COVID-19 Is Associated with Endothelial Dysfunction and Enhanced Plasma Thrombin Generation Despite Pharmacological Thromboprophylaxis

Abstract Background Hospitalised patients with severe COVID-19 (requiring critical care level support) appear to be at increased risk of thrombosis despite standard pharmacological thromboprophylaxis. The magnitude of thrombotic risk in patients with COVID-19 of moderate severity (not requiring critical care) is less clear. The optimal approach to thromboprophylaxis (and the role of intensified thromboprophylaxis) remains to be determined. Evidence of endothelial dysfunction has been widely reported in COVID-19 (particularly in severe COVID) and this may contribute to hypercoagulability. Aim To assess differences in patterns of hypercoagulability and endothelial dysfunction between a group of patients with moderate COVID-19 and a group of age-matched hospitalized patients (SARS-CoV-2 PCR negative) receiving low molecular weight heparin (LMWH) thromboprophylaxis. Methods Blood was collected from individuals admitted to hospital with COVID-19 of moderate severity (not requiring critical care level support) and a group of age-matched patients admitted with infective/inflammatory illness (SARS-CoV-2 PCR negative). All subjects received standard-dose LMWH thromboprophylaxis, with blood drawn at 12 hours post-dose (and with measurement of anti-FXa activity levels). Circulating levels of endothelial &amp; fibrinolytic markers including ICAM, PAI-1, VCAM, soluble thrombomodulin (sTM), and tissue plasminogen activator (tPA) were determined by ELISA. Thrombin generation (TG) in platelet-poor plasma was assessed by calibrated automated thrombography in the presence of tissue factor (Final concentration, 1pM &amp; 5pM), thrombomodulin (TM) (Final concentration, 6.25nM), and an inhibitory anti-tissue factor pathway inhibitor antibody (anti-TFPI; Final concentration 100μg/mL). Results 14 COVID-19 positive subjects and 11 hospitalized controls were recruited. There were no differences in mean age (69.7±4.5 vs 61.6±4.7 years; p= 0.2) or mean Body mass index (25.7±1.1 vs 22.7±1.2 Kg/m2; p=0.1) between groups. No COVID-19 patient or control required critical care support. In the COVID group, radiological evidence of pneumonitis [diffuse (n=3) or peripheral infiltrates (n=7)] was present in the majority of cases. None of the COVID-19 cases were requiring supplemental oxygen at the time of recruitment. All controls were admitted with either respiratory or urinary infection [radiological evidence of pneumonia in 4/11; supplemental oxygen requirement in 2/11, (28-36% FiO2 via nasal cannula)]. Plasma levels of sTM, ICAM, PAI-1 &amp; VCAM were similar in both groups. Levels of t-PA were significantly higher in the COVID group (8.31±4.35 vs 4.91±2.37 ng/mL; p= 0.005). Despite similar plasma anti-Xa activity in both groups (0.06 vs 0.04 IU/mL; p=0.2), mean endogenous thrombin potential (ETP) was significantly higher in the COVID group (1929±119.7 vs 1528±138.9 nM*min; p=0.02), although peak thrombin was similar (173.6±26 vs 161.5±31nM). ETP-TM ratio was similar between groups (0.3±0.1 vs 0.2±0.1; p=0.3). Despite increased ETP, the lag time to thrombin generation was significantly prolonged in the COVID group (8.3±0.6 vs 5.8±0.5 mins, p= 0.006). This pattern has previously been observed in vascular diseases associated with altered plasma tissue factor pathway inhibitor (TFPI) activity. In the presence of an anti-TFPI antibody, the difference in lagtime between groups was attenuated (4.7±0.2 vs 3.5±0.1 mins; p= 0.002) and the difference in overall thrombin generation (delta TG) between both groups became significantly increased (Fig.1). Conclusion Plasma thrombin generation is enhanced in patients with non-severe COVID-19 despite pharmacological thromboprophylaxis. Endothelial dysfunction is also observed in this group and appears to modulate parameters of plasma thrombin generation. The clinical implications of these observations are not known although clinical studies of intensified thromboprophylaxis in attenuating thrombotic risk and other complications are ongoing. Fig 1. Inhibition of TFPI activity enhances thrombin generation in COVID-19. In the presence of an inhibitory anti-TFPI antibody, peak plasma thrombin generation was enhanced in COVID-19 in contrast to that observed among SARS-CoV-2 PCR negative hospitalised patients (339.6+25.2 vs 247.4+10.1, p=0.01). Figure 1 Figure 1. Disclosures Maguire: Actelion: Research Funding; Bayer Pharma: Research Funding. Ni Ainle: Daiichi-Sankyo: Research Funding; Actelion: Research Funding; Leo Pharma: Research Funding; Bayer Pharma: Research Funding. Kevane: Leo Pharma: Research Funding. </jats:sec

Predictors of Healthcare Utilization in Newly Diagnosed Myeloma

Introduction The introduction of novel therapies has significantly improved outcomes in myeloma. However, the economic burden of enhanced healthcare utilization is significant and cannot be discounted. This study sought to identify baseline characteristics that may influence outcomes and subsequent healthcare utilization. Patients were also stratified by induction therapy to determine the impact newer combinations have on healthcare utilization. Methods This retrospective single-center study enrolled all newly diagnosed patients with myeloma between 2005 and 2020. Three outcome measures were used to determine healthcare utilization - total inpatient length of stay (LOS), number of admissions, and day ward attendances. Univariate and multivariable analyses were performed to identify significant covariates related to overall survival (OS) and healthcare utilization. Outcomes were subsequently adjusted for duration of follow-up and per patient year. Results There were 113 patients included; 60 (53.1%) female; median age at diagnosis was 67 years (IQR 62, 73 years) and 22.1% were high risk International Staging System (ISS). Further baseline demographics are presented in Table 1. Median duration of follow up was 3.2 years (IQR 1.50, 6.55). Sixty patients (53.1%) died, 91.7% attributable to myeloma or its treatment. Predictors of OS by multivariable analysis were advanced stage [ISS III (p&amp;lt;0.001)] and IgA idiotype [(IgA vs IgG) (p=0.0002)]. Stem cell transplant eligibility was associated with improved OS (p=0.003). The total number of admissions to hospital was 547 (median 4; IQR 2, 7), with 55.4% unplanned. In the multivariable analysis, younger age (p=0.020), higher paraprotein levels (p=0.045), dialysis (p=0.037), and SCT eligibility (p=0.0012) were predictive of greater number of admissions. During the study period, there were 7000 inpatient bed occupancy days (median 46; IQR 26, 80). Only younger age remained significant (p=0.0028) in the multivariable analysis. There were a total of 5987 day care attendances during the study period. Multivariable analysis identified younger age at diagnosis (p&amp;lt;0.0001), WBC (p=0.0072), and light chain (kLC vs lLC) (p=0.0027) as predictive of increased day ward attendance. Healthcare utilization correlated with increased survival, as depicted in figure 1. There was no significant relationship between treatment type and LOS (p=0.055); this remained unchanged when adjusted per patient year (p=0.24). There was significant relationship between treatment type and total number of admissions (p=0.015). Patients receiving anthracycline based therapy (p=0.003), Immunomodulatory (IMiD)/Proteasomal Inhibition (PI)/Steroid (p=0.020), or PI/Steroid (p=0.021) were more likely to have a greater number of admissions. However, when adjusted per patient year, this association was no longer evident (p=0.19). A highly significant relationship between treatment type and day ward attendances was identified (p&amp;lt;0.0001). Alkylator based (pp=0.005), alkylator/PI/Steroid (p=0.006), anthracycline based (p=0.0002), IMiD/PI/Steroid (p=0.0007), or PI/Steroid (0.0002) were more likely to have greater day ward attendance. When adjusted per patient year, this significant association between treatment type and day ward attendance remained (p=0.0002). Conclusion Studies assessing healthcare utilization in patients with myeloma are mostly limited to relapsed refractory setting. In this population, younger age at presentation was a significant predictor for all three measures of healthcare utility. Whilst treatment type did not demonstrate a significant impact of LOS, we did determine that novel triplet therapy combinations were associated with increased number of admissions and day care attendances. We also showed that healthcare utilization increased with survival time. While survival outcomes with novel agents have improved, given current financial and capacity limitations within which the majority of health systems function, resource demand implications must be considered when planning future service provision and novel treatment strategies. Disclosures No relevant conflicts of interest to declare. </jats:sec