Thrombosis Journal最新文献

Background: Previous studies using genetically modified mouse models and inhibitors have shown that protein disulfide isomerase (PDI) family plays a significant role in arterial thrombosis. However, their role in venous thrombosis remains unknown. In this study, using gene-modified mouse models, we determined whether PDI family members contribute to venous thrombosis.

Methods: Mice deficient of the PDI family members, including PDI, PDIp, ERp57, PDIr, ERp5, ERp27, ERp29, TMX4, ERdj5, and ERp18, were generated. The venous thrombosis phenotype of these deficient strains was evaluated using an inferior vena cava (IVC) stenosis model. Moreover, the recombinant human ERp18 (rhERp18) protein was generated and its reductase activity was assessed using a Di-E-GSSG method. The effect of ERp18 in venous thrombosis was tested in the IVC stenosis model. The levels of von Willebrand factor (vWF) at the site of venous thrombi were measured.

Results: The mice deficient in PDI, PDIp, ERp57, PDIr, ERp5, ERp27, ERp29, TMX4, and ERdj5 had no effects on venous thrombosis in the IVC stenosis model. However, the mice lacking ERp18 developed significantly less venous thrombosis compared with the WT mice. ERp18 contains one CGAC active motif. When WT or ERp18-KO mice received injection of rhERp18-WT or inactive rhERp18-mutant (Mut) protein whose CGAC was mutated to SGAS, rhERp18-Mut protein inhibited venous thrombosis in the IVC stenosis model, suggesting that the role of ERp18 is dependent on its enzymatic activity. As determined by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence staining, the levels of vWF in the plasma at the site of venous thrombus in ERp18-KO mice were significantly lower than those in WT mice.

Conclusion: ERp18 enhances the development of venous thrombosis, and its function and its enzymatic activity and regulation of the vWF release are involved.

Objectives: Ischaemic stroke (IS) has become a major health problem globally as it is one of the leading causes of long-term disability and death. This study aimed to evaluate the association between red cell distribution width (RDW) to lymphocyte (LYM) ratio (RLR) and 30-day mortality risk in patients with IS.

Methods: The present study employed a retrospectively cohort study design with the adult data extracted from the Medical Information Mart for Intensive Care (MIMIC-III, MIMIC-IV) databases between 2001 and 2019. The RLR was measured using RDW and LYM. Confounders were adjusted in Cox proportional hazards model. The outcome was 30-day mortality. Univariable and multivariable Cox proportional hazards models were establised. A further analysis was conducted on the basis of subgroup stratification by heart failure (HF) (yes or no), atrial fibrillation or flutter (yes or no), hypertension (yes or no), dyslipidemia (yes or no), sepsis (yes or no), and age (≥ 65 years and < 65 years).

Results: In this study, 1,127 adult patients with IS were finally identified. Among them,818 patients survived (the survival group) and 309 patients died (the death group). The mean age was older in individuals from the death group than those from the survival group (70.19 years vs. 64.56 years). The elevated levels of RLR were linked to an increased risk of mortality within 30 days in patients with IS, with an HR of 1.70 (95% CI: 1.34-2.17). Subgroup analyses showed that high RLR levels was a significant risk factor for mortality at 30 days particularly in IS patients aged ≥ 65 years, HF, no atrial fibrillation or flutter, no hypertension, no dyslipidemia, and no sepsis.

Conclusion: Our study shows that high levels of RLR were associated with an increased risk of 30-day mortality in patients with IS, providing additional prognostic information for the treatment and supportive care of these patients.

Background: Lupus anticoagulant (LA) is an in vitro phenomenon with prolongation of a phospholipid-dependent coagulation test which is not due to an inhibitor specific to a coagulation factor. Occasionally, addition of normal pooled plasma to patient plasma with lupus anticoagulant potentiates the inhibitory effect of lupus anticoagulant in the mixture, resulting in a paradoxical prolongation instead of shortening of clotting time. The phenomenon has been termed the "lupus cofactor effect". Lupus anticoagulant are known to be associated with lymphoma and immunoglobulin M (IgM) paraproteinaemia. Cases of lymphoplasmacytic lymphoma with concomitant IgM paraproteinaemia and lupus anticoagulant demonstrating lupus cofactor phenomenon on activated partial thromboplastin time (APTT) assay has been reported previously. However, to our best knowledge, there were no reported cases of low grade B-cell lymphoma with positive LA results and lupus cofactor effect demonstrated on dilute Russell's viper venom time (DRVVT) and/or silica clotting time (SCT) assays in the literature.

Case presentation: We report two cases of low grade B-cell lymphoma associated with monoclonal IgM paraprotein, high levels of anti-cardiolipin IgM antibody and presence of lupus anticoagulant with lupus cofactor phenomenon on DRVVT and/or SCT assay.

Conclusions: Our cases demonstrate a possible novel association between low grade B-cell lymphoma, IgM paraproteinaemia, high levels of anti-cardiolipin IgM antibody and the presence of lupus cofactor effect on DRVVT and SCT assays. The DRVVT assay in the first patient and SCT assay in second patient were falsely negative in the neat sample or less diluted sample, and the lupus anticoagulant activities were only revealed on dilution of samples with normal pooled plasma. This highlights the potential importance of dilution of samples with normal pooled plasma while evaluating the LA status of low grade B-cell lymphoma patients with a markedly prolonged APTT and/or prolonged PT by DRVVT and SCT assays, especially if there is concomitant IgM paraproteinaemia and a high level of anti-cardiolipin IgM antibody.

Background: Antithrombin (AT) is a serine protease inhibitor which exerts its anticoagulant effect through binding to serine residues in the active centers of procoagulant serine proteases. Its deficiency is associated with increased risk of venous thrombosis. We aim to investigate the pathogenic mechanism of two natural mutants (W221C and M284R) in inherited AT deficiency.

Methods: We analyzed 9 unrelated patients with inherited AT deficiency by extracting peripheral blood DNA and sequencing the SERPINC1 gene after amplification by polymerase chain reaction. Enzyme-linked immunosorbent assay and heparin affinity chromatography were used to assess AT secretion and purification efficiency. The mutant AT models were evaluated via computational simulations.

Results: Among the 9 patients with inherited AT deficiency, 8 patients had type I AT deficiency, and one patient had type II AT deficiency with subtype of reactive site mutation. Seven of them experienced venous thrombotic events and all patients were found genetic mutations including missense (n = 6), deletion (n = 2) and insertion (n = 1). Two point mutations, W221C and M284R, were identified and were hypothesized to affect AT by destabilizing the central β-sheet. Based on immunoassays and heparin purification, the W221C mutant may impair AT secretion, whereas M284R mutant decreased the total AT production (696.8 ± 151.6 ng/ml versus 3833.72 ± 315.4 ng/ml, p = 0.029). Both mutants delayed the peak of AT release in heparin affinity chromatography.

Conclusions: Our study demonstrates that two mutations in SERPINC1 gene altered the production and structure of AT by in vitro protein expression and functional studies, including protein secretion and production. These findings enhance our understanding of the genetic basis of AT deficiency and its possible clinical implications.

Background: The gut microbiota of venous thromboembolism (VTE) patients exhibited significant alterations. However, the causal relationship between gut microbiota and VTE has not been fully understood. This study aimed to assess the causal relationship between gut microbiota and the risk of VTE using a two-sample Mendelian Randomization (MR) study.

Methods: The gut microbiota and VTE genetic data were collected from the MiBioGen consortium and the UK biobank, respectively. The potential causal relationship between gut microbiota and VTE was investigated using a two-sample MR analysis, including inverse variance weighted (IVW), weighted median, MR-Egger, simple mode, and weighted mode methods. Cochran's Q-test, MR-PRESSO, and MR-Egger regression intercept analysis were utilized to perform sensitivity analysis.

Results: At the genus level, the results of MR analysis found that Coprococcus1 (OR: 1.0029, 95% CI: 1.0005-1.0054, p = 0.0202) was suggestively linked with an increased risk of VTE, while Slackia (odds ratio (OR): 0.9977, 95% confidence interval (CI): 0.9957-0.9998, p = 0.0298), Butyricicoccus (OR: 0.9971, 95% CI: 0.9945-0.9997, p = 0.0309), Eubacterium coprostanoligenes group (OR: 0.9972, 95% CI: 0.9946-0.9999, p = 0.0445), and Bacteroides (OR: 0.9964, 95% CI: 0.9932-0.9995, p = 0.0234) were suggestively associated with a reduced risk of VTE. No heterogeneity and horizontal pleiotropy was detected.

Conclusion: This study found that there were potential causal relationships between five gut microbiota and VTE. Our findings may provide new insights into the mechanisms of VTE.

Background: Many studies have indicated that hyperuricemia is positively correlated with secondary deep venous thrombosis (DVT); however, the risk factors for idiopathic DVT based on gender differences, such as serum uric acid (SUA) and hyperuricemia, have not been fully examined.

Objectives: To investigate the association between hyperuricemia and the occurrence of idiopathic lower extremity DVT based on gender differences.

Methods: This was a retrospective analysis of 4299 patients who were hospitalized at the Affiliated Hospital of Qingdao University from January 2012 to October 2021 and who underwent ultrasound of the lower limbs. A total of 930 patients were diagnosed in the DVT group, and 3369 patients were diagnosed in the control group without DVT. The baseline SUA and other important baseline data were compared between the two groups, and sex was stratified. Multivariate logistic regression analysis models adjusted for potential confounders were used to investigate the associations between hyperuricemia and idiopathic lower extremity DVT.

Results: The SUA level in patients with idiopathic DVT was significantly greater than that in patients without DVT (total: 6.00 ± 1.75 vs. 5.40 ± 1.56 mg/dL, respectively; male: 6.42 ± 1.60 vs. 5.87 ± 1.57 mg/dL, respectively; female: 5.58 ± 1.79 vs. 4.72 ± 1.27 mg/dL, respectively; all P < 0.001). The proportion of patients with hyperuricemia in the idiopathic DVT group was significantly greater than that in the control group (total: 29.03% vs. 16.10%, respectively; male: 35.26% vs. 23.19%, respectively; female: 22.73% vs. 5.74%, respectively; all P < 0.001). The incidence of DVT in patients with hyperuricemia was significantly greater than patients with normouricemia (33.29% vs. 18.92%, respectively), and this difference was particularly prominent among women (58.01%). According to the univariate model, hyperuricemia was significantly associated with a grester risk of idiopathic DVT. After adjustment for potential confounders, this association remained significant. The risk of idiopathic lower extremity DVT in patients with hyperuricemia was 2.643-fold greater than that in patients with normouricemia (Model 3: OR: 2.643, 95% CI: 2.165-3.228). After stratification by sex, the risk of idiopathic lower extremity DVT in female patients with hyperuricemia was 7.482-fold greater than that in patients with normouricemia (Model 3, OR: 7.482, 95% CI: 4.999-11.199).

Conclusion: In the Chinese population, hyperuricemia is closely related to an increased risk of idiopathic lower extremity DVT, especially in female patients.

This critique evaluates a retrospective observational study on the impact of extracorporeal membrane oxygenation (ECMO) treatments on acquired von Willebrand syndrome (AVWS) in patients with out-of-hospital cardiac arrest (OHCA). The study is praised for its detailed observational methodology, robust statistical analyses, and comprehensive overview of patient outcomes. These strengths enhance the applicability of the results to real-world clinical practice. However, the study's retrospective design poses inherent risks of bias and confounding factors, which the authors acknowledge but do not extensively address. The absence of a control group of OHCA patients who did not receive ECMO is a significant limitation, as it weakens the ability to isolate the impact of ECMO on AVWS development. Additionally, a more in-depth exploration of the mechanisms by which ECMO contributes to AVWS is needed. Despite these limitations, the study contributes valuable insights into ECMO-related complications and underscores the necessity for vigilant management strategies to mitigate AVWS risks in this high-risk population. The critique concludes by calling for future prospective studies and the development of preventative protocols to improve patient outcomes in ECMO-treated OHCA patients.

Background: The relationship between venous thromboembolism and both insulin resistance and metabolic syndrome is still a matter of debate. The objective of this work was to investigate the possible association between cerebral venous sinus thrombosis (CVST) and both insulin resistance and metabolic syndrome. We aimed also to assess micro-RNA-122 serum levels in patients with CVST in comparison to controls.

Methods: This case-control study was conducted on patients having a clinical and neuroimaging diagnosis of acute CVST (within 1 week from the onset). Patients with inconclusive brain imaging, those with a history of malignancy, diabetic patients, and patients on drugs known to affect the insulin sensitivity or lipid profile were excluded from the study. Metabolic syndrome in the included cases and controls was evaluated by measuring waist circumference and blood pressure in addition to assessment of Triglycerides, HDL, and fasting blood sugar. The state of insulin resistance was established if the Homeostasis model assessment-insulin resistance (HOMA-IR) value > 2.5. Serum micro-RNA-122 serum level was measured for both patients and controls.

Results: In the present study, 36 cases diagnosed as having CVST and 34 age & sex matched controls were included. There were statistically significant differences between patients with CVST and controls regarding BMI, waist circumference, TG, fasting glucose, fasting insulin & HOMA- IR (P-value = 0.002, 0.001, 0.004, 0.003, 0.021, 0.008 respectively). There was no statistically significant difference between patients with CVST and controls regarding micro-RNA-122 serum level (P-value = 0.376), whereas CVST patients with insulin resistance had a significantly higher micro-RNA-122 serum level in comparison to those without (P-value < 0.001). Patients with CVST had a significantly higher frequency of both metabolic syndrome and insulin resistance in comparison to controls (P-value = 0.008, 0.002 respectively).

Conclusion: There is a significant association between CVST and both insulin resistance and metabolic syndrome.

The high incidence of deep vein thrombosis (DVT) in evacuees has been recognized since the 2004 Niigata-Chuetsu Earthquake in Japan. We hypothesized that the number and location of communicating branches of the soleal veins might influence thrombus development and that the median septum of the soleus muscle influences the venous network of the soleal veins. This study aimed to investigate how the network of soleal veins varies with the shape and thickness of the median septum and to elucidate factors predisposing soleal veins to DVT. The lower legs of 30 sides from 15 formalin-preserved cadavers were observed. The central soleal vein, the predilection site for thrombus among the six veins within the soleus muscle, divides into three branches: medial, central, and lateral. The soleus muscle has a unique architecture with converging muscle fibers on the anterior surface of the median septum. We examined the positional relationship between the central soleal vein and the median septum. The median septum morphology was either straight (14 sides, 46.7%) or curved (16 sides, 53.3%). The number of communicating branches was significantly higher in the curved type. The curved type also had a communicating vein penetrating the median septum, with the central branch passing deeper than in the straight type. The median septum could restrict the enlargement of communicating branches, causing thrombosis through disturbance of venous blood flow. Future research will clarify the median septum's influence on the soleal vein, potentially identifying soleus muscles at high risk of developing DVT.