Clot Club – ISTH 2021
David L. McGlasson, MS, MLS(ASCP)
Attending the International Society of Thrombosis and Hemostasis 2021 virtually from July 17-21, 2021 was quite a challenge this year. There were lots of information ranging from clinical, to what I would call “futuristic” research, that we might not see put into clinical practice for several years. I really missed strolling the posters and rubbing shoulders with the presenters. Also, visiting the exhibits and the companies that give us the tools that allow us “clotters” to provide clinicians the best results possible to aid in the treatment process.
In this latest edition of CLOT CLUB, I try to pick out my “highlights” of the meeting. I aim to summarize the presentations, review the sessions and point out the posters I found interesting. I want to give the audience information that they can take back to their institutions and may make their jobs a little easier.
Many great topics that were presented simultaneously. I picked out a few to discuss.
Control of Anticoagulation was a Scientific Session, moderated by Dr. Adam Cuker. Anytime I get a chance, I will attend a session moderated or presented by this colleague. There were 6 talks in this session that took current issues concerning how and when to anticoagulate patients in various disease states. Ah-ha! The primary role of a “clotter”, to figure out when/how to keep the blood flowing or slow it down.
The first topic was a study of ”Inferior Vena Cava Thrombosis International Registry on the Diagnosis and Treatment of Inferior Vena Cava Thrombosis or SIVECT”. The object of study was to (1) Report systemic risk factor for IVC thrombosis, (2) Assess the effectiveness and safety of current treatment options in patients with IVC thrombosis, (3) Describe the long-term outcomes of patients with IVC thrombosis including rates of post-thrombotic syndrome. This is a two-year study that will be completed in 2024. They will have information on 2 time points of clinical outcomes following treatments.
The second topic was extremely timely because it discussed the ”International Registry on the use of the Direct Oral Anticoagulants (DOACs) for the Treatment of Unusual Site Venous Thromboembolism (DUST study)”. The background discusses the use of LMWH, UFH, fondaparinux and VKA, and consists primarily of standard treatment of sites of unusual thrombosis. However, in current literature there are many case reports and case series of DOACs that look at the use of DOACS in unusual VTEs. New ISTH guidelines suggest DOACs can be the first line of treatment for non-malignant and non-cirrhotic acute site venous thrombosis (SVT). They also presented preliminary data of studies that DOACs were used in patients in different doses after they were first treating with heparinoids. The most common reasons for choosing the DOACs included the drug safety issues, patients’ preference, and physicians experience in the treatment of unusual VTE.
[Note on the topic of anticoagulation and DOACs: A previous study reports that prior Coumadin users, now on DOACs, claimed that they would only return to warfarin use if it was a life or death choice. McGlasson DL, Fritsma GA. Measuring Dabigatran with the Dilute Russell Vivper Venom Confirm Assay in an Anticoagulation Clinic Population. Blood Coagulation and Fibrinolysis. 2016;27(1):53-57.]
The third presentation was by Dr. Ravi Sarode, “Toward a Universal Anti-Xa Assay.” This is a timely and much needed study. The primary reason for this is in the issue on when and whether to use a reversal agent such as ANNEXA-4 in situations in DVT, TIA, PE and MI where bleeding has occurred. What is needed is a specific assay that is universal in nature for measuring FXa levels. Some considerations:
- Use the same heparin anti-Xa activity principle in chromogenic assay
- Show an excellent correlation with liquid chromatography mass spectrometry (LCMS)
- Require drug specific calibrators and controls which may slow the turn-around-time (TAT)
- Most centers cannot perform specific assays 24/7
- These tests have not been FDA approved.
Dr. Sarode described several different study protocols in subjects with acute bleeding that show the need for a rapid method to identify patients that may need their DOAC levels measured. Can we run these assays using a universal method? Since many centers have the protocols to run the heparin methods with individual calibrators, the presenter feels that this can be done with single DOAC calibrators. The reagents are liquid and have long shelf life on the instruments used. These tests can cut down the use of expensive reversal agents. Several comparisons between different reagent/instrument combinations were presented with great correlations. Therefore, is the thought was that ISTH should propose a universal anti-Xa assay for measuring UFH, LMWH, and FXa levels using IU/mL unit, which is familiar to physicians.
The next presentation dealt with the “Management of Antithrombotic Therapy after Gastrointestinal Bleeding”. This was presented by Dr. Deborah M Siegal. This was a mixed methods study of health care providers. The primary point of this study was to determine when to start anticoagulation after bleeding occurs. DOACs were permanently stopped in up to 50% of GI bleeds., then subjects were exposed to thrombosis. The question is then when do you restart the therapy? Timing varies widely when to start again and there are no randomized trials to determine the time point. Therefore, this is an unmet clinical question for evidence-based strategies. What do physicians determine when managing anticoagulation after a GI bleed? 1) Identify factors that influence physician decisions, 2) Determine the relative importance of the bleed, and; 3) Explore the preference groups. The discussions through various group studies were then analyzed to determine when anticoagulation should be started in the issue of anticoagulating subjects after a GI bleed. It was concluded that most responders believe that a one-month period should pass before restarting anticoagulation of the GI bleeds.
A presentation by Dr. Nakisa Khorsand dealt with hemostatic effectiveness interventions to stop a major bleed. The aim of the group was to standardize the treatment plan to stop a major bleed and look at when to use antidotes such as Idarucizumab, andexanet Alfa and Prothrombin Complex Concentrates.The stoppage of bleeding within 4 h cessation focused on what to do with a visible bleed, musculoskeletal bleed, intracranial bleed, non-visible bleed. The summary was as follows for the ISTH-SSC definition for effective hemostasis:
- Non-visible bleeding->Hgb level stable at 48h (10% reduced)
- Visible bleeding->Stoppage of visible bleed in 4 h
- Musculoskeletal bleed->Pain and swelling not worse within 24h
- Intracranial bleed ->Hematoma volume in follow-up CT within 12 h is max 35% increased-> No deterioration at 1-24h.
- For all bleeding states at 48h no need for further infusion of hemostatic agents or blood products. Invasive interventions are avoided or carried out with normal blood loss.
The final topic was covering ”DOACs use in Obese Subjects with Venous Thromboembolism: Updated Guidance from the SSC on Control of Anticoagulation.” This topic was covered by Dr. Karlyn Martin. The data was summarized as follows:
- Recommend any DOAC is appropriate in BMI up to 40kg/m2 or weight of 120 kg
- Suggest that rivaroxaban or apixaban are among appropriate anticoagulant options regardless of high BMI and weight
- Suggest not to use dabigatran, edoxaban or betrixaban in patients with BMI >40 kg/m2 or weight >120 kg.
- Suggest not to regularly follow peak or trough dug-specific DOAC levels.
In the Education and Scientific Assembly Programs, I found the presentation of “Suppression of fibrinolysis and hypercoaguablity link with lung injury and mortality in severe COVID-19” by Dr. Lyra Beatriz Olson interesting.
In this presentation, Dr. Olson discussed how SARS-CoV-2 infection is marked by a coagulopathy that is directly linked with the severity of the disease. A Duke University study of survivors and non-survivors were observed with various stages of disease and treatment. An analysis of samples using ROTEM revealed a severe COVID-19 phenotype. In ECMO the same test showed a consumptive coagulopathy. Patients that required ECMO had concurrent markers that showed a vast difference between survivors vs non-survivors with fibrinogen levels, D-Dimers, vWF and ADAMSTS13. PAI-1 was another biomarker elevated in severe thrombotic events in subjects with endotheliopathy. The PAI-1 levels mirrored ARDS severity. The study concluded the following: (1) Endotheliopathy markers were elevated in severe disease with inflamed and injured endothelium releasing vWF and PAI-1. (2) Prothrombotic ECMO circuitry coupled with hypercoagulable phenotype of COVID-19 results in both thrombotic and hemorrhagic events. (3) PAI-1 levels were elevated with severe ARDS and major thrombotic events, with fibrinogen suppression, are implicated in both micro- and macrovascular thrombosis in severe COVID-19.
There were several presentations of Antiphospholipid Antibody Syndrome in both the SSC and the Scientific Sessions. They were quite good presentations and we have previously covered much of the topic in previous CLOT CLUB blogs (see here and here). We used many similar references and resources in those discussions.
In the Education and Scientific Assembly, the presentation put forth interesting data.
- Clinical characteristics and prognosis of antiphospholipid syndrome patients based on cluster analysis: a 10-year cohort study.
- Predictors of Lupus Anticoagulant Test Variability Over Time and its Associations with Future Thrombotic Events: Results from the Vienna Lupus Anticoagulant and Thrombosis Study (LATS).
- Progression of ischemic and hemorrhagic brain lesions on MRI in APS patients on antithrombotic therapy.
- Origin of Antiphospholipid Antibodies in Autoimmunity and viral infection.
The overall conclusions of these presentations were many and varied, however the one thing that stood out for me was that effective coagulation strategies in COVID-19 subjects may require targeting added anti-inflammatory benefits and improved patient outcomes.
Another presentation that piqued my interest was titled: ”What’s New in VTE Prophylaxis: Extended VTE Prophylaxis in Medically Ill Patients”. The presenter took us through the objectives:
Explain-rationale for the extended duration of thromboprophylaxis(EDT) in medically ill patients; Appraise-the current clinical landscape around EDT;
Explore-actions that may influence a wider adoption of EDT;
Propose-strategies to be best prepared for potential increased use for EDT.
The presenter then took the audience through topics including the impact of patient heterogeneity, impact of evolving healthcare, and the current clinical identification of the “right” patients for EDT landscape. This was followed by VTE and bleed risk assessment of the future with COVID-19 as a catalyst. Through all that, the following conclusions were reached to date:
- Optimal approaches to easily and consistently identify patients that drive net clinical benefit EDT are not yet known.
- Newer innovative approaches are promising but cannot yet be recommended.
- Other events, such as the pandemic and revised quality measures, catalyzed an increase in exploration of EDT use.
A plan for anticoagulation stewardship was then laid out for treatment of EDT. Clinicians and healthcare systems should prepare for safe efficacy by utilizing core elements of anticoagulation stewardship.
Another topic on “Health Outcomes in VTE” gave several presentations that touched on studies, such as the The Global Anticoagulant Registry in the FIELD (GARFIELD-VTE), that are both ongoing and completed. It was orated by Dr. Alexander GG Turpie. This was a 36-month clinical outcome study of a protocol of subjects with VTE. Age, gender, and ethnicity were also among the variables evaluated. This also was a multi-country study, and the subjects were followed for 3 years. Almost all subjects were on anticoagulation at start of the study with a wide variety of conditions such as stroke/TIA, major bleed, non-major bleed, MI, cancer.
The study provided a global perspective of long-term anticoagulation patterns with DOACs broadly being favored over VKA use. Over 36 months, death was the most frequent major adverse outcome on VTE patients, almost half of which were cancer-related. The risk of all clinical outcomes is highest in the first 12 months compared to the subsequent 24 months.
As clinical obstacles continue to arise throughout the world, the importance of expanding the laboratory-based knowledge in hemostasis continues to also increase. New and better strategies for appropriately providing clotting tests and solutions, drives the need for more meetings to exchange ideas and will keep ISTH 2022 as an event to look forward to attending. See you in London!