Patients hospitalized for COVID-19 are at high risk of thrombotic complications and organ failure, and often exhibit severe inflammation, which may contribute to hypercoagulability.
Patients with stage 5 chronic kidney disease (CKD5D) have a higher risk of developing neurocognitive deficits. Stroke, cervical carotid artery disease (CCAD), and intracranial atherosclerotic disease (ICAD) are causes of such deficits in CKD5D. Chronic inflammation from renal failure elevates risk for these diseases through oxidative stress and vascular dysfunction. The adverse impact on the carotid and intracranial vasculatures contributes to the multifactorial pathophysiology of stroke. Eleven plasma biomarker levels in patients with CKD5D (n = 97) and healthy controls (n = 17-50) were measured using sandwich enzyme-linked immunosorbent assay (ELISA) method. Of the 97 patients with CKD5D, 24 had CCAD, 19 had ICAD, and 23 had acute stroke. Elevations in NACHT, LRR, and PYD domains-containing protein 3 (NALP3) levels in patients with CKD5D (+)CCAD (1.80 ± 0.11 ng/mL) compared to patients with (−)CCAD (1.55 ± 0.08 ng/mL) were statistically significant ( P = .0299). Differences in D-dimer levels were also found to be statistically significant ( P = .0258) between CKD5D (+)stroke (1.83 ± 0.42 μg/mL) and (−)stroke (0.89 ± 0.13 μg/mL) groups. The ages of the (+) neurovascular disease groups were found to be significantly elevated compared to the (−) neurovascular disease groups ( P = .0002 carotid AD; P < .0001 ICAD; P = .0157 stroke). D-dimer levels were positively correlated with age in CKD5D ( P = .0375). With the possible exception of NALP3 for CCAD, profiling levels of specific biomarkers for risk stratification of neurovascular diseases in the CKD5D population warrants further investigation.
Background Angiopoietin‐2 (Ang‐2) is a 70 kDa glycoprotein which plays multiple roles in angiogenesis, inflammation, and vascular development. Ang‐2 is upregulated in vascular stress, and circulates at high levels in certain pathologic conditions such as sepsis. Ang‐2 upregulation may be related to the severity of sepsis associated coagulopathy (SAC), and therefore it may have a predictive role in the clinical outcome of this syndrome. Aim The aim of this study is to measure Ang‐2 levels in a defined cohort of patients with sepsis and suspected disseminated intravascular coagulation (DIC), to compare the circulating levels of this biomarker to controls, and to demonstrate its predictive value for the clinical outcome and severity of SAC. Methods Plasma samples were collected from 102 patients with sepsis and suspected DIC at ICU admission and immediately frozen at −80°C for batch analysis. Control plasma represented 50 normal samples which were commercially obtained from George King (Orland Park, KS). Ang‐2 levels were quantified using a sandwich ELISA method (R&D Systems, Minneapolis, MN, USA). This method employs a monoclonal antibody specific for human Ang‐2. DIC scores in all 102 patients were evaluated using the ISTH scoring algorithm. Results Table 1 shows that in comparison to normal levels, the samples collected from all patients showed significantly higher levels of Ang‐2 for all groups (p=0.0005). Table 2 shows that the Ang‐2 levels were also significantly different between the survivors and non‐survivors for 28‐day mortality outcome by the Mann‐Whitney test (p=0.001). Conclusion This study demonstrates that Ang‐2 levels are significantly upregulated in SAC, and this biomarker can be used to risk stratify the severity of this disease. Ang‐2 level can also be used to differentiate non‐overt and overt DIC. Furthermore, Ang‐2 level at the time of initial diagnosis provides a predictive biomarker for mortality outcome. Ang‐2 levels in patients with Sepsis and Suspected DIC Broken Down by ISTH DIC Score Category Normals + Sepsis−DIC + Sepsis + Non‐Overt DIC + Sepsis + Overt DIC ISTH DIC Score N/A 0–2 3–4 ≥ 5 n 50 20 57 24 Ang‐2 Mean ± SEM (ng/mL) 1.87 ± 0.15 8.34 ± 2.50 11.53 ± 1.40 29.44 ± 6.27 Ang‐2 Std. Deviation (ng/mL) 1.07 11.19 10.54 30.73 Significant Difference in Ang‐2 Level Between Survivors and Non‐Survivors Survivors Non‐Survivors n 86 15 Ang‐2 Mean ± SEM (ng/mL) 12.54 ± 1.54 30.17 ± 8.62 Ang‐2 Std. Deviation (ng/mL) 14.28 33.39
The role of the endothelium in sepsis-associated disseminated intravascular coagulation (DIC) is multifaceted and may contribute substantially to disease severity and outcome. The purpose of this study was to quantify measures of endothelial function, including markers of activation (endocan, Angiopoietin-2 [Ang-2], and von Willebrand Factor), endogenous anticoagulants (tissue factor pathway inhibitor and protein C), and damage-associated factors (High Mobility Group Box 1 [HMGB-1]) in the plasma of patients with sepsis and DIC, and to determine the relationship of these factors with severity of illness and outcome. Plasma samples were collected from 103 adult patients with sepsis within 48 hours of intensive care unit admission. Biomarker levels were measured using commercially available, standardized methods. Disseminated intravascular coagulation was diagnosed according to the International Society of Thrombosis and Hemostasis scoring algorithm. Twenty-eight-day mortality was used as the primary end point. In this study, endothelial damage and dysfunction were associated with the severity of coagulopathy and mortality in DIC patients. Loss of the endogenous anticoagulant protein C and elevation in the vascular regulator Ang-2 were associated with the development of overt DIC. In addition to Ang-2 and protein C, endocan, a biomarker of endothelial activation, and HMGB-1, a mediator of endothelial damage and activation, were significantly associated with mortality. This underscores the contribution of the endothelium to the pathogenesis of sepsis-associated DIC.
The development of coagulation abnormalities is common in patients with sepsis. Sepsis-associated coagulopathy (SAC) is typically diagnosed by prothrombin time (PT) prolongation or elevated international normalized ratio (INR) in conjunction with reduced platelet count. INR is also used to monitor warfarin-treated patients. However, due to the different natures of SAC and warfarin anticoagulation, it is likely that the same INR value provides different information in these two patient populations. The purpose of this study was to compare measures of coagulation function and clotting factor levels in patients with SAC to those observed in patients receiving warfarin anticoagulation. Deidentified plasma samples were collected at baseline from patients diagnosed with SAC and from patients receiving warfarin. These plasma samples were evaluated for PT/INR, activated partial thromboplastin time (aPTT), fibrinogen, and functional and immunologic levels of factors VII, IX, and X. Both aPTT and fibrinogen correlated with INR in patients with SAC, but not in patients treated with warfarin. Factors VII, IX, and X showed an inverse relationship with INR in the anticoagulated patients; however, no relationship between factor level and INR was observed in patients with SAC. Distinct patterns of coagulopathy were observed in patients with SAC and patients receiving warfarin anticoagulation, and equivalent INR values were associated with distinct coagulation profiles in the two patient groups. These results suggest that an abnormal INR provides different information about the coagulation status in patients with disseminated intravascular coagulation than in patients receiving warfarin. This may indicate that an equivalently increased INR predicts different bleeding risks in these two patient groups.
