Properties of Plasma Clots in Adult Patients Following Fontan Procedure: Relation to Clot Permeability and Lysis Time—Multicenter Study

Objectives: thromboembolic complications are a major cause of morbidity and mortality following Fontan (FO) surgery. It is also well established that altered FO circulation results in systemic complications, including liver and endothelium damage. We sought to evaluate whether dysfunctions of these sources of hemostatic factors may result in changes of fibrin clot properties. Methods: a permeation coefficient (Ks) and clot lysis time (CLT) were assessed in 66 FO patients, aged 23.0 years [IQR 19.3–27.0], and 59 controls, aged 24.0 years [IQR 19.0–29.0]. Ks was determined using a pressure-driven system. CLT value was measured according to assay described by Pieters et al. Endothelium and liver-derived hemostatic factors along with liver function parameters were evaluated. The median time between FO operation and investigation was 20.5 years [IQR 16.3–22.0]. Results: FO patients had lower Ks (p = 0.005) and prolonged CLT (p < 0.001) compared to that of controls. Ks correlated with CLT (r = −0.28), FVIII (r = −0.30), FIX (r = −0.38), fibrinogen (r = −0.41), ALT (r = −0.25), AST (r = −0.26), GGTP (r = −0.27) and vWF antigen (r = −0.30), (all p < 0.05). CLT correlated with the time between FO operation and investigation (r = 0.29) and FIX (r = 0.25), (all p < 0.05). After adjustment for potential cofounders, TAFI antigen and GGTP were independent predictors of reduced Ks (OR 1.041 per 1% increase, 95% CI 1.009–1.081, p = 0.011 and OR 1.025 per 1 U/L increase, 95% CI 1.005–1.053, p = 0.033, respectively). Protein C and LDL cholesterol predicted prolonged CLT (OR 1.078 per 1% increase, 95% CI 1.027–1.153, p = 0.001 and OR 6.360 per 1 μmol/L increase, 95% CI 1.492–39.894, p = 0.011, respectively). Whereas elevated tPA was associated with lower risk of prolonged CLT (OR 0.550 per 1 ng/mL, 95% CI 0.314–0.854, p = 0.004). GGTP correlated positively with time between FO surgery and investigation (r = 0.25, p = 0.045) and patients with abnormal elevated GGTP activity (n = 28, 42.4%) had decreased Ks, compared to that of the others (5.9 × 10−9 cm2 vs. 6.8 × 10−9 cm2, p = 0.042). Conclusion: our study shows that cellular liver damage and endothelial injury were associated with prothrombotic clot phenotype reflected by Ks and CLT.

Hemostatic Factors and Its Correlation with Outcomes of COVID-19 Confirmed Patients in Ulin Regional Hospital Banjarmasin

Background: Corona Virus Disease (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) has become a Global Pandemic and has spread to more than 200 countries including Indonesia. Previous studies show that poor prognosis has a correlation with coagulopathy conditions. Objectives: To identify coagulopathy condition and its correlation with the outcomes of COVID-19 confirmed patients at Ulin Regional Hospital Banjarmasin in the period March-August 2020. Methods: A retrospective study by extracting laboratory data from medical record of 309 patients confirmed with COVID-19 at Ulin Regional Hospital Banjarmasin in the period March-August 2020. Results: This study showed that mean values of D-Dimer level in the COVID-19 cases were increased both in survivor and non survivor cases. The mean values of PT, APTT, INR and D-Dimer were higher in non survivor cases (PT 12.31 seconds; APTT 31.78 seconds; INR 1.15; D-Dimer 4.6 mg/L) than survivor case (PT 11.63 seconds; APTT 28.43 seconds; INR 1.12; D-Dimer 2.31 mg/L) while the platelet count was the opposite (288.28 in survivor cases; 281.89 in non survivor cases). The difference was statistically significant (P <0.005) in PT, APTT and D-Dimer variables between survivor and non survivor cases. However, the relationship between hemostasis factors and outcome of patient with COVID-19 was found to be very weak on the platelets, PT, APTT and INR variables (ρ = 0-0.25; P <0.005) and weak on the D-Dimer variable (ρ = 0.26-0.50; P <0.005). Conclusions: Most COVID-19 cases cause coagulopathy conditions. However, considering the risk of poor outcomes, further studies should investigate the prognostic role of hemostatic parameters in COVID-19 patients.

Sex Differences in Hemostatic Factors in Patients With Ischemic Stroke and the Relation With Migraine—A Systematic Review

Background: Women are more affected by stroke than men. This might, in part, be explained by sex differences in stroke pathophysiology. The hemostasis system is influenced by sex hormones and associated with female risk factors for stroke, such as migraine.Aim: To systematically review possible sex differences in hemostatic related factors in patients with ischemic stroke in general, and the influence of migraine on these factors in women with ischemic stroke.Results: We included 24 studies with data on sex differences of hemostatic factors in 7247 patients with ischemic stroke (mean age 57–72 years, 27–57% women) and 25 hemostatic related factors. Levels of several factors were higher in women compared with men; FVII:C (116% ± 30% vs. 104% ± 30%), FXI (0.14 UI/mL higher in women), PAI-1 (125.35 ± 49.37 vs. 96.67 ± 38.90 ng/mL), D-dimer (1.25 ± 0.31 vs. 0.95 ± 0.24 μg/mL), and aPS (18.7% vs. 12.0% positive). In contrast, protein-S (86.2% ± 23.0% vs. 104.7% ± 19.8% antigen) and P-selectin (48.9 ± 14.4 vs. 79.1 ± 66.7 pg/mL) were higher in men. Most factors were investigated in single studies, at different time points after stroke, and in different stroke subtypes. Only one small study reported data on migraine and hemostatic factors in women with ischemic stroke. No differences in fibrinogen, D-dimer, t-PA, and PAI-1 levels were found between women with and without migraine.Conclusion: Our systematic review suggests that sex differences exist in the activation of the hemostatic system in ischemic stroke. Women seem to lean more toward increased levels of procoagulant factors whereas men exhibit increased levels of coagulation inhibitors. To obtain better insight in sex-related differences in hemostatic factors, additional studies are needed to confirm these findings with special attention for different stroke phases, stroke subtypes, and not in the least women specific risk factors, such as migraine.

Von Willebrand Factor Expression in Endothelium in a Co-Culturing System of Acute Lymphoblastic Leukemia

Background: Acute lymphoblastic leukemia (ALL) is the most common cause of cancer and death from cancer among children, with an incidence of 1 in 1,750 children. A previous Dutch cohort study highlighted that 7.6% of children with ALL also developed venous thromboembolism (VTE; n=55/778). VTE increases the risk of morbidity and mortality in cancer patients. However, the mechanisms of hemostatic abnormality in ALL is not well understood. Von Willebrand factor (vWF) is involved in thrombosis and is a well-established marker for endothelial dysfunction. High vWF levels and qualitative abnormality of the protein have been documented in patients with ALL and may contribute to the prothrombotic state observed in these patients. Objective: To determine whether co-culturing cancerous ALL cells with healthy human umbilical vein endothelial cells (HUVECs) may increase vWF secretion from endothelial cells. Methods: HUVECs were obtained from Lonza Bioscience Solutions (Basel, Switzerland) and leukemic B-lymphoblasts (ALL cells) derived from bone marrow were obtained from ATCC (Manassas, Virginia, USA). Passages 3 to 5 were used in this study and cell lines were grown as per manufacturer's instruction. A confluent monolayer of HUVECs was established before the co-culturing experiments. Firstly, ALL cells and HUVECs were grown together (co-cultured) at a 1:1 ratio. Then, the conditioned media and cell lysates were harvested at three different time points and the vWF levels were quantitated by a vWF-ELISA. To further evaluate the effect of leukemic cells on the endothelium, ALL cells were also co-cultured at a 10:1 ratio to endothelial cells. All experiments were conducted in biological triplicates. Results: Cells were monitored throughout the study period and no morphological changes to the endothelial cells were observed. An accumulation of vWF was recorded over time in both the conditioned media and cell lysates. The differences in vWF levels between the co-culture group and HUVEC-only group at three time points (24, 48 and 72 hours) were not statistically significant. In addition, 10-fold differences in ratio between leukemic and endothelial cells did not have a meaningful effect on vWF levels. Discussions: In an in vitro co-culture system, ALL cells do not appear to induce an increase vWF secretion in HUVECs. Contrary to prior evidence, this study suggests that increased vWF secretion from endothelial cells may not be a contributor to the prothrombotic state observed in ALL. The circulating lymphoblasts may have a more pronounced effect on other endothelial layers where vWFs are highly expressed such as the pulmonary endothelium. On the other hand, peripheral blood pediatric leukemic lymphoblasts have been demonstrated to produce hemostatic factors, which may contribute the hemostatic imbalance in the progression of disease. In addition, the pathogenesis of thrombosis in ALL is likely to be therapeutically related since thrombosis rarely occurs at presentation. Alternative mechanisms, such as ADAMST13 and hemostatic factors' level and function or the use of chemotherapeutic agents, ought to be explored. Figure 1 Figure 1. Disclosures Matino: Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Spark: Other: research grants; Octopharma: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Sobi: Membership on an entity's Board of Directors or advisory committees, Other: personal fees.

Hemostatic factors in the pathogenesis of neuroinflammation in multiple sclerosis

Background: A growing body of evidence has shed light on the role of the hemostatic pathway and its components in the pathogenesis of multiple sclerosis (MS), particularly in enhancing and sustaining neuroinflammation. Objective: To review the clinical, experimental, and neuroimaging evidence supporting the role of different components of the hemostatic pathway in the pathogenesis of neuroinflammation in MS and discuss their translational potential as disease biomarkers and therapeutic targets. Methods: A literature search for most relevant articles from 1956 to 2020 was conducted in PubMed and Scopus. Results: Hemostasis components appear to be involved in different key events of neuroinflammation in MS including mononuclear cell diapedesis, microglia activation, and neuronal damage. Conclusion: The findings on the interplay between hemostatic and thrombotic molecular pathways in the pathogenesis of neuroinflammation in MS open new opportunities for developing novel biomarkers for disease monitoring and prognosis, as well as novel therapeutic targets.

Plasma Levels of Leptin and Risk of Future Incident Venous Thromboembolism

Background Circulating levels of leptin, an adipocyte-derived hormone, are frequently elevated in obesity. Leptin has been reported to upregulate prothrombotic hemostatic factors in vitro and could potentially mediate venous thromboembolism (VTE) risk in obesity. However, whether leptin is associated with VTE remains uncertain. Objective This article investigates the association between plasma leptin and risk of incident VTE, and the potential of leptin to mediate VTE risk in obesity. Methods A population-based nested case–control study with 416 VTE cases and 848 age- and sex-matched controls was derived from the Tromsø Study. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE across leptin quartiles. Analyses were performed separately in men and women using sex-specific quartile cut-offs determined in controls. Results In the age-adjusted model, the VTE risk increased across leptin quartiles, particularly in men. Compared with the lowest quartile, the ORs for VTE in the highest quartile were 1.70 (95% CI 1.04–2.79) in men and 1.36 (95% CI 0.85–2.17) in women. However, with additional adjustment for body mass index (BMI), risk estimates were markedly attenuated in men (OR 1.03, 95% CI 0.55–1.93) and women (OR 0.82, 95% CI 0.45–1.48). The ORs for VTE were increased in obese men and women (BMI ≥ 30 kg/m2) and were only marginally affected after adjustment for leptin. Conclusion Our results indicate that the apparent association between plasma leptin levels and VTE risk is confounded by BMI and that leptin is not a relevant mediator for VTE risk in obesity.