Redefining thalassemia as a hypercoagulable state

Cappellini, Maria Domenica; Motta, Irene; Musallam, Khaled M.; Taher, Ali T.

doi:10.1111/j.1749-6632.2010.05548.x

Cited by 85 publications

(74 citation statements)

References 38 publications

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“…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. 28,96 Thus, although a complete understanding of how JAK2 inhibitors achieve this effect is BLOOD, 20 OCTOBER 2011 ⅐ VOLUME 118, NUMBER 16…”

Section: Jak2 Inhibitor Improves Ie Reverses Splenomegaly and Lowermentioning

confidence: 88%

“…Furthermore, a recent study reported that patients with TI who had undergone splenectomy have a significantly higher rate of complications (eg, pulmonary hypertension, heart failure, thrombosis) relative to patients with TI not having undergone splenectomy. 12,13 Finally, thrombotic complications were found to occur 4.4 times more frequently in patients with TI who had undergone splenectomy than patients with TM (P Ͻ .001). 14 Taken together, splenectomy is temporarily effective in partially ameliorating anemia or delaying/lowering transfusion need in TI.…”

Section: Clinical Characteristicsmentioning

confidence: 99%

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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: 88%

Section: Clinical Characteristicsmentioning

confidence: 99%

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

Ginzburg

Rivella

2011

Blood

177

207

View full text Add to dashboard Cite

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“…58 Several other factors have also been identified and it is often a combination of these factors that leads to a hypercoagulable state resulting in clinical thrombosis (Figure 4). [59][60][61] Clinically, the prevalence of thrombotic events in patients with β-thalassemia intermedia can reach up to 20%, compared to less than 1% in patients with β-thalassemia major. 30,[62][63][64] These events are mostly venous and primarily occur in splenectomized patients (22.5% vs. 3.5% prevalence rate in splenectomized vs. non-splenectomized patients; P<0.001).…”

Section: 57mentioning

confidence: 99%

Non-transfusion-dependent thalassemias

Musallam

Rivella

Vichinsky³

et al. 2013

Haematologica

244

268

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“…(We note that sometimes fibrinolysis is assessed via D-dimer formation, 163 but that when this is increased one cannot normally tell whether that is due to an increase in fibrinolysis or simply because there had previously been hypercoagulation.) Note that in the case of b-thalassaemia there is a particularly noticeable amount of hypercoagulation [323][324][325][326][327][328][329][330][331][332][333][334][335] but that fibrinolysis seems to be enhanced, 324,336,337 albeit not by enough to overcome the hypercoagulation. The same seems to be true of psoriasis 66,[338][339][340] and of asthma.…”

Section: The Relationship Between Hypercoagulability and Hypofibrinolmentioning

confidence: 99%

The simultaneous occurrence of both hypercoagulability and hypofibrinolysis in blood and serum during systemic inflammation, and the roles of iron and fibrin(ogen)

Kell

Pretorius

2014

Integrative Biology

127

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Although the two phenomena are usually studied separately, we summarise a considerable body of literature to the effect that a great many diseases involve (or are accompanied by) both an increased tendency for blood to clot (hypercoagulability) and the resistance of the clots so formed (hypofibrinolysis) to the typical, 'healthy' or physiological lysis. We concentrate here on the terminal stages of fibrin formation from fibrinogen, as catalysed by thrombin. Hypercoagulability goes hand in hand with inflammation, and is strongly influenced by the fibrinogen concentration (and vice versa); this can be mediated via interleukin-6. Poorly liganded iron is a significant feature of inflammatory diseases, and hypofibrinolysis may change as a result of changes in the structure and morphology of the clot, which may be mimicked in vitro, and may be caused in vivo, by the presence of unliganded iron interacting with fibrin(ogen) during clot formation. Many of these phenomena are probably caused by electrostatic changes in the iron-fibrinogen system, though hydroxyl radical (OH ) formation can also contribute under both acute and (more especially) chronic conditions. Many substances are known to affect the nature of fibrin polymerised from fibrinogen, such that this might be seen as a kind of bellwether for human or plasma health. Overall, our analysis demonstrates the commonalities underpinning a variety of pathologies as seen in both hypercoagulability and hypofibrinolysis, and offers opportunities for both diagnostics and therapies.

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Redefining thalassemia as a hypercoagulable state

Cited by 85 publications

References 38 publications

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

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

Non-transfusion-dependent thalassemias

The simultaneous occurrence of both hypercoagulability and hypofibrinolysis in blood and serum during systemic inflammation, and the roles of iron and fibrin(ogen)

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