February 2025: New In Coagulation
by Donna Castellone • February 12, 2025
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Lupus Patients See More Vascular Risk, but It's Modifiable
In a prospective study in Greece, 95 SLE patients and patients age 71 age and sex matched with healthy individuals were followed for 10 years. All participants were white and 90% were women. Median bp for patients was 116/71 mm Hg for patients and 120/76 mm Hg among controls. Some 45% of patients and 31% of controls were current smokers, and slightly more patients had a family history of coronary artery disease (14% vs 12%). Median LDL cholesterol values were 108 and 121 mg/dL and median BMI was 25 in patients and 24 in controls.
Atherosclerotic plaque was seen on carotid ultrasound in 52 patients and 21 controls resulting in an incidence rate ratio of 2.26. Cardiovascular events were more common in SLE patients versus control (8 vs 1). Persistent positivity for lupus anticoagulant appeared particularly important, with a hazard ratio of 12.99. However aPL testing was not performed in controls.
Implementing risk reduction factors resulting in a 32% decrease in likelihood of plaque, these included covered blood pressure, lipid levels, smoking, physical activity, and body weight and size. Staying in remission for at least 75% of the follow up period resulted in a 43% reduction in risk of progression.
Limitations of the study included the lack of racial-ethnic diversity and the loss of 20 controls for follow up prior to year 10.
Higher-Dose Anticoagulation Not a Sure Bet for Hospitalized COVID Patients
Analysis of both a systematic review and prospective meta-analysis of anticoagulation in hospitalized patients (n=11,733, age 50-74, mostly male) for COVID-19 did not show an advantage for increasing dosing of heparin for short term survival. A review of 22 studies showed the risk of all-cause mortality at 28 days were: lower with therapeutic dose versus prophylactic-dose anticoagulation, higher with therapeutic dose versus intermediate dose anticoagulation, however not statistically significant, as well as for intermediate-dose versus prophylactic dose. When higher doses were used there was a greater risk for major bleeding but fewer thromboembolic events.
Interpretation of results were difficult since there were different doses of anticoagulation that were compared and severity of illness at randomization also differed. The 22 trials examined enoxaparin, tinzaparin, or UFH, only one looked at a DOAC. But regardless of the results' impact on a particular patient subgroup it is not assured that higher dose anticoagulation could be applicable to COVID-19 patients today. There needs to be harmonization of interventions and outcomes to compare and pool results. Also, trial data needs to be analyzed in the face of changing pathogens and pandemic dynamics and know that things that may be beneficial in one circumstance may not be the same when changes occur.
Key Takaways
- Therapeutic-dose anticoagulation with heparins reduced 28-day mortality compared with prophylactic doses in patients hospitalized with COVID-19.
- Higher-dose anticoagulation was associated with a greater risk for major bleeding, but fewer thromboembolic events, compared with lower-dose anticoagulation.
- Notably, the 22 trials included in this meta-analysis had primarily evaluated heparins, with only one study examining a direct oral anticoagulant.
What's With All the UFH Infusions for Acute Pulmonary Embolism?
The current guidelines recommend LMWH or DOACs in patients who present with PE, however UFH remains the initial choice for many US physicians. Several common themes seem to be the reason behind this practice. The cohort included in the qualitative study included a 30 minute Zoom interviews with 46 participants in emergency medicine (54.3%), hospital medicine (37.0%), interventional cardiology and interventional radiology (8.7%). Median age was 43, 71.7% male, 60% white and 32% Asian from various geographic settings in the US.
The first reason is left over from training, in particular in emergency physicians and hospitalists including an indifference toward anticoagulation choice. New practices of LMWH and DOACs over UFH are due to the alternatives achieving therapeutic anticoagulation quicker and are associated with fewer bleeding complications.
General feeling is that choice of hospital anticoagulation did not matter and as a result there has been an increase in treatment of PE with UFH from 41.9% in 2011 to 56.3% in 2020. The most common reasons are due to: using it for decades, rarely switching to LMWH or DOAC because it is inconvenient to transition, culture in an organization of using UFH, short half-life of UFH more reassuring, a misconception that UFH is stronger than other anticoagulant and can be turned on and off due to IV administration. Also, LMWH can only be partially reversed (about 60%) and DOACs require prothrombin complex or specific reversal agents.
Changing practices will require trials of anticoagulation effectiveness and safety in clinical setting, targeted educational programs from professional societies and adopting evidence based polices by institutional quality committees to modernize choices and improve outcomes in patients with PE.
Key Takaways
- Professional guidelines recommend LMWH and DOACs over UFH for the majority of patients hospitalized for acute PE.
- Yet physicians expressed general indifference toward anticoagulation choice, or the belief that the choice of in-hospital anticoagulation ultimately did not matter.
- Misperceptions include the idea that UFH users are less prone to bleeding, and that UFH is a stronger anticoagulant.
Guidance for the Role of rFVIIa in the Management of Severe Postpartum Hemorrhage (European Experts Consensus Group, 2024)
European Experts Consensus Group
These are some of the highlights of the guidelines without analysis or commentary. For more information, please go to Postpartum Hemorrhage.
- Recommendations from a panel of European experts for managing severe PPH emphasize early administration of recombinant factor VIIa (rFVIIa) in patients who do not respond to first-line therapies (ie, uterotonics and tranexamic acid) and highlight the importance of optimization of hematologic parameters before rFVIIa is given.
- After vaginal delivery, rFVIIa should be administered once first-line measures have been exhausted but before laparotomy or uterine artery embolization is performed.
- During a cesarean delivery, rFVIIa should be used after first-line surgical measures (uterine compression sutures, vessel ligation, uterine tamponade) have failed but before uterine artery embolization or hysterectomy is performed
- After a cesarean delivery, administration of rFVIIa should be considered (eventually with uterine artery embolization) for persistent nonsevere bleeding. For severe intra-abdominal bleeding, emergency revision laparotomy should be undertaken without delay.
- In the setting of a peripheral birthing unit, rFVIIa should be administered during transfer setup to stabilize the patient's condition, without delaying transfer or the use of second-line treatments.
During a postpartum hysterectomy, consider administration of rFVIIa in conjunction with standard measures if severe bleeding persists.
Injectable Anticoagulant Substantially Cuts Bleeding Risk in Afib
The AZALEA-TIMI 71 trial looked at two one monthly doses (90mg and 150mg) of abelacimab in patents with atrial fibrillation (Afib). There were 1287 randomly assigned to either abelacimab injections or oral rivaroxaban, median age 74, 44% female and 95% white. CHA2DS2-VASc score was 5 and HAS-BLED score 2 or 3. There were 92% who received an anticoagulation previously for at least 60 days, with 66% of those having taken a DOAC. Results showed that this factor XI/XIa inhibitor demonstrated lower safety risks compared with the DOAC rivaroxaban. It reduced major or clinically relevant nonmajor bleeding. Including a very low (0.5%) incidence of major GI bleeding as opposed to 4.25 in the DOAC group. To date, this is the only drug that shows a lower rate of GI bleeding than warfarin. The trial was stopped early due to the large reduction in bleeds, however it needs to be determined if it is clinically effective for stroke prevention in this cohort.
The action of abelacimab, which is a human monoclonal antibody, binds to the inactive form of factor XI and blocks its activation, preventing thrombosis. It is also not metabolized by the cytochrome P-450 system so drug-drug interactions are reduced and no dose adjustments are required for age or renal or hepatic status. Both doses eliminated free factor XI in the trial in patients with a moderate-high risk for stroke. The reduction was 99% at 150mg and 97% at the 90mg dose at 3 months. However it is not known if the antibody can show clinical efficacy, the present study was not large enough to make that conclusion. The LILAC-TIMI 76 trial is looking at the 150mg dose for the prevention of ischemic stroke and systemic embolization in high-risk AF with bleeding risk factors.
A New Drug Application Has Been Submitted for FDA Review for a Pediatric ITP Therapy
The thrombopoetin-receptor agonist Avatrombopag works to treat ITP by stimulating the bone marrow to produce more platelets in the bloodstream. Presently it is used only in patients who fail to respond to other therapies. The FDA has accepted to determine if this can be used in the 1-18 year old pediatric population. It is being tested as an oral pill or oral suspension. It is a priority review and should be completed by July of 2025. This will mean that children and adolescents with ITP will have another treatment to manage their ITP that can improve bleeding risks and overall quality of life.
JOURNAL CLUB
Intra-Arterial Tenecteplase Following Endovascular Reperfusion for Large Vessel Occlusion Acute Ischemic Stroke: The POST-TNK Randomized Clinical Trial
Jiacheng Huang, MD1; Jie Yang, MD; Chang Liu, MD; et alLinyu Li, MD; Dahong Yang, MD; Changwei Guo, MD; Guoyong Zeng, MD; Jiaxing Song, MD; Jinfu Ma, MD; Xu Xu, MD; Xiaolei Shi, MD; Shihai Yang, MD; Wenzhe Sun, MD; Zhixi Wang, MD; Yufeng Tang, MD; Maojun Jiang, MD; Li Wang, MD; Xiangping Cheng, MD; Jun Luo, MD; Peiyang Zhou, MD; Xing Fang, MD; Guangsen Cheng, MD; Zhongfan Ruan, MD; Jinglun Li, MD; Jincheng Liu, MD; Bo Lei, MD; Yaoyu Tian, MD; Xiaolin Tan, MD; Guangxiong Yuan, MD; Jian Wang, MD; Xinyuan Huang, MD; Shengling Deng, MD; Zhenglong Jin, MD; Xin Zou, MD; Jie Zhang, MD; Daoyou Cheng, MD; Xiaojun Luo, MD; Jiasheng Liao, MD; Jian Miao, MD; Zhenqiang Li, MD; Yaxuan Sun, MD; Guohui Jiang, MD; Deyan Kong, MD; Shuyu Jiang, MD; Zhiyuan Wang, MD; Duolao Wang, MD; Johannes Kaesmacher, MD, PhD; Thanh N. Nguyen, MD; Raul G. Nogueira, MD; Jeffrey L. Saver, MD; Yangmei Chen, MD; Wenjie Zi, MD, PhD; for the POST-TNK Investigators
Abstract
Importance The impact of adjunctive intra-arterial tenecteplase administration following near-complete to complete reperfusion by endovascular thrombectomy (EVT) for acute ischemic stroke is unknown.
Objective To assess the efficacy and adverse events of adjunctive intra-arterial tenecteplase in patients with large vessel occlusion stroke who had achieved near-complete to complete reperfusion (defined as a score on the expanded Thrombolysis in Cerebral Infarction [eTICI] scale of 2c to 3) after EVT.
Design, Setting, and Participants Investigator-initiated, randomized, open-label, blinded outcome assessment trial implemented at 34 hospitals in China among 540 patients with stroke due to proximal intracranial large vessel occlusion within 24 hours of the time they were last known to be well, with an eTICI score of 2c to 3 after EVT, and without prior intravenous thrombolysis. Recruitment took place between October 26, 2022, and March 1, 2024, with final follow-up on June 3, 2024.
Interventions Eligible patients were randomly assigned to receive intra-arterial tenecteplase (n = 269) at 0.0625 mg/kg or no intra-arterial thrombolysis (control group; n = 271).
Main Outcomes and Measures The primary efficacy outcome was freedom from disability, defined as a score of 0 or 1 on the modified Rankin Scale (range, 0 [no symptoms] to 6 [death]) at 90 days. The primary safety outcomes were death at 90 days and symptomatic intracranial hemorrhage within 48 hours.
Results A total of 539 participants (99.8%) completed the trial (median age, 69 years; 221 female [40.9%]). The proportion with a modified Rankin Scale score of 0 or 1 at 90 days was 49.1% (132/269) in the intra-arterial tenecteplase group and 44.1% (119/270) in the control group (adjusted risk ratio, 1.15 [95% CI, 0.97-1.36];
Conclusions and Relevance In patients with acute ischemic stroke due to large vessel occlusion presenting within 24 hours of time last known to be well and who had achieved near-complete to complete reperfusion after EVT, adjunctive intra-arterial tenecteplase did not significantly increase the likelihood of freedom from disability at 90 days.
Anti-Xa Activity Test Is Needed but Is Not Enough for Monitoring Fondaparinux Therapy Among Critically Ill Patients
Liqin Ling, Chaonan Liu, Xunbei Huang, Siqi Liu, Juan Liao, Jin Jia, Yang Fu, Jing Zhou
Arch Pathol Lab Med. 2025 Jan 1;149(1):e11-e18
Abstract
Context: Fondaparinux monitoring is not required among noncritically ill patients due to a predictable dose-response effect. However, this is debatable among critically ill patients, because fondaparinux bioavailability can be influenced by complicated medical conditions.
Objective: To investigate fondaparinux monitoring among the critically ill.
Design: Retrospective analysis of patients admitted in intensive care unit from February 2021 to December 2021 who received prophylactic fondaparinux and had anti-Xa activity tests.
Results: Of 156 anti-Xa values, 86 (55.1%) were within 0.10-0.50 μg/mL (the recommended prophylactic range), 38 (24.4%) were less than 0.10 μg/mL, and 32 (20.5%) were greater than 0.50 μg/mL, demonstrating an unpredictable dose-response effect. Among 70 patients, thrombotic tendency was controlled in 32 (45.7%), thrombosis progressed in 22 (31.4%), and bleeding events occurred in 16 (22.9%). Patients with progressed thrombosis had 17 of 54 (31.5%) anti-Xa values less than 0.10 μg/mL; even though this proportion was greater than that of patients with controlled thrombotic tendency (11 of 72, 15.3%), it was similar to that of patients with bleeding (10 of 30, 33.3%), indicating a weak practicability of anti-Xa for monitoring fondaparinux efficacy. Thrombin-antithrombin complex showed a gradual decline among patients with controlled thrombotic tendency but a bounce-back effect among patients with progressed thrombosis. Thrombelastography R value above the upper reference value occurred more frequently among patients with bleeding (4 of 6, 66.7%) compared to patients without bleeding (4 of 22, 18.2%) (P = .01).
Conclusions: The fondaparinux dose-response effect was unpredictable among the critically ill; anti-Xa activity combined with thrombin-antithrombin complex and thrombelastography can be helpful to guide a precise fondaparinux therapy in this population.
Concordance and discordance of anticoagulation assays in children supported by ECMO: The truth is out there
Carlos A Carmona, Jesse Bain, Oliver Karam
Perfusion 2024 Dec 24
Abstract
Introduction: Extracorporeal membrane oxygenation (ECMO) provides critical support to patients in severe cardiac and respiratory failure, but it requires anticoagulation to prevent complications like bleeding and thrombosis. Heparin, the primary anticoagulant utilized, is monitored by activated partial thromboplastin time (aPTT) and anti-Factor Xa (AntiXa) levels. Discordance between the two assays complicates its titration and the impact on patient outcomes is not well-established. This study examines the prevalence of discordance, its impact on heparin dosing, and the association of bleeding, thrombosis, ICU-free days, and mortality in pediatric ECMO patients.
Methods: This secondary analysis of the Bleeding and Thrombosis on Extracorporeal Membrane Oxygenation study consisted of 511 patients under 19 years. Demographics, laboratory results, ECMO indications, daily heparin doses, and clinical outcomes were collected. Discordance was categorized as major or minor, and adjustments to heparin dosing were analyzed for appropriateness based on normal ranges of aPTT and AntiXa. Logistic regression models assessed the impact of heparin titration strategies on bleeding, clotting, ICU-free days, and mortality.
Results: Major discordance occurred on 17.5% of days with high aPTT and low AntiXa being most common. Titrating heparin based on AntiXa in scenarios of discordance was associated with an 11% lower incidence of bleeding compared to aPTT (
Conclusion: Discordance is common in pediatric ECMO patients. AntiXa-guided heparin titration, notably during discordant periods, is associated with fewer bleeding and clotting events. This emphasizes the need for improved anticoagulation protocols since discordance does not demonstrate worse ICU-free days or mortality.
Keywords: anticoagulant; critical illness; extracorporeal membrane oxygenation; factor Xa Inhibitor; heparin; partial thromboplastin time.
Unfractionated heparin monitoring by anti-factor Xa versus activated partial thromboplastin time strategies during venoarterial extracorporeal life support
Iris Feng, Tanner R Powley, Christine G Yang, Paul A Kurlansky, Lauren D Sutherland, Jonathan M Hastie, Yuji Kaku, Justin A Fried, Koji Takeda
Perfusion 2024 Dec 26:
Abstract
Introduction: No clear guidelines exist for unfractionated heparin (UFH) monitoring in adult patients on veno-arterial extracorporeal life support (VA-ECLS) for refractory cardiogenic shock. In this study, we sought to compare outcomes between anti-factor Xa (FXa) and activated partial thromboplastin time (aPTT) strategies for UFH monitoring during VA-ECLS.
Methods: This is a single-center, retrospective review of VA-ECLS patients who received UFH in the cardiothoracic intensive care unit between July 2019 and November 2023. Standard protocol for UFH titration was aPTT goal of 45-60 sec (n = 52) before September 2021, then transitioned to FXa goal of 0.1-0.2 U/mL (n = 50) thereafter. Inverse probability of treatment weighting was used to balance baseline differences between cohorts.
Results: In adjusted analyses, 89.3% of FXa patients and 76.0% of aPTT patients achieved goal range for their respective assay. Total UFH duration (4.0 vs 4.0 days,
Conclusions: In adult VA-ECLS patients at our institution, bleeding and thromboembolic complications occurred at a similar rate regardless of which UFH monitoring strategy was utilized. Further studies in larger and more institutionally diverse cohorts are warranted.