Haematological Manifestations of SARS-CoV-2: Insights into Erythropoiesis, Hepcidin Regulation, and Cytokine Storm

By SWA

The emergence of SARS-CoV-2 (COVID-19) has unveiled a complex interplay between the virus and the host's hematopoietic system, leading to significant haematological manifestations. Among these, disruptions in erythropoiesis, dysregulation of hepcidin, and the effects of the cytokine storm on red blood cell production and iron metabolism have been widely observed. This article delves into these critical aspects to shed light on the pathophysiological mechanisms behind COVID-19-related haematological abnormalities.

Erythropoiesis in the Context of SARS-CoV-2

Erythropoiesis, the process by which red blood cells (RBCs) are produced, is a highly regulated system that ensures the continuous supply of oxygen to tissues. Disruptions in erythropoiesis have been noted in COVID-19 patients, often manifesting as anemia or altered red blood cell indices.

Impact of SARS-CoV-2 on Erythropoiesis

  1. Hypoxia and Erythropoietin (EPO) Dysregulation:

    • COVID-19 frequently induces hypoxemia due to respiratory compromise. This hypoxia would typically stimulate erythropoietin (EPO) production in the kidneys, leading to increased erythropoiesis. However, in many COVID-19 patients, a paradoxical blunted EPO response has been observed, leading to inadequate RBC production despite hypoxia.
    • The inflammatory environment generated by the virus may impair EPO signaling or directly damage renal tissue, further reducing EPO synthesis.

  2. Bone Marrow Suppression:

    • In severe cases, SARS-CoV-2 has been associated with direct infection of hematopoietic progenitor cells, potentially mediated by the ACE2 receptor expressed in some bone marrow cells.
    • Systemic inflammation and cytokines such as interleukin-6 (IL-6) can suppress erythropoiesis by altering the bone marrow microenvironment, reducing the proliferation of erythroid precursors.

  3. Oxidative Stress and Hemoglobin Dysfunction:

    • SARS-CoV-2 has been suggested to induce oxidative stress, which can damage RBCs, impair hemoglobin function, and increase erythrocyte turnover. This further contributes to anemia and necessitates increased RBC production, putting additional strain on erythropoiesis.

Hepcidin Regulation and Iron Metabolism in COVID-19

Iron homeostasis is critical for erythropoiesis, as it is a key component of hemoglobin. The liver-derived peptide hormone hepcidin regulates iron availability by controlling the absorption of dietary iron and the release of stored iron. In COVID-19, hepcidin dysregulation is a prominent feature that contributes to anemia and iron sequestration.

Role of Hepcidin in COVID-19-Related Anemia

  • Cytokine-Induced Hepcidin Upregulation:

    • Elevated levels of inflammatory cytokines, particularly IL-6, during the cytokine storm lead to increased hepcidin synthesis. High hepcidin levels block ferroportin (an iron exporter) on enterocytes and macrophages, trapping iron in storage sites and reducing its availability for erythropoiesis.
    • This state, termed anemia of inflammation, is a hallmark of many COVID-19 patients and is characterized by low serum iron levels despite adequate iron stores.

  • Iron Overload and Oxidative Damage:

    • In contrast, some COVID-19 patients with comorbid conditions like hemoglobinopathies or chronic liver disease may experience dysregulated iron metabolism, leading to iron overload. Excess iron can exacerbate oxidative stress and organ damage.

Cytokine Storm and Its Effects on Hematopoiesis

The cytokine storm—a hyperinflammatory response seen in severe COVID-19—is one of the key drivers of haematological abnormalities. Elevated levels of cytokines, including IL-6, IL-1β, TNF-α, and interferons, significantly impact the production, survival, and function of blood cells.

Key Mechanisms Linking the Cytokine Storm to Haematological Manifestations

  1. Suppression of Erythroid Precursors:

    • Pro-inflammatory cytokines suppress erythroid progenitor cell proliferation and differentiation, leading to reduced RBC production.
    • IL-6, in particular, has been implicated in altering bone marrow function and increasing hepcidin synthesis, compounding the effects on erythropoiesis.

  2. Hemophagocytic Lymphohistiocytosis (HLH):

    • In severe cases, cytokine storms may trigger secondary HLH, a hyperinflammatory syndrome in which activated macrophages engulf blood cells, including erythrocytes, further contributing to anemia.

  3. Increased Red Blood Cell Turnover:

    • The heightened inflammatory and oxidative environment during cytokine storms can lead to increased RBC destruction, exacerbating the need for erythropoiesis.

Clinical Implications and Management Strategies

The interplay between erythropoiesis, hepcidin regulation, and cytokine storms in COVID-19 patients has important clinical implications. The following approaches can help mitigate the haematological complications of SARS-CoV-2:

  1. Addressing Anemia of Inflammation:

    • Anti-inflammatory therapies, such as IL-6 inhibitors (e.g., tocilizumab), can help reduce cytokine-driven hepcidin overproduction and improve iron availability for erythropoiesis.

  2. Erythropoietin Therapy:

    • In patients with inadequate EPO production or response, recombinant erythropoietin therapy may stimulate erythropoiesis and alleviate anemia.

  3. Iron Supplementation:

    • Careful use of intravenous iron supplements may be warranted in patients with functional iron deficiency (low serum iron despite normal or elevated ferritin).

  4. Managing Hyperinflammation:

    • Targeted therapies to dampen the cytokine storm, such as corticosteroids and JAK inhibitors, can improve hematopoiesis by restoring the bone marrow microenvironment.

  5. Monitoring and Treating Coagulopathies:

    • Thrombocytopenia, disseminated intravascular coagulation (DIC), and microthrombosis are additional haematological complications of COVID-19 that require careful management to prevent morbidity and mortality.

Conclusion

SARS-CoV-2 has profound effects on the hematopoietic system, with disruptions in erythropoiesis, hepcidin regulation, and cytokine-mediated inflammation playing central roles in its haematological manifestations. Understanding these mechanisms provides valuable insights into the pathophysiology of COVID-19-related anemia and offers a basis for developing targeted therapeutic interventions. As research progresses, addressing these haematological abnormalities will remain a critical component of comprehensive COVID-19 management.

Reference: 

Haematological Manifestations of SARS-CoV-2: Insights into Erythropoiesis, Hepcidin Regulation, and Cytokine Storm https://www.mdpi.com/1422-0067/26/3/874

© 2000-2025 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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