ABSTRACT
Background: Post-COVID syndrome (PCS) is an increasingly recognised complication of acute SARS-CoV- 2 infection, characterised by persistent fatigue, reduced exercise tolerance, chest pain, shortness of breath and cognitive slowing. Acute COVID-19 is strongly linked with increased risk of thrombosis;a prothrombotic state. Elevated Von Willebrand Factor (VWF) Antigen (Ag):ADAMTS13 ratio is associated with severity of acute COVID-19 infection. Aim(s): We hypothesised that the pro-thrombotic state is implicated in the pathogenesis of PCS. We investigated specialist coagulation parameters associated with reduced exercise capacity in patients with PCS to identify the utility of these parameters to determine ongoing disease activity. We also investigated if an association exists between elevated VWF(Ag):ADAMTS13 ratio and impaired exercise capacity in patients with PCS. Method(s): Retrospective analysis of VWF(Ag):ADAMTS13 ratio in patients with PCS at a dedicated post-COVID clinic. VWF(Ag):ADAMTS13 ratio was correlated with symptoms including exercise capacity as assessed by 1 minute sit-to- stand (STS) test and/or 6 minute walk test (6MWT). Peripheral oxygen desaturation >=3% for 6MWT and STS test, and increase in lactate>1 from baseline during 6MWT were taken as markers of impaired exercise capacity. Result(s): Elevated VWF(Ag):ADAMTS13 ratio (>=1.5) was found to be four times (OR 4.3) more likely in patients with impaired exercise capacity. 20% (56/276) had impaired exercise capacity, of which 55% (31/56) had a raised VWF(Ag):ADAMTS13 ratio >=1.5 (p < 0.0001). A higher median VWF(Ag):ADAMTS13 ratio of 1.5 (IQR 1.2-1.7) in patients with abnormal exercise testing compared to 1.1 (IQR 0.9-1.4) in patients with normal exercise testing was found (p < 0.0001). FVIII and VWF(Ag) were elevated in 26% and 18% respectively and support a hypercoagulable state in patients with PCS. Conclusion(s): These findings suggest possible ongoing microvascular/ endothelial dysfunction in the pathogenesis of PCS and highlight the potential role for prophylactic anticoagulation in the management of these patients.
ABSTRACT
Rationale: SARS-CoV-2 infection has been recognised to cause endotheliitis and a pro-thrombotic state during acute illness. Following acute infection, a phenomenon described as 'Long COVID' can cause persisting morbidity with multiple symptoms including exercise intolerance. In recent months preliminary data has proposed persistence of micro-clots as a mechanism for Long COVID. We sought to further understand if a thromboinflammatory processes could be contributing to clinical phenotypes in patients assessed in a UK Post COVID service. Methods: Retrospective analysis of real-world electronic health data relating to patients attending between May 2020 and Jan 2022 (both post hospital and community managed). D-dimer levels, Von Willebrand Factor antigen (vWFAg), date of acute COVID infection and attendance source were available in 1607 patients (1163 community managed and 444 post hospitalisation with acute SARS-CoV-2). vWFAg: ADAMTS13 ratio was reviewed in a subset of 329 patients and correlated with symptoms and functional assessments such as the 6 minute walk test and/or 1 minute sit-tostand test. vWF(Ag):ADAMTS13 ratio was also calculated on 50 voluntary normal controls (Medical Research Ethics Committee Numbers 08/H0810/54 and 08/H0716/72). Results: In the overall cohort D-dimer and vWF(Ag) levels were mostly in the normal range. However, in post-hospitalised patients 21/90 (23.3%) and 65/500(11.5%) community-managed patients had a D-dimer > 550mg/L more than 180 days from acute infection (figure 1). vWF(Ag) levels showed a similar spectrum of abnormalities. In the subgroup with vWF(Ag):ADAMTS13 ratios analysis, 70 (21%) had evidence of abnormal exercise testing as confirmed by desaturation ≥3% and/or an increase in lactate levels >1 above baseline. 43 (61%) of this group had elevated vWF(Ag):ADAMTS13 >1.5. Abnormal exercise testing was associated with a higher vWF(Ag):ADAMTS13 with a median of 1.5 (IQR 1.2-1.7) compared with 1.2 (IQR 0.9-1.4) in those with normal exercise test (p<0.0001), OR 4.955 [2.850-8.612], p<0.0001). Conclusions: This cohort of patients demonstrates a subgroup with persistently elevated D-dimer and vWFAg levels suggesting these markers of thromboinflammatory processes could be of relevance in defining phenotypes within long COVID. The spectrum of abnormality seen, together with the observed correlation of vWF(Ag): ADAMTS13 ratios with impaired exercise tolerance warrants further evaluation of microvascular/ endothelial dysfunction as a mechanism in Long COVID. Further mechanistic studies are in progress.