Evaluating the Impact of Cardiopulmonary Bypass Priming Fluids on Bleeding After Pediatric Cardiac Surgery: A Systematic Review and Meta-Analysis.

OBJECTIVES: Cardiopulmonary bypass (CPB) predisposes young children to coagulopathy. The authors evaluated possible effects of CPB priming fluids on perioperative bleeding in pediatric cardiac surgery. DESIGN: Meta-analysis and systematic review of previously published studies. SETTING: Each study was conducted in a surgical center or intensive care unit. PARTICIPANTS: Studies investigating patients <18 years without underlying hematologic disorders were included. INTERVENTIONS: The authors evaluated randomized controlled trials (RCTs) published between 1980 and 2020 on MEDLINE, EMBASE, PubMed, and CENTRAL databases. The primary outcome was postoperative bleeding; secondary endpoints included blood product transfusion, mortality, and safety. MEASUREMENTS AND MAIN RESULTS: Twenty eligible RCTs were analyzed, with a total of 1,550 patients and a median of 66 patients per study (range 20-200). The most frequently assessed intervention was adding fresh frozen plasma (FFP) to the prime (8/20), followed by albumin (5/20), artificial colloids (5/20), and blood-based priming solutions (3/20). Ten studies with 771 patients evaluated blood loss at 24 hours in mL/kg and were included in a meta-analysis. Most of them investigated the addition of FFP to the priming fluid (7/10). No significant difference was found between intervention and control groups, with a mean difference of -0.13 (-2.61 to 2.34), p = 0.92, I2 = 69%. Further study endpoints were described but their reporting was too heterogeneous to be quantitatively analyzed. CONCLUSIONS: This systematic review of current evidence did not show an effect of different CPB priming solutions on 24-hour blood loss. The analysis was limited by heterogeneity within the dataset regarding population, type of intervention, dosing, and the chosen comparator, compromising any conclusions.

Graduated Compression Stockings as an Adjunct to Low Dose Low Molecular Weight Heparin in Venous Thromboembolism Prevention in Surgery: A Multicentre Randomised Controlled Trial.

BACKGROUND: The evidence base upon which current global venous thromboembolism (VTE) prevention recommendations have been made is not optimal. The cost of purchasing and applying graduated compression stockings (GCS) in surgical patients is considerable and has been estimated at £63.1 million per year in England alone. OBJECTIVE: The aim was to determine whether low dose low molecular weight heparin (LMWH) alone is non-inferior to a combination of GCS and low dose LMWH for the prevention of VTE. METHODS: The randomised controlled Graduated compression as an Adjunct to Pharmacoprophylaxis in Surgery (GAPS) Trial (ISRCTN 13911492) will randomise adult elective surgical patients identified as being at moderate and high risk of VTE to receive either the current "standard" combined thromboprophylactic LMWH with GCS mechanical thromboprophylaxis, or thromboprophylactic LMWH pharmacoprophylaxis alone. To show non-inferiority (3.5% non-inferiority margin) for the primary endpoint of all VTE within 90 days, 2236 patients are required. Recruitment will be from seven UK centres. Secondary outcomes include quality of life, compliance with stockings and LMWH, overall mortality, and GCS or LMWH related complications (including bleeding). Recruitment commenced in April 2016 with the seven UK centres coming "on-line" in a staggered fashion. Recruitment will be over a total of 18 months. The GAPS trial is funded by the National Institute for Health Research Health Technology Assessment in the UK (14/140/61).

Risk of symptomatic venous thromboembolism following emergency appendicectomy in adults.

BACKGROUND: Appendicectomy is the commonest intra-abdominal emergency surgical procedure, and little is known regarding the magnitude and timing of the risk of venous thromboembolism (VTE) after surgery. This study aimed to determine absolute and relative rates of symptomatic VTE following emergency appendicectomy. METHODS: A cohort study was undertaken using linked primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care data of patients who had undergone emergency appendicectomy from 2001 to 2011. Crude rates and adjusted incidence rate ratios (IRRs) for VTE were calculated using Poisson regression, compared with baseline risk in the year before appendicectomy. RESULTS: A total of 13 441 patients were identified, of whom 56 (0·4 per cent) had a VTE in the first year after surgery. The absolute rate of VTE was highest during the in-hospital period, with a rate of 91·29 per 1000 person-years, which was greatest in those with a length of stay of 7 days or more (267·12 per 1000 person-years). This risk remained high after discharge, with a 19·1- and 6·6-fold increased risk of VTE in the first and second months respectively after discharge, compared with the year before appendicectomy (adjusted IRR: month 1, 19·09 (95 per cent c.i. 9·56 to 38·12); month 2, 6·56 (2·62 to 16·44)). CONCLUSION: The risk of symptomatic VTE following appendicectomy is relatively high during the in-hospital admission and remains increased after discharge. Trials of extended thromboprophylaxis are warranted in patients at particularly high risk.

A critical appraisal of point-of-care coagulation testing in critically ill patients.

Derangement of the coagulation system is a common phenomenon in critically ill patients, who may present with severe bleeding and/or conditions associated with a prothrombotic state. Monitoring of this coagulopathy can be performed with conventional coagulation assays; however, point-of-care tests have become increasingly attractive, because not only do they yield a more rapid result than clinical laboratory testing, but they may also provide a more complete picture of the condition of the hemostatic system. There are many potential areas of study and applications of point-of-care hemostatic testing in critical care, including patients who present with massive blood loss, patients with a hypercoagulable state (such as in disseminated intravascular coagulation), and monitoring of antiplatelet treatment for acute arterial thrombosis, mostly acute coronary syndromes. However, the limitations of near-patient hemostatic testing has not been fully appreciated, and are discussed here. The currently available evidence indicates that point-of-care tests may be applied to guide appropriate blood product transfusion and the use of hemostatic agents to correct the hemostatic defect or to ameliorate antithrombotic treatment. Disappointingly, however, only in cardiac surgery is there adequate evidence to show that application of near-patient thromboelastography leads to an improvement in clinically relevant outcomes, such as reductions in bleeding-related morbidity and mortality, and cost-effectiveness. More research is required to validate the utility and cost-effectiveness of near-patient hemostatic testing in other areas, especially in traumatic bleeding and postpartum hemorrhage.

Variation in the risk of venous thromboembolism following colectomy.

BACKGROUND: Guidelines recommend extended thromboprophylaxis following colectomy for malignant disease, but not for non-malignant disease. The aim of this study was to determine absolute and relative rates of venous thromboembolism (VTE) following colectomy by indication, admission type and time after surgery. METHODS: A cohort study of patients undergoing colectomy in England was undertaken using linked primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care data (2001-2011). Crude rates and adjusted hazard ratios (HRs) were calculated for the risk of first VTE following colectomy using Cox regression analysis. RESULTS: Some 12,388 patients were identified; 312 (2·5 per cent) developed VTE after surgery, giving a rate of 29·59 (95 per cent c.i. 26·48 to 33·06) per 1000 person-years in the first year after surgery. Overall rates were 2·2-fold higher (adjusted HR 2·23, 95 per cent c.i. 1·76 to 2·50) for emergency compared with elective admissions (39·44 versus 25·78 per 1000 person-years respectively). Rates of VTE were 2·8-fold higher in patients with malignant disease versus those with non-malignant disease (adjusted HR 2·84, 2·04 to 3·94). The rate of VTE was highest in the first month after emergency surgery, and declined from 121·68 per 1000 person-years in the first month to 25·65 per 1000 person-years during the rest of the follow-up interval. Crude rates of VTE were similar for malignant and non-malignant disease (114·76 versus 120·98 per 1000 person-years respectively) during the first month after emergency surgery. CONCLUSION: Patients undergoing emergency colectomy for non-malignant disease have a similar risk of VTE as patients with malignant disease in the first month after surgery.

The current place of tranexamic acid in the management of bleeding.

There has been an explosion of interest in the ability of tranexamic acid to reduce morbidity and mortality in surgical and traumatic bleeding. Tranexamic acid has been shown to reduce mortality due to traumatic bleeding by a third, without apparent safety issues. It is now clearly established that intravenous tranexamic acid reduces blood loss in patients with surgical bleeding and the need for transfusion. It can also be used topically to reduce bleeding. Its use is being explored further in large pragmatic trials in traumatic head injury, postpartum haemorrhage and in upper gastro-intestinal haemorrhage. There are few side effects from the use of tranexamic acid except when administered in high dose where neurological events have been noted, possibly relating to tranexamic acid interfering with cerebral GABA and glycine receptors. However, clinical studies suggest that there is no increased efficacy in using a higher dose, and that a dose of 1 g intravenously in an adult patient has maximal efficacy, which is not increased by higher doses. The CRASH-2 trauma trial clearly showed no increase in thrombotic events after its use in trauma, indeed there was a significant reduction in myocardial infarction. However, trials of tranexamic acid in surgery have failed to adequately study its effects on the risk of postoperative venous and possible reduction in arterial thrombo-embolism, and this needs to be the subject of future research.

Diabetes and gout: efficacy and safety of febuxostat and allopurinol.

AIM: Assess influences of demographics and co-morbidities of gout patients with or without diabetes on safety and efficacy of urate-lowering agents. METHODS: Post-hoc analysis of 312 diabetic and 1957 non-diabetic gout patients [baseline serum urate levels (sUA) ≥8.0 mg/dl] enrolled in a 6-month randomized controlled trial comparing urate-lowering efficacy (ULE) and safety of daily xanthine oxidase inhibitors (XOIs) febuxostat (40 mg or 80 mg) and allopurinol (200 mg or 300 mg). We compared baseline demographic, gout and co-morbid characteristics, ULE, and safety of XOI treatment in diabetic and non-diabetic gout patients. ULE was measured by the proportion of diabetic and non-diabetic patients in each treatment group achieving final visit sUA < 6.0 mg/dl. Safety was monitored throughout the trial. RESULTS: Diabetic gout patients were older, more frequently female, and had longer gout duration. Co-morbidities were more frequent among diabetic patients: cardiovascular disease; impaired renal function; hyperlipidemia; and obesity (body mass index >30 kg/m²) (p < 0.001 for all comparisons). Febuxostat 80 mg ULE exceeded that of febuxostat 40 mg or allopurinol (p < 0.050) at all levels of renal function, achieving sUA goal range in the majority of diabetic and non-diabetic patients. Diabetics and non-diabetics reported self-limiting diarrhoea and URIs as the most common adverse events. CONCLUSIONS: Despite higher co-morbidity rates in diabetic patients, febuxostat and allopurinol were safe in both groups at the doses tested. Febuxostat 80 mg achieved sUA <6.0 mg/dl more often than febuxostat 40 mg or allopurinol at commonly prescribed doses.

Plasminogen receptors and their role in the pathogenesis of inflammatory, autoimmune and malignant disease.

Plasminogen is the proenzyme of plasmin, the key protease of the fibrinolytic system, but its role is not limited to fibrinolysis regulation. Plasminogen binds not only to fibrin, but also to different receptors on cell surfaces, including the heterotetrameric complex Annexin A2-S100A10, enolase-1, histone H2B and the plasminogen receptor Plg-R(KT) . These receptors localize plasmin generation to the cell surface and provide a broad spectrum of reactions including proteolytic activity, cell migration and recruitment as well as signaling pathway activation. These plasminogen-binding proteins are involved in both physiologic and pathologic processes such as inflammation, thrombosis and cancer. Thus, plasminogen is at the center of a complex tightly controlled and regulated system where plasminogen-binding proteins have a crucial role, suggesting new therapeutic and diagnostic strategies. This review will discuss currently available information on plasminogen receptors, particularly their mechanisms of action and their roles in inflammatory, autoimmune and malignant disease.

The incidence and magnitude of fibrinolytic activation in trauma patients.

BACKGROUND: Trauma is a global disease, with over 2.5 million deaths annually from hemorrhage and coagulopathy. Overt hyperfibrinolysis is rare in trauma, and is associated with massive fatal injuries. Paradoxically, clinical trials suggest a much broader indication for antifibrinolytics. OBJECTIVE: To determine the incidence and magnitude of fibrinolytic activation in trauma patients and its relationship to clot lysis as measured by thromboelastometry. METHODS: A prospective cohort study of 303 consecutive trauma patients admitted between January 2007 and June 2009 was performed. Blood was drawn on arrival for thromboelastometry (TEM) and coagulation assays. Follow-up was until hospital discharge or death. TEM hyperfibrinolysis was defined as maximum clot lysis of > 15%. Fibrinolytic activation (FA) was determined according to plasmin-antiplasmin (PAP) complex and D-dimer levels. Data were collected on demographics, mechanism, severity of injury, and baseline vital signs. The primary outcome measure was 28-day mortality. The secondary outcome measures were 28-day ventilator-free days and 24-h transfusion requirement. RESULTS: Only 5% of patients had severe fibrinolysis on TEM, but 57% of patients had evidence of 'moderate' fibrinolysis, with PAP complex levels elevated to over twice normal (> 1500 µg L(-1)) without lysis on TEM. TEM detected clot lysis only when PAP complex levels were increased to 30 times normal (P < 0.001) and antiplasmin levels were < 75% of normal. Patients with FA had increased 28-day mortality as compared with those with no FA (12% vs. 1%, P < 0.001), fewer ventilator-free days, and longer hospital stay. CONCLUSIONS: FA occurs in the majority of trauma patients, and the magnitude of FA correlates with poor clinical outcome. This was not detected by conventional TEM, which is an insensitive measure of endogenous fibrinolytic activity.

The coagulopathy and thrombotic risk associated with L-asparaginase treatment in adults with acute lymphoblastic leukaemia.

The dramatic improvements seen in the outcome of paediatric patients with acute lymphoblastic leukaemia (ALL) have led to increasing incorporation of L-asparaginase (L-Asp) in adult treatment protocols. However, its use is associated with a disruption in the physiological balance between haemostatic and anticoagulant pathways, with the predominant clinical manifestation being thrombosis. Although L-Asp therapy is known to be associated with an acquired deficiency of antithrombin (AT), the concurrent depletion of fibrinogen and other haemostatic proteins means that the precise mechanism of thrombosis remains to be defined. In vitro coagulation assays are often prolonged but thrombosis rather than haemorrhage is the primary concern. Management of thrombotic events in these patients is based around agents that rely on AT for their anticoagulant effect, even though it is usually depleted. There is currently only limited evidence supporting the use of AT concentrates in either primary prevention or management following an established event. Evidence-based guidelines for prevention and management strategies are lacking.

Management strategies for acute proximal deep vein thrombosis: a Delphi consensus.

OBJECTIVES: Deep vein thrombosis (DVT) is a leading cause of cardiovascular disease. We tested the hypothesis that there is a consensus regarding the treatment of acute DVT among clinicians experienced in DVT management. METHOD: A Delphi consensus approach was used to gather expert opinion regarding attitudes towards the treatment of acute proximal DVT and management of specific cases. Strength of preference for various treatment strategies across a number of case scenarios was quantified. Univariate and multivariate analyses were performed to quantify the influence of various factors on treatment modality selected. RESULTS: Respondents strongly agreed that DVT was a significant health problem and that further research was a priority. A multidisciplinary team approach with access to various treatment strategies was encouraged. Pregnancy and recent surgery independently predicted preference for medical treatment, whereas proximal DVT and May-Thurner syndrome were associated with interventional strategies. CONCLUSION: Acute proximal DVT is a significant health problem for which a variety of treatments are available. This study demonstrates that no consensus exists as to the optimum strategy for certain patient groups. Trends in opinion based on local experience and case-series exist, but the results of ongoing randomized trials will ultimately inform best practice.

Pregnancy outcome and fibrinolytic, endothelial and coagulation markers in women undergoing uterine artery Doppler screening at 23 weeks.

BACKGROUND: Pre-eclampsia (PET) and/or fetal growth restriction (FGR) remain a major cause of maternal and fetal morbidity and mortality. In pregnancy, fibrinolysis is controlled by the maternal endothelium and placenta, both of which are central to the pathogenesis of PET/FGR. Clinically, uterine artery Doppler screening at 23 weeks is used to predict PET/FGR. An abnormal uterine artery Doppler finding is defined as early diastolic bilateral uterine artery notching (BN) in the waveform. However, about 50% of mothers with BN do not develop PET/FGR. OBJECTIVES: We investigated fibrinolytic changes and uterine artery Doppler findings in the second trimester, and related them to pregnancy outcome; in particular assessing whether fibrinolytic markers could discriminate between normal and abnormal outcome in mothers with BN. PATIENTS/METHODS: Plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), plasminogen activator inhibitor-2 (PAI-2), plasmin-alpha(2) antiplasmin (PAP), D-dimers and markers of endothelial dysfunction were measured with Doppler ultrasound at 23 weeks. RESULTS: Those with BN had decreased PAP and D-dimer levels, and raised PAI-1 and thrombomodulin levels. Mothers with BN and PET/FGR had significantly increased t-PA levels and reduced PAI-2 levels. CONCLUSIONS: BN at 23 weeks of gestation is associated with increased PAI-1 levels. Within the BN group, mothers who developed PET/FGR had increased t-PA levels and decreased PAI-2 levels, although there was no net change in fibrinolysis as measured by D-dimer levels. No single fibrinolytic marker is helpful in determining pregnancy outcome in those with BN, but t-PA and PAI-2 are worthy of study in a multifactorial algorithm.

Microangiopathic haemolytic anaemia secondary to lupus nephritis: an important differential diagnosis of thrombotic thrombocytopenic purpura.

Systemic lupus erythematosus (SLE) has been described as a cause of microangiopathic haemolytic anaemia (MAHA), however there is little literature to support this assertion. We report on three patients presenting with SLE and MAHA with a clinical picture indistinguishable from thrombotic thrombocytopenic purpura (TTP), who had underlying lupus nephritis. They all had significant proteinuria and normal Von Willebrand Factor cleaving protease (vWF-CP) levels. Their MAHA fitted better for haemolytic syndrome (HUS) and their cerebral signs were explained either by malignant hypertension or cerebral lupus. Their MAHA only improved when the appropriate treatment for lupus nephritis was given. We propose that the previously described association between SLE and MAHA, in actuality relates to the underlying presence of lupus nephritis causing haemolytic uraemic syndrome, not TTP. Significant proteinuria was present in all cases of MAHA due to lupus nephritis, so may be a useful discriminatory sign. Furthermore the demonstration of a normal vWF-CP assay aided in the distinction between TTP and MAHA due to lupus nephritis. All our patients responded to mycophenolate mofetil suggesting this may be useful in other cases of lupus nephritis causing HUS.

The placental bed in pregnancies complicated by primary antiphospholipid syndrome.

UNLABELLED: Pregnancy in women with primary antiphospholipid syndrome (APS) is frequently associated with placental insufficiency leading to intrauterine growth restriction (IUGR)+/-fetal death, pre-eclampsia, placental abruption, premature delivery or thrombosis. The aim of this study was to investigate the placental bed in APS pregnancies for evidence of impaired trophoblast invasion, endothelial cell activation (ECA) and macrophage infiltration. METHODS: Biopsies from the presumed site of the placental bed were obtained from 12 women with treated primary APS and 16 controls. Immunohistochemical methods were employed to investigate expression of cytokeratin (trophoblasts), alpha-actin (smooth muscle), CD68 (macrophages) and VCAM-1 (as marker of ECA). Fibrinoid and elastin distribution and expression were determined by periodic acid/Schiff and orcein stain, respectively. RESULTS: Three APS pregnancies developed IUGR, one with concurrent pre-eclampsia. Eight of 12 APS biopsies were confirmed to be from the placental bed; one patient failed to meet APS criteria and was excluded from analysis; six included spiral arteries in the biopsy; 11 of 16 controls' biopsies were from the placental bed. APS biopsies had a higher concentration of inflammatory cells (p=0.0001), particularly macrophages (p=0.014). Three APS biopsies showed necrosis with hyperplastic vessels; one demonstrated arterial thromboses, but none had profound vasculopathy/atherosis or ECA. CONCLUSION: Inflammatory mechanisms in the placental bed may contribute to APS pregnancy complications.

Comparison of structured use of routine laboratory tests or near-patient assessment with clinical judgement in the management of bleeding after cardiac surgery.

BACKGROUND: Using algorithms based on point of care coagulation tests can decrease blood loss and blood component transfusion after cardiac surgery. We wished to test the hypothesis that a management algorithm based on near-patient tests would reduce blood loss and blood component use after routine coronary artery surgery with cardiopulmonary bypass when compared with an algorithm based on routine laboratory assays or with clinical judgement. METHODS: Patients (n=102) undergoing elective coronary artery surgery with cardiac bypass were randomized into two groups. In the point of care group, the management algorithm was based on information provided by three devices, the Hepcon, thromboelastography and the PFA-100 platelet function analyser. Management in the laboratory test group depended on rapidly available laboratory clotting tests and transfusion of haemostatic blood components only if specific criteria were met. Blood loss and transfusion was compared between these two groups and with a retrospective case-control group (n=108), in which management of bleeding had been according to the clinician's discretion. RESULTS: All three groups had similar median blood losses. The transfusion of packed red blood cells (PRBCs) and blood components was greater in the clinician discretion group (P<0.05) but there was no difference in the transfusion of PRBCs and blood components between the two algorithm-guided groups. CONCLUSION: Following algorithms based on point of care tests or on structured clinical practice with standard laboratory tests does not decrease blood loss, but reduces the transfusion of PRBCs and blood components after routine cardiac surgery, when compared with clinician discretion. Cardiac surgery services should use transfusion guidelines based on laboratory-guided algorithms, and the possible benefits of point of care testing should be tested against this standard.

The effects of aprotinin on thromboelastography with three different activators.

BACKGROUND: Thromboelastography is used for assessment of hemostasis. Adherence to thromboelastography-guided algorithms and aprotinin administration each decrease bleeding and blood product usage after cardiac surgery. Aprotinin, through inhibition of kallikrein, causes prolongation of the celite-activated clotting time and the activated partial thromboplastin ratio. The aim of this study was to assess the effects of aprotinin on the thromboelastography trace. METHODS: Three activators were used in the thromboelastography: celite (which is widely established), kaolin, and tissue factor. Assessment was performed on blood from volunteers and from patients before and after cardiac surgery. RESULTS: The tissue factor-activated thromboelastography trace was unaffected by the addition of aprotinin. When celite and kaolin were used as activators in the presence of aprotinin, the reaction time (time to clot formation) of the thromboelastography trace was prolonged (P < 0.0001) and the maximum amplitude (clot strength) was decreased (P < 0.05). With celite as an activator, the addition of aprotinin decreased (P < 0.05) the thromboelastography alpha angle (rate of clot extension). The reaction time of the celite-activated trace correlated with the activated partial thromboplastin ratio (P < 0.01). The reaction time of the tissue factor-activated trace correlated with the international normalized ratio (P < 0.01). CONCLUSION: The thromboelastography trace is altered in the presence of aprotinin when celite and kaolin are used as activators but not when tissue factor is the activator.