Issue nr. 1

March 2022

News on EMLTD

Editor: Joao Morais

European and Mediterranean League against Thrombotic Diseases

President's corner

Professor Alexandros Tselepis

Dear Colleagues,

I am very pleased to introduce the first EMLTD e-Newsletter, which is intended to convey to you, every three months, the latest information on Society activities as well as the recent advances on thrombosis and antithrombotic therapies. Editor of the EMLTD e-Newsletters will be Professor Joao Morais, member of the EMLTD Executive Board. I am confident that our e-Newsletters will be scientifically useful to clinicians as well as to scientists performing basic research on thrombosis.

The EMLTD President

Alexandros Tselepis, MD, PhD

Professor

Editor´s corner

Joao Morais (PT)

The European Mediterranean League Against Thrombotic Diseases (EMLTD) is a scientific society aiming to aggregate all with a particular interest in the field of thrombosis. Clinicians, basic scientists, medical students, researchers with multiple background, PhD students, all are welcome following EMLTD activities.

This is the 1st issue of a Newsletter which will be published on a regular basis. With this publication we plan to share with our members the activities of EMLTD but we are more ambicious wishing to get the contribution of our readers, sending suggestions, information of their scientific activities, new projects, new publications.

We will invite personalities asking them to share with us their plans on research, as well as their expectations for the future.

If you have something interesting to be shared with the EMLTD community please feel free contacting us. Please send to us your ideas, and tell us what you would like to see published in this space.

If you are not member of EMLTD please visit our website to know us.

EMLTD activities

Teresa Padró (SP)

- Participation with a special Symposium on “Recent Advances in VTE pathophysiology and treatment” in ALPIC 2021, international course on “Advanced Learning on Platelets & Thrombosis” that is yearly organized by the EMLTD Foundation since 2018.

- Organization of the EMLTD WEBinar on COVID-19 and Thrombosis held in July 1st, 2021 (organized by Prof. Donati, Italy)

- Virtual ICT 2021 on 26-27 November 2021 with 2 Keynote lectures on “Deep Learning and Artificial Intelligence” (Prof. Panos Vardas) and “Personalized Antithrombotic Therapy in CAD with a Focus on Factor Xa Inhibition” (Prof. Paul Gurbel), a state of the arte session on COVID-19, with special focus on vaccines and thrombosis. The ICT-2021 also included specific sessions aimed to meet expert and discuss with them relevant and burning topics in the thrombosis field, in addition to clinical seminars and workshops. Special to be mentioned is the “Interactive Workshop on “Real World Data on Thrombosis Incidence and Treatment”, which was attended by representatives of different member countries of the EMLTD and the particular situation in them was discussed.

News on antithrombotics I

Comment by Vittorio Pengo (IT) on

INHALED NEBULISED UNFRACTIONATED HEPARIN FOR THE TREATMENT OF HOSPITALISED PATIENTS WITH COVID-19: A MULTICENTRE CASE SERIES OF 98 PATIENTS

Frank M P van Haren, et al. Br J Clin Pharmacol doi: 10.1111/bcp.1521

Background. The pathophysiology of COVID-19 associated lung injury is characterised by diffuse alveolar damage, hyperinflammation, coagulopathy, DNA neutrophil extracellular traps (NETS), hyaline membranes and microvascular thrombosis. Therefore, there is the scientific rationale for the use of inhaled nebulised unfractionated heparin (UFH) as a treatment for COVID-19. The anti-inflammatory and anticoagulant effects of inhaled UFH are thought to reduce pulmonary hyperinflammation and the generation of DNA NETs, limit fibrin deposition, hyaline membrane formation and microvascular thrombosis, which are all important features of COVID-19 associated lung injury. Animal studies of nebulised UFH in different acute lung injury models have consistently shown a positive effect on pulmonary coagulation, inflammation and oxygenation

Researchers from all over the world published in British Journal of Clinical Pharmacology (Br J Clin Pharmacol. 2022;1–12) a paper on the use of inhaled unfractionated heparin (UHF) for thrombosis prophylaxis in patients with COVID-19.

It is well known that drugs highly negatively charged as heparin cannot be adsorbed through the intestinal tract and their administration is only parenteral. For many years having oral administered heparin has been only a dream.

Methods. In this retrospective, uncontrolled multicentre single-arm case series, hospitalised patients with laboratory-confirmed COVID-19 were treated with inhaled nebulised UFH (5000 IU q8h, 10 000 IU q4h, or 25 000 IU q6h) for 6 ± 3 (mean ± standard deviation) days. Outcomes were activated partial thromboplastin time (APTT) before treatment (baseline) and highest-level during treatment (peak), and adverse events including bleeding. Exploratory efficacy outcomes were oxygenation, assessed by ratio of oxygen saturation to fraction of inspired oxygen (FiO2) and FiO2, and the World Health Organisation modified ordinal clinical scale.

Results. There were 98 patients included. In patients on stable prophylactic or therapeutic systemic anticoagulant therapy but not receiving therapeutic UFH infusion, APTT levels increased from baseline of 34 ± 10 seconds to a peak of 38 ± 11 seconds (P < .0001). In 3 patients on therapeutic UFH infusion, APTT levels did not significantly increase from baseline of 72 ± 20 to a peak of 84 ± 28 seconds (P.17). Two patients had serious adverse events: bleeding gastric ulcer requiring transfusion and thigh haematoma; both were on therapeutic anticoagulation. Minor bleeding occurred in 16 patients, 13 of whom were on therapeutic anticoagulation. The oxygen saturation /FiO2 ratio and the FiO2 worsened before and improved after commencement of inhaled UFH (change in slope, P < .001).

Conclusion: Inhaled nebulised UFH in hospitalised patients with COVID-19 was safe. Although statistically significant, inhaled nebulised UFH did not produce a clinically relevant increase in APTT (peak values in the normal range). Urgent randomised evaluation of nebulised UFH in patients with COVID-19 is warranted and several studies are currently underway.

Interesting for the clinicians

Comment by Joao Morais (PT) on

NON-VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS IN OLDER AND FRAIL PATIENTS WITH ATRIAL FIBRILLATION

Robert P. Giugliano. European Heart Journal Supplements (2022) 24 (Supplement A), A1–A10

ABSTRACT

Elderly and frail patients with atrial fibrillation (AF) are at increased risk of thrombotic events, bleeding, and death compared to their counterparts, making their management challenging. With the introduction of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) in the past decade, the risk : benefit balance in such high-risk patients with AF has tipped in favor of treating these patients with anticoagulation, and in most cases with a NOAC instead of a VKA. In patients >75 years of age with AF, each of the 4 approved NOACs reduced stroke or systemic embolism and vs warfarin in their landmark clinical trial and lowered mortality. However, only apixaban and edoxaban significantly reduced major bleeding vs warfarin. A similar pattern was seen in even older cohorts (> 80 and > 85 years). Among patients age > 80 who are not candidates for oral anticoagulants at the approved dose, edoxaban 15 mg may be a reasonable alternative. In elderly or frail individuals who are on multiple comedications (particularly if > 1 moderate or strong cytochrome P-450 inhibitor), only edoxaban consistently reduced major bleeding compared to warfarin. Regardless of the specific OAC selected, appropriate dosing in the elderly (who frequently qualify for dose reduction per the prescribing label) is critical. In elderly and frail patients with AF, factors that may modify the efficacy-safety profile of specific oral OACs should be carefully considered to permit the optimal selection and dosing in these vulnerable patients.

In the current manuscript doctor Giugliano presents two interesting Tables showing the results of NOACs in the elderly and very elderly population, as well as Forest plot of a trial level meta-analysis of NOACs vs. warfarin in patients age > 75 years from the RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials.

Another interesting observation regards NOAC vs. warfarin stratified by degree of polypharmacy, taking into consideration polypharmacy as one important predictor of risk in special in frail patients.