Recent Advances in Thrombosis and Hemostasis—Part XII

Do not trust your memory, it is a net full of holes the most beautiful prizes slip through it.

— Georges Duhamel, French author and physician, 1884–1966

In medicine, we have known fine networks—reticulum—since centuries and more specifically in hemostasis we are familiar with the fibrin network. However, in 2004 Brinkmann et al described in Science the neutrophil extracellular traps, abbreviated as NETs, that consisted of granular proteins and chromatin fibers that were released from neutrophils and served to kill bacteria.[1]

This started an intensive area of research, and a search on this term in PubMed will now yield more than 7,000 results.

The first article in this issue compilation reviews the structure, function, and interplay of NETs with the various components of the hemostatic system.[2] We are also provided with insight on the role of NETs in promoting thrombosis and in sepsis and malignancy. Recently discovered players in the formation of NETs, peptidyl-arginine-deiminase enzymes, and how they act in the citrullination of hemostatic components are described in detail.

Next, data from the TriNetX Research Network were used for analysis of the association between cystic fibrosis and venous thromboembolism (VTE), comparing over 7,000 children with cystic fibrosis with over 22 million controls.[3] VTE occurred almost 20 times more often among children with cystic fibrosis, and independent risk factors were acute pancreatitis, biliary disease, and malabsorption/malnutrition. The authors share with us some speculations on the potential mechanisms behind these associations.

In a systematic review and meta-analysis, Ismail et al have evaluated the risk of deep vein thrombosis (DVT) in adult patients infected with the human immunodeficiency virus (HIV).[4] Although the occurrence of DVT was recorded in 14% of patients living with HIV, there were significant differences between Africa and Europe and also between countries in Africa. Hospitalization, opportunistic infections, malignancies, hypertension, and diabetes appeared to be risk factors for DVT in this population.

Some of the new antidiabetic drugs have proven beneficial for cardiovascular protection, but it is unclear how they might influence the risk of VTE. Chen et al have performed a review of the literature on the sodium–glucose cotransporter 2 inhibitors, the glucagon-like peptide-1 receptor agonists, and the dipeptidyl-peptidase IV inhibitors.[5] The authors found the evidence was not of high quality, with mainly observational studies and with few VTE events in the randomized controlled trials. Nevertheless, there were no convincing data indicating a protective effect.

Xie et al have, starting from a case of left ventricular mass, misdiagnosed as papillary myxoma, reviewed the literature on antiphospholipid syndrome with intracardiac mass.[6] They identified 50 cases, including their own, and have summarized the data on clinical manifestations, initial misdiagnosis, and outcomes of treatment. Many of these patients were young. About one-third of cases were subjected to open-heart surgery for removal and diagnosis of the mass.

Continuing on the pediatric VTE theme, Kiskaddon et al have reviewed the data on anticoagulation therapy in children with renal impairment.[7] These include both heparins and oral anticoagulants, including vitamin K antagonists and direct oral anticoagulants; the authors review pharmacokinetics, dosing, monitoring, and reversal.

The next three full articles in this issue deal with consequences after VTE. Multiple studies have reported on an increased risk for arterial events after a VTE. Using data from a French cohort study on VTE, Noumegni et al have derived from 1,999 study participants information on predictors for recurrent VTE as well as for major adverse cardiovascular events (MACE).[8] They then developed risk scores for recurrent VTE and for MACE, both with separation into low, moderate, and high risk and performed validation using bootstrapping of 10,000 cases. Finally, they constructed an algorithm, showing all possible outcomes of the two risk scores and providing suggestions for antithrombotic treatment(s).

The following contribution is an evaluation of two clinical prediction rules for risk of death at 30 and 90 days after pulmonary embolism.[9] The two are the Hestia score and the simplified pulmonary embolism severity index, and each of them is assessed on its own or in combination with right ventricular dysfunction. The latter did not improve the prediction provided by the original scores, and both scores were acceptably good to identify patients at high risk for the 30-day mortality but less so for the 90-day mortality.

The main outcomes of interest in studies following patients after VTE have so far been recurrent VTE and mortality, but increasingly we are seeing a focus on functional limitations in the long term. In a prospective cohort study of 290 patients with acute VTE, Steiner et al collected several biomarkers and analyzed the association with the post-VTE functional status scale at 3 months after the VTE.[10] The authors identified several biomarkers that were independently associated with poor functional status, but the area under the curve was not higher than 0.62, which is rather poor.

Acute lymphoblastic leukemia and lymphoblastic lymphoma are the dominant malignancies in children and have been treated quite successfully with L-asparaginase, which unfortunately also increases the risk of thrombosis by inhibiting the liver synthesis of mainly antithrombin. Pegaspargase is a newer derivative with prolonged half-life, but it has been associated with increased risk of cerebral venous sinus thrombosis (CVST). In this retrospective study of 716 children treated with pegaspargase, screening with magnetic resonance venography was done at the end of the chemotherapy induction period.[11] Detection of CVST increased from 1.6 to 8.4%, and more than half of the diagnosed cases were asymptomatic. All patients with CVST received anticoagulation, and those with asymptomatic CVST did not experience long-term complications. It is obviously not clear from this study what proportion of asymptomatic patients would suffer long-term complications if not anticoagulated.

Next, we have a commentary on nebulized heparin, focusing on six recently published studies.[12] Half of those were with patients suffering from coronavirus disease (COVID) 2019 and the others were in patients with either pneumonia or with smoke inhalation, typically hospitalized in the intensive care setting. There seems to be good effectiveness and low risk of bleeding by using this formulation.

Finally, we have three Letters to the Editor. The first is a chart review study evaluating the combination of International Classification of Diseases-10 codes with present-on-admission (POA) indicators to more accurately identify patients with new pulmonary embolism when using health care databases.[13] So far POA indicators are only collected in a limited number of countries, but this might become more widespread in the future.

Thereafter, a letter encompasses a case-based discussion on the association of high levels of lipoprotein(a) with not only cardiovascular disease but also with risk for VTE and specifically for CVST and recurrent CVST.[14] There is so far no effective therapy to reduce both the level of lipoprotein(a) and the clinical outcomes, but several agents are currently in clinical trials.

The last letter reports a search in a US database to understand the risk of fatal pulmonary embolism in patients with the post-COVID-19 syndrome (also called long-COVID).[15] Only 89 cases with fatal pulmonary embolism were found or 3.3% of all deaths and many of them occurred at home.

To summarize, this theme issue on recent advances in thrombosis contains a wide variety of topics, covering pathogenesis, epidemiology, risk factors, diagnostics, risk assessment models, and therapies. There should be interesting reading for everyone and hopefully also fruit for new ideas.

Publication History

Article published online:
12 September 2025

• References

• 1 Brinkmann V, Reichard U, Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663) 1532-1535
• 2 Varjú I, Tanka-Salamon A, Kolev K. Neutrophil extracellular traps: at the interface of thrombosis and comorbidities. Semin Thromb Hemost 2025; 51 (07) 724-735
• 3 Trocchia C, Ashour D, Mosha M. et al. Venous thromboembolism occurrence and association with gastrointestinal disorders in children with cystic fibrosis: an analysis from the TriNetX Research Network Global Multicenter Real-World Dataset. Semin Thromb Hemost 2025; 51 (07) 736-744
• 4 Ismail A, Olawumi AL, Abdulkadir Z. et al. Deep vein thrombosis in adults with HIV: a systematic review and meta-analysis of prevalence and risk factors. Semin Thromb Hemost 2025; 51 (07) 745-755
• 5 Chen Q, Anijs RJS, Verlaan JPL, Scheres LJJ, Klok FA, Cannegieter SC. Novel antidiabetic drugs and risk of venous thromboembolism: a literature review. Semin Thromb Hemost 2025; 51 (07) 756-767
• 6 Xie H, Sun Q, Liu M, Xu Y, Wu Q, Li D. Clinical features of antiphospholipid syndrome with intracardiac mass. Semin Thromb Hemost 2025; 51 (07) 768-775
• 7 Kiskaddon AL, Witt DM, Betensky M. et al. Anticoagulants in children with renal impairment: a narrative review. Semin Thromb Hemost 2025; 51 (07) 776-787
• 8 Noumegni SR, Espinasse B, Didier R. et al. Prediction of recurrent venous thromboembolism and arterial cardiovascular events after discontinuation of anticoagulation: the R-VTE-predict and MACE-predict risk scores. Semin Thromb Hemost 2025; 51 (07) 788-799
• 9 Osei Bonsu K, Young SW, Lee T, Nguyen HV, Chitsike RS. Comparative analysis of four risk stratification models to identify patients with acute pulmonary embolism at risk of short-term mortality. Semin Thromb Hemost 2025; 51 (07) 800-808
• 10 Steiner D, Nopp S, Hoberstorfer T. et al. Hemostatic and inflammatory biomarkers are associated with functional limitations after venous thromboembolism: a prospective cohort study. Semin Thromb Hemost 2025; 51 (07) 809-817
• 11 Zhang X, Fu Y, Wang H. et al. Magnetic resonance screening for cerebral venous sinus thrombosis during treatment with pegaspargase. Semin Thromb Hemost 2025; 51 (07) 818-825
• 12 Lippi G, Favaloro EJ. Nebulized heparin in 2025: at the interface between promising benefits and the need for further research. Semin Thromb Hemost 2025; 51 (07) 826-828
• 13 Rashedi S, Leyva H, Pfefferman M. et al. Use of present-on-admission indicators to improve accuracy of pulmonary embolism identification from electronic health record data. Semin Thromb Hemost 2025; 51 (07) 829-833
• 14 Sandre AR, Panju A, Anand SS. Lipoprotein(a) and cerebral venous sinus thrombosis: a case and the evidence. Semin Thromb Hemost 2025; 51 (07) 834-837
• 15 Lippi G, Mattiuzzi C, Favaloro EJ. Mortality from pulmonary embolism in patients with post-COVID syndrome. Semin Thromb Hemost 2025; 51 (07) 838-840