Alterations in coagulation following major liver resection.

The international normalised ratio is frequently raised in patients who have undergone major liver resection, and is assumed to represent a potential bleeding risk. However, these patients have an increased risk of venous thromboembolic events, despite conventional coagulation tests indicating hypocoagulability. This prospective, observational study of patients undergoing major hepatic resection analysed the serial changes in coagulation in the early postoperative period. Thrombin generation parameters and viscoelastic tests of coagulation (thromboelastometry) remained within normal ranges throughout the study period. Levels of the procoagulant factors II, V, VII and X initially fell, but V and X returned to or exceeded normal range by postoperative day five. Levels of factor VIII and Von Willebrand factor were significantly elevated from postoperative day one (p < 0.01). Levels of the anticoagulants, protein C and antithrombin remained significantly depressed on postoperative day five (p = 0.01). Overall, the imbalance between pro- and anticoagulant factors suggested a prothrombotic environment in the early postoperative period.

Patient blood management to reduce surgical risk.

BACKGROUND: Preoperative anaemia and perioperative blood transfusion are both identifiable and preventable surgical risks. Patient blood management is a multimodal approach to address this issue. It focuses on three pillars of care: the detection and treatment of preoperative anaemia; the reduction of perioperative blood loss; and harnessing and optimizing the patient-specific physiological reserve of anaemia, including restrictive haemoglobin transfusion triggers. This article reviews why patient blood management is needed and strategies for its incorporation into surgical pathways. METHODS: Studies investigating the three pillars of patient blood management were identified using PubMed, focusing on recent evidence-based guidance for perioperative management. RESULTS: Anaemia is common in surgical practice. Both anaemia and blood transfusion are independently associated with adverse outcomes. Functional iron deficiency (iron restriction due to increased levels of hepcidin) is the most common cause of preoperative anaemia, and should be treated with intravenous iron. Intraoperative blood loss can be reduced with antifibrinolytic drugs such as tranexamic acid, and cell salvage should be used. A restrictive transfusion practice should be the standard of care after surgery. CONCLUSION: The significance of preoperative anaemia appears underappreciated, and its detection should lead to routine investigation and treatment before elective surgery. The risks of unnecessary blood transfusion are increasingly being recognized. Strategic adoption of patient blood management in surgical practice is recommended, and will reduce costs and improve outcomes in surgery.

Thromboelastography (TEG®) compared with total platelet count in thrombocytopenia haematological malignancy patients with bleeding: a pilot observational study.

BACKGROUND: There has been no reported use of Thromboelastography(®) (TEG(®) ) in assessing thrombocytopenic haematological malignancy (HM) patients experiencing bleeding. OBJECTIVES: To assess whether there are differences in TEG(®) variables in thrombocytopenic HM patients experiencing clinically significant bleeding compared with those not experiencing bleeding. METHODS: Thirty adult patients with HM and a total platelet count (TPC) of ≤ 30 × 10(9) L(-1) were observed for greater than or equal to grade two World Health Organisation (WHO) bleeding episodes for 72 h. They had TPC, TEG(®) parameters [maximal amplitude (MA), reaction time (R-time), alpha (α-angle) and functional fibrinogen (FF) levels], activated partial thromboplastin time (APTT) and prothrombin time (PT) measured at inclusion, 24 and 48 h. RESULTS: Five patients had nine significant bleeding episodes. Patients bleeding (n) were all more hypocoaguable when measured by TEG(®) than patients not bleeding at inclusion n = 4 (MA: 16.9 vs 31.8 mm, P < 0.01; R-time: 10.1 vs 7.5 min, P = 0.02; α-angle: 18.8 vs 28.4, P < 0.01; FF: 182.4 vs 204 mg dL(-1), P < 0.01), at 24 h n = 3 (MA 18 vs 29.4 mm, P = 0.02; R-time: 9.4 vs 7.4 mins, P = 0.02; α-angle: 21.6 vs 26.5, P = 0.04 and FF: 168 vs 201 mg dL(-1) P = 0.01) and at 48 h n = 2 (MA: 29.7 vs 23.0, P = 0.02; R-time: 8.1 vs 6.7 mins, P = 0.05; α-angle: 22.6 vs 26.5, P = 0.04; FF: 170 vs 208 mg dL(-1), P = 0.01). There were no significant differences in TPC, APTT or PT between patients that bled and those that did not at each time point. CONCLUSIONS: Thrombocytopenic HM patients experiencing bleeding are hypocoaguable on TEG(®).

An in vitro study comparing two dose regimes of fresh frozen plasma on conventional and thromboelastographic tests of coagulation after major hepatic resection.

BACKGROUND: After hepatic resection, post-operative increases in international normalised ratio (INR) are frequent, but rarely associated with bleeding complication. Coagulation as assessed by thrombin generation may be normal, despite the increased INR. This study tests the hypothesis that viscoelastic tests (VET) of coagulation remain normal, despite mild elevations in INR, examines the efficacy of fresh frozen plasma (FFP) in reversing prolongation of INR in such patients and determines the effect of FFP on VET. METHODS: A prospective cohort study of 47 patients undergoing major hepatectomy. In vitro spiking with FFP (7·5 and 15 mL kg(-1)) was carried out if post-operative day 2 (POD2) INR levels were ≥1·5. Thromboelastography (TEG®) and INR were measured before and after FFP spiking. RESULTS: Blood from patients with an INR ≥ 1·5 on POD2 was spiked with FFP. There was a significant reduction in the INR from 1·94 [standard deviation (SD): 0·59] to 1·46 (SD: 0·27, P = 0·005) and 1·36 (SD: 0·18, P = 0·0007) with FFP 7·5 or 15 mL kg(-1), respectively. At baseline, the TEG R-time [6·17 min (NR, 9-27 min)] and maximum amplitude (MA) [66·9 mm (NR, 44-64 mm)] were hypercoagulable, and remained so on POD2 for the R-time (6·7 min), but fell to within the normal range for the MA (54·0 mm). FFP spiking had no significant effect on TEG variables. CONCLUSIONS: Despite the rise in INR after hepatectomy, VET do not show evidence of hypocoagulability. In vitro addition of FFP had no significant effect on TEG parameters. Clinical use of FFP in this situation is questionable.

Point-of-care monitoring of haemostasis.

Recent research in the management of haemorrhage has led to several changes in clinical practice. Evidence is accumulating that point-of-care testing results in fewer transfusions, improved patient outcomes, and reduced hospital costs. However, there is still insufficient high quality evidence to support transfusion guidelines and algorithms based on point-of-care tests alone, and more robust studies are needed. The implementation of point-of-care testing requires institutional support and senior clinical leadership to realise the benefits, with educational programmes, audit, and feedback regarding transfusion practice. A change in philosophy is required, from performing testing only when there is an obvious bleeding problem, towards the concept of routinely monitoring high-risk patients throughout the surgical procedure. This informs clinical practice, establishes normal ranges for that population, identifies patients at risk and allows early identification and treatment of evolving coagulopathy.

Risk of bleeding and adverse outcomes predicted by thromboelastography platelet mapping in patients taking clopidogrel within 7 days of non-cardiac surgery.

BACKGROUND: Patients often fail to stop clopidogrel appropriately before non-cardiac surgery. Thromboelastography platelet mapping (TEG-PM) can be used to measure the percentage adenosine 5'-diphosphate platelet receptor inhibition (ADP-PRI) by clopidogrel in these patients. METHODS: This prospective case-control study investigated the risk of bleeding in patients who had taken clopidogrel within 7 days of scheduled operation. Patients underwent TEG-PM to stratify their bleeding risk. Low-risk (ADP-PRI below 30 per cent) and urgent priority high-risk (ADP-PRI 30 per cent or more) patients proceeded to surgery. The outcomes of these patients were compared with those of matched controls. Regression analysis, with bootstrapping validation, was used to identify independent risk factors for bleeding and an optimal cut-off value of ADP-PRI for cancellation of surgery. RESULTS: From May 2008 to October 2013, 182 patients failed to discontinue clopidogrel. No correlation was observed between duration of clopidogrel omission and percentage ADP-PRI; 112 low-risk and 19 high-risk patients proceeded to surgery. High-risk patients had significantly greater intraoperative packed red blood cell (PRBC) transfusion in comparison with their matched controls, and a strong positive correlation between percentage ADP-PRI and units of intraoperative PRBCs transfused (r = 0·749, 95 per cent confidence interval (c.i.) 0·410 to 0·940; P < 0·001). Percentage ADP-PRI was the only independent risk factor for intraoperative PRBC transfusion (odds ratio 1·07, 95 per cent c.i. 1·02 to 1·13; P = 0·005). CONCLUSION: An objective measure of platelet inhibition with TEG-PM, using an ADP-PRI cut-off of 34 per cent, can be used to prevent unnecessary cancellations, while minimizing patient risk.

Epidural anaesthesia and analgesia for liver resection.

Although epidural analgesia is routinely used in many institutions for patients undergoing hepatic resection, there are unresolved issues regarding its safety and efficacy in this setting. We performed a review of papers published in the area of anaesthesia and analgesia for liver resection surgery and selected four areas of current controversy for the focus of this review: the safety of epidural catheters with respect to postoperative coagulopathy, a common feature of this type of surgery; analgesic efficacy; associated peri-operative fluid administration; and the role of epidural analgesia in enhanced recovery protocols. In all four areas, issues are raised that question whether epidural anaesthesia is always the best choice for these patients. Unfortunately, the evidence available is insufficient to provide definitive answers, and it is clear that there are a number of areas of controversy that would benefit from high-quality clinical trials.

Use of thromboelastography to demonstrate persistent anticoagulation after stopping enoxaparin.

Peri-operative guidelines exist for neuraxial anaesthesia and anticoagulant therapy. We describe the use of thromboelastography to assess the coagulation status of a patient with moderate renal impairment who had been receiving enoxaparin and was being managed in accordance with current recommendations. This report demonstrates that current guidelines for discontinuing treatment with enoxaparin may not allow a sufficient safety margin in all patient groups and that thromboelastography is a useful tool in such situations.

The impact of aprotinin on renal function after liver transplantation: an analysis of 1,043 patients.

Renal dysfunction is frequently seen after orthotopic liver transplantation (OLT). Aprotinin is an antifibrinolytic drug which reduces blood loss during OLT. Recent studies in cardiac surgery suggested a higher risk of postoperative renal complications when aprotinin is used. The impact of aprotinin on renal function after OLT, however, is unknown. In 1,043 adults undergoing OLT, we compared postoperative renal function in patients who received aprotinin (n = 653) or not (n = 390). Using propensity score stratification (C-index 0.82) and multivariate regression analysis, aprotinin was identified as a risk factor for severe renal dysfunction within the first week, defined as increase in serum creatinine by >or= 100% (OR = 1.97, 95% CI = 1.14-3.39; p = 0.02). No differences in renal function were noted at 30 and 365 days postoperatively. Moreover, no significant differences were found in the need for renal replacement therapy (OR = 1.52, 95% CI = 0.94-2.46; p = 0.11) or in 1-year patient survival rate (OR = 1.14, 95% CI = 0.73-1.77; p = 0.64) in patients who received aprotinin or not. In conclusion, aprotinin is associated with a higher risk of transient renal dysfunction in the first week after OLT, but not with a higher need for postoperative renal replacement therapy or an increased risk of mortality.

Use of the platelet function analyser (PFA-100) to quantify the effect of low dose aspirin in patients with ischaemic heart disease.

Continuing aspirin up until surgery in cardiac surgical patients may increase peri-operative blood loss. It is possible that there is a subset of patients particularly sensitive to aspirin. The platelet function analyser (PFA-100) can demonstrate the antiplatelet effect of aspirin. This study was designed to assess the effect of daily 75 mg aspirin on platelet function, as measured by the PFA-100, in 92 patients with ischaemic heart disease. Patients were classified into three groups according to their PFA-100 results; aspirin hyper-responders (16%), aspirin normal responders (33%) and aspirin non-responders (51%). The PFA-100 has potential as a screening tool to identify patients who are either hyper-responsive or resistant to aspirin. Pre-operative PFA-100 screening to isolate aspirin hyper-responders could enable the vast majority of patients to continue with aspirin therapy pre-operatively, avoiding the risks of stopping treatment.

The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid-base and electrolyte status and gastric mucosal perfusion in elderly surgical patients.

UNLABELLED: The IV administration of sodium chloride solutions may produce a metabolic acidosis and gastrointestinal dysfunction. We designed this trial to determine whether, in elderly surgical patients, crystalloid and colloid solutions with a more physiologically balanced electrolyte formulation, such as Hartmann's solution and Hextend, can provide a superior metabolic environment and improved indices of organ perfusion when compared with saline-based fluids. Forty-seven elderly patients undergoing major surgery were randomly allocated to one of two study groups. Patients in the Balanced Fluid group received an intraoperative fluid regimen that consisted of Hartmann's solution and 6% hetastarch in balanced electrolyte and glucose injection (Hextend). Patients in the Saline group were given 0.9% sodium chloride solution and 6% hetastarch in 0.9% sodium chloride solution (Hespan). Biochemical indices and acid-base balance were determined. Gastric tonometry was used as a reflection of splanchnic perfusion. Postoperative chloride levels demonstrated a larger increase in the Saline group than the Balanced Fluid group (9.8 vs 3.3 mmol/L, P = 0.0001). Postoperative standard base excess showed a larger decline in the Saline group than the Balanced Fluid group (-5.5 vs -0.9 mmol/L, P = 0.0001). Two-thirds of patients in the Saline group, but none in the Balanced Fluid group, developed postoperative hyperchloremic metabolic acidosis (P = 0.0001). Gastric tonometry indicated a larger increase in the CO2 gap during surgery in the Saline group compared with the Balanced Fluid group (1.7 vs 0.9 kPa, P = 0.0394). In this study, the use of balanced crystalloid and colloid solutions in elderly surgical patients prevented the development of hyperchloremic metabolic acidosis and resulted in improved gastric mucosal perfusion when compared with saline-based solutions. IMPLICATIONS: This prospective, randomized, blinded trial showed that, in elderly surgical patients, the use of balanced IV solutions can prevent the development of hyperchloremic metabolic acidosis and provide better gastric mucosal perfusion compared with saline-based fluids.

Reducing red blood cell transfusion in elective surgical patients: the role of audit and practice guidelines.

In 1996, we prospectively audited peri-operative transfusion practice in elective surgical patients over a 3-month period. Two-unit transfusions represented 60% of all transfusions. Haemoglobin was measured infrequently prior to transfusion and the main 'trigger' for transfusion was an estimated blood loss in excess of 500 ml. Transfusion guidelines that required the haemoglobin level to be measured immediately before transfusion were introduced. The audit was repeated in 1998; transfusion 'triggers' and the number of transfusions for the two periods were compared. In the second audit, the total number of transfusions decreased by 43%. The mean estimated blood loss associated with a 2-unit transfusion had increased from 608 (373) ml to 1320 (644) ml (p < 0.01) and the estimated haemoglobin concentration after transfusion had decreased from 12.4 (1.8) g.dl-1 to 9.9 (2.4) g.dl-1 (p < 0.01). These results suggest that transfusion guidelines can have a significant impact on clinical practice.

Anticoagulant-induced pseudothrombocytopenia in a patient presenting for coronary artery bypass grafting.

A 73-yr-old man with severe ischaemic heart disease presented for coronary artery bypass grafting. His preoperative platelet count, obtained from an ethylene diamine tetraacetic acid (EDTA) sampling bottle, was 61 x 10(9) litre-1, but he had no history of bleeding problems. Previous platelet counts demonstrated results ranging from 16 x 10(9) litre-1 to 254 x 10(9) litre-1 with variable degrees of in vitro platelet clumping. Preoperative thrombelastography reflected a normal coagulation profile. The laboratory findings and the absence of a history of haemorrhagic complications suggested a diagnosis of EDTA-dependent pseudothrombocytopenia. We present the perioperative implications of this in vitro phenomenon and methods of detecting the functional and numerical integrity of circulating platelets.

Use of heparinase modified thrombelastography in liver transplantation.

Severe coagulopathies can occur during liver transplantation, particularly after reperfusion of the grafted liver. Heparin release has been proposed as one of the factors contributing to this coagulopathy. We have analysed the thrombelastograph (TEG) traces of 55 patients after reperfusion using native and heparinase-treated samples. In almost all cases an abnormal native TEG was improved in vitro by heparinase, demonstrating the presence of heparin or a heparin-like substance. The heparinase-modified TEG allowed assessment of the underlying coagulation status, providing a rational guide to blood component replacement or treatment of fibrinolysis.