Evolution of Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disease characterized by thrombosis and/or pregnancy complications caused by antiphospholipid antibodies (aPL). The history of APS can be traced back to observations made during screening programs for syphilis conducted in the mid-20th century, with identification of patients with the so-called biological false-positive serological reactions for syphilis. Initial observation linking aPL with recurrent miscarriages was first reported more than 40 years ago. Since then, our understanding of the pathogenesis and management of APS has evolved markedly. Although APS is an autoimmune disease, anticoagulation mainly with vitamin K antagonists (VKAs) rather than immunomodulation, is the treatment of choice for thrombotic APS. Direct acting oral anticoagulants are inferior to VKAs, especially those with triple-positive APS and arterial thrombosis. Inflammation, complement activation, and thrombosis in the placenta may contribute to pathogenesis of obstetric APS. Heparin, mainly low-molecular-weight heparin, and low-dose aspirin represent the treatments of choice for women with obstetric complications. Increasingly, immunomodulatory agents such as hydroxychloroquine for thrombotic and obstetric APS are being used, especially in patients who are refractory to present standard treatment.

Thoracic surgery in patients on veno-venous extracorporeal membrane oxygenation for COVID-19 associated acute respiratory distress syndrome.

OBJECTIVES: The COVID-19 pandemic has generated a new type of acute respiratory distress syndrome (ARDS) arising as a complication of COVID-19 pneumonia. Extreme cases require the support of extracorporeal membrane oxygenation (ECMO). Here we present the outcomes of patients that underwent surgical tracheostomy or thoracic surgery at a single tertiary centre whilst on ECMO support for COVID-19 related ARDS. METHODS: 18 patients requiring thoracic input whilst on ECMO support during the first wave of COVID-19 (March-June 2020) were included. Thoracic surgery was required both for performing surgical tracheostomies in the operating theatre and for treating emergencies arising under the ECMO treatment such as bleeding complications. RESULTS: Thirteen patients underwent a surgical tracheostomy, whilst five patients had an invasive thoracic procedure. Anticoagulation was withheld for at least 12 h in the perioperative setting regardless of the indication. One patient was re-operated for haemothorax immediately after the end of the primary operation. 94.5% of the patients were successfully decannulated from ECMO support. Overall 30-day mortality in the cohort was 5.5% (1/18). CONCLUSIONS: Thoracic surgeons can play a valuable role in supporting an ECMO unit during the COVID pandemic, by treating ECMO related complications and by safely performing surgical tracheostomies. Withholding anticoagulation in the perioperative window was not associated with increased thromboembolic events and is desirable when interventions or surgery is indicated in this patient cohort to avoid excessive bleeding.

Impact of aspirin on bleeding and blood product usage in off-pump and on-pump coronary artery bypass graft surgery.

Major bleeding is linked to poorer outcomes following cardiac surgery. Current guidelines recommend continuation of aspirin prior to coronary artery by-pass graft (CABG) but the effect of continuing aspirin in patients with prior indication for aspirin, in particular during off-pump CABG (OPCABG), has not been systematically assessed. In this study, we analysed the effect of continuing aspirin prior to OPCABG and on-pump CABG with respect to bleeding and blood product usage. We compared propensity-matched cohorts of patients who continued aspirin until the day of OPCABG or CABG to controls (no antiplatelet) and to patients discontinuing aspirin 5-7 days prior. Length of hospital stay, 30-day mortality and thromboembolism rates were similar for both OPCABG and CABG. During OPCABG, aspirin-continued patients received more intraoperative red cell units compared to controls without difference in bleeding. Aspirin-continued patients received more blood products perioperatively and bled more than aspirin-discontinued patients undergoing OPCABG. The only difference during CABG was a small increase in the volume of cells salvaged among aspirin-continued patients compared to controls. Current guidelines on the continuation of aspirin prior to CABG and OPCABG are safe. Continuation of aspirin prior to OPCABG may result in more bleeding and blood product usage.

Optimal Tests to Minimise Bleeding and Ischaemic Complications in Patients on Extracorporeal Membrane Oxygenation.

Patients supported with extracorporeal membrane oxygenation (ECMO) experience a very high frequency of bleeding and ischaemic complications, including stroke and systemic embolism. These patients require systemic anticoagulation, mainly with unfractionated heparin (UFH) to prevent clotting of the circuit and reduce the risk of arterial or venous thrombosis. Monitoring of UFH can be very challenging. While most centres routinely monitor the activated clotting time and activated partial thromboplastin time (aPTT) to assess UFH, measurement of anti-factor Xa (anti-Xa) level best correlates with heparin dose, and appears to be predictive of circuit thrombosis, although aPTT may be a better predictor of bleeding. Although monitoring of prothrombin time, platelet count and fibrinogen is routinely undertaken to assess haemostasis, there is no clear guidance available regarding the optimal test.Additional tests, including antithrombin level and thromboelastography, can be used for risk stratification of patients to try and predict the risks of thrombosis and bleeding. Each has their specific role, strengths and limitations. Increased thrombin generation may have a role in predicting thrombosis. Acquired von Willebrand syndrome is frequent with ECMO, contributing to bleeding risk and can be detected by assessing the von Willebrand factor activity-to-antigen ratio, while the platelet function analyser can be used in urgent situations to detect this, with a high negative predictive value. Tests of platelet aggregation can aid in the prediction of bleeding.To personalise management, a selection of complementary tests to collectively assess heparin-effect, coagulation, platelet function and platelet aggregation is proposed, to optimise clinical outcomes in these high-risk patients.

The clinical course of COVID-19 in pregnant versus non-pregnant women requiring hospitalisation: results from the multicentre UK CA-COVID-19 study.

The impact of COVID-19 infection on pregnant women remains relatively unknown but the physiological changes of pregnancy and hypercoagulability of COVID-19 may further increase thrombotic risk. In this retrospective multicentre observational study, we report clinical characteristics and outcomes in 36 pregnant women requiring hospitalisation for COVID-19 compared to a propensity-matched cohort of non-pregnant women. Pregnant women had a lower haemoglobin and higher lymphocyte counts but no differences in other haematological or biochemical parameters on admission compared to non-pregnant women. There was no significant difference in the duration of hospitalisation; median two days (1-77) for pregnant versus eight days (1-49) for non-pregnant women. A higher proportion of non-pregnant women required mechanical ventilation [11/36 (31%) vs 3/36 (8%), P = 0·03] and received thromboprophylaxis with low-molecular-weight heparin (LMWH) within 24 h of admission [25/36 (69%) vs 15 /36(42%), P = 0·03] compared to pregnant women. One pregnant woman required extracorporeal membrane oxygenation. The rate of thrombosis was similar in both groups (one in each group). No women developed major bleeding or died. Data suggest that although non-pregnant women had a severe clinical course, overall outcomes were not different between women with or without pregnancy. The use of thromboprophylaxis was inconsistent, demonstrating a need for establishing evidence-based guidance for COVID-19 during pregnancy.

Role, Laboratory Assessment and Clinical Relevance of Fibrin, Factor XIII and Endogenous Fibrinolysis in Arterial and Venous Thrombosis.

Diseases such as myocardial infarction, ischaemic stroke, peripheral vascular disease and venous thromboembolism are major contributors to morbidity and mortality. Procoagulant, anticoagulant and fibrinolytic pathways are finely regulated in healthy individuals and dysregulated procoagulant, anticoagulant and fibrinolytic pathways lead to arterial and venous thrombosis. In this review article, we discuss the (patho)physiological role and laboratory assessment of fibrin, factor XIII and endogenous fibrinolysis, which are key players in the terminal phase of the coagulation cascade and fibrinolysis. Finally, we present the most up-to-date evidence for their involvement in various disease states and assessment of cardiovascular risk.

Outcome of Major Hemorrhage at a Major Cardiothoracic Center in Patients with Activated Major Hemorrhage Protocol versus Nonactivated Protocol.

This study aimed to determine the impact of major hemorrhage (MH) protocol (MHP) activation on blood administration and patient outcome at a UK major cardiothoracic center. MH was defined in patients (> 16 years) as those who received > 5 units of red blood cells (RBCs) in < 4 hours, or > 10 units in 24 hours. Data were collected retrospectively from patient electronic records and hospital transfusion databases recording issue of blood products from January 2016 to December 2018. Of 134 patients with MH, 24 had activated MHP and 110 did not have activated MHP. Groups were similar for age, sex, baseline hemoglobin, platelet count, coagulation screen, and renal function with no difference in the baseline clinical characteristics. The total number of red cell units (median and [IQR]) transfused was no different in the patients with activated (7.5 [5-11.75]) versus nonactivated (9 [6-12]) MHP (p = 0.35). Patients in the nonactivated MHP group received significantly higher number of platelet units (median: 3 vs. 2, p = 0.014), plasma (median: 4.5 vs. 1.5, p = 0.0007), and cryoprecipitate (median: 2 vs. 1, p = 0.008). However, activation of MHP was associated with higher mortality at 24 hours compared with patients with nonactivation of MHP (33.3 vs. 10.9%, p = 0.005) and 30 days (58.3 vs. 30.9%, p = 0.01). The total RBC and platelet (but not fresh frozen plasma [FFP]) units received were higher in deceased patients than in survivors. Increased mortality was associated with a higher RBC:FFP ratio. Only 26% of patients received tranexamic acid and these patients had higher mortality at 30 days but not at 24 hours. Deceased patients at 30 days had higher levels of fibrinogen than those who survived (median: 2.4 vs. 1.8, p = 0.01). Patients with activated MHP had significantly higher mortality at both 24 hours and 30 days despite lack of difference in the baseline characteristics of the patients with activated MHP versus nonactivated MHP groups. The increased mortality associated with a higher RBC:FFP ratio suggests dilutional coagulopathy may contribute to mortality, but higher fibrinogen at baseline was not protective.

Prevalence of Thrombotic Complications in ICU-Treated Patients With Coronavirus Disease 2019 Detected With Systematic CT Scanning.

OBJECTIVES: Severe coronavirus disease 2019 is associated with an extensive pneumonitis and frequent coagulopathy. We sought the true prevalence of thrombotic complications in critically ill patients with severe coronavirus disease 2019 on the ICU, with or without extracorporeal membrane oxygenation. DESIGN: We undertook a single-center, retrospective analysis of 72 critically ill patients with coronavirus disease 2019-associated acute respiratory distress syndrome admitted to ICU. CT angiography of the thorax, abdomen, and pelvis were performed at admission as per routine institution protocols, with further imaging as clinically indicated. The prevalence of thrombotic complications and the relationship with coagulation parameters, other biomarkers, and survival were evaluated. SETTING: Coronavirus disease 2019 ICUs at a specialist cardiorespiratory center. PATIENTS: Seventy-two consecutive patients with coronavirus disease 2019 admitted to ICU during the study period (March 19, 2020, to June 23, 2020). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All but one patient received thromboprophylaxis or therapeutic anticoagulation. Among 72 patients (male:female = 74%; mean age: 52 ± 10; 35 on extracorporeal membrane oxygenation), there were 54 thrombotic complications in 42 patients (58%), comprising 34 pulmonary arterial (47%), 15 peripheral venous (21%), and five (7%) systemic arterial thromboses/end-organ embolic complications. In those with pulmonary arterial thromboses, 93% were identified incidentally on first screening CT with only 7% suspected clinically. Biomarkers of coagulation (e.g., d-dimer, fibrinogen level, and activated partial thromboplastin time) or inflammation (WBC count, C-reactive protein) did not discriminate between patients with or without thrombotic complications. Fifty-one patients (76%) survived to discharge; 17 (24%) patients died. Mortality was significantly greater in patients with detectable thrombus (33% vs 10%; p = 0.022). CONCLUSIONS: There is a high prevalence of thrombotic complications, mainly pulmonary, among coronavirus disease 2019 patients admitted to ICU, despite anticoagulation. Detection of thrombus was usually incidental, not predicted by coagulation or inflammatory biomarkers, and associated with increased risk of death. Systematic CT imaging at admission should be considered in all coronavirus disease 2019 patients requiring ICU.

The heparin-von Willebrand factor interaction and conventional tests of haemostasis - the challenges in predicting bleeding in cardiopulmonary bypass.

Bleeding is a significant complication of cardiopulmonary bypass (CPB), despite routine anticoagulation monitoring. This is likely to be multifactorial. In this prospective, single-centre cohort study of 30 patients undergoing CPB surgery, our aim was to characterise the changes in von Willebrand factor (VWF) function, platelet interaction and the global coagulation changes during and after CPB surgery and to determine whether bleeding can be predicted. Samples were taken at six time points before, during and after CPB surgery. We observed a significant rise in VWF antigen (VWF:Ag) throughout surgery, which continued postoperatively. The absolute VWF collagen-binding assays (VWF:CB) and VWF ristocetin cofactor (VWF:RCo) rose significantly but the VWF:CB/VWF:Ag and VWF:Ag/VWF:RCo fell significantly (P = 0·0015 and P = 0·0143), suggesting loss of large multimers. We detected a non-significant trend to loss of VWF:RCo after heparinisation and a significant recovery after protamine reversal which could reflect a direct heparin effect. There was a significant increase in the R and K times with a fall in alpha angle and maximum amplitude after heparin administration, using heparinase-thromboelastography (TEG). The parameters both significantly improved following protamine (P = 0·007 and P = 0·0054). The activated clotting time (ACT) and heparin anti-Xa level correlated poorly; neither predicted clinically significant bleeding. None of these parameters had a relationship with intraoperative blood loss or requirement for blood product replacement.

Effect of direct-acting oral anticoagulants (DOACs) on bleeding and blood product usage in cardiac surgery compared to warfarin and controls.

In this retrospective, single-centre, observational study, we assessed (i) use of anticoagulant and antiplatelet (AP) therapy, (ii) the duration of direct-acting oral anticoagulant (DOAC) discontinuation, (iii) renal function and (iv) PT and APTT as predictors of bleeding and blood product usage; in adults (>18 years) undergoing major cardiac surgery from 01.01.2015 to 31.12.2018. Comparisons were made between each treatment group (warfarin, DOAC and DOAC + AP) and untreated controls, and between warfarin and DOAC. A total of 2928 patients were included for analysis. Median (range) of DOAC discontinuation prior to surgery was five days (1-22) for DOAC and five days (2-7) for DOAC + AP. There were no differences in bleeding between anticoagulant groups versus control, or DOAC versus warfarin. There were no differences in blood product use between DOAC and warfarin patients. The duration of DOAC discontinuation but not the creatinine clearance influenced bleeding and blood products use. Thrombosis occurred in 0·7% and 3·1% in controls and patients on warfarin respectively (P = 0·099) with none among patients on DOAC or DOAC + AP. The PT/APTT had no predictive value. Median five-day discontinuation of DOAC +/- AP irrespective of renal function prevents an increase in bleeding compared to patients on warfarin or controls with no increase in thrombosis.

What is the appropriate anticoagulation strategy for thrombotic antiphospholipid syndrome?

Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder mediated by a heterogeneous group of autoantibodies collectively known as antiphospholipid antibodies (aPL). They include lupus anticoagulant (LA), IgG and IgM anticardiolipin antibodies (aCL) and anti-ß2-glycoprotein I (anti-ß2GPI) antibodies. It has been shown that those patients with all three aPL (triple positive) are at highest risk of both a first thrombotic event and of a recurrence, despite anticoagulation. In response to publication of a meta-analysis and a randomised controlled trial assessing the safety and efficacy of rivaroxaban versus warfarin in triple-positive APS with venous and/or arterial thrombosis, the Medicines and Healthcare Products Regulatory Agency (MHRA) and European Medicines Agency (EMA) issued recommendations that direct-acting oral anticoagulant (DOACs) should not be used for secondary prevention of thrombosis in all APS patients (although they did draw specific attention to the high risk of triple-positive patients). As there is less evidence for patients with single- or dual-positive patients with APS, this may be an over-interpretation of the data. In this review, we explore the available evidence on safety and efficacy of DOACs in thrombotic APS, the problem of detecting LA while on DOAC, and provide some practical guidance for managing this problem.

Frequency of Thrombocytopenia and Heparin-Induced Thrombocytopenia in Patients Receiving Extracorporeal Membrane Oxygenation Compared With Cardiopulmonary Bypass and the Limited Sensitivity of Pretest Probability Score.

OBJECTIVES: To ascertain: 1) the frequency of thrombocytopenia and heparin-induced thrombocytopenia; 2) positive predictive value of the Pretest Probability Score in identifying heparin-induced thrombocytopenia; and 3) clinical outcome of heparin-induced thrombocytopenia in adult patients receiving venovenous- or venoarterial-extracorporeal membrane oxygenation, compared with cardiopulmonary bypass. DESIGN: A single-center, retrospective, observational cohort study from January 2016 to April 2018. SETTING: Tertiary referral center for cardiac and respiratory failure. PATIENTS: Patients who received extracorporeal membrane oxygenation for more than 48 hours or had cardiopulmonary bypass during specified period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical and laboratory data were collected retrospectively. Pretest Probability Score and heparin-induced thrombocytopenia testing results were collected prospectively. Mean age (± SD) of the extracorporeal membrane oxygenation and cardiopulmonary bypass cohorts was 45.4 (± 15.6) and 64.9 (± 13), respectively (p < 0.00001). Median duration of cardiopulmonary bypass was 4.6 hours (2-16.5 hr) compared with 170.4 hours (70-1,008 hr) on extracorporeal membrane oxygenation. Moderate and severe thrombocytopenia were more common in extracorporeal membrane oxygenation compared with cardiopulmonary bypass throughout (p < 0.0001). Thrombocytopenia increased in cardiopulmonary bypass patients on day 2 but was normal in 83% compared with 42.3% of extracorporeal membrane oxygenation patients at day 10. Patients on extracorporeal membrane oxygenation also followed a similar pattern of platelet recovery following cessation of extracorporeal membrane oxygenation. The frequency of heparin-induced thrombocytopenia in extracorporeal membrane oxygenation and cardiopulmonary bypass were 6.4% (19/298) and 0.6% (18/2,998), respectively (p < 0.0001). There was no difference in prevalence of heparin-induced thrombocytopenia in patients on venovenous-extracorporeal membrane oxygenation (8/156, 5.1%) versus venoarterial-extracorporeal membrane oxygenation (11/142, 7.7%) (p = 0.47). The positive predictive value of the Pretest Probability Score in identifying heparin-induced thrombocytopenia in patients post cardiopulmonary bypass and on extracorporeal membrane oxygenation was 56.25% (18/32) and 25% (15/60), respectively. Mortality was not different with (6/19, 31.6%) or without (89/279, 32.2%) heparin-induced thrombocytopenia in patients on extracorporeal membrane oxygenation (p = 0.79). CONCLUSIONS: Thrombocytopenia is already common at extracorporeal membrane oxygenation initiation. Heparin-induced thrombocytopenia is more frequent in both venovenous- and venoarterial-extracorporeal membrane oxygenation compared with cardiopulmonary bypass. Positive predictive value of Pretest Probability Score in identifying heparin-induced thrombocytopenia was lower in extracorporeal membrane oxygenation patients. Heparin-induced thrombocytopenia had no effect on mortality.

Apixaban enhances endogenous fibrinolysis in patients with atrial fibrillation.

AIMS: Approximately 20% of ischaemic stroke patients exhibit spontaneous arterial recanalization, attributable to endogenous fibrinolysis, which strongly relates to improved functional outcome. The impact of oral anticoagulants on endogenous fibrinolysis is unknown. Our aim was to test the hypothesis that apixaban enhances endogenous fibrinolysis in non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: In a prospective cross-sectional analysis, we compared endogenous fibrinolysis in NVAF patients (n = 180) taking aspirin, warfarin, or apixaban. In a prospective longitudinal study, patients were tested before and after apixaban (n = 80). Endogenous fibrinolysis was assessed using the Global Thrombosis Test (GTT) and thromboelastography (TEG). Endogenous fibrinolysis [measured by GTT lysis time (LT)] was shorter on apixaban compared with warfarin or aspirin [median 1850 (IQR 1591-2300) vs. 2758 (2014-3502) vs. 2135 (1752-2463) s, P < 0.0001]. Among TEG indices, a small but significant difference in clot lysis time (CLT) was observed [apixaban 60.0 (45.0-61.0) vs. warfarin 61.0 (57.0-62.0) vs. aspirin 61.0 (59.0-61.0) min, P = 0.036]. Apixaban improved endogenous fibrinolysis measured using the GTT [LT pre-treatment 2204 (1779-2738) vs. on-treatment 1882 (1607-2374) s, P = 0.0003], but not by using TEG. Change in LT (ΔLT) with apixaban correlated with baseline LT (r = 0.77, P < 0.0001). There was weak correlation between ΔLT and ΔCLT in response to apixaban (r = 0.28, P = 0.02) and between on-apixaban LT and CLT (r = 0.25, P = 0.022). CONCLUSION: Apixaban enhances endogenous fibrinolysis, with maximal effect in those with impaired fibrinolysis pre-treatment. Apixaban-treated patients exhibit more favourable fibrinolysis profiles than those taking warfarin or aspirin. Whether apixaban may confer additional thrombotic risk reduction in NVAF patients with impaired fibrinolysis, compared to warfarin, merits further study.