Optimal management of cardiac surgery patients using direct oral anticoagulants: recommendations for clinical practice.

OBJECTIVES: Literature is scarce on the management of patients using direct oral anticoagulants (DOACs) undergoing elective, urgent and emergency surgery. Therefore, we summarize the current evidence and provide literature-based recommendations for the management of patients on DOACs in the perioperative phase. METHODS: A general literature review was conducted on the pharmacology of DOACs and for recommendations on the management of cardiac surgical patients on DOACs. Additionally, we performed a systematic review for studies on the use of direct DOAC reversal agents in the emergency cardiac surgical setting. RESULTS: When surgery is elective, the DOAC cessation strategy is relatively straightforward and should be adapted to the renal function. The same approach applies to urgent cases, but additional DOAC activity drug level monitoring tests may be useful. In emergency cases, idarucizumab can be safely administered to patients on dabigatran in any of the perioperative phases. However, andexanet alfa, which is not registered for perioperative use, should not be administered in the preoperative phase to reverse the effect of factor Xa inhibitors, as it may induce temporary heparin resistance. Finally, the administration of (activated) prothrombin complex concentrate may be considered in all patients on DOACs, and such concentrates are generally readily available. CONCLUSIONS: DOACs offer several advantages over vitamin K antagonists, but care must be taken in patients undergoing cardiac surgery. Although elective and urgent cases can be managed relatively straightforwardly, the management of emergency cases requires particular attention.

Hemostasis and fibrinolysis in COVID-19 survivors 6 months after intensive care unit discharge.

BACKGROUND: The prothrombotic phenotype has been extensively described in patients with acute coronavirus disease 2019 (COVID-19). However, potential long-term hemostatic abnormalities are unknown. OBJECTIVE: To evaluate the changes in routine hemostasis laboratory parameters and tissue-type plasminogen activator (tPA) rotational thromboelastometry (ROTEM) 6 months after COVID-19 intensive care unit (ICU) discharge in patients with and without venous thromboembolism (VTE) during admission. METHODS: Patients with COVID-19 of the Maastricht Intensive Care COVID cohort with tPA ROTEM measurement at ICU and 6-month follow-up were included. TPA ROTEM is a whole blood viscoelastic assay that illustrates both clot development and fibrinolysis due to simultaneous addition of tissue factor and tPA. Analyzed ROTEM parameters include clotting time, maximum clot firmness (MCF), lysis onset time (LOT), and lysis time (LT). RESULTS: Twenty-two patients with COVID-19 were included and showed extensive hemostatic abnormalities before ICU discharge. TPA ROTEM MCF (75 mm [interquartile range, 68-78]-59 mm [49-63]; P ≤ .001), LOT (3690 seconds [2963-4418]-1786 seconds [1465-2650]; P ≤ .001), and LT (7200 seconds [6144-7200]-3138 seconds [2591-4389]; P ≤ .001) normalized 6 months after ICU discharge. Of note, eight and four patients still had elevated fibrinogen and D-dimer concentrations at follow-up, respectively. In general, no difference in median hemostasis parameters at 6-month follow-up was observed between patients with (n=14) and without (n=8) VTE, although fibrinogen appeared to be lower in the VTE group (VTE-, 4.3 g/L [3.7-4.7] vs VTE+, 3.4 g/L [3.2-4.2]; P = .05). CONCLUSIONS: Six months after COVID-19 ICU discharge, no persisting hypercoagulable or hypofibrinolytic profile was detected by tPA ROTEM. Nevertheless, increased D-dimer and fibrinogen concentrations persist up to 6 months in some patients, warranting further exploration of the role of hemostasis in long-term morbidity after hospital discharge.

Shifts of Transfusion Demand in Cardiac Surgery After Implementation of Rotational Thromboelastometry-Guided Transfusion Protocols: Analysis of the HEROES-CS (HEmostasis Registry of patiEntS in Cardiac Surgery) Observational, Prospective Open Cohort Database.

OBJECTIVES: Rotational thromboelastometry (ROTEM)-guided transfusion algorithms in cardiac surgery have been proven to be successful in reducing blood loss in randomized controlled trials. Using an institutional hemostasis registry of patients in cardiac surgery (HEROES-CS), the authors hypothesized that the use of ROTEM-guided transfusion algorithms would save blood products and overall costs in cardiac surgery in every day practice. DESIGN: Observational, prospective open cohort database. SETTING: Single-center academic hospital. PARTICIPANTS: Cardiac surgery patients. INTERVENTIONS: Implementation of ROTEM-guided bleeding management. MEASUREMENTS AND MAIN RESULTS: A classical-guided algorithm and a ROTEM-guided algorithm were used for patient blood management in 2 cohorts. Primary outcome was the use and amount of blood products and hemostatic medication. Secondary outcomes were amount of rethoracotomies, length of stay, and 30-day mortality. Finally, costs and savings were calculated. The classical-guided cohort comprised 204 patients, and ROTEM-guided cohort comprised 151 patients. Baseline characteristics showed excellent similarities after propensity score matching of 202 patients. Blood loss was lower after ROTEM guidance (p < 0.001). Absolute risk reduction was 17% for red blood cells (p = 0.024), 12% for fresh frozen plasma (p = 0.019), and 4% for thrombocyte concentrates (p = 0.582). More tranexamic acid was given, but not more fibrinogen concentrate, while desmopressin was given less often. Hospital length of stay was reduced by an overall median of 2 and a mean of 4 days (p < 0.001). Mortality and rethoracotomy rates were not affected. Potential savings were about €4,800 ($5,630) per patient. CONCLUSIONS: Implementation of a ROTEM-guided transfusion algorithm in cardiac surgery patients reduced the use of blood products and hemostatic medication, hereby saving costs. Reductions in mortality and rethoracotomy rates could not be found.

Assessment and determinants of whole blood and plasma fibrinolysis in patients with mild bleeding symptoms.

Enhanced clot lysis is associated with bleeding, but assessment of lysis capacity remains difficult. The plasma turbidity lysis and whole blood tissue Plasminogen Activator-Rotational Thromboelastometry (tPA-ROTEM) assays estimate fibrinolysis under more physiological conditions than clinically used assays. We hypothesized that these assays could find signs of enhanced lysis capacity in patients who report bleeding symptoms, but are not diagnosed with bleeding disorders. We also aimed to gain insight in determinants of the results of these lysis assays. Data from 240 patients with and 95 patients without self-reported bleeding symptoms were obtained, who were included in a study that primarily aimed to assess prevalence of haemostatic abnormalities in preoperative patients. ROTEM and turbidity assays were performed with rtPA. Blood counts, fibrinolysis and coagulation factor activities were determined. Data were analysed using multivariable linear regression models. Remarkably, patients reporting bleeding symptoms showed signs of significantly impaired lysis capacity in the tPA-ROTEM, but not in the turbidity lysis assay. In these patients, the tPA-ROTEM results depended on FII, FXII, plasminogen, α2-antiplasmin, PAI-1 and TAFI levels. The turbidity lysis results were significantly influenced by fibrinogen, α2-antiplasmin, PAI-1 and TAFI. In conclusion, the tPA-ROTEM and the turbidity lysis assay could not detect enhanced fibrinolytic capacity in patients with bleeding symptoms. This suggests that these symptoms are not caused by enhanced fibrinolytic activity. As both assays were sensitive to important determinants of fibrinolysis they may be able to detect a fibrinolytic imbalance, but this needs to be validated in patients with known hypo- or hyperfibrinolytic disorders.

Preoperative screening for bleeding disorders: A comprehensive laboratory assessment of clinical practice.

BACKGROUND: Patients with mild bleeding disorders are at risk of perioperative bleeding, but screening for these disorders remains challenging. OBJECTIVES: We aimed to assess the prevalence of hemostatic abnormalities in patients with and without reported bleeding symptoms on a preoperative questionnaire, consisting of guideline-proposed questions, and appraised the diagnostic value of several screening modalities for the identification of patients with hemostatic abnormalities. METHODS: In this observational study, 240 patients with and 95 patients without bleeding symptoms on the preoperative questionnaire were included. Patients with known bleeding disorders, antithrombotic drugs, thrombocytopenia, and anemia were excluded. Preoperatively, all patients underwent elaborate hemostatic testing. Hemostatic abnormalities were defined as coagulation, vWF, or fibrinolysis factor levels below reference range and platelet function defects. Screening modalities included the ISTH Bleeding Assessment Tool (ISTH-BAT), PT, aPTT, TT, Euglobulin Lysis Time (ELT), and Platelet Function Analyser (PFA). RESULTS: In 21 of 240 (8.8%) patients reporting bleeding symptoms, hemostatic abnormalities were found, including 7 reduced coagulation factor levels, 10 platelet function abnormalities, and 4 reduced vWF levels. In comparison, 10 of 95 (10.5%) patients not reporting bleeding symptoms had abnormalities. The ISTH-BAT could not identify patients with abnormalities, while PT, aPTT, TT, ELT, and PFA had high specificity but low sensitivity to detect abnormalities. CONCLUSIONS: The prevalence of hemostatic abnormalities in both patients with and without reported bleeding symptoms was 9%-10%. This suggests that the guideline-based questionnaire cannot differentiate between patients with and without abnormalities, while the discriminative power of the screening modalities is also limited.

Routine haemostasis testing before transplanted kidney biopsy: a cohort study.

Kidney biopsy can result in bleeding complications. Prebiopsy testing using bleeding time (BT) is controversial. New whole blood haemostasis tests, such as platelet function analyser-100 (PFA-100) and multiple electrode aggregometry (MEA), might perform better. We postulated that PFA-100 would be suitable to replace BT prebiopsy. In 154 patients, transplanted kidney biopsies were performed after measurement of bleeding time, PFA-100, MEA and mean platelet volume (MPV). Bleeding outcome (haemoglobin (Hb) drop, haematuria (±bladder catheterization), ultrasound finding of a bleeding, need for (non)surgical intervention and/or transfusion) after the biopsy was correlated to each test. Male-female ratio was 2:1. 50% had a surveillance biopsy at either three or 12 months. Around 17% (had) used acetylsalicylic acid (ASA) prebiopsy. Of 17 bleeding events, one subject needed a transfusion. Most bleeding events were Hb reductions over 1 mmol/l and all resolved uneventful. BT, PFA-100, MEA and MPV did not predict a bleeding outcome; prior ASA use however could (odds ratio 3.19; 95%-CI 1.06 to 9.61). Diagnostic performance data and Bland-Altman analysis showed that BT could not be substituted by PFA-100. ASA use was the best determinant of bleeding after kidney biopsy. Routine haemostasis testing prebiopsy has no added value.

The use of regression analysis in determining reference intervals for low hematocrit and thrombocyte count in multiple electrode aggregometry and platelet function analyzer 100 testing of platelet function.

Low platelet counts and hematocrit levels hinder whole blood point-of-care testing of platelet function. Thus far, no reference ranges for MEA (multiple electrode aggregometry) and PFA-100 (platelet function analyzer 100) devices exist for low ranges. Through dilution methods of volunteer whole blood, platelet function at low ranges of platelet count and hematocrit levels was assessed on MEA for four agonists and for PFA-100 in two cartridges. Using (multiple) regression analysis, 95% reference intervals were computed for these low ranges. Low platelet counts affected MEA in a positive correlation (all agonists showed r2 ≥ 0.75) and PFA-100 in an inverse correlation (closure times were prolonged with lower platelet counts). Lowered hematocrit did not affect MEA testing, except for arachidonic acid activation (ASPI), which showed a weak positive correlation (r2 = 0.14). Closure time on PFA-100 testing was inversely correlated with hematocrit for both cartridges. Regression analysis revealed different 95% reference intervals in comparison with originally established intervals for both MEA and PFA-100 in low platelet or hematocrit conditions. Multiple regression analysis of ASPI and both tests on the PFA-100 for combined low platelet and hematocrit conditions revealed that only PFA-100 testing should be adjusted for both thrombocytopenia and anemia. 95% reference intervals were calculated using multiple regression analysis. However, coefficients of determination of PFA-100 were poor, and some variance remained unexplained. Thus, in this pilot study using (multiple) regression analysis, we could establish reference intervals of platelet function in anemia and thrombocytopenia conditions on PFA-100 and in thrombocytopenia conditions on MEA.

Early platelet recovery following cardiac surgery with cardiopulmonary bypass.

Coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) is frequently associated with low platelet count (PC) and disturbed platelet function (PF). While PC is easy to measure, PF is more difficult to assess. Moreover, the time-related platelet dysfunction and recovery after CPB is not fully elucidated. Platelet dysfunction could lead to bleeding but also to coronary graft failure. Laboratory tests could provide more insights into PF after CABG. The aim of the current study was to investigate the time-related PF induced by CPB. Blood samples of 20 patients with a preoperative PC of more than 250 × 109/L were collected before incision, after weaning from CPB, and 24 h postoperative. Platelet contribution to coagulation was quantified by PLTEM (calculated by means of EXTEM and FIBTEM results). PF was assessed by multiple electrode impedance aggregometry (MEIA) in whole blood and by light transmission aggregometry (LTA) in platelet-rich plasma after stimulation with arachidonic acid (AA), adenosine diphosphate, collagen, and thrombin-receptor-activating peptide. LTA and MEIA analysis demonstrated significant platelet dysfunction after CPB, with partial recovery within 24 h after surgery. AA-induced platelet aggregation increased to higher levels within 24 h after surgery compared to baseline values as measured by LTA. PLTEM maximum clot firmness remained unchanged throughout the study. Correlation analyses revealed that MEIA and rotational thromboelastometry (ROTEM), but not LTA, were dependent on PC and hematocrit. No correlations were found between LTA, MEIA, ROTEM, PC, and clinical outcome parameters. Our results demonstrate a reversible platelet dysfunction recovering within 24 h after CPB. Interestingly, AA-induced platelet aggregation increases to higher levels during the first 24 h postoperatively, which might be important for early initiation of antiplatelet therapy after CABG. MEIA as POC test is able to detect platelet dysfunction during cardiac surgery with a PC of ≥150 × 109/L.

Validation of a modified thromboelastometry approach to detect changes in fibrinolytic activity.

BACKGROUND: Thus far, validated whole blood assays used in in vitro fibrinolysis experiments using thromboelastometry (ROTEM) are lacking or have yet to be tested in humans. The objective was first, to establish a standardized modified ROTEM approach to detect both hypo- and hyperfibrinolysis. And second, to perform a technical and clinical validation of the assay. METHODS: Blood was used of healthy volunteers, patients with sepsis, patients after cardiothoracic surgery, pregnant women, and cirrhotic liver disease patients. A whole blood tissue factor (TF) activated ROTEM assay with and without the addition of recombinant tissue plasminogen activator (rTPA) was developed. Plasma fibrinolysis determinants were measured in all volunteers and patients. RESULTS: Thirty five pM TF and additions of 125 and 175 ng/ml rTPA resulted in full lysis within 60 min in healthy volunteers. Coefficients of variation were below 10 % without and below 20 % with rTPA addition. In sepsis the hypofibrinolytic ROTEM profiles with 175 ng/ml rTPA were in line with the plasma determinants (high PAI-1, high fibrinogen, low tPA activity, and high d-dimers). After cardiothoracic surgery, reduced fibrinogen and platelet levels accounted for the reduced maximum clot firmness. The hypofibrinolytic profile is attributed to tranexamic acid use and elevated PAI-1 levels. The lowest rTPA concentration in cirrhosis resulted in hyperfibrinolysis in only few of the patients. In pregnancy normal profiles were found. DISCUSSION: Our high rTPA concentration demonstrates hypofibrinolytic profiles adequately in sepsis and after cardiothoracic surgery. Our low rTPA concentration of 125 ng/ml seems too high for demonstrating hyperfibrinolysis in cirrhotic liver disease. CONCLUSIONS: We were able to present a validated whole blood ROTEM approach to fibrinolysis testing using added rTPA, which can be of added value next to classical plasma based fibrinolysis assays.

Rapid and correct prediction of thrombocytopenia and hypofibrinogenemia with rotational thromboelastometry in cardiac surgery.

OBJECTIVES: In the present study, the authors have investigated whether rotational thromboelastometry (ROTEM) could predict thrombocytopenia and hypofibrinogenemia in cardiac surgery using the clot amplitude after 5 minutes (A5). Another parameter, PLTEM, in which the contribution of fibrinogen is eliminated by subtracting a fibrin-specific ROTEM test (FIBTEM) from an extrinsically-activated ROTEM test (EXTEM), was investigated. Furthermore, the turnaround time of ROTEM was compared to conventional laboratory tests. DESIGN: Prospective cohort study. SETTING: Single academic medical center. PARTICIPANTS: Ninety-seven patients undergoing cardiac surgery between July 2011 until August 2012. INTERVENTIONS: The correlations between EXTEM/FIBTEM A5, A10, and maximal clot formation (MCF), EXTEM/PLTEM (A5/A10, and MCF) and platelet count, and FIBTEM (A5/A10, and MCF) and fibrinogen were evaluated using the Pearson's correlation coefficient and receiver-operating characteristic curves. Turnaround times of ROTEM tests and conventional laboratory tests were assessed in the central laboratory. MEASUREMENTS AND MAIN RESULTS: EXTEM A5 and FIBTEM A5 showed an excellent correlation with A10 (R:0.99/1.00) and MCF (R:0.97/0.99). The correlation between EXTEM A5 and platelet count (R:0.74) was comparable with the correlation of A10 (R:0.73) and MCF (R:0.70) with platelet count. FIBTEM A5 predicted fibrinogen levels (R:0.87) as well as A10 (R:0.86) and MCF (R:0.87). PLTEM A5 (R:0.85) correlated better with platelet count than EXTEM A5 (R:0.74; p = 0.04) and showed significantly better area under the curve values than EXTEM for predicting thrombocytopenia (A5 p = 0.012, A10 p = 0.019). Turnaround time for ROTEM tests, 12 minutes, was comparable with emergency requests for platelet count, 13 minutes, and shorter than emergency requests for fibrinogen levels, 37 minutes. CONCLUSIONS: Implementation of PLTEM and FIBTEM A5 in ROTEM-guided transfusion protocols may improve transfusion management.

The effects of pneumatic tube system transport on ROTEM analysis and contact activation assessed by thrombin generation test.

UNLABELLED: Thromboelastometry (ROTEM) is a popular point-of-care test. It generates results quickly and may benefit individualised guided haemostatic therapy. However, processing of specimens by non-technicians might decrease the quality and reproducibility of results. Centralised laboratory equipment receiving specimens through a pneumatic tube system (PTS) could avoid this. This study aimed to evaluate the influence of PTS transport on ROTEM results and its contribution to contact activation assessed by thrombin generation (TG). METHODS: Specimens from 44 patients were drawn immediately after arterial puncture. Two were anticoagulated by citrate and two by citrate/corn trypsin inhibitor, a Factor XIIa pathway inhibitor. Both types of samples were transported by walking and PTS. Subsequently, analysis was performed: ROTEM on citrated blood, and TG on citrated and corn trypsin inhibitor (CTI) blood using either 0 or 1 pM tissue factor (TF). RESULTS: In ROTEM analysis the NATEM assay showed significant differences. The EXTEM assay revealed small significant differences for clot formation time: 65 seconds (SD ± 20) versus 67 seconds (SD ± 17), and alpha angle 79° (SD ± 3) versus 77° (SD ± 3). The results remained within reference range. TG was not significantly affected by the type of tube transport, independent of the amount of TF. CONCLUSION: PTS for ROTEM analysis is feasible except for NATEM assays. The amount of contact activation via Factor XIIa in terms of TG is independent of transport type. However, due to the different characteristics of pneumatic systems, hospitals should check its impact on the results before introducing this route of transport.

The procoagulant effects of fine particulate matter in vivo.

Inhalation of fine particulate matter (<2.5 µm; fine PM) has been shown to increase the risk for cardiovascular events. In this letter, we reappraise the role of tissue factor (TF) antigen and we also summarize changes in measured coagulation proteins in humans and rodents by other studies with fine PM. By considering all studies including ours, we conclude that monitoring the overall coagulation state by measuring capacity assays such as thrombin generation, and quantification of TF activity would be more suitable than determining single coagulation proteins (such as TF antigen) in order to better assess the systemic prothrombotic effects of fine PM.

Platelet monitoring follow-up in a pregnant patient with HELLP syndrome.

Monitoring the course of platelet function in HELLP (haemolysis, elevated liver-enzymes and low platelets) syndrome is important for clinical decision-making. We present a primigravid woman developing HELLP syndrome at 29 weeks and 6 days. Platelet function was monitored by multiple electrode aggregometry (MEA), platelet function analyzer (PFA-100®), platelet count and mean platelet volume (MPV) over an 11-day period. MPV and PFA-100® seem better predictors for platelet function than platelet levels.