The Megakaryocytes in Idiopathic Thrombocytopenic Purpura, a Form of Hypersplenism

Abstract

1. The megakaryocytes of the sternal bone marrow at biopsy were studied in 11 cases of idiopathic thrombocytopenic purpura and compared with those of 10 normal cases, 5 of thrombocytopenic purpura associated with various types of splenomegaly, and of a large group of miscellaneous hematologic conditions, including leukemia, associated with a reduction in platelets. 2. Megakaryocyte counts expressed in terms of a million nucleated red cells and differential counts of megakaryocytes were performed. The megakaryocytes were classified as megakaryoblasts, promegakaryocytes, and mature forms, and were further subdivided into those showing granularity, platelet production, degenerated forms, and mitoses. 3. In the normal cases, not more than 300 megakaryocytes per million nucleated red cells were present, and an average of 68.6 per cent showed platelet production. 4. In acute idiopathic thrombocytopenic purpura, although the platelets in the circulating blood were rare, megakaryocytes were increased, being present in a proportion of 366 to 743 per million nucleated red cells. Platelet production was, however, greatly diminished and found in only 8 to 19 per cent of all megakaryocytes. Following splenectomy, there was a striking increase in platelet production, which was now present in 69 to 85 per cent of all cells; the large masses of new platelets in the marrow were often very striking. 5. In chronic idiopathic thrombocytopenic purpura, the megakaryocytes were considerably increased over normal values, but showed great diminution in platelet production; following splenectomy, extreme degrees of platelet production from megakaryocytes took place. 6. In splenomegaly of nonleukemic origin (cirrhosis, splenic vein thrombosis, Gaucher's disease, Felty's syndrome), the megakaryocytes were somewhat increased, but platelet production was normal. 7. In aplastic anemia, lymphosarcoma, acute leukemia, and other diseases invading or destroying the bone marrow, the megakaryocytes were conspicuously reduced, the few remaining cells present being of normal morphology. 8. The origin of the blood platelets from megakaryocytes, certain regulatory mechanisms for platelet production and delivery, and the possible relationship of the spleen to these mechanisms are discussed. 9. The findings of increased megakaryocytes and greatly diminished platelet production in the marrow before splenectomy and the striking increase in platelet production after splenectomy indicate a definite pathogenetic relationship of the spleen to the disease. Idiopathic thrombocytopenic purpura is probably a form of hypersplenism (splenic thrombopenia) in which, through a possible hormonal mechanism, the megakaryocytes of the bone marrow are inhibited from normal platelet production and delivery. 10. The marrow findings in idiopathic thrombocytopenic purpura are sufficiently characteristic to be of diagnostic value in differentiating the disease from leukemia and other conditions associated with a low blood platelet count.

CD8+ T cells suppress autologous megakaryocyte apoptosis in idiopathic thrombocytopenic purpura

“…However, our present work showed unexpected results: as more CD8 + T cells were present in ITP cultures, megakaryocyte count was boosted while maturation and ability to produce platelets were suppressed. Unlike the hypothesis that CD8 + T cells may equally lyse megakaryocytes, our finding was compatible with early morphological studies of ITP bone marrow, which showed normal or increased numbers of megakaryocytes (Dameshek & Miller, 1946), and with the findings that plasma thrombopoietin (TPO) levels in ITP patients were normal to slightly elevated, indicating that the total megakaryocytic mass was not decreased in ITP (Porcelijn et al, 1998;Kappers-Klunne et al, 2001;Sun et al, 2006). According to these studies, we believe that CD8 + T cells of ITP patients might affect megakaryocytopoiesis through mechanisms other than cell-mediated lysis exerted on peripheral platelets.…”

Studies of the Life Span and Fate of Platelets

“…An initiaL suggestion by Schwartz and Kaplan (1950) that:the presence of marrow eosinophilia coriel\1-,~~d' i:ith an increased remission rate has not been supported by subsequent experience (Lozner, 1953). Similarly, the number and morphology of megakaryocytes were early proposed by Dameshek and Miller (1946) to be helpful in predicting the response to therapy; but this also has not proved of great value (Walker and Walker, 1961). It has been suggested by Harrington et alii (1953) that the response to splenectomy parallels the presence or absence of demonstrable platelet agglutinins ; but there has been difficulty in correlating the results of different methods of antibody detection (Cohen et alii, 1961) so that this test has limited value in assessing prognosis in this disease.…”

“…Controversy about the role of the spleen in the pathogenesis of thrombocytopenia persists, and is reflected, in part, in the disagreement 333 about ideal therapy in idiopathic thrombocytopenic purpura (Dameshek et alii, 1958 ;Carpenter et alii, 1959). Although morphology of the bone marrow (Dameshek and Miller, 1946) and the presence of demonstrable platelet agglutinins (Harrington et alii, 1953) have both been used to aid prognosis, there has not been uniform agreement about the possibility of predicting the response to therapy in this disease.…”

Pathogenesis of chronic immune thrombocytopenia: increased platelet destruction and/or decreased platelet production

“…In studies dating back to the 1940s, bone marrow from ITP patients examined by light microscopy showed morphological evidence of: (i) abnormal thrombopoiesis, including normal or increased megakaryocyte numbers with a larger percentage of younger forms lacking cytoplasmic granularity or evidence of platelet formation, (ii) degenerative changes in both nuclei and cytoplasm (Dameshek & Miller, 1946;Diggs & Hewlitt, 1948). Phase contrast studies in the 1950s confirmed these findings and also showed that infusing healthy controls with plasma from ITP patients produced these same abnormalities in megakaryocytes (Pisciotta et al, 1953).…”