August 2025: New In Coagulation
by Donna Castellone • August 07, 2025
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Early Start to Post-Stroke DOACs? Near Conclusive Evidence From Meta-Analysis — Four trials pooled to show clinical benefit without uptick in brain bleeding
Based on the pooled results of four clinical trials, the initiation of DOACs soon after stroke could be considered safe and effective for some patients. In patients with acute ischemic stroke and AF who received DOACs within 4 days greatly reduced the chance of subsequent strokes at 30 days (2.1 vs 3.0%) regardless of severity, reperfusion treatment and previous use of OAC. However, symptomatic ICH was 0.4% in both groups. Results support early initiation.
The trials included TIMING, ELAN, OPTIMAS and START (n=5441, median age 77.7, 45.4% female, stroke scale of 5), however these patients had mild to moderate strokes, while those with severe strokes were not represented, so different decisions may need to be made with these patients. Other comorbidities should be assessed such as advanced age, polypharmacy, and frailty when delayed DOAC therapy might derive increased benefits. The type of OAC used needs to be considered, most patients were on apixaban making dabigatran, edoxaban and rivaroxaban understudied.
Intravenous Thrombolysis in Patients With Recent Intake of Direct Oral Anticoagulants: A Target Trial Analysis and Comparison With Reversal Agent Use
Patients who have taken DOAC and then receive IV thrombolysis is controversial. Data from 28 stroke centers have been analyzed and included patients on DOACs if they met IVT criteria with a Stroke scale of ≥ 2 and DOAC intake was within 48 hours.
Safety and efficacy outcomes (symptomatic intracerebral hemorrhage, any intracerebral hemorrhage, major bleeding, 90-day mortality, and good functional outcome [modified Rankin Scale score of 0–2 or return to baseline]) were compared between those receiving IVT versus no IVT and IVT with versus without reversal.
The study included 1342 patients with a median age of 80, 50% were female, 52% received endovascular therapy, IVT was given in 342/1342 patients. Of these 41.2% had verified DOAC intake <12 hours prior to admission and 26.9% had taken it within 12-24 hours. ICH occurred in 3.0% of patients with IVT and 5.9% of patients not receiving IVT. Those with IVT had good functional outcomes.
The study supports the safety of off label IVT with recent DOAC intake.
Bristol Myers Squibb and Pfizer Announce Direct-to-Patient Eliquis® (Apixaban) Option
As of September 8, all eligible US patients on Eliquis may purchase the medication directly through Eliquis 360 Support at https://www.eliquis.bmscustomerconnect.com/support with a discounted rate of 40% less than the current list price. This will provide an opportunity for uninsured, underinsured or self-pay patients to lower their out-of-pocket costs. This will increase patient access and affordability. There have been more than 15 million people prescribed apixaban since it was first launched resulting in almost 3 billion dollars in healthcare cost saving and avoidance.
ELIQUIS is a prescription medicine used in adults to:
- Reduce the risk of stroke and blood clots in people who have atrial fibrillation (AFib), a type of irregular heartbeat, not caused by a heart valve problem.
- Treat blood clots in the veins of the legs (deep vein thrombosis – DVT) or lungs (pulmonary embolism – PE), and reduce the risk of them occurring again after receiving treatment for blood clots.
- Help prevent a blood clot in the legs (DVT) and lungs (PE) of people who have just had hip or knee replacement surgery.
JOURNAL CLUB
The safety and efficacy of factor XIa inhibitors for the prevention of stroke and thromboembolism: A systematic review and meta-analysis of randomized controlled trials
Nayab Zahid, Fatima Iqbal, Amber Siddique, Anushah Nadeem, Waqar Hussain, Amna Ishaq, Mansoor Ahmed, Nauman Lal, Saad Abdullah, Humyoun Yousaf, Uzair Jafar, Muhammad Ayyan, Muzammil Farhan, Muhammad Ameen Noushad, Raheel Ahmed
J Stroke Cerebrovasc Dis. 2025 Jun 19;34(8):108381.
Abstract
Background: Stroke and thromboembolism remain the leading causes of mortality worldwide. Factor Xia inhibitors (FXIa) might prevent thromboembolism without interfering with hemostasis, thus leading to a lower risk of bleeding than direct oral anticoagulants (DOACs).
Methods: We conducted a systematic search using PubMed, Embase, and Clinicaltrials.gov to retrieve randomized controlled trials comparing FXIa inhibitors to placebo or DOACs in patients at risk of stroke or thromboembolism. All statistical analyses were carried out using RevMan 5.4, using a random effects model.
Results: Our meta-analysis included 14 RCTs involving 30,952 patients. FXIa inhibitors significantly decreased the risk of major bleeding (RR 0.47, 95% CI: 0.33-0.66, I2= 46%) with no significant change in systemic embolism or thromboembolism (RR 0.83, 95% CI: 0.64-1.07, I2= 70%). There was no significant change between the two groups when assessing the rate of all bleeding events (RR 0.78, 95% CI: 0.55-1.11, I2= 73%), all-cause mortality (RR 0.87, 95% CI: 0.70-1.09, I2= 0%), ischemic stroke (RR 0.99, 95%CI: 0.49-1.98, I2= 86%), myocardial infarction (RR 1.30; 95% CI, 0.54 - 3.13; I2 = 68%), and intracranial hemorrhage (RR 0.49, 95% CI: 0.23- 1.05, I2= 9%). The rate of all adverse events (RR 1.05, 95% CI: 0.86-1.29, I2= 79%) and serious adverse events (RR 1.16, 95% CI: 0.86-1.55, I2= 74%) remained comparable between the two groups.
Conclusion: In conclusion, FXIa inhibitors show promise as safer anticoagulant agents, demonstrating favorable bleeding outcomes without changing thromboembolism, mortality, or other safety outcomes. The presence of heterogeneity across various subgroups warrants data from further high-quality, large-scale RCTs to establish evidence of its clinical benefit. This is especially important in atrial fibrillation, where conflicting evidence regarding thromboembolism warrants cautious interpretation and further investigation.
Evaluating DOAC dipstick testing in the management of acute stroke: protocol for a multicentre, prospective, observational registry study
Edward Patrick Callaly, Peter Shuangyue Tan, Emily Schembri, Marija Borosak, Helen Dewey, Philip Choi
BMJ Open 2025 Jun 27;15(6):e102092.
Abstract
Introduction: Direct oral anticoagulants (DOACs) are preferred over vitamin K antagonists for stroke prophylaxis in non-valvular atrial fibrillation. Yet, DOAC use is regarded as a contraindication for intravenous thrombolysis in acute ischaemic stroke. The stratification of patients into 'on-therapy' and 'off-therapy' categories based on their plasma DOAC concentrations is particularly crucial in the acute phase of stroke when decisions for thrombolysis or anticoagulation reversal are time-sensitive. The novel point-of-care DOAC dipstick assay (DOASENSE) rapidly assesses urine for clinically significant DOAC levels, potentially broadening eligibility for thrombolysis or targeted reversal therapy. This multicentre prospective observational registry study aims to evaluate the accuracy and clinical utility of DOAC dipstick testing compared with plasma DOAC assays in acute stroke management across regional Australian hospitals.
Methods and analysis: This multicentre, prospective, observational study will enrol participants presenting to hospitals across Victoria and Tasmania with acute ischaemic stroke or intracerebral haemorrhage with DOAC ingestion within 48 hours of presentation. Plasma DOAC concentrations measured by chromogenic assays will be compared with rapid urine dipstick results from DOASENSE testing. There is a target sample size of 146 participants. The primary outcomes are as follows: (1) proportion of ischaemic stroke participants with off-therapy plasma DOAC levels and (2) eligibility for reperfusion therapy based on DOASENSE and plasma DOAC concentrations. Secondary outcomes are follows: (1) ischaemic stroke aetiology for participants with on-therapy vs off-therapy DOAC levels; (2) proportion of participants meeting criteria for pharmacological DOAC reversal based on DOASENSE outcomes; (3) incidence of false-negative and false positive DOASENSE results in clinically significant DOAC plasma concentrations at a threshold of ≥30 ng/mL and (4) an exploratory analysis of any false negative DOASENSE assays to identify potential contributing factors.
Disseminated intravascular coagulation
Satoshi Gando , Marcel Levi , Cheng-Hock Toh
J Intensive Care 2025 Jun 6;13(1):32.
Abstract
Background: Disseminated intravascular coagulation (DIC) is characterized by systemic coagulation activation, anticoagulation pathway impairment, and persistent fibrinolysis suppression, resulting in widespread microvascular thrombosis, followed by hemorrhagic consumption coagulopathy and multiple organ dysfunction syndrome. This article aimed to provide a comprehensive and updated DIC overview.
Main body: The International Society on Thrombosis and Hemostasis provides definitions, underlying disorders, diagnostic algorithms, and management guidelines for DIC. Two clinical features of DIC are hemorrhagic consumption coagulopathy, characterized by oozing and difficult-to-control bleeding, and microvascular thrombosis, leading to dysfunctions in multiple vital organs. Histones derived from cellular damage play central roles in the innate-immune-based coagulation model, comprising the initiation, amplification, propagation, and reinforcement phases, which, if dysregulated, develop into DIC. Thus, the innate immune-mediated pathogenic pathways in DIC have become clear. Cell death, damage-associated molecular patterns (including histones), crosstalk between hypoxic inflammation and coagulation, and the serine protease network (comprising coagulation and fibrinolysis, the Kallikrein-Kinin system, and complement pathways) play major roles in DIC pathogenesis. Conversely, these pathogenic pathways and DIC synergistically contribute to organ dysfunction, leading to poor prognoses. Effective DIC management requires treating the underlying condition, along with substitution therapies and, in some cases, antifibrinolytics. Anticoagulant use has been extensively debated; however, the selection of optimal target patients could optimize their application and improve patient outcomes in the near future.
Conclusions: This review provides an updated overview of DIC, aiming to help readers understand various aspects of DIC today.
Lupus anticoagulant testing in Belgian laboratories: a comparison with the 2020 International Society on Thrombosis and Haemostasis Scientific and Standardization Committee (ISTH-SSC) guidelines
Benedicte Vanhove, Lieve Van Hoovels, Sylvia Broeders, Wim Coucke, Marco W J Schreurs, Carolien Bonroy, Sofie Schouwers, Robin Vanstokstraeten, Els Bailleul, Katrien M J Devreese
Acta Clin Belg 2025 Jun;80(3):62-70.
Abstract
Objectives: We investigated lupus anticoagulant (LA) testing in Belgium and verified these findings against the 2020 International Society on Thrombosis and Haemostasis Scientific and Standardization Committee (ISTH-SSC) Guidelines.
Methods: A survey, interrogating pre- and post-analytical aspects of antiphospholipid antibodies, including LA analysis, was distributed to all Belgian laboratories (
Results: About 66% of the laboratories responding to the entire survey (58%) performed LA analysis. About 78% used thrombocyte-free citrated plasma. Most (90%) used the combination of dilute Russell's viper venom time (dRVVT) and activated partial thromboplastin time (aPTT), performing dRVVT (82%) and aPTT (78%) if the screening test was prolonged. A variety of instrument/reagent combinations were used. Normal pooled plasma (PNP) for mixing tests was used by 83%, either commercially lyophilized (56%) or frozen (44%), mostly (98%) in a 1:1 PNP: patient plasma ratio. Interpretation was based on normalized clotting time ratio, using manufacturers' or own study data as cutoff values. About 61% gave a final conclusion. About 88% added comments, mainly (94%) with a positive result. All laboratories programmed a barring period after an initial positive result. About 66% performed LA detection in patients receiving direct oral anticoagulants, 74% after using sample pretreatment with active charcoal absorption. LA testing for vitamin K antagonists and heparin-treated patients was done by 54%, regardless of international normalized ratio (64%) or anti-FXa results (82%).
Conclusions: The survey shows adherence to ISTH-SSC guidelines, especially for sample preparation and test methodologies. Additional efforts are required to harmonize LA detection in anticoagulated patients and result interpretation.
Thrombophilia Testing in Venous Thromboembolism
Kristina Vrotniakaite-Bajerciene, Anne Angelillo-Scherrer, Lana A Castellucci
Med Clin North Am, 2025 Jul;109(4):907-921.
Abstract
Hereditary thrombophilias, comprising factor V Leiden mutation, prothrombin G20210A mutation, protein C, S, and antithrombin deficiency, and acquired antiphospholipid antibody syndrome, predispose venous thromboembolism (VTE) in various mechanisms. Not only the thrombophilia testing and result interpretation requires special laboratory and expertise but also the indications for thrombophilia testing are variable across centers. This is because the role of thrombophilia in VTE management is still under investigation. This narrative review describes the main thrombophilias to be tested, summarizes the indications for thrombophilia testing, and reports the current evidence regarding their role in the duration and choice of anticoagulation in VTE.
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 Aug: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 Jul;55(7):1174-1183.
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.
Diagnostics and management of direct oral anticoagulants-induced bleeding
Christian von Heymann, Arash Afshari, Aamer Ahmed, Eleni Arnaoutoglou, Daniel Bolliger, Oliver Grottke
Curr Opin Anaesthesiol 2025 Aug 1;38(4):353-360.
Abstract
Purpose of review: To provide evidence-based management of patients on direct oral anticoagulants (DOAC) needing acute procedures, including those facing hemorrhage.
Recent findings: Standard coagulation parameters are insufficient for precise DOAC plasma level measurement; calibrated anti factor X activated assays are reliable, and point-of-care assays may be useful in urgent situations. For intracerebral hemorrhage (ICH) in patients on DOACs, direct reversal strategies seem to be more effective than nonspecific hemostatic agents, but evidence still remains unclear in terms of efficacy and safety compared to nonspecific hemostatic agents. Before invasive procedures like neuraxial anesthesia or cerebral thrombectomy, idarucizumab is recommended for dabigatran-treated patients, despite recent observational data not fully supporting this. No recommendations can be made for FXa inhibitors because of the lack of data.
Summary: Clinicians should assess the overall risk of bleeding for an acute procedure or the severity of any ongoing hemorrhage in DOAC-treated patients before initiating any reversal treatment, regardless of current evidence levels.
The Clinical Significance of Non-Criteria Antiphospholipid Antibodies in Atypical Antiphospholipid Syndrome
Yue Xiong, Tingting Wu, Lei Wang, Xinyi Shen, Yufeng Yin, Jian Wu, Tian Ren, Jing Cao, Tao Cheng, Mingjun Wang
Mod Rheumatol. 2025 Jul 11:roaf060.
Abstract
Objective: To analyse the correlation between non-criteria antiphospholipid antibodies (non-criteria aPLs) and clinical symptoms (recurrent miscarriage) in patients with seronegative antiphospholipid syndrome (SNAPS).Methods:Ninety-four SNAPS patients who were treated in the First Affiliated Hospital of Soochow University from May 2022 to May 2024 were included. Chemiluminescence immunoassay was used to detect anti-β2 glycoprotein I antibody (aβ2GPI), anti-cardiolipin antibody (aCL), and lupus anticoagulant. ELISA was used to detect the levels of anti-annexin A5 (ANXA5), anti-phosphatidylethanolamine antibody (aPE), anti-prothrombin IgG antibody (aPT IgG), anti-prothrombin IgM antibody (aPT IgM), anti-phosphatidylserine/prothrombin IgG antibody (aPS/PT IgG), and anti-phosphatidylserine/prothrombin IgM antibody (aPS/PT IgM). The correlation between non-criteria antiphospholipid antibodies and clinical events was analysed.
Results: Compared with the non-criteria antibody-negative group, the positive group had a higher rate of positive antinuclear antibodies (p < 0.05). The proportion of recurrent miscarriage in the positive non-criteria antibody group was significantly higher than in the negative group (p = 0.002). Compared with the negative group, patients with positive anti-annexin A5 antibody and aPT IgM were more likely to have recurrent miscarriage (p < 0.05). Compared with the aPE-negative group, those with aPE-positive were more likely to experience early miscarriage (p = 0.039). Both aPT IgM subtype (p = 0.004) and ANXA5 (p = 0.013) antibodies were the risk factors for recurrent miscarriage. Patients with positive ANXA5, aPT IgG, and aPT/PS IgM antibodies showed a significant decrease in antibody titers after treatment (p < 0.05).
Conclusion: Detection of non-criteria aPLs contributes to improving the diagnosis of SNAPS, assessing its development trends, and intervening promptly to prevent recurrent miscarriage.