Persistent Antiphospholipid Antibodies, Mast Cell Activation Syndrome, Postural Orthostatic Tachycardia Syndrome and Post-COVID Syndrome: 1 Year On


Senior Member
This is the first case report of a patient with post-COVID-19 postural orthostatic tachycardia syndrome (POTS) with multiple persistent antiphospholipid antibody (aPL)-positivity more than a year after illness onset who also meets Global Consensus-2 criteria for mast cell activation syndrome (MCAS), suggesting pathological activation of the acquired and innate immune systems by SARS-CoV-2. While the patient continues to meet criteria for POTS 1 year on, her functional ability has improved significantly with therapy directed at MCAS, POTS and aPL-positivity.

  • A subset of long-haul COVID-19 patients have postural orthostatic tachycardia syndrome (POTS), which can be diagnosed by a 10-minute in-office stand test.
  • Antiphospholipid antibodies may be associated with POTS in patients with long-haul COVID-19 and have important clinical implications.
  • Mast cell activation syndrome (MCAS) may be associated with long-haul COVID-19 (with or without POTS) and can often be easily treated, including with over-the-counter medications, supplements and dietary changes.
This patient’s history shows that post-COVID POTS may be very prolonged and possibly chronic. This is the first report describing the persistence of of multiple aPL more than one year after COVID-19 in a patient with clinical manifestations that have been published in association with aPL, that is, POTS. Autonomic neuropathy may be the initial manifestation of aPL-positivity [7]. Skin biopsy evaluating for suspected autonomic neuropathy was not performed because it would not change management. An abnormal skin biopsy is helpful for insurance approval when considering a trial of intravenous immunoglobulin, but as the present case illustrates, not all patients with autoimmunity and dysautonomia require immunoglobulin therapy.
APL-positivity in acute COVID-19 has been published by several groups [8, 9]. Infections are known to induce transient aPL production--a phenomenon which led to the requirement for persistent aPL positivity for ≥12 weeks before considering a diagnosis of antiphospholipid syndrome (APS) [10]. Only two studies have reported repeat aPL testing in acute COVID-19 patients. In one, 9 of 10 patients were aPL-negative 1 month later [8] and in another [9], three patients had persistent aPL-positivity, but only as late as 77 days after illness onset.
The persistent presence of aPL has important clinical implications, including an increased thrombotic risk as well as risk of pregnancy morbidity. While thrombosis and/or specific pregnancy morbidity are required for a ‘definite’ diagnosis of APS [10], the identification of aPL provides the opportunity to prevent thrombosis by avoiding exogenous oestrogen, controlling for vascular risk factors which act synergistically with aPL, and the use of thromboprophylaxis postoperatively or postpartum. In women of childbearing age, aPL identification provides the opportunity to reduce pregnancy morbidity.
This patient also met Global Consensus-2 criteria [11] for MCAS. Afrin et al. [4] recently published their hypothesis that excessive MCA in people with unrecognized and thus untreated MCAS may be at the root of severe acute as well as long-haul COVID-19. This patient fits their hypothesis. Medications which inhibit MCA have demonstrated efficacy and/or are being studied in COVID-19 [4].
The specific diagnoses of POTS, MCAS and aPL-positivity were critical to achieving clinical improvement in this case and suggest that patients with prolonged symptoms after COVID-19 should undergo stand testing to evaluate for POTS and serological testing for autoimmunity. Owing to the limitations of MCAS testing as well as the excellent safety profile of most agents used in the treatment of MCAS[11], consideration should be given to empiric treatment trials in long-haul COVID-19 patients with multisystem allergic and/or inflammatory symptoms suggesting MCAS. Patients with persistent aPL-positivity and migraine may respond dramatically to antithrombotic therapy [12]. Lastly, definite autoimmunity in a patient with severely disabling dysautonomia not improving with conservative therapies would support a trial of intravenous immunoglobulin which often results in dramatic improvement in this context [13].
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While SARS-CoV-2, like other autoimmune triggers, may incite a pathological innate and/or acquired immune response that may be prolonged, proper diagnoses and directed management may result in clinical improvement. Large studies of long-haul COVID-19 patients are imperative to better understand these complex multisystem disorders.
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