June 2025: New In Coagulation
by Donna Castellone • June 11, 2025
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Cervical Artery Dissection and Stroke; Preventing Clotting in Cancer Patients
A study in Neurology looked at trends and risks of recurrent stroke of cervical artery dissections in the US (2005-19). Dissection is a common cause of acute ischemic stroke in patients under the age of 55. Researchers looked at the annual average percent change of cervical artery dissection incidence and then readmission risk, without acute ischemic stroke and assessing death as a competing risk.
Database research showed over 125,000 patients with spontaneous cervical artery dissection. There was an increase from 10.7 cases per million in 2005 to 45.6 cases per million in 2019; in particular in older people and Blacks and Hispanic populations. This population is at a higher risk and should be evaluated. Results showed a 5-fold increase in detection due to the increase in availability using MRI or CT scans, as a result it is difficult to say the incidence is increased as opposed to the detection.
Cervical artery dissection is unlikely to recure, but it could be detected incidentally in people who present with local symptoms who haven't had a stroke but presenstpresent with symptoms and may subsequently have a stroke. The incidence was in patients 65 and older when previously the common cause was in a younger population, so it wasn't investigated in this older population. This data suggests that attention should be given to the possibility of cervical artery dissection since it appears to be more frequent than previously thought.
People with cancer are at a higher risk of developing VTE, which can become dislodged and cause a PE, which is life threatening. Due to this risk, patients are recommended to be on anticoagulation for a minimum of 6 months or longer as long as the patient has no bleeding episodes. To prevent bleeding, investigators looked at 1800 individuals who presented with VTE or PE and on anticoagulation for 6 months. Therapy was completed at standard dose apixaban 5 mg twice daily. Patients were then randomized to continue on that dose or half the dose with a one-year followup.Results showed the risk of recurrent VTE or PE was the same for both groups however those on the reduced dose, had a 25% lower risk of bleeding and slightly lower mortality. This may change the way patients are treated.
New Thrombolytic Choices: Is One Better?
Alteplase was introduced 30 years ago and changed ischemic stroke care. Tenecteplase (TNKase) another tpa activator, has been approved and the question is which one is a better choice for certain patients. TNKase is given as a single 5-sec IV bolus, while alteplase is given as an IV bolus followed by a 60-min infusion.
The EXTEND-IA TNK study looked at 202 patients randomized to tenecteplase or alteplase. Tenecteplase before thrombectomy was associated with a higher incidence of reperfusion and better functional outcome than alteplase among patients treated within 4.5 h after symptom onset.
The results of 79,550 patients with or without thrombectomy from the Get With the Guidelines study showed similar safety and efficacy between the two drugs. No differences in outcomes were seen in functional independence at discharge, freedom from disability at discharge, discharge to home and independent ambulation at discharge. Outcome of ICH within 36 hours and hospital mortality or hospice did not differ. Outcomes were better in patients who received tenectplase in those who were eligible for thrombectomy but did not receive it due to baseline disability, advanced age, patient or family refusal or unavailability of a specialist.
An advantage of Tenecteplase is the bolus dose may provide faster treatment without increasing the risk of bleeding. Tenecteplase has not been shown to be superior to thrombectomy.
DAPT After TAVR: Harm Bleeds Into Mortality Territory
Observational data showed that after TAVR, beyond bleeding alone, DAPT was associated with excess mortality. The TRITAVI Registry, showed a significant increase in deaths by 180 days compared with single antiplatelet therapy (SAPT). Hazard ratios in men 2.08, women 1.53, patients with CAD 1.83 and without CAD 1.52. SAPT was associated with a better outcome, in particular in those with a high risk for bleeding.
The POPular TAVI in 2020 showed the increased bleeding with DAPT. In TRITAVI, DAPT increased morality and major bleeding with no reduction in incident ischemic events when compared to SAPT. There was an increase in cardiovascular and noncardiovascular deaths. This may be due to patients with DAPT generally with higher mortality. TAVR patients are usually old with a lot of comorbidities on multiple drugs.
Guidelines recommend antithrombotics after TAVR consist of SAPT (aspirin or clopidogrel).
The TRITAVI registry included 10,071 consecutive TAVR patients at 20 EU centers since 2012. Inclusion criteria was met by 5,514 subjects who had no procedural complications, no ACE or PCI 12 months prior to TAVR and discharged alive. Patients were assigned to SAPT (n=3,197) or DAPT (n=2,317). Average age was 81, SAPT including 50. 8% male, 45.2% female and more people with NY Heart Association class III or IV symptoms. Those with DAPT were more likely to have had a prior MI and PCI. These imbalances, were indicative of bias in the observational dataset.
Prasugrel Strategy Rolls Short DAPT and De-Escalation Into One
A prasugrel based antiplatelet drug used in ACS reduced bleeding without compromising ischemic protection after PCI. The investigators of 4D-ACS trial found that post placement of a drug coated stent (DCS) the adverse event at 1 year was reduced to 4.9% after using DAPT (aspirin and prasugrel) for 1 month, followed by reduced dose prasugrel as compared to 8.8% in those receiving 12 months of DAPT.
Major bleeding was decreased at 0.6% versus 4.6% with major cardiovascular events similar at 2.4% versus 3.7%. Stent thrombosis did not occur in either arm of the study.
The study was conducted at three Korean centers and enrolled 656 patients with a mean age of 61, 80% male with up to 12% considered at being at a high bleeding risk. The primary endpoint was death, nonfatal MI, ischemia-driven target vessel revascularization (TVR), stroke, and bleeding.
The limitations of the study included the limited representation of elderly as well as extrapolating it to Western populations. Validation is needed in diverse populations.
Tenecteplase Before Thrombectomy Improves Outcomes
The BRIDGE-TNK trial from China showed that IV Tenecteplase boosted the benefit of endovascular thrombectomy in acute ischemic stroke presented within 4.5 hours of onset. These patients were more likely to retain functional independence at 90 days versus those who just got thrombectomy (52.9% versus 44.1%). Tenecteplase achieved reperfusion faster even before patients received thrombectomy. ICH, 90 day mortality as well as other safety outcomes were similar between groups. These results support clinical practice and IV administration and EVT should be performed as soon as possible after arrival to the hospital. Alteplase has not been shown to improve functional outcomes when used in bridging.
The trial randomized 550 patients from 39 hospitals in China with 4.5 hours of onset of acute ischemic stroke due to large vessel occlusion. It took just 16 minutes from administration of tenecteplase to arterial puncture. Time from thrombectomy puncture to reperfusion was a median of 55 minutes in the tenecteplase-thrombectomy group compared with 64 minutes in the thrombectomy-alone group, a factor that may have accounted for the difference in functional outcomes between the two treatment groups.
One key limitation of BRIDGE-TNK was its open-label design, although with independent clinical event adjudication in a blinded fashion. Other limitations included exclusion of interhospital transfer patients and those presenting more than 4.5 hours after time last known well.
JOURNAL CLUB
Electronic Monitoring of Medication Adherence to Direct Oral Anticoagulants: A Systematic Review
Eliska Maskova, Simona Slivarichova, Josef Maly, Katerina Mala-Ladova
2025 Apr 7:19:921-939
Abstract
Strict medication adherence, which reflects the process by which patients take their medication as prescribed, is crucial for the use of direct oral anticoagulants (DOACs). Therefore, technological devices may serve as promising tools for assessing adherence. We aimed to systematically review the literature focusing on electronically monitored adherence (EMA) to DOACs. All studies indexed in EMBASE, Cochrane Library, MEDLINE, Scopus, and Web of Science from inception until September 1, 2023, were searched. Original studies targeting the query topics were included, findings were categorized and narratively synthetized. Adherence data, including the quality of data reporting bias, were evaluated using the EMERGE guideline. The review protocol was registered in the PROSPERO database (ID CRD42023441161). Out of the 5911 potential hits, 19 articles, comprising 15 research studies, were identified. These studies enrolled 4163 patients (median 72.1 years; 57.9% males), usually chronically treated with DOACs for atrial fibrillation. EMA was measured in 3451 patients by seven different devices from eight manufacturers; the median population tracked with electronic monitoring was 56 patients over 5 months per study. Observational studies resulted in 88.6% and interventional studies resulted in 92.5% of EMA to DOACs, mostly monitoring regimen and taking adherence. Two studies reported high-quality adherence data, whereas 11 reported low-quality adherence data. The item described in the EMERGE guideline as affecting adherence by measurement method, as appropriate, has rarely been addressed. This review broadens the understanding of the overall high EMA to DOACs reported across various study populations and designs. Furthermore, due to the identified gaps in current literature, it highlights the pressing need for standardized methodologies and improved adherence reporting. This study was supported by the GAUK 328322 and SVV 220665.
Prevalence of Heparin-Induced Thrombocytopenia in Hospitalized Patients with Antiphospholipid Syndrome or Lupus with Antiphospholipid Antibodies
Vincent Tran, Amy Schmitt, Shanthini Kasturi MS
Am J Med 2025 Apr 12:S0002-9343(25)00235-9.
Abstract
Objective: This study aims to investigate the prevalence of heparin-induced thrombocytopenia among hospitalized patients with antiphospholipid syndrome or systemic lupus erythematosus with antiphospholipid antibodies.
Methods: A retrospective cohort study was performed on patients hospitalized at a tertiary care medical center who met criteria for antiphospholipid syndrome or lupus with antiphospholipid antibodies and were evaluated for heparin-induced thrombocytopenia with anti-platelet factor 4 or serotonin release assay. Pretest probabilities of heparin-induced thrombocytopenia were estimated using a 4T score. Proportions of patients with positive anti-platelet factor 4 and serotonin release assay tests were calculated, and the number of patients meeting clinical criteria for heparin-induced thrombocytopenia was determined.
Results: Of 33 patients identified in screening, 23 met inclusion criteria. Pretest probability for heparin-induced thrombocytopenia based on 4T scores was intermediate in 9 (39%) and high in no patients. Only one patient (4%) tested positive for anti-platelet factor 4. Serotonin release assay was tested in four patients (17%) and was negative in all cases.
Conclusion: Among 23 hospitalized patients with antiphospholipid syndrome or lupus with antiphospholipid antibodies who were tested, none were diagnosed with heparin-induced thrombocytopenia. Most patients had low pretest probability for heparin-induced thrombocytopenia based on 4T scores but were still tested for anti-platelet factor 4. Our study suggests that heparin-induced thrombocytopenia is rare among hospitalized patients with antiphospholipid syndrome or lupus with antiphospholipid antibodies.
Factor V Leiden
JAMA. Published online April 30, 2025.
Factor V Leiden (FVL) is the most common inherited thrombophilia and is caused by a missense variant in coagulation factor V that results in resistance to activated protein C (APC). As APC is an endogenous anticoagulant that inactivates factor V, FVL promotes a prothrombotic state. The prevalence of heterozygous FVL is 5% in the US population of European descent and 0.1% to 2.2% in those with non-European ancestry. The homozygous state is rare (<1% of the US population).
The incident lifetime venous thromboembolism (VTE) risk for individuals heterozygous for FVL and older than 45 years was 17% in a study using prospective data from the Cardiovascular Health Study (N = 5414) and the Atherosclerosis Risk in Communities study (N = 14 185). In a pooled analysis of case-control and cohort studies (11 239 cases and 21 521 controls), heterozygous FVL was associated with an increased risk of VTE (odds ratio [OR], 4.22 [95% CI, 3.35-5.32]) compared with noncarriers of FVL, and homozygous FVL was associated with a VTE OR of 11.45 (95% CI, 6.79-19.29; absolute rates not provided). A pooled analysis of 24 observational studies (N = 13 571) that prospectively assessed patients with prior VTE reported that the relative risk of recurrent VTE in those heterozygous for FVL was 1.4, with an absolute risk of 7% to 14% per year. A meta-analysis of 56 case-control or cohort studies that included 10 229 adults with arterial ischemic stroke and 31 816 controls reported that patients with arterial stroke were more likely to have FVL (irrespective of zygosity status) than controls (pooled OR, 1.25 [95% CI, 1.08-1.44]).
A study of 2034 healthy nulliparous women who underwent screening for thrombophilia polymorphisms reported no association between FVL (homozygous or heterozygous) and a composite outcome of pregnancy complications, including severe preeclampsia, fetal growth restriction, placental abruption, stillbirth, or neonatal death. A trial of 326 women with an inherited thrombophilia (58% heterozygous for FVL) and 2 or more unexplained miscarriages reported no improvement in live birth rate with prophylactic low-molecular-weight heparin vs no treatment.
FVL testing is performed by DNA analysis of peripheral blood using polymerase chain reaction testing or by a functional coagulation test that assesses plasma APC resistance. Individuals with APC resistance should undergo genetic testing to confirm the FVL genetic variant and determine if 1 or 2 copies of FVL are present. FVL genotyping is not covered by all health insurers, so cost should be discussed prior to testing (Figure).
Approach to Testing
Testing in Patients With Symptomatic VTE
Testing for FVL is not recommended unless it affects clinical management (eg, length of anticoagulation), and most VTE anticoagulation management decisions are not affected by FVL test results. Unnecessary testing for FVL increases health care costs and can result in overdiagnosis, unnecessary worry, or false reassurance.
The 2023 American Society of Hematology (ASH) guidelines provided conditional recommendations against testing for FVL and other tests for thrombophilia (eg, prothrombin 20210A sequence variation; deficiencies of antithrombin, protein C, or protein S; and antiphospholipid antibodies) to guide anticoagulation duration in patients with unprovoked VTE (defined as VTE events not associated with a major transient risk factor). The ASH guidelines also conditionally recommended against thrombophilia testing to determine duration of anticoagulant treatment in patients with VTE provoked by a surgical procedure who have completed a short-term course (typically 3 months) of therapeutic anticoagulation.
Controversy exists about the role of FVL testing after VTE in patients with nonsurgical major transient risk factors (eg, confinement to a hospital bed for ≥3 days with an acute illness) and/or hormonal risk factors (eg, pregnancy, post partum, use of combined oral contraceptives [COCs]). While the 2023 ASH guidelines provided a conditional recommendation for thrombophilia testing in patients with VTE provoked by nonsurgical major transient risk factors, some professional societies, such as the British Society for Haematology, do not recommend such testing, as the risk of recurrent VTE is low.
For patients with unprovoked VTE involving unusual sites, such as cerebral and splanchnic veins, thrombophilia testing (including FVL) is recommended only if the information would inform decisions about duration of anticoagulation. If indefinite anticoagulation is already planned, thrombophilia testing is not recommended. However, if discontinuation of anticoagulation is being considered after primary short-term treatment, the ASH guidelines conditionally recommended thrombophilia testing, with consideration of extended anticoagulation if thrombophilia is identified.
Among people without a prior VTE who have a first-degree relative with FVL, FVL testing is not recommended.
Testing in Individuals Planning Pregnancy or Who Are Pregnant
Testing for FVL is recommended for individuals with a family history of VTE and known homozygous FVL or compound heterozygosity (ie, concurrent heterozygous FVL and heterozygous prothrombin 20210A). If a person is homozygous for FVL or compound heterozygous, thromboprophylaxis antepartum and postpartum is recommended. In contrast, for individuals who are heterozygous for FVL, the ASH guidelines suggest no antepartum or postpartum thromboprophylaxis. However, some thrombosis experts recommend postpartum prophylaxis in this situation if other thrombosis risk factors, such as cesarean delivery or obesity, are present. Although FVL testing of individuals with a family history of VTE and heterozygous FVL is not recommended, it may be useful in patients with other thrombosis risk factors.
Testing Prior to Use of COCs or Hormone Therapy
Routine FVL testing of individuals without family history of VTE prior to starting COCs or hormone therapy is not recommended because the absolute VTE risk in these populations is low.6 VTE rarely occurs in individuals using COCs (~0.01% per year), and the absolute risk of VTE remains low for FVL heterozygotes (1/345 [0.3%] annually) and for FVL homozygotes (1/116 [0.86%] annually).
Asymptomatic Individuals With FVL
Asymptomatic individuals should not routinely be tested for FVL. However, if an asymptomatic individual is tested (eg, using commercially available genetic testing to learn about ancestry and genetic health risks) and found to have FVL, they should be counseled about signs and symptoms of VTE. Although they should not routinely be treated with prophylactic anticoagulation, in high-risk settings, such as an operation, extending typical thromboprophylaxis (eg, prophylactic dose of a low-molecular-weight heparin) for a longer than standard duration (typically for as long as the person remains hospitalized) may be considered, especially in those with other VTE risk factors (eg, obesity, cancer, and aged ≥65 years).
Conclusions
Testing for FVL in patients with VTE should only be performed when the results may affect management decisions about anticoagulation, such as duration of anticoagulation in splanchnic vein thrombosis or use of prophylactic anticoagulation in pregnant individuals with a family history of VTE and known homozygous FVL or compound heterozygosity. Testing for FVL is not routinely recommended for asymptomatic individuals, those with unprovoked VTE, or VTE provoked by a surgical procedure.
Update on the Laboratory Diagnosis of Lupus Anticoagulant: Current Challenges and Clinical Involvement
Ana Marco-Rico
J Clin Med 2025 Apr 18;14(8):2791
Abstract
Lupus anticoagulant (LAC) is a heterogeneous mix of autoimmune antibodies that prolongs phospholipid-dependent clotting assays. Its diagnosis can be a real challenge in the hemostasis laboratory. In this review, the author describes the main pitfalls affecting the preanalytical phase and how to proceed to reduce interferences. Because of the heterogeneity of these autoantibodies, two assays with different mechanism of action should be performed to detect the majority of LACs. The dilute Russell's viper venom test and the use of a reagent very sensitive to LAC derived from the activated partial thromboplastin time, using silica as the activator, are the most frequent techniques. The algorithms for LAC detection are reported here, and every laboratory is encouraged to introduce its own diagnostic procedure. Results should be expressed in ratio to reduce inter- and intravariability. In addition, the effect of anticoagulation in LAC assays and possible strategies for a correct diagnosis are provided.
Successful Treatment With the Oral Factor Xa Inhibitor Edoxaban in Heparin-Induced Thrombocytopenia With Thrombosis
Mateo Porres-Aguilar, Carolina Najera, Adriana C Mares, Ilham Benzidia, Swathi Prakash, Benjamin Crichi
Angiology 2025 May;76(5):453-457.
Abstract
Abstract
Heparin-induced thrombocytopenia with thrombosis (HITT) is a rare immune reaction to the drug heparin that causes increased blood clotting, putting patients at risk for arterial and venous thromboembolism which can have severe consequences. We present a case of HITT successfully treated with the direct oral anticoagulant (DOAC), edoxaban. A 56-year-old man had surgery to remove a colorectal mass. After discharge, he developed chest discomfort, shortness of breath, and low oxygen levels and was diagnosed with a right-sided lobar pulmonary embolism. His platelet count dropped, his tests confirmed a diagnosis of HITT, and he was initially treated with fondaparinux. After showing clinical and laboratory improvement, he was switched to edoxaban. Despite being diagnosed with colonic adenocarcinoma during follow-up, the patient's platelet count returned to normal, and he did not experience any more blood clots or serious bleeding events. The use of DOACs like edoxaban as potential therapies for HITT is promising; further research is being conducted to evaluate their effectiveness, safety, and potential benefits for treating this acquired high-risk thrombophilia.
How we treat severe inherited antithrombin deficiency: lessons from cases homozygous for the Budapest 3 variant
Carlos Bravo-Pérez, Javier Corral, Christelle Orlando, Vera Ignjatovic, Péter Ilonczai, Zsuzsanna Bereczky
J Thromb Haemost, 2025 May;23(5):1648-1656.
Abstract
Background: Antithrombin deficiency represents one of the most severe inherited thrombophilias. Albeit a rare disorder, available knowledge suggests that antithrombin deficiency is underestimated due to the limitations of current diagnostic algorithms. The high clinical variability of this patient population may be another cause of underdiagnosis. Heterozygous type I (quantitative) variants are normally associated with a severe thrombophilic phenotype, while heterozygous type II (qualitative) variants are heterogeneous, including heparin-binding site defects, which are mild/moderate and the most prevalent. Antithrombin Budapest 3 (p.Leu131Phe) is the most frequent type II/heparin-binding site deficiency in Europe, particularly in the Roma population, with a remarkable existence of homozygous subjects.
Objectives: To determine the clinical features, diagnostic procedures, and management of patients with severe antithrombin deficiency, leveraging the study of cases homozygous for the antithrombin Budapest 3 variant.
Methods: Patients were selected from 699 subjects with antithrombin deficiency and recruited over 25 years from reference centers in Spain, Belgium, and Hungary.
Results: Guided by 2 illustrative cases with homozygous antithrombin Budapest 3, we report the spectrum and clinical management of patients with this disorder. These cases, with very low antithrombin activity (<20%) and juvenile and recurrent venous thromboembolism, recapitulate numerous issues that one might encounter when treating patients with antithrombin deficiency. In addition, special clinical scenarios for which no formal evidence-based guidelines exist might be found more frequently in these patients, including heparin resistance, vena cava anomalies, and obstetric complications.
Conclusion: Expert proposals on the optimal management of these controversial areas, as well as future perspectives, are also formulated.
Immune Thrombotic Thrombocytopenic Purpura: A Review
Allyson M. Pishko, MD, MSCE; Ang Li, MD, MS; Adam Cuker, MD, MS
Abstract
Importance Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy that presents with microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. Worldwide annual incidence of iTTP is 2 cases per million to 6 cases per million.
Observations Immune TTP is caused by an autoantibody to a disintegrin and metallopeptidase with thrombospondin type 1 motif 13 (ADAMTS13), an enzyme that cleaves von Willebrand factor (vWF). With severely low ADAMTS13 activity (<10%), large multimers of vWF accumulate and bind platelets, forming microvasculature thromboses that cause ischemic organ injury (eg, myocardial infarction and stroke). The incidence of iTTP is higher in adults than children (incident rate ratio [IRR], 31.62 per million person-years [95% CI, 14.68-68.10]), females than males (IRR, 3.19 [95% CI, 2.65-3.85]), and Black compared with non-Black individuals (IRR, 7.09 [95% CI, 6.05-8.31]). Common presenting symptoms are neurologic (eg, headache, confusion, or seizures [39%-80%]) and abdominal pain (35%-39%). For patients presenting with MAHA and thrombocytopenia, clinical prediction scores for iTTP using laboratory data, such as platelet count less than 30 × 109/L and creatinine level less than 2.0 mg/dL (176.8 μmol/L), can help guide empirical treatment initiation for iTTP before ADAMTS13 results are available. Prompt initiation of therapy with therapeutic plasma exchange, corticosteroids, and rituximab improves survival with iTTP from almost zero to approximately 93%. Caplacizumab, a synthetic small antibody (nanobody) that blocks platelet binding to vWF, administered concurrently with immunosuppression and therapeutic plasma exchange and continued until ADAMTS13 recovery, reduces the time to normalization of platelet count and decreases the risk of early recurrence (defined as within 30 days of completing therapeutic plasma exchange) compared with placebo (risk difference [RD], −29% [95% CI, −42 to −14%]) but increases bleeding risk (RD, 17% [95% CI, 4%-30%]). After obtaining clinical remission (defined as at least 30 days of sustained normalization of platelet count, decreased serum lactate dehydrogenase level, and absence of new or progressive ischemic organ injury without therapeutic plasma exchange or caplacizumab), 16% of patients have at least 1 relapse of iTTP. Regular monitoring of ADAMTS13 activity in remission and administration of rituximab when ADAMTS13 activity is less than 20% reduces risk of relapse (odds ratio, 0.09 [95% CI, 0.04-0.24]).
Conclusions and Relevance Immune TTP is a rare immune-mediated disorder that presents with thrombocytopenia and MAHA and may cause life-threatening thrombosis. Treatment with therapeutic plasma exchange, corticosteroids, and rituximab is associated with 30-day survival rates of more than 90%. Addition of caplacizumab shortens time to normalization of platelet count and reduces recurrences while receiving the drug but increases bleeding risk. Monitoring ADAMTS13 activity in survivors and initiation of rituximab for those with low ADAMTS13 activity reduces the risk of clinical relapse.
Low-Density Lipoprotein Cholesterol Levels and Bleeding Risk in Venous Thromboembolism
Carmine Siniscalchi, MD, PhD; Tiziana Meschi, MD, PhD; Pierpaolo Di Micco, MD, PhD; et alEgidio Imbalzano, MD; Luis Hernández-Blasco, MD, PhD; Isabelle Mahé, MD, PhD; José Luis Fernández-Reyes, MD; Alberto García-Ortega, MD, PhD; Peter Verhamme, MD, PhD; Joaquín Alfonso-Megido, MD; Manuel Monreal, MD, PhD; and the RIETE Investigators
Introduction
Low-density lipoprotein cholesterol (LDL-C) levels are a well-established therapeutic target for cardiovascular risk reduction, but their role in hemostasis remains less understood. While previous studies3-5 suggest that aggressive LDL-C lowering may increase bleeding risk in patients with arterial disease, this association has not been explored in patients receiving anticoagulation for venous thromboembolism (VTE). We sought to evaluate LDL-C levels and bleeding risk during anticoagulation in patients with acute VTE.
Methods
We conducted a case-control analysis using data from the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry, a large multicenter, observational registry enrolling consecutive patients with objectively diagnosed VTE.6 The study was conducted in accordance with the declaration of Helsinki. Ethics committee approval was obtained from Comité de Ética de la Investigación del Hospital Universitario Germans Trias i Pujol (Badalona, Spain). All participants provided written informed consent. The study included patients from March 2009 to July 2024 who had available baseline LDL-C levels. Because measuring LDL-C is not routine, 75.6% of patients did not have available LDL-C values. Therefore, we checked for potential selection bias by comparing baseline characteristics of patients with and without LDL-C measurements and found no major differences among patients without LDL-C measurements (eTable in Supplement 1). Bleeding events during the first 90 days of anticoagulation were classified as major or nonmajor bleeding according to standard definitions. We reported standardized differences between patients in both subgroups. Standardized differences greater than 0.1 in absolute value were considered relevant. Multivariable Cox proportional hazards regression models, adjusted for competing risks using the Fine-Gray method, were used to assess LDL-C levels and bleeding outcomes. This study followed the STROBE reporting guideline. Data were analyzed using SPSS version 20 (IBM Corp). To identify comparisons of clinical relevance, we reported standardized differences between patients in both subgroups. A standardized difference greater than 0.1 in absolute value was considered relevant.
Results
Among 19 237 patients with available LDL-C levels, 2502 (13.0%) had LDL-C levels less than 70 mg/dL (to convert to mmol/L, multiply by 0.0259). Compared with those with LDL-C levels of 70 mg/dL or higher, these patients were older, more frequently male, and had a higher prevalence of hypertension, diabetes, prior arterial disease, anemia, and active cancer (Table 1). Compared with those with LDL-C levels of 70 mg/dL or higher, these patients were older (standardized difference, 0.228), more frequently male (standardized difference, 0.125), and had a higher prevalence of hypertension (standardized difference, 0.254), diabetes (standardized difference, 0.355), prior arterial disease (standardized difference, 0.144), anemia (standardized difference, 0.436), and active cancer (standardized difference, 0.159). During the first 90 days of anticoagulation, 743 patients (3.9%) experienced bleeding events: 294 major bleeding, 449 nonmajor bleeding, and 32 fatal bleeding cases (Table 2). Patients with LDL-C levels less than 70 mg/dL had an increased risk of overall bleeding (adjusted hazard ratio [AHR], 1.40; 95% CI, 1.16-1.69) and nonmajor bleeding (AHR, 1.49; 95% CI, 1.17-1.90), with hematomas being the most frequent bleeding site (AHR, 2.11; 95% CI, 1.49-2.98). The increased bleeding risk was observed early during anticoagulation and was independent of statin use.
Discussion
Study limitations include the high proportion of missing LDL-C data due to the lack of routine lipid testing. However, the lack of important baseline differences between included and excluded patients is notable. Additionally, our multivariable analysis confirmed that the association between LDL-C levels and bleeding risk was independent of these variables. Another limitation is the inability to account for LDL-C fluctuations over time, which may have affected bleeding risk, particularly in patients undergoing lipid-lowering therapy adjustments.
In this study, low LDL-C levels were associated with an increased risk of bleeding, particularly hematomas, in patients receiving anticoagulation for VTE. Given that LDL-C is not currently considered in bleeding risk stratification, our findings suggest a potential new factor for risk assessment in this population. Future studies should explore whether LDL-C levels can refine existing bleeding risk models and whether strategies to mitigate this risk are warranted.
Oral Anticoagulation and Risk of Adverse Clinical Outcomes in Venous Thromboembolism
Sungho Bea, PharmD, PhD; Geetha S. Iyer, PhD; Dae Hyun Kim, MD, MPH, ScD; et alKueiyu Joshua Lin, MD, ScD, MPH; Yichi Zhang, MS; Heidi Zakoul, BS; Helen Tesfaye, PharmD, MSc; Katsiaryna Bykov, PharmD, ScD
Abstract
Importance Over the past decade, there has been a considerable shift in the use of pharmacologic agents for venous thromboembolism (VTE), with direct oral anticoagulants replacing warfarin as the drugs of choice for VTE recurrence prevention; however, evidence from head-to-head comparison studies remains limited.
Objective To compare the effectiveness and safety of 3 common oral anticoagulants (apixaban, rivaroxaban, and warfarin) in patients with VTE.
Design, Setting, and Participants This population-based cohort study used Medicare and 2 commercial insurance databases from 2016 up to 2024 to identify patients 18 years and older who initiated an oral anticoagulant following VTE and had at least 1 year of continuous insurance enrollment before the index date.
Exposure Initiation of apixaban, rivaroxaban, or warfarin within 30 days after VTE discharge.
Main Outcomes and Measures The primary effectiveness outcome was hospitalization for recurrent VTE. The primary safety outcome was major bleeding. Patients were followed up from treatment initiation until outcome occurrence, treatment discontinuation/switch, disenrollment, death, or end of available data. Propensity score–matching weights were used to adjust for confounding. Weighted Cox proportional hazard models estimated weighted hazard ratios (HRs) and 95% CIs.
Results Among 163 593 eligible individuals (mean [SD] age, 71.4 [13.5] years; 56.7% female), 58.5% initiated apixaban, 25.7% initiated rivaroxaban, and 15.8% initiated warfarin. Overall, 3270 hospitalizations for recurrent VTE and 4229 hospitalizations for bleeding events occurred. Compared with warfarin, patients taking apixaban (HR, 0.67; 95% CI, 0.61-0.75) and rivaroxaban (HR, 0.77; 95% CI, 0.69-0.87) had a lower risk of recurrent VTE. Apixaban showed a further decrease in risk compared with rivaroxaban (HR, 0.87; 95% CI, 0.78-0.96). Patients taking apixaban also had a lower risk of major bleeding compared with warfarin (HR, 0.70; 95% CI, 0.64-0.76) and rivaroxaban (HR, 0.69; 95% CI, 0.63-0.75). No difference in bleeding risk was observed between rivaroxaban and warfarin (HR, 1.02; 95% CI, 0.92-1.12). These findings were consistent across subgroups defined by age, sex, cancer, chronic kidney disease, bleeding history, and frailty.
Conclusions and Relevance In this cohort study of patients with VTE who initiated an oral anticoagulant, apixaban was associated with a lower risk of VTE recurrence and major bleeding compared with rivaroxaban and warfarin. These results provide evidence to guide the selection of appropriate initial oral anticoagulant regimens for adult patients with VTE.