Critical Review: Systemic Medical Neglect in Lab-Confirmed Antiphospholipid Syndrome (APS) with von Willebrand Factor (vWF) Abnormalities and Stevens-Johnson Syndrome (SJS)

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1. Overview

This review examines the intersection of underdiagnosed autoimmune disease, coagulation disorders, and drug-induced harm, particularly in patients with laboratory-confirmed Antiphospholipid Syndrome (APS) and von Willebrand Factor (vWF) abnormalities. Special focus is given to cases of Stevens-Johnson Syndrome (SJS) triggered by medications such as allopurinol and methotrexate (MTX)—both known, albeit rare, culprits.

Despite clear laboratory confirmation, these patients are frequently misdiagnosed, undertreated, or prescribed high-risk medications without appropriate pharmacogenetic or clinical screening. The consequences include irreversible neurologic injury, systemic inflammation, life-threatening dermatologic reactions, and in some cases, preventable death.

2. APS and vWF Dysregulation: A High-Risk but Overlooked Profile

APS is defined by:

  • Clinical criteria: arterial or venous thrombosis, and/or pregnancy morbidity

  • Laboratory criteria: persistent presence of antiphospholipid antibodies (LA, aCL IgG/IgM, or anti-β2GPI IgG/IgM), confirmed on two occasions at least 12 weeks apart 

    In a subset of patients, APS coexists with von Willebrand Factor (vWF) abnormalities, including:


  • Type 2: qualitative platelet adhesion defects

  • Type 5: rare multimer structure variants

This overlap presents a complex clinical profile with both thrombotic and hemorrhagic risks, often dismissed or misinterpreted.

Complications include:

  • Microvascular ischemia

  • CNS involvement (stroke, encephalopathy, white matter changes)

  • Mucocutaneous bleeding

  • Delays in appropriate anticoagulation or immunomodulation

3. Neurologic Injury in APS with vWF Abnormalities: A Dual Mechanism of Harm

Neurological complications of APS arise from thrombotic occlusion and immune-mediated inflammation of cerebral vessels and brain tissue. These effects are exacerbated by coagulopathy from vWF abnormalities.

Symptoms include:

  • Cognitive dysfunction ("brain fog")

  • Seizures

  • Migraines and visual changes

  • Neuropsychiatric symptoms (e.g., mood disorders, psychosis)

  • Stroke or transient ischemic attacks (TIAs)

Mechanisms:

  • Thrombosis limits cerebral perfusion

  • Antiphospholipid antibodies disrupt the blood-brain barrier, leading to neuroinflammation

  • vWF dysfunction impairs platelet function and microcirculatory regulation

Despite this, patients often face misdiagnosis or delayed treatment due to systemic clinical skepticism, particularly when CNS symptoms present without overt thrombosis.

4. Methotrexate and Stevens-Johnson Syndrome (SJS)

Though rare, methotrexate (MTX)—a drug commonly used in autoimmune diseases and oncology—can trigger Stevens-Johnson Syndrome (SJS), a life-threatening mucocutaneous reaction.

In a documented case series, two 14-year-old girls undergoing chemotherapy for osteosarcoma developed SJS following MTX administration. Symptoms included:

  • Purplish macular rash

  • Cutaneous and mucosal erosions

  • Oral and ocular ulcerations

Both patients were treated with systemic corticosteroids (1 mg/kg/day) and recovered.

Key implications:

  • MTX-induced SJS is rare but serious, particularly in immunocompromised or genetically predisposed patients

  • Prompt discontinuation of the drug is critical

  • Re-exposure to the culprit drug is contraindicated

  • Risk must be considered in APS or coagulopathy patients already prone to immune-mediated reactions

Reference:

5. Allopurinol, HLA-B*5801, and Drug-Induced SJS

Allopurinol, frequently used to manage hyperuricemia, is a well-known trigger for SJS/TEN in individuals carrying the HLA-B*5801 allele—especially common in East Asian populations.

Clinical features of SJS/TEN include:

  • Painful, blistering rash with mucosal involvement

  • Skin detachment

  • Multi-organ dysfunction (e.g., hepatic, renal)

  • Mortality rate up to 30%

Despite the availability of genetic screening, allopurinol is still often prescribed without testing, even in high-risk patients.

References:

6. Inappropriate Use of DOACs in APS

Despite evidence from the TRAPS study and others, Direct Oral Anticoagulants (DOACs), such as rivaroxaban and apixaban, are still prescribed in APS, including in triple-positive patients who are at highest risk.

Associated outcomes:

  • Increased risk of stroke and recurrent thrombotic events

  • Reduced efficacy in preventing arterial thrombosis

  • Misleading safety assumptions due to general DOAC guidelines not applicable to APS

Treatment of the antiphospholipid syndrome with direct oralanticoagulants
https://leitlinien.dgk.org/2020/treatment-of-the-antiphospholipid-syndrome-with-direct-oralanticoagulants/

References:

7. Systemic Patterns of Medical Neglect

Recurring failures in APS management include:

  • Ignoring repeat-testing requirements for aPLs

  • Dismissing vWF abnormalities as incidental

  • Prescribing contraindicated drugs (e.g., allopurinol, MTX, DOACs) without screening

  • Misdiagnosing autoimmune CNS symptoms as psychiatric

  • Failure to involve rheumatology, hematology, neurology early in care

These failures disproportionately affect:

  • Women

  • Ethnic minorities

  • Adolescents and young adults with overlapping autoimmune presentations

The result is often severe, avoidable harm, including long-term neurologic damage and fatal drug reactions.

8. Conclusion: Preventable Harm from Clinical Blind Spots

APS with coagulopathy and immune overlap is a diagnostically and therapeutically manageable condition, yet outcomes are often poor due to systemic medical neglect. The addition of rare but known drug risks such as MTX-induced SJS and allopurinol hypersensitivity further demands vigilant clinical awareness.

When guidelines are ignored, testing protocols skipped, and unsafe medications prescribed, the result is a cascade of avoidable injury—including neurologic disability, mucocutaneous failure, organ dysfunction, and death.

This must change—through education, protocol reform, and above all, clinical vigilance.

**References**

1. **Neurologic Manifestations of the Antiphospholipid Syndrome — An Update**

   *Kraus SS, Levine SR. Current Rheumatology Reports (2021)*

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200381/

2. **Encephalitis: Symptoms and Causes – Mayo Clinic**

   *Mayo Clinic Health Information Resource*
https://www.mayoclinic.org/diseases-conditions/encephalitis/symptoms-causes/syc-20356136

3. **TRAPS Study – Rivaroxaban in High-Risk APS**

   *Pengo V et al., Blood (2018)*

   "Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome"
https://pubmed.ncbi.nlm.nih.gov/29540395/

4. **Guidelines on the Investigation and Management of Antiphospholipid Syndrome**

   *British Journal of Haematology (2012)*
https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2012.09125.x

5. **Allopurinol Hypersensitivity Syndrome and Toxicity**
Allopurinol: https://www.ncbi.nlm.nih.gov/books/NBK548098/

6. **HLA-B*5801 Association with Allopurinol-Induced SJS/TEN**

   *Hirata J et al. Nature Genetics (2006)*
   "A high-resolution HLA and SNP haplotype map for disease association studies"
https://pubmed.ncbi.nlm.nih.gov/16998491/

7. **rs3095318 SNP – Linked to HLA-B*5801 and SJS Risk**
   *SNPedia: rs3095318*
https://www.snpedia.com/index.php/Rs3095318

8. **Warfarin Dosing and Management Guidelines (ACCP)**
   *American College of Chest Physicians (CHEST Guidelines)*
   https://journal.chestnet.org/article/S0012-3692%2813%2960019-5/fulltext

9.**Hydroxychloroquine Use in Antiphospholipid Syndrome**
    *Erkan D et al., Lupus (2019)*
    "Long-term use of hydroxychloroquine in patients with antiphospholipid antibodies"
https://pubmed.ncbi.nlm.nih.gov/30761995/

10. **EULAR Recommendations for Management of APS**
    *European League Against Rheumatism (EULAR) – 2019 Guidelines*
https://ard.bmj.com/content/78/10/1296

11. **SJS/TEN Overview and Clinical Management**
https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1213889/full

12. **Methotrexate Induced Stevens-Johnson Syndrome: Two Cases Reports** 
https://clinmedjournals.org/articles/cmrcr/clinical-medical-reviews-and-case-reports-cmrcr-9-395.php?jid=cmrcr

13.**Antiphospholipid syndrome, ferritin and fever: Hyperferritinemic syndrome, a nosological ally** (PDF) https://rjr.com.ro/rjr-vol-32-no-2-year-2023/

    *UpToDate: Stevens-Johnson syndrome and toxic epidermal necrolysis*
https://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-clinical-features-diagnosis-and-pathogenesis *(Subscription required)*

Keywords: Antiphospholipid Syndrome (APS), von Willebrand Factor (vWF) Type 2 & 5, Brain Inflammation, Thrombosis, Encephalitis, Drug Reactions, Methotrexate (MTX), HLA-B*5801, Allopurinol, Warfarin, DOACs, Medical Neglect, Stevens-Johnson Syndrome (SJS)

© 2025-2030 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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