July 2025: New In Coagulation
by Donna Castellone • July 02, 2025
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Novel Anticoagulant Flops for Staving Off Graft Thrombosis in Dialysis Patients
A study looked at 502 patients with end stage kidney disease (ESKD) (average age 60.5, 52% women, 55% white, on dialysis for 5.3 years) who were receiving hemodialysis via an arteriovenous graft (AVG). Inclusion criteria included dialysis at least three times per week for 3 or more hours per session as well as a normally functioning AVG. Patients were given 6mg of MK-2060 or 20 mg of MK-2060 and compared it to a placebo. MK-2060 is a monoclonal antibody that blocks the activation of factor XI and it's downstream activity. However, it did not prevent AVG thrombosis nor the time to first major cardiovascular event as well as fatal bleeding when compared to the placebo. There was no difference between the doses. This cohort of patients are at a very high risk of thromboembolic events, access failure is usually due to AVG thrombosis. Anticoagulation in the ESKD population is tough since they have an elevated bleeding risk due to uremia-related platelet and endothelial dysfunction.
AI Tool Linked to Fewer Recurrent Events After Stroke
A randomized trial looked at an artificial intelligence (AI) based clinical decision support system to aid in the decision making of acute ischemic stroke. It was found to be associated with a significant reduction in recurrent vascular events. The AI system with clinician input and imaging of 20,000 patients in China to help guide patient management regarding stroke etiology and secondary prevention. It is important to note that this is based on Chinese guidelines which differ from US and UK guidelines.
The GOLDEN BRIDGE II trial was designed to aid in rapid and accurate decision-making which is critical in acute stroke management. AI tools offering automated imaging analysis, stroke subtyping and treatment recommendations hold promise for standardizing care and improving outcomes. It randomized patients to use AI or usual care. AI provided automated MRI lesion detection, and lesion characteristics analysis, algorithmic classification of stroke etiology and pathogenesis, with real-time, guideline-based recommendations for secondary prevention.
There were 21,603 patients with acute ischemic stroke, median age 67, 35% women with 96% completing a 12 month follow up. Primary endpoint included occurrence of new vascular events, at 3 months after stroke.
The patients in the AI model had significantly fewer recurrent vascular events (P < .001) when AI was compared to the control group. 2.9% vs 3.9% at 3 months; 3.4% vs 4.8% at 6 months; and 4.0% vs 5.5% at 12 months. As well as lower all-cause mortality at 6 months(2.0% vs 2.3%) and 12 months (3.0% vs 3.5%). AI patients also had a higher composite acute ischemic stroke quality score (91.4 vs 897%).
Questions regarding this outcome include how did the AI improve clinical practice, was it the imaging, or better adherence to guidelines or stroke subtype classification or better individualized treatment?
The results are impressive, but would need to be conducted in the Western world to be used in Europe or North America to determine benefits in this cohort. It is important to understand the data sources used to train this model to avoid bias that AI can amplify. Also, when using an algorithm, how do you keep it updated to incorporate changes in clinical practice, a trial cannot be performed for every update to determine if a wrong decision could be made and cause harm.
The Prevalence of Thrombotic Events Following SARS-CoV2 Vaccine Receipt: Data from the ITP Natural History Study Registry
This study aimed at determining the prevalence of thrombotic events reported in the ITP Natural History Study Registry post COVID-19 vaccine. It was implemented in February 2021 and consisted of three surveys including both children and adults with ITP. Groups were divided into groups that clotted and those that did not clot. A total of 695 participants (667 adults and 28 children) were included. No children reported a clotting event and 8 adults reported a clot post COVID-19 vaccine. Of those, three had a previous history of clotting, and one had surgery in the three months prior to receiving the shot.
Most participants were female, having primary ITP, 75% of those in the clotting group had a BMI of greater than 35 versus 21% in the non-clotting group. Those in the clotting group were older. In the non-clotting group 9% presented with another autoimmune disease. Regarding treatment, more participants (37%) in the clotting group reported receiving a thrombopoietin-receptor agonist (TPO-RA) within the last six months compared to 18% in the non-clotting group.
Based on these findings, blood clots post a COVID-19 vaccine were uncommon among ITP patients. Those who reported a blood clot had a history of thrombosis or other risk factors. The risk is greater in ITP patients who are obese and have a splenectomy.
ASH and ISTH Publish Revised Clinical Practice Guidelines for Pediatric Venous Thromboembolism
The ISTH and ASH have new and updated VTE clinical guidelines. These guidelines incorporate the latest research in the field since the previous 2018 edition. There were 16 updated recommendations and four were added. The most notable is the recommendation that advised the use of DOACs such as dabigatran or rivaroxaban over therapies such as LMWH and vitamin k antagonist.
The incidence of VTE in children in the general population is low, but higher in children who are hospitalized. It is complicated in children with complex illnesses and conditions and can impact long-term outcomes for these patients.
Hemophilia B Gene Therapy Sustains Efficacy Over a Decade Later
A longitudinal study has shown that a single infusion of AAV-mediated gene therapy in hemophilia B, factor IX, has demonstrated after 13 years sustained clinical benefit and no late onset safety concerns. This was shown in 10 men across dose groups with seven not receiving factor IX prophylaxis. Bleeding rates decreased from 14 episodes to 1.5 and the use of factor IX concentrate decreased by a factor of 12.4. These findings support long-term safety and efficacy. The first infusion was given in 2014. Additional studies lead to the FDA approval of etranacogene dezaparvovec (Hemgenix) and fidanacogene elaparvovec (Beqvez) in adults with severe hemophilia. However, uncertainties remain regarding the durability of transgene expression.
A total of 354 adverse events have been reported, 15 associated with AAV gene therapy including transient elevations of liver aminotransferase in 4/6 treated with high vector dose. Two cases of cancer developed, lung in a patient who smoked for 7 years after receipt of therapy and prostrate cancer in a 74 year old, 11.6 years after therapy. However based on an expert multidisciplinary team it was suggested the cancers were not associated with gene therapy. There were no cases of FIX inhibition, thrombosis, recurrent transaminitis or death.
After 13 years, FIX activity remained stable with mean levels of 1.7 IU/dL in the low-dose cohort, 2.3 IU/dL in the intermediate-dose cohort, and 4.8 IU/dL in the high-dose cohort. Three patients with severe hemophilic arthropathy resumed factor IX prophylaxis within 4 years due to spontaneous joint bleeds. Levels of 1-3 IU for FIX were insufficient to prevent bleeding in these patients.
Spectrum of anti-PF4 disorders widens
HITT, or heparin induced thrombocytopenia with thrombosis, gave way to VITT, or vaccine induced thrombotic thrombocytopenia, during the COVID 19 pandemic. Now there is the classification of VITT-like in cases when the patient has not received heparin or a vaccine. This now is called monoclonal gammopathy of thrombotic significance (MGTS). This disorder has been called VITT-like MGTS, HIT-like MGTS and MGTS that is neither HIT or VITT like. This is considered a chronic condition and may become part of a thrombophilia profile.
MGTS was not previously recognized, but it is characterized by platelet activating monoclonal antiplatelet factor 4 antibodies. This relative of HIT behaves as a consumptive, DIC mircroangiopathy as opposed to VITT which behaves as a consumptive DIC.
The incidences of VITT in the adenoviral vector vaccines were one in 100,000, so very rare and in normal times would not have been identified. Patients presented with reduced platelet counts, increased D-dimer and other markers of hypercoagulability, which looked similar to HIT. VITT and HIT antibodies recognize distinct regions on the PF4 protein. Both are detected in ELISA testing, but rapid test only detect HIT demonstrating they are different antibodies. VITT antibodies linger longer than HIT antibodies.
MGTS is rare and hard to diagnose and the prevalence is hard to determine. It is important for clinicians to understand that certain tests for HIT do not identify VITT antibodies. The solid-phase HIT ELISAs are useful for VITT/VITT-like MGTS antibodies, however the test is not specific. New testing is being developed for VITT. The test requires platelets that are treated with PF4 to confirm the presence of the antibody. The SRA assay also requires PF4 to detect VITT antibody with high sensitivity.
Information on this disorder is evolving. However it is important to be aware of the existence of this disorder.
Ticagrelor doubts: inaccuracies uncovered in key studies for AstraZeneca’s billion dollar drug
Ticagrelor becomes a generic drug this year. An investigation by the British Medical Journal discovered data integrity problems in the 18000 person PLATO study which found this drug had an advantage over cheaper rivals in patients with acute coronary syndrome. They found several incidents of misreporting. They were as follows:
- The primary endpoint results for both clinical trials were inaccurately reported in Circulation
- More than 60 of 282 readings from platelet machines used in the trials were not present in US Food and Drug Administration datasets
- One active trial investigator never became a study author, while one author told The BMJ he was not involved in the trial. Most investigators, including the principal investigator, were unreachable or declined to be interviewed
Findings included the failure in AstraZeneca's study reporting statistical significance in a journal, but did not reach significance. Additionally, there were many episodes of rebound making patients prone to thrombosis and excessive platelet inhibition putting patients at an increased risk for bleeding.
In the ONSET/OFFSET and RESPOND trial the reports stated that ticagrelor provided faster and greater inhibition of platelets than clopidogrel. Leading to a decreased incidence of thrombosis. The benefits of ticagrelor's faster inhibition was not clearly seen and questioned in the initial review of PLATO. The subjects required 6 blood draws per visit without paying the participants. This resulted in difficulty in recruiting patients. When trying to substantiate clinical trial information authors did not respond or were put on the paper as authors, however were not involved in the study. There was no evidence of training for interpretation of the platelet studies since they must be performed on site and there is no evidence they were standardized in order to be able to compare results from different sites.
In datasets submitted to the FDA it was noted that machines and supplies were shipped to various trial sites. However information is not clear as to which sites received the instrument and test kits. Timing of this did not correspond with the reporting of testing. Additionally in analyzers that were retrieved it was found that data existed that was never reported in the trials which contained platelet activity levels that were higher than those reported in the trials. Also, three of the eight active study sites failed to test baseline platelet aggregation but continued to draw these patients 11 times, but their data was excluded from the trial. Baseline platelet aggregation in several patients were recorded as less than 50% which is lower than expected for these patients, these resulted in several having an increased aggregation post treatment which may point to an inaccurate laboratory reading. If data was adjusted it should have been reported in the trial report for complete transparency.
JOURNAL CLUB
Platelet Transfusion 2025 AABB and ICTMG International Clinical Practice Guidelines
Ryan A. Metcalf, MD; Susan Nahirniak, MD; Gordon Guyatt, MD; et alAarti Bathla, MPH; Sandra K. White, MS; Arwa Z. Al-Riyami, MD; Rachel C. Jug, MB, BCh, BAO; Ursula La Rocca, MD; Jeannie L. Callum, MD; Claudia S. Cohn, MD; Abe DeAnda, MD; Robert A. DeSimone, MD; Allan Dubon, MLS; Lise J. Estcourt, MB, BChir; Daniela C. Filipescu, MD; Mark K. Fung, MD; Ruchika Goel, MD; Aaron S. Hess, MD; Heather A. Hume, MD; Richard M. Kaufman, MD; Peter Kranke, MD; Vernon J. Louw, MBChB, MMed, PhD; Morten H. Møller, MD; Michael F. Murphy, MD; Jennifer A. Muszynski, MD; Cian J. O’Kelly, MD; Monica B. Pagano, MD; Gopal K. Patidar, MD; Katerina Pavenski, MD; Jacqueline N. Poston, MD; Nabiha H. Saifee, MD, PhD; Moritz Stolla, MD; Zbigniew M. Szczepiorkowski, MD, PhD; Aaron A.R. Tobian, MD; Raman Uberoi, MD; Jonathan Waters, MD; Brittney Williams, MD; Erica M. Wood, MD; Nicole D. Zantek, MD, PhD; Michelle P. Zeller, MD; Brenda J. Grossman, MD; Simon J. Stanworth, MD, DPhil
JAMA. May 29, 2025
Abstract
Importance Platelet transfusion is a frequent procedure with benefits and risks.
Objective To provide recommendations in adult and pediatric populations in whom platelet transfusions are commonly performed.
Evidence Review Grading of Recommendations Assessment Development and Evaluation (GRADE) methodology was applied to findings from 21 randomized trials and 13 observational studies in contexts of limited randomized clinical trial data. Transfusion strategies using fewer (restrictive) vs greater (liberal) amounts of platelets were compared.
Findings Evidence demonstrated that restrictive transfusion strategies probably did not cause increases in mortality or bleeding relative to liberal strategies across predefined clinical populations. Exceedingly low incidence of spinal hematoma was identified in patients with thrombocytopenia undergoing lumbar puncture. Because definitions of restrictive strategies varied across trials, recommendations reflect practical guidance. The following recommendations are strong recommendations with high/moderate–certainty evidence. For hypoproliferative thrombocytopenia in nonbleeding patients receiving chemotherapy or undergoing allogeneic stem cell transplant, platelet transfusion is recommended when platelet count is less than 10 × 103/μL. For consumptive thrombocytopenia in neonates without major bleeding, platelet transfusion is recommended when platelet count is less than 25 × 103/μL. In patients undergoing lumbar puncture, platelet transfusion is recommended when platelet count is less than 20 × 103/μL. In patients with consumptive thrombocytopenia due to Dengue without major bleeding, platelet transfusion is not recommended. The following recommendations are conditional recommendations with low/very low–certainty evidence. For hypoproliferative thrombocytopenia in nonbleeding adults undergoing autologous stem cell transplant or with aplastic anemia, prophylactic platelet transfusion is not recommended. In adults with consumptive thrombocytopenia without major bleeding, platelet transfusion is recommended when platelet count is less than 10 × 103/μL. In adults undergoing central venous catheter placement in compressible anatomic sites, platelet transfusion is recommended when platelet count is less than 10 × 103/μL. In adults undergoing interventional radiology, platelet transfusion is recommended when platelet count is less than 20 × 103/μL for low-risk procedures and less than 50 × 103/μL for high-risk procedures. For adults undergoing major nonneuraxial surgery, platelet transfusion is recommended when platelet count is less than 50 × 103/μL. For patients without thrombocytopenia undergoing cardiovascular surgery in the absence of major hemorrhage, including those receiving cardiopulmonary bypass, platelet transfusion is not recommended. For nonoperative intracranial hemorrhage in adults with platelet count greater than 100 × 103/μL, including those receiving antiplatelet agents, platelet transfusion is not recommended.
Conclusions And Relevance A consistent pattern of evidence supports the implementation of restrictive platelet transfusion strategies. Restrictive strategies reduce risk of adverse reactions, mitigate platelet shortages, and reduce costs. It is good practice to consider overall clinical context and alternative therapies in the decision to perform platelet transfusion.
Asundexian or Apixaban in Patients With Atrial Fibrillation According to Prior Oral Anticoagulant Use: A Subgroup Analysis of the OCEANIC-AF Randomized Clinical Trial
John H. Alexander, MD, MHS; Elizabeth J. Lydon, MB, MS; Jonathan P. Piccini, MD; et alThomas Viethen, MD, MHBA; Jonas Oldgren, MD, PhD; Shaun G. Goodman, MD, MSc; Jan Steffel, MD; Andrea M. Russo, MD; Isabelle C. van Gelder, MD, PhD; Keith C. Ferdinand, MD; Renato D. Lopes, MD, PhD; Hardi Mundl, MD; Bela Benczur, MD; Juan José Gómez-Doblas, MD; Michael Glikson, MD; Assen Goudev, MD, DSc; Erik L. Grove, MD, PhD; Sigrun Halvorsen, MD, PhD; Tuomas Kiviniemi, MD, PhD; Anne-Céline Martin, MD, PhD; Roopinder K. Sandhu, MD, MPH; Dragos Vinereanu, MD, PhD; Frank W. Rockhold, PhD; Valeria Caso, MD, PhD; Rosa Coppolecchia, DO, MPH; Manesh R. Patel, MD
JAMA March 2025
Abstract
Importance In patients with atrial fibrillation (AF), oral anticoagulants (OACs) reduce the risk of stroke.
Objective To investigate if patients with less prior OAC exposure respond differently to a new OAC than patients with more OAC exposure.
Design, Setting, and Participants In this prespecified exploratory subgroup analysis of the Oral Factor 11a Inhibitor Asundexian as Novel Antithrombotic–Atrial Fibrillation (OCEANIC-AF) randomized clinical trial, patients enrolled in the OCEANIC-AF trial were categorized as OAC naive or OAC experienced based on whether they had 6 or fewer weeks or more than 6 weeks of prior OAC use. The effect of asundexian vs apixaban was then compared on outcomes among patients who were OAC naive and OAC experienced. The study setting included 1035 sites in 38 countries, and participants were those enrolled in the OCEANIC-AF trial. Data were analyzed from June to July 2024.
Interventions Asundexian, a novel factor XIa inhibitor, was compared with apixaban in patients with AF.
Main Outcomes and Measures The primary efficacy outcome was stroke or systemic embolism. The main safety outcome was major bleeding.
Results Of patients in the OCEANIC-AF trial, 2493 (17%) were OAC naive (mean [SD] age, 72.6 [8.6] years; 1464 male [59%]) and 12 317 (83%) were OAC experienced (mean [SD] age, 74.2 [7.5] years; 8132 male [66%]). In the asundexian arm, patients who were OAC naive had a stroke or systemic embolism rate of 0.8% (10 of 1238) compared with 1.4% (88 of 6177) in those who were OAC experienced. In the apixaban arm, patients who were OAC naive had a stroke or systemic embolism rate of 0.6% (7 of 1255) compared with 0.3% (19 of 6140) in those who were OAC experienced. Thus, patients who were OAC naive had a smaller increase in stroke or systemic embolism with asundexian compared with apixaban (hazard ratio [HR], 1.42; 95% CI, 0.54-3.73) than patients who were OAC experienced (HR, 4.66; 95% CI, 2.84-7.65; P for interaction =.03). Bleeding rates were lower among both OAC-naive patients (0.2% [2 of 1228]) and OAC-experienced patients (0.2% [15 of 6145]) assigned asundexian than among OAC-naive patients (1.0% [13 of 1249]) and OAC-experienced patients (0.7% [40 of 6115]) assigned apixaban.
Conclusions and Relevance In the OCEANIC-AF randomized clinical trial, patients with AF who were OAC naive had a smaller increase in stroke or systemic embolism and a similar lower rate of bleeding with asundexian compared with apixaban than patients who were OAC experienced. The mechanism of these findings is unknown and deserves further research.
Systematic Literature Review of DOACs as Treatment for Confirmed or Suspected Heparin-Induced Thrombocytopenia (HIT)
Shoshana Steinmetz, Anastasiya Shor, Michelle Jakubovics
Ann Pharmacother, 2025 May 24.
Abstract
Objective: To analyze available literature on the use of direct oral anticoagulants (DOACs) in the treatment of confirmed or suspected heparin-induced thrombocytopenia (HIT).
Data sources: PubMed and Embase databases were searched through December 16, 2024, to identify studies assessing DOAC use in the treatment of acute confirmed or suspected HIT.
Study selection and data extraction: Included studies analyzed use of apixaban, dabigatran, edoxaban, or rivaroxaban in patients with confirmed or suspected HIT.
Data synthesis: Ten studies including 275 patients met the inclusion criteria. Eight were retrospective cohort studies and 2 were prospective. No randomized control trials were identified. A 4Ts score was reported for 259 patients; an antibody immunoassay was reported for 149 patients; and a serotonin release assay was reported for 109 patients. Eight, 6, and 2 studies reported use of rivaroxaban, apixaban, and dabigatran, respectively. Thrombosis rates ranged from 0% to 8.3%, 0% to 13.7%, and 0% to 2.5% for rivaroxaban, apixaban, and dabigatran respectively. Major bleeding was reported in 1 patient receiving rivaroxaban.
Relevance to patient care and clinical practice: The 2018 American Society of Hematology HIT guidelines conditionally recommend DOAC use due to very low certainty of effects. Direct oral anticoagulants (DOACs) are an attractive treatment option for acute HIT due to ease of administration and reduced need for monitoring. Analysis of the recently published relevant data can support and guide appropriate use of DOACs in these patients.
Conclusions: This systematic review strengthens previously published evidence that DOACs are likely a safe and effective treatment for confirmed or suspected HIT. Study design, small study size, and varying diagnostic criteria reduce data certainty.
Control of warfarin treatment in patients with antiphospholipid syndrome and falsely high INR at point-of-care-testing
Jørn Dalsgaard Nielsen, Thomas Steffen Hermann, Konstantinos Dimopoulos, Anne Storgaard Nørskov
Thromb Res 2025 May 28:252:109361.
Abstract
Background: The standard of care for thrombotic antiphospholipid syndrome (APS) is anticoagulation with vitamin K antagonists (VKA). Several studies have indicated that lupus anticoagulant (LA) can interfere with the international normalized ratio (INR) results obtained by point-of-care testing (POCT) devices. A subset of patients with APS has clinically significant systematic differences between POCT INR and plasma INR (P-INR) measured in the hospital laboratory.
Objectives: We aimed to investigate a potential correlation between POCT INR (CoaguChek, Roche Diagnostics) and P-INR in these patients.
Materials and methods: In our anticoagulation clinic, we compared 363 paired CoaguChek-INR (CC-INR) with P-INR results using Owren's method from 37 patients with APS receiving self-managed VKA. Each patient had a minimum of three paired measurements of CC-INR and P-INR and a median CC-INR/P-INR ratio > 1.20.
Results: In all patients, we found a strong linear correlation between CC-INR and P-INR (median R2: 0.89; IQR: 0.78-0.94). Each patient had their own characteristic regression line from which CC-INR could be converted to P-INR. Thirty-four patients continued with self-managed treatment and the use of a conversion table. However, 3 patients had to switch to INR control in the anticoagulation clinic, as the upper limit of their therapeutic CC-INR interval exceeded the maximum (INR: 8.0) on their CoaguChek device.
Conclusions: In a subset of patients with APS who, during self-managed VKA therapy, had persistently higher POCT INR than P-INR, the majority could continue with self-managed therapy using a conversion table, as the falsely elevated POCT INR values were linearly correlated to P-INR.
2025 Guidelines for direct oral anticoagulants: a practical guidance on the prescription, laboratory testing, peri-operative and bleeding management
Huyen A Tran, Eileen Merriman, Ross Baker, Jennifer Curnow, Laura Young, Chee Wee Tan, Simon McRae, Sanjeev D Chunilal
Intern Med J. 2025 May 31.
Abstract
Direct oral anticoagulants (DOACs) are widely prescribed to prevent and treat venous and arterial thromboembolism, supported by published evidence, and are preferred over warfarin in many guidelines. Although the risk of major bleeding, in particular intracranial haemorrhage (ICH), is decreased with DOACs, gastrointestinal bleeding is increased with some DOACs, and the case fatality rate of bleeding remains high. Therefore, it is important to (i) prescribe DOACs appropriately, (ii) have strategies to manage major bleeding including the use of specific reversal agents and (iii) interrupt and resume DOACs for procedures. The main recommendations are as follows: (i) Select the appropriate dose of DOAC according to indications and consider patient factors to minimise bleeding risks; (ii) DOACs do not require routine laboratory testing; (iii) for life-threatening uncontrollable bleeding, specific agents can be used to reverse the anticoagulant effects of DOACs; and (iv) DOACs can be interrupted for planned procedures without the need for 'bridging' with low-molecular-weight heparin (LMWH). The anticoagulant effects of DOACs can be reversed with specific agents, such as andexanet for apixaban and rivaroxaban and idarucizumab for dabigatran. If not available, pro-haemostatic agents such as prothrombin complex concentrates or activated prothrombin complex concentrates can be considered. DOACs can be interrupted and resumed for procedures without the need for 'bridging' with LMWH.