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.

Development and Publication of Clinical Practice Parameters, Reviews, and Meta-analyses: A Report From the Society of Cardiovascular Anesthesiologists Presidential Task Force.

The Society of Cardiovascular Anesthesiologists (SCA) is committed to improving the quality, safety, and value that cardiothoracic anesthesiologists bring to patient care. To fulfill this mission, the SCA supports the creation of peer-reviewed manuscripts that establish standards, produce guidelines, critically analyze the literature, interpret preexisting guidelines, and allow experts to engage in consensus opinion. The aim of this report, commissioned by the SCA President, is to summarize the distinctions among these publications and describe a novel SCA-supported framework that provides guidance to SCA members for the creation of these publications. The ultimate goal is that through a standardized and transparent process, the SCA will facilitate up-to-date education and implementation of best practices by cardiovascular and thoracic anesthesiologists to improve patient safety, quality of care, and outcomes.

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.

Mean distance from skin to epiglottis in parturients as measured by airway ultrasound.

Introduction: There is an increasing interest in using airway ultrasound to predict difficult intubation. Studies to date have excluded pregnant women in reporting airway measurements. We performed this study to compare the mean distance from skin to epiglottis in parturients to that reported in previously published studies. We also assessed the correlation of mean distance from skin to epiglottis with other elements of the airway examination. Methods: A total of 100 parturients were recruited from a tertiary hospital's labor and delivery floor. Standard physical examination parameters were recorded in addition to the mean distance from skin to epiglottis for all subjects. The ratio of height-to-thyromental distance was used to classify airways as potentially favorable or unfavorable. Results: The average mean distance from skin to epiglottis in parturients was 19.9 ± 3.3 mm and followed a normal distribution. The mean distance from skin to epiglottis was moderately correlated with height and body mass index. There was no difference in mean distance from skin to epiglottis between subjects with favorable versus unfavorable airways as classified by ratio of height-to-thyromental distance. Conclusion: The typical mean distance from skin to epiglottis in parturients falls between previously published values in mixed populations. Previously published cut-off values using airway ultrasound to predict difficult intubation are not likely to apply to parturients.

Defining heparin resistance: communication from the ISTH SSC Subcommittee of Perioperative and Critical Care Thrombosis and Hemostasis.

The term heparin resistance (HR) is used by clinicians without specific criteria. We performed a literature search and surveyed our SSC membership to better define the term when applied to medical and intensive care unit patients. The most common heparin dosing strategy reported in the literature (53%) and by survey respondents (80.4%) was the use of weight-based dosing. Heparin monitoring results were similar based on the proportion of publications and respondents that reported the use of anti-Xa and activated partial thromboplastin time. The most common literature definition of HR was >35 000 U/d, but no consensus was reported among survey respondents regarding weight-based and the total dose of heparin when determining resistance. Respondent consensus on treating HR included antithrombin supplementation, direct thrombin inhibitors, or administering more heparin as the strategies available for treating HR. A range of definitions for HR exist. Given the common use of heparin weight-based dosing, future publications employing the term HR should include weight-based definitions, monitoring assay, and target level used. Further work is needed to develop a consensus for defining HR.

A Sticky Situation: Variable Agreement Between Platelet Function Tests Used to Assess Anti-platelet Therapy Response.

Background: Platelet function testing to monitor antiplatelet therapy is important for reducing thromboembolic complications, yet variability across testing methods remains challenging. Here we evaluated the agreement of four different testing platforms used to monitor antiplatelet effects of aspirin (ASA) or P2Y12 inhibitors (P2Y12-I). Methods: Blood and urine specimens from 20 patients receiving dual antiplatelet therapy were analyzed by light transmission aggregometry (LTA), whole blood aggregometry (WBA), VerifyNow PRUTest and AspirinWorks. Result interpretation based on pre-defined cutoff values was used to calculate raw agreement indices, and Pearson's correlation coefficient determined using individual units of measure. Results: Agreement between LTA and WBA for P2Y12-I-response was 60% (r = 0.65, high-dose ADP; r = 0.75, low-dose ADP). VerifyNow agreed with LTA in 75% (r = 0.86, high-dose ADP; r = 0.75, low-dose ADP) and WBA in 55% (r = 0.57) of cases. Agreement between LTA and WBA for ASA-response was 45% (r = 0.09, high-dose collagen WBA; r = 0.19, low-dose collagen WBA). AspirinWorks agreed with LTA in 60% (r = 0.32) and WBA in 35% (r = 0.02, high-dose collagen WBA; r = 0.08, low-dose collagen WBA) of cases. Conclusions: Overall agreement varied from 35 to 75%. LTA and VerifyNow demonstrated the highest agreement for P2Y12-I-response, followed by moderate agreement between LTA and WBA. LTA and AspirinWorks showed moderate agreement for aspirin response, while WBA showed the weakest agreement with both LTA and AspirinWorks. The results from this study support the continued use of LTA for monitoring dual antiplatelet therapy, with VerifyNow as an appropriate alternative for P2Y12-I-response. Integration of results obtained from these varied testing platforms with patient outcomes remains paramount for future studies.

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.

COVID-19 patient plasma demonstrates resistance to tPA-induced fibrinolysis as measured by thromboelastography.

Patients critically ill with COVID-19 are at risk for thrombotic events despite prophylactic anticoagulation. Impaired fibrinolysis has been proposed as an underlying mechanism. Our objective was to determine if fibrinolysis stimulated by tissue plasminogen activator (tPA) differed between COVID patients and controls. Plasma from 14 COVID patients on prophylactic heparin therapy was obtained and compared with heparinized plasma from 14 different healthy donors to act as controls. Kaolin activated thromboelastography with heparinase was utilized to obtain baseline measurements and then repeated with the addition of 4 nM tPA. Baseline fibrinogen levels were higher in COVID plasma as measured by maximum clot amplitude (43.6 ± 6.9 mm vs. 23.2 ± 5.5 mm, p < 0.0001) and Clauss assay (595 ± 135 mg/dL vs. 278 ± 44 mg/dL, p < 0.0001). With the addition of tPA, fibrinolysis at 30 min after MA (LY30%) was lower (37.9 ± 16.5% vs. 58.9 ± 18.3%, p = 0.0035) and time to 50% lysis was longer (48.8 ± 16.3 vs. 30.5 ± 15.4 min, p = 0.0053) in the COVID-19 samples. Clotting times and rate of fibrin polymerization ('R' or 'α' parameters) were largely the same in both groups. Clot from COVID patients contains a higher fibrin content compared to standard controls and shows resistance to fibrinolysis induced by tPA. These findings suggest the clinical efficacy of thrombolytics may be reduced in COVID-19 patients.

Therapeutic plasma exchange for COVID-19-associated hyperviscosity.

BACKGROUND: Recent data suggests an association between blood hyperviscosity and both propensity for thrombosis and disease severity in patients with COVID-19. This raises the possibility that increased viscosity may contribute to endothelial damage and multiorgan failure in COVID-19, and that therapeutic plasma exchange (TPE) to decrease viscosity may improve patient outcomes. Here we sought to share our experience using TPE in the first 6 patients treated for COVID-19-associated hyperviscosity. STUDY DESIGN AND METHODS: Six critically ill COVID-19 patients with plasma viscosity levels ranging from 2.6 to 4.2 centipoise (cP; normal range, 1.4-1.8 cP) underwent daily TPE for 2-3 treatments. RESULTS: TPE decreased plasma viscosity in all six patients (Pre-TPE median 3.75 cP, range 2.6-4.2 cP; Post-TPE median 1.6 cP, range 1.5-1.9 cP). TPE also decreased fibrinogen levels in all five patients for whom results were available (Pre-TPE median 739 mg/dL, range 601-1188 mg/dL; Post-TPE median 359 mg/dL, range 235-461 mg/dL); D-dimer levels in all six patients (Pre-TPE median 5921 ng/mL, range 1134-60 000 ng/mL; Post-TPE median 4893 ng/mL, range 620-7518 ng/mL); and CRP levels in five of six patients (Pre-TPE median 292 mg/L, range 136-329 mg/L; Post-TPE median 84 mg/L, range 31-211 mg/L). While the two sickest patients died, significant improvement in clinical status was observed in four of six patients shortly after TPE. CONCLUSIONS: This series demonstrates the utility of TPE to rapidly correct increased blood viscosity in patients with COVID-19-associated hyperviscosity. Large randomized trials are needed to determine whether TPE may improve clinical outcomes for patients with COVID-19.

Trends and diagnostic value of D-dimer levels in patients hospitalized with coronavirus disease 2019.

Coronavirus disease 2019 (COVID-19) has been associated with increased incidence of venous thromboembolic events (VTE) as well as mortality. D-dimer is a marker of fibrinolysis and has been used as a diagnostic and prognostic marker in VTE among other diseases. The purpose of our study is to describe outcomes from out center and to examine trends in D-dimer levels as it relates to VTE and mortality.Patients admitted with confirmed COVID-19 cases to Emory Healthcare from March 12, 2020 through April 6, 2020 with measured plasma D-dimer levels were included in our retrospective analysis. Relevant data about comorbidities, hospitalization course, laboratory results, and outcomes were analyzed.One hundred fifteen patients were included in our study. Mean age was 64 ±â€Š15 years, 47 (41%) females and 84 (73%) African-American. Hypertension was present in 83 (72%) and diabetes in 60 (52%). Mean duration of hospitalization was 19 ±â€Š11 days with 62 (54%) patients intubated (mean duration of 13 ±â€Š8 days). VTE was diagnosed in 27 (23%) patients (mean time to diagnosis 14 ±â€Š9 days). Median D-dimer within the first 7 days of hospitalization was higher (6450 vs. 1596 ng/mL, p < 0.001) in VTE cases compared to non-VTE cases, and was predictive of VTE (area under the curve [AUC] = 0.72, optimal threshold 2500 ng/mL) although not of mortality (AUC 0.55, P = .34). Change in D-dimer level (AUC = 0.72 P = .004) and rate of D-dimer rise (AUC = 0.75 P = .001) were also predictive of VTE, though neither predicted death (P > .05 for all). Within the first 7 days of hospitalization, peak D-dimer level of >2500 ng/mL and a rate of change exceeding 150 ng/mL/d were predictive of future diagnosis of VTE. Rise in D-dimer >2000 ng/mL within any 24 hour period through hospital day 10 had 75% sensitivity and 74% specificity for diagnosis of VTE.We found that both magnitude and rate of rise in d-dimer within the first 10 days of hospitalization are predictive of diagnosis of VTE but not mortality. These parameters may aid in identifying individuals with possible underlying VTE or at high risk for VTE, thereby guiding risk stratification and anticoagulation policies in COVID-19 patients.

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.