Journal of Thrombosis and Haemostasis最新文献

Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare blood disorder that leads to microvessel clots and brain injury. While modern treatments have improved survival during initial disease onset, long-term complications such as cognitive decline are now a prominent concern for reasons that are not yet fully understood.

Objectives: This prospective study aimed to investigate the effects of iTTP on the brain in the postremission phase to address a critical gap in our understanding of iTTP-brain pathophysiology.

Methods: We followed 22 iTTP survivors over 1 year. Participants underwent advanced brain magnetic resonance imaging (MRI) to assess white matter integrity, computed tomography perfusion to evaluate cerebral blood perfusion and blood-brain barrier (BBB) integrity, and cognitive testing.

Results: At baseline, most patients (82%) showed brain abnormalities on MRI, and all presented with compromised BBB integrity (mean permeability surface product, 0.43 ± 0.13 mL/min/100 g). After 12 months, BBB function improved (0.37 ± 0.10 mL/min/100 g; P = .04) but remained compromised. Over this period, MRI revealed progressive brain volume loss, and diffusion imaging showed reduced white matter integrity in tracts related to memory and verbal processing. Cognitive scores remained lower than those of controls, especially in the memory and verbal domains.

Conclusion: These findings suggest that brain injury and cognitive dysfunction in patients with iTTP are not limited to the acute phase but continue to progress after remission. This progression may be underpinned by persistent vascular injury, including BBB dysfunction and reduced perfusion. Long-term brain monitoring and early neuroprotective strategies may be needed to improve the quality of life of iTTP survivors.

Background: Rapid and accurate coagulation analysis is essential for managing critical care and surgical patients, patients with coagulation disorders, and patients with cardiovascular disease on anticoagulant therapy. Traditional assays often require large sample volumes, posing iatrogenic risks in vulnerable populations, including pediatric and elderly patients. Integrated quasistatic acoustic tweezing thromboelastometry (i-QATT) offers a comprehensive, noncontact assessment of coagulation using a 4- to 6-μL drop of blood that minimizes diagnostic errors associated with sample-container surface interactions.

Objectives: This study aims to assess the preliminary clinical utility of the i-QATT technique.

Methods: Using blood samples from healthy volunteers and liver transplant patients, as well as control plasmas, we established the reference ranges for i-QATT coagulation parameters and validated them across several abnormal conditions, including single-factor deficiencies, abnormal fibrinogen levels, unfractionated heparin anticoagulation, and coagulopathy.

Results: i-QATT identified coagulation abnormalities within 3 to 8 minutes. Its parameters showed strong correlations with gold-standard assay data, for example, activated partial thromboplastin time (r ≥ 0.81), international normalized ratio (r ≥ 0.74), thromboelastography (TEG) citrated kaolin channel parameters (R, K, α, and maximum width of TEG tracing [MA]; r ≥ 0.65), citrated rapid TEG (MA; r = 0.64), and TEG citrated functional fibrinogen (MA; r ≥ 0.64). i-QATT data demonstrated a near-linear response to unfractionated heparin concentrations spanning the prophylactic and therapeutic ranges (0-1 IU/mL; R² = 0.98), and the anticoagulation reversal by heparinase was reliably detected. i-QATT accurately assessed the functional level of fibrinogen and platelet activity in normal and abnormal blood samples.

Conclusions: This study positions i-QATT as a highly sensitive, rapid, and ultra-low-volume alternative to conventional coagulation assays, with strong potential to transform point-of-care diagnostics across a wide range of clinical settings.

Background: Sphingosine-1-phosphate (S1P) is a bioactive signaling sphingolipid secreted by platelets during activation. Platelets express distinct S1P receptors on their surface, and a comprehensive understanding of their effects is yet to be achieved.

Objectives: Here, we describe the regulation of fibrinogen binding in activated platelets via S1P receptor type 4 (S1PR₄).

Methods: Thrombus formation and platelet function on an S1PR4-deficient (S1pr₄^-/-) background were assessed in an ex vivo flow chamber setting and by rotational thromboelastometry. In vivo coagulation was studied in a murine model of polymicrobial abdominal sepsis. Fibrinogen binding was assessed by flow cytometry in the murine and human systems.

Results: In the colon ascendens stent peritonitis model, an increased incidence of disseminated intravascular coagulation was observed in S1pr₄^-/- mice. Murine platelets from S1pr₄^-/- mice showed excessive fibrinogen binding and disorganized thrombus formation compared with wild-type platelets. Rotational thromboelastometry confirmed these results, showing a reduced clotting time and an increased clot size in S1pr₄^-/- mice. Flow cytometry analysis of glycoprotein IIb/IIIa expression indicated an increased low-to-high-affinity switch for increased fibrinogen binding in S1pr₄^-/- platelets. Analysis of human platelets using a specific antagonist showed that S1PR₄ signaling impacted fibrinogen binding.

Conclusion: These findings strongly suggest that S1P signaling via S1PR₄ acts as a negative regulator of fibrinogen binding in activated platelets.

Background: Emerging evidence suggests that platelet activation and aggregation are common factors in both metabolic syndrome (MetS) and severe COVID-19, emphasizing the need to investigate their biological connection.

Objectives: We hypothesized that enhanced platelet aggregation mediates the association between MetS and severe COVID-19. This study aimed to determine whether platelet aggregation serves as a mechanistic link between MetS and COVID-19 severity and to develop an image-based biomarker capable of predicting severe disease.

Methods: We conducted massive image-based profiling of circulating platelets in a retrospective cohort of 327 COVID-19 patients (63.9% male; median age, 59.0 years) with metabolic records. Morphologic features of platelets, including shape, density and radial distribution, and texture, were extracted. A machine learning model was developed to construct the COVID-19 Platelet Aggregate Formation Index (CoPAFI), which could quantitatively reflect platelet aggregation and predict severe COVID-19. Mediation analysis was then performed to quantify the extent to which platelet aggregation mediated the association between components of MetS and severe COVID-19.

Results: The CoPAFI predicted severe COVID-19 with an area under the curve of 0.82 and an odds ratio of 3.76 (95% CI, 2.63-5.38). The CoPAFI was strongly associated with a hypercoagulable state and served as a reliable indicator for assessing the risk of severe COVID-19. In patients with components of MetS, platelet aggregation, as measured by the CoPAFI, accounted for approximately 25% of the increased severity of COVID-19.

Conclusion: Enhanced platelet aggregation partially mediates the impact of components of MetS on COVID-19 severity, accounting for approximately 25% of the association, emphasizing the need for integrated metabolic and coagulation management in COVID-19 treatment.

Patients with decompensated cirrhosis commonly have indications for anticoagulation, including stroke prevention in atrial fibrillation and the prevention and treatment of venous thromboembolism, particularly portal vein thrombosis. While the rates of anticoagulation in those with indications for therapy have improved over time, the concern for bleeding due to altered hepatic elimination of anticoagulants and exclusion of patients with cirrhosis from pivotal randomized trials of direct oral anticoagulants and warfarin continue to create challenges in defining best practices for anticoagulation in patients with cirrhosis, especially in decompensated disease. In this review, we present 3 commonly encountered clinical scenarios in patients with decompensated cirrhosis requiring consideration of anticoagulation: a patient with atrial fibrillation and elevated baseline international normalized ratio, a patient with atrial fibrillation and recurrent bleeding while on anticoagulation, and a patient with portal vein thrombosis and thrombocytopenia. For each scenario, we discuss the available literature and propose a management approach.

Background: Fibrinogen is a critical coagulation factor that plays an essential role in thrombosis and is elevated in individuals with chronic inflammation.

Objectives: Here, we used fibrinogen as a representative quantitative measure of procoagulant risk and evaluated metabolites associated with fibrinogen levels using nontargeted plasma metabolomics profiling (Broad and Metabolon platforms).

Methods: Our analysis included 10 533 individuals across 6 United States-based cohorts representing diverse population groups. The cross-sectional relationship between each of the 789 metabolites tested and plasma fibrinogen concentration was assessed after adjustment for relevant covariates, including age, cohort-reported sex, body mass index, and circulating lipoprotein levels.

Results: Meta-analysis of per-cohort results revealed 270 metabolites significantly associated with fibrinogen levels (false discovery rate-adjusted P value < .05). Lipid species, such as glycerophospholipids, sphingolipids, and fatty acyls, were among the most significantly associated metabolites; some of these may capture effects of inflammation, as supported by sensitivity analyses adjusted for C-reactive protein. Significant associations between fibrinogen levels and serotonin, thyroxine, and sex hormone derivatives may capture endogenous influences on fibrinogen levels. Exogenous compounds and microbial cometabolites were significantly associated with fibrinogen, also implicating lifestyle and microbiome risk factors. Only a portion of fibrinogen-associated metabolites (30%) has been associated with cardiovascular disease outcomes in a prior study, suggesting that the associations discovered here may provide insights into vascular biology that case-control studies may not yet be powered to detect.

Conclusion: These findings contribute to the growing list of metabolite biomarkers that may influence coagulation and inflammation pathways and, thereby, vascular risk.

Background: Thrombotic and bleeding complications in myelodysplastic syndromes (MDS) can affect therapy, but how they impact overall survival remains unclear.

Objectives: Evaluating the impact of venous thromboembolism (VTE) and bleeding on survival in older MDS patients.

Methods: Incident MDS cases were collected from the Surveillance, Epidemiology, and End Results Medicare database (2007-2017) and followed from diagnosis until death. Baseline demographics, comorbidities, and the Surveillance, Epidemiology, and End Results Medicare MDS Risk Score were assessed. VTE and bleeding events were identified using validated algorithms and modeled as time-varying covariates. Cox regression, adjusted for age, sex (male vs female), race, National Cancer Institute Comorbidity Index, and Surveillance, Epidemiology, and End Results Medicare MDS Risk Score, estimated the hazard ratio (HR) for death.

Results: Among 13 995 MDS patients (median age, 82 years; 46% female), 1114 VTE and 1905 bleeding events occurred. VTE was associated with increased mortality within <3 months (HR, 3.21; 95% CI, 2.84-3.62) and 3 to 6 months (HR, 1.51; 95% CI, 1.23-1.85), but not for 6 to 12 months (HR, 1.18; 95% CI, 0.98, 1.42) or >12 months (HR, 1.00; 95% CI, 1.91, 1.11). Bleeding was associated with mortality for all postevent time periods assessed: <3 months (HR, 4.25; 95% CI, 3.89, 4.65), 3 to 6 months (HR, 2.11; 95% CI, 1.82, 2.45), 6 to 12 months (HR, 1.60; 95% CI, 1.39, 1.85), and >12 months (HR, 1.43; 95% CI, 1.31, 1.57). Case-crossover analysis confirmed these associations for bleeding but revealed potential unmeasured confounders for VTE.

Conclusion: Bleeding was associated with subsequent mortality in MDS patients. For VTE, this risk seems to be affected by potential unmeasured confounders. These findings underscore the need for strategies to mitigate bleeding risk in this population.

Background: Pregnant women with von Willebrand disease (VWD) receive prophylactic von Willebrand factor (VWF) concentrate based on third trimester VWF/factor (F)VIII levels to reduce the risk of severe postpartum hemorrhage (PPH, ≥ 1000 mL). Due to high severe PPH rates, Dutch guidelines were revised in 2018. Consensus was reached to increase the third trimester threshold for prophylaxis from < 50 to < 80 IU/dL, and peak target levels during childbirth from ≥ 100 to ≥ 150 IU/dL.

Objectives: To assess the severe PPH incidence after guideline revision.

Methods: Pregnant Dutch women with VWD were prospectively enrolled (2018-2024). VWF/FVIII activity levels and hematologic and obstetric outcomes were compared with those of a historical cohort (2012-2017). Statistics included descriptives and logistic regression to correct for confounders.

Results: Severe PPH occurred in 18.1% (n = 29/160) without thrombosis or exsanguinations. Prophylaxis in those with third trimester levels of < 80 IU/dL led to PPH rates similar to those with spontaneous a rise > 80 IU/dL. Compared with the historical cohort (prophylaxis cutoff, < 50 IU/dL), severe PPH incidence did not decrease (n = 20/151 vs n = 29/160; odds ratio [OR], 1.45; 95% CI, 0.78-2.69). Moreover, in the third trimester 50- to 80-IU/dL subgroup and third trimester < 50-IU/dL subgroup, the risk for severe PPH was similar (n = 31/160 vs n = 23/151; OR, 0.86; 95% CI, 0.23-3.28; and n = 64/160 vs n = 48/151; OR, 2.59; 95% CI, 0.78-8.60, respectively), despite increased peak target levels of 150 IU/dL.

Conclusion: Increasing the third trimester VWF and FVIII cutoff to < 80 IU/dL and aiming for ≥ 150 IU/dL at delivery did not decrease severe PPH. More research is needed on optimal peripartum hemostatic prophylaxis in VWD.