Pleiotropic Effects of Heparin and its Monitoring in the Clinical Practice.

Unfractionated heparin (UFH) was uncovered in 1916, has been used as an anticoagulant since 1935, and has been listed in the World Health Organization's Model List of Essential Medicines. Despite the availability of many other anticoagulants, the use of heparin (either low molecular weight heparin [LMWH] or UFH) is still substantial. Heparin has pleotropic effects including anticoagulant and several nonanticoagulant properties such as antiproliferative, anti-inflammatory activity, and anticomplement effects. Although UFH has been widely replaced by LMWH, UFH is still the preferred anticoagulant of choice for patients undergoing cardiopulmonary bypass surgery, extracorporeal membrane oxygenation, and patients with high-risk mechanical cardiac valves requiring temporary bridging with a parenteral anticoagulant. UFH is a highly negatively charged molecule and binds many positively charged molecules, hence has unpredictable pharmacokinetics, and variable anticoagulant effect on an individual patient basis. Therefore, anticoagulant effects of UFH may not be proportional to the dose of UFH given to any individual patient. In this review, we discuss the anticoagulant and nonanticoagulant activities of UFH, differences between UFH and LMWH, when to use UFH, different methods of monitoring the anticoagulant effects of UFH (including activated partial thromboplastin time, heparin anti-Xa activity level, and activated clotting time), while discussing pros and cons related to each method and comparison of clinical outcomes in patients treated with UFH monitored with different methods based on available evidence.

Dilemmas in the diagnosis and management of antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is characterized by thrombosis (which may be venous, arterial, or microvascular) and/or pregnancy morbidity in association with persistently positive antiphospholipid antibodies. Although thrombosis and pregnancy morbidity are the main clinical criteria for a diagnosis of APS in the revised Sapporo (Sydney) criteria, recently published American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for APS have significantly refined the diagnostic algorithm to include a scoring system clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular thrombosis, obstetric, cardiac valve, and hematologic). Diagnosis of APS is complicated by the fact that significant heterogeneity exists in patients' clinical presentation, underlying vascular risk factors, and methods of detecting antiphospholipid antibodies. Despite the autoimmune nature of APS, anticoagulation remains the main strategy for secondary prevention of thrombosis. Furthermore, optimal antithrombotic treatment in APS patients with arterial thrombosis remains controversial due to a paucity of data from randomized controlled studies. In this paper, we present 2 cases and highlight the diagnostic and therapeutic challenges they pose and how we approach them in the light of current evidence.

Impact of very low dose rivaroxaban in addition to dual antiplatelet therapy on endogenous fibrinolysis in acute coronary syndrome: The VaLiDate-R study.

BACKGROUND: Impaired endogenous fibrinolysis is adverse cardiovascular risk factor in acute coronary syndrome (ACS) patients. Addition of very low dose rivaroxaban (VLDR) to dual antiplatelet therapy (DAPT) reduces cardiovascular events but increases bleeding. OBJECTIVE: We aimed to assess whether addition of VLDR to DAPT can enhance endogenous fibrinolysis. METHODS: In a prospective, open-label trial, we assessed endogenous fibrinolysis in whole blood, in 549 patients with ACS using the Global Thrombosis Test (GTT) and Thromboelastography (TEG). Patients (n = 180) who demonstrated impaired endogenous fibrinolysis (lysis time [LT] >2000s with the GTT) were randomised 1:1:1 to (i) clopidogrel 75 mg daily; (ii) clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily; or (iii) ticagrelor 90 mg twice daily, for 30 days, in addition to aspirin. Fibrinolytic status was assessed at 0, 2, 4 and 8 weeks. The primary outcome was the change in LT from admission to week 4. We also measured thrombotic occlusion time (OT) at high shear, and rivaroxaban level. RESULTS: There was no difference between the groups with respect to LT or clot lysis with TEG, and no change in these parameters compared to baseline during study drug allocation. In the rivaroxaban plus clopidogrel group, OT was prolonged compared to the other groups, although rivaroxaban levels were low, suggesting non-compliance. CONCLUSION: Addition of rivaroxaban 2.5 mg twice daily to DAPT does not affect endogenous fibrinolysis of thrombus formed at either high or low shear. Further studies are needed to determine whether higher doses of rivaroxaban can favourably modulate fibrinolysis. CONDENSED ABSTRACT: Impaired endogenous fibrinolysis is a strong risk factor in ACS. We aimed to assess whether adding very low dose rivaroxaban (VLDR) to DAPT can enhance fibrinolysis. Fibrin and clot lysis were assessed in whole blood. ACS patients with impaired fibrinolysis were randomised 1:1:1 to clopidogrel 75 mg daily; clopidogrel 75 mg plus VLDR; or ticagrelor 90 mg twice daily, in addition to aspirin. At 30-days, there was no difference in lysis time between the groups, nor change from baseline. VLDR does not improve fibrinolysis at high or low shear. Further studies are needed to determine whether alternative antithrombotic regimens can enhance endogenous fibrinolysis.

Adult Highlights From the Extracorporeal Life Support Organization Registry: 2017-2022.

The Extracorporeal Life Support Organization (ELSO) registry captures clinical data and outcomes on patients receiving extracorporeal membrane oxygenation (ECMO) support across the globe at participating centers. It provides a very unique opportunity to benchmark outcomes and analyze the clinical course to help identify ways of improving patient outcomes. In this review, we summarize select adult ECMO articles published using the ELSO registry over the past 5 years. These articles highlight innovative utilization of the registry data in generating hypotheses for future clinical trials. Members of the ELSO Scientific Oversight Committee can be found here: https://www.elso.org/registry/socmembers.aspx .

The immunology of long COVID.

Long COVID is the patient-coined term for the disease entity whereby persistent symptoms ensue in a significant proportion of those who have had COVID-19, whether asymptomatic, mild or severe. Estimated numbers vary but the assumption is that, of all those who had COVID-19 globally, at least 10% have long COVID. The disease burden spans from mild symptoms to profound disability, the scale making this a huge, new health-care challenge. Long COVID will likely be stratified into several more or less discrete entities with potentially distinct pathogenic pathways. The evolving symptom list is extensive, multi-organ, multisystem and relapsing-remitting, including fatigue, breathlessness, neurocognitive effects and dysautonomia. A range of radiological abnormalities in the olfactory bulb, brain, heart, lung and other sites have been observed in individuals with long COVID. Some body sites indicate the presence of microclots; these and other blood markers of hypercoagulation implicate a likely role of endothelial activation and clotting abnormalities. Diverse auto-antibody (AAB) specificities have been found, as yet without a clear consensus or correlation with symptom clusters. There is support for a role of persistent SARS-CoV-2 reservoirs and/or an effect of Epstein-Barr virus reactivation, and evidence from immune subset changes for broad immune perturbation. Thus, the current picture is one of convergence towards a map of an immunopathogenic aetiology of long COVID, though as yet with insufficient data for a mechanistic synthesis or to fully inform therapeutic pathways.

Thombosis, major bleeding, and survival in COVID-19 supported by veno-venous extracorporeal membrane oxygenation in the first vs second wave: a multicenter observational study in the United Kingdom.

BACKGROUND: Bleeding and thrombosis are major complications of veno-venous (VV) extracorporeal membrane oxygenation (ECMO). OBJECTIVES: To assess thrombosis, major bleeding (MB), and 180-day survival in patients supported by VV-ECMO between the first (March 1 to May 31, 2020) and second (June 1, 2020, to June 30, 2021) waves of the COVID-19 pandemic. METHODS: An observational study of 309 consecutive patients (aged ≥18years) with severe COVID-19 supported by VV-ECMO was performed in 4 nationally commissioned ECMO centers in the United Kingdom. RESULTS: Median age was 48 (19-75) years, and 70.6% were male. Probabilities of survival, thrombosis, and MB at 180 days in the overall cohort were 62.5% (193/309), 39.8% (123/309), and 30% (93/309), respectively. In multivariate analysis, an age of >55 years (hazard ratio [HR], 2.29; 95% CI, 1.33-3.93; P = .003) and an elevated creatinine level (HR, 1.91; 95% CI, 1.19-3.08; P = .008) were associated with increased mortality. Correction for duration of VV-ECMO support, arterial thrombosis alone (HR, 3.0; 95% CI, 1.5-5.9; P = .002) or circuit thrombosis alone (HR, 3.9; 95% CI, 2.4-6.3; P < .001) but not venous thrombosis increased mortality. MB during ECMO had a 3-fold risk (95% CI, 2.6-5.8, P < .001) of mortality. The first wave cohort had more males (76.7% vs 64%; P = .014), higher 180-day survival (71.1% vs 53.3%; P = .003), more venous thrombosis alone (46.4% vs 29.2%; P = .02), and lower circuit thrombosis (9.2% vs 28.1%; P < .001). The second wave cohort received more steroids (121/150 [80.6%] vs 86/159 [54.1%]; P < .0001) and tocilizumab (20/150 [13.3%] vs 4/159 [2.5%]; P = .005). CONCLUSION: MB and thrombosis are frequent complications in patients on VV-ECMO and significantly increase mortality. Arterial thrombosis alone or circuit thrombosis alone increased mortality, while venous thrombosis alone had no effect. MB during ECMO support increased mortality by 3.9-fold.

Mechanisms regulating heterogeneity of hemostatic gene expression in endothelial cells.

The hemostatic system involves an array of circulating coagulation factors that work in concert with platelets and the vascular endothelium to promote clotting in a space- and time-defined manner. Despite equal systemic exposure to circulating factors, bleeding and thrombotic diseases tend to prefer specific sites, suggesting an important role for local factors. This may be provided by endothelial heterogeneity. Endothelial cells differ not only between arteries, veins, and capillaries but also between microvascular beds from different organs, which present unique organotypic morphology and functional and molecular profiles. Accordingly, regulators of hemostasis are not uniformly distributed in the vasculature. The establishment and maintenance of endothelial diversity are orchestrated at the transcriptional level. Recent transcriptomic and epigenomic studies have provided a global picture of endothelial cell heterogeneity. In this review, we discuss the organotypic differences in the hemostatic profile of endothelial cells; we focus on 2 major endothelial regulators of hemostasis, namely von Willebrand factor and thrombomodulin, to provide examples of transcriptional mechanisms that control heterogeneity; finally, we consider some of the methodological challenges and opportunities for future studies.

A Comparison of Long-Term Outcomes in Patients Managed With Venovenous Extracorporeal Membrane Oxygenation in the First and Second Waves of the COVID-19 Pandemic in the United Kingdom.

OBJECTIVES: Early studies of venovenous extracorporeal membrane oxygenation (ECMO) in COVID-19 have revealed similar outcomes to historical cohorts. Changes in the disease and treatments have led to differences in the patients supported on venovenous ECMO in the first and second waves. We aimed to compare these two groups in both the acute and follow-up phase. DESIGN: Retrospective single-center cohort study comparing mortality at censoring date (November 30, 2021) and decannulation, patient characteristics, complications and lung function and quality of life (QOL-by European Quality of Life 5 Dimensions 3 Level Version) at first follow-up in patients supported on venovenous ECMO between wave 1 and wave 2 of the COVID-19 pandemic. SETTING: Critical care department of a severe acute respiratory failure service. PATIENTS: Patients supported on ECMO for COVID-19 between wave 1 (March 17, 2020, to August 31, 2020) and wave 2 (January 9, 2020, to May 25, 2021). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred twenty-three patients were included in our analysis. Survival at censoring date (χ 2 , 6.35; p = 0.012) and decannulation (90.4% vs 70.0%; p < 0.001) was significantly lower in the second wave, while duration of ECMO run was longer (12.0 d [18.0-30.0 d] vs 29.5 d [15.5-58.3 d]; p = 0.005). Wave 2 patients had longer application of noninvasive ventilation (NIV) prior to ECMO and a higher frequency of barotrauma. Patient age and NIV use were independently associated with increased mortality (odds ratio 1.07 [1.01-1.14]; p = 0.025 and 3.37 [1.12-12.60]; p = 0.043, respectively). QOL and lung function apart from transfer coefficient of carbon monoxide corrected for hemoglobin was similar at follow-up across the waves. CONCLUSIONS: Most patients with COVID-19 supported on ECMO in both waves survived in the short and longer term. At follow-up patients had similar lung function and QOL across the two waves. This suggests that ECMO has an ongoing role in the management of a carefully selected group of patients with COVID-19.

Impact of thromboprophylaxis on hospital acquired thrombosis following discharge in patients admitted with COVID-19: Multicentre observational study in the UK.

Post-discharge thromboprophylaxis in patients admitted with COVID-19 remains controversial. We aimed to determine the impact of thromboprophylaxis on hospital acquired thrombosis (HAT) in patients (≥18 years) discharged following admission for COVID-19 in an observational study across 26 NHS Trusts in the UK (01.04.2020-31.12.2021). Overall, 8895 patients were included to the study: 971 patients were discharged with thromboprophylaxis and propensity score matched (PSM) with a desired ratio of 1:1, from patients discharged without thromboprophylaxis. Patients with heparin induced thrombocytopenia, major bleeding during admission and pregnant women were excluded. As expected from 1:1 PSM, no difference was observed in parameters between the two groups, including duration of hospital stay, except the thromboprophylaxis group had a significantly higher proportion who had received therapeutic dose anticoagulation during admission. There were no differences in the laboratory parameters especially D-dimers between the two groups at admission or discharge. Median duration of thromboprophylaxis following discharge from hospital was 4 weeks (1-8 weeks). No difference was found in HAT in patients discharged with TP versus no TP (1.3% vs. 0.92%, p = 0.52). Increasing age and smoking significantly increased the risk of HAT. Many patients in both cohorts had raised D-dimer at discharge but D-dimer was not associated with increased risk of HAT.

Hydroxychloroquine as an Immunomodulatory and Antithrombotic Treatment in Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is an acquired highly prothrombotic disorder in which thrombo-inflammatory antiphospholipid antibodies (aPL) cause thrombosis via multiple mechanisms, including endothelial damage and activation. Obstetric complications in APS are caused by placental thrombosis, inflammation and complement activation. Anticoagulation is poorly effective in some patients especially those with triple positive aPL who are at ~30% risk of thrombosis recurrence within 10 years. Increasing therapeutic anticoagulation intensity may be beneficial but leads to excess bleeding with serious complications, such as intracerebral haemorrhage. Nonetheless, anticoagulation is still the mainstay of treatment despite the autoimmune nature of APS. The antimalarial immunomodulatory drug hydroxychloroquine (HCQ) has been used for many years for the treatment of inflammatory rheumatic diseases. HCQ has complex pleiotropic mechanisms of action upon multiple cell types. The proposed biological processes that HCQ regulates support the hypothesis that it may be a successful adjunctive treatment in the prevention of recurrent thrombosis and pregnancy complications.

Bleeding and thrombotic complications and their impact on mortality in patients supported with left ventricular assist device for cardiogenic shock.

INTRODUCTION: Thrombosis and bleeding are major complications in patients supported with left ventricular assist devices (LVADs). We aimed to assess the incidence of bleeding and thrombosis in patients supported with a HeartWare left ventricular assist device (HVAD), their predictive factors and their impact on mortality. METHODS: A single centre retrospective observational study of patients supported with HVAD over 5 years from January 2015 to October 2020. RESULTS: A total 139 patients (median age 52.5, 72.1% male) were included for analysis. The probability of 1-year survival was 73.1%. Advanced age (>60 years) and EuroSCORE II score (>20%) were independently associated with reduced survival. Major bleeding and thrombosis occurred in 46.8% and 35.3% respectively. Secondary mechanical circulatory support (MCS) increased likelihood of experiencing major bleeding (HR: 2.76, 95%1.65-4.62, p < 0.0001) whilst patients receiving aspirin were protected from bleeding and thrombosis (HR: 0.34 95% CI 0.19-0.58, p < 0.001). Pre-operative anaemia (HR: 3.02, 95% CI: 1.6-5.7, p = 0.014) and use of a secondary MCS device (HR: 2.78, 95% CI: 1.2-6.3, p = 0.001) were associated with an increased risk of thrombosis. Patients with any major bleeding (with or without thrombosis) had a 7.68-fold (95% CI 3.5-16.8) increased risk of death compared to those without. In contrast, 'thrombosis only' patients had 4.23-fold (95% CI 1.8-10.2) increased risk of death compared to those without thrombosis. The risk of mortality was increased in patients with any thrombosis and the risk of death was highest in patients with major bleeding and thrombosis (HR: 16.49 [95% CI 7.7-35.3]). CONCLUSIONS: Major bleeding and thrombosis significantly increase the 1-year mortality. Optimal perioperative haemostasis and anticoagulation remains crucial in patients supported with HVAD.

Complement activation during cardiopulmonary bypass and association with clinical outcomes.

In this prospective, single-centre observational study of 30 patients undergoing cardiopulmonary bypass (CPB), the effect of unfractionated heparin (UFH), CPB surgery and protamine sulphate on complement and on post-operative blood loss were assessed. Although C3 and C4 levels decreased significantly immediately following the administration of UFH, C3a, C5a, Bb fragment and SC5b-9 remained unchanged. During CPB, C3 and C4 continued to fall whilst both alternative and classical pathways activation markers, Bb, C3a, C5a and SC5b-9 increased significantly. Protamine sulphate had no effect on classical pathway components or activation markers but decreased alternative pathway activation marker Bb. Over the 12-24 h post-surgery, both classical and alternative pathway activation markers returned to baseline, whilst C3 and C4 levels increased significantly but not to baseline values. Total drain volume 24 h after the surgery showed a moderate inverse correlation with post-protamine C3 (r = -0.46, p = 0.01) and C4 (r = -0.57, p = 0.0009) levels, whilst a moderate positive correlation was observed with post-protamine C3a (r = 0.46, p = 0.009), C5a (r = 0.37, p = 0.04) and SC5b-9 (r = 0.56, p = 0.001) levels but not with Bb fragment (r = 0.25, p = 0.17). Thus, inhibition of complement activation may be a therapeutic intervention to reduce post-operative blood in patients undergoing CPB.

Anticoagulation for Percutaneous Ventricular Assist Device-Supported Cardiogenic Shock: JACC Review Topic of the Week.

Interest in the use of mechanical circulatory support for patients presenting with cardiogenic shock is growing rapidly. The Impella (Abiomed Inc), a microaxial, continuous-flow, short-term, ventricular assist device (VAD), requires meticulous postimplantation management. Because systemic anticoagulation is needed to prevent pump thrombosis, patients are exposed to increased bleeding risk, further aggravated by sepsis, thrombocytopenia, and high shear stress-induced acquired von Willebrand syndrome. The precarious balance between bleeding and thrombosis in percutaneous VAD-supported cardiogenic shock patients is often the main reason that patient outcomes are jeopardized, and there is a lack of data addressing optimal anticoagulation management strategies during percutaneous VAD support. Here, we present a parallel anti-Factor Xa/activated partial thromboplastin time-guided anticoagulation algorithm and discuss pitfalls of heparin monitoring in critically ill patients. This review will guide physicians toward a more standardized (anti)coagulation approach to tackle device-related morbidity and mortality in this critically ill patient group.