Clinical and economic implications of false-positive heparin-induced thrombocytopenia immunoassays: utility of the 4T score.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic condition induced by platelet-activating IgG antibodies that recognize PF4/heparin complexes. Diagnosis of HIT relies on enzyme immunologic assays (EIAs) and functional assays [serotonin release assay (SRA)]. Our institution uses a latex immunoturbidimetric assay (LIA), which has shown a positive-predictive value (PPV) of 55.6%, and a negative-predictive value (NPV) of 99.7%. The low PPV of EIAs/LIAs, in combination with the clinical delay in obtaining results of a SRA, commonly leads to a false-positive diagnosis of HIT and inappropriate treatment. We performed a single-institution retrospective study at a large tertiary center to assess patient management decisions and economic costs following a false-positive HIT (LIA) test. This study found an 89.5% incidence of false-positive HIT (LIA) tests. 97.4% of patients underwent anticoagulation changes. 69.6% of patients were switched to argatroban. Of patients with a false-positive HIT immunoassay (LIA), 42 (40.7%) patients were on a prophylactic dose of anticoagulation at the time of HIT (LIA) positivity, of which 22 (52.4%) were switched to full anticoagulation with either argatroban or fondaparinux. Of the 22 patients switched to full anticoagulation, 15 (68%) had low-probability 4T scores. Seven (8.8%) of patients had bleeding events after HIT (LIA) positivity. All seven patients were switched to argatroban from a full-dose heparin anticoagulation. Five of the seven patients were considered major bleeds. Utilization of argatroban incurred substantial costs, estimated at approximately $73 000 for false-positive HIT cases. False-positive HIT (LIA) tests contribute to unwarranted anticoagulation changes, increased bleeding risks, and substantial healthcare costs. Incorporating the 4T score into diagnostic algorithms may help mitigate these risks by guiding appropriate clinical decisions. Future research should focus on refining diagnostic approaches and standardizing management strategies to improve patient outcomes and cost-effectiveness in HIT diagnosis and management.

Anticoagulation stewardship: Improving adherence to clinical guidelines and reducing overuse of venous thromboembolism prophylaxis in hospitalized medical patients.

Adherence to guideline recommendations for venous thromboembolism prophylaxis (VTE) in hospitalized medical patients is suboptimal despite national policies and institutional interventions. The aim of this quality improvement project was to improve adherence to guidelines and decrease the overuse of VTE prophylaxis in order to reduce the institutional cost for heparins. A multidisciplinary anticoagulation stewardship program (ACSP) using the audit and feedback strategy was implemented on the medicine inpatient units at a teaching hospital in Canada. The primary outcome measure was a comparison, pre and post introduction of the ACSP, of the costs per 6-month period for prophylactic dose enoxaparin and unfractionated heparin on the medicine units. The balancing measures were the 90-day VTE rate and major bleeding rate during the hospitalization. Six months after the implementation of the ACSP, the cost was decreased by >50 % without any observed negative impact on patient safety. This study demonstrates the potential for anticoagulation stewardship programs to optimize the use of VTE prophylaxis and reduce the associated costs and risks.

Assessment of symptomatic response to intravesical alkalinized lidocaine, bupivacaine, heparin and steroids in patients with bladder pain syndrome.

Bladder Pain Syndrome (BPS) is a puzzling and complicated disorder. 12 such patients, with a mean age 48.3 years, were treated with weekly intravesical instillation of admixture of alkalinized lidocaine, bupivacaine, heparin and steroids for six weeks. Evaluating the benefits of this therapy, patients experienced 82.2% & 90.9% relief at 3rd & 6th week of instillation. After completion of six cycles of therapy, patients experienced 68.7% & 65.3% relief at 3rd & 6th month follow up, concluding the early and long term relief of BPS.

Surfactant-based supramolecular dye assembly: A highly selective and economically viable platform for quantification of heparin antidote.

Herein, we have employed a supramolecular assembly of a cationic dye, LDS-698 and a common surfactant sodium dodecyl sulfate (SDS) as a turn-on fluorescent sensor for protamine (Pr) detection. Addition of cationic Pr to the solution of dye-surfactant complex brings negatively charged SDS molecules together through strong electrostatic interaction, assisting aggregation of SDS way before its critical micellar concentration (CMC). These aggregates encapsulate the dye molecules within their hydrophobic region, arresting non-radiative decay channels of the excited dye. Thus, the LDS-698•SDS assembly displays substantial enhancement in fluorescence intensity that follows a nice linear trend with Pr concentration, providing limit of detection (LOD) for Pr as low as 3.84(±0.11) nM in buffer, 124.4(±6.7) nM in 1% human serum and 28.3(±0.5) nM in 100% human urine. Furthermore, high selectivity, low background signal, large stokes shift, and emission in the biologically favorable deep-red region make the studied assembly a promising platform for Pr sensing. As of our knowledge it is the first ever Pr sensory platform, using a very common surfactant (SDS), which is economically affordable and very easily available in the market. This innovative approach can replace the expensive, exotic and specialized chemicals considered for the purpose and thus showcase its potential in practical applications.

Value function assessment to different RL algorithms for heparin treatment policy of patients with sepsis in ICU.

Heparin is a critical aspect of managing sepsis after abdominal surgery, which can improve microcirculation, protect organ function, and reduce mortality. However, there is no clinical evidence to support decision-making for heparin dosage. This paper proposes a model called SOFA-MDP, which utilizes SOFA scores as states of MDP, to investigate clinic policies. Different algorithms provide different value functions, making it challenging to determine which value function is more reliable. Due to ethical restrictions, we cannot test all policies on patients. To address this issue, we proposed two value function assessment methods: action similarity rate and relative gain. We experimented with heparin treatment policies for sepsis patients after abdominal surgery using MIMIC-IV. In the experiments, TD(0) shows the most reliable performance. Using the action similarity rate and relative gain to assess AI policy from TD(0), the agreement rates between AI policy and "good" physician's actual treatment are 64.6% and 73.2%, while the agreement rates between AI policy and "bad" physician's actual treatment are 44.1% and 35.8%, the gaps are 20.5% and 37.4%, respectively. External validation using action similarity rate and relative gain based on eICU resulted in agreement rates of 61.5% and 69.1% with the "good" physician's treatment, and 45.2% and 38.3% with the "bad" physician's treatment, with gaps of 16.3% and 30.8%, respectively. In conclusion, the model provides instructive support for clinical decisions, and the evaluation methods accurately distinguish reliable and unreasonable outcomes.

Cost-utility analysis of 4% tetrasodium ethylenediaminetetraacetic acid, taurolidine, and heparin lock to prevent central line-associated bloodstream infections in children with intestinal failure.

BACKGROUND: Central line-associated bloodstream infections (CLABSI) are a serious complication in children with intestinal failure. This study assessed the incremental costs of 4% tetrasodium ethylenediaminetetraacetic acid (EDTA) compared with taurolidine lock and heparin lock per quality-adjusted life-year (QALY) gained in children with intestinal failure from the healthcare payer and societal perspective. METHODS: A Markov cohort model of a 1-year-old child with intestinal failure was simulated until the age of 17 years (time horizon), with a cycle length of 1 month. The health outcome measure was QALYs, with results expressed in terms of incremental costs and QALYs. Model parameters were obtained from published literature and institutional data. Deterministic, probabilistic, and scenario sensitivity analyses were performed. RESULTS: 4% Tetrasodium EDTA was dominant (more effective and less expensive) compared with taurolidine and heparin, yielding an additional 0.17 QALYs with savings of CAD$88,277 compared with heparin, and an additional 0.06 QALYs with savings of CAD$52,120 compared with taurolidine lock from the healthcare payer perspective. From the societal perspective, 4% tetrasodium EDTA resulted in savings of CAD$90,696 compared with heparin and savings of CAD$36,973 compared with taurolidine lock. CONCLUSIONS: This model-based analysis indicates that 4% tetrasodium EDTA can be considered the optimal strategy compared with taurolidine and heparin in terms of cost-effectiveness. The decision uncertainty can be reduced by conducting further research on the model input parameters. An expected value of perfect information analysis can identify what model input parameters would be most valuable to focus on.

Evaluation of the use of a heparin dose-response test in dogs to determine the optimal heparin dose during intravascular procedures and assessment of the in vitro heparin response in healthy dogs.

BACKGROUND: No guidelines for administering and monitoring anticoagulants intraprocedurally are currently available in dogs, despite the prevalence of procedures necessitating systemic anticoagulation with heparin. OBJECTIVES: To evaluate an activated clotting time (ACT)-based heparin dose-response (HDR) test to predict the individual required heparin dose in dogs during intravascular procedures, and to investigate both the in vitro heparin - ACT and in vitro heparin - factor anti-Xa activity (anti-Xa) relationships in dogs. METHODS: Blood was collected from eight healthy beagles undergoing a cardiac procedure and utilised to establish baseline ACT and for in vitro evaluation. Subsequently, 100 IU/kg heparin was administered intravenously (IV) and ACT was remeasured (HDR test). The required heparin dose for an ACT target response ≥300 s was calculated for each individual and ACT was remeasured after administration of this dose. For in vitro testing, a serial heparin blood dilution (0-0.5-1-2-4 international unit (IU)/mL) was prepared and ACT and anti-Xa were determined using whole blood and frozen plasma, respectively. RESULTS: The HDR test overestimated the required heparin dose in 3/7 dogs. In vitro, ACT and anti-Xa increased significantly with increasing blood heparin concentration. Heparin - ACT was nonlinear in 4/8 dogs at heparin concentrations >2 IU/mL, whereas heparin - anti-Xa remained linear throughout the tested range. CONCLUSIONS: The HDR test poorly estimated the required heparin dose in dogs. This is most likely attributed to a nonlinear heparin - ACT relationship, as observed in vitro. Anti-Xa is a promising alternative for ACT; however, unavailability as a point-of-care test and lack of in vivo target values restrict its current use.

Clinical and dermoscopic assessment of ablative carbon dioxide laser versus intradermal heparin sodium in xanthelasma.

BACKGROUND: Ablative carbon dioxide (CO2 ) laser is still a cornerstone in the management of xanthelasma. However, post-laser complications such as post-inflammatory hyperpigmentation or scarring have to be considered. Heparin sodium was recently suggested as an effective therapeutic modality for xanthelasma. OBJECTIVE: The aim of this work was to compare the therapeutic value of ablative CO2 laser versus intradermal heparin sodium in xanthelasma. METHODS: This study was piloted on 30 xanthelasma patients, whose lesions were randomly categorized into two groups. Group A was managed with CO2 laser ablation (2 sessions scheduled every 4 weeks), whereas Group B was managed with intradermal heparin sodium injections (10 sessions scheduled every week). Pre- and post-treatments evaluations were done both clinically and dermoscopically. RESULTS: Significant reduction of xanthelasma lesions was reported in response to both therapeutic interventions. However, the ablative CO2 laser was more significantly effective than intradermal heparin sodium. Interestingly, intradermal injection of heparin sodium was nearly as effective as ablative CO2 laser in early (<2 years duration) grade I and II xanthelasma, with a lower incidence of post-therapy side effects. CONCLUSIONS: Intradermal injection of heparin sodium could be suggested as a safe and cost-effective therapeutic technique for early mild grade I and II xanthelasma. Moreover, it could be recommended as a pre-operative management of grade III and IV xanthelasma to reduce the lesions to be easily ablated with CO2 laser.

Performance Assessment of Anti-Xa Assay-Based Heparin Dosing Protocol in Pediatric Patients on Extracorporeal Membrane Oxygenation.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) in the postoperative cardiac critical care setting is evolving. Anticoagulation monitoring is among the most challenging aspects of pediatrics. However, there is no consensus on the optimal dosing and monitoring of unfractionated heparin in this setting. To address this, we developed an anti-Xa assay-based protocol derived from the best available clinical and anecdotal evidence of ECMO use and assessed its effectiveness in achieving the anti-Xa assay therapeutic target. METHODS: This prospective single-arm study was conducted in the pediatric carcardiac-surgery intensive care unit of a large tertiary hospital. We used two different anti-Xa assay intensity levels based on the patients' bleeding status. RESULTS: The median patient age was 7 (interquartile range [IQR]: 5-11.25) months, and the median weight was 5.7 (IQR: 3.8-13.82) kg. The median ECMO duration was 6 (IQR: 4.5-7.5) days. The bleeding protocol was used for most patients. Seventy percent achieved the anti-Xa assay therapeutic target during the study period (median: 75.5 h, IQR: 60.5-117.5 h). Hemorrhagic complications were reported in 40% of the patients, and thrombotic complications were reported in 25%. The median length of stay was 37 (IQR: 22-43) days, with a survival-to-discharge rate of 75%. CONCLUSIONS: Despite a failure to achieve the anti-Xa assay target within the first ECMO days, most patients achieved the target by the median ECMO duration. Moreover, using two different anti-Xa assay levels reduced thrombotic complications.

Assessment of bleeding risk in low-weight patients receiving prophylactic subcutaneous unfractionated heparin.

BACKGROUND: Underweight patients may be at an increased risk of bleeding while receiving venous thromboembolism (VTE) prophylaxis. Additional evidence is needed to identify patient-specific factors associated with bleeding. The objective of the study was to describe the incidence and identify risk factors associated with bleeding in low-weight (⩽ 60 kg) adult patients receiving subcutaneous unfractionated heparin (SQH) for VTE prophylaxis. METHODS: This was a single-center, retrospective, nested case-control study of low-weight patients receiving SQH for VTE prophylaxis for ⩾ 48 hours. Cases, patients with clinically relevant bleeding while receiving SQH, and controls, patients without a bleeding event, were matched in a 1:3 ratio for age, sex, primary service (surgical or medical), and time at risk of bleeding on SQH to determine factors associated with bleeding. RESULTS: A total of 3761 patients met the inclusion criteria, of which 38 cases of clinically relevant bleeding were identified. The bleeding incidence was 1% at hospital day 6 and 2.8% at hospital day 14. Most patients in this study (69%) received SQH 5000 units three times daily. ICU admission at SQH start was associated with bleeding, OR 2.97 (95% CI 1.21-7.29). CONCLUSION: Bleeding in low-weight patients on prophylactic SQH was uncommon. Patients admitted to the ICU at time of SQH start may be at a higher risk of bleeding. Further studies are needed to detect additional risk factors associated with bleeding and investigate the effects of reduced dosing in this population.

Management of venous thromboembolism in pediatric patients: Quality assessment of clinical practice guidelines and variations in recommendations.

INTRODUCTION: We performed a quality assessment and comparison of clinical practice guidelines (CPGs) for the prevention and treatment of venous thromboembolism (VTE) in pediatric patients and to provide a clinical reference. MATERIALS AND METHODS: Electronic databases, guideline development organizations, and professional societies were searched to identify CPGs for VTE in pediatric patients between January 1, 2012, and April 7, 2022. The Appraisal of Guidelines Research & Evaluation (AGREE) II instrument was used to evaluate quality. Recommendations for preventing and treating VTE in pediatric patients were extracted via descriptive synthesis. RESULTS: Six CPGs were included. The median scores (interquartile range [IQR]) for each AGREE II domain were as follows: scope and purpose, 88.89 % (IQR: 8.33 %); stakeholder involvement, 88.89 % (25 %); rigor of development, 67.71 % (24.47 %); clarity and presentation, 88.89 % (0 %); applicability, 50 % (42.71 %); and editorial independence, 66.67 % (50.00 %). In total, 268 key recommendations were extracted, and traditional anticoagulants (heparin and warfarin) remain the standard treatment. However, in recent years direct oral anticoagulants (DOACs) have shown similar efficacy and safety results for the treatment of VTE in children to those reported in adults; therefore, this practice is recommended in recent guidelines. CONCLUSIONS: Variability exists in the development and reporting of CPGs for VTE in pediatric patients. There may be changes to the recommendations for the prevention and treatment of VTE in pediatrics in the future due to the efficacy of DOACs in children, and recommendations should be revised periodically as new evidence emerges.

Evaluation of the registry DIALYREG for the assessment of continuous renal replacement techniques in the critically ill patient.

Continuous renal replacement techniques (CRRT) can induce complications and monitoring is crucial to ensure patient safety. We designed a prospective multicenter observational and descriptive study using the DIALYREG registry, an online database located on a REDCap web-based platform that allows real-time data analysis. Our main objective was to identify CRRT-related complications in our intensive care units (ICUs) and implement security measures accordingly. From January 2019 to December 2020, we included 323 patients with admission diagnoses of medical illness (54%), sepsis (24%), postoperative care (20%), and trauma (2%). CRRT indications were homeostasis (42%), oliguria (26%), fluid overload (15%), and hemodynamic optimization (13%). The median initial therapy dose was 30 ml/kg/h (IQR 25-40), and dynamic adjustment was performed in 61% of the treatments. Sets were anticoagulated with heparin (40%), citrate (38%) or no anticoagulation (22%). Citrate anticoagulation had several advantages: more frequent dynamic CRRT dose adjustment (77% vs. 58% with heparin and 56% without anticoagulation, p < 0.05), longer duration of set (median of 55 h, IQR 24-72 vs. 23 h, IQR 12-48 with heparin and 12 h, IQR 12-31 without anticoagulation, p < 0.05), less clotting of the set (26% vs. 46.7% with heparin, p < 0.05), and lower incidence of hypophosphatemia (1% citrate vs. 6% with heparin and 5% without anticoagulation). It was also safe and effective in subgroup analysis of patients with liver disease or sepsis. The main global complications were hypothermia (16%), hypophosphatemia (13%) and metabolic acidosis (10%). Weaning of the therapy was achieved through early discontinuation (56%), nocturnal therapy transition (26%) and progressive SLED (18%). 52% of the patients were discharged from the hospital, while 43% died in the ICU and 5% died during hospitalization. We can conclude that the DIALYREG registry is a feasible tool for real-time control of CRRT in our ICU.

Analysis of Wholesale Drug Acquisition and Laboratory Assessment Costs Between Heparin Compared With Bivalirudin-Based Systemic Anticoagulation Strategies in Adult Extracorporeal Membrane Oxygenation.

OBJECTIVES: To assess the wholistic costs of systemic anticoagulation delivery in heparin versus bivalirudin-based maintenance of adult patients supported on extracorporeal membrane oxygenation (ECMO). DESIGN: Single-center retrospective cohort study. SETTING: Large academic ECMO center. PATIENTS: Adults on ECMO receiving heparin or bivalirudin for primary maintenance systemic anticoagulation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Electronic data were abstracted from a database maintained by our ECMO center, which transitioned to a preferred bivalirudin-based anticoagulation management in 2017. The pretransition group consisted of 126 patients (123 heparin and three bivalirudin), whereas the posttransition group included 275 patients (82 heparin and 193 bivalirudin). Drug costs were estimated using the wholesale acquisition cost, and laboratory assays costs were estimated using reimbursement fee schedules. Cost data were normalized to the duration of the ECMO run and reported in U.S. Dollar per ECMO day. Following the practice change, bivalirudin patients were less likely to receive AT supplementation (31.0 vs 12.4%; p < 0.0001) and had fewer coagulation assays ordered (6.1 vs 5.4 per ECMO day; p = 0.0004). After the transition, there was a dramatic decrease in costs related to AT assay assessments ($11.78 [interquartile range {IQR}, $9.48-$13.09] vs $1.03 [IQR, $0-$5.75]; p < 0.0001) and AT supplementation ($0 [IQR, $0-$312.82] vs $0 [IQR, $0-$0]; p < 0.0001) per ECMO day. Unadjusted survival at 28 days was higher posttransition (64.3 vs 74.9%; p = 0.0286). CONCLUSIONS: Antithrombin assays and supplementation compromise a significant proportion of heparin-based anticoagulation costs in ECMO patients and is substantially reduced when a bivalirudin-based anticoagulation strategy is deployed. A favorable association exists between the aggregate cost of administration of bivalirudin compared with heparin-based systemic anticoagulation in adults supported on ECMO driven by reductions in antithrombin activity assessments and the cost of antithrombin replacement.

In-hospital mortality of heparin-induced thrombocytopenia in end-stage kidney disease. A retrospective national population-based cohort study.

AIM: Heparin induced thrombocytopenia (HIT) and end stage kidney disease (ESKD) are independent conditions associated with increased mortality and morbidity, however, whether ESKD is an independent risk factor for increased mortality in HIT admissions is not well studied. Therefore, we aimed to compare in-hospital mortality in HIT admissions based on their ESKD status. METHODS: This is a retrospective cohort study of HIT hospitalizations aged 18 and older using the 2016-2019 national inpatient sample (NIS) database. RESULTS: From 2016 to 2019 we had 12 161 admissions for HIT among 28 484 087 total hospitalizations. The annual incidence rate for HIT admissions per 100 000 admissions were: 47, 46, 41.1, and 36.6, respectively (p < .001) in 2016, 2017, 2018, and 2019 respectively. Among HIT admissions, the mean age was 64.3 years, 46.8% were females, 68% were Whites and 16% were Blacks. Black patients have a significantly higher likelihood of in-hospital mortality than White patients (aOR 1.25; 95% CI: 1.06, 1.48; p = .007). Patients who did not have any insurance or self-pay had higher mortality compared to Medicare (aOR 1.64; 95% CI: 1.13, 2.38; p = .009). ESKD status was not associated with higher or lower in-hospital mortality among HIT admissions (aOR 1.002; 95% CI: 0.84, 1.19; p = .981) after adjusting for age, sex, race, and insurance status. CONCLUSION: There are no higher or lower odds of in-hospital mortality in the ESKD subgroup in HIT admissions in adults. Decreasing incidence of HIT hospitalizations was seen over the years from 2016 to 2019.

Assessment of the Stability of Midregional Proadrenomedullin in Different Biological Matrices.

Midregional proadrenomedullin (MR-proADM) has been shown to play a key role in endothelial dysfunction, with increased levels helping to prevent early stages of organ dysfunction. Recent clinical evidence has demonstrated MR-proADM to be a helpful biomarker to identify disease severity in patients with sepsis as well as pneumonia. This biomarker is helpful at triage in emergency departments to assess risk level of patients. The aim of this study is to evaluate the stability of MR-proADM in different biological matrices. The results, obtained by Bland-Altman and scatter plot analyses, demonstrate that deviation of MR-proADM concentration in serum compared to EDTA plasma unequivocally shows that serum should not be used as a sample matrix. Instead, the excellent correlation of heparin plasma vs EDTA plasma samples shows that heparin plasma can be used without reservation in clinical routine and emergency samples.

Cost-effectiveness of bivalirudin in pediatric ventricular assist devices.

BACKGROUND: Despite recent data suggesting improved outcomes with bivalirudin vs heparin in pediatric Ventricular assist devices (VAD), higher costs remain a barrier. This study quantified trends in bivalirudin use and compared outcomes, resource utilization, and cost-effectiveness associated with bivalirudin vs heparin. METHODS: Children age 0 to 6 year who received VAD from 2009 to 2021 were identified in Pediatric Health Information System. Bivalirudin use was evaluated using trend analysis and outcomes were compared using Fine-Gray subdistrubtion hazard ratios (SHR). Daily-level hospital costs were compared due to differences in length of stay. Cost-effectiveness was evaluated using incremental cost-effectiveness ratio (ICER). RESULTS: Of 691 pediatric VAD recipients (median age 1 year, IQR 0-2), 304 (44%) received bivalirudin with 90% receiving bivalirudin in 2021 (trend p-value <0.01). Bivalirudin had lower hospital mortality (26% vs 32%; adjusted SHR 0.57, 95% CI 0.40-0.83) driven by lower VAD mortality (20% vs 27%; adjusted SHR 0.46, 95% CI 0.32-0.77) after adjusting for year, age, diagnosis, and center VAD volume. Post-VAD length of stay was longer for bivalirudin than heparin (median 91 vs 64 days, respectively, p < 0.001). Median daily-level costs were lower among bivalirudin (cost ratio 0.87, 95% CI 0.79-0.96) with higher pharmacy costs offset by lower imaging, laboratory, supply, and room/board costs. Estimated ICER for bivalirudin vs heparin was $61,192 per quality-adjusted life year gained with a range of $27,673 to $131,243. CONCLUSIONS: Bivalirudin use significantly increased over the past decade and is now used in 90% young pediatric VAD recipients. Bivalirudin was associated with significantly lower hospital mortality and an ICER <$65,000, making it a cost-effective therapy for pediatric VAD recipients.

Low-Molecular-Weight Heparin Resistance and Its Viscoelastic Assessment in Critically Ill COVID-19 Patients.

Critically ill COVID-19 patients present an inflammatory and procoagulant status with a high rate of relevant macro- and microvascular thrombosis. Furthermore, high rates of heparin resistance have been described; yet, individualized anticoagulation by drug monitoring has not been sufficiently researched. We analyzed data from critically ill COVID-19 patients treated at Innsbruck Medical University Hospital with routinely adapted low-molecular-weight heparin (LMWH) doses according to anti-Xa peak levels, and regularly performed ClotPro analyses (a viscoelastic hemostatic whole blood test). A total of 509 anti-Xa peak measurements in 91 patients were categorized as below (<0.008 IU/mL/mg), within (0.008-0-012 IU/mL/mg) or above (> 0.012 IU/mL/mg) expected ranges with respect to the administered LMWH doses. Besides intergroup comparisons, correlations between anti-Xa levels and ClotPro clotting times (CTs) were performed (226 time points in 84 patients). Anti-Xa peak levels remained below the expected range in the majority of performed measurements (63.7%). Corresponding patients presented with higher C-reactive protein and D-dimer but lower antithrombin levels when compared with patients achieving or exceeding the expected range. Consequently, higher enoxaparin doses were applied in the sub-expected anti-Xa range group. Importantly, 47 (51.6%) patients switched between groups during their intensive care unit (ICU) stay. Anti-Xa levels correlated weakly with IN test CT and moderately with Russell's viper venom (RVV) test CT. Critically ill COVID-19 patients present with a high rate of LMWH resistance but with a variable LMWH response during their ICU stay. Therefore, LMWH-anti-Xa monitoring seems inevitable to achieve adequate target ranges. Furthermore, we propose the use of ClotPro's RVV test to assess the coagulation status during LMWH administration, as it correlates well with anti-Xa levels but more holistically reflects the coagulation cascade than anti-Xa activity alone.

Assessment of Rotational Thromboelastometry and Thrombin Generation Assay to Identify Risk of High Blood Loss and Re-Operation After Cardiac Surgery.

Introduction: We aimed to investigate parameters for prediction of post-operative blood loss and re-operation in patients who underwent cardiopulmonary bypass. Methods: Thrombin generation assay, activated partial thromboplastin time, activated clotting time and rotational thromboelastometry (ROTEM) tests were performed at 4 time points in 65 patients: before skin incision (T1), after heparin injection (T2), after protamine reversal (T3) and before skin closure (T4). Results: Pre-operative endogenous thrombin potential (ETP) and peak thrombin levels were significantly lower in patients with high post-operative blood loss (≥ 800 mL) within 24 h than in those with low blood loss (< 800 mL). Clotting time (CT), maximal clotting firmness, clotting firmness time and alpha angle values of ROTEM measured at T2, T3 or T4 were significant predictors for high post-operative blood loss. An increase in CT-EXTEM over 4 time points was significant in patients who had a re-operation within 48 h compared to their counterparts. Conclusions: This study indicates that pre-operative ETP could predict high post-operative blood loss and that intra-operative ROTEM also helps to stratify risks of high post-operative blood loss and re-operation.

Assessment of immunological anti-platelet factor 4 antibodies for vaccine-induced thrombotic thrombocytopenia (VITT) in a large Australian cohort: A multicenter study comprising 1284 patients.

BACKGROUND: Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare complication of adenovirus-based vaccines aimed to prevent and minimize COVID-19 and related pathophysiology. OBJECTIVES: To describe patterns of testing for anti-platelet factor 4 (PF4) antibodies using various ELISA assays in a large Australian cohort and comparative functional platelet activation assays in a subset. PATIENTS/METHODS: Asserachrom HPIA IgG ELISA was performed in 1284 patients over a period of 12 months, supplemented in select cohorts by comparative ELISA using three other methods (n = 78-179), three different functional assays (flow cytometry, serotonin release assay, and/or Multiplate; n = 476), and rapid immunological chemiluminescence anti-PF4 assay (n = 460), in a multicenter study. RESULTS: For first episode presentations, 190/1284 (14.8%) ELISA tests were positive. Conversely, most (445/460; 96.7%) chemiluminescence anti-PF4 test results were negative. All functional assays showed associations of higher median ELISA optical density with functional positivity and with high rates of ELISA positivity (64.0% to 85.2%). Data also identified functional positivity in 14.8%-36.0% of ELISA negative samples, suggesting false negative VITT by HPIA IgG ELISA in upward of one third of assessable cases. CONCLUSION: To our knowledge, this is the largest multicenter evaluation of anti-PF4 testing for investigation of VITT. Discrepancies in test results (ELISA vs. ELISA or ELISA vs. functional assay) in some patients highlighted limitations in relying on single methods (ELISA and functional) for PF4 antibody detection in VITT, and also highlights the variability in phenotypic test presentation and pathomechanism of VITT.