Clinical outcomes of patients receiving long-term fondaparinux for thrombotic antiphospholipid syndrome.

INTRODUCTION: Vitamin-K antagonists (VKA) are considered the first-line anticoagulants for thrombotic antiphospholipid syndrome (TAPS), particularly with triple positivity or arterial events. However, thrombotic recurrence remains high despite anticoagulation and other clinical issues may arise. Long-term parenteral anticoagulants may therefore be considered, however little is known about the viability of fondaparinux in this setting. MATERIALS AND METHODS: We describe the efficacy and safety of long-term fondaparinux for TAPS (>3-months duration) treated at a single centre in the UK. Clinical features and the outcomes of recurrence and bleeding were reviewed using electronic patient records. RESULTS: 46 patients were identified with history of either venous or arterial TAPS and a total 175 patient-years using fondaparinux (median duration 2.7 years/patient (IQR 1.4-4.8)). 43 (93%) had VKA as first-line anticoagulation with a median duration of 6.5 years (IQR 4.0 - 9.8). All patients received fondaparinux as second-to fourth-line anticoagulation.Thrombosis recurrence occurred in 1 (1%) patient (0.6 events/100-patient years). Major, clinically relevant non-major (CRNM) or minor bleeding occurred in 2 (7%), 5 (10.9%) and 8 (17.4%) patients respectively. Major/CRNM bleeding rates were 1.1 and 2.9 events/100-patient-years. Age >65years was associated with bleeding (p = .047) and concurrent antiplatelets were associated with major/CRNM bleeding (p = .011). Logistic regression showed increasing age was associated with bleeding (OR = 1.097, p = .009). CONCLUSIONS: We suggest that fondaparinux may be used for TAPS when VKA is not appropriate. Thrombotic recurrence was infrequent, and the number of major bleeding events appeared comparable to conventional therapies.

Temporal changes in markers of coagulation and fibrinolysis in adults during extracorporeal membrane oxygenation.

INTRODUCTION: Bleeding and thrombotic events (BTE) are frequent during extracorporeal membrane oxygenation (ECMO). They occur at varying timepoints and may be affected by temporal changes in coagulation and fibrinolysis. We aimed to assess various coagulation and fibrinolytic markers over time and their relationship with BTE. METHODS: A single-centre prospective study was performed in 17 patients with severe respiratory failure receiving veno-venous ECMO. Blood samples were collected before and during ECMO, and around circuit decannulation. RESULTS: Prior to ECMO, D-Dimer, Plasmin-Antiplasmin complexes (PAP), Plasminogen-Activator Inhibitor-1 (PAI-1) and fibrinogen were elevated. There was an increase in D-Dimer and Prothrombin Fragments 1+2 (PF1+2) (729 to 1305pmol/L, p = .034) by day 1 and PAP increased by day 2 from baseline levels (median 1022 to 1797 µg/L, p = .023). There was a strong positive correlation in PAP, PF1+2 and thrombin-antithrombin complexes (TAT) to D-Dimer. BTE were frequent - 18% had major extracranial haemorrhage and 24% had intracranial haemorrhage. Over time, there was a progressive elevation PAP in patients developing subsequent extracranial haemorrhage, whereas D-Dimer, PAP and PF1+2 increased after intracranial haemorrhage. CONCLUSIONS: There were early changes in coagulation activity during ECMO by PF1+2 followed by subsequent fibrinolysis by PAP. Changes in PAP, PF1+2 and TAT were associated with major haemorrhage.

Bleeding related hospitalizations and mortality in England 2014-2019.

Acute bleeding is common and associated with increased morbidity and mortality. Epidemiological studies evaluating trends in bleeding-related hospitalisations and mortality are important as they have potential to guide resource allocation and service provision, however, despite this literature evaluating the national burden and annual trends are lacking. Our objective was to report the national burden and incidence of bleeding-related hospitalisation and mortality.This was a population-based review of all people in England between 2014 and 2019 either admitted to an acute care ward of a National Health Service (NHS) English hospital, or who died. Admissions and deaths were required to have a primary diagnosis of significant bleeding.There was a total of 3,238,427 hospitalisations with a mean of 539,738 ± 6033 per year and 81,264 deaths with a mean of 13,544 ± 331 per year attributable to bleeding. The mean annual incident rate for bleeding-related hospitalisations was 975 per 100,000 patient years and for mortality was 24.45. Over the study period there was a significant 8.2% reduction in bleeding related deaths (χ2 test for trend 91.4, p < 0.001). A direct relationship between increasing age and incidence of bleeding-related hospitalisation and mortality was seen.Bleeding remains a common cause of hospitalisation and death. The reduction in bleeding related mortality requires further investigation. This data may serve to guide future interventions designed to reduce bleeding-related morbidity and mortality.

A Comparison of Thrombosis and Hemorrhage Rates in Patients With Severe Respiratory Failure Due to Coronavirus Disease 2019 and Influenza Requiring Extracorporeal Membrane Oxygenation.

OBJECTIVES: Extracorporeal membrane oxygenation is a lifesaving therapy for patients with severe acute respiratory distress syndrome refractory to conventional mechanical ventilation. It is frequently complicated by both thrombosis and hemorrhage. A markedly prothrombotic state associated with high rates of venous thromboembolism has been described in patients with severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019) infection. These rates have currently not been described during extracorporeal membrane oxygenation in comparison to other viral pneumonias. DESIGN: Retrospective observational study. SETTING: Single high-volume tertiary critical care department at a university hospital. PATIENTS: Patients 16 years old or greater receiving venovenous extracorporeal membrane oxygenation between March 1, 2020, and May 31, 2020, with coronavirus disease 2019 were compared with a cohort of patients with influenza pneumonia between June 1, 2012, and May 31, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The rates of venous thromboembolism and hemorrhage were compared in patients with coronavirus disease 2019 against a historic population of patients with influenza pneumonia who required extracorporeal membrane oxygenation. There were 51 patients who received extracorporeal membrane oxygenation due to coronavirus disease 2019 and 80 patients with influenza. At cannulation for extracorporeal membrane oxygenation, 37% of patients with coronavirus disease 2019 compared with 8% of patients with influenza had filling defects on CT pulmonary angiography (p = 0.0001). Catheter-associated deep vein thrombosis shown on ultrasound Doppler after decannulation was present in 53% with coronavirus disease 2019 versus 25% with influenza (p = 0.01). The rates of intracranial hemorrhage at the time of cannulation were 16% with coronavirus disease 2019 and 14% with influenza (p = 0.8). Elevated d-dimer levels were seen in both conditions and were significantly higher in those with pulmonary thromboembolism than those without in coronavirus disease 2019 (p = 0.02). Fibrinogen and C-reactive protein levels were significantly higher in those with coronavirus disease 2019 than influenza (p < 0.01). CONCLUSIONS: Significant rates of pulmonary thromboembolism and of catheter-associated deep vein thrombosis were seen in both viral infections but were greater in those requiring the use of extracorporeal membrane oxygenation in coronavirus disease 2019 than for influenza.

The effect of hydroxychloroquine on haemostasis, complement, inflammation and angiogenesis in patients with antiphospholipid antibodies.

Objectives: HCQ has been described as having a beneficial effect in patients with APS but its mechanism of action is unclear. We hypothesized that HCQ may have effects on subnormal angiogenesis, inflammation and haemostatic biomarkers seen in APS. The aim of our study was to assess laboratory markers [annexin A5 (AnxA5) anticoagulant activity, tissue factor (TF) levels, thromboelastography (TEG), CRP, Bb, C3a and VEGF] in HCQ-naïve patients with aPL at baseline and after commencing HCQ. Methods: Twenty-two patients with aPL [20 female, 2 male, median age 55 (range 18-70) years] had blood taken pre- and 3 months after starting HCQ 200 mg daily. Results: Soluble TF levels were significantly reduced comparing baseline and 3 months after HCQ commencement [401.8 (152.8) vs 300.9 (108) pg/ml (P = 0.010)]. No significant changes were found in the following [reported as pre- and post-HCQ commencement, mean (s.d.)]: AnxA5 anticoagulant ratio [187.1 (29.5) vs 193 (31) (P = 0.157)], anti-domain1 ß2 glycoprotein1 IgG activity [1.8 (2) vs 1.2 (1.4) µg/ml (P = 0.105)], complement C3a-des-Arg [147.8 (84.5) vs 154.4 (88.1) ng/ml (P = 0.905)], complement Bb [1.3 (0.7) vs 1.1 (0.7) µg/ml (P = 0.422)], VEGF [68.8 (40) vs 59.4 (19.6) pg/ml (P = 0.454)] and CRP [7 (3.5) vs 7 (3.9) µg/ml (P = 0.917)]. TEG results including TEG reaction time, achievement of clot firmness, TEG maximum amplitude and TEG percentage lysis 30 and 60 min after maximum amplitude showed no significant difference. Conclusion: HCQ significantly reduced soluble TF levels in patients with aPL. No significant change was observed in AnxA5 activity, anti-domain 1 IgG activity, TEG, CRP, complement Bb and C3a-des-Arg, and VEGF. Further studies of a larger patient cohort are needed.

Two Year Outcome After Chronic Iliac Vein Occlusion Recanalisation Using the Vici Venous Stent®.

OBJECTIVE/BACKGROUND: The aim was to assess two year outcomes with placement of the Vici Venous Stent® in patients with chronic iliofemoral venous occlusions (complete blockage). METHODS: This was a retrospective single centre study comprising patients treated with the Vici Venous Stent for venographically verified iliofemoral venous occlusion and post-thrombotic syndrome (Villalta score ≥ 5 points) at least 12 months after acute deep vein thrombosis. Venography and intravascular ultrasound were used peri-operatively; duplex ultrasound was used to assess stent patency during follow up. RESULTS: Eighty-eight patients (101 limbs) had stent placement between March 2014 and October 2016. Median pre-treatment Villalta score was 14 (range 5-33). Stenting extended across the inguinal ligament in 63 limbs (62%) in order to land in a healthy venous segment. Six patients (7%) required endophlebectomy and fistula creation. Median imaging follow up was 21 months (range 0-41 months). Primary, assisted primary and secondary patency rates at one year were 59%, 78%, and 87%, respectively, and two years 51%, 73%, and 82%, respectively. Forty-three limbs (43%) had re-intervention (lysis, venoplasty, and/or placement of stent) during follow up; median time to re-intervention was 32 days (range 0-520 days). At 24 months, 37 of 53 limbs (70%) with available Villalta assessment showed clinically significant improvement (>30% reduction of baseline score). Villalta scores at the 6, 12, and 24 month clinical follow up were significantly lower than before stenting (p < .001, all time points). In a subset analyses of limbs with stenting terminating above and below the inguinal ligament, secondary cumulative patency rates at 24 months were 90% and 79%, respectively; clinical outcome showed 58% vs. 73% of limbs with clinically significant improvement, respectively. There was no statistically significant difference in patency or clinical outcomes. CONCLUSION: The Vici Venous Stent is associated with a good secondary patency rate and durable and substantial symptomatic resolution in patients with chronic post-thrombotic occlusions, regardless of whether stents extended beneath the inguinal ligament.

Contemporary management of acute and chronic deep venous thrombosis.

INTRODUCTION: This review aims to provide an update on the management of deep vein thrombosis (DVT). SOURCES OF DATA: A systematic search of PubMed, Google Scholar and Cochrane databases was carried out. AREAS OF AGREEMENT: Direct oral anticoagulants (DOACs) are as effective and easier to use than vitamin K antagonists for the treatment of DVT. Catheter-directed thrombolysis can reduce post thrombotic syndrome in patients with iliofemoral DVT. Compression bandaging can help heal a venous ulcer. AREAS OF CONTROVERSY: Compression hosiery to prevent post thrombotic syndrome. Long-term evidence to show clinical benefit of using endovenous therapies to restore deep vein patency. GROWING POINTS: Developing imaging methods to identify patients who would benefit from venous thrombolysis. The evolution of dedicated venous stents. AREAS TIMELY FOR DEVELOPING RESEARCH: Understanding the mechanisms that lead to stent occlusion and investigation into the appropriate treatments that could prevent in-stent thrombosis is required.

The Efficacy and Safety of DOACs in Inherited Antithrombin Deficiency: A Cohort Study from a Tertiary Referral Center.

BACKGROUND: Individuals with inherited antithrombin deficiency (IATD) have a high risk of venous thromboembolism (VTE). Most VTEs are managed with direct oral anticoagulants (DOACs), but the utility of DOACs in antithrombin deficiency (ATD) is unreported. MATERIALS AND METHODS: Patients with IATD treated with DOAC were identified from our institutions' IATD registry. We assessed patients' characteristics, ATD type, and initial VTE characteristics, thrombosis recurrence and bleeding rates. RESULTS: Thirty-three patients received DOACs for 73 (38.5-111.5) months (median (interquartile range)). Prior to taking DOACs, 12 (36%) patients had VTE recurrence: these occurred after anticoagulation was ceased (4), nonadherence to VKA prior to DOAC use (3), or during heparin use in pregnancy (5). There were no VTE recurrences on standard-dose DOAC, except in a noncompliant patient receiving dabigatran. There was one recurrence with compliant DOAC use-a patient receiving rivaroxaban 10 mg. Six (18%) patients experienced clinically relevant bleeding, which was predominantly menorrhagia (5/6). One major bleeding event, intracranial hemorrhage, occurred in a patient receiving full-dose rivaroxaban who had refractory hypertension (0.5 events/100 patient-years). In this cohort, compliant DOAC users had an overall VTE recurrence rate of 0.5/100 patient-years, whereas with low-dose DOACs the event rate was 3.5/100 patient-years. CONCLUSION: Standard-dose DOACs appear efficacious and relatively safe in IATD.

Nitrous oxide misuse: a clue not to be missed in young patients with venous thromboembolism.

A 27-year-old man presented with altered mental status and unilateral right lower limb swelling. Brain imaging and cerebrospinal fluid analysis were unremarkable. He reported history of nitrous oxide misuse after he recovered from his delirium. The diagnosis of drug induced psychosis was made. The right lower limb swelling was found to be due to extensive deep vein thrombosis. In another case, a 21-year-old woman presented with headache, vomiting and dipoplia. Brain imaging showed extensive cerebral venous sinus thrombosis. She also misused nitrous oxide. Both cases had low-normal vitamin B12 and elevated methylmalonic acid, consistent with nitrous oxide misuse. The woman was found to have elevated homocysteine because of functional vitamin B12 deficiency. Homocysteine was not measured in the man. Raised homocysteine is associated with increased thrombosis risk. Fourteen cases of nitrous oxide misuse associated arterial and venous thrombosis have been reported. These two cases highlighted the importance of inquiring about recreational drug use in young patients who presented with apparently unprovoked venous thromboembolism.

Interventional therapies in acute pulmonary embolus-current trends and future directions.

Venous thromboembolic disease presenting with acute pulmonary embolus (PE) can be treated in a variety of ways from anticoagulation as an outpatient to surgical embolectomy with many new interventional therapies being developed. Mortality in these patients can be as high as 50% and many of these treatments are also considered to be high risk. Early involvement of a multidisciplinary team and patient risk stratification can aid management decisions in these complex patients who can suddenly deteriorate.In this review, we summarise the evidence behind new and developing interventional therapies in the treatment of high and intermediate-high risk PE including catheter-directed thrombolysis, pharmacomechanical thrombolysis, thromboaspiration and the growing role of extracorporeal membrane oxygenation in the stabilisation and management of this cohort of patients.

Nirmatrelvir/ritonavir Use With Tacrolimus in Lung Transplant Recipients: A Single-center Case Series.

BACKGROUND: Limited data and guidelines exist for using nirmatrelvir/ritonavir in solid organ transplant recipients stabilized on tacrolimus for the treatment of mild-to-moderate coronavirus disease. Concern exists regarding the impact of utilizing a 5-d course of nirmatrelvir/ritonavir with calcineurin inhibitors because of significant drug-drug interactions between ritonavir, a potent cytochrome P450 3A inhibitor, and other cytochrome P450 3A substrates, such as tacrolimus. METHODS: We report the successful use of nirmatrelvir/ritonavir in 12 outpatient lung transplant recipients with confirmed severe acute respiratory syndrome coronavirus 2 infection stabilized on tacrolimus immunosuppression. All patients stopped tacrolimus and started nirmatrelvir/ritonavir 10 to 14 h after the last dose of tacrolimus. Tacrolimus was withheld and then reinitiated at a modified dose 48 h following the completion of nirmatrelvir/ritonavir therapy. Tacrolimus trough levels were checked during nirmatrelvir/ritonavir therapy and tacrolimus reinitiation. RESULTS: Ten (10/12) patients were able to resume their original tacrolimus dose within 4 d of completing nirmatrelvir/ritonavir therapy and maintain therapeutic levels of tacrolimus. No patients experienced tacrolimus toxicity or acute rejection during the 30-d postcompletion of nirmatrelvir/ritonavir therapy. CONCLUSIONS: In this cohort of lung transplant recipients on tacrolimus, we demonstrated that nirmatrelvir/ritonavir can be safely used with close monitoring of tacrolimus levels and appropriate dose adjustments of tacrolimus. Further confirmatory studies are needed to determine the appropriate use of therapeutic drug monitoring and tacrolimus dose following completion of nirmatrelvir/ritonavir in the solid organ transplant population.

The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia.

Coagulopathy occurs in most patients with (APML) and is life-threatening; therefore prompt diagnosis and recognition of any coagulation defect is imperative. Unfortunately haemorrhage remains a major cause of early death, preventing some from reaching treatment. The coagulopathy is caused directly or indirectly by the leukaemic cells through expression of activators of coagulation and fibrinolysis, proteases and cytokine generation, compounded by failure of platelet production due to marrow invasion. At presentation the predominant feature is usually hyperfibrinolysis. Since the introduction of all-trans retinoic acid (ATRA), patient outcome has dramatically improved; yet, haemorrhagic complications remain the most frequent cause of mortality. Thrombotic complications occur but are less well recognized and potentially underreported. Supportive measures and prompt initiation of ATRA currently represent the mainstay of treatment of the coagulopathy in patients with suspected APML, but unanswered questions remain as to the optimal approach to further decrease the associated haemorrhagic and thrombotic risks. In particular, it is unclear how to best predict and monitor the coagulopathy; whether there is a role for the early use of antifibrinolytics; the most appropriate trigger for giving fibrinogen replacement and the value of low-dose anticoagulation to suppress coagulation activation once fibrinolysis has been suppressed.

Meeting the family: measuring effectiveness of family meetings in a specialist inpatient palliative care unit.

OBJECTIVE: The World Health Organization (WHO) definition of palliative care as "an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness …" recognizes the importance of family members in this setting. In practice, family meetings account for a significant amount of the weekly workload in a specialist inpatient palliative care unit. Despite this, there is little empirical evidence to support the benefits of family meetings from the perspective of family members. METHOD: A prospective study over 6 months, invited a designated family member to complete a self-report instrument (SRI) and the Family Inventory of Needs (FIN) questionnaire prior to, immediately following, and 48 hours after a planned family meeting attended by several members of the multidisciplinary team. RESULTS: Thirty-one designated family members completed the study. The SRIs completed prior to a family meeting identified particular areas of concern and worry for family members, and also helped to generate an agenda based on the family's particular needs. The pre-meeting FIN identified areas of patient care of greatest importance to each family member, and asked them to rate whether particular care needs were presently met or unmet, in their opinion, by the healthcare team caring for the patient. Following the family meeting, repeat SRIs showed an overall reduction in concerns and increased confidence in dealing with those issues raised. Post-family meeting FIN scores confirmed a greater number of met care needs compared with pre-meeting scores, all of which were sustained over time. SIGNIFICANCE OF RESULTS: This study confirms the value of planned multidisciplinary family meetings for patients in specialist inpatient palliative care units. It identifies the often unmet needs of family members and the sustained benefits associated with formal family meetings.

Medium-term outcomes after inferior vena cava reconstruction for acute and chronic deep vein thrombosis and retroperitoneal fibrosis.

OBJECTIVE: In the present study, we evaluated the technical and clinical outcomes after endovascular inferior vena cava (IVC) reconstruction in patients with nonmalignant obstruction. METHODS: The preoperative, procedural, and follow-up medical records and imaging studies were retrospectively reviewed for 59 consecutive patients who had undergone endovascular IVC reconstruction for nonmalignant obstruction from February 2014 to January 2019. The patients were classified into three groups according to the quality of their infrainguinal inflow vessels. The outcomes measured were the primary, primary-assisted, and secondary patency rates, reintervention rates, and symptomatic resolution. RESULTS: The indications for treatment were post-thrombotic syndrome (n = 41), acute deep vein thrombosis (n = 12), and retroperitoneal fibrosis (n = 6). The median patient age was 37 years, 11 months, 71.2% were men, and 32.2% had a diagnosis of thrombophilia, with no significant difference in these demographics between the three inflow groups. The median follow-up duration was 2 years, 3 months (range, 6 months to 6 years, 5 months). The whole-cohort primary patency was 91.2%, 71.0%, and 24.1% at 1, 3, and 5 years, respectively. Secondary patency was 76.7% at 1 year and 66.4% at both 3 and 5 years. Inflow group A (no post-thrombotic disease in the femoral or deep femoral veins) demonstrated significantly higher primary patency compared with group B (stenotic disease in one or two infrainguinal inflow veins; P = .009) and significantly higher secondary patency than for both groups B (P = .008) and C (all three infrainguinal inflow veins had stenosed or femoral and/or deep femoral vein occlusion was present; P = .04). In post-thrombotic syndrome patients, the Villalta scores had decreased from a mean of 14.2 to 8.1 at 1 year and 6.8 at 2 years, and the Venous Insufficiency Epidemiological and Economic Study Quality of Life score had improved from a mean of 19.8 to 54.1 and 57.3 at 1 and 2 years, respectively. In the patients with acute deep vein thrombosis, the Villalta score was 2.8 at 1 year and 0 at 2 years. In the patients with retroperitoneal fibrosis, the Venous Insufficiency Epidemiological and Economic Study Quality of Life score had improved from a mean of 25.3 at baseline to 44 at 6 months. CONCLUSIONS: Endovascular IVC reconstruction for nonmalignant obstruction can achieve good patency and clinical improvement, although the outcomes were poorer for patients with post-thrombotic disease of the femoral and deep femoral veins.