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DOI: 10.1055/s-0045-1807740
Editorial Compilation—XVII
Welcome to the latest issue of Seminars in Thrombosis and Hemostasis (STH) published under the “banner” of “Editorial Compilation,” this being the 17th such issue ([Table 1]). Historically, STH is a theme-driven publication; however, ongoing opportunities emerge to disseminate wide-ranging contributions of current interest or controversy, which do not directly suit an ongoing themed issue. We also require a medium to enable publication of peer-reviewed “unsolicited” manuscripts if accepted, as well as contributions from our Eberhard F. Mammen Young Investigator Award winners (see [Table 2] for previous editorials related to the Eberhard F. Mammen awards). As is now standard for this compilation series, the current issue contains a mixture of articles that comprise the above elements, as well as broadly fitting within the standard themes of “thrombosis” and “bleeding.”
This issue begins with several manuscripts focused on laboratory and/or treatment aspects of thrombosis and hemostasis. First, Ichinose et al discuss the diagnosis and treatment of autoimmune acquired coagulation factor deficiencies, primarily from a Japanese perspective, given their national approach.[1] Among the acquired coagulation factor deficiencies, autoimmune coagulation factor deficiencies (AiCFDs) are rare and result from autoantibody production against various coagulation factors. In Japan, a nationwide survey on AiCFD has been in progress since 2009. Autoimmune factor XIII, factor VIII, von Willebrand factor, factor V, and factor X deficiencies (AiF13D, AiF8D, AiVWFD, AiF5D, and AiF10D, respectively) have been enacted as “designated intractable disease-282.” The incidence of AiF8D, AiF13D, and AiF5D was 1.83, 0.044, and 0.038 per million people/year, respectively, whereas that of AiVWFD and AiF10D was not calculable owing to the small number of patients. AiF13D and AiF8D were often idiopathic, whereas AiVWFD was often associated with plasma cell neoplasms. Epistaxis was a characteristic symptom of AiVWFD, intramuscular bleeding was frequent in AiF13D and AiF8D, and subcutaneous bleeding (purpura) was frequent in AiF13D and AiF10D, although no symptoms were specific to any one disease. Differential diagnosis cannot be made based on bleeding symptoms alone, so that rapid and accurate testing is mandatory. Definitive diagnosis of AiCFD necessitates identifying the presence of coagulation factor “inhibitors” and/or “autoantibodies” and these tests should always be performed upon unexplained severe acquired coagulation factor deficiencies. The mainstay of treatment for AiCFD was hemostatic therapy and autoantibody eradication therapy, which included the replacement of coagulation factors or “bypass” agents and administration of immunosuppressants. The rate of hemorrhagic death was high in AiF13D (13%), followed by AiF5D (7%) and Ai10D (5%). Early diagnosis and optimal treatment are hence essential for AiCFDs. Given the unknown long-term prognosis, “intractable disease platform registries” have begun to accumulate in Japan.
Next, Thonon and colleagues provide some guidance around hemostasis testing in the emergency department (ED).[2] Routine laboratory screening is typically performed at initial evaluation of the vast majority of presentations to the ED. These laboratory results are crucial to the diagnostic process, as they may influence up to 70% of clinical decisions. However, despite the usefulness of biological assessments, many tests performed are inappropriate or of doubtful clinical relevance. This overutilization rate of laboratory testing in hospitals, which represents a significant medical-economic burden, range from 20 to 67%, with coagulation tests at the top of the list. While reviews frequently focus on nonintensive care units, there are few published assessments of emergency-specific interventions or guidelines/guidance to date. The aim of this review is to highlight current recommendations for hemostasis evaluation in the emergency setting, with a specific analysis of common situations leading to ED admissions, such as suspected venous thrombosis or severe bleeding. The authors revisit the evidence related to the assessment of patient's hemostatic capacity based on comprehensive history taking and physical examination as well as best practice recommendations for blood sample collection to ensure the reliability of test results. This review also includes an examination of various currently available point-of-care tests (POCTs) and a comprehensive discussion on indications, limitations, and interpretation of these tests.
This issue of STH continues with a review and recommendations on stability of hemostasis parameters in whole blood, plasma, and frozen plasma, from the SFTH (French Society of Thrombosis and Haemostasis), by Flaujac and colleagues.[3] Preanalytical sample management is critical for the proper assessment of hemostasis parameters, but may differ depending on prescribed tests or additional tests considered to be necessary after initial results are reported. Although there is considerable literature on this issue, the Working Group of the SFTH deemed it necessary to undertake an in-depth literature review and propose recommendations for the proper handling of samples prior to hemostasis assays. This extensive assessment is accessible online in French at the SFTH Web site. In this issue of STH, a more synthetic view of these recommendations is proposed, supported by easy-to-use tables. The latter respectively deal with the stability of whole blood or fresh plasma, frozen samples, and proper handling of samples forwarded on dry ice. Procedures are classified as recommended, acceptable, not conformed, and lacking data. This work involved the retrieval of 125 references, first screened by a working group of 6 experts, then reviewed by 13 other experts in the field. The highly detailed conditions summarized in these tables will hopefully help hemostasis laboratories secure the conditions recommended for sample collection and transportation. Moreover, as some conditions clearly lacked recommendations, this review can open new fields of investigation for hemostasis pre-analytics.
Next, Bavinck et al review POCT in patients with hereditary disorders of primary hemostasis.[4] Inherited disorders of primary hemostasis, such as von Willebrand disease and congenital platelet disorders, can cause extensive, typically mucocutaneous bleeding. Assays to diagnose and monitor these disorders, such as von Willebrand factor activity assays and light transmission aggregometry, are usually performed in specialized hemostasis laboratories, but are commonly unavailable in local hospitals. Due to the complexity and relative scarcity of these conventional specialized assays, POCT might be an attractive alternative in patients with hereditary bleeding disorders. Tests such as thromboelastography are increasingly used to assess hemostasis in patients with acquired hemostatic defects, aiding clinical decision-making in critical situations, such as during surgery or childbirth. In comparison, the use of these assays in patients with hereditary hemostasis defects remains relatively unexplored. Therefore, this review aims to give an overview of POC hemostasis tests in patients with hereditary disorders of primary hemostasis. A summary of the literature reporting on the performance of currently available and experimental POCT in these disorders is given and the potential utility of the assays in various use-scenarios is discussed. Altogether, the studies included in this review reveal that several POCTs are capable of identifying and monitoring severe defects in the primary hemostasis, POCT that can reliably detect milder defects of primary hemostasis is currently lacking. The authors indicate that a better understanding of the strengths and limitations of POCT in assessing hereditary defects of primary hemostasis is needed, after which these tests may become available for clinical practice, potentially targeting a large group of patients with milder defects of primary hemostasis.
Talasaz et al then review pharmacokinetic and pharmacodynamic interactions between food or herbal products and oral anticoagulants (OACs).[5] Interactions between food and OACs, particularly vitamin K antagonists (VKAs) such as warfarin, are widely recognized and may also be clinically relevant for direct OACs. Pharmacokinetic and pharmacodynamic interactions with food or herbs can lead to anticoagulation potentiation, increased risk of bleeding, or reduced drug efficacy, all compromising patient safety. The authors conducted a systematic search for randomized controlled trials (RCTs) on PubMed for assessments of interactions between OACs and various ingestants. Since the RCT evidence was slim, they further reviewed prospective longitudinal studies, case series, and case reports to identify possible associations between foods and anticoagulation therapy. They also referred to basic or translational studies that shared putative explanations for such interactions, but the authors failed to identify high-quality evidence in most cases. The limited evidence, small sample size of the studies, conflicting results, and possible heterogeneity in the contents of herbal products prevent a conclusive assessment of these interactions. Existing evidence suggests that: (1) cranberry juice consumption (up to 240 mL/day and probably even more) with warfarin is safe. (2) Use of green leafy vegetables with a high daily content (more than 250 μg) of vitamin K should be cautioned for patients receiving warfarin because it may decrease its efficacy. It is also advisable for patients to maintain highly constant intake of green leafy vegetables to ensure stable warfarin effectiveness. (3) Ginger, even in small quantities (excluding commercial ginger-flavored beverages which contain only negligible amounts of ginger) and mango (more than one fruit) can both potentiate warfarin effects. (4) Patients taking OACs should avoid St. John's wort due to diminished anticoagulant effect. (5) Consumption of less than 240 mL of grapefruit juice daily is unlikely to interact with OACs. The authors conclude that future longitudinal observational cohort studies and RCTs with larger sample sizes are needed to study specific interactions between food or herbal products and OACs.
A review on the regulatory effect of platelet-derived growth factor (PDGF) and its receptor (PDGFR) on hematopoiesis follows from the authorship team of Liu et al.[6] PDGF is a critical cytokine with substantial regulatory effects on hematopoiesis. Recent research highlights the essential role of PDGF in the modulation of hematopoietic stem/progenitor cells (HSPCs), megakaryocytes/platelets, and thrombopoietin (TPO) synthesis within the bone marrow microenvironment. PDGF directly stimulates proliferation and differentiation of HSPCs, while also inhibiting apoptosis. In addition, PDGF indirectly enhances the production of other growth factors, including granulocyte–macrophage colony-stimulating factor. Further, PDGF regulates TPO production and influences the bone marrow milieu, thus impacting hematopoiesis and platelet formation. Mechanistically, PDGF binds to its receptor (i.e., PDGFR), thus activating the PDGF/PDGFR signaling pathway. This pathway subsequently activates phosphoinositide 3-kinase/protein kinase B, leading to the activation of downstream cytokines, including C-Fos and NF-E2, while inhibiting caspase-3 activation. Collectively, these actions have pro-differentiation and anti-apoptotic effects on megakaryocytes, thereby regulating platelet production. This review provides a comprehensive analysis of the regulatory role of the PDGF/PDGFR axis in hematopoiesis, with a particular focus on platelet production, by summarizing all studies on PDGF/PDGFR from the authors' group and globally.
Next is an updated narrative review from Napolitano and colleagues[7] on anti-platelet factor 4 (anti-PF4) antibody-mediated disorders. Anti-PF4 antibody-mediated disorders represent a heterogeneous group of diseases characterized by the presence of highly pathogenic immunoglobulins G directed against PF4 and/or PF4/heparin complexes. These antibodies activate platelets, neutrophils, and monocytes, thus resulting in thrombocytopenia and a hypercoagulable state. Five different forms of anti-PF4 antibody-mediated disorders have now been identified: (1) classic heparin-induced thrombocytopenia (HIT) mediated by heparin and certain polyanionic drugs; (2) autoimmune HIT characterized by the presence of anti-PFA/polyanion antibodies that can strongly activate platelets even in the absence of heparin; (3) spontaneous HIT characterized by thrombocytopenia and thrombosis without proximate exposure to heparin, with two subtypes: (i) post-total knee arthroplasty and cardiac surgery using cardiopulmonary bypass or extracorporeal membrane oxygenation and (ii) post-infections; (4) vaccine-induced immune thrombotic thrombocytopenia (VITT) characterized by thrombocytopenia, arterial and/or venous thrombosis, or secondary hemorrhage after receiving adenoviral vector vaccines for coronavirus disease 2019; (5) VITT-like disorders triggered by adenoviral infections. Although extremely rare and largely unknown, there has been growing interest in the VITT syndrome in recent years due to its clinical relevance. Timely detection of these antibodies is crucial for the diagnosis and treatment of anti-PF4 antibody-mediated disorders, via anti-PF4 antibody immunoassays using several antibody capture systems (e.g., enzyme-linked immunosorbent assay-based, particle gel, turbidimetry) and functional assays (e.g., serotonin release assay or heparin-induced platelet activation). The authors aim to present the latest on laboratory findings, clinical characteristics, and therapeutic approaches for anti-PF4 antibody-mediated disorders.
This is followed by a case description and literature review around the use of alternative therapy to VKAs in prosthetic mechanical aortic valve due to warfarin hypersensitivity due to factor IX (FIX) pro-peptide variants by Tufano and coworkers.[8] Bleeding is the most common side effect during treatment with VKAs. Sometimes, VKAs cause bleeding episodes due to rare variants in the FIX pro-peptide that modify the affinity of FIX pro-peptide to the binding of γ-glutamyl carboxylase. The authors report on a 51-year-old patient who presented with recurrent spontaneous and severe intramuscular and cutaneous bleedings during VKA (warfarin) treatment because of a prosthetic mechanical aortic valve. Laboratory evaluation revealed international normalized ratio (INR) within the therapeutic range with markedly prolonged activated partial thromboplastin time (aPTT) and large reduction in plasma FIX levels. Laboratory parameters significantly improved when warfarin was replaced with low-molecular-weight heparin. Next-generation sequencing analysis revealed the variant p.(Ala37Thr) in the F9 gene, which has been previously associated with VKA sensitivity. As an alternative to warfarin, apixaban 5 mg twice daily and aspirin 100 mg daily was started, with no thrombosis or recurrence of hemorrhage and normalization of INR, aPTT, and FIX levels, at 12 months of follow-up. The authors also performed a literature search across PubMed and Scopus, until January 2025. Their analysis evidenced five case reports and two case series. The mechanisms of this rare VKA hypersensitivity are also reviewed. The authors conclude that while VKA hypersensitivity is a rare phenomenon, awareness toward this complication and the current accessibility to molecular testing make it important to identify patients at risk. Furthermore, the efficacy/safety of direct thrombin or factor Xa inhibitors in patients with mechanical heart valve and VKA hypersensitivity due to F9 p.(Ala37Thr) variant deserves more attention and further investigations.
The final full-length article in this issue of STH is by Lianou and coworkers on the topic of hemostatic manifestations of invasive fungal infections.[9] Sepsis is a life-threatening condition that has challenged many clinicians over the years. The immune and hemostatic systems are the primary pillars of sepsis pathogenesis. Dysregulation of these intricate mechanisms significantly worsens the prognosis. Coagulopathy is a critical aspect of sepsis, with the degree of hemostatic impairment being a key determinant of poor outcomes. Although the concept of sepsis caused by bacteria has been well investigated, the fungal impact in the complexity of sepsis-related hemostatic derangement is not yet fully unraveled. In addition, sepsis occurs in patients across all age groups, with a particular concern for neonates, whose immature and vulnerable systems amplify the challenges. Notably, despite the high incidence of fungal septicemia in neonatal intensive care units, along with its significant morbidity, mortality, and adverse neonatal outcomes, the impact of fungal sepsis on the neonatal hemostatic system—an essential determinant of prognosis—remains largely unexplored. The authors' review delves into the pathophysiologic mechanisms of sepsis-induced coagulopathy attributed to fungal infection, the mechanisms of fungal involvement in the hemostatic derangement, and attempts to contextualize this knowledge within the unique neonatal population. Finally, they aim to raise awareness of the critical need for a deep understanding of this hazardous condition to guide the development of optimal therapeutic strategies.
As usual for these nonthematic issues of STH, the issue continues with some correspondence. First, Galstyan et al discuss the possibility of tailored treatment of immune thrombotic thrombocytopenic purpura.[10] Next, Raimondi and colleagues describe a case of heparin-like anticoagulant in a metastatic biliopancreatic cancer.[11]
As always, we once again thank all the authors to this latest issue of “Editorial Compilations” for their original and comprehensive contributions, and we hope our readership enjoys this latest instalment in this series.
Finally, a reminder that STH has transitioned to an online submission system. If any reader is interested in submitting a manuscript, feel free to do so at: https://mc.manuscriptcentral.com/sth.
Publikationsverlauf
Artikel online veröffentlicht:
13. Juni 2025
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References
- 1 Ichinose A, Osaki T, Souri M. Diagnosis and treatment of autoimmune acquired coagulation factor deficiencies: an evidence-based review of Japanese practice. Semin Thromb Hemost 2025; 51 (05) 491-505
- 2 Thonon H, Van Nieuwenhove M, Thachil J, Lippi G, Hardy M, Mullier F. Hemostasis testing in the emergency department: a narrative review. Semin Thromb Hemost 2025; 51 (05) 506-523
- 3 Flaujac C, Delassasseigne C, Hurtaud-Roux MF, Delahousse B, Boissier E, Desconclois C. Working Group on Preanalytics in the French Society of Thrombosis Haemostasis. Stability of hemostasis parameters in whole blood, plasma, and frozen plasma: literature review and recommendations of the SFTH (French Society of Thrombosis and Haemostasis). Semin Thromb Hemost 2025; 51 (05) 524-540
- 4 Bavinck AP, Heerde WV, Schols SEM. Point-of-care testing in patients with hereditary disorders of primary hemostasis: a narrative review. Semin Thromb Hemost 2025; 51 (05) 541-559
- 5 Talasaz AH, McGonagle B, HajiQasemi M. et al. Pharmacokinetic and pharmacodynamic interactions between food or herbal products and oral anticoagulants: evidence review, practical recommendations, and knowledge gaps. Semin Thromb Hemost 2025; 51 (05) 560-571
- 6 Liu Y, Huang J, Li L. et al. Regulatory Effect of PDGF/PDGFR on Hematopoiesis. Semin Thromb Hemost 2025; 51 (05) 572-577
- 7 Napolitano A, Spiezia L, Biolo M. et al. Anti-platelet factor 4 antibody-mediated disorders: an updated narrative review. Semin Thromb Hemost 2025; 51 (05) 578-593
- 8 Tufano A, Fierarossa C, Cirillo F. et al. Use of oral anti-Xa inhibitor in prosthetic mechanical aortic valve with warfarin hypersensitivity due to the FIX p.(Ala37Thr) pro peptide variant: case report and literature review. Semin Thromb Hemost 2025; 51 (05) 594-599
- 9 Lianou A, Tsantes AG, Piovani D. et al. hemostatic manifestations of invasive fungal infections: a comprehensive review of pathophysiological mechanisms in sepsis-induced hemostatic disturbances, with a focus on the neonatal population. Semin Thromb Hemost 2025; 51 (05) 600-618
- 10 Galstyan GM, Klebanova E, Mamleeva S, Fidarova Z, Drokov M, Bessmertniy D. Tailored treatment of immune thrombotic thrombocytopenic purpura. Semin Thromb Hemost 2025; 51 (05) 619-622
- 11 Raimondi R, Aguirre S, Monserrat V, Pons S, Contardo D, Scazziota A. Heparin-Like Anticoagulant: First Case Described in a Metastatic Biliopancreatic Cancer. Semin Thromb Hemost 2025; 51 (05) 623-626