Agranulocytosis: A Severe and Life-Threatening Blood Disorder

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Agranulocytosis is a rare but potentially life-threatening disorder of the blood, characterized by an almost complete absence of granulocytes in the blood. Granulocytes are a critical subtype of white blood cells (leukocytes) that play a central role in the immune defense, particularly in the fight against bacterial infections. Without granulocytes, the body becomes highly susceptible to infections, and even minor bacterial invasions can lead to severe, rapidly progressing complications.

Definition and Clinical Criteria

Agranulocytosis is defined as a severe reduction in the number of granulocytes, typically neutrophils, in the peripheral blood. Medically, this condition is diagnosed when the absolute neutrophil count (ANC) falls below 500 cells per microliter of blood. At this level, the immune defense is critically impaired, exposing patients to a high risk of overwhelming infections.

Metamizole by other names: 

Generic names 

  • Dipyrone
  • Sulpyrine
  • Noramidopyrine methanesulfonic acid
  • Novaminsulfon

    • Pathophysiology and Causes

    The most common cause of agranulocytosis is an adverse reaction to certain medications. In many cases, the reaction is idiosyncratic, meaning it is unpredictable and not dose-dependent. It may be due to:

    • Immune-mediated destruction of granulocytes or their precursors.

    • Direct toxic effects on the bone marrow, where granulocytes are produced.

    Medications frequently implicated include:

    • Metamizole (Novaminsulfon): A non-opioid analgesic and antipyretic. While effective for pain and fever, it carries a rare but serious risk of agranulocytosis.

    • Clozapine: An antipsychotic used for treatment-resistant schizophrenia, known for its potential to cause neutropenia and agranulocytosis.

    • Chemotherapeutic agents (cytostatics): These drugs directly suppress bone marrow function, often leading to neutropenia and agranulocytosis.

    • Others: Antibiotics (e.g., beta-lactams), antithyroid medications, antihistamines, ACE inhibitors, and certain antihypertensive drugs have also been associated.

    Clinical Presentation and Symptoms

    Because of the severely reduced number of white blood cells, particularly neutrophils, patients often present with signs and symptoms of infection, which may be the first clinical clue to an underlying agranulocytosis. Common symptoms include:

    • High fever

    • Chills

    • Fatigue

    • Sore throat

    • Painful oral ulcers (often a manifestation of so-called angina agranulocytotica)

    • Difficulty swallowing due to mucosal lesions

    If not promptly recognized and treated, the condition can progress rapidly to sepsis and multi-organ failure.

    Case Example: Metamizole-Induced Agranulocytosis

    A typical case involves a patient, often previously healthy, developing acute symptoms such as fever, malaise, sore throat, and oral ulcers shortly after starting metamizole. One documented case describes a 29-year-old man who experienced a marked deterioration in general health, fever, and difficulty swallowing after using metamizole for pain relief. Laboratory tests revealed a dangerously low neutrophil count, confirming agranulocytosis.

    Immediate withdrawal of metamizole and initiation of supportive care, including antibiotics and possibly granulocyte-colony stimulating factor (G-CSF), are essential for survival.

    Diagnosis

    Diagnosis is based on:

    • Complete blood count (CBC) showing a severe reduction in neutrophils.

    • Bone marrow biopsy (in unclear cases) to determine if the bone marrow is failing or if peripheral destruction is responsible.

    • History of recent medication use, especially known risk drugs such as metamizole or clozapine.

    Management and Treatment

    The cornerstone of treatment is immediate discontinuation of the causative agent and management of infections.

    Key components of treatment include:

    1. Stopping the offending drug immediately.

    2. Broad-spectrum antibiotics to treat or prevent infections.

    3. Granulocyte-colony stimulating factor (G-CSF) to accelerate neutrophil recovery in severe cases.

    4. Isolation precautions to protect immunocompromised patients from opportunistic infections.

    5. Monitoring with frequent CBCs to follow blood count recovery.

    Metamizole and Regulatory Concerns

    Metamizole is a widely used analgesic in countries like Germany, but it has been banned in countries such as Sweden, the UK, and the USA due to its rare but potentially fatal risk of agranulocytosis.

    In June 2024, the European Medicines Agency (EMA) initiated a formal safety review of metamizole-containing products across the EU. This decision followed reports from Finland, where new cases of agranulocytosis continued to occur despite enhanced risk minimization strategies. Finnish authorities observed that even adding warnings to packaging and patient cards was insufficient, prompting the sole marketing authorization holder to withdraw the product from the Finnish market.

    The EMA's investigation will assess:

    • Whether current risk mitigation strategies are effective.

    • If additional regulatory action, such as restriction or withdrawal, is necessary.

    • How to harmonize the drug’s safety profile management across EU member states.

    In Germany, metamizole remains available and is prescribed for:

    • Severe acute pain (postoperative or injury-related)

    • Tumor-related pain

    • Colic

    • High fever unresponsive to other treatments

    Despite being categorized as a very rare side effect (affecting fewer than 1 in 10,000 users), the risk of agranulocytosis is taken seriously due to the condition’s sudden onset and high mortality if untreated.

    Prevention and Monitoring

    For drugs known to carry a risk of agranulocytosis:

    • Baseline and routine blood monitoring are essential, particularly for Clozapine, where strict blood count protocols are enforced.

    • Patient education is critical: Patients should be informed of early warning signs like fever or sore throat and instructed to seek immediate medical care if symptoms appear.

    • Pharmacovigilance should remain active, with healthcare providers reporting suspected cases to drug safety authorities.

    Conclusion

    Agranulocytosis is a medical emergency that demands immediate recognition and response. Although rare, its potential for rapid deterioration and fatal outcomes makes it a critical consideration when prescribing high-risk medications. Metamizole, while effective, continues to pose challenges in drug safety management, prompting ongoing review at both national and international levels.

    Healthcare professionals must remain vigilant, ensuring early detection, appropriate laboratory monitoring, and rapid intervention to minimize harm. Patient safety must guide regulatory and clinical decisions surrounding the continued use of high-risk medications like metamizole.

    References: 

    Metamizole-containing medicinal products: Risk of agranulocytosis - referral
    https://www.ema.europa.eu/en/medicines/human/referrals/metamizole-containing-medicinal-products-0

    Metamizole https://en.wikipedia.org/wiki/Metamizole

    Metamizole [Dipyrone]
    https://www.ncbi.nlm.nih.gov/books/NBK604194/#:~:text=Rare%20but%20potentially%20serious%20adverse,1:1%2C000%2C000%20exposed%20persons).

    What is Metamizole used for? https://www.drugs.com/medical-answers/metamizole-3566997/

    Single dose dipyrone (metamizole) for acute postoperative pain in adults
    https://pmc.ncbi.nlm.nih.gov/articles/PMC6540653/

    Granulocytes: https://www.youtube.com/watch?v=hCKk5pDXKuU

    © 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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