April 2025: New In Coagulation
by Donna Castellone • April 07, 2025
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Anti-Factor XI Anticoagulants: Breakthrough or Bust?
The OCEANIC- AF phase 3 trial failed to demonstrate efficacy of the anti- XI peptide asundexian revealing a fourfold risk of ischemia when compared with DOACs. leading cardiologists to question if they will be widely used in the prevention of ischemic risk. Otamixaban was also rejected because of unsatisfactory result in post-acute coronary syndrome. The OCEANIC-STROKE trial evaluated evaluating the efficacy of 50mg/ml d of asundexian poststroke is ongoing as an alternative to DOAC. Results have yet to be revealed. The drug FXI-ASO administered sub cutaneously after knee replacement showed superiority to enoxaparin. While fesomersen reduced DVT by 86% and injected monthly.
The supposed benefits to these inhibitors was preventing strokes, cardiovascular events and VT without increasing the risk of bleeding. The role of factor XI in thromboembolism is not fully understood but it may affect thrombus formation without compromising physiological hemostasis. These could play a role in high-risk patients including end stage renal disease or cancer and those at a risk for thrombosis involving artificial surfaces such as those with mechanical heart valves, ECMO or possibly during angioplasty.
Small peptide inhibitors of FXIa can be orally administered, and have a 2-4 hour duration and can be taken once or twice daily. Asundexian was evaluated in the phase 2 PACIFIC-AF trial compared to apixaban in AF patients with a high bleeding risk. It was associated with a 60%-70% reduction in risk for major bleeding.
The OCEANIC-AF phase 3 trial (n=14,810) compared asundexian’s non-inferiority to apixaban. Participants were randomized to receive either asundexian (50 mg once daily) or apixaban (5 mg twice daily). Asundexian had fewer bleeding events, but stroke and embolic events were four times more frequent in this group leading to termination of the trial. It may have been due to its short half-life and once daily dosing.
Milvexian is administered once or twice daily at a higher dose. This is being evaluated for the prevention of ischemic events in AF, poststroke or postinfarction in the Librexia STROKE, Librexia ACS, and Librexia AF trials and have enrolled more than 50,000 patients.
Pfizer to Discontinue Its Hemophilia B Gene Therapy
One year after approval, Pfizer will discontinue its hemophilia B gene therapy fidanacogene elaparvovec (Beqvez) across all global markets due to the limited interest patients and doctors have demonstrated in this type of therapy. The therapy had a list price of 3.5 million dollars. It will focus on marstacimab which is a non-factor treatment option. It is an IgG1 monoclonal antibody that helps clotting was FDA approved in adults and adolescents. The other therapy etranacogene dezaparvovec (Hemgenix) -- approved for treatment of hemophilia B is still used.
Treatment Of Heavy Menstrual Bleeding (HMB) With Tranexamic Acid (TXA)
Many women with ITP suffer with heavy menstrual bleeding (HMB). This can lead to iron deficiency resulting in iron deficiency anemia. HMB is defined as bleeding longer than 8 days, soaking through one or more pads/tampons every two hours on multiple days including changing a pad during the night, passing blood clots and losing more than 80mls of blood. TXA has be shown to be an effective treatment in these patients reducing blood loss by 26-60% and more effective than NSAIDS and hormonal therapy. It has improved quality of life and has few side effects. It may increase the risk of thrombosis in women taking oral contraceptives. TXA works by slowing the rate of lysis decreasing the intensity and duration of bleeding. It doesn’t raise the platelet count, so if bleeding is due to that, it will not help.
Cancer Diagnoses Cluster in Bleeders on Anticoagulation Therapy
There appears to be a correlation between patients on OAC who bled and the occurrence of a cancer diagnosis., People with AF on OAC from Ontario had a 21.8% incidence of bleeding within 2 years and 4.9% were diagnosed with a malignancy. This was also based on the site of malignancy and bleeding. These included any cancer with GI bleeding, cancer at the site of GI bleeding, and cancer with genitourinary bleeding, respiratory bleeding, as well as at the site of those cancers. Patients should be investigated for a malignancy if they have bled after OAC, which may result in an earlier diagnosis and cure. Weaker associations were seen between cancer and ICH, nasopharyngeal bleeds, and breast cancer did not show any association.
AF has been linked to a higher incidence of cancer, but causation has not been established because it is possible that OAC can unmask the bleeding from an occult malignancy.
The study looked at 119,480 OAC patients median age 77, 52% male with 69.3% on DOACs the remaining on warfarin. Data showed more cancers were diagnosed at an earlier stage after bleeding (27.6% stage 4 after bleeding vs 31.3% without bleeding. Limitations include that some patients may have been taking aspirin or dual antiplatelet therapy in addition to OAC which may have increased their risk of bleeding.
More Evidence Supports Later Thrombolysis for Ischemic Stroke
The HOPE trial looked at IV administration of alteplase between 4.5-24.0 hours post stroke onset in which imaging confirmed salvageable brain tissue. There was an increase in ICH, but no difference in mortality. Patients presented with stroke caused by either large vessel occlusion or distal medium vessel occlusion. This supports other studies that extending the therapeutic window may improve outcomes in these patients. This treatment could be the new standard in hospitals that use CT perfusion imaging.
The HOPE trial included 372 stroke patients who presented within the 4.5-24 hour window with salvageable brain tissue. They were randomly assigned to receive IV thrombolysis with alteplase or standard stroke care of antiplatelet therapy at the discretion of the investigation. The primary endpoint was a favorable outcome. This was demonstrated in 40.3% of alteplase patients versus 26.3% of the control group. ICH was increased in the alteplase group compared to the control (3.8% vs 0.5%) however the mortality rate was not increased.
Apixaban Has Edge Over Other OACs for Older HIV Patients With Afib
Medicare records show that people with HIV and AF on OAC may have a higher bleeding risk than others requiring hospitalization for major bleeding over 365 days depending on the OAC they were using. Warfarin was associated with more risk than apixaban in those on antiretroviral therapy. Rivaroxaban had a higher risk than apixaban in these patients, while risk was comparable between rivaroxaban and warfarin. This is the first study to look at the safety of OAC and HIV and evidence-based results suggesting that apixaban is a safer choice that other OAC.
The study was unable to conclude whether there are drug interactions between ART and OAC. The metabolism of apixaban and rivaroxaban is thought to be affected by concurrent CYP3A4-, P-glycoprotein-inhibiting ART. At present, clinical guidelines recommend using warfarin, however studies have shown that ART may induce or inhibit warfarin metabolism increasing the risk for drug interaction and adverse outcomes.
Blood Clot Prevention in Fracture Patients: No Difference for Aspirin vs LMWH
The PREVENT CLOT study showed there was no difference in patients with traumatic bone fractures and bleeding using aspirin or LMWH. This was tested in 12,000 patients in 11 high risk groups including prevention of PE, DVT or bleeding. No difference was found in those treated with aspirin or LMWH.
Three groups: head injury, thoracic injury and severe injury had a higher rate of DVT in those who took aspirin versus LMWH, however it was not statistically significant. The initial endpoint of 90-day mortality, two groups who received LMWH had higher rates than those that received aspirin in patients with head injury and spine injury, but not statistically significant. These findings are consistent with results from the primary analysis of the PREVENT CLOT trial. With a conservative interpretation, we found no evidence that aspirin or LMWH provided superior protection against the five outcomes in any of the 11 key subpopulations. With a less conservative interpretation, aspirin was superior to LMWH in preventing death in orthopedic trauma patients with an additional head or spine injury. Similarly, LMWH was superior to aspirin in preventing distal DVT in patients with an additional head injury, chest injury, or multi-trauma patients.
DVT Management: Is Stopping Anticoagulation Too Risky?
What are the pros and cons of stopping anticoagulation therapy in patients with unprovoked DVT and whether to extend it beyond 3-6 months?
An argument in favor of extending it showed that as early as 1990, 3 months of treatment significantly reduced events as compared to 4 weeks without a risk of bleeding. When comparing 6-weeks versus 6-months, the recurrence rates were reduced by half in the treatment groups (20.8% vs 10.3%). CHEST guidelines currently recommend 3 months and then evaluating patients to determine if additional therapy is necessary. What is needed to be determined is whether to continue anticoagulation beyond 3-6 months, and to balance the risk against bleeding.
The 10-year recurrence risk is patients after discontinuing anticoagulant in these patients is about 50% versus 20% in those with transient risk factors. Unprovoked DVT may be considered a chronic disease. A meta-analysis shows that VTE is significantly higher in those with short term anticoagulation versus those with extended treatment. Bleeding risks have been low in DOAC patients (1.2 per 100 person-years). CHEST guidelines recommend extending DOAC treatment in DVT patients with persistent risk factors. Using a lower dose of apixaban (2.5mg) prevents recurrence without a risk for major bleeding. The VTE-PREDICT risk score can assist in identifying recurrence and bleeding risk.
The major reason against extending anticoagulation is the risk of bleeding not only during therapy, but also the post anticoagulation risk. While the VTE-PREDICT score provides estimates but may underestimate bleeding risk. Both bleeding and VTE recurrence should be considered in patients with VTE. Data from the RIETE study included 8,000 patients who discontinued anticoagulant after isolated DVT or PE confirmed that DVT and PE recurring was common, and bleeding episodes were often severe. The 30-day mortality rates were 0.4% for recurrent DVT, 4.6% for recurrent PE, and 24% for major bleeds.
First Generics for Low-Dose Rivaroxaban Get FDA Approval
The FDA approved the first generics of the DOAC rivaroxaban (2.5mg tablets).and are considered equivalent to the name brand Xarelto. This low dose is used to reduce the risk of major cardiovascular events in CAD patents. And to reduce the risk of major thrombotic vascular events in those with PAD. This will increase the treatment options in American patients. The factor Xa inhibitor was originally approved in 2011 at a 10mg dose in patients undergoing joint replacement to prevent DVT. It then received approval for AF. The COMPASS trial approved the 2.5 mg dose (2x daily) fr events in CAD and PAD plus aspirin as a better benefit than just aspirin. The drug contains a warning for a risk of bleeding. Higher doses 10 mg, 15 mg, and 20 mg tablets from Lupin and Taro are under tentative approval by the FDA. Several other manufacturers are also waiting to have generics approved.
FDA Okays Tenecteplase for Acute Ischemic Stroke
The FDA has approved Tenecteplase for the treatment of acute ischemic stroke in adults. It is given as a single 5 second IV dose as opposed to alteplase which is standard of care and given as a 60-minute infusion. The approval was the result of the AcT trial which compared alteplase to Tenecteplase. A safety analysis showed that 3.4% of Tenecteplase and 3.2% of alteplase groups had 24- hour symptomatic ICH with no difference in deaths at 90 days post treatment.
Hypercoagulability Can Haunt Patients With Acute Severe UC Long After Discharge
Both VTE and PE are complications of inflammatory bowel disease (IBD) and can result in morbidity and mortality. Routine VTE prophylaxis is recommended in these patients however clinicians are cautious due to the risk of mucosal bleeding. There is also limited data on post-discharge VTE.
A study looked at the coagulation profiles of patients with acute severe ulcerative colitis (ASUC) from admission through 12 weeks discharge. It looked at prothrombotic and antithrombotic factors as well as global markers of fibrinolysis, thrombin generation and rotational thromboelastometry (ROTEM) and compared then to normal patients. Those with ASUC exhibited a hypercoagulable profile that persisted post discharge for several weeks despite VTE prophylaxis. This supports extending VTE prophylaxis in high-risk patients post discharge.
JOURNAL CLUB
Development of new anticoagulants targeting coagulation factor XI and prospects for clinical use
Masahiro Ieko, Kazumasa Ohmura, Sumiyoshi Naito, Mika Yoshida, Osamu Kumano
J Cardiol, 2025 Feb 13:S0914-5087(25)00061-9.
Abstract
Thrombosis is a potentially fatal condition for which various anticoagulant therapies have been used for prevention and treatment. However, bleeding events remain a concern with all anticoagulant drugs. Recent evidence suggests that inhibiting coagulation factor XI (FXI) and activated FXI (FXIa) plays a greater role in the formation of pathological thrombi in thrombosis than in normal hemostatic thrombi, allowing for the potential to address these two events separately. Consequently, FXI/XIa inhibition has become the focus of anticoagulant drug research, leading to the development of numerous FXI-targeting compounds with diverse mechanisms of action. Herein, we aimed to review FXI/FXIa inhibitors under development, discussing the role of FXI in the coagulation reaction and the advantages and disadvantages associated with its deficiency. The results of a Phase II study showed that FXI/XIa inhibitors provide efficacy comparable to that of low molecular weight heparin therapy while reducing clinically significant bleeding events. Additionally, in a study of patients with atrial fibrillation, FXI/XIa inhibitors reduced bleeding events compared to those with direct oral anticoagulants. Furthermore, when combined with antiplatelet therapy, FXI/XIa inhibitors did not significantly increase bleeding risk in non-cardioembolic stroke or acute coronary syndrome. However, conflicting trial results have also been reported, highlighting the difficulty in assessing the clinical benefit of FXI/XIa inhibitors in different clinical settings, such as atrial fibrillation and acute myocardial infarction. Future large, well-designed Phase III studies are needed to evaluate the safety and efficacy of FXI/XIa inhibitors across diverse populations requiring antithrombotic therapy.
Low Molecular Weight Heparin-Induced Thrombocytopenia: A Case Series Study of Newly Admitted Hemodialysis Patients
Hui Ren, Wei Liang, Aihong Wang, Zibo Xiong, Guang Yang
Hemodial Int, 2025 Feb 17.
Abstract
Low molecular weight heparin (LMWH), a common anticoagulant in hemodialysis, can cause the dangerous condition of heparin-induced thrombocytopenia (HIT) in rare cases. The present study reviews five cases of HIT diagnosed in our center, which treats more than 400 maintenance hemodialysis patients annually over a 30-year period. All five cases occurred in incident patients who were being exposed to LMWH for the first time. Treatment involved stopping LMWH and using alternative anticoagulants. Both the 4Ts score and antibody tests were used to confirm the diagnosis of HIT. Following diagnosis, close monitoring was performed for 10-15 days in typical cases or 30 days in severe cases until blood platelet levels recovered to near normal values. Our results suggest that while uncommon, HIT associated with use of LMWH can occur in hemodialysis patients, especially when patients are being exposed to this anticoagulant for the first time.
Patient self-management of warfarin therapy - a long-term follow up study
Erland Hegardt Hall, Marit Holm Sølsnes, Sverre Sandberg, Una Ørvim Sølvik
Thromb J, 2025 Feb 10;23(1):14.
Abstract
Background: Patient self-management (PSM) of anticoagulant treatment with vitamin K antagonist (VKA) has emerged as an effective approach for maintaining the international normalized ratio (INR) within the therapeutic range. The objective of this quality assurance project, conducted in clinical practice, was to evaluate the long-term effectiveness and safety of anticoagulant treatment with warfarin during PSM compared to conventional treatment administered by general practitioners (GPs).
Methods: This cohort study, using a retrospective and prospective design, included 400 patients who underwent PSM training for a 21-week period between 2011 and 2020. Clinical data extracted from the patient journal systems included hospitalization due to severe clinical complications. The primary outcome was any difference in the yearly risk of hospitalization between the conventional and PSM periods. Secondary outcomes included variations in time within the therapeutic range (TTR), INR fluctuations, and incidence of extreme INR values.
Results: The median treatment duration was 2.45 years (25th-75th percentile 0.80, 7.35) for the conventional period and 4.99 years (25th-75th percentile 2.41, 7.43) for the PSM period. The annual risk for hospitalization due to severe bleeding was 1.25% during PSM compared to 1.69% during conventional treatment (p = 0.885). The yearly risk for hospitalization due to thrombosis was 0.67% during PSM versus 1.48% during conventional treatment (p = 0.256), and the annual risk for hospitalization due to spontaneous bleeding, thrombosis, or thromboemboli was 1.12% versus 2.76% (p = 0.112). Median TTR (25th-75th percentile) increased from 71.6% (60.0, 82.7) to 78.6% (67.9, 91.7) (p < 0.001), while INR variance decreased from 21.0% to 16.5% (p < 0.001). The proportion of extreme subtherapeutic INR values (≤ 2.0 (≤ 1.5 for patients with mechanical ON-X aortic valve prostheses)) decreased from 14.0% to 5.0% (p < 0.001) during PSM, whereas the proportion of high-level INR (≥ 5.0) remained unchanged (0.6%).
Conclusions: The long-term evaluation of PSM of warfarin treatment in clinical practice suggests that PSM for suitable patients selected by GPs is as safe as conventional GP treatment.
Thromboelastography may assess the effect of anticoagulation reversal in intracranial hemorrhage
A Zepeski, B A Faine, M Ghannam, H M Olalde, L Wendt, A Naidech, N M Mohr, E C Leira
J Stroke Cerebrovasc Dis 2025 Mar;34(3):108228.
Abstract
Background: Intracranial hemorrhage (ICH) is a complication of oral anticoagulation and is associated with significant morbidity and mortality. Clinical need exists for biomarkers to measure anticoagulation in patients with factor Xa inhibitor-associated ICH to assess the hemostatic effect of reversal agents. This study explored the utility of thromboelastography (TEG) to assess anticoagulation in emergency department (ED) patients who received activated prothrombin complex concentrate (aPCC) reversal for factor Xa-inhibitor-associated ICH.
Methods: This was a prospective, single-center, cohort study in a convenient sample of adult patients presenting to the ED with acute factor Xa-associated ICH. Exclusion criteria included pregnancy, incarceration, polytrauma, hepatic failure, or other known coagulopathic conditions. TEG samples were collected prior to anticoagulation reversal, as well as at 30-minutes, 12-hours, and 24-hours post-reversal. Only patients who received aPCC reversal were included in the final analysis.
Results: Pre-reversal TEG was collected on 10 participants prior to aPCC administration. A significant decrease in TEG R-time was observed at 30 minutes post-aPCC reversal (Beta = -0.91, p = 0.035). R-time increased at 12- and 24-hours post-aPCC reversal to baseline levels. Significant changes were not observed in K-time, clot strength, maximum amplitude, or coagulation index.
Conclusions: TEG R-time decreases acutely after anticoagulation reversal with aPCC and rebounds at 12- and 24-hours post-reversal. TEG R-time may serve as a potential sensitive biomarker of the residual anticoagulation activity of factor Xa inhibitors in patients with ICH that undergo anticoagulation reversal with aPCCs.
Population-Scale Studies of Protein S Abnormalities and Thrombosis
Sharjeel A. Chaudhry, MD; Amelia K. Haj, MD, PhD; Justine Ryu, MD; et alSean J. Jurgens, MD, Ph; Alfonso Rodriguez Espada, MD; Xin Wang, MBBS, MPH; Seung Hoan Choi, PhD; Simone Sanna-Cherchi, MD; Steven P. Grover, PhD; Kenneth A. Bauer, MD; Patrick T. Ellinor, MD, PhD; Pavan K. Bendapudi, MD
JAMA. Published online March 3, 2025.
Abstract
Importance Clinical decision-making in thrombotic disorders is impeded by long-standing uncertainty regarding the magnitude of venous and arterial thrombosis risk associated with low protein S. Population-scale multiomic datasets offer an unprecedented opportunity to answer questions regarding the epidemiology and clinical impacts of protein S deficiency.
Objective To evaluate the risk associated with protein S deficiency across multiple thrombosis phenotypes.
Design, Setting, and Participants Cross-sectional study using longitudinal population cohorts derived from the UK Biobank (n = 426 436) and the US National Institutes of Health All of Us (n = 204 006) biorepositories. UK Biobank participants were enrolled in 2006-2010 (last follow-up, May 19, 2020) and underwent whole exome sequencing, with a subset (n = 44 431) having protein S levels measured by high-throughput plasma proteomics. Recruitment for All of Us began in 2017 and is ongoing, with participants receiving germline whole genome sequencing. Both cohorts include individual-level data on demographics, laboratory measurements, and clinical outcomes.
Exposure Presence of rare germline genetic variants in PROS1, segmented by functional impact score (FIS), an in silico prediction of the probability that a genetic variant will disrupt protein activity.
Main Outcomes and Measures Firth logistic regression and linear regression modeling were used to evaluate the thrombosis risk associated with low plasma protein S levels and PROS1 variants across a range of FIS ratings.
Results The UK Biobank cohort was 54.3% female, with a median age of 58.3 (IQR, 50.5-63.7) years at enrollment. Most participants (95.6%) were of European ancestry, and 18 011 had experienced a venous thromboembolism (VTE). In this population cohort, heterozygosity for the highest-risk PROS1 variants with an FIS of 1.0 (nonsense, frameshift, and essential splice site disruptions) was rare (adjusted prevalence, 0.0091% in the UK and 0.0178% in the US) and associated with markedly increased risk of VTE (odds ratio [OR], 14.01; 95% CI, 6.98-27.14; P = 9.09 × 10−11). Plasma proteomics (n = 44 431) demonstrated that carriers of these variants had total protein S levels that were 48.0% of normal (P = .02 compared with noncarriers). In contrast, less damaging missense variants (FIS ≥0.7) occurred more commonly (adjusted prevalence, 0.22% in the UK and 0.20% in the US) and were associated with marginally reduced plasma protein S concentrations and a smaller point estimate for VTE risk (OR, 1.977; 95% CI, 1.552-2.483; P = 1.95 × 10−7). Associations between PROS1 and VTE at both FIS cutoffs were independently validated in the All of Us cohort with similar effect sizes. No association was detected between the presence of coding PROS1 variants and 3 forms of arterial thrombosis: myocardial infarction, peripheral artery disease, and noncardioembolic ischemic stroke. The presence of PROS1 variants correlated poorly with low plasma protein S levels, and protein S deficiency was significantly associated with VTE and peripheral artery disease regardless of PROS1 variant carrier status. The elevated risk of VTE associated with germline loss of function in PROS1 was evident in Kaplan-Meier survival analysis and appeared to persist throughout life (log-rank P = .0005).
Conclusions and Relevance True inherited loss of function in PROS1 is rare but represents a stronger risk factor for VTE in the general population than previously understood. Acquired, environmental, or trans-acting genetic factors are more likely to cause circulating protein S deficiency than coding variation in PROS1, and low plasma protein S is associated with VTE.