Generation of potentially inhibitory autoantibodies to ADAMTS13 in coronavirus disease 2019, 2023, Doevelaar et al.

[SNT Gatchaman]

Generation of potentially inhibitory autoantibodies to ADAMTS13 in coronavirus disease 2019
Doevelaar, Adrian A. N.; Bachmann, Martin; Hölzer, Bodo; Seibert, Felix S.; Rohn, Benjamin J.; Zgoura, Panagiota; Witzke, Oliver; Dittmer, Ulf; Brenner, Thorsten; Paniskaki, Krystallenia; Yilmaz, Serap; Dittmer, Rita; Schneppenheim, Sonja; Wilhelm, Jochen; Stervbo, Ulrik; Babel, Nina; Budde, Ulrich; Westhoff, Timm H.

It has recently been shown that von Willebrand factor (VWF) multimers contribute to immunothrombosis in Coronavirus disease 2019 (COVID-19). Since COVID-19 is associated with an increased risk of autoreactivity, the present study investigates, whether the generation of autoantibodies to ADAMTS13 contributes to this finding.

In this observational prospective controlled multicenter study blood samples and clinical data of patients hospitalized for COVID-19 were collected from April to November 2020. The study included 156 individuals with 90 patients having confirmed COVID-19 of mild to critical severity. 30 healthy individuals and 36 critically ill ICU patients without COVID-19 served as controls. ADAMTS13 antibodies occurred in 31 (34.4%) COVID-19 patients.

Antibodies occurred more often in critically ill COVID-19 patients (55.9%) than non-COVID-19 ICU patients and healthy controls (5.6% and 6.7%; p < 0.001), respectively. Generation of ADAMTS13 antibodies in COVID-19 was associated with lower ADAMTS13 activity (56.5%, interquartile range (IQR) 21.25 vs. 71.5%, IQR 24.25, p = 0.0041), increased disease severity (severe or critical in 90% vs. 62.3%, p = 0.019), and a trend to higher mortality (35.5% vs. 18.6%, p = 0.077). Median time to antibody development was 11 days after first positive SARS-CoV-2-PCR specimen. Gel analysis of VWF multimers resembled the constellation in patients with TTP.

The present study demonstrates for the first time, that generation of ADAMTS13 antibodies is frequent in COVID-19, associated with lower ADAMTS13 activity and increased risk of an adverse disease course. These findings provide a rationale to include ADAMTS13 antibodies in the diagnostic workup of SARS-CoV-2 infections.

Link | PDF (Nature Scientific Reports)

 

[SNT Gatchaman]

the present study demonstrates for the first time, that a substantial part of patients with COVID-19 develop autoantibodies to ADAMTS13 in the course of their disease, occurring in approximately one third of hospitalized patients, which could not be seen in ICU patients without COVID-19.

Occurrence of antibodies is associated with a significantly lower ADAMTS13 activity, which causes a decreased degeneration of large and ultralarge vWf multimers likely contributing to SARS-CoV-2 induced immunothrombosis.

The findings that the antibodies predict outcome in a dose-dependent manner and that they are associated with impaired ADAMTS13 activity suggest a potential functional relevance.

 

[SNT Gatchaman]

 

[SNT Gatchaman]

Expanding on The ADAMTS13‐von Willebrand factor axis in COVID‐19 patients (2021, Journal of Thrombosis and Haemostasis) in acute patients —

We found a significant alteration of the VWF-ADAMTS13 axis in COVID-19 patients, with an elevated VWF:Ag to ADAMTS13 activity ratio that was strongly associated with disease severity. Such an imbalance enhances the hypercoagulable state of COVID-19 patients and their risk of microthrombosis

Does this persist and contribute to LC findings (+/- symptoms)? Is this specific to LC and not present in ME from non-SARS2 causes?

Long-term persistence is suggested in Analysis of thrombogenicity under flow reveals new insights into the prothrombotic state of patients with post-COVID syndrome (2022, Journal of Thrombosis and Haemostasis) —

Together, these data present, for the first time, a dynamic assay showing a prothrombotic tendency in patients who have been suffering from PCS for approximately 2 years. Our results confirm a hypercoagulable state in patients with PCS related to an increase in VWF(Ag):ADAMTS13 ratio and thrombin generation but not in α2-antiplasmin levels.

 

[SNT Gatchaman]

On post-Covid long-term symptoms relating to vWF:ADAMTS13 we had —

Impaired exercise capacity in post-COVID syndrome: the role of VWF-ADAMTS13 axis (2022)

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).

 

[SNT Gatchaman]

I'm not sure how this could work. Perhaps the degree of effect on ADAMTS13 and the ratio with vWF is relatively mild and/or the specific antibody has a different effect. The extreme end of this condition is thrombotic thrombocytopaenic purpura, which is a very bad condition that is quite well known, but previously was pretty fatal.

Now it's treatable, eg summary from Wikipedia —

With plasma exchange the risk of death has decreased from more than 90% to less than 20%. Immunosuppressants, such as glucocorticoids, and rituximab may also be used. Platelet transfusions are generally not recommended.

A state of the art paper: TTP: long-term outcomes following recovery (2018, Hematology) has the following abstract —

Although risk for relapse may be the greatest concern following recovery from acquired, autoimmune thrombotic thrombocytopenic purpura (TTP), there are multiple other major health issues that must be recognized and appropriately addressed. Depression may be the most common disorder following recovery from TTP and may be the most important issue for the patient’s quality of life. Severe or moderate depression has occurred in 44% of Oklahoma Registry patients. Recognition of depression by routine screening evaluations is essential; treatment of depression is effective. Minor cognitive impairment is also common. The recognition that cognitive impairment is related to the preceding TTP can provide substantial emotional support for both the patient and her family. Because TTP commonly occurs in young black women, the frequency of systemic lupus erythematosus, as well as other autoimmune disorders, is increased. Because there is a recognized association of TTP with pregnancy, there is always concern for subsequent pregnancies. In the Oklahoma Registry experience, relapse has occurred in only 2 of 22 pregnancies (2 of 13 women). The frequency of new- onset hypertension is increased. The most striking evidence for the impact of morbidities following recovery from TTP is decreased survival. Among the 77 patients who survived their initial episode of TTP (1995-2017), 16 (21%) have subsequently died, all before their expected age of death (median difference, 22 years; range 4-55 years). The conclusion from these observations is clear. Following recovery from TTP, multiple health problems occur and survival is shortened. Therefore, careful continuing follow-up is essential.

and had the following passage on fatigue —

The symptoms of minor cognitive impairment are similar to the symptoms of depression, except for the risk of suicide. Similar to depression, patients may dismiss their problems with concentration, memory, and fatigue as only a normal part of their lives. It was during the discussions at our support group meetings that our former patients and their families recognized that others in the group also had these symptoms and that they had occurred following their recovery from TTP. Then, the patients focused on convincing me that these symptoms were real. This was the beginning of our studies to document cognitive impairment. The patients were eager to participate and to document that their problems with concentration, memory, and fatigue were real.

 

[SNT Gatchaman]

I'm assuming ADAMTS13 and vWF will have been looked at long ago in ME/CFS itself. I can't find anything in PubMed, but maybe my search terms are inadequate?

A permissive search of "((chronic fatigue syndrome[MeSH Terms]) OR (myalgic encephalomyelitis[MeSH Terms]) OR (fibromyalgia[MeSH Terms])) AND (adamts13)" gives zero hits.

Similarly "((chronic fatigue syndrome[MeSH Terms]) OR (myalgic encephalomyelitis[MeSH Terms]) OR (fibromyalgia[MeSH Terms])) AND (von willebrand factor)" gives zero hits.

A "control" search of "((chronic fatigue syndrome[MeSH Terms]) OR (myalgic encephalomyelitis[MeSH Terms]) OR (fibromyalgia[MeSH Terms])) AND (virus)" has 794 hits.

Similarly "((thrombotic thrombocytopenic purpura[MeSH Terms]) AND (adamts13))" gives 1557 hits.

 

[Hoopoe]

Possibly related:

Higher serine protease SERPINA5, which is involved in hemostasis, was correlated with higher SF-36 general health scores in ME/CFS.

SERPINA5 is an anticoagulant.

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04179-3

 

[Hutan]

On post-Covid long-term symptoms relating to vWF:ADAMTS13 we had —

Impaired exercise capacity in post-COVID syndrome: the role of VWF-ADAMTS13 axis (2022)

I've had a look at that study and have made some comments on the thread. I don't find the paper particularly compelling as far as the ratio being correlated with ME/CFS symptoms. It seems to be more likely to be a product of age (and/or possibly acute covid-19 severity).