Eva Schaden

Measuring the activity of apixaban and rivaroxaban with rotational thrombelastometry.

BACKGROUND Routine drug monitoring is not required for the two novel direct factor Xa inhibitors apixaban and rivaroxaban. Rapidly available test results might be beneficial in case of bleeding or prior to urgent surgery. OBJECTIVES The aim of this study was to evaluate the applicability of the two rotational thrombelastometry (ROTEM®) -modifications Low-tissue factor activated ROTEM® (LowTF-ROTEM®) and Prothrombinase induced clotting time - activated ROTEM® (PiCT®-ROTEM®) for determination of apixaban and rivaroxaban in vitro and ex vivo. METHODS Blood samples from 20 volunteers were spiked with apixaban / rivaroxaban to yield samples with ascending drug concentrations ranging from 50 - 400ng/mL. LowTF - and PiCT® modified ROTEM® tests and determination of the corresponding antifactor Xa activity were performed in duplicate in 280 samples. LowTF-ROTEM® tests were performed in samples from 20 patients on apixaban or rivaroxaban therapy and 20 controls. RESULTS There was a strong correlation between apixaban / rivaroxaban plasma concentrations and the LowTF-ROTEM® parameters Clotting time (CT; spearman correlation coefficient (SCC) 0.81 and 0.81, respectively) and Time to maximum velocity (t,MaxVel; SCC: 0.81 and 0.80, resp.) and a low to moderate correlation for the PiCT®-ROTEM® parameters CT (SCC: 0.38 and 0.59, resp.) and t,MaxVel. (0.51 and 0.69, resp.) in the in vitro experiments. LowTF-ROTEM CT was significantly prolonged in patients on apxiaban or rivaroxaban therapy compared to controls. CONCLUSIONS LowTF-ROTEM® could be a valuable diagnostic tool for rapid determination of the effect of apixaban and rivaroxaban at the point of care.

Coagulation pattern in critical liver dysfunction.

Purpose of reviewThis article reviews the current literature dealing with pathophysiology, diagnostics, bleeding management, and thromboprophylaxis in patients with acute and chronic liver dysfunction. Recent findingsRoutine coagulation tests such as prothrombin time and International Normalized Ratio (INR) are not able to define whether a patient with critical liver dysfunction is hypocoagulable or hypercoagulable and are not able to predict the risk of bleeding in patients with liver dysfunction. Therefore, prophylactic transfusion of fresh frozen plasma and platelets in order to correct laboratory values is not appropriate. Notably, patients with liver dysfunction and increased INR are not ‘autoanticoagulated’. In contrast, thrombin generation assays in the presence and absence of thrombomodulin or Protac, a snake venom that activates protein C in a manner similar to thrombomodulin, as well as viscoelastic tests (thrombelastography/thromboelastometry) indicate that patients with liver dysfunction are rather hypercoagulable with the inherent risk of thrombosis. SummaryCoagulopathy in patients with critical liver dysfunction is complex and can quickly decompensate to bleeding as well as to thrombosis. Both are associated with worse outcome. Hemostatic interventions should only be performed in case of clinically relevant bleeding and thromboprophylaxis should strongly be considered.

Fibrinogen function after severe burn injury

BACKGROUND Evidence regarding hypercoagulability in the first week after burn trauma is growing. This hypercoagulable state may partly be caused by increased fibrinogen levels. Rotational thrombelastometry offers a test which measures functional fibrinogen (FIBTEM(®)). To test the hypothesis that in patients with severe burn injury fibrinogen function changes over time, we simultaneously measured FIBTEM(®) and fibrinogen concentration early after burn trauma. METHODS After Ethics Committee approval consecutive patients with severe burn trauma admitted to the burn intensive care unit of the General Hospital of Vienna were included in the study. Blood examinations were done immediately and 12, 24 and 48 h after admission. At each time point fibrinogen level (Clauss) and 4 commercially available ROTEM(®) tests were performed. RESULTS 20 consecutive patients were included in the study. Fibrinogen level and FIBTEM(®) MCF were within the reference range until 24 h after burn trauma but increased significantly 48 h after trauma. There was a significant correlation between FIBTEM(®) MCF and fibrinogen level (R=0.714, p<0.001). CONCLUSION The results of this prospective observational clinical study show that fibrinogen function changes early after burn trauma and can be visualized by ROTEM(®) with the fibrinogen-sensitive FIBTEM(®) test.

Effect of the carrier solution for hydroxyethyl starch on platelet aggregation and clot formation

BACKGROUND Hydroxyethyl starch (HES) solutions alter blood coagulation, mainly platelet function and fibrinogen polymerization. Haemostasis can also be impaired by dilutional-hyperchloraemic acidosis induced by the HES carrier solution. We hypothesized that a saline-based tetrastarch carrier solution impairs parameters of blood coagulation more than a balanced carrier solution. METHODS The study was designed as a prospective, double-blinded, randomized, cross-over trial in healthy male volunteers. At intervals of at least 10 days, 13 subjects received 20 ml kg(-1) of balanced or saline-based tetrastarch over 2 h. Blood was subjected to blood gas analysis, assessment of platelet function [with multiple electrode aggregometry (MEA)], and clot formation (with rotational thrombelastometry). RESULTS Maximum aggregation in response to adenosine diphosphate (ADP) decreased after saline-based HES infusion, but not after balanced solution-based HES infusion. ADP-induced platelet aggregation was significantly lower after saline-based HES compared with baseline (21%; P<0.025) and compared with balanced solution-based HES (17%; P<0.025). There were no significant changes in platelet aggregation induced by thrombin receptor-activating peptide and in any parameter of rotational thrombelastometry. Chloride concentrations were significantly higher after saline-based HES compared with balanced solution-based HES. CONCLUSIONS The carrier solution for HES up to 20 ml kg(-1) had little impact on platelet aggregation or clot formation as assessed by MEA and rotational thrombelastometry, respectively. Further clinical studies are required to verify this finding in patients and to correlate results of whole blood aggregometry and rotational thrombelastometry with perioperative bleeding and transfusion requirements.

Determination of enoxaparin with rotational thrombelastometry using the prothrombinase-induced clotting time reagent

Drug monitoring of low molecular weight heparin is generally not recommended, but could be reasonable in critically ill patients, whose risk for bleeding or thrombosis shows a high interpatient variability. Anti-Xa assays are not available around the clock even in central hospitals, whereas rotational thrombelastometry (ROTEM) becomes increasingly used at the bedside. Prothrombinase-induced clotting time (PiCT) reagent allows determination of factor Xa-inhibition in plasma. The aim of our study was to evaluate enoxaparin determination in whole blood with the ROTEM using specific test modifications, including PiCT. After ethics committees approval, citrated whole blood obtained from overall 16 healthy volunteers was incubated with enoxaparin at 16 different anti-Xa concentrations. Main endpoint was the clotting time (CT) in ROTEM representing initial activation of clot formation. CT was determined in the new PiCT-ROTEM test, in a low-tissue factor-activated modification (LowTF-ROTEM) as well as in the commercially available heparin-sensitive ROTEM assays (HEPTEM and INTEM). In the absence of enoxaparin, CT values were 168.6 ± 6.1 s (PiCT-ROTEM), 247.3 ± 18.6 s (LowTF-ROTEM), and –6.2 ± 7.9 s (INTEM-HEPTEM). A linear dependency (P < 0.01) between anti-Xa concentration and CT was found for PiCT-ROTEM, LowTF-ROTEM, and for INTEM-HEPTEM with correlation coefficients of 0.93 for PiCT-ROTEM, 0.94 for LowTF-ROTEM, and 0.81 for INTEM-HEPTEM. This in-vitro experiment demonstrates a strong correlation between enoxaparin anti-Xa concentrations and specific ROTEM tests. These promising assays should be further evaluated for monitoring anticoagulation in high-risk patients in clinical studies.

Fibrinogen but not factor XIII deficiency is associated with bleeding after craniotomy

BACKGROUND Postoperative haemorrhage in neurosurgery is associated with significant morbidity and mortality. There is controversy whether or not factor XIII (FXIII) deficiency leads to bleeding complications after craniotomy. Decreased fibrinogen levels have been associated with an increased incidence of bleeding complications in cardiac and orthopaedic surgery. The aim of this study was to assess perioperative fibrinogen and FXIII levels in patients undergoing elective intracranial surgery with and without severe bleeding events. METHODS Perioperative FXIII and fibrinogen levels were prospectively assessed in 290 patients undergoing elective craniotomy. Patients were divided into two groups according to the presence or absence of severe bleeding requiring surgical revision. Coagulation test results of these groups were compared using Students t-test. RESULTS The incidence of postoperative severe bleeding was 2.4%. No differences in FXIII levels were observed, but postoperative fibrinogen levels were significantly lower in patients suffering from postoperative haematoma compared with those without postoperative intracranial bleeding complications [237 mg dl(-1) (standard deviation, SD 86) vs 170 mg dl(-1) (SD 35), P=0.03]. The odds ratio for postoperative haematoma in patients with a postoperative fibrinogen level below 200 mg dl(-1) was 10.02 (confidence interval: 1.19-84.40, P=0.03). CONCLUSIONS This study emphasizes the role of fibrinogen as potentially modifiable risk factor for perioperative bleeding in intracranial surgery. Future randomized controlled trials will be essential to identify patients who might benefit from fibrinogen substitution during neurosurgical procedures.

Monitoring of unfractionated heparin with rotational thrombelastometry using the prothrombinase-induced clotting time reagent (PiCT®).

PURPOSE To achieve sufficient and safe anticoagulation with unfractionated heparin (UFH) a close and reliable drug monitoring is necessary. In general, the activated partial thromboplastin time (APTT) is used for this purpose. In acute phase response, however, the APTT test procedure might be unreliable e.g. with false low results in the presence of elevated factor VIII. In this so called heparin resistance, measurement of anti-Xa activity is recommended over APTT to avoid potentially harmful dose escalation. A combination of anti-Xa measurement and global hemostatic testing with ROTEM® employing the anti-Xa sensitive PiCT® reagent showed high correlation with enoxaparin levels. This test modification could also be suitable for monitoring UFH. Aim of the study was to evaluate the correlation between PiCT®-ROTEM® and levels of UFH. METHODS In this in-vitro study blood samples from healthy volunteers were spiked with UFH and subjected to different ROTEM® tests. RESULTS There was a linear correlation between UFH level and clotting time (CT) in the PiCT®-ROTEM® test with an excellent correlation coefficient of 0.92. Additional endpoints showed similar results (PiCT®-ROTEM® MaxVel r = -0.85 and PiCT®-ROTEM® t_MaxVel r = 0.88). CONCLUSIONS As a point-of-care applicable tool ROTEM® is immediately at hand. If further clinical studies confirm sensitivity in heparin resistance, PiCT®-ROTEM® could permit rapid UFH dose adjustments especially required in critical illness with acute phase response.

Therapiezieländerungen auf der Intensivstation – Definitionen, Entscheidungsfindung und Dokumentation

The present work provides assistance for physicians concerning decision making in clinical borderline situations in the ICU. Based on a structured checklist the two fundamental aspects of any medical decision, the medical indication and the patients preference are queried in a systematic way. Four possible steps of withholding and/or withdrawing therapy are discussed. Finally, recommendations regarding appropriate documentation of end of life decisions are provided.

Point-of-Care Testing in Burn Patients

&NA; Severe burn injury has an impact on the coagulation system, but a unique definition regarding these changes is still missing. The results of conventional coagulation assays (CCAs) measured in daily clinical practice are often interpreted as coagulopathic, which implies a bleeding tendency. However, viscoelastic coagulation assays (VCA) like Rotational Thromboelastometry (ROTEM) and Thromboelastography (TEG) depict a hypercoagulable state. Therefore, hemostatic interventions should not be indicated according to deranged CCA results, but only in case of clinically relevant bleeding plus indicative VCA results. Massive blood loss mainly results from surgical excision of burn wounds. VCAs seem to be capable of guiding target‐oriented coagulation management in this context. Owing to the increased thromboembolic risk, it appears rational to individualize pharmacologic venous thromboembolism prophylaxis by using sensitive laboratory tests and drug monitoring. Studies evaluating the use of new VCA test modifications are highly warranted and may substantially improve outcome in this difficult‐to‐treat patient population.

Effect of combined treatment with immunoadsorption and membrane filtration on plasma coagulation—Results of a randomized controlled crossover study

The combined use of immunoadsorption (IA) and membrane filtration (MF) may markedly enhance removal of IgM and complement component C1q, supporting its use as an element of recipient desensitization in antibody‐incompatible transplantation. However, coagulation factor removal may contribute to altered hemostasis, posing a risk of bleeding in the perioperative setting. This secondary endpoint analysis of standard coagulation assays and rotational thromboelastometry (ROTEM®) was performed in the context of a randomized controlled crossover study designed to assess the effect of combined IA (GAM‐146‐peptide) and MF on levels of ABO antigen‐specific IgM. Fourteen patients with autoimmune disorders were randomized to a single treatment with IA+MF followed by IA alone, or vice versa. MF was found to markedly enhance fibrinogen depletion (57% vs. 28% median decrease after IA alone, P < 0.001), whereby four patients showed post‐treatment fibrinogen concentrations below 100 mg dL−1. In support of a critical contribution of fibrinogen depletion to impaired coagulation, extrinsically activated ROTEM® analysis revealed a marked reduction in fibrinogen‐dependent clot formation upon IA+MF (59% median decrease in FIBTEM mean clot firmness (MCF) as compared to 24% after IA alone, P < 0.001). Moreover, the addition of MF led to a substantial prolongation of activated partial thromboplastin time, possibly due to depletion of macromolecular coagulation factors contributing to intrinsically activated coagulation. Our study demonstrates substantial effects of combined IA+MF on clot formation, which may be mainly attributable to fibrinogen depletion. We suggest that the use of combined apheresis in the setting of transplant surgery may necessitate a careful monitoring of coagulation. J. Clin. Apheresis 31:29–37, 2016.