Impaired exercise capacity in post-COVID syndrome: the role of VWF-ADAMTS13 axis, 2022, Prasannan et al

[LarsSG]

Key Points

• VWF(Ag):ADAMTS13 ratio ≥1.5 was evident in 28% of PCS cohort
• 55% of patients with impaired exercise capacity had a raised VWF(Ag):ADAMTS13 ratio ≥1.5 (OR 4)

Post-COVID syndrome (PCS) or Long-COVID 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, quantified by elevated Von Willebrand Factor (VWF) Antigen (Ag):ADAMTS13 ratio, and is associated with severity of acute COVID-19 infection. We investigated if patients with PCS also had evidence of a pro-thrombotic state associating with symptom severity. In a large cohort of patients referred to a dedicated post-COVID-19 clinic, thrombotic risk including VWF(Ag):ADAMTS13 ratio, was investigated.

An elevated VWF(Ag):ADAMTS13 ratio (≥1.5) was raised in nearly one-third of the cohort and four times more likely in patients with impaired exercise capacity as evidenced by desaturation ≥3% and/or rise in lactate level more than 1 from baseline on 1-minute sit to stand test and/or 6-minute walk test (p<0.0001). 20% (56/276) had impaired exercise capacity, of which 55% (31/56) had a raised VWF(Ag):ADAMTS13 ratio ≥1.5 (p<0.0001). FVIII and VWF(Ag) were elevated in 26% and 18% respectively and support a hypercoagulable state in some patients with PCS. These findings suggest possible ongoing microvascular/endothelial dysfunction in the pathogenesis of PCS and highlight a potential role for antithrombotic therapy in the management of these patients.

Link with full text PDF

 

[Hutan]

ADAMTS13 regulates VWF. In acute Covid, an increase in VWF:Ag(antigen) and a decrease in ADAMTS13 has been reported.

VWF plays a major role in primary hemostasis, and multimeric size is regulated by ADAMTS13 (a disintegrin and metalloprotease with thrombospondin 1 repeats, number 13). In acute COVID-19–infected patients, an increase in VWF:Ag (antigen), which may be associated with a relative reduction in ADAMTS13 and therefore an increase in VWF(Ag)/ADAMTS13 ratio is recognized, and this increase is likely to contribute to the hypercoagulable state and risk of microvascular thrombosis in these patients.8,9 Enhanced thrombin generation, decreased fibrinolytic activity, raised levels of FVIII and plasminogen-activator inhibitor type 1,10,11 high endothelin-1 levels,12 and increased D-dimer13 have also been identified in patients with PCS, suggesting a role for endothelial cell dysfunction and hypercoagulability.

50 healthy controls were used to determine the healthy VWF(Ag)/ADAMTS13 ratio. They don't say whether some/all the healthy controls had recovered from Covid-19, or the age or sex ratio of the controls.

The VWF(Ag)/ADAMTS13 ratio was calculated on 50 voluntary healthy controls (Medical Research Ethics Committee approvals 08/H0810/54 and 08/H0716/72). The VWF(Ag)/ADAMTS13 ratio was also calculated in the cohort of patients with PCS and correlated with symptoms including exercise tolerance, as assessed by 1-minute sit-to-stand (STS) test and/or 6-minute walk test (6MWT).

72% of the patients reported fatigue - overall this was a mixed patient group reporting a range of symptoms including chest discomfort. 3% of the patient group are reported as being asymptomatic.


So, median VWF(Ag)/ADAMTS13 ratio in controls was 0.98 (interquartile range 0.76 to 1.34). The ratio in patients was 1.2 (0.9-1.5). I think it is a bit of a stretch to say these are different if we take into account confounding factors like age.

Of the 330 patients with PCS, 85 (26%) had high FVIII, ranging from 2.1 to 5.1 IU/mL (normal range [NR], 0.5-2 IU/mL), and 60 (18%) had a high level of VWF(Ag), ranging from 1.7 to 3.3 IU/mL (NR, 0.5-1.6 IU/mL). ADAMTS13 activity ranged from 68.2 to 159.3 IU/dL (NR, 60-146 IU/dL).

The median VWF(Ag)/ADAMTS13 ratio was 0.98, with an IQR of 0.76 to 1.34 in 50 historical stored healthy control samples. Based on this IQR, a VWF(Ag)/ADAMTS13 ratio of ≥1.5 was considered to show an increase. The median VWF(Ag)/ADAMTS13 ratio was 1.2 (IQR, 0.9-1.5) across the 330 patients. Of the 330 patients in the cohort, 92 (28%) had a VWF(Ag)/ADAMTS13 ratio ≥1.5.

Execise test:

Peripheral oxygen desaturation ≥3% for 6MWT and STS test, as well as an increase in lactate >1 from baseline during 6MWT were taken as markers of impaired exercise capacity.

I don't think the exercise test measure is a very sensitive test of exercise capacity in ME/CFS. Below, the chart comparing the ratios of those patients with normal and abnormal exercise test performance. The y axis is 0,1,2,3,4. Perhaps there is something there, bearing in mind the median of the healthy controls was approximately 1. I think we'd need to see the analysis repeated with just people reporting fatigue to begin to get an idea as to whether this is relevant to people with ME/CFS-like symptoms.

The VWF(Ag)/ADAMTS13 ratio was divided into 2 groups: <1.5 (normal) and ≥1.5 (abnormal). The groups were assessed separately against patient symptoms and results of exercise tolerance testing via the 1-minute STS exercise test and/or 6MWT. Of the 97% of symptomatic patients, 72% (230 of 320) had a VWF(Ag)/ADAMTS13 ratio <1.5, and 28% (90 of 320) had a ratio ≥1.5. Of the total cohort, 3% (10 of 330) was asymptomatic and had a median VWF(Ag)/ADAMTS13 ratio of 1.1. Therefore, the VWF(Ag)/ADAMTS13 ratio did not correlate with presenting clinical symptoms.

The chart is only for the subset who completed the test - not all patients did the exercise test, and some attempting it did not complete it.

However, a VWF(Ag)/ADAMTS13 ratio ≥1.5 did correlate with abnormal exercise intolerance. Of the 330 patients assessed, 54 (16%) did not undergo exercise testing or failed to complete the test. Of those, 276 (84%) completed exercise testing (Figure 1B), and 220 (80%) were able to perform the tasks without impairment.

The risk of an increased VWF(Ag)/ADAMTS13 ratio was found to be 4 times more likely in those with abnormal exercise test results (OR, 4.3; 95% CI, 2.3-7.9; P < .0001), demonstrating a strong association by univariate analysis.

It's of note that older people had higher ratios - perhaps this accounts for the difference with the controls?

VWF(Ag)/ADAMTS13 ratio and exercise test results were analyzed according to 3 age groups: ≤40 years, 41 to 60 years, and >60 years. The median VWF(Ag)/ADAMTS13 ratio was found to be 1 (IQR, 0.8-1.3), 1.2 (IQR, 1-1.5), and 1.6 (IQR, 1.2-2), respectively (P < .0001), showing a difference in ratio across the age groups.

 

[Hutan]

Of the 330 patients, 273 had acute COVID-19 infection managed in the community. Community-managed (83%) and hospitalized (16%) patients had a comparable median VWF(Ag)/ADAMTS13 ratio of 1.2 (IQR, 1-1.4 and 0.9-1.5, respectively; P= .71). There was no significant difference in median VWF(Ag)/ADAMTS13 ratio in the hospitalized patients who required oxygen support, noninvasive ventilation, or intubation and ventilation, with median follow-up ratios of 1.2 (IQR, 1-1.4), 1.1 (IQR, 0.7-1.4), and 1.3 (1.2-1.6), respectively (0.22). Of the 53 hospitalized patients, 21 received dexamethasone. The median VWF(Ag)/ADAMTS13 ratios at follow-up were 1.3 and 1.1 (P = .10), respectively, in patients who received dexamethasone and those who did not.

I had thought that the older people might have been more likely to have severe disease, and so the higher ratio might just have been a result of lung or heart damage, or of their treatments. It doesn't look as though hospitalisation/severe acute disease alone accounts for higher ratios here.

An analysis of the coagulation parameters led to investigation of the VWF(Ag)/ADAMTS 13 ratio, and a higher ratio was particularly seen in the most severe COVID-19 cases.8,9

But it looks as though a previous study did find a relationship between severe acute disease and the ratio; perhaps that is mediated by age?

A markedly high VWF(Ag)/ADAMTS13 ratio with a median of 6.07 has been shown during the acute phase of COVID-19 infection.8 Measurement of VWF(Ag)/ADAMTS13 levels was not increased when analyzed against several clinical symptoms, including fatigue, headaches, and abnormalities in cognition, with a median VWF(Ag)/ADAMTS13 ratio of 1.2 in our PCS cohort, which was a median of 6 months past acute COVID-19 infection. This finding therefore suggests that the high VWF(Ag)/ADAMTS13 ratio observed in patients with acute COVID-19 infection may settle over time, despite ongoing symptoms of PCS, with a reversal of the ratio to normal in most patients. However, a limitation is that longitudinal measurements repeated over time are lacking in this study. The VWF(Ag)/ADAMTS13 ratio remained >1.5 in a proportion of patients with impaired exercise capacity measured objectively.

It's not clear to me what the basis of the authors saying that the ratio was not correlated with fatigue presence. The report is a bit patchy.

I'm not finding the VWF(Ag): ADAMSTS13 ratio very compelling as a reason for ME/CFS-like symptoms.