Seminars in thrombosis and hemostasis最新文献

Fibrinolysis is initiated by the activation of plasminogen to plasmin via tissue-plasminogen activator (tPA) and urokinase-plasminogen activator (uPA); plasmin then converts fibrin to fibrin degradation products (FDPs). The antifibrinolytics counterbalancing this system include plasminogen activator inhibitor-1 (PAI-1), which inhibits tPA and uPA, α-2 antiplasmin (α₂AP), which inhibits plasmin, and thrombin activatable fibrinolysis inhibitor, which inhibits the conversion of fibrin to FDP. Inherited disorders of the fibrinolytic pathway are rare and primarily have hemorrhagic phenotypes in humans: PAI-1 deficiency, α₂AP deficiency, and Quebec platelet disorder. Patients with these disorders are usually treated for bleeds or receive prophylaxis to prevent bleeds in the surgical setting, with pharmacological antifibrinolytics such as aminocaproic acid and tranexamic acid. Disorders of the fibrinolytic pathway with fibrin deposition are extremely rare, mostly noted in patients with plasminogen deficiency, who have more recently benefited from advances in human plasma-derived plasminogen concentrates administered intravenously or locally. These disorders can be very difficult to diagnose using conventional or even specialized coagulation testing, as testing can be nonspecific or have low sensitivity. Testing of the corresponding protein's activity and antigen (where applicable) can be obtained in specialized centres, and routine laboratory measures are not diagnostic. Genetic testing of the pathogenic mutations is recommended in patients with a high suspicion of an inherited disorder of the fibrinolytic pathway.

Vitamin K-dependent coagulation factors deficiency (VKCFD) is a rare autosomal recessive genetic disease characterized by impaired levels of multiple coagulation factors (II, VII, IX, and X) and natural anticoagulants (proteins C and S). VKCFD is part of familial multiple coagulation factor deficiencies, reporting overall 50 affected families thus far. Disease manifestations are quite heterogeneous, bleeding symptoms may vary, and even, although generally mild, some patients may succumb to fatal outcomes. VKCFD diagnosis may be delayed because the disease phenotype simulates the most frequently acquired deficiencies of vitamin K. First-line coagulation assays, prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT), are both prolonged; mixing test typically normalizes the clotting times; and vitamin K-dependent coagulation factors will be variably decreased. Molecularly, VKCFD is associated with mutations in γ-glutamyl-carboxylase (GGCX) or vitamin K epoxide reductase complex subunit 1 (VKORC1) genes. Vitamin K is involved not only in the biosynthesis of coagulation proteins but also in bone metabolism and cell proliferation. Therapeutic options are based on vitamin K supplementation, coagulation factors (prothrombin complex), and fresh frozen plasma, in case of severe bleeding episodes. Two case studies here illustrate the diagnostic challenges of VKCFD: case 1 depicts a woman with a history of bleeding episodes, diagnosed, only in her third decade of life with inherited homozygous GGCX gene mutation. Case 2 shows a man with an acquired vitamin K deficiency caused by Crohn's disease. Better understanding of GGCX and VKORC1 mutations aids in prognosis and treatment planning, with emerging insights suggesting potential limitations in the effectiveness of vitamin K supplementation in certain mutations.

Since their discovery in 2004, neutrophil extracellular traps (NETs) have been in the center of multidisciplinary attention. While a key tool in neutrophil-mediated immunity, these filamentous, enzyme-enriched DNA-histone complexes can be detrimental to tissues and have been identified as an underlying factor in a range of pathological conditions. Building on more than 20 years of research into NETs, this review places thrombosis, the pathological formation of blood clots, in the spotlight. From this point of view, we discuss the structure and formation of NETs, as well as the interaction of their components with the hemostatic system, dissecting the pathways through which NETs exert their marked effect on formation and the dissolution of thrombi. We pay distinct attention to the latest developments in the research of a key player in NET-formation, peptidyl-arginine-deiminase (PAD) enzymes: their types, sources, and potential cross-play with the hemostatic machinery. Besides these molecular details, we elaborate on the link between pathological thrombosis, NETs, and widespread conditions that represent a debilitating public health burden worldwide, such as sepsis and neoplasms. Finally, future implications on the treatment of thrombosis-related conditions will be discussed.

Chronic liver disease is a frequently encountered disorder and a major concern worldwide with a complex pathophysiology, which often affects the hemostatic system. Such alterations, which affect both primary and secondary hemostasis, are heterogenous, including prohemorrhagic (i.e., decreased coagulation factors, increased fibrinolysis, thrombocytopenia, and platelet dysfunction) and prothrombotic (i.e., decreased natural anticoagulants) changes. As a consequence of this unstable balance, patients with liver cirrhosis may experience both hemorrhagic complications and venous thromboembolic events, which are often unpredictable and whose management is particularly challenging for clinicians. This narrative review will address the most recent advances in the pathophysiology of key derangements of hemostasis in patients with chronic liver disease, focusing on their clinical implications and management.

"The publisher would like to inform you that this article has been temporarily removed due to technical issues. This temporary removal is not content related. A revised version will be made available under the same DOI as soon as possible. Thank you for your understanding and patience. For any questions, please feel free to contact us at: am-query@thieme.com.

Travel-related thrombosis (TRT), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), poses a significant health risk associated with long-haul travel. Prolonged immobility, dehydration, and cabin pressure changes during flights contribute to venous stasis, hypoxia, and hypercoagulability, collectively increasing the risk of venous thromboembolism (VTE). While the absolute risk of TRT is relatively low in the population overall, it rises significantly among high-risk groups, including individuals with a history of VTE, thrombophilia, pregnancy, or recent surgery. This review explores the epidemiology, pathophysiology, clinical presentation, and diagnostic evaluation of TRT while highlighting the importance of early recognition and prevention. Risk assessment models can provide guidance for identifying at-risk travelers. Preventive strategies include pharmacological prophylaxis with low-molecular-weight heparin (LMWH) for high-risk individuals and nonpharmacological measures such as compression stockings, intermittent pneumatic compression, mobility exercises, and hydration. Guidelines from international societies recommend tailored interventions based on individual risk profiles, as randomized controlled trials are scarce. Given that long-haul travel dramatically expands, this review critically analyzes the available TRT management strategies in various clinical settings, aiming to increase awareness of this global health issue.

Bleeding is the most common side effect during treatment with vitamin K antagonists (VKAs). Sometimes, VKA use causes bleeding episodes due to rare variants in the factor IX (FIX) pro peptide that modify the affinity of FIX pro peptide to the binding of γ-glutamyl carboxylase. We report on a 51-year-old patient who presented with recurrent spontaneous and severe intramuscular and cutaneous bleedings during VKA (warfarin) treatment for the presence of prosthetic mechanical aortic valve. Laboratory evaluation revealed INR within the therapeutic range with markedly prolonged aPTT and large reduction of FIX levels. Laboratory parameters significantly improved when warfarin was switched 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 follow-up. We also performed a literature search across PubMed and Scopus, until January 2025. The analysis evidenced 5 case reports and 2 case series. The mechanisms of this rare VKA hypersensitivity have also been reviewed. In conclusion, while VKA hypersensitivity is a rare phenomenon, awareness towards this complication and the current accessibility to molecular testing make it important to identify patients at risk. 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.

Anti-platelet factor 4 (PF4) antibody-mediated disorders are a heterogeneous group of diseases characterized by the presence of highly pathogenic immunoglobulins G directed against PF4 and/or PF4/heparin complexes. These antibodies are able to activate platelets, neutrophils, and monocytes, thus resulting in thrombocytopenia and a hypercoagulable state. Five different forms of anti-PF4 antibody-mediated disorders have 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: (a) post-total knee arthroplasty and cardiac surgery using cardiopulmonary bypass or extracorporeal membrane oxygenation and (b) postinfections; (4) vaccine-induced immune thrombotic thrombocytopenia (VITT) characterized by thrombocytopenia, arterial and 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). We aimed to present the latest on laboratory findings, clinical characteristics, and therapeutic approaches for anti-PF4 antibody-mediated disorders.

Bleeding is a well-known and severe complication of cardiac surgery. Cardiopulmonary bypass, along with heparinization and hemodilution, is thought to affect all pathways of the hemostatic process, leading to excessive bleeding and worsened morbidity and mortality. The traditionally used standard laboratory tests (SLTs) were not designed for the surgical setting, have long turnaround times, and are poor predictors of bleeding. This review aims to give an overview of viscoelastic assays (VEAs), compare VEAs to conventional testing methods, and summarize the evidence for VEAs in cardiac surgery. A search of Medline via Pubmed, Scopus, and Embase yielded 2,868 papers, which we reviewed and summarized the key findings. VEAs such as rotational thromboelastometry and thromboelastography provide a quick turnaround, graphical, global impression of hemostasis in whole blood. VEAs allow for the analysis of specific contributors to the coagulation process and may facilitate cause-oriented hemostatic treatment and the development of treatment algorithms. VEAs have been found to have a high specificity and high negative predictive value for coagulopathic bleeding. Patients treated with VEA-based algorithms have been shown to have lower rates of bleeding, transfusion requirements, and exposure to allogeneic blood products. However, VEA-based algorithms have not demonstrated a mortality benefit and evidence for outcomes such as surgical re-exploration and hospital length of stay remains equivocal. In conclusion, VEAs have been shown to be comparable if not superior to SLTs in cardiac surgery. Further large-scale studies are needed to better evaluate the impact of VEAs on clinical outcomes.