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Circulating Biomarkers for Hematological Disorders - A Diagnostic Tool

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Biomarkers in blood circulation can act as alternative non-invasive tools to diagnose and detect the prognosis of a hematological disorder.

Written by

Dr. Varshini

Medically reviewed by

Dr. Dheeraj Kela

Published At March 27, 2024
Reviewed AtMarch 27, 2024


Hematological disorders are a group of conditions that affect the blood or its cellular components. Such a dysfunction can result in benign or life-threatening diseases. So, an early diagnosis is essential to prevent or plan the treatment accordingly.

What Are the Circulating Biomarkers in Hematological Disorders?

Biomarkers are circulating components in the blood that can help assess disease status and predict the condition's prognosis. Various molecules and cellular components that act as biomarkers for hematological disorders are circulating in the blood. Some of them are:

Cell-Free DNA:

  • When any cell undergoes necrosis or apoptosis, the DNA fragments from the dead cells are released into circulation. These are called cell-free DNA. Cell-free DNA can detect mutations in FLT3-ITD and NPM1 genes that are responsible for the causation of chronic myeloid leukemia. Cell-free DNA analysis is also widely used to detect genetic derangements in clonal immunoglobulin for lymphoma.

  • Myelodysplastic syndrome and neoplasms occur due to gene derangements in TP53, SF3B1, TET2, JAK2, CALR, and MPL. This not only helps diagnose these conditions but also helps assess patients' response to chemotherapy.

Circulating Tumor Cells:

These are rare biomarkers that circulate in the blood. Tumor cells circulate in the blood when they detach from the original neoplastic lesion. The presence of circulating tumor cells also indicates the progression of the disease, saying that the condition is widely disseminated. This circulating biomarker is especially used in hematological disorders like multiple myeloma and acute leukemia.


MicroRNAs are a part of the cell structure regulating gene expression. Dysregulation of specific microRNAs (miRNAs) has been implicated in the pathogenesis of several hematological disorders. MiRNAs such as miR-155, miR-181a, and miR-34a are dysregulated in acute myeloid leukemia patients. Similarly, miR-15a, miR-16, and miR-29 have been identified in chronic lymphocytic leukemia patients. MiRNA expression profiles may also distinguish between indolent and aggressive forms of chronic lymphocytic leukemia. MiRNAs such as miR-21 and miR-155 are dysregulated in Hodgkin lymphoma patients and associated with clinical outcomes. In certain diseases like non-Hodgkin lymphoma, particularly diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma, the aberrations of microRNAs are responsible for the pathogenesis of the condition. Also, key pathways involved in the growth and progression of a tumor, like multiple myeloma, are determined by microRNAs.

Proteins as Biomarkers:

  • Proteins that help regulate inflammation and the immune response can act as a biomarker for hematological disorders. This includes chemokines and cytokines. Dysregulation of cytokine and chemokine levels is commonly observed in hematological disorders such as lymphoma, leukemia, and myeloma. For example, elevated levels of interleukin-6 (IL-6) have been associated with disease progression and poor prognosis in multiple myeloma.

  • Various growth factors are necessary in the body for normal blood cell production and proliferation. Any disturbance to the growth factor can result in various blood disorders. Growth factors such as erythropoietin, granulocyte colony-stimulating factor (G-CSF), and thrombopoietin play essential roles in regulating hematopoiesis. Abnormal levels of these growth factors can indicate underlying hematological disorders such as anemia (reduced erythrocytes), neutropenia or agranulocytosis, and thrombocytopenia (lesser number of thrombocytes than usual).

  • Hemoglobin and hemoglobin variants also act as circulating biomarkers for diagnosing hematological conditions. Reduced hemoglobin levels point to anemia, while increased levels indicate polycythemia vera. Abnormal forms of the hemoglobin molecule are seen in blood disorders like thalassemia or sickle cell anemia.

  • Abnormalities in coagulation factors and platelet proteins can contribute to bleeding disorders such as hemophilia, Christmas disease, and thrombocytopenia. Measurement of factors such as factor VIII, factor IX, and von Willebrand factor (vWF) levels is necessary for diagnosing and managing these hematological disorders.

  • Monoclonal gammopathies, including multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS), are characterized by abnormal blood monoclonal proteins (M-proteins). In such cases, detecting and quantifying the levels of immunoglobulins ( IgG, IgA, IgM) and M-proteins is essential.

  • Various enzymes in the body may show abnormal levels in hematological disorders. This includes enzymes like alkaline phosphatase, lactate dehydrogenase, or aspartate aminotransferase. This directly indicates the presence of inflammation accompanied by tissue damage secondary to a hematological or a neoplastic condition.

  • Surface markers and receptors expressed on hematopoietic cells are important for immunophenotyping and subclassifying hematological malignancies. Detection of markers such as CD20, CD19, CD33, and CD38 can be useful for blood diseases like lymphoma and leukemia.

  • Hemolytic disorders such as autoimmune hemolytic anemia and paroxysmal nocturnal hemoglobinuria (PNH) are characterized by the release of hemoglobin and other markers of hemolysis into the bloodstream. Measuring haptoglobin, lactate dehydrogenase (LDH), and free hemoglobin can help diagnose and monitor these conditions.


  • Exosomes are tiny extracellular components or vesicles that contain protein, lipid, and other molecules derived from their parent cells (like hematopoietic, tumor, or stromal cells), reflecting the physiological and pathological status of the cells from which they originate. These exosomes can help diagnose and predict the prognosis of hematological disorders.
  • Exosomal proteins such as CD63, CD81, and CD9 are commonly used as exosome isolation and characterization markers. In addition, tumor-specific antigens, oncogenic proteins, and genetic material (e.g., mutated DNA, microRNAs) found within exosomes can help in the easy diagnosis of hematological disorders.

  • Changes to the levels of these exosomes can help assess a hematological disorder's prognosis. This is particularly useful in malignancies of hematological origin.

What Are the Challenges in Using Circulating Biomarkers for Blood Disorders?

  • Hematological disorders exhibit varied clinical manifestations and disease biology. Using a specific biomarker in the circulation in such cases becomes difficult.

  • When circulating biomarkers are used, the sensitivity and specificity of their usage for a particular blood disorder are markedly reduced. Also, biomarkers should be able to distinguish disease and non-disease physiological states. Discriminating between disease-specific biomarker changes and non-specific fluctuations due to other factors can be challenging and may require additional clinical evaluation. This quality needs to be included among biomarkers and can be improved only when extensive research is performed for their usage.

  • Standardization of sample collection, processing, and analysis protocols is essential for ensuring the reproducibility and reliability of circulating biomarker assays. Variability in pre-analytical factors, such as blood collection methods or processing of the obtained sample, can introduce bias to the test and affect the accuracy of biomarker measurements.

  • Biomarkers should not be used for theoretical purposes. Integrating it into clinical practice is vital as it can be an important non-invasive alternative to routine investigations.


Overall, circulating biomarkers are considered effective non-invasive tools for diagnosis, prognosis, and prediction of disease progress. Unlike invasive methods like bone marrow biopsy, which can be painful and apprehensive for patients, detecting biomarker levels can be an excellent alternative for hematological disorders.

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Dr. Dheeraj Kela
Dr. Dheeraj Kela

General Medicine


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