Chapter 103. Polycythemia Vera and Other Myeloproliferative Diseases (Part 9)

EtiologyMegakaryocytopoiesis and platelet production depend upon thrombopoietin and its receptor, Mpl. As in the case of early erythroid and myeloid progenitor cells, early megakaryocytic progenitors require the presence of interleukin 3 (IL-3) and stem cell factor for optimal proliferation in addition to thrombopoietin. Their subsequent development is also enhanced by the chemokine stromal cell–derived factor 1 (SDF-1). However, megakaryocyte maturation and differentiation require thrombopoietin.Megakaryocytes are unique among hematopoietic progenitor cells because reduplication of their genome is endomitotic rather than mitotic. In the absence of thrombopoietin, endomitotic megakaryocytic reduplication and, by extension, the cytoplasmic development necessary for platelet production are...
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Chapter 103. Polycythemia Vera and Other Myeloproliferative Diseases (Part 9) Chapter 103. Polycythemia Vera and Other Myeloproliferative Diseases (Part 9) Etiology Megakaryocytopoiesis and platelet production depend upon thrombopoietinand its receptor, Mpl. As in the case of early erythroid and myeloid progenitorcells, early megakaryocytic progenitors require the presence of interleukin 3 (IL-3)and stem cell factor for optimal proliferation in addition to thrombopoietin. Theirsubsequent development is also enhanced by the chemokine stromal cell–derivedfactor 1 (SDF-1). However, megakaryocyte maturation and differentiation requirethrombopoietin. Megakaryocytes are unique among hematopoietic progenitor cells becausereduplication of their genome is endomitotic rather than mitotic. In the absence ofthrombopoietin, endomitotic megakaryocytic reduplication and, by extension, thecytoplasmic development necessary for platelet production are impaired. Likeerythropoietin, thrombopoietin is produced in both the liver and the kidneys, andan inverse correlation exists between the platelet count and plasma thrombopoieticactivity. Like erythropoietin, plasma levels of thrombopoietin are controlledlargely by the size of its progenitor cell pool. In contrast to erythropoietin, but likeits myeloid counterparts, granulocyte- and granulocyte-macrophage colony-stimulating factors, thrombopoietin not only enhances the proliferation of its targetcells but also enhances the reactivity of their end-stage product, the platelet. Inaddition to its role in thrombopoiesis, thrombopoietin also enhances the survival ofmultipotent hematopoietic stem cells. The clonal nature of ET was established by analysis of glucose-6-phosphatedehydrogenase isoenzyme expression in patients hemizygous for this gene, byanalysis of X-linked DNA polymorphisms in informative women patients, and bythe expression in patients of nonrandom, though variable, cytogeneticabnormalities. Although thrombocytosis is its principal manifestation, like theother chronic myeloproliferative disorders, a multipotent hematopoietic progenitorcell is involved in ET. Furthermore, a number of families have been described inwhich ET was inherited, in one instance as an autosomal dominant trait. Inaddition to ET, IMF and PV have also been observed in some kindreds. Clinical Features Clinically, ET is most often identified incidentally when a platelet count isobtained during the course of a routine medical evaluation. Occasionally, reviewof previous blood counts will reveal that an elevated platelet count was present butoverlooked for many years. No symptoms or signs are specific for ET, but thesepatients can have hemorrhagic and thrombotic tendencies expressed as easybruising for the former and microvascular occlusions for the latter, such aserythromelalgia, ocular migraine, or TIAs. Physical examination is generallyunremarkable except occasionally for mild splenomegaly. Massive splenomegalyis more indicative of another myeloproliferative disorder, in particular PV, IMF, orCML. Anemia is unusual, but a mild neutrophilic leukocytosis is not. The bloodsmear is most remarkable for the number of platelets present, some of which maybe very large. The LAP score is either normal or elevated. The large mass ofcirculating platelets may prevent the accurate measurement of serum potassiumdue to release of platelet potassium upon blood clotting. This type of hyperkalemiais a laboratory artifact and not associated with electrocardiographic abnormalities.Similarly, arterial oxygen measurements can be inaccurate unlessthrombocythemic blood is collected on ice. The prothrombin and partialthromboplastin times are normal, while abnormalities of platelet function such as aprolonged bleeding time and impaired platelet aggregation can be present.However, in spite of much study, no platelet function abnormalities arecharacteristic of ET, and no platelet function test predicts the risk of clinicallysignificant bleeding or thrombosis. The elevated platelet count may hinder marrow aspiration, but marrowbiopsy usually reveals megakaryocyte hyperplasia and hypertrophy, as well as anoverall increase in marrow cellularity. If marrow reticulin is increased, anotherdiagnosis should be considered. The absence of stainable iron demands anexplanation because iron deficiency alone can cause thrombocytosis, and absentmarrow iron in the presence of marrow hypercellularity is a feature of PV. Nonrandom cytogenetic abnormalities occur in ET but are uncommon, andno specific or consistent abnormality is notable, even those involvingchromosomes 3 and 1, where the genes for thrombopoietin and its receptor Mpl,respectiv ...