Assessing the impact of different heparin dosing regimens for cardiopulmonary bypass on anticoagulation: the HepDOSE pilot study.

PURPOSE: It has been suggested that a larger heparin dose during cardiopulmonary bypass (CPB) is associated with reduced perioperative coagulopathy and thromboembolic complications. We investigated the effect of different heparin doses during routine elective cardiac surgery. Our primary outcomes include blood loss and transfusion and secondary outcomes investigate the effects on coagulation biomarkers. METHODS: In this prospective pilot trial, we allocated 60 patients undergoing cardiac surgery on CPB in a single tertiary cardiac centre into three groups to receive an initial dose of 300, 400, or 500 units (U) per kilogram of intravenous heparin prior to the commencement of CPB. Blood was sampled after induction of anesthesia, at 30 and 60 min of CPB, and three minutes after heparin reversal with protamine. Samples were analyzed for fibrinopeptide A (FPA), fibrinopeptide B (FPB), D-dimer, and thrombin-antithrombin (TAT) complexes. Postoperative blood loss and transfusion was measured for the first 24-hr period after surgery. RESULTS: The total mean (95% CI) administered heparin dose in the 300 U·kg-1, 400 U·kg-1, and 500 U·kg-1 groups were 39,975 (36,528 to 43,421) U, 43,195 (36,940 to 49,449) U and 47,900 (44,807 to 50,992) U, respectively. There were no statistically significant differences in FPA, FPB or D-dimer levels at the measured time intervals. There was a trend towards lower TAT levels while on CPB with greater heparin dosing, which was statistically significant after the administration of protamine. The clinical significance appears to be negligible, as there is no difference in overall blood loss and amount of packed red blood cell transfusion or other blood product transfusion. CONCLUSION: This pilot study indicates that, while larger heparin dosing for routine cardiac surgery results in subtle biochemical changes in coagulation, there is no demonstrable benefit in postoperative blood loss or transfusion requirements.

RéSUMé: OBJECTIF: Il a été suggéré qu'une dose plus élevée d'héparine pendant la circulation extracorporelle (CEC) serait associée à une réduction de la coagulopathie périopératoire et des complications thromboemboliques. Nous avons étudié l'effet de différentes doses d'héparine au cours d'une chirurgie cardiaque non urgente de routine. Nos critères d'évaluation principaux comprenaient la perte de sang et la transfusion, et les critères d'évaluation secondaires exploraient les effets sur les biomarqueurs de la coagulation. MéTHODE: Dans cette étude pilote prospective, nous avons réparti 60 patient·es bénéficiant d'une chirurgie cardiaque sous CEC dans un seul centre cardiaque tertiaire en trois groupes à recevoir une dose initiale de 300, 400 ou 500 unités (U) par kilogramme d'héparine intraveineuse avant le début de la CEC. Le sang a été prélevé après l'induction de l'anesthésie, à 30 et 60 minutes de CEC, et trois minutes après la neutralisation de l'héparine avec la protamine. Les échantillons ont été analysés pour les complexes fibrinopeptide A (FPA), fibrinopeptide B (FPB), D-dimère et thrombine-antithrombine (TAT). La perte de sang postopératoire et la transfusion ont été mesurées pendant la première période de 24 heures après la chirurgie. RéSULTATS: La dose moyenne totale (IC 95 %) d'héparine administrée dans les 300 U·kg−1, 400 U·kg−1, et 500 U·kg−1 était de 39 975 (36 528 à 43 421) U, 43 195 (36 940 à 49 449) U et 47 900 (44 807 à 50 992) U, respectivement. Il n'y avait aucune différence statistiquement significative dans les taux de FPA, FPB ou D-dimères aux intervalles de temps mesurés. Une tendance à des niveaux de TAT plus bas pendant la CEC a été observée avec une dose d'héparine plus élevée, ce qui était statistiquement significatif après l'administration de protamine. La signification clinique semble négligeable, car il n'y a pas de différence dans la perte de sang globale et la quantité de transfusion de concentrés globulaires ou d'autres produits sanguins. CONCLUSION: Cette étude pilote indique que, bien qu'une dose plus importante d'héparine pour la chirurgie cardiaque de routine entraîne des changements biochimiques subtils dans la coagulation, il n'y a aucun avantage démontrable en matière de saignement postopératoire ou de besoins transfusionnels.

Transplant-associated thrombotic microangiopathy and immune haematological complications following intestine-containing organ transplantation: experience from over 100 consecutive cases.

Descriptions of passenger lymphocyte syndrome (PLS), immune cytopenias and transplant-associated thrombotic microangiopathy (TA-TMA) after intestine-containing transplants remain scarce. We describe our centre's experience of these complications from 2007 to 2019. Ninety-six patients received 103 transplants. PLS occurred in 9 (9%) patients (median 12 days post-transplant); all due to ABO antibodies. There were 31 minor ABO mismatch transplants. No patient required change in immunosuppression. Immune cytopenias (excluding PLS) occurred in six patients at an incidence of 1·7/100 patient years; three immune haemolysis, one immune thrombocytopenia, one acquired Glanzmann's and one immune neutropenia; 50% occurred with other cytopenias. All cases eventually responded to treatment, with a median of four treatments (range 1-8) and 5/6 were treated with rituximab. One patient with immune haemolysis required bortezomib. Complications were common in patients with immune cytopenias; 4/6 with infection needing intravenous antibiotics and 3/6 with venous thromboembolism. In 3/6 cases, a secondary cause for the immune cytopenia was evident. Switching from tacrolimus to ciclosporin was not necessary. There were five cases of transplant-associated thrombotic microangiopathy (TA-TMA; 1·5/100 patient years) requiring calcineurin inhibitor withdrawal; two cases associated with acute rejection. Two cases were managed with plasma exchange, one with plasma infusions and one with eculizumab. Further research in this patient group is required.

Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.

A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multidisciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbor variants associated with rare bleeding, thrombotic, or platelet disorders (BTPDs). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count, and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 745 unique variants, including copy number variants (CNVs) and intronic variants, as pathogenic, likely pathogenic, or variants of uncertain significance. Half of these variants (50.9%) are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BTPDs. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 894 index patients providing evidence that introducing an HTS genetic test is a valuable addition to laboratory diagnostics in patients with a high likelihood of having an inherited BTPD.

Evaluation of Point-of-Care ACT Coagulometers and Anti-Xa Activity During Cardiopulmonary Bypass.

OBJECTIVE: The activated clotting time (ACT) is used worldwide to confirm safe heparin anticoagulation for cardiopulmonary bypass. For the present study, the performances of 2 commonly used ACT devices were compared with each other and with anti-Xa levels throughout the surgical procedure in order to understand whether they can be used interchangeably. DESIGN: Prospective study. SETTING: Tertiary care center. PARTICIPANTS: The study comprised 33 elective adult cardiac surgical patients. INTERVENTIONS: Blood samples were taken at standard times throughout the surgery (after induction, after heparin bolus, 4 samples at 30-minute intervals during cardiopulmonary bypass, after protamine), and ACTs and anti-Xa levels were analyzed. Data were compared using receiver operating characteristics and LOESS regression. MEASUREMENTS AND MAIN RESULTS: The correlation between anti-Xa levels and the Hemochron ACT (Instrumentation Laboratory, Bedford, MA) was acceptable (r = 0.82, 95% confidence interval [CI] 0.757-0.868; p < 0.0001), as was the correlation between anti-Xa levels and the i-STAT (Abbott Point of Care, Abbott Park, IL) (r = 0.81, 95% CI 0.738-0.858; p < 0.0001). The correlation between the 2 ACT methods was poorer (r = 0.77, 95% CI 0.707-0.828; p < 0.0001) than their correlation to anti-Xa levels. When compared with anti-Xa levels, the sensitivity and specificity were mediocre for both devices, although the i-STAT performed better than the Hemochron ACT. The Hemochron ACT read higher values than the i-STAT ACT throughout the course of the surgery. CONCLUSION: The correlation between the Hemochron ACT and i-STAT ACT is moderate, and they have different sensitivity and specificity when compared with anti-Xa levels. This suggests that ACT devices should not be used interchangeably, but cut-off values for safe anticoagulation during cardiopulmonary bypass should be determined for each type of device, particularly when switching supplier.

Are We Able to Dose Protamine Accurately Yet? A Review of the Protamine Conundrum.

Without anticoagulation, cardiopulmonary bypass would not have developed over the last nearly 60 years into one of the most influential innovations in medicine; without the ability to reverse anticoagulation, cardiac surgery might not have become the common intervention, which is now practiced globally. Despite the recent breathtaking developments in extracorporeal technology, heparin and protamine remain the pillars of anticoagulation and its reversal until this day. However, there is still much controversy in particular about protamine dosing regimens. A number of recent publications investigating various approaches to dosing protamine have rekindled this debate. This review is seeking to capture the current thinking about protamine dosing after cessation of cardiopulmonary bypass.

Persistence of Imported Malaria Into the United Kingdom: An Epidemiological Review of Risk Factors and At-risk Groups.

BACKGROUND: The United Kingdom documented a decline of >30% in imported cases of malaria annually between 1996 and 2003; however, there are still approximately 1700 cases and 5-10 deaths each year. Prophylaxis health messages focus on families returning to their country of origin. METHODS: We reviewed 225 records of patients seen in Cambridge University Hospital Foundation Trust [CUHFT], a tertiary referral center in Cambridge, England. All records of patients seen in CUHFT between 2002-2016 were analyzed in the context of national figures from Public Health England. RESULTS: Between 2004-2016, there was no decrease in imported cases of malaria locally or nationally. Plasmodium falciparum remains responsible for most imported infections (66.7%); Plasmodium vivax contributed 15.1%, Plasmodium malariae 4%, and Plasmodium ovale 6.7%; 7.5% (17/225) of patients had an incomplete record. Most cases were reported in people coming from West Africa. Sierra Leone and the Ivory Coast had the highest proportions of travelers being infected at 8 and 7 per 1000, respectively. Visiting family in the country of origin (27.8%) was the commonest reason for travel. However, this was exceeded by the combined numbers traveling for business and holidays (22.5% and 20.1%, respectively). Sixty percent of patients took no prophylaxis. Of those who did, none of the patients finished their chemoprophylaxis regimen. CONCLUSIONS: Significant numbers of travelers to malarious countries still take no chemoprophylaxis. Health advice about prophylaxis before travel should be targeted not only at those visiting family in their country of origin but also to those traveling for holiday and work.

Catastrophic sickling crisis in patient undergoing cardiac transplantation with sickle cell trait.

There is debate in the literature regarding management of patients with sickle cell trait (SCT) undergoing cardiac surgery, since it is recognized that cardiopulmonary bypass presents many precipitating risk factors for a sickling crisis. Despite this, many report successful outcomes without any modification to perioperative management. A 49-year-old woman with SCT (HbS 38%) with postpartum cardiomyopathy underwent cardiac transplantation. The patient was cooled to 34.0°C and retrograde cold blood cardioplegia was infused continuously. The cold ischemic time was 219 minutes and warm ischemic time 46 minutes. After weaning from bypass, she developed global cardiac dysfunction requiring veno-arterial extracorporeal membrane oxygenation. The circuit suddenly stopped, requiring emergency reinstitution of bypass; the circuit had clotted. Transesophageal-echocardiogram revealed thrombus within the left atrium and ventricle. There was no recovery of cardiac function and the patient developed multiorgan failure. At postmortem there was extensive myocardial infarction with evidence of widespread catastrophic intravascular red-cell sickling. This case highlights the danger of complacency in patients with SCT, offering a learning opportunity for the cardiothoracic community to highlight the most serious complication that can occur in this group of patients. We have learned that SCT and cardiac surgery is not a benign combination.

Three consecutive cases of fatal intraoperative intracardiac thrombosis associated with the initiation of venoarterial extracorporeal membrane oxygenation in the presence of aprotinin.

Central venoarterial extracorporeal membrane oxygenation has been used since the 1970s to support patients with cardiogenic shock following cardiac surgery. Despite this, in-hospital mortality is still high, and although rare, thrombus within the cardiac chambers or within the extracorporeal membrane oxygenation circuit is often fatal. Aprotinin is an antifibrinolytic available in Europe and Canada, though not currently in the United States. Due to historical safety concerns, use of aprotinin is generally limited and is commonly reserved for patients with the highest bleeding risk. Given the limited availability of aprotinin over the last decade, it is not surprising to find a complete absence of literature describing the use of venoarterial extracorporeal membrane oxygenation in the presence of aprotinin. We present three consecutive cases of rapid fatal intraoperative intracardiac thrombosis associated with post-cardiotomy central venoarterial extracorporeal membrane oxygenation in patients receiving aprotinin.

Hb Penang [ß78(EF2)Leu→Pro, HBB: c.236T>C]: a Novel ß-Globin Variant.

We report a novel hemoglobin (Hb) variant with a ß chain amino acid substitution at codon 78 (CTG>CCG) (HBB: c.236T>C), detected through prenatal screening via capillary electrophoresis (CE) in an otherwise healthy and asymptomatic 38-year-old female of Southeast Asian ancestry. The variant, named Hb Penang after the proband's Malaysian city of origin, underwent further characterization through high performance liquid chromatography (HPLC), reversed phase HPLC, Sanger sequencing, isopropanol stability testing and isoelectric focusing (IEF).

The place of viscoelastic testing in clinical practice.

Hellmut Hartert was the first person to exploit the viscoelastic properties of clotting blood to measure blood coagulation in 1948. Since then, the technology has improved, allowing these analyses to be performed as point-of-care tests with immediately-available results. The addition of several activators and inhibitors to the original assay creates a panel of tests able to quantify the different aspects of blood clotting that can rival conventional laboratory assays. However, although much progress has been made, the standardization and validation of these tests still need improvement. Viscoelastic analyses of blood coagulation are mainly used to guide haemostatic therapy in bleeding patients and have proven superior to standard clotting tests in some circumstances. There is potential to extend their use to other areas, such as drug monitoring, and diagnosis and management of congenital bleeding disorders. The forthcoming cartridge-based assays are expected to improve the reliability and usability of viscoelastic assays of blood coagulation but high quality clinical trials remain urgently needed to determine their exact place, benefit and cost effectiveness.

Agreement between ACT and aPTT during extracorporeal membrane oxygenation shows intra- and inter-individual variation.

AIM: We explored the relationship between activated clotting time (ACT) and activated partial thromboplastin time (aPTT) when used to monitor anticoagulation in patients undergoing extracorporeal membrane oxygenation (ECMO) support. METHODS: Data obtained in patients undergoing ECMO support between October 2012 and August 2013 in a single centre were reviewed. Clinical data were extracted from our Clinical Information System and ECMO database. ACT and aPTT values were paired when taken from the same patient, with the ACT preceding the aPTT and the heparin infusion rate was kept constant between samples. The aPTT and ACT were normalized by dividing by the mean of their respective reference ranges and are referred to as APR and N-ACT, respectively. Bivariate analysis and Bland-Altman plots were used to assess correlation and agreement. Mixed effects regression was used to model the effects of variables, including platelet count, creatinine and urea levels, plasma free haemoglobin, white cell count and ECMO flow rate on concordance between APR and N-ACT measurements. RESULTS: The Pearson product-moment correlation coefficient in 15 patients was calculated as r=0.55. The Bland-Altman plot shows a mean difference between the APR and the N-ACT of -0.08. The 95% limits of agreement were -0.67 to 0.51. Results from mixed effects regression analysis on data from the 15 patients identified platelet count (and thrombocytopenia) and urea as significant independent predictors of concordance between APR and N-ACT. CONCLUSION: We report a moderate degree of positive correlation between APR and N-ACT. We conclude that there is poor agreement between the ACT and aPTT for the heparin concentrations in patients supported with ECMO. Our results indicate that platelet count and urea are significant independent variables affecting concordance between ACT and aPTT measurements.

Extracorporeal membrane oxygenation for the treatment of adult sickle cell acute chest syndrome.

Sickle cell disease (SCD) is a hereditary haemoglobinopathy that results in polymerization of haemoglobin molecules and subsequent vaso-occlusion. A common cause of death in adults is acute chest syndrome (AChS) with resulting hypoxemic respiratory failure.Veno-venous extracorporeal membrane oxygenation (VV-ECMO) has been used successfully in acutely reversible respiratory failure when conventional mechanical ventilation has been unable to adequately oxygenate and ventilate in a lung-protective fashion.We present an adult SCD patient with severe respiratory failure due to AChS, successfully treated with VV-ECMO. We also discuss some of the technical challenges and considerations when using ECMO in the SCD patient.

Hb Kalavasos [HBA2: c.275T > A; p.Leu92His]: a Novel α Chain Hemoglobin Variant.

We present a case of a novel pathogenic variant, Hb Kalavasos [α91(FG3)Leu→His (α2); HBA2: c.275T > A; p.Leu92His (NM_000517.4)]; this codon was previously numbered 91 on the α2-globin gene that was discovered following routine Hb A1c testing on a 65-year-old female of Cypriot origin. The band, seen by high performance liquid chromatography (HPLC) but not capillary zone electrophoresis (CZE), was confirmed as a hitherto undescribed a chain variant, that we have named Hb Kalavasos for the Cypriot village of family origin of the proband.

An exploratory cohort study comparing prothrombin complex concentrate and fresh frozen plasma for the treatment of coagulopathy after complex cardiac surgery.

BACKGROUND: Administration of coagulation factor concentrates to treat bleeding after cardiac surgery with cardiopulmonary bypass might be a strategy for reducing allogeneic blood transfusions, particularly for patients treated with warfarin preoperatively. We performed an exploratory analysis on whether the use of prothrombin complex concentrate (PCC) is safe and effective compared with fresh frozen plasma (FFP) to treat coagulopathy after pulmonary endarterectomy surgery with deep hypothermic circulatory arrest. METHODS: Consecutive adult patients who underwent pulmonary endarterectomy surgery between January 2010 and September 2012 and received PCC or FFP to treat coagulopathy were studied. Blood loss during the first 12 hours of admission to the intensive care unit and patient outcomes were compared with propensity score adjustment. RESULTS: Three hundred fifty-one patients underwent pulmonary endarterectomy surgery, all of whom had warfarin discontinued for up to 5 days before surgery; bleeding complications requiring transfusion of blood products were observed in 108 (31%) patients. Of those, 55 received only FFP and 45 received only PCC, whereas 8 received both. Blood loss was significantly greater in the FFP group compared with the PCC group after 12 hours (median [interquartile range], 650 mL [325-1075] vs 277 mL [175-608], P = 0.008). However, there was no difference in the frequency of patients receiving a red blood cell transfusion (number [percent], 44 [80%] vs 34 [76%], P = 0.594) or in the number of units of red blood cells transfused (median [interquartile range], 2 [1-4] vs 3 [1-5] units, P = 0.181). The final propensity score included preoperative international normalized ratio, postoperative activated partial thromboplastin time, and postoperative platelet count. After inclusion of the propensity score in the regression analyses, there were no differences between patients receiving only PCC and patients receiving only FFP in the need for renal replacement therapy (odds ratio [OR] 2.39, 95% confidence interval [CI] 0.51-11.20, P = 0.27), 30-day-mortality (OR 0.32, 95% CI 0.03-3.36, P = 0.35), intracranial hemorrhage (OR 0.73, 95% CI 0.14-3.89, P = 0.71), hospital length of stay (hazard ratio 0.77, 95% CI 0.50-1.19, P = 0.24), or duration of intensive care stay (hazard ratio 0.91, 95% CI 0.59-1.40, P = 0.66). CONCLUSIONS: This retrospective analysis suggests that PCC may be an alternative to FFP in patients previously treated with warfarin who are coagulopathic after major cardiac surgery. Randomized controlled studies powered to evaluate efficacy and important postoperative outcomes for patients receiving PCC versus FFP for coagulopathic bleeding after cardiopulmonary bypass are warranted.