In Search of the Holy Grail of Artificial Hearts: Are We There Yet?

The total artificial heart (TAH) has a long and rich history, being the product of decades of innovation, hard work, and dedication. This review examines the history of the TAH, a device that has revolutionized the treatment of end-stage biventricular heart failure. It reviews the development of the device from early concepts to the current state-of-the-art device, the SynCardia TAH, which has been implanted in over 2,000 patients worldwide. The article also discusses the challenges and successes experienced by researchers, clinicians, and patients throughout the development of TAH devices. Our focus will also be on discussing the hemostatic alterations in patients implanted with TAH and anticoagulation strategies to decrease associated thromboembolic risks. The article concludes with a look at other novel TAH devices and the future of TAH as an increasingly viable treatment for end-stage heart failure.

The TEG 6s System: System Description and Protocol for Measurements.

A new generation of thromboelastography, TEG 6s (Haemonetics, Boston, MA), that assesses blood viscoelastic properties by resonance technology has recently been developed. This newer methodology represents a cartridge-based, automated assay aimed to improve on historical TEG performance and precision. In a previous chapter, we reviewed the advantages and limitations of TEG 6s as well as factors that affect TEG 6s and which must be considered when interpreting tracings. In the present chapter, we provide a description of the TEG 6s principle and its operation protocol.

The Quantra System: System Description and Protocols for Measurements.

Over the past two decades, the TEG 5000 (Haemonetics Corp, Braintree, MA) and ROTEM delta (Werfen, Bedford, MA) have been the principal viscoelastic (VET) technologies. These legacy technologies are based on the "cup and pin" principle. The Quantra System (HemoSonics, LLC, Durham, NC) is a new device that assesses blood viscoelastic properties by ultrasound (SEER Sonorheometry). It is cartridge based, automated device that provides simplified specimen management and increased results reproducibility. In the present chapter, we provide a description of the Quantra and its principle of operation, currently available cartridges/assays with their respective clinical indications, device operation, and results interpretation.

The TEG 5000 System: System Description and Protocol for Measurements.

The thromboelastograph (TEG) has undergone several modifications, but the concept on which the original TEG was based (cup and pin technology) remained up to the TEG 5000 analyzer (Haemonetics, Braintree, MA). In a previous chapter, we reviewed the advantages and limitations of TEG 5000 as well as factors that affect TEG and which must be considered when interpreting tracings. In the present chapter, we provide a description of the TEG 5000 principle and its operation protocol.

Measurement of Blood Viscoelasticity Using Thromboelastography.

Thromboelastography (TEG) was the first viscoelastic test (VET), invented in Germany in 1948 by Dr. Hartert, and which evaluates the hemostatic competence of whole blood. Thromboelastography was introduced before the activated partial thromboplastin time (aPTT), which was devised in 1953. TEG was not widely used until the introduction of a cell-based model of hemostasis (1994) showing the importance of platelets and tissue factor in hemostasis. Nowadays, VET has become an essential method for assessing hemostatic competence in cardiac surgery, liver transplantation, and trauma. TEG has undergone several modifications, but the concept on which the original TEG was based (cup and pin technology) remained in up to the TEG 5000 analyzer (Haemonetics, Braintree, MA). A new generation of thromboelastography, TEG 6s (Haemonetics, Boston, MA), that assesses blood viscoelastic properties by resonance technology has recently been developed. This newer methodology represents a cartridge-based, automated assay aimed to improve on historical TEG performance and precision. In the present chapter, we will review the advantages and limitations of TEG 5000 and TEG 6s systems as well as factors that affect TEG and which must be considered when interpreting TEG tracings.

Reply to Bareille et al. Are Viscoelastometric Assays of Old Generation Ready for Disposal? Comment on "Volod et al. Viscoelastic Hemostatic Assays: A Primer on Legacy and New Generation Devices. J. Clin. Med. 2022, 11, 860".

We are pleased to see that Bareille et al. have written a Commentary: "Are viscoelastometric assays of old generation ready for disposal?" [...].

Changes in Coagulation Testing During a National Shortage of Blue-Top Tubes.

OBJECTIVES: Manufacturer recalls and altered supply chains during the coronavirus disease 2019 (COVID-19) pandemic caused a nationwide shortage of blue-top tubes (BTTs). Most non-point-of-care coagulation tests use these tubes, leaving laboratories and health care facilities in short supply. The Department of Pathology and Laboratory Medicine at Cedars-Sinai Medical Center implemented interventions to conserve supply without sacrificing patient safety. METHODS: In a retrospective quality improvement analysis, we examined coagulation testing and BTT utilization over the 3-month interval during which our interventions were applied. Our study assessed the interventions' effectiveness by evaluating changes in BTT utilization, coagulation testing volume, and patient impact. RESULTS: Average daily use (ADU) of BTT before and after the intervention were 476 and 403, respectively-a 15.2% reduction. Notably, the Emergency Department had a reduction in ADU of 43.3%. Average daily volumes of coagulation assays performed decreased from 949 to 783-a 17.5% reduction. No adverse events from the Pharmacy Department were identified during the study period. CONCLUSIONS: Interventions resulting in significant reductions were in divisions with effective management and supervision. Success in navigating the BTT shortage stemmed from timely announcements, action, and effective communication. Our recommendations established more effective coagulation assay utilization, decreased overall BTT use, and prevented patients with coagulopathic disorders from experiencing adverse consequences.

Viscoelastic Testing in the Management of Adult Patients on Mechanical Circulatory Support Devices with Focus on Extracorporeal Membrane Oxygenation.

Thromboembolic and hemorrhagic complications continue to remain frequent complications that significantly impact the morbidity and mortality of patients implanted with mechanical circulatory support devices (MCSDs). The severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) has resulted in a number of COVID-19 patients being supported by MCSDs, specifically extracorporeal membrane oxygenation (ECMO), which in turn has created a crucial need for rapid assessment of hemostatic status in these patients to avoid bleeding and thrombotic complications. Currently, conventional plasma-based coagulation assays such as prothrombin time and activated partial thromboplastin time (aPTT) are used to assess hemostasis, and the activated clotting time (ACT) and aPTT are the most common tests used to monitor heparin anticoagulation in patients on ECMO. Unfractionated heparin remains the mainstay anticoagulation therapy for patients on ECMO. Extracorporeal Life Support Organization (ELSO) offers little guidance on the subject but does state that each institution should create its internal anticoagulation protocols. Viscoelastic assays (VEAs) are increasingly recognized by ELSO and ECMO community for their potential to assess hemostatic derangements in patients implanted with MCSDs as well as guidance for appropriate hemostatic therapy. This review focuses on the evidence for the use of viscoelastic assays to assess overall hemostasis and to guide the treatment of adult patients connected to an ECMO circuit. Limitations of the use of conventional assays, ACT, and VEA are also discussed.

Viscoelastic Hemostatic Assays: A Primer on Legacy and New Generation Devices.

Viscoelastic hemostatic assay (VHAs) are whole blood point-of-care tests that have become an essential method for assaying hemostatic competence in liver transplantation, cardiac surgery, and most recently, trauma surgery involving hemorrhagic shock. It has taken more than three-quarters of a century of research and clinical application for this technology to become mainstream in these three clinical areas. Within the last decade, the cup and pin legacy devices, such as thromboelastography (TEG® 5000) and rotational thromboelastometry (ROTEM® delta), have been supplanted not only by cartridge systems (TEG® 6S and ROTEM® sigma), but also by more portable point-of-care bedside testing iterations of these legacy devices (e.g., Sonoclot®, Quantra®, and ClotPro®). Here, the legacy and new generation VHAs are compared on the basis of their unique hemostatic parameters that define contributions of coagulation factors, fibrinogen/fibrin, platelets, and clot lysis as related to the lifespan of a clot. In conclusion, we offer a brief discussion on the meteoric adoption of VHAs across the medical and surgical specialties to address COVID-19-associated coagulopathy.

Interlaboratory Performance in Measurement of Dabigatran and Rivaroxaban.

CONTEXT.­: Assessing direct oral anticoagulant (DOAC) drug levels by reliable laboratory assays is necessary in a number of clinical scenarios. OBJECTIVE.­: To evaluate the performance of DOAC-specific assays for various concentrations of dabigatran and rivaroxaban, assess the interlaboratory variability in measurement of these DOACs, and investigate the responsiveness of the routine clotting assays to various concentrations of these oral anticoagulants. DESIGN.­: College of American Pathologists proficiency testing survey data from 2013 to 2016 were summarized and analyzed. RESULTS.­: For dabigatran, the interlaboratory coefficient of variation (CV) of ecarin chromogenic assay was broad (ranging from 7.5% to 29.1%, 6.3% to 15.5%, and 6.8% to 9.0% for 100-ng/mL, 200-ng/mL, and 400-ng/mL targeted drug concentrations, respectively). The CV for diluted thrombin time for dabigatran was better overall (ranging from 11.6% to 17.2%, 9.3% to 12.3, and 7.1% to 11.2% for 100 ng/mL, 200 ng/mL, and 400 ng/mL, respectively). The rivaroxaban-calibrated anti-Xa assay CVs also showed variability (ranging from 11.5% to 22.2%, 7.2% to 10.9%, and 6.4% to 8.1% for 50-ng/mL, 200-ng/mL, and 400-ng/mL targeted drug concentrations, respectively). The prothrombin time (PT) and activated partial thromboplastin time (aPTT) showed variable dose- and reagent-dependent responsiveness to DOACs: PT was more responsive to rivaroxaban and aPTT to dabigatran. The undiluted thrombin time showed maximum prolongation across all 3 dabigatran concentrations, making it too sensitive for drug-level monitoring, but supporting its use as a qualitative screening assay. CONCLUSIONS.­: DOAC-specific assays performed reasonably well. While PT and aPTT cannot be used safely to determine DOAC degree of anticoagulation, a normal thrombin time excludes the presence of dabigatran.

Diagnosing heparin-induced thrombocytopenia in mechanical circulatory support device patients.

BACKGROUND: Mechanical circulatory support device (MCSD) patients with positive heparin-induced thrombocytopenia (HIT) screening pose a unique challenge, as clinicians must make rapid decisions about their anticoagulation and whether they can safely undergo cardiopulmonary bypass. We identified screening practices at our institution and other institutions nationwide that differed from American Society of Hematology (ASH) guidelines. This discovery prompted a data review to confirm the applicability of guidelines to this unique population and to highlight complications of "gestalt" screening. METHODS: Our study included MCSD patients with HIT testing from April 2014 to August 2020. We evaluated 510 PF4 IgG ELISA results. RESULTS: HIT was confirmed in 4.2% of patients. There was an increased prevalence of HIT in patients with nondurable (5.3%) vs durable devices (2.9%) or those in the preimplantation setting (1.3%), however this difference was not statistically significant (p = 0.26). None of the patients with a low probability 4T Score had HIT. All patients with a high probability 4T Score and PF4 immunoassay OD >2.0 had HIT. False positive results occurred in 22% of assays ordered for patients with a low probability 4T Score. Twelve patients with a low probability 4T Score and a false positive immunoassay were switched to a direct thrombin inhibitor (DTI) while awaiting confirmatory results. Two patients experienced clinically significant bleeding after conversion to a DTI. An organ was refused in one patient with false positive HIT screening. CONCLUSIONS: Our findings demonstrate that an opportunity exists to improve clinical outcomes by re-emphasizing the utility of established guidelines and highlighting their safe use in the MCSD patient population.

Rotational Thromboelastometry Derivative Fibrinogen-Platelet Ratio Predicts Thrombosis in Microsurgery.

BACKGROUND: Early detection of thrombotic events is of paramount importance for microsurgical procedures. Here, we present findings that underscore the value of rotational thromboelastometry (ROTEM) to aid in decision-making for pre- and postoperative anticoagulation, as well for patients with suspected hypercoagulability. METHODS: We prospectively collected pre- and postoperative ROTEM values on all free flap cases at the University of California, San Francisco, from 2015 to 2016. Patient age, body mass index, comorbidities, operative reports, risk factors, thrombotic complications, and outcomes were collected from electronic medical records. Two-sample t-tests were used to compare ROTEM values between cohorts. Modeling for sensitivity, specificity, and accuracy was done for threshold fibrinogen-to-platelet ratio (FPR). RESULTS: Of 52 patients who underwent free-tissue transfer, 15 had a thrombotic event either intraoperatively or postoperatively that required revision of the vascular anastomosis. Eight patients were clinically hypercoagulable preoperatively, seven of which had a thrombotic event. Several pre- and postoperative ROTEM values differed significantly between thrombotic and nonthrombotic cases. Preoperative (p = 0.027) and postoperative (p = 0.013) FPR were statistically significant when comparing the thrombotic to the nonthrombotic cohort. Threshold FPR ≥ 30 was the most sensitive and FPR ≥ 40 was the most specific. CONCLUSION: Our study affirms other studies that established ROTEM as an effective predictive tool for thrombotic events during free-tissue transfer. However, a lower threshold for FPR improves catchment of thrombotic events and flap failure with acceptable sensitivity. Our results support the routine use of ROTEM for detecting hypercoagulability in patients who would potentially benefit from intervention to prevent thrombotic complications.

Improvement in plasma D-dimer level in severe SARS-CoV-2 infection can be an indicator of fibrinolysis suppression: Case reports.

RATIONALE: Fibrinolysis shutdown associated with severe thrombotic complications is a recently recognized syndrome that was previously seldom investigated in patients with severe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It presents a unique therapeutic dilemma, as anticoagulation with heparin alone is insufficient to address the imbalance in fibrinolysis. And while the use of fibrinolytic agents could limit the disease severity, it is often associated with bleeding complications. There is a need for biomarkers that will guide the timely stratification of patients into those who may benefit from both anticoagulant and fibrinolytic therapies. PATIENT CONCERNS: All 3 patients presented with shortness of breath along with comorbidities predisposing them to severe SARS-CoV-2 infection. One patient (Patient 3) also suffered from bilateral deep venous thrombosis. DIAGNOSES: All 3 patients tested positive for SARS-CoV-2 RNA by reverse transcription polymerase chain reaction (RT-PCR) and were eventually diagnosed with respiratory failure necessitating intubation. INTERVENTIONS: All 3 patients required mechanical ventilation support, 2 of which also required renal replacement therapy. All 3 patients were also placed on anticoagulation therapy. OUTCOMES: In Patients 1 and 2, the initial D-dimer levels of 0.97 µg/ml fibrinogen equivalent units (FEU) and 0.83 µg/ml FEU were only slightly elevated (normal <0.50 µg/ml FEU). They developed rising D-dimer levels to a peak of 13.21 µg/ml FEU and >20.0 µg/ml FEU, respectively, which dropped to 1.34 µg/ml FEU 8 days later in Patient 1 and to 2.94 µg/ml on hospital day 13 in Patient 2. In Patient 3, the D-dimer level on admission was found to be elevated to >20.00 µg/ml FEU together with imaging evidence of thrombosis. And although he received therapeutic heparin infusion, he still developed pulmonary embolism (PE) and his D-dimer level declined to 5.91 µg/ml FEU. Despite "improvement" in their D-dimer levels, all 3 patients succumbed to multi-system organ failure. On postmortem examination, numerous arterial and venous thromboses of varying ages, many consisting primarily of fibrin, were identified in the lungs of all patients. LESSONS: High D-dimer levels, with subsequent downtrend correlating with clinical deterioration, seems to be an indicator of fibrinolysis suppression. These findings can help form a hypothesis, as larger cohorts are necessary to demonstrate their reproducibility.

Viscoelastic hemostasis assays in septic, critically ill coronavirus disease 2019 patients: a practical guide for clinicians.

Coronavirus disease 2019 (COVID-19)-associated coagulopathy is unusual, poorly defined and is linked with significant hypercoagulability and microthrombotic and macrothrombotic complications leading to worse outcomes and higher mortality. Conventional coagulation assays do not always actively reflect these derangements and might fail to detect this coagulopathy. Viscoelastic hemostatic assays (VHA) provide a possible tool that adds to conventional coagulation assays in identifying this hypercoagulable state. VHA has been mostly used in surgery and trauma but it's still not well defined in sepsis patients with lack of large randomized trials. Few studies described VHA findings in patients with COVID-19 showing significant hypercoagulability and fibrinolysis shutdown. Clinicians taking care of these patients might have little experience interpreting VHA results. By reviewing the available literature on the use of VHA in sepsis, and the current knowledge on COVID-19-associated coagulopathy we provide clinicians with a practical guide on VHA utilization in patients with COVID-19.

Acute ophthalmic artery occlusion in a COVID-19 patient on apixaban.

We report a case of ophthalmic artery occlusion (OAO) in a young patient with COVID-19 infection that was on therapeutic anticoagulation with apixaban for deep venous thrombosis (DVT). A 48-year-old man with obesity was hospitalized with a severe form of COVID-19 infection, complicated with acute respiratory failure, septic shock, dilated cardiomyopathy and fungemia. Despite treatment with prophylactic enoxaparin (initial D-Dimer 1.14 µg/ml FEU (normal < 0.05 µg/ml FEU), D-Dimer increased to above 20 µg/ml FEU and patient continued to spike high fevers. This prompted further investigations and upper and lower extremities DVTs were confirmed and managed with enoxaparin 1 mg/kg twice daily. D-dimer level decreased to 4.98 µg/ml FEU while on therapeutic anticoagulation. Three weeks later pending hospital discharge, the anticoagulation was switched to oral apixaban 10 mg twice daily. Patient developed acute severe right eye visual loss of no light perception and was diagnosed with incomplete OAO. D-Dimer was elevated at 2.13 µg/ml FEU. Stroke etiological work-up found no embolic sources, resolution of the dilated cardiomyopathy and negative antiphospholipid antibodies. Treatment was changed to enoxaparin and no thrombotic events were encountered to date. Ocular vascular complications have not yet been reported in COVID-19. Controversy exists on the best management algorithm for the hypercoagulable state associated to COVID-19 Either direct oral anticoagulants or low-molecular-weight-heparin are considered appropriate at discharge for patients with venous thromboembolism. The optimum regimen for ischemic stroke prevention and the significance of D-Dimer for anticoagulation monitoring in COVID-19 remain unclear.

Platelet Mapping by Thromboelastography and Whole Blood Aggregometry in Adult Patients Supported by Mechanical Circulatory Support Device on Aspirin Therapy.

Patients on mechanical circulatory support (MCS) devices are placed on aspirin and may require platelet function testing (PFT) to monitor the adequacy of therapy. Routine laboratory PFT is performed using whole blood aggregation (WBA) which typically has a long turnaround time (4-5 hours) and may not be readily available. By contrast, platelet mapping by thromboelastography (TPM) can provide results within 45 minutes. The objective of this study was to compare the results of TPM with WBA. We compared platelet mapping maximal amplitude (MA) by TPM with that of arachidonic acid (AA) to WBA with AA by impedance. We analyzed paired samples where both TPM and WBA were available. Of 45 paired samples, 34 were from 29 MCS patients and 11 were from non-MCS patients. When applying institutional interpretation guidelines with an MAActivator cutoff of ≤40 mm, WBAAA vs TPM MAAA in non-MCS and MCS patients correlated well with an accuracy of 100 and 94.4%, respectively. MAActivator >40 had poor correlation with an accuracy of 37.5%. Irrespective of MAActivator value, TPM AA inhibition expressed in percent of inhibition had poor accuracy. When used with proper guidelines for interpretation, specifically when MAActivator ≤ 40 mm, TPM is a suitable and reliable test to use for MCS patients on aspirin.

Assessing Cerebrovascular Hemodynamics Using Transcranial Doppler in Patients with Mechanical Circulatory Support Devices.

BACKGROUND AND PURPOSE: Mechanical circulatory support (MCS) devices are commonly used in heart failure patients. These devices carry risk for presumably embolic and additionally hemorrhagic stroke. Alterations in blood flow play a key role in stroke pathophysiology, and we aimed to learn more about hemodynamic compromise. In this study, we used transcranial Doppler (TCD) ultrasound to define hemodynamics of commonly used nonpulsatile MCS devices, as well as pulsatile devices, with special attention to the total artificial heart (TAH). METHODS: From 2/2013 through 12/2016, we prospectively enrolled patients with MCS who underwent TCD imaging. We analyzed TCD parameters, including peak systolic velocity, end-diastolic velocity, pulsatility indices (PIs), and number of high-intensity transient signals. Waveform morphologies were compared between various MCS devices. RESULTS: We performed 132 TCD studies in 86 MCS patients. Waveforms in patients supported by venoarterial-extracorporeal membrane oxygenation demonstrated continuous flow without clear systolic peaks with an average (±SD) PI of .43 (±.2). PIs were low in patients with continuous-flow left ventricular assist devices with a mean PI of .32 (±.13). Impella patients had morphologically distinct pulsatile waveforms and a higher mean PI of .65 (±.24). In intra-arterial balloon pump patients, mean PI was 1.01 (±.16) and diastolic upstrokes were pronounced. In TAH patients, mean middle cerebral artery velocity of 79.69 (±32.33) cm/seconds and PI of .74 (±.14) approached normal values. CONCLUSION: TCD can detect characteristic waveforms in patients supported by various MCS devices. These device-specific TCD patterns are recognizable and reproducible.