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.

Computational analysis of peripheral blood smears detects disease-associated cytomorphologies.

Many hematological diseases are characterized by altered abundance and morphology of blood cells and their progenitors. Myelodysplastic syndromes (MDS), for example, are a group of blood cancers characterised by cytopenias, dysplasia of hematopoietic cells and blast expansion. Examination of peripheral blood slides (PBS) in MDS often reveals changes such as abnormal granulocyte lobulation or granularity and altered red blood cell (RBC) morphology; however, some of these features are shared with conditions such as haematinic deficiency anemias. Definitive diagnosis of MDS requires expert cytomorphology analysis of bone marrow smears and complementary information such as blood counts, karyotype and molecular genetics testing. Here, we present Haemorasis, a computational method that detects and characterizes white blood cells (WBC) and RBC in PBS. Applied to over 300 individuals with different conditions (SF3B1-mutant and SF3B1-wildtype MDS, megaloblastic anemia, and iron deficiency anemia), Haemorasis detected over half a million WBC and millions of RBC and characterized their morphology. These large sets of cell morphologies can be used in diagnosis and disease subtyping, while identifying novel associations between computational morphotypes and disease. We find that hypolobulated neutrophils and large RBC are characteristic of SF3B1-mutant MDS. Additionally, while prevalent in both iron deficiency and megaloblastic anemia, hyperlobulated neutrophils are larger in the latter. By integrating cytomorphological features using machine learning, Haemorasis was able to distinguish SF3B1-mutant MDS from other MDS using cytomorphology and blood counts alone, with high predictive performance. We validate our findings externally, showing that they generalize to other centers and scanners. Collectively, our work reveals the potential for the large-scale incorporation of automated cytomorphology into routine diagnostic workflows.

Evaluation of COVID-19 coagulopathy; laboratory characterization using thrombin generation and nonconventional haemostasis assays.

INTRODUCTION: Patients with COVID-19 are known to have a coagulopathy with a thrombosis risk. It is unknown whether this is due to a generalized humoral prothrombotic state or endothelial factors such as inflammation and dysfunction. The aim was to further characterize thrombin generation using a novel analyser (ST Genesia, Diagnostica Stago, Asnières, France) and a panel of haematological analytes in patients with COVID-19. METHODS: Platelet poor plasma of 34 patients with noncritical COVID-19 was compared with 75 patients with critical COVID-19 (as defined by WHO criteria) in a retrospective study by calibrated automated thrombography and ELISA. Patients were matched for baseline characteristics of age and gender. RESULTS: Critical patients had significantly increased fibrinogen, CRP, interleukin-6 and D-dimer compared to noncritical patients. Thrombin generation, in critical patients, was right shifted without significant differences in peak, velocity index or endogenous thrombin potential. Tissue plasminogen activator (tPA), tissue factor pathway inhibitor (TFPI) and vascular endothelial growth factor (VEGF) were significantly increased in the critical versus noncritical patients. Critically ill patients were on haemodiafiltration (31%; heparin used in the circuit) or often received escalated prophylactic low-molecular weight heparin. CONCLUSION: These results confirm increased fibrinogen and D-dimer in critical COVID-19-infected patients. Importantly, disease severity did not increase thrombin generation (including thrombin-antithrombin complexes and prothrombin fragment 1 + 2) when comparing both cohorts; counter-intuitively critical patients were hypocoaguable. tPA, TFPI and VEGF were increased in critical patients, which are hypothesized to reflect endothelial dysfunction and/or contribution of heparin (which may cause endothelial TFPI/tPA release).

Post-operative of bleeding, haemolysis and coagulation in mechanical circulatory support patients.

There are unique complications arising from mechanical support devices but some of the long-term systemic haematological complications are indistinguishable from management problems affecting the care of other patients receiving intermediate to long term care in the cardiac ICU. The field of mechanical cardiac assist device (MCAD) is evolving. Despite major changes in design of these devices the most feared haematological complications have remained unchanged, namely haemolysis, pump thrombosis or thromboembolism. This review article gives an overview over the pathophysiology of MCAD related haematological complications, their management and where possible an outlook on future strategies to prevent such complications. The impact of MCAD on blood is discussed, starting with rheology, common pump mechanisms, current and future pump surface coating materials, anatomical considerations of the connection of the circuit and design of the circuit itself. Moreover, the duration of the cardiovascular support, impact of bleeding complications and other patient factors. This article also covers the impact of long term mechanical cardiac support on the properties of platelets, the anticoagulation strategies and a basic guide to the differential diagnosis of haemolysis is reviewed. The section on anaemia considers anaemia in the wider perioperative setting for patients in critical care having undergone cardiac surgery and also discusses transfusion alternatives.

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.

Pulsatile Versus Nonpulsatile Flow During Cardiopulmonary Bypass: Extent of Hemolysis and Clinical Significance.

Pulsatile flow has been used during cardiopulmonary bypass (CPB) for decades and its use is increasing with advancing extracorporeal technology. Pulsatile flow generates higher circuit pressures and shear forces than nonpulsatile flow at comparable pump flow and patient mean arterial pressure. Very little is known about the effect this has on erythrocytes. We included 62 adult patients (32 in the pulsatile group and 30 in the nonpulsatile group) undergoing elective coronary artery bypass grafting in this prospective observational study. Blood samples were collected at routine sampling times throughout surgery and were analyzed for the presence of free heme and globin using mass spectroscopy. Patient characteristics, CPB, and aortic cross-clamp times, pump flow as well as patient mean arterial pressure were similar in both groups. Maximum circuit pressure in the pulsatile flow group was statistically significantly higher than that in the nonpulsatile flow group (257.12 vs. 190.64 mmHg, p < 0.0001). Both heme and globin levels were higher in the pulsatile flow group. This reached statistical significance with globin at 30 minutes of CPB and with heme after aortic unclamping. We conclude that pulsatile CPB using roller pumps results in a greater extent of hemolysis. The clinical significance, however, is not yet known.

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.

A hypercoagulable state leading to venous limb gangrene associated with occult lung adenocarcinoma.

We report a case of lung adenocarcinoma-associated hypercoagulability leading to venous limb gangrene, managed successfully with argatroban and then dabigatran. Use of idarucizumab permitted diagnostic investigations, leading to targeted antineoplastic therapy with crizotinib, surgical resection with curative intent, and continued survival over 2 years after the index event.

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.

Retrospective Review of a Prothrombin Complex Concentrate (Beriplex P/N) for the Management of Perioperative Bleeding Unrelated to Oral Anticoagulation.

A multicenter, retrospective, observational study of 4-factor prothrombin complex concentrate (PCC) and/or fresh frozen plasma (FFP) use within routine clinical care unrelated to vitamin K antagonists was conducted. The PCC was administered preprocedure for correction of coagulopathy (prophylactic cohort) and treatment of bleeding postsurgery (treatment cohort). Of the 445 patients included, 40 were in the prophylactic cohort (PCC alone [n = 16], PCC and FFP [n = 5], FFP alone [n = 19]) and 405 were in the treatment cohort (PCC alone [n = 228], PCC and FFP [n = 123], FFP alone [n = 54]). Cardiovascular surgery was the most common setting. PCC doses ranged between 500 and 5000 IU. Effectiveness (assessed retrospectively) was reported as effective in 93.0% in the PCC-only group (95% confidence interval, 89.1% to 95.9%), 78.9% (70.8% to 85.6%) with PCC and FFP, and 86.3% (76.2% to 93.2%) with FFP alone. In the treatment cohort, international normalized ratio was significantly reduced in all 3 groups. In patients who received PCC, the rate of thromboembolic events (1.9%) was below rates in the literature for similar procedures. PCCs offer a potential alternative to FFP in the management of perioperative bleeding unrelated to oral anticoagulant therapy.

Current misconceptions in diagnosis and management of iron deficiency.

The prevention and treatment of iron deficiency is a major public health goal. Challenges in the treatment of iron deficiency include finding and addressing the underlying cause and the selection of an iron replacement product which meets the needs of the patient. However, there are a number of non-evidence-based misconceptions regarding the diagnosis and management of iron deficiency, with or without anaemia, as well as inconsistency of terminology and lack of clear guidance on clinical pathways. In particular, the pathogenesis of iron deficiency is still frequently not addressed and iron not replaced, with indiscriminate red cell transfusion used as a default therapy. In our experience, this imprudent practice continues to be endorsed by non-evidence-based misconceptions. The intent of the authors is to provide a consensus that effectively challenges these misconceptions, and to highlight evidence-based alternatives for appropriate management (referred to as key points). We believe that this approach to the management of iron deficiency may be beneficial for both patients and healthcare systems. We stress that this paper solely presents the Authors' independent opinions. No pharmaceutical company funded or influenced the conception, development or writing of the manuscript.

Haemophagocytic lymphohistiocytosis: an elusive syndrome.

Haemophagocytic lymphohistiocytosis is a rare inflammatory condition. It can present in adult general medical patients and is a challenging diagnostic conundrum. This article provides an overview of the pathophysiology and clinical presentation of the syndrome for the general physician who will be rarely confronted with this problem but will have to act promptly when the situation arises. Treatment is also briefly discussed, although this usually occurs in a specialist setting after the diagnosis has been established.

Pulmonary endarterectomy is effective and safe in patients with haemoglobinopathies and abnormal red blood cells: the Papworth experience.

OBJECTIVES: Patients with haemoglobinopathies and congenital haemolytic anaemia constitute a unique population more predisposed to developing chronic thromboembolic pulmonary hypertension (CTEPH). Although pulmonary endarterectomy (PEA) is accepted as the best treatment for CTEPH, PEA in these patients poses significant practical challenges. Apart from a few case reports, the results of PEA in this patient population have not been previously reported. The aim of this study was to review the outcome of PEA in this patient population. METHODS: We performed a retrospective analysis, from our dedicated CTEPH database, of all patients who underwent PEA surgery and had abnormal haemoglobin or congenital haemolytic anaemia. We reviewed diagnosis, exchange transfusions on cardiopulmonary bypass, preoperative and postoperative pulmonary haemodynamic and functional data and outcomes for this group. Paired data analysis was performed by Student's t-test; P < 0.05 was statistically significant. RESULTS: Between the start of our PEA programme in 1997 and April 2015, we performed PEA in 19 patients with haemoglobinopathy or congenital haemolytic anaemia. The mean age was 52 ± 15 years. There were 9 patients with sickle cell trait, 2 with coexisting alpha+ thalassaemia trait, 2 patients with HbSC disease, 2 patients with beta-thalassaemia major, 3 patients with hereditary spherocytosis, 2 patients with stomatocytosis (one with the cryohydrocytosis subtype) and 1 patient with HbC trait. In the 9 HbAS patients, the mean HbS% was 31.9 ± 6%, and in the HbSC patients, the mean HbS% was 46.5 ± 1.3% preoperatively. To reduce this HbS to ≤20%, for safe PEA with deep hypothermic circulatory arrest, we used exchange blood transfusion. Immediately postoperatively, there was a significant improvement in pulmonary vascular resistance (938 ± 462 to 260 ± 167 dyne s cm(-5); P < 0.0001). One patient died 81 days following surgery; 18 patients are alive at a median follow-up of 3.4 ± 3 years. Six months postoperatively, the patients showed significant improvement in New York Heart Association status (P < 0.0001), and in 6-min walk distance from 251 ± 111 to 399 ± 69 m (P < 0.0001). CONCLUSIONS: Results of PEA in this complex patient group were satisfactory. Expert haematological advice is important and exchange blood transfusions may be necessary. The presence of abnormal haemoglobin does not contra-indicate PEA surgery.

Clinical use of low haemoglobin density, transferrin saturation, bone marrow morphology, Perl's stain and other plasma markers in the identification of treatable anaemia presenting for cardiac surgery in a prospective cohort study.

OBJECTIVES: The differential diagnosis between iron deficiency anaemia (IDA) and anaemia of chronic disease (ACD) with or without associated iron deficiency can be challenging. We assessed the use of different parameters, both classical like ferritin, transferrin saturation and stainable bone marrow iron stores, and novel markers such as low haemoglobin density (LHD) and hepcidin to help discriminate between the three entities. This would allow the detection of patients with ACD with associated iron deficiency, which could benefit from iron supplementation that would have otherwise remained undetected. MATERIALS AND METHODS: Prospective and observational cohort study from 2012 to 2013 where 200 anaemic cardiac surgical patients were recruited and 165 were studied. Detailed blood and bone marrow analyses were performed to establish the aetiology of anaemia. RESULTS: Seventy-four patients (44.8%) had ACD and 29 (39%) of these had an elevated LHD indicating concomitant iron deficiency. Hepcidin was inappropriately normal or increased in the IDA and ACD group. Mean hepcidin was however lower in the group with IDA (4.8 ng/mL) than in the ACD group (15.0 ng/mL; p=0.002). Median hepcidin was lower in patients with ACD and iron restriction as indicated by LHD >4% (17.5 ng/mL) than on those with no iron restriction (25.9 ng/mL; p=0.045). In patients with ACD there was no concordance between Perl's stain and LHD. CONCLUSIONS: LHD was superior to hepcidin and bone marrow iron stores in identifying patients with ACD and associated iron deficiency, which would potentially benefit from parenteral iron therapy.

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.