Does one size really fit all? The case for personalized antiplatelet therapy in interventional cardiology.

Cardiovascular disease is the leading cause of death worldwide. Dual antiplatelet therapy (DAPT), with aspirin plus a P2Y12 inhibitor, is currently recommended as a default for patients after acute coronary syndrome (ACS) and following percutaneous coronary intervention (PCI). However, controversies arise over the role of aspirin, the optimal duration of DAPT after drug-eluting stent (DES) implantation, the choice of P2Y12 inhibitor and the variability in individual responses to antiplatelet agents. Recent data indicate that monotherapy with a P2Y12 inhibitor may have adequate anti-ischemic effects with lower bleeding risk. Additionally, discrepancies in DAPT duration recommendations and the optimal P2Y12 inhibitor, provides more uncertainty. We ask the question "does one size really fits all?" or should a more personalized strategy should be implemented.

Diseases affecting the heart and blood circulation are the leading cause of death worldwide. Treatment with drugs that prevents platelets from clumping (called antiplatelets) like aspirin plus another drug group (called P2Y12 inhibitors) like clopidogrel, ticagrelor and prasugrel, is currently recommended as a default for patients after heart attack and/or in whom coronary stents are inserted. However, it is very well documented that the response of any individual to these drugs is highly variable, and that the patients who don't respond as well to them are at increased risk of having clot events in their coronary arteries. On the other hand, people who respond to the drugs very sensitively have a higher bleeding risk. Despite these observations, there is no attempt to test the response of individuals patients to their antiplatelet drugs in routine practice. This review article looks in detail and whether the currently used strategy of "One size fits all" should be changed, given that there may well now be the chance to perform routine testing on everyone, and personalize their treatment accordingly.

In vitro protamine addition for coagulation assessment using TEG 6s system during cardiopulmonary bypass: a pilot study.

OBJECTIVE: Systemic heparinization during cardiopulmonary bypass (CPB) can significantly affect thromboelastography (TEG). This study investigated the feasibility of adding protamine in vitro to allow assessment of coagulation status using the TEG 6s system during CPB. METHODS: In this prospective observational study, 21 patients undergoing elective cardiac valve surgery were evaluated. During CPB, protamine was added in vitro to the heparinized blood of these patients at a concentration of 0.05 mg/mL and analyzed with the TEG 6s (Pre). The TEG parameters were compared to those analyzed after CPB withdrawal and systemic protamine administration (Post). RESULTS: The citrated kaolin maximal amplitude (CK-MA) and the citrated functional fibrinogen maximal amplitude (CFF-MA) exhibited strong correlations between Pre and Post measurements (r = 0.790 and 0.974, respectively, P < 0.001 for both), despite significant mean differences (-2.23 mm for CK-MA and -0.68 mm for CFF-MA). Bland-Altman analysis showed a clinically acceptable agreement between Pre and Post measurement of CK-MA and CFF-MA (the percentage error was 10.6% and 12.2%, respectively). In contrast, the citrated kaolin reaction time (CK-R) showed no significant correlation between Pre and Post measurements (r = 0.328, P = 0.146), with a mean difference of 1.42 min (95% CI: -0.45 to 3.29). CONCLUSIONS: In vitro protamine addition allows assessment of coagulation status during CPB using the TEG 6s system. CK-MA and CFF-MA measured during CPB using this method revealed a strong correlation and agreement with post-CPB measurements, suggesting that our method potentially facilitates early prediction of post-CPB coagulation status and decision-making on transfusion strategies. CLINICAL TRIAL REGISTRATION: The study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR, registration number: UMIN000041097, date of registration: July 13, 2020, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000046925 ) before the recruitment of participants.

Validity and Utility of Early Parameters in TEG6s Platelet Mapping to Assess the Coagulation Status During Cardiovascular Surgery With Cardiopulmonary Bypass.

Background The aim of this retrospective observational study was to explore the early predictive parameters for maximum amplitudein the kaolin with heparinase (HKH) assay (MAHKH) of TEG6s Platelet Mapping in cardiovascular surgery including cardiopulmonary bypass (CPB) period. The relationship between each parameter of the assay and laboratory data was also assessed. Methods We included the patients who underwent TEG6s Platelet Mapping during cardiovascular surgery under CPB between November 2021 and May 2022. The correlation between MAHKH and the early parameters was assessed. The association between each parameter of Platelet Mapping and a combination of fibrinogen concentration > 150 mg/dL and platelet count > 100,000µL was also evaluated by the receiver operating characteristic (ROC) curve. Results In 23 patients who underwent TEG6s Platelet Mapping during the study period, 62 HKH assay data including 59 pairs of data (HKH assay and laboratory data) were analyzed. K and angle, but not R, were significantly correlated with MAHKH (r [95% CI]: -0.90 [-0.94, -0.83], p < 0.0001 for K, and 0.87 [0.79, 0.92], p < 0.0001 for angle). Furthermore, ROC curves suggested that these parameters predicted a combination of fibrinogen concentration > 150 mg/dL and platelet count > 100,000/µL with high accuracy. Similar results were confirmed in the heparinized blood samples obtained during CPB. Conclusion These findings suggest that not only MAKHK but also K and angle, which are early parameters in the HKH assay, provide clinically significant information that will facilitate rapid decision-making regarding coagulation strategies during cardiovascular surgery including the CPB period.

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.

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.

Comparison between the Rotational Thromboelastometry (ROTEM) Delta device against the Cartridge-based Thromboelastography 6s and Quantra in a healthy third trimester pregnant cohort.

Rotational Thromboelastometry (ROTEM) Delta has been described in several postpartum hemorrhage algorithms, but this device requires pipetting and careful mixing of reagents to initiate the clotting reaction. In contrast, thromboelastography (TEG 6s) and the Quantra devices operate utilizing an automated pre-mixed cartridge that only requires a blood sample to start the clot strength analysis. We compared the correlation between 3 point of care viscoelastic testing (POCVT) devices to laboratory Clauss fibrinogen and platelets, their inter-device correlation, and the total running time difference between Quantra and ROTEM. A high correlation was noted between the Clauss fibrinogen and the fibrinogen parameters from ROTEM (r = 0.76-0.84, P < 0.0001), TEG6s (r = 0.71, P < 0.0001) and Quantra (r = 0.72, P = 0.0001). A moderate correlation between laboratory platelets and the ROTEM (r = 0.54;0.45, P < 0.0001; P = 0.0013) and Quantra (r = 0.66, P = 0.0001) parameters was noted. The inter-device correlation showed to be high when comparing the fibrinogen parameters of TEG6s and Quantra to that of ROTEM (r = 0.88 and 0.74, P < 0.0001, respectively). In contrast, a moderate correlation was noted between the platelet parameters of Quantra and ROTEM (r = 0.51, p = 0.0036). The Quantra device resulted 20.9 min (95% CI -0.2 to 4.7, P = 0.07) faster than the ROTEM if the warming and pipetting of reagents of the latter were considered. All the POCVT devices demonstrated a high correlation to laboratory Clauss fibrinogen, making each beneficial for the early recognition and management of hypofibrinogenemia.

Changes of Coagulation and Fibrinolytic Status Detected by Thromboelastography (TEG6s®) in Pregnancy, Labor, Early Postpartum, Postpartum Hemorrhage and Heparin Treatment for Perinatal Venous Thrombosis.

The aims of this study are to evaluate coagulation and fibrinolytic features using TEG6s® in normal pregnant courses, in the early postpartum period and in cases with postpartum hemorrhage (PPH) caused by uterine atony. We also analyze cases with deep venous thrombosis (DVT) and/or pulmonary embolism (PE) under treatment with unfractionated heparin. The non-pregnant women (n = 13) and healthy pregnant women (at 9-13 weeks of gestation (n = 13), at 27-30 weeks of gestation (n = 14), at 35-38 weeks of gestation (n = 14)) were cross-sectionally studied, while the normal pregnant women at delivery (n = 14) were sequentially investigated. Blood samples from those patients with PPH (n = 15) and DVT and/or PE (n = 11) were also obtained and compared with those of normal women. Significant changes of clot formation parameters were observed in all parameters and, interestingly, fibrinolytic parameter (LY30) was maintained at a low value even within 120 min after placental delivery (median of LY30; 0) and also in cases with uterine atony (median of LY30; 0.1). The parameter that indicates the effectiveness of heparin showed strong correlation (R = 0.788) with activated partial thromboplastin time. Thromboelastography may be less sensitive to fibrinolysis in the conditions of uterine atonic bleeding.

Comparison of assessment of coagulation in healthy dogs by the TEG 6s and TEG 5000 viscoelastic analyzers.

The TEG 6s (Haemonetics) point-of-care viscoelastic analyzer is portable, compact, simple to use, and has the potential for rapid viscoelastic analysis that can guide the treatment of veterinary patients at the site of care. Although approved for use in people, the TEG 6s has yet to be evaluated for hemostatic analysis in veterinary medicine. Citrated whole blood (CWB) was collected from 27 healthy dogs. An aliquot of CWB from each dog was diluted by 33% with an isotonic crystalloid, representing an in vitro model of hemodilution. Unaltered and diluted CWB samples were analyzed using 2 TEG 6s and 6 TEG 5000 (Haemonetics) analyzers. The 6 TEG 5000 analyzers ran duplicate analyses of either unaltered or diluted samples using 1 of 3 reagents (Haemonetics): Kaolin TEG, RapidTEG, or TEG Functional Fibrinogen. Duplicate TEG 5000 analyses were averaged and compared with a single TEG 6s analysis. Lin concordance correlation coefficient and Bland-Altman plots were used to evaluate agreement of reaction time, kinetic time, alpha angle, maximum amplitude (MA), and G value (G) for samples activated with Kaolin TEG, and agreement of MA for samples activated with RapidTEG between the 2 machines. Overall, agreement between the TEG 6s and TEG 5000 analyzers was poor. Viscoelastic measurements by the TEG 6s and TEG 5000 in healthy dogs were not all interchangeable. Agreement was satisfactory only for MA and G measurements of diluted blood samples activated with Kaolin TEG, and MA measurements for both unaltered and diluted blood samples activated with RapidTEG.

Utility of viscoelastography with TEG 6s to direct management of haemostasis during obstetric haemorrhage: a prospective observational study.

BACKGROUND: The TEG 6s is an automated cartridge-based device with limited description of use in obstetric haemorrhage. The aim of this analysis was to describe the utility of TEG 6s in identifying abnormal laboratory results of coagulation and platelet count, and inform an interventional treatment algorithm for postpartum haemorrhage. METHODS: A prospective observational cohort study of 521 women with moderate to severe obstetric haemorrhage (>1000 mL blood loss), including 372 women with at least one TEG 6s test. A non-pregnant control group was used for reference. TEG 6s test parameters Citrated Functional Fibrinogen (CFF), Citrated Kaolin TEG (CK) and Citrated Rapid TEG (CRT) were compared with paired laboratory tests of fibrinogen, PT/aPTT and platelet count, obtained during haemorrhage. RESULTS: Among 456 TEG 6s tests, 389 were matched with laboratory coagulation results. The receiver operator characteristic area-under-the-curve (95% CI) for CFF amplitude by 10 min to detect Clauss fibrinogen ≤2 g/L was 0.95 (0.91 to 0.99) (P<0.0001, sensitivity 0.74 and specificity 0.97 at ≤17 mm). False positives had median (IQR) Clauss fibrinogen of 2.4 (2.3-2.7) g/L. The CK-R time had some utility for detecting prolonged PT/aPTT, however a threshold for fresh frozen plasma transfusion was not established. A CRT maximum amplitude <57 mm, when CFF was ≥15 mm, identified four of eight samples with platelet count <75 × 109/L. CONCLUSION: The TEG 6s CFF can be used to identify low fibrinogen during obstetric haemorrhage. A value to identify transfusion thresholds for PT/aPTT and platelets was not established, and laboratory results should continue to be used.

Site-Of-Care Viscoelastic Assay in Major Trauma Improves Outcomes and Is Cost Neutral Compared with Standard Coagulation Tests.

Major hemorrhage is often associated with trauma-induced coagulopathy. Targeted blood product replacement could achieve faster hemostasis and reduce mortality. This study aimed to investigate whether thromboelastography (TEG®) goal-directed transfusion improved blood utilization, reduced mortality, and was cost effective. Data were prospectively collected in a U.K. level 1 trauma center, in patients with major hemorrhage one year pre- and post-implementation of TEG® 6s Hemostasis Analyzers. Mortality, units of blood products transfused, and costs were compared between groups. Patient demographics in pre-TEG (n = 126) and post-TEG (n = 175) groups were similar. Mortality was significantly lower in the post-TEG group at 24 h (13% vs. 5%; p = 0.006) and at 30 days (25% vs. 11%; p = 0.002), with no difference in the number or ratio of blood products transfused. Cost of blood products transfused was comparable, with the exception of platelets (average £38 higher post-TEG). Blood product wastage was significantly lower in the post-TEG group (1.8 ± 2.1 vs. 1.1 ± 2.0; p = 0.002). No statistically significant difference in cost was observed between the two groups (£753 ± 651 pre-TEG; £830 ± 847 post-TEG; p = 0.41). These results demonstrate TEG 6s-driven resuscitation algorithms are associated with reduced mortality, reduced blood product wastage, and are cost neutral compared to standard coagulation tests.

Prospective Longitudinal Evaluation of Coagulation with Novel Thromboelastography Technology in Patients After Subarachnoid Hemorrhage: A Pilot Study.

BACKGROUND: There is limited knowledge of whether hypercoagulability is present after subarachnoid hemorrhage (SAH) or about its timing of onset, duration, and severity. To conduct a pilot new-generation thromboelastography (TEG) technology (TEG6s)-based and conventional coagulation test-supported longitudinal assessment of coagulation in patients with SAH. METHODS: We prospectively enrolled patients with nontraumatic SAH on admission from May 2015 to May 2016. We performed TEG6s measurements and conventional coagulation tests on days 1, 2, 3, 5, 7, 10, and 14 and compared them with TEG6s parameters in healthy volunteers. RESULTS: We studied 14 patients and 72 TEG6s measurements. Of these patients, 10 (71.4%) were admitted to the intensive care unit. Mean age was 57.5 (±14.5) years, Acute Physiology and Chronic Health Evaluation III score 58.2 (±26.6), length of hospital stay was 23 (±11.7) days, and mortality was 14.3%. At baseline, conventional coagulation tests were within normal range. However, TEG6s parameters already showed increased coagulability. Thereafter, alpha angle, reaction time, functional fibrinogen level, and maximum amplitude rapidly and significantly increased (P < 0.01) compared with healthy controls. Ten (71.4%) patients demonstrated a >20% increase in coagulability based on TEG6s parameters from their baseline. Moreover, TEG6s hypercoagulability peaked at day 10 and only showed an initial partial decline towards normal by day 14. Similarly, platelet counts and fibrinogen levels increased over this period (P < 0.01) CONCLUSIONS: Using TEG6s technology, we found significant and progressive hypercoagulability in 70% of patients, with an early dominant contribution from hyperfibrinogenemia and increased fibrin formation and partial contribution from thrombocytosis, beginning on the first day, increasing to peak values by day 10, and then partly declining toward normal by day 14.

Determination of non-Vitamin K oral anticoagulant (NOAC) effects using a new-generation thrombelastography TEG 6s system.

Non vitamin K oral anticoagulants (NOACs) do not require regular monitoring but information about their pharmacodynamic effect may be importantin situations like trauma, stroke oremergent surgery. Currently, no standardized point-of-care test is available to evaluate the anticoagulant effects of NOACs. We evaluated the anticoagulant effect of NOACs with the next generation point-of-care TEG assay (TEG® 6S) based on a fully-automated thrombelastography system. We used two TEG® 6S assays, the DTI assay and Anti-Factor Xa (AFXa) assay, to detect anticoagulant effects and classify NOACs. Blood from healthy volunteers (n = 26) was used to obtain a baseline reference range. Data derived from patients on factor Xa inhibitors (FXi) (rivaroxaban and apixaban) (n = 39), and direct thrombin inhibitors (DTIs) (dabigatran) (n = 25) were compared against the reference range for detection of drug effect and drug classification. TEG®6s R-time highly correlated to each NOAC. Presence of NOACs caused elongation of R-time on the AFXa assay compared to the reference range (4.3 ± 1.7 vs. 1.3 ± 0.3 min. for FXi, p < 0.001 and 3.5 ± 1.2 vs. 1.3 ± 0.3 min. for DTI, p < 0.001). R-time on the DTI assay was elongated only in presence of a DTI (3.4 ± 1.0 vs. 1.5 ± 0.2 min, p < 0.001). The cutoff for detection of a DTI effect was an R time of 1.9 min and for anti-Xa effect was 1.95 min. For detection of NOAC therapy, there was ≥92% sensitivity and ≥95% specificity. The automated TEG®6s NOAC assay may be an effective tool to identify an anticoagulant effect from NOAC therapy and facilitate care of patients with bleeding or at risk of bleeding in the event of needing emergency surgery.