Essential thrombocytosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Soujanya Thummathati, MBBS [2]

Overview

Essential thrombocytosis arises from hematopoietic stem cells which give rise to megakaryocytes which give rise to platelets (thrombocytes), that are normally involved in blood clotting. Development of essential thrombocytosis is the result of a genetic mutation in the janus kinase 2 (''JAK2'') gene in 50% of the patients. Other genes that may be involved in the pathogenesis of essential thrombocytosis are CALR, MPL, and THPO genes. On microscopic histopathological analysis, thrombocytosis, bone marrow hyperplasia with hyperlobated megakaryotic nuclei evident of thrombopoiesis are characteristic findings of essential thrombocytosis.

Pathophysiology

• As defined by WHO, essential thrombocytosis is a clonal proliferation of pluripotent stem cells with predominantly megakaryocytic differentiation in the bone marrow, resulting in an abnormally increased number of platelets released into the circulation.
• Janus kinase 2, a non-receptor tyrosine kinase protein belonging to the Janus kinase family that helps in signaling pathways involved in hematopoiesis (including thrombopoietin, erythropoietin, granulocyte-colony stimulating factor, Bcl-2, interleukin-3,5). A point mutation G to T, results in the substitution of valine for phenylalanine at amino acid 617 of the JAK2 protein, that activates the tyrosine kinase in JAK2, resulting in the activation of the JAK-STAT pathway. This results in abnormal differentiation and proliferation of the precursor cells, releasing the increased pool of platelets into the circulation.
• MPL and THPO genetic mutations also result in the activation of JAK-STAT pathway resulting in abnormal platelet proliferation.
• Thrombopoietin (TPO) is a hormone produced predominantly by the liver, bone marrow and kidney, that regulates the stimulation, production and proliferation of megakaryocytes. Once thrombopoietin binds to the TPO receptors on the megakaryocytes, it is destroyed thus making the megakaryocyte unavailable for further hormonal interaction.
  • With high platelet counts, essential thrombocytosis should hypothetically present with lower thrombopoietin levels. However, there is a paradoxical increase in free circulating levels of thrombopoietin as the abnormal platelets in essential thrombocytosis have defective TPO receptors that do not allow proper binding of thrombopoietin.
• Platelets contain different types of granules: alpha (contain P-selectin, platelet factor 4, transforming growth factor-β1, platelet-derived growth factor, fibronectin, B-thromboglobulin, vWF, fibrinogen, and coagulation factors V and XIII), delta (δ) or dense granules (contain ADP or ATP, calcium, and serotonin), gamma (γ) and lambda (λ) granules. With defective granules in essential thrombocytosis, there is a deficiency in clotting factors like fibrinogen and von Willebrand (vWF) that impairs the process of aggregation.
• On the other hand, patients with secondary or reactive thrombocytosis have normal platelet activity with no defects in aggregation.

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  CFU-Me (pluripotential hemopoietic stem cell or hemocytoblast) -> megakaryoblast -> promegakaryocyte -> megakaryocyte.

Genetics

• Essential thrombocytosis is associated with mutations in janus kinase 2 (JAK2) gene in 50% of the patients.
• For unknown reasons, a point mutation in the amino acid 617 of JAK2 protein, results in the substitution of valine for phenylalanine from a G to T replacement. This activates the janus kinase protein, signaling the process of hematopoiesis that results in the differentiation and proliferation of platelets.
• In recent studies, another mutation in the Calreticulin (''CALR'') gene has been identified in patients with essential thrombocytosis who lacked JAK2 mutations. The mechanism by which the mutation triggers the disease remains unknown.
• Other genes that may be involved in the pathogenesis of essential thrombocytosis are ''MPL'' and ''THPO'' genes.

Microscopic findings of essential thrombocytosis

• A complete blood count shows marked elevation of platelet count greater than or equal to 600,000/μL of blood and sometimes even higher.
• The platelet shape and size usually remain unchanged, but variations may occur.
• The red cell morphology depends on the presence and severity of bleeding.
• The white cell count remains slightly elevated.
• Bone marrow biopsy is the definitive diagnostic test for essential thrombocytosis. The bone marrow is usually hypercellular, though it can be normocellular. The megakaryocytes are bigger in size and have hyperlobated nuclei which is the characteristic feature of increased thrombopoiesis. Cells are usually stainable with iron, provided the patient had no significant hemorrhagic events. Collagen fibrosis is typically absent.

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  This represents a platelet count between 1.5 and 2 million per microliter (normal range is between 0.150 and 0.450 million). The patient had had an elevated count for at least 15 years but is asymptomatic.

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  Histopathological image representing a bone marrow aspirate in a patient with essential thrombocythemia. Hematoxylin & eosin stain.

References

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