Cirrhosis-Associated RAS-Inflammation-Coagulation Axis Anomalies: Parallels to Severe COVID-19

(1) Background: Cirrhotic patients have an increased risk for severe COVID-19. We investigated the renin-angiotensin-aldosterone system (RAS), parameters of endothelial dysfunction, inflammation, and coagulation/fibrinolysis in cirrhotic patients and in COVID-19 patients. (2) Methods: 127 prospectively characterized cirrhotic patients (CIRR), along with nine patients with mild COVID-19 (mild-COVID), 11 patients with COVID-19 acute respiratory distress syndrome (ARDS; ARDS-COVID), and 10 healthy subjects (HS) were included in the study. Portal hypertension (PH) in cirrhotic patients was characterized by hepatic venous pressure gradient (HVPG). (3) Results: With increased liver disease severity (Child−Pugh stage A vs. B vs. C) and compared to HS, CIRR patients exhibited higher RAS activity (angiotensin-converting enzyme (ACE), renin, aldosterone), endothelial dysfunction (von Willebrand-factor (VWF) antigen), inflammation (C-reactive protein (CRP), interleukin-6 (IL-6)), and a disturbed coagulation/fibrinolysis profile (prothrombin fragment F1,2, D-dimer, plasminogen activity, antiplasmin activity). Increased RAS activity (renin), endothelial dysfunction (vWF), coagulation parameters (D-dimer, prothrombin fragment F1,2) and inflammation (CRP, IL-6) were significantly altered in COVID patients and followed similar trends from mild-COVID to ARDS-COVID. In CIRR patients, ACE activity was linked to IL-6 (ρ = 0.26; p = 0.003), independently correlated with VWF antigen (aB: 0.10; p = 0.001), and was inversely associated with prothrombin fragment F1,2 (aB: −0.03; p = 0.023) and antiplasmin activity (aB: −0.58; p = 0.006), after adjusting for liver disease severity. (4) Conclusions: The considerable upregulation of the RAS in Child−Pugh B/C cirrhosis is linked to systemic inflammation, endothelial dysfunction, and abnormal coagulation profile. The cirrhosis-associated abnormalities of ACE, IL-6, VWF antigen, and antiplasmin parallel those observed in severe COVID-19.

Critical role of oxidized LDL receptor-1 in intravascular thrombosis in a severe influenza mouse model

Although coagulation abnormalities, including microvascular thrombosis, are thought to contribute to tissue injury and single- or multiple-organ dysfunction in severe influenza, the detailed mechanisms have yet been clarified. This study evaluated influenza-associated abnormal blood coagulation utilizing a severe influenza mouse model. After infecting C57BL/6 male mice with intranasal applications of 500 plaque-forming units of influenza virus A/Puerto Rico/8/34 (H1N1; PR8), an elevated serum level of prothrombin fragment 1 + 2, an indicator for activated thrombin generation, was observed. Also, an increased gene expression of oxidized low-density lipoprotein (LDL) receptor-1 (Olr1), a key molecule in endothelial dysfunction in the progression of atherosclerosis, was detected in the aorta of infected mice. Body weight decrease, serum levels of cytokines and chemokines, viral load, and inflammation in the lungs of infected animals were similar between wild-type and Olr1 knockout (KO) mice. In contrast, the elevation of prothrombin fragment 1 + 2 levels in the sera and intravascular thrombosis in the lungs by PR8 virus infection were not induced in KO mice. Collectively, the results indicated that OLR1 is a critical host factor in intravascular thrombosis as a pathogeny of severe influenza. Thus, OLR1 is a promising novel therapeutic target for thrombosis during severe influenza.

Soluble P-selectin and correlation with Prothrombin Fragment 1 + 2 in myeloid malignancies in Cipto Mangunkusumo general hospital

Background Myeloid cells express microparticles that could increase the expression of adhesion molecules including P-selectin. We aimed to evaluate the level of soluble P-selectin (sP-selectin) and prothrombin fragment 1 + 2 (F1 + 2), and to determine correlation of sP-selectin with leukocyte count and F1 + 2 levels in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) patients. Methods Patients with newly diagnosed AML (n = 25), CML (n = 13), and controls (n = 17) were recruited in this study. The diagnosis of AML and CML is based on 2001 WHO and/or FAB criteria. Levels of sP-selectin and F1 + 2 were determined using enzyme-linked immunosorbent assay kits (Behring ELISA Processor-III® and Behring Enzygnost F1 + 2). Results sP-selectin was significantly elevated in CML patients compared to AML patients (p = 0.001). Levels of F1 + 2 in AML and CML patients were significantly increased in comparison to controls (p < 0.001 and p = 0.043). Levels of sP-selectin were significantly correlated to leukocyte count (r = 0.437; p = 0.029) and F1 + 2 (r = 0.436; p = 0.029) in AML patients. Conclusions AML and CML patients had an increased tendency to thrombosis. While CML patients had higher platelet and/or endothelial activation, hypercoagulable state are more pronounced in AML patients.

Soluble P-selectin and Correlation with Prothrombin Fragment 1+2 in Myeloid Malignancies in Cipto Mangunkusumo General Hospital

Background Patients with hematological malignancies carry increased risk of cancer-associated thrombosis and adhesion molecule plays an important role in the mechanism of thrombus formation. The study aimed to evaluate the soluble P-selectin and prothrombin fragment 1 + 2 (F1 + 2) and to determine the correlation of sP-selectin with leukocyte count and F1 + 2 levels in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) patients. Methods A cross-sectional study of newly diagnosed AML and CML patients, aged 18 years or older. The exclusion criteria were pregnancy, severe infection, immobilization for at least 3 days or during intensive chemotherapy. Controls were healthy people, without anticoagulant and/or antiplatelet medication. Complete blood count was measured by ABX Micros 60®, and sP-selectin and F1 + 2 levels were determined using Behring ELISA Processor-III® and Behring Enzygnost F1 + 2. Results A total of 55 subjects, consisted of 25 AML and 13 CML patients and 17 controls. Soluble P-selectin was significantly elevated in AML patients compared to CML patients (median 0.14 vs 0.25 ng/mL, p = 0.001). Levels of F1 + 2 in AML (median 519.03 pmol/L) and CML patients (median 370.16 pmol/L) were significantly increased compared to controls (p < 0.001 and p = 0.043). Soluble P-selectin were significantly correlated to leukocyte count (R = 0.437; p = 0.029) and F1 + 2 (R = 0.436; p = 0.029) in AML, but not in CML patients. Conclusions AML and CML patients had increased expression of sP-selectin and coagulation activation. While CML patients had higher sP-selectin, AML patients had the highest state of hypercoagulability. Soluble P-selectin was correlated with leukocyte count and F1 + 2 in AML patients.

Abstract 12894: Suppressed Local Coagulative Response After Newer-generation Ultrathin Strut SES Implantation Compared to Older-generation SES Implantation

Background: We have previously demonstrated local persistent hypercoagulation after durable polymer (DP)-sirolimus-eluting stent (SES) implantation by measuring plasma prothrombin fragment 1+2 (F1+2) levels. The aim of this study is to evaluate local coagulative response after newer-generation ultrathin strut SES implantation. Method: Forty-five patients who were treated about 6-12 months earlier with coronary stenting, with no evidence of restenosis, were studied [DP-SES (Cypher): 26pts, biodegradable polymer (BP)-SES (older BP-SES, Ultimaster): 12pts and ultrathin strut BP-SES (newer BP-SES, Orsiro): 7pts]. We measured plasma levels of F1+2 sampled in coronary sinus (CS) and sinus of Valsalva (V). The transcardiac gradient (Δ) was defined as CS level minus V level. Results: No significant difference was observed in the percent diameter stenosis among DP-SES, older BP-SES, and newer BP-SES groups (10.1 ± 16.5 vs 13.1 ± 12.9 vs 12.1 ± 11.9 %). The ΔF1+2 was significantly lower in the BP-SES groups than in the DP-SES group (8.9 ± 10.1 vs 23.4 ± 21.1 pmol/l, p<0.05). The ΔF1+2 was lower in the newer BP-SES group than in the older BP-SES group, however, significant difference was not observed (7.0 ± 7.0 vs 9.7 ± 12.3 pmol/l). Conclusion: Suppressed local coagulative response after newer-generation ultrathin strut SES implantation was observed. These findings might indicate that lower strut thickness is more important factor than faster polymer resorption in the newer-generation DES era.