POTS in post-COVID-19 long-hauler patients is associated with platelet storage pool deficiency, 2025, William T. Gunning et al

[Mij]

Introduction: Postural orthostatic tachycardia syndrome (POTS), a type of dysautonomia, has been an enigma to many healthcare providers. As many as 80% of coronavirus disease 2019 (COVID-19) long-hauler patients meet the diagnostic criteria for POTS, highlighting awareness of this debilitating multisystem disorder. The etiology of POTS has not been entirely defined, but researchers have speculated that an immunological stressor such as a viral infection might be an initiating event. Prior to the pandemic, we reported that POTS patients have a bleeding diathesis with platelet dense granule storage pool deficiency (δ-SPD).

Methods: This report presents a prospective case–control study (n = 252) involving four cohorts, comprising two groups of POTS patients and two groups of healthy controls, to evaluate abnormal bleeding and patient demographics. We compared POTS patients and controls that were naïve to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus with subjects that had been infected and subsequently developed POTS or who recovered healthy. Questionnaires were employed to assess bleeding tendencies and the severity of clinical symptoms commonly reported with POTS. We utilized electron microscopy to assess platelet dense granules and enzyme-linked immunosorbent assay (ELISA) to assess COVID-19 and Epstein–Barr viral titers.

Results: The most common bleeding symptom was easy bruising in POTS patients naïve to COVID-19 (79.7%) and POTS post-COVID-19 patients (90.5%). Both groups had δ-SPD with means of 2.52 ± 0.9 and 2.44 ± 0.9 DG/PL, respectively, in contrast to a mean of 4.33 ± 0.6 DG/PL for controls naïve to SARS-CoV-2 infection and 4.19 ± 1.0 DG/PL for controls recovered from the virus (p < 0.001).

Discussion: We found that the results between the two POTS groups have no statistically significant difference. Our results identify an additional comorbidity (δ-SPD) in COVID-19 “long haulers”/post-acute sequela of COVID-19 (PASC) patients, frequently seen in POTS, that could explain several disparate symptoms often affecting the severity of the condition.
LINK

 

[Hutan]

It's a nicely written study (as far as I have read, the Introduction and Methods), and of a good size.

The definition of postural orthostatic tachycardia syndrome in our clinic is the presence of symptoms of orthostatic intolerance associated with an increased heart rate of 30 beats per minute (BPM) from the basal rate or a rate that exceeds 120 BPM that occurs within the first 10 min of standing or upright tilt (2–4). The disorder is an abnormal physiological state commonly caused by the inability of the peripheral vasculature to maintain adequate resistance in response to orthostatic stress, resulting in excessive pooling of blood in the more dependent areas of the body (5–7). This functional decline in circulatory volume causes a compensatory increase in heart rate and myocardial contractility.

In severe cases, the peripheral vasculature resistance is unable to compensate fully, resulting in a reduction in effective circulation and varying degrees of cerebral hypoperfusion. A decrease in arterial blood pressure below the level of cerebral autoregulation due to venous pooling may result in various symptoms, including dizziness, light-headedness, near syncope, and ultimately syncope (2, 8–34).

I'm just wondering about the exclusion criteria for controls:

Exclusion criteria for controls were applied after the time of venipuncture. Sixteen individuals were excluded from the naïve control group after ELISA screening for COVID-19 nuclear protein data was obtained, indicating that they had experienced an asymptomatic infection. In addition, exclusion criteria for control groups included a self-reported inflammatory condition (i.e., Hashimoto’s disease, inflammatory bowel disease, other
autoimmune disorder), taking a SSRI medication, or indications of abnormal bleeding.

The exclusion of 'indications of abnormal bleeding' in controls is a bit vague in the Methods; that exclusion might account for differences in reported bruising for example. Perhaps it will become clearer later in the paper.

 

[Hutan]

Platelet-rich dense granules?

Dense granules are readily apparent due to contrast with the platelet cytosol as calcium ions are stored in the same organelle that contains adenine nucleotides (mostly ADP), serotonin, and pyrophosphates. Previous studies from our laboratory have established a mean normal value of 4.60+ 0.47 DG/PL(SE), consistent with the established literature (60).

Platelet-rich plasma was dried onto a plate and then the average number of dense granules per platelet was assessed, viewing the plate with an electron microscope. The Method doesn't say anything about blinding. If there wasn't blinding, there would have been scope for bias. Figure 1 has a picture of a platelet showing the dense granules; I think it demonstrates that counting the dense granules could be subjective.


Are the dense granules the black dots? If so, then there looks to be a lot more than the two to five per platelet that were reported as being in the participants' cells.

 

[Hutan]

Results

Our study recruited both men and women; the naïve controls were 73% women, naïve POTS were 91% women, COVID-19 recovered controls were 79% women, and POTS post-COVID-19 were 96% women. This is consistent with the established literature that POTS is a disorder of young premenopausal Caucasian women (28, 64).

I think the differences in sex ratios is a significant problem for self-reported bruising.

Men's skin is generally 20-25% thicker than women's skin, primarily due to higher levels of testosterone. This added thickness, particularly in the dermis, gives men's skin a firmer, tougher texture and helps protect it from external aggressors.

Add in some extra hairiness to help cushion the impact of bumps, and I think there would be sex differences in self-reported bruising. Perhaps the study will do a sensitivity analysis, but it's a shame the control groups weren't more similar to the disease groups.

I also didn't see any mention of adjustment in symptom counts for the fact that things like migraine and of course menstrual issues are more common in women.

 

[Hutan]

Although the BAT was not designed for self-assessment, we found our modified version serviceable. The mean BAT scores for our control groups were normal (scores = 1), whereas our POTS groups had higher bleeding scores (scores = 5+). Regardless of being naïve to COVID-19 infection or having PACS, our POTS patients had BAT scores suggestive of increased bleeding tendencies.

As noted above, I think there is an issue here with the selection of controls. I suspect controls were rejected if their self-reported bleeding scores were more than 1. No information is given about how many controls were rejected for having abnormal bleeding.

 

[Hutan]

That's the chart of the average number of platelet dense granules per platelet. There's some overlap between controls (green and black) and POTS patients (red and yellow). As I noted above, I'm not sure how much of a role bias in the counting played in the assessment. (ie subjectivity in what platelets were chosen for assessment, how many platelets were assessed, what counted as a dense granule). This paper does not provide enough information to be totally convincing.

Discussion

More than 90% of our patients reported fatigue (Table 3). The most common bleeding symptom for both POTS groups was easy bruising, but frequent nose bleeds and heavy menstrual bleeding were also reported. The results of our electron microscopy assay of platelet dense granules for all four groups correlate well with our BAT and menses scores, as well as the clinical symptoms commonly associated with platelet dysfunction disorders, including easy bruising, epistaxis, and heavy menstrual bleeding, which are seen in our POTS patients. Our observation of mucocutaneous bleeding in these patients is not as severe as seen in other coagulation system anomalies, typically needed to cause significant bleeding.

Most publications of PACS that describe coagulopathies report on thrombosis. Still, one recent study reports “that hemorrhage and risk of hemorrhage are not necessarily an infrequent finding in COVID-19, albeit most probably associated with contributing factors” (85, 86). This report provides support to our findings that both COVID-19-induced POTS and POTS naïve to COVID-19 may be associated with platelet dysfunction, specifically platelet δ-SPD. Both of our control groups were found to have normal numbers of dense granules per platelet.

That's interesting about so many of the POTS patients reporting fatigue, again suggesting that the labels people get may depend more on who is doing the diagnosing than the actual symptoms.

They wrestle there with the issue of both bleeding disorders and coagulopathies being reported.