Overview of Megakaryocytic Disorders

Overview of Megakaryocytic Disorders

Kaaren K. Reichard, MD

This BM core biopsy illustrates the typical, small hyperchromatic megakaryocytes with minimal cytoplasm image seen in HIV infection. Although abnormal, these megakaryocytes are not neoplastic.

This BM core biopsy shows megakaryocytic hyperplasia with numerous dysplastic, small, and hypolobated forms image in a case of myelodysplasia with isolated deletion 5q.



  • Immune thrombocytopenia (ITP)

  • Myelodysplasia (MDS)

  • Myeloproliferative neoplasm (MPN)

  • Acute myeloid leukemia (AML)


Age Range

  • Full spectrum

  • Constitutional disorders

    • Predominate in the young

    • Diagnosed in early childhood/infancy

  • Acquired disorders

    • Tend to predominate in adults

      • Key exceptions: ITP, neonatal thrombocytopenia

    • May be neoplastic or nonneoplastic


  • Constitutional megakaryocytic disorders

    • Rare

  • Acquired, reactive thrombocytosis and thrombocytopenia

    • More common than constitutional/neoplastic counterparts


Constitutional Disorders

  • Often result of underlying genetic mutation

  • Predisposition to malignancy

Acquired Disorders

  • Nonneoplastic

    • Nonclonal

    • Variety of causes

      • Infection

      • Inflammatory conditions

      • Drug

      • Autoimmune-related phenomena

  • Neoplastic

    • Clonal

    • Exposure to toxic substances

      • Carcinogens

      • Chemotherapy

      • Radiation

    • Acquired genetic mutations


Clinical Presentation

  • Constitutional megakaryocytic disorders

    • Often associated with physical abnormalities

    • May be associated with mental deficiency

    • Presentation in early childhood/infancy

    • Abnormal complete blood cell count (CBC)

      • Thrombocytosis

      • Thrombocytopenia

    • Bleeding tendency with thrombocytopenia

    • Some predisposition to thrombosis with thrombocytosis

  • Acquired platelet/megakaryocytic disorders, nonneoplastic

    • Reactive thrombocytosis

      • Clinically benign

      • Generally transient phenomenon

      • Treat underlying cause

    • Mild thrombocytopenia

      • Usually not associated with catastrophic clinical consequences

    • Moderate or severe thrombocytopenia

      • Often requires medical attention

      • Platelet transfusion

      • Plasma exchange

      • Control of underlying disorder: ITP, collagen vascular disease, HIV, neonatal alloimmune thrombocytopenia, other infections

  • Acquired megakaryocytic disorders, neoplastic

    • Abnormal CBC

    • Bone marrow failure, except for MPN

    • Cytopenias

      • Bleeding

      • Infection

    • Cytoses

      • Thrombosis


Normal Megakaryopoiesis

  • Megakaryocytes originate from hematopoietic stem cells

  • Cells committed to megakaryocytic lineage

    • Immunophenotypic identification

      • Expression of CD41a, CD42b, CD31, and von Willebrand factor (vWF)

  • Thrombopoietin is primary regulator

    • Loss of MPL or THPO gene results in profound thrombocytopenia

    • TPO normally binds to its receptor (Mpl)

  • Megakaryocytic maturation

    • DNA replication without cell division

    • Process termed endomitosis

      • Results in markedly enlarged cell with large amounts of cytoplasm

    • Megakaryocytes are multilobulated

    • Megakaryocytes are polyploid

      • Often 16N or occasionally 32N or 64N

    • 1,000-3,000 platelets shed from cytoplasm of each megakaryocyte

  • Megakaryocyte morphology

    • Megakaryoblasts are difficult to identify in BM

      • Blasts may show cytoplasmic blebbing

    • Immature (young) megakaryocytes

      • Smaller overall size

      • Higher nuclear to cytoplasmic ratio

      • More basophilic cytoplasmic appearance

      • Fewer nuclear lobes

    • Mature megakaryocytes

      • Voluminous, granular, pink cytoplasm

      • May exhibit broad range in size

      • May exhibit broad range in nuclear lobation

    • Assessment in BM aspirate

      • Megakaryocytes tend to reside in particles

      • In particles, more difficult to assess cytomorphology

      • In contrast to core biopsy, no sectioning artifact

    • Assessment in BM core biopsy

      • Advocated by many experts

      • Recall sectioning artifact when identifying hypolobated megakaryocytes

      • Due to large size, sectioning through megakaryocytes may distort morphology

  • Megakaryocyte BM topography

    • Predominantly individually distributed

    • Rarely, may see loose clusters

    • On average, range from 1-5 megakaryocytes on typical 40x magnification

    • Megakaryocytes typically reside adjacent to BM sinuses

      • Facilitates prompt shedding of platelets into circulation

      • Facilitates transmigration of other nucleated cells (e.g., neutrophils) through their cytoplasm (a.k.a. emperipolesis)

      • Highlight location with immunohistochemistry (CD31)

Normal Platelet Production and Appearance

  • Platelets are formed from pseudopodial megakaryocytic projections

  • Adult human can produce 1011 platelets per day; more if needed

  • Typical size: 2-4 µm

  • Typical count: 150-400 × 109/L in peripheral blood (PB)

  • Typically well granulated

  • Circulating megakaryocytes/megakaryocytic nuclei

    • Typically seen along feathered edge of blood smear

    • May be seen in neoplastic and nonneoplastic conditions

    • Nonneoplastic conditions

      • Acute stress

      • Severe infection

      • Trauma

      • Surgery

      • Burn

    • Neoplastic conditions

      • Variety of disorders: Mainly primary hematopoietic

Abnormal Megakaryopoiesis

  • Abnormal cytomorphology

    • Hypolobation/monolobation

      • Characteristic of myeloid neoplasms, particularly a myelodysplasia-related change

      • Cytoplasm remains eosinophilic with mature appearance

      • Not specific for clonal disorder: ITP, HIV infection, collagen vascular disease, certain drugs (e.g., valproate)

    • Megakaryocytes with distinctly separate nuclei

      • Characteristic of MDS

      • So-called pawn ball in the literature

    • Marked hyperlobulation

      • Sufficient numbers generally indicate a myeloid neoplasm

      • Megakaryocytes with > 64N (2N is normal diploid)

    • Pleomorphic and bizarre nuclei

      • Sufficient numbers generally indicate a myeloid neoplasm

      • Hyperchromasia

    • Naked nuclei

      • Prominent feature of ITP and HIV infection

      • Also seen in MPNs, namely primary myelofibrosis and polycythemia vera

  • Abnormal clustering

    • Characteristic of myeloid, particularly myeloproliferative, neoplasms

    • Not specific for clonal disorder

      • May be seen as early regenerative phenomenon after BM injury/toxic insult

  • Intrasinusoidal location

    • Characteristic of myeloproliferative neoplasms

    • Often indicative of extramedullary hematopoiesis

    • Not specific for clonal disorder

Abnormal Platelets

  • Abnormal size

    • Large

      • Macrothrombocytopenic disorders (e.g., ITP, MYH9-related diseases, Bernard-Soulier, Gray platelet syndrome)

    • Small

      • Thrombocytopenic disorders (e.g., WiskottAldrich syndrome)

  • Hypogranular/gray

  • Abnormal number

    • Thrombocytopenia

    • Thrombocytosis


Constitutional vs. Acquired Disorder

  • May further subclassify based on platelet count on number of BM megakaryocytes

  • Thrombocytosis defined as > 450 × 109/L

  • Thrombocytopenia defined as < 150 × 109/L

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Jun 13, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Overview of Megakaryocytic Disorders
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