Thalassemia and hypercoagulability

Taher, Ali T.; Otrock, Zaher K.; Uthman, Imad; Cappellini, Maria Domenica

doi:10.1016/j.blre.2008.04.001

Cited by 147 publications

(137 citation statements)

References 46 publications

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“…However, splenectomy appears to predispose patients to thrombotic events. 43,99,100 Avoiding the need for splenectomy in patients with ␤-thalassemia may reduce the escalation of the transfusion requirement and may prevent thrombosis in this disorder. 13 We also demonstrate that JAK2 inhibitors in ␤-thalassemic mice decreased the number of cells expressing cell cycle-related genes and partially reversed the IE, ameliorating the ratio between erythroid precursors and enucleated RBCs.…”

Section: Jak2 Inhibitor Improves Ie Reverses Splenomegaly and Lowermentioning

confidence: 99%

β-thalassemia: a model for elucidating the dynamic regulation of ineffective erythropoiesis and iron metabolism

Ginzburg

Rivella

2011

Blood

177

207

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␤-thalassemia is a disease characterized by anemia and is associated with ineffective erythropoiesis and iron dysregulation resulting in iron overload. The peptide hormone hepcidin regulates iron metabolism, and insufficient hepcidin synthesis is responsible for iron overload in minimally transfused patients with this disease. Understanding the crosstalk between erythropoiesis and iron metabolism is an area of active investigation in which patients with and models of ␤-thalassemia have provided significant insight. The dependence of erythropoiesis on iron presupposes that iron demand for hemoglobin synthesis is involved in the regulation of iron metabolism. Major advances have been made in understanding iron availability for erythropoiesis and its dysregulation in ␤-thalassemia. In this review, we describe the clinical characteristics and current therapeutic standard in ␤-thalassemia, explore the definition of ineffective erythropoiesis, and discuss its role in hepcidin regulation. In preclinical experiments using interventions such as transferrin, hepcidin agonists, and JAK2 inhibitors, we provide evidence of potential new treatment alternatives that elucidate mechanisms by which expanded or ineffective erythropoiesis may regulate iron supply, distribution, and utilization in diseases such as ␤-thalassemia. IntroductionErythroid cells are highly dependent on iron for survival. In light of this dependence, mutual regulation of erythropoiesis and iron metabolism has been proposed. However, how iron demand for erythropoiesis is communicated to the iron regulatory machinery is incompletely understood. In the past few decades, significant progress has been made to advance our understanding of iron metabolism and its regulation. Furthermore, several diseases, ␤-thalassemia in particular, have provided glimpses of the crosstalk between iron regulation and erythropoiesis. By exploring ineffective erythropoiesis (IE) and its associated dysfunctional iron regulation, this disease may lay the foundation for more completely understanding, diagnosing, and treating patients with different forms of ␤-thalassemia as well as other anemias or iron overloadrelated disorders. In this review, we focus on the current state of knowledge on the regulation of iron metabolism and attempt to elucidate the interface between iron regulation and erythropoiesis with the use of evidence in part derived from animal models of ␤-thalassemia; despite being all nonhuman models of disease, their utility as in vivo tools for experimentation is worthy of note. We discuss potential ways in which this new knowledge can be translated into clinical application for patients with ␤-thalassemia. ␤-thalassemia Clinical characteristics␤-thalassemias are caused by mutations in the ␤-globin gene or its promoter, resulting in reduced or absent ␤-globin synthesis. 1 Patients either homozygous or compound heterozygous for mutation in the ␤-globin gene present with a broad range of clinical severity; the disease course can be associated with severe transfusion dep...

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Section: Jak2 Inhibitor Improves Ie Reverses Splenomegaly and Lowermentioning

confidence: 99%

β-thalassemia: a model for elucidating the dynamic regulation of ineffective erythropoiesis and iron metabolism

Ginzburg

Rivella

2011

Blood

177

207

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“…Our study provides a link between the increased prevalence of the NMDA-receptor in SCD patients [50] and the symptoms of the vascoocclusive crisis. Further examples where disorders in the ion homeostasis of RBCs are associated with thrombotic events are malaria [51] and thalassemia [52,53]. Therefore, we propose that the Ca 2+ increase, independent of the entry pathway, followed by PS exposure and RBC aggregation is a general mechanism that may become relevant under pathological conditions.…”

Section: Relevance To In Vivo Conditionsmentioning

confidence: 90%

Stimulation of human red blood cells leads to Ca2+-mediated intercellular adhesion

et al. 2012

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Red blood cells (RBCs) are a major component of blood clots, which form physiologically as a response to injury or pathologically in thrombosis. The active participation of RBCs in thrombus solidification has been previously proposed but not yet experimentally proven. Holographic optical tweezers and single-cell force spectroscopy were used to study potential cell-cell adhesion between RBCs. Irreversible intercellular adhesion of RBCs could be induced by stimulation with lysophosphatidic acid (LPA), a compound known to be released by activated platelets. We identified Ca 2+ as an essential player in the signaling cascade by directly inducing Ca 2+ influx using A23187. Elevation of the internal Ca 2+ concentration leads to an intercellular adhesion of RBCs similar to that induced by LPA stimulation. Using single-cell force spectroscopy, the adhesion of the RBCs was identified to be approximately 100 pN, a value large enough to be of significance inside a blood clot or in pathological situations like the vasco-occlusive crisis in sickle cell disease patients.

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“…16 Peningkatan jumlah trombosit memicu pembentukan trombin dan stimulasi aktivitas prokoagulan. 7 Absennya fungsi lien pada splenektomi meningkatkan jumlah trombosit, meningkatkan aktivitas prokoagulan, agregasi trombosit, dan memperberat status aktivasi trombosit kronik [17][18][19][20] sehingga terdapat hubungan langsung antara splenektomi dengan jumlah trombosit yang meningkat. Proses hemolisis dan peningkatan produksi free iron menyebabkan cedera endotel vaskular kronik akibat toksisitas stres oksidatif.…”

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“…Proses hemolisis dan peningkatan produksi free iron menyebabkan cedera endotel vaskular kronik akibat toksisitas stres oksidatif. 19,21 Penelitian hiperkoagulasi thalassemia sebelumnya terbatas pada kelainan primer genetik 6 dan tipe thalassemia intermedia. 15,18,21 Tujuan penelitian ini adalah untuk mengetahui faktor risiko usia, lama sakit, derajat dan tipe thalassemia, kadar hemoglobin pretransfusi rata-rata, jumlah trombosit, dan kadar feritin serum yang memengaruhi hiperkoagulasi pada thalassemia anak.…”

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