Thrombocytopenia in Patients With Myelodysplastic Syndromes

Bryan, Jeffrey C.; Jabbour, Elias; Prescott, Hillary; Kantarjian, Hagop M.

doi:10.1053/j.seminhematol.2010.02.006

Cited by 31 publications

(37 citation statements)

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“…Surprisingly, after treatment with eltrombopag daily, 11 of 25 subjects had a haematological response with six subjects ultimately having a trilineage increase as well as increased bone marrow cellularity (Olnes et al , ). With already highly elevated TPO levels, it is unclear whether eltrombopag is producing this beneficial effect via the TPO receptor of some other ‘off‐target’ effect. MDS patients have thrombocytopenia and this often occurs before other cytopenias (Kantarjian et al , ; Bryan et al , ; Al Ameri et al , ). Treatment of 250 patients with International Prognostic Scoring System low/intermediate‐1 MDS with romiplostim (167 patients) produced an increase in platelet count, reduced need for transfusion and reduced bleeding compared with treatment with placebo (83 patients).…”

Section: Clinical Outcomes With Tpo Receptor Agonistsmentioning

confidence: 99%

Milestones in understanding platelet production: a historical overview

Kuter

2014

Br J Haematol

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SummaryThe discovery of thrombopoietin (TPO, also termed THPO) in 1994 was a major achievement in understanding the regulation of platelet production. In prior decades, physiological studies had demonstrated that platelets were produced from bone marrow megakaryocytes and that the megakaryocytes responded to thrombocytopenia by increasing their number, size and DNA ploidy. In 1958, it was proposed that a 'thrombopoietin' must exist that regulated this interaction between the circulating platelet mass and the bone marrow megakaryocytes. After over three decades of effort, TPO was finally purified by five independent laboratories. TPO stimulated megakaryocyte colony-forming cell growth and increased the number, size and ploidy of megakaryocytes. When the genes for TPO or TPO receptor were eliminated in mice, megakaryocytes grew and platelets were made, but at 15% of their normal number. A first generation of recombinant human (rh) TPO molecules [rhTPO and pegylated recombinant human megakaryocyte growth and development factor (PEG-rhMGDF)] rapidly entered clinical trials in 1995 and increased platelet counts in humans undergoing nonmyeloablative chemotherapy but not in those undergoing stem cell transplantation. Antibodies developed against PEGrhMGDF and development of these recombinant thrombopoietins ended. A second generation of TPO receptor agonists (romiplostim and eltrombopag) was then developed. Neither of these TPO receptor agonists demonstrated any significant untoward effects and both are now licensed in many countries for the treatment of immune thrombocytopenia. This review describes the significant experiments that have surrounded the discovery of TPO and its clinical development.

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Section: Clinical Outcomes With Tpo Receptor Agonistsmentioning

confidence: 99%

Milestones in understanding platelet production: a historical overview

Kuter

2014

Br J Haematol

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“…43,44 Deficient platelet production is one of the hallmarks of leukemia and myelodyplastic syndrome, and bleeding from low platelet counts is one of the most common causes of death in these patients. 45,46 Therapeutic modalities are being developed to interfere with stathmin expression to inhibit cell proliferation, angiogenesis, and cell migration in several types of cancer. 47,48 The present study opens new avenues of investigation into the mechanisms responsible for MK maturation that may prove relevant for hematologic malignancies in which stathmin expression and/or functions are altered.…”

Section: Effects Of Stathmin Expression On Platelet Formationmentioning

confidence: 99%

Down-regulation of stathmin expression is required for megakaryocyte maturation and platelet production

Iancu‐Rubin

Gajzer

Tripodi

et al. 2011

Blood

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The final stages of of megakaryocyte (MK) maturation involve a series of steps, including polyploidization and proplatelet formation. Although these processes are highly dependent on dynamic changes in the microtubule (MT) cytoskeleton, the mechanisms responsible for regulation of MTs in MKs remain poorly defined. Stathmin is a highly conserved MTregulatory protein that has been suggested to play a role in MK differentiation of human leukemic cell lines. However, previous studies defining this relationship have reached contradictory conclusions. In this study, we addressed this controversy and investigated the role of stathmin in primary human MKs. To explore the importance of stathmin down-regulation during megakaryocytopoiesis, we used a lentiviral-mediated gene delivery system to prevent physiologic down-regulation of stathmin in primary MKs. We demonstrated that sustained expression of constitutively active stathmin delayed cytoplasmic maturation (ie, glycoprotein GPIb and platelet factor 4 expression) and reduced the ability of MKs to achieve high levels of ploidy. Moreover, platelet production was impaired in MKs in which downregulation of stathmin expression was prevented. These studies indicate that suppression of stathmin is biologically important for MK maturation and platelet production and support the importance of MT regulation during the final stages of thrombopoiesis. (Blood. 2011; 117(17):4580-4589) IntroductionMegakaryocytopoiesis is a complex process in which hematopoietic stem cells proliferate, differentiate, undergo terminal maturation, and give rise to circulating platelets. 1 During the early stages of megakaryocytopoiesis, megakaryocyte (MK) progenitors are diploid, proliferative and express early markers of the MK lineage. In the later stages, MKs cease to divide but continue to replicate their DNA and become polyploid (ie, DNA content Ͼ 2N). This is accompanied by expression of more MK-specific markers and an increase in nuclear complexity and cell size. Lastly, mature MKs develop long cytoplasmic extensions, known as proplatelets, that release large numbers of platelets into the circulation. 2 The processes of polyploidization and proplatelet formation are unique to the MK lineage. Both processes are characterized by dramatic changes in the organization of the microtubule (MT) cytoskeleton. After multiple rounds of normal cell divisions, MK progenitors switch from a normal to a form of abortive mitosis, known as endomitosis, in which MKs enter and progress normally through mitosis but fail to undergo cytokinesis and divide. [3][4][5] This process is mediated by an atypical organization of MTs that forms a complex, spherical mitotic spindle. 4,6 Recent studies have suggested that the failure of MKs to complete cytokinesis is associated, in part, with defective elongation of spindle MTs. 5 On the other hand, studies by Patel et al have demonstrated that the cytoplasm of mature MKs contains bundles of polymerized MTs that extend into the proplatelets and provide their structural scaffold ...

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“…Transfusion-refractory thrombocytopenia is an important clinical challenge that is commonly seen in MDS and other hematologic malignancies. In MDS, thrombocytopenia is seen in approximately 45 -65% of cases [8] , the severity of which increases with higher-risk disease [9] . Hemorrhagic complications are a major cause of morbidity and mortality in the MDS population, with estimated incidence of 14 -24% of MDS-related deaths, only second to infection [10] .…”

Section: Discussionmentioning

confidence: 99%

Splenic artery embolization as a bridge to splenectomy in severe transfusion-refractory thrombocytopenia secondary to myelodysplastic syndrome

Emadi¹,

Holtzman²,

Duong³

et al. 2016

IJHT

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Transfusion-refractory thrombocytopenia is an important clinical challenge in the treatment of patients with myelodysplastic syndrome. Hypersplenism can play a major role in splenic platelet sequestration and transfusion refractoriness, and though rare in myelodysplastic syndrome, it can commonly be seen in a wide range of other benign and malignant conditions. Splenectomy has been an effective approach in management of hypersplenism-induced cytopenias, however those who are unresponsive to platelet transfusions are not surgical candidates making this an unfeasible treatment option. There has been increasing interest in the therapeutic value of the less invasive procedure of splenic artery embolization. Here we report the first case of a patient with myelodysplastic syndrome complicated by hypersplenism and severe transfusion-refractory thrombocytopenia in which a splenic artery embolization was successfully used as a bridge to splenectomy, which resulted in platelet transfusion responsiveness and correction of her thrombocytopenia. Reversal of severe thrombocytopenia has multiple important therapeutic values including allowing patients to safely continue receiving myelosuppressive chemotherapy treatments which are sometimes delayed or dose-adjusted due to cytopenias, safely undergo surgical interventions and also open the door for candidacy for stem cell transplantation. In conclusion, splenic artery embolization with or without subsequent splenectomy is highly recommended as a safe therapeutic option in patients with hematologic malignancies.

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Thrombocytopenia in Patients With Myelodysplastic Syndromes

Cited by 31 publications

References 38 publications

Milestones in understanding platelet production: a historical overview

Milestones in understanding platelet production: a historical overview

Down-regulation of stathmin expression is required for megakaryocyte maturation and platelet production

Splenic artery embolization as a bridge to splenectomy in severe transfusion-refractory thrombocytopenia secondary to myelodysplastic syndrome

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