Early Goal-Directed Hemostatic Therapy for Severe Acute Bleeding Management in the Intensive Care Unit: A Narrative Review.

This is a narrative review of the published evidence for bleeding management in critically ill patients in different clinical settings in the intensive care unit (ICU). We aimed to describe "The Ten Steps" approach to early goal-directed hemostatic therapy (EGDHT) using point-of-care testing (POCT), coagulation factor concentrates, and hemostatic drugs, according to the individual needs of each patient. We searched National Library of Medicine, MEDLINE for publications relevant to management of critical ill bleeding patients in different settings in the ICU. Bibliographies of included articles were also searched to identify additional relevant studies. English-language systematic reviews, meta-analyses, randomized trials, observational studies, and case reports were reviewed. Data related to study methodology, patient population, bleeding management strategy, and clinical outcomes were qualitatively evaluated. According to systematic reviews and meta-analyses, EGDHT guided by viscoelastic testing (VET) has been associated with a reduction in transfusion utilization, improved morbidity and outcome in patients with active bleeding. Furthermore, literature data showed an increased risk of severe adverse events and poor clinical outcomes with inappropriate prophylactic uses of blood components to correct altered conventional coagulation tests (CCTs). Finally, prospective, randomized, controlled trials point to the role of goal-directed fibrinogen substitution to reduce bleeding and the amount of red blood cell (RBC) transfusion with the potential to decrease mortality. In conclusion, severe acute bleeding management in the ICU is still a major challenge for intensive care physicians. The organized and sequential approach to the bleeding patient, guided by POCT allows for rapid and effective bleeding control, through the rational use of blood components and hemostatic drugs, since VET can identify specific coagulation disorders in real time, guiding hemostatic therapy with coagulation factor concentrates and hemostatic drugs with individual goals.

Prospective assessment of platelet function in patients undergoing elective resection of glioblastoma multiforme.

This prospective study was aimed to test changes in hemostasis in patients with GBM, occurring at baseline (before surgery, time 0, T0) and 2 (T2), 24 (T24), and 48-hour (T48) after surgery. We enrolled consecutive patients subjected to GBM resection (GBR group; N = 60), laparoscopic colon cancer resection (comparative CCR group; N = 40), and healthy blood donors (HBD group; N = 40). We performed 1. conventional coagulation tests 2. ROTEM (rotational thromboelastometry) parameters and 3. platelet function tests, including PFA-200 closure time when stimulated by collagen/epinephrine (COL-EPI) and ROTEM platelet, using three different activators (arachnoid acid in ARATEM, adenosine diphosphate in ADPTEM, and thrombin receptor-activating peptide-6 in TRAPTEM). Variables associated with unfavorable 1-year clinical outcome were investigated, too. We observed in GBR patients that platelet aggregometry, as assessed by ROTEM platelet parameters, was significantly impaired along with a shortened closure time. These changes were evident from T0 to T48. A decreased area under the aggregation curve in TRAPTEM was associated with improved survival (adjusted odd ratio (95% CI), 1.03 (1.01-1.06)). This study suggests that patients with GBM presented a decreased platelet aggregation from before surgery and thorough the postoperative period. Decreased platelet aggregation improved clinical outcome.

What is the context? Glioblastoma has an impact on the platelet number and the functional state of platelets. Platelets can be activated by tumor cells, and platelets count and function may impact patient survival. It has been showed an association between thrombocytosis and a decreased overall survival, with a small reduction in glioma risk associated with the long-term use of low-dose aspirin.Platelet function before and during the perioperative period in patients with glioblastoma has not been systematically investigated. Limited data suggest that platelet function may be impaired before and throughout the perioperative period, and that impaired platelet function affects clinical outcome.What is new? In this prospective study, we systematically investigated how glioblastoma provokes systemic alterations of hemostasis. We enrolled 60 consecutive patients (sample size calculated) subjected to resection of glioblastoma multiforme, and other 40 consecutive patients undergoing laparoscopic resection of colon cancer, as a comparative group, in order to differentiate hemostasis and coagulation profiles of two tumors (glioblastoma and colon adenocarcinoma) with high prothrombotic power. Forty healthy volunteers were also included to establish local reference values.We performed 1. conventional coagulation tests 2. ROTEM (rotational thromboelastometry) parameters and 3. platelet function tests, including PFA-200 closure time when stimulated by collagen/epinephrine (COL-EPI) and ROTEM platelet, using three different activators (arachnoid acid in ARATEM, adenosine diphosphate in ADPTEM, and thrombin receptor-activating peptide-6 in TRAPTEM). Variables associated with unfavorable 1-year clinical outcome were investigated, too. All these analyses were carried out at baseline (T0, time 0, before surgery) and 2 (T2), 24(T24) and 48-hour (T48) after surgery.We observed in GBR patients that platelet aggregometry, as assessed by ROTEM platelet parameters, was significantly impaired along with a shortened closure time. These changes were evident from T0 to T48. A decreased area under the aggregation curve in TRAPTEM was associated with improved survival (adjusted odd ratio (95% CI), 1.03 (1.01­1.06)).What is the impact? This study provides further evidence that patients with GBM presented a decreased platelet aggregation from before surgery and thorough the postoperative period. Decreased platelet aggregation improved clinical outcome.The cut-offs obtained can potentially to provide risk stratification for clinical outcome and to be hypothesis generating research to be confirmed by RCTs.

Detection and quantification of perioperative heparin-like effects by rotational thromboelastometry in living-donor liver transplant recipients: A prospective observational study.

Background and Aims: Heparin-like effects (HLEs) can affect hemostasis during liver transplantation. The aim of this study was to assess the perioperative incidence and severity of HLE with rotational thromboelastometry (ROTEM) and activated partial thromboplastin time (aPTT). Material and Methods: ROTEM and aPTT were measured intraoperatively and on postoperative days (POD) 1, 3, and 7. HLE was identified if ROTEM INTEM/HEPTEM CT-ratio was >1.25 and severe forms of HLE when ratio was ≥2. Based on aPTT, HLE was defined when aPTT ratio was >1.25 (patient aPTT/control aPTT). Results: Thirty-eight recipients were included. Variable degrees of HLE were detected by aPTT-ratio and INTEM/HEPTEM CT ratio. No significant correlation existed between both ratios. Based on INTEM/HEPTEM CT ratio, HLE was detected in 7/38 during anhepatic phase, 19/38 post-reperfusion, 10/38 on POD1, 4/38 on POD3, and 0/38 on POD7. Four cases of severe HLE were identified by INTEM/HEPTEM CT ratio only in the anhepatic phase. Postoperative infusion of unfractionated heparin led to mild-moderate HLE on POD1 and 3 as evident by both tests. Red blood cell and plasma transfusion were higher with severe HLE (1350 ± 191 ml and 3558 ± 1407 ml). Composite adverse outcome of any complication or death within 3 months for patients without HLE, mild-moderate HLE, and severe HLE as detected by ROTEM was 27.8%, 42.9%, and 66.7%, respectively. Conclusion: INTEM/HEPTEM CT ratio was able to detect and quantify HLE as aPTT ratio. The ability of the INTEM/HEPTEM CT ratio to identify severe HLE earlier in the anhepatic phase needs to be studied in a larger population. HLE is self-limiting, but when identified in a severe form, it is associated with worse outcome.

Modified thromboelastometric tests provide improved sensitivity and specificity to direct oral anticoagulants compared to standard thromboelastometric tests in-vitro.

BACKGROUND: The detection of direct oral anticoagulants (DOACs) is still challenging but important in emergency patients. We recently demonstrated that modified thromboelastometry can detect rivaroxaban and dabigatran. Data on the detection rates of modified compared to standard thromboelastometric tests of apixaban and edoxaban, are missing. The aim of this in-vitro dose-effect-study was to add data on these DOACs and to evaluate thromboelastometric tests in-vitro using data of both studies. METHODS: The study was approved by the Ludwig-Maximilians-University ethics committee (No 17-525-2). Written informed consent was obtained from all individuals. Blood samples of healthy volunteers and samples of 10 volunteers for each DOAC were used. Blood samples were spiked with six different concentrations of edoxaban and apixaban (0ng/ml; 31.25ng/ml; 62.5ng/ml; 125ng/ml; 250 ng/ml; 500ng/ml). Modified tests (low-tissue-factor test TFTEM and ecarin-based test ECATEM) as well as standard tests (e.g. FIBTEM) analyzing extrinsic pathway of coagulation were used. Receiver operating characteristics analyzes were performed as well as regression analyzes. RESULTS: TFTEM CT correlated well with anti-Xa levels of apixaban and edoxaban (apixaban: r2 = 0.8064 p < 0.0001; edoxaban: r2 = 0.8603; p < 0.0001). The detection of direct FXa inhibitors (> 30 ng/mL) was successful with FIBTEM CT with a sensitivity and specificity of 81% and 90%, respectively. As expected, ECATEM CT was not prolonged by direct FXa-inhibitors due to its specificity for direct thrombin inhibitors. Again, TFTEM CT provided the highest sensitivity and specificity for the detection of direct FXa inhibitors with 96% and 95%, respectively. ECATEM test showed 100% sensitivity and 100% specificity for the detection of dabigatran. CONCLUSIONS: Our study presents modified thromboelastometric tests with improved detection of even low DOAC concentrations > 30 ng/mL, including apixaban in-vitro. The study thus complements the previously published data on dabigatran and rivaroxaban. Validation studies must confirm the results due to the explanatory design of this study.

Haemostasis patterns in patients with acute-on-chronic liver failure and acute decompensation of cirrhosis including thromboelastometric tests with and without the addition of Protac: a pilot study.

BACKGROUND: Thromboelastometry is considered the best method to assesses hemostasis in liver disease. Diagnostic performance could be improved by adding protein C activators such as thrombomodulin or Protac®. We assessed changes in ROTEM parameters after the addition of Protac® in patients with acute-on-chronic liver failure (ACLF), acute decompensation (AD), and healthy individuals (HI) to define different hemostasis patterns, considering standard and velocity ROTEM parameters, and assess whether Protac® can improve the definition of the pattern. METHODS: Pre-test, we investigated whether diluted EXTEM reagent improved the effect of Protac® on the clotting time (CT)-ratio with and without Protac®. Ten ACLF and 20 AD patients and 21 HI were included in the main study. RESULTS: Standard EXTEM was used in the main study. INTEM CFT, INTEM A5 (inverse), and INTEM TPI (inverse) were the parameters that best differentiated liver disease from HI (ROC AUC, 0.921, 0.906, and 0.928, respectively; all P-values < 0.001). Combining INTEM CFT with EXTEM LI60-ratio only slightly improved the diagnostic performance (ROC AUC, 0.948; P < 0.001). EXTEM LI60 and INTEM maxV-t were the parameters that best differentiated between ACLF and AD patients (ROC AUC, 0.743, P = 0.033; and 0.723, P = 0.050; respectively). Combining EXTEM LI60 + INTEM maxV-t moderately improved the diagnostic performance (ROC AUC, 0.81, P < 0.001). CONCLUSIONS: ROTEM velocity, fibrinolysis parameters and the indices calculated improve the diagnosis in combination with standard parameters (e.g., CFT and A5). Ratios calculated with and without Protac® (e.g., EXTEM LI60-ratio) only slightly increased the diagnostic performance in discriminating hemostasis patterns.

Point-of-care detection and differentiation of anticoagulant therapy - development of thromboelastometry-guided decision-making support algorithms.

BACKGROUND: DOAC detection is challenging in emergency situations. Here, we demonstrated recently, that modified thromboelastometric tests can reliably detect and differentiate dabigatran and rivaroxaban. However, whether all DOACs can be detected and differentiated to other coagulopathies is unclear. Therefore, we now tested the hypothesis that a decision tree-based thromboelastometry algorithm enables detection and differentiation of all direct Xa-inhibitors (DXaIs), the direct thrombin inhibitor (DTI) dabigatran, as well as vitamin K antagonists (VKA) and dilutional coagulopathy (DIL) with high accuracy. METHODS: Following ethics committee approval (No 17-525-4), and registration by the German clinical trials database we conducted a prospective observational trial including 50 anticoagulated patients (n = 10 of either DOAC/VKA) and 20 healthy volunteers. Blood was drawn independent of last intake of coagulation inhibitor. Healthy volunteers served as controls and their blood was diluted to simulate a 50% dilution in vitro. Standard (extrinsic coagulation assay, fibrinogen assay, etc.) and modified thromboelastometric tests (ecarin assay and extrinsic coagulation assay with low tissue factor) were performed. Statistical analyzes included a decision tree analyzes, with depiction of accuracy, sensitivity and specificity, as well as receiver-operating-characteristics (ROC) curve analysis including optimal cut-off values (Youden-Index). RESULTS: First, standard thromboelastometric tests allow a good differentiation between DOACs and VKA, DIL and controls, however they fail to differentiate DXaIs, DTIs and VKAs reliably resulting in an overall accuracy of 78%. Second, adding modified thromboelastometric tests, 9/10 DTI and 28/30 DXaI patients were detected, resulting in an overall accuracy of 94%. Complex decision trees even increased overall accuracy to 98%. ROC curve analyses confirm the decision-tree-based results showing high sensitivity and specificity for detection and differentiation of DTI, DXaIs, VKA, DIL, and controls. CONCLUSIONS: Decision tree-based machine-learning algorithms using standard and modified thromboelastometric tests allow reliable detection of DTI and DXaIs, and differentiation to VKA, DIL and controls. TRIAL REGISTRATION: Clinical trial number: German clinical trials database ID: DRKS00015704 .

Paving the way for E-vita open NEO hybrid prosthesis implantation for complex aortic arch disease in Asia-Pacific.

We report first in man implantations of the newly designed Evita-open-NEO hybrid prosthesis for complex aortic arch disease from three different countries in Asia-Pacific including instructions on how to proceed with perioperative coagulation management.

Monitoring of COVID-19-Associated Coagulopathy and Anticoagulation with Thromboelastometry.

INTRODUCTION: Thrombosis occurs frequently in COVID-19. While the exact mechanism is unclear, 3 processes seem to play important roles in sepsis-related thrombosis and mortality: tissue factor expression on circulating monocytes and microparticles, hypercoagulability (increased clot firmness), and hypofibrinolysis. Rotational thromboelastometry is a point-of-care viscoelastic technique that uses the viscoelastic properties of blood to monitor coagulation. Using various assays, viscoelastometry could monitor this triad of changes in severely ill, COVID-19-positive patients. Similarly, with the increased incidence of coagulopathy, many patients are placed on anticoagulants, making management more difficult depending on the agents utilized. Viscoelastometry might also be used in these settings to monitor anticoagulation status and guide therapy, as it has in other areas. CASE PRESENTATION: We present a case series of 6 patients with different stages of disease and different management plans. These cases occurred at the height of the pandemic in New York City, which limited testing abilities. We first discuss the idea of using the NaHEPTEM test as a marker of tissue factor expression in COVID-19. We then present cases where patients are on different anticoagulants and review how viscoelastometry might be used in a patient on anticoagulation with COVID-19. CONCLUSION: In a disease such as COVID-19, which has profound effects on hemostasis and coagulation, viscoelastometry may aid in patient triage, disease course monitoring, and anticoagulation management.

Patient blood management in India - Review of current practices and feasibility of applying appropriate standard of care guidelines. A position paper by an interdisciplinary expert group.

In a developing country like India, with limited resources and access to healthcare facilities, dealing with massive hemorrhage is a major challenge. This challenge gets compounded by pre-existing anemia, hemostatic disorders, and logistic issues of timely transfer of such patients from peripheral hospitals to centers with adequate resources and management expertise. Despite the awareness amongst healthcare providers regarding management modalities of bleeding patients, no uniform Patient Blood Management (PBM) or perioperative bleeding management protocols have been implemented in India, yet. In light of this, an interdisciplinary expert group came together, comprising of experts working in transfusion medicine, hematology, obstetrics, anesthesiology and intensive care, to review current practices in management of bleeding in Indian healthcare institutions and evaluating the feasibility of implementing uniform PBM guidelines. The specific intent was to perform a gap analysis between the ideal and the current status in terms of practices and resources. The expert group identified interdisciplinary education in PBM and bleeding management, bleeding history, viscoelastic and platelet function testing, and the implementation of validated, setting-specific bleeding management protocols (algorithms) as important tools in PBM and perioperative bleeding management. Here, trauma, major surgery, postpartum hemorrhage, cardiac and liver surgery are the most common clinical settings associated with massive blood loss. Accordingly, PBM should be implemented as a multidisciplinary and practically applicable concept in India in a timely manner in order to optimize the use the precious resource blood and to increase patients' safety.

COVID-19-Associated Coagulopathy and Inflammatory Response: What Do We Know Already and What Are the Knowledge Gaps?

Patients with coronavirus disease 2019 (COVID-19) frequently experience a coagulopathy associated with a high incidence of thrombotic events leading to poor outcomes. Here, biomarkers of coagulation (such as D-dimer, fibrinogen, platelet count), inflammation (such as interleukin-6), and immunity (such as lymphocyte count) as well as clinical scoring systems (such as sequential organ failure assessment [SOFA], International Society on Thrombosis and Hemostasis disseminated intravascular coagulation [ISTH DIC], and sepsis-induced coagulopathy [SIC] score) can be helpful in predicting clinical course, need for hospital resources (such as intensive care unit [ICU] beds, intubation and ventilator therapy, and extracorporeal membrane oxygenation [ECMO]) and patient's outcome in patients with COVID-19. However, therapeutic options are actually limited to unspecific supportive therapy. Whether viscoelastic testing can provide additional value in predicting clinical course, need for hospital resources and patient's outcome or in guiding anticoagulation in COVID-19-associated coagulopathy is still incompletely understood and currently under investigation (eg, in the rotational thromboelastometry analysis and standard coagulation tests in hospitalized patients with COVID-19 [ROHOCO] study). This article summarizes what we know already about COVID-19-associated coagulopathy and-perhaps even more importantly-characterizes important knowledge gaps.

Comparison of Two Different Fibrinogen Concentrates in an in vitro Model of Dilutional Coagulopathy.

INTRODUCTION: Fibrinogen concentrates are widely used to restore clot stability in situations of bleeding. Fibrinogen preparations are produced using different production methods, resulting in different compounds. Thus, different preparations might have a distinct impact on blood coagulation. We tested the effect of fibrinogen concentrates Haemocomplettan® (CSL Behring, Marburg, Germany) and fibryga® (Octapharma GmbH, Langenfeld, Germany) on the impairments induced by 60% dilutional coagulopathy in vitro. MATERIALS AND METHODS: The influence of the fibrinogen concentrates fibryga® and Haemocomplettan® on colloid (gelatine, hydroxyethyl starch [HES], albumin)-induced or crystalloid (Ringer's acetate)-induced dilutional coagulopathy was analysed using rotational thromboelastometry (ROTEM®) and standard laboratory tests. The following experimental conditions were analysed in vitro: whole blood, 60% dilution (40% blood and 60% diluent) ± 50 or 100 mg/kg-1 fibryga® or Haemocomplettan®, respectively. RESULTS: Dilution with either diluent resulted in prolonged clotting time (CT) in an extrinsic activated test (CTEXTEM) and decreased maximum clot firmness (MCFFIBTEM) as expressed, e.g., by gelatine: (59.5 s [62/54.8] vs. 95 s [102.8/86.8]; p < 0.001 and 14 mm [16/10.5] vs. 3 mm [4-3]; p < 0.001). Substitution after 60% dilution with HES resulted in no difference between the preparations, except for shorter thrombin time with fibryga® (14 s [15/14] vs. 18 s [18.8/17]; p = 0.0093; low dose). CTEXTEM was higher with Haemocomplettan® in a gelatine-induced dilution (51 s [54.5/47.5] vs. 63 s [71/60.3]; p = 0.0202; low dose) whereas thrombin time was lower with fibryga® (19.5 s [20.8/19] vs. 27 s [29/25.3]; p = 0.0017). In dilution with albumin, differences in CTEXTEM (69 s [76.5/66] vs. 56 s [57/53.3]; p = 0.0114; low dose) and thrombin time (18 s [18/17] vs. 24.5 s [25.8/24]; p = 0.0202; low dose) were seen. In dilution with crystalloid solution, again differences in CTEXTEM (53.5 s [57.8/53] vs. 45 s [47/43]; p = 0.035; low dose) and thrombin time (17 s [17/16] vs. 23.5 s [24/23]; p = 0.0014; low dose) were seen. Fibrinogen levels were more increased by high-dose substitution of both preparations. CONCLUSION: Based on this data it can be stated that both fibryga® and Haemocomplettan® had the same performance in our in vitro model except for CTEXTEM and thrombin time.

Platelet Reactivity in Patients on Aspirin and Clopidogrel Therapy Measured by a New Bedside Whole-Blood Assay.

Various tests are available for measuring on-treatment platelet reactivity. The pharmacologically most specific assays are time-consuming and elaborate. A highly specific and convenient assay would be desirable for clinical routine. In this pilot study, we aimed to examine the ability of a novel bedside whole-blood assay-ROTEM platelet-to evaluate platelet inhibition compared with established assays. Platelet reactivity was investigated in 93 patients. Forty-Seven patients were on permanent aspirin therapy and 46 on dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. We used ROTEM platelet impedance aggregometry (ROTEM-PTL), light transmission aggregometry (LTA), Multiplate electrode aggregometry (MEA) and vasodilator-stimulated phosphoprotein flow cytometry. Receiver operating characteristic (ROC) analyses showed ROTEM-PTL differentiates well between patients on medication and healthy individuals: aspirin: ROCAUC 0.99 (95% confidence interval, 0.97-1.01); P < 0.0001; DAPT treatment: ROCAUC 0.80 (95% confidence interval, 0.69-0.91); P < 0.001. Pearson regression analyses showed moderate correlations between assays. Aspirin: MEA versus ROTEM-PTL r = 0.435, P ≤ 0.001; LTA versus ROTEM-PTL r = 0.048, P = 0.180. DAPT: MEA versus ROTEM-PTL r = 0.398, P = 0.001; LTA versus ROTEM-PTL r = 0.409, P = 0.001; vasodilator-stimulated phosphoprotein versus ROTEM-PTL r = 0.164, P = 0.055. ROTEM platelet distinguished well between treated and healthy individuals but correlated moderately with other assays. Clinical trials are needed to investigate the ability of this new assay to identify patients at risk of adverse events.

Monitoring of argatroban and lepirudin anticoagulation in critically ill patients by conventional laboratory parameters and rotational thromboelastometry - a prospectively controlled randomized double-blind clinical trial.

BACKGROUND: Argatroban or lepirudin anticoagulation therapy in patients with heparin induced thrombocytopenia (HIT) or HIT suspect is typically monitored using the activated partial thromboplastin time (aPTT). Although aPTT correlates well with plasma levels of argatroban and lepirudin in healthy volunteers, it might not be the method of choice in critically ill patients. However, in-vivo data is lacking for this patient population. Therefore, we studied in vivo whether ROTEM or global clotting times would provide an alternative for monitoring the anticoagulant intensity effects in critically ill patients. METHODS: This study was part of the double-blind randomized trial "Argatroban versus Lepirudin in critically ill patients (ALicia)", which compared critically ill patients treated with argatroban or lepirudin. Following institutional review board approval and written informed consent, for this sub-study blood of 35 critically ill patients was analysed. Before as well as 12, 24, 48 and 72 h after initiation of argatroban or lepirudin infusion, blood was analysed for aPTT, aPTT ratios, thrombin time (TT), INTEM CT,INTEM CT ratios, EXTEM CT, EXTEM CT ratios and maximum clot firmness (MCF) and correlated with the corresponding plasma concentrations of the direct thrombin inhibitor. RESULTS: To reach a target aPTT of 1.5 to 2 times baseline, median [IQR] plasma concentrations of 0.35 [0.01-1.2] µg/ml argatroban and 0.17 [0.1-0.32] µg/ml lepirudin were required. For both drugs, there was no significant correlation between aPTT and aPTT ratios and plasma concentrations. INTEM CT, INTEM CT ratios, EXTEM CT, EXTEM CT ratios, TT and TT ratios correlated significantly with plasma concentrations of both drugs. Additionally, agreement between argatroban plasma levels and EXTEM CT and EXTEM CT ratios were superior to agreement between argatroban plasma levels and aPTT in the Bland Altman analysis. MCF remained unchanged during therapy with both drugs. CONCLUSION: In critically ill patients, TT and ROTEM parameters may provide better correlation to argatroban and lepirudin plasma concentrations than aPTT. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00798525 , registered on 25 Nov 2008.

Perioperative Thromboelastometry for Adult Living Donor Liver Transplant Recipients with a Tendency to Hypercoagulability: A Prospective Observational Cohort Study.

BACKGROUND: Hypercoagulability can lead to serious thromboembolic events. The aim of this study was to assess the perioperative coagulation status in liver transplant recipients with a tendency to hypercoagulability. METHODS: In a prospective observational study (South African Cochrane Registry 201405000814129), 151 potential liver transplant recipients were screened for thrombophilic factors from October 2014 to June 2017, and 57 potential recipients fulfilled the inclusion criterion of presenting two or more of the following thrombophilic factors: low protein C, low protein S, low anti-thrombin, increased homocystein, increased antiphospholipid IgG/IgM antibodies, increased lupus anticoagulant, and positive Factor V Leiden mutation. Seven patients were excluded from the study because they fulfilled the exclusion criteria of cancelling the liver transplantation, oral anticoagulation, or intraoperative treatment with rFVIIa. Accordingly, 50 patients were included in the final analysis. Thromboelastometry (ROTEM) (EXTEM, INTEM and FIBTEM) and conventional coagulation tests (CCT) were performed preoperatively, during the anhepatic phase, post reperfusion, and on postoperative days (POD) 1, 3 and 7. ROTEM was used to guide blood product transfusion. Heparin was infused (60-180 U/kg/day) postoperatively for 3 days and then was replaced by low-molecular-weight heparin (20 mg/12 h). RESULTS: FIBTEM MCF significantly increased postoperatively above reference range on POD 7 despite normal fibrinogen plasma concentrations (p < 0.05). Both EXTEM and INTEM demonstrated significant changes with the phases of transplantation (p < 0.05), but with no intra- or postoperative hypercoagulability observed. INTEM CT (reference range, 100-240 s) normalized on POD 3 and 7 (196.1 ± 69.0 and 182.7 ± 63.8 s, respectively), despite prolonged aPTT (59.7 ± 18.7 and 46.4 ± 15.7 s, respectively; reference range, 20-40 s). Hepatic artery thrombosis (HAT) and portal vein thrombosis (PVT) were reported in 12.0% and 2.0%, respectively, mainly after critical care discharge and with high FIBTEM MCF values in 57% on POD 3 and 86% on POD 7. Receiver operating characteristics curve analyses of FIBTEM MCF were significant predictors for thromboembolic events with optimum cut-off, area under the curve and standard error on POD 3 (>23 mm, 0.779 and 0.097; p = 0.004) and POD 7 (>28 mm, 0.706 and 0.089; p = 0.020). Red blood cells (mean ± SD, 8.68 ± 5.81 units) were transfused in 76%, fresh frozen plasma (8.26 ± 4.14 units) in 62%, and cryoprecipitate (12.0 ± 3.68 units) in 28% of recipients. None of the recipients received intraoperative platelet transfusion or any postoperative transfusion. Main transplant indication was hepatitis C infection in 82%. 76% of recipients included in this highly selected patient population showed increased lupus anticoagulant, 2% increased antiphospholipid IgG/IgM antibodies, 20% increased homocysteine, 74% decreased anti-thrombin, 78% decreased protein C, 34% decreased protein S, and 24% a positive Factor V Leiden mutation. Overall 1-year survival was 62%. CONCLUSION: A significant postoperative step-wise increase in FIBTEM MCF beyond the reference range was observed despite normal fibrinogen plasma concentrations, and FIBTEM MCF was a predictor for thromboembolic events in this study population, particularly after POD 3 and 7 on surgical wards when CCTs failed to detect this condition. However, the predictive value of FIBTEM MCF for postoperative HAT and PVT needs to be confirmed in a larger patient population. A ROTEM-guided anticoagulation regime needs to be developed and investigated in future studies.

Efficacy and safety of a single occipital nerve blockade in episodic and chronic cluster headache: A prospective observational study.

Background Treatment options for cluster headache (CH) include acute, transitional and prophylactic strategies. We assessed the efficacy and safety of a single occipital nerve block (ONB) in patients with episodic (eCH) and chronic CH (cCH). Methods In this prospective, observational study 101 CH were treated with a single ONB using triamcinolone 10 mg and bupivacaine. Attack frequency, pain intensity and side effects were assessed at days 1 and 7 after ONB and thereafter weekly for 60 days until recurrence of attacks. Results Baseline mean daily attack frequency was 2.9 ± 2.5 (eCH) and 3.3 ± 2.9 (cCH), which was reduced to 0.7 ± 1.2 (eCH) and 1.1 ± 1.4 (cCH) after one day ( p = 0.08 for group difference) and to 1.1 ± 1.6 (eCH) and 1.9 ± 2.3 (cCH) after seven days ( p = 0.01 for group difference). In patients with eCH the pain-free period lasted longer compared to cCH ( p = 0.004). There was no association between the presence of local anesthesia and treatment response ( p = 0.88). No serious adverse events occurred. Conclusion ONB is an easy, safe and effective transitional treatment option in case of insufficient response of CH to treatment both in patients with eCH and cCH. Patients with eCH have a better and more sustainable treatment response.

Anticoagulant Effect of Sugammadex: Just an In Vitro Artifact.

BACKGROUND: Sugammadex prolongs activated partial thromboplastin time (aPTT) and prothrombin time (PT) suggestive of anticoagulant effects. To pinpoint its presumed anticoagulant site of action, the authors assessed Sugammadex's impact on a panel of coagulation assays. METHODS: Sugammadex, Rocuronium, Sugammadex and Rocuronium combined, or saline were added to blood samples from healthy volunteers and analyzed using plasmatic (i.e., aPTT, thrombin time, and fibrinogen concentration) (n = 8 each), PT (quick), activities of plasmatic coagulation factors, and whole blood (extrinsically and intrinsically activated thromboelastometry) assays (n = 18 each). Furthermore, dose-dependent effects of Sugammadex were also assessed (n = 18 each) in diluted Russel viper venom time (DRVVT) assays with low (DRVVT1) and high (DRVVT2) phospholipid concentrations and in a highly phospholipid-sensitive aPTT assay. RESULTS: Sugammadex increased PT (+9.1%; P < 0.0001), aPTT (+13.1%; P = 0.0002), and clotting time in extrinsically (+33.1%; P = 0.0021) and intrinsically (+22.4%; P < 0.0001) activated thromboelastometric assays. Furthermore, activities of factors VIII, IX, XI, and XII decreased (-7%, P = 0.009; -7.8%, P < 0.0001; -6.9%, P < 0.0001; and -4.3%, P = 0.011, respectively). Sugammadex dose-dependently prolonged both DRVVT1 and the highly phospholipid-sensitive aPTT assays, but additional phospholipids in the DRVVT2 assay almost abolished these prolongations. Thrombin time, a thromboelastometric thrombin generation assay, clot firmness, clot lysis, fibrinogen concentration, and activities of other coagulation factors were unaltered. Rocuronium, Sugammadex and Rocuronium combined, and saline exerted no effects. CONCLUSION: Sugammadex significantly affects various coagulation assays, but this is explainable by an apparent phospholipid-binding effect, suggesting that Sugammadex`s anticoagulant effects are likely an in vitro artifact.