Journal of Thrombosis and Haemostasis最新文献

Hemophilia A and hemophilia B are inherited bleeding disorders caused by a deficiency or absence of coagulation factor [F]VIII and FIX, respectively. The severity of bleeding manifestations generally correlates with the degree of factor deficiency, which is determined by the type of pathogenic variant in the F8 or F9 gene, both of which are located on the X-chromosome. The classical and most frequent site of bleeding is the musculoskeletal system, commonly into the ankle, knee, and elbow joints. Clinical diagnosis of hemophilia is typically confirmed through laboratory testing using 1-stage factor assays. The armamentarium of treatment includes desmopressin, FVIII/FIX concentrates, FVIII mimetics, rebalancing agents, and gene therapy. Despite advances in therapeutic options, hemophilic arthropathy remains a significant clinical complication. As life expectancy in persons with hemophilia increases, they become more susceptible to age-related comorbidities, including cardiovascular disease. Given the complex treatment modalities, hemophilia-specific complications, and quality-of-life concerns, optimal hemophilia care requires a multidisciplinary approach.

Background: Sickle cell disease (SCD) is characterized by chronic hemolytic anemia and recurrent vaso-occlusive events. Polymerization of deoxygenated sickle hemoglobin (HbS) increases erythrocyte rigidity, promoting microvascular occlusion, tissue hypoxia, and hemolysis. SCD is associated with a heightened risk of deep venous thrombosis, but the mechanisms remain unclear.

Objectives: To determine the causal role of SCD in venous thrombosis and to evaluate the therapeutic potential of hemoglobin degradation by Plasmodium falciparum plasmepsin I (PMI).

Methods: Venous thrombosis was induced by femoral vein ligation in SCD and wild-type (WT) mice. Thrombus morphology was analyzed by scanning electron microscopy. Plasma-free hemoglobin levels were measured during coagulation, and the effects of recombinant PMI on free hemoglobin and thrombus formation were assessed. In addition, in vitro assays evaluated the impact of HbS on clotting time compared with normal hemoglobin.

Results: Thrombi developed in all SCD mice and most WT controls following ligation. Scanning electron microscopy demonstrated distinct thrombus architecture in SCD, featuring rigid, elongated erythrocytes interconnected by fibrin-like strands and frequent membrane disruption, compared with polyhedrocyte-rich WT thrombi. Plasma-free hemoglobin increased during static incubation of SCD blood and was consumed during coagulation, implicating it in clot formation. In vitro, HbS addition shortened the clotting time compared with normal hemoglobin. Treatment with PMI reduced free plasma hemoglobin and significantly decreased thrombus size in SCD mice.

Conclusion: Sickle hemoglobin contributes to venous thrombogenesis through procoagulant activity and thrombus stabilization. Targeting free HbS with hemoglobinase therapy may represent a novel therapeutic strategy for thrombotic complications in SCD.

Background: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a transient prothrombotic process, although recent data suggest that VITT anti-platelet factor 4 (PF4) antibodies are more persistent than those in heparin-induced thrombocytopenia.

Objectives: We sought to interrogate whether anti-PF4 antibody persistence in VITT is related to the continued persistence of antibody clones from the acute phase or to the development of novel anti-PF4 antibodies due to epitope spreading.

Methods: Samples from 6 patients with Ad26.COV2.S-associated VITT with a median time to follow-up of 244 days from acute presentation (range, 114-664 days) were studied in antigenic/functional assays and by mass spectrometry. One patient with ChAdOx1 nCoV-19-associated VITT was tested >4 years after acute presentation.

Results: Upon affinity-enrichment of anti-PF4 antibodies, mono/oligoclonal anti-PF4 antibodies were observed despite negative results in serum protein electrophoresis/"Mass-Fix" testing of native sera. Anti-PF4 antibody abundance decreased over time, with no evidence of novel anti-PF4 antibody production after acute presentation. Although previous studies indicate a stereotypical pairing of VITT antibodies with lambda light chains, 1 patient with VITT produced antibodies with a kappa light chain. Long-term thrombocytopenia/thrombosis was not seen in any of the 6 Ad26.COV2.S-associated VITT patients; however, platelet-activating anti-PF4 antibodies were seen 4 years after the acute event in an additional patient with ChAdOx1 nCoV-19-associated VITT with chronic low-grade thrombocytopenia.

Conclusion: VITT, unlike monoclonal gammopathy of thrombotic significance, appears to be a monoclonal gammopathy of unknown significance-negative state, but it needs confirmation in larger studies. VITT antibodies can be composed of lambda or kappa light chains, and some patients with VITT exhibit persistent thrombocytopenia many years after the acute event.

Anaphylaxis is an unpredictable hypersensitivity reaction characterized by acute, life-threatening cardiopulmonary dysfunction, including shock, angioedema, and bronchospasm. Although coagulopathy and disseminated intravascular coagulation (DIC) have been reported in association with anaphylaxis, they remain uncommon manifestations. Based on limited case reports, proposed mechanisms of anaphylaxis-associated coagulopathy include the release of mast cell-derived mediators such as tryptase, platelet-activating factor, and heparin, as well as activation of the contact system. DIC may result from systemic coagulopathy as a consequence of the physiologic effects of shock, including ischemic hepatitis ("shock liver"). DIC is a pathological state due to a secondary cause and is diagnosed based on laboratory findings such as prolonged prothrombin time, thrombocytopenia, and elevated D-dimer and low fibrinogen levels. Recent systematic review data suggest an approximate 50% mortality in reported cases of anaphylaxis-associated DIC; while bleeding is the predominant clinical manifestation, thrombotic complications account for most fatal outcomes. This review examines the available clinical and mechanistic evidence for anaphylaxis-associated coagulopathy, explores diagnostic challenges, and highlights implications for patient management.

Venous thromboembolism (VTE) is a frequent disease associated with high mortality in case of pulmonary embolism and long-term complications that dramatically affect patient quality of life. Anticoagulants are the cornerstone of treatment and should be administered once VTE has been diagnosed to prevent early fatal and nonfatal recurrences. However, despite therapeutic advances, the long-term prognosis of VTE remains poor and is associated with increased bleeding risk due to the anticoagulant treatment. Studies have established that VTE is associated with the generation of a wide range of damage-associated molecular patterns, cytokines, and chemokines, promoting the recruitment of immune cells. This review summarized how these cells contribute to thrombus formation and resolution. We also discussed how the different cell types involved in VTE might interact with each other in these disease settings. We highlighted a major role of monocyte phenotypes in the different phases of VTE and how manipulating these cells might represent an interesting therapeutic strategy in addition to the anticoagulants. Finally, we discussed the critical implications these mechanisms might have in preventing or reducing the occurrence of long-term complications, including postthrombotic and postpulmonary embolism syndromes. Future directions should consider deciphering how inflammation is regulated in VTE to propose new therapeutic strategies to improve therapeutic management and patient outcomes.

The anti-Xa test is regarded as the standard assay to measure unfractionated heparin activity in a laboratory setting, but its use during arterial procedures has not been established. The objectives of this systematic review, designed as a scoping review, were to structure the existing body of evidence, identify possible research gaps, and provide guidance for future research on the applicability of anti-Xa to measure the heparin activity during arterial procedures. Literature search resulted in 55 included reports (cardiac procedures: 44 reports; noncardiac procedures: 9 reports; cardiac and noncardiac procedures: 2 reports). During arterial procedures, anti-Xa is widely used as reference laboratory test to validate heparin point-of-care assays, compare different heparinization strategies and measure residual heparin activity at the end of the procedure or after heparin reversal using protamine. There is considerable heterogeneity among included reports, which hampers the ability to draw firm conclusions. The available literature is insufficient to define optimal periprocedural heparin activity measured by anti-Xa. Currently, anti-Xa is not used as a primary heparin monitoring assay during arterial procedures. The impact of alterations in periprocedural anti-Xa activity on clinical outcomes has been rarely investigated. Anti-Xa measurements appear to be reproducible compared with point-of-care heparin activity essays but require standardization. In conclusion, anti-Xa is useful as a reference test to evaluate point-of-care heparin testing and compare heparin strategies during arterial procedures, but there is a high need for studies to investigate correlation of anti-Xa levels with clinical outcomes and to determine optimal anti-Xa levels for arterial procedures.

Background: While early outcomes after catheter-directed therapies are widely described, longer-term results are not.

Objectives: To evaluate short- and long-term all-cause and pulmonary embolism (PE)-related mortality in consecutive unselected patients with intermediate-high and high-risk PE treated with large-bore mechanical thrombectomy (LBT).

Methods: The first 100 consecutive patients with high- and intermediate-high-risk PE who underwent LBT at a single academic center were retrospectively analyzed. Baseline characteristics, procedural parameters, and periprocedural complications were collected from electronic records. Kaplan-Meier estimated survival in prespecified windows, whereas nonproportional Cox regression was used to establish mortality predictors at different time points.

Results: Five-year all-cause and PE-related mortality were 34% and 9%, respectively. High-risk patients required higher oxygen needs and intubation. Periprocedural complications and short-term mortality were also greater. The intermediate-high-risk group suffered no PE-related mortality. Across the complete cohort, European Society of Cardiology severity, presence of cardiac arrest, and active malignancy emerged as time-dependent mortality predictors within the early window period. Long-term mortality was influenced by malignancy status and oxygen requirements preceding the intervention. Within the intermediate-high-risk stratum, proposed markers of subtle hemodynamic compromise failed to predict mortality.

Conclusions: These real-world outcomes provide context to PE trials by reflecting a single-center first experience with LBT. Despite the substantially reduced survival at 5 years in both groups, intermediate-high-risk patients suffered no PE-related mortality. Long-term mortality was largely influenced by active malignancy and oxygenation needs at presentation.

Background: Platelets are generated by megakaryocytes (MKs) in the bone marrow. A key step in this process involves the extension of MK protrusions across the sinusoidal vessel barrier through tiny endothelial pores. While the MK cell body remains in the marrow stroma, proplatelets elongate in the bloodstream. Transendothelial migration and elongation impose strong deformation and stretching on the plasma membrane.

Objectives: Since MKs are known to sense and respond to mechanical cues, we investigated the contribution of stretch-activated mechanosensitive calcium channels to this process.

Results: Absence of calcium prevented proplatelet formation from MK differentiated in a 3-dimensional medium but not in a 2-dimensional liquid medium. We found that the confined 3-dimensional environment promoted selective overexpression of both transient receptor potential vanilloid (TRPV) 4 and TRPV2 stretch-activated calcium channels. Using genetic and pharmacologic approaches, we showed that TRPV4 is essential for optimal proplatelet formation, independent of substrate adhesion. Mechanistically, the absence of TRPV4 maintained abnormally high active Ras homolog family member A levels, preventing optimal proplatelet formation. The TRPV2 receptor also contributes, as blocking both TRPV4 and TRPV2 produces an additive inhibitory effect. We confirmed these findings in human platelet formation. Inhibition of both TRPV4 and TRPV2 reduces platelet production from CD34⁺-derived MKs in culture.

Conclusions: These results highlight TRPV4 and TRPV2 as key mechanosensitive channels in platelet biogenesis, presenting potential targets to enhance platelet production.