and CCF-FVII were significant for lag time (P < 0.001 and P = 0.005, respectively), time to thrombin peak (P < 0.001 and P = 0.004, respectively), velocity index (P < 0.001 and P = 0.019, respectively), thrombin peak height (P < 0.001 for both comparisons), and endogenous thrombin potential (P = 0.034 and P = 0.019, respectively). The computational model generated subject-specific predictions and identified typical patterns of TG improvement. CONCLUSIONS: In this study of the effects of hemodilution, CCF-AT supplementation improved the dilution-impaired plasma TG potential in a more balanced way than either rFVIIa alone or CCF-FVII supplementation. Predictive computational modeling can guide plasma dilution/supplementation experiments.

Antithrombin: anti-inflammatory properties and clinical applications.

Many humoral and cellular components participate in bidirectional communication between the coagulation and inflammation pathways. Natural anticoagulant proteins, including antithrombin (AT), tissue factor pathway inhibitor, and protein C, suppress proinflammatory mediators. Conversely, inflammation blunts anticoagulant activity and, when uncontrolled, promotes systemic inflammation-induced coagulation, such as those that occur in disseminated intravascular coagulation and severe sepsis. This review discusses the mechanisms of action and clinical use of AT concentrate in critically ill patients and in the settings of perioperative anticoagulation management for surgery and obstetrics. AT is a serine protease inhibitor with broad anticoagulant activity and potent anti-inflammatory properties. In clinical conditions associated with hereditary or acquired AT deficiency, administration of AT concentrate has been shown to restore proper haemostasis and attenuate inflammation. Of note, AT modulates inflammatory responses not only by inhibiting thrombin and other clotting factors that induce cytokine activity and leukocyte-endothelial cell interaction, but also by coagulation-independent effects, including direct interaction with cellular mediators of inflammation. An increasing body of evidence suggests that AT concentrate may be a potential therapeutic agent in certain clinical settings associated with inflammation. In addition to the well-known anticoagulation properties of AT for the treatment of hereditary AT deficiency, AT also possesses noteworthy anti-inflammatory properties that could be valuable in treating acquired AT deficiency, which often result in thrombotic states associated with an inflammatory component.

Perioperative coagulation management in the intensive care unit.

PURPOSE OF REVIEW: Coagulopathy in an ICU setting is multifactorial, but newer anticoagulation agents are the potentially contributing causes. Critically ill patients may suffer from disorders because of surgery or trauma, in addition to acquired causes including antiplatelet agents and the new oral anticoagulants. An understanding of the coagulopathy, hemostatic considerations, and therapeutic approaches is important when managing these patients. RECENT FINDINGS: All anticoagulation agents may contribute to coagulopathy in critically ill patients. Options for management include hemodialysis, transfusion of blood products, and prohemostatic drugs. Recombinant and purified coagulation therapies are also now available in most countries that provide clinicians with specific agents to treat targeted deficiencies. SUMMARY: Coagulopathy occurs in ICU patients because of multiple factors including anticoagulants, dilution, fibrinolysis, and factor consumption. Therapeutic prohemostatic pharmacologic approaches, in addition to standard transfusion therapy, need to be considered in managing coagulopathy in the ICU setting.

Prohemostatic treatment in cardiac surgery.

Cardiac surgical patients represent a unique group of patients where coagulopathy occurs due to multiple causes besides simple hemorrhagic blood loss. Hemodilution, inflammation, and hemostatic activation while on cardiopulmonary bypass all contribute to this problem and provide targets for therapeutic intervention. Current pharmacological strategies to reduce the need for allogeneic transfusions include both preemptive agents to decrease the potential for bleeding as well as prohemostatic agents to promote the coagulation process. This article will discuss pharmacological agents including antifibrinolytics, protamine, desmopressin, fibrinogen, purified protein concentrates, recombinant factor VIIa, factor XIII, and topical agents used in cardiac surgery.

Managing clotting: a North American perspective.

PURPOSE OF REVIEW: Bleeding in a perioperative setting occurs due to multiple causes, but newer anticoagulant and antiplatelet therapies are increasingly used preoperatively. As a result, patients often can present for surgery with underlying hemostatic disorders due to these acquired disorders or following major surgery or trauma. Because bleeding occurs due to multiple causes, the addition of pharmacologic agents creates an acquired defect that complicates the surgical injury and may result in increased blood loss. An understanding of hemostasis and therapeutic approaches, especially those in our current clinical settings, is crucial in managing these patients. RECENT FINDINGS: Pharmacologic agents including antifibrinolytics and prohemostatic proteins are commonly administered, but a multimodal approach to management is important. Of note is that aprotinin has been reintroduced into the Canadian market in September 2011. Recombinant and purified coagulation therapies are under investigation, and provide clinicians specific agents to treat targeted deficiencies. SUMMARY: Nonsurgical bleeding in the operating room is the result of a multitude of factors including preoperative anticoagulants, dilution, fibrinolysis, and factor consumption. Therapeutic prohemostatic pharmacologic approaches, in addition to standard transfusion therapy, need to be considered in the prevention and treatment of coagulopathy in surgical patients.

Activation of the hemostatic system during cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) is a unique clinical scenario that results in widespread activation of the hemostatic system. However, surgery also results in normal increases in coagulation activation, platelet activation, and fibrinolysis that are associated with normal wound hemostasis. Conventional CPB interferes with normal hemostasis by diluting hemostatic cells and proteins, through reinfusion of shed blood, and through activation on the bypass circuit surface of multiple systems including platelets, the kallikrein-kinin system, and fibrinolysis. CPB activation of the kallikrein-kinin system increases activated factor XIIa, kallikrein, bradykinin, and tissue plasminogen activator levels, but has little effect on thrombin generation. Increased tissue plasminogen activator and circulating fibrin result in increased plasmin generation, which removes hemostatic fibrin. The nonendothelial surface of the bypass circuit, along with circulating thrombin and plasmin, lead to platelet activation, platelet receptor loss, and reduced platelet response to wounds. In this review, we highlight the major mechanisms responsible for CPB-induced activation of the hemostatic system and examine some of the markers described in the literature. Additionally, strategies used to reduce this activation are discussed, including limiting cardiotomy suction, increasing circuit biocompatibility, antithrombin supplementation, and antifibrinolytic use. Determining which patients will most benefit from specific therapies will ultimately require investigation into genetic phenotypes of coagulation protein expression. Until that time, however, a combination of approaches to reduce the hemostatic activation from CPB seems warranted.

Bleeding and management of coagulopathy.

Bleeding after cardiac surgery remains a significant problem, increasing both length of stay and mortality, and is caused by multiple factors including dilutional changes, ongoing fibrinolysis, and platelet dysfunction. The evaluation of coagulopathy is problematic because of the long turnaround time of standard coagulation tests. Algorithms involving point of care testing, including thromboelastography and thromboelastometry, have been published; all have the potential to reduce transfusion requirements. Massive transfusion coagulopathy that occurs in trauma can also be seen in complex aortic surgery and other massive bleeding patients and should prompt consideration of a transfusion protocol involving fixed ratios of fresh frozen plasma, platelets, and red blood cells. Pharmacologic agents such as antifibrinolytics are commonly administered, but a multimodal approach to management is important. Recombinant and purified coagulation products are being studied and provide clinicians specific agents to treat targeted deficiencies. A general multi-modal approach is required and recommendations are made for the management of bleeding and coagulopathy in cardiac surgical patients.

Plasma and cerebral spinal fluid tranexamic acid quantitation in cardiopulmonary bypass patients.

A method for the determination of tranexamic acid (TXA) in human plasma and cerebral spinal fluid (CSF) was developed. Analyses were performed by ultra performance liquid chromatography with tandem mass spectrometry detection (UPLC-MS/MS) using ɛ-aminocaproic acid (ACA) as an internal standard. TXA and ACA were extracted from a 50 µL sample of plasma or CSF using a methanol protein crash protocol, and chromatographic separation was performed on an ACQUITY™ TQD mass spectrometer using a UPLC C18 BEH 1.7 µm column with a water and methanol gradient containing 0.1% formic acid. The detection and quantitation was performed by positive ion electrospray ionization using the multiple reaction monitoring (MRM) mode. The method was linear over the concentration range of 0.1-10.0 µg/mL, with lower limit of quantitation of 0.1 µg/mL for TXA. The intra- and inter-assay precision was less than 12% and 13% respectively at the plasma and CSF TXA concentrations tested. The present method provides a relatively simple and sensitive assay with short turn-around-time. The method has been successfully applied to assess the plasma and CSF concentrations of tranexamic acid achieved with only one dosing regimen of tranexamic acid in patients undergoing cardiopulmonary bypass surgery (CPB).

Changing from aprotinin to tranexamic acid results in increased use of blood products and recombinant factor VIIa for aortic surgery requiring hypothermic arrest.

OBJECTIVE: Aprotinin, once used to reduce allogeneic blood product transfusion during cardiac surgery, was withdrawn from the market in late 2007 over concerns of causing increased mortality. This study was undertaken to determine what, if any, the impact of changing antifibrinolytic agents (from aprotinin to tranexamic acid) for deep hypothermic circulatory arrest cases would have on blood bank resource utilization. DESIGN: This a retrospective review. SETTING: All cases were performed at a single university hospital. PARTICIPANTS: All patients underwent cardiac surgical procedures requiring deep hypothermic circulatory arrest performed by a single cardiac surgeon between January 2006 and November 2008. INTERVENTION: All patients prior to November 15, 2007 received aprotinin as antifibrinolytic therapy, while those after that date received tranexamic acid for antifibrinolytic therapy. MEASUREMENTS AND MAIN RESULTS: Blood transfusion data and recombinant factor VIIa use during the pre- and immediate postoperative period was collected for all patients during the study time period. There were no significant differences between the aprotinin (n = 82) and tranexamic acid (n = 78) groups with regard to baseline coagulation status or operative characteristics. Patients treated with tranexamic acid required more fresh frozen plasma (2.5 units, p < 0.001), platelets (0.5 units, p < 0.01), and cryoprecipitate (25 units, p < 0.001), and had a higher incidence of recombinant factor VIIa use (34.6% v 12.2%, p < 0.01) compared with patients in the aprotinin group. CONCLUSIONS: Patients treated with tranexamic acid required more clotting factors than the control group receiving aprotinin.