The molecular basis for the prothrombotic state in sickle cell disease

Shet, Arun; Lizarralde-Iragorri, Maria A.; Naik, Rakhi P.

doi:10.3324/haematol.2019.239350

Cited by 45 publications

(26 citation statements)

References 138 publications

(212 reference statements)

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“…This review provides a comprehensive overview of the broad range of heme’s actions as a modulator of blood coagulation, thereby in particular emphasizing its relevance in hemolysis-driven thrombosis. A role of heme in the development of thrombotic complications in SCD has in particular been proposed [ 18 , 253 ].…”

Section: Resultsmentioning

confidence: 99%

Linking Labile Heme with Thrombosis

Hopp

Imhof

2021

JCM

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Thrombosis is one of the leading causes of death worldwide. As such, it also occurs as one of the major complications in hemolytic diseases, like hemolytic uremic syndrome, hemorrhage and sickle cell disease. Under these conditions, red blood cell lysis finally leads to the release of large amounts of labile heme into the vascular compartment. This, in turn, can trigger oxidative stress and proinflammatory reactions. Moreover, the heme-induced activation of the blood coagulation system was suggested as a mechanism for the initiation of thrombotic events under hemolytic conditions. Studies of heme infusion and subsequent thrombotic reactions support this assumption. Furthermore, several direct effects of heme on different cellular and protein components of the blood coagulation system were reported. However, these effects are controversially discussed or not yet fully understood. This review summarizes the existing reports on heme and its interference in coagulation processes, emphasizing the relevance of considering heme in the context of the treatment of thrombosis in patients with hemolytic disorders.

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Section: Resultsmentioning

confidence: 99%

Linking Labile Heme with Thrombosis

Hopp

Imhof

2021

JCM

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“… 53 The increased risk of thromboses in SCD is well known—in tandem with vaso-occlusion, in which selectins are intricately involved. 54 , 55 One patient in the placebo arm and no patients in the crizanlizumab arm had a thrombotic event in the SUSTAIN study. 33 In Philadelphia chromosome-negative, JAK2V617F-positive myeloproliferative neoplasms, constitutively active JAK2 results in downstream activation of JAK2 kinase that initiates intracellular signaling of various type 1 cytokine receptors such as erythropoietin and thrombopoietin receptors.…”

Section: Role Of P-selectin Beyond Vaso-occlusive Pain Crisismentioning

confidence: 99%

P-Selectin Blockade in the Treatment of Painful Vaso-Occlusive Crises in Sickle Cell Disease: A Spotlight on Crizanlizumab

Karki¹,

Kutlar²

2021

JPR

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Microvascular vaso-occlusion driven pain crisis is the hallmark of sickle cell disease with profound morbidity and increased mortality. Selectins, most notably P-selectins have an integral role in this phenomenon. P-selection was first identified in 1989. In 2019, after 3 decades of basic, translational, and clinical work with this pathway, the US Food and Drug Administration approved a P-selectin antibody, crizanlizumab to reduce frequency of pain crisis in patients more than 16 years with sickle cell disease. We review the fundamentals of P-selectin pathobiology, P-selectin blocking agents, clinical data with the use of crizanlizumab and prospects of this novel class of drugs in the context of other treatments for painful vaso-occlusive episodes.

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“…However, no correlation studies have been performed to our knowledge. If SCD chronic hypercoagulable state has been associated with an increased risk of limited complications such as venous thrombosis ( 72 , 73 ), pulmonary hypertension ( 74 ) and in situ thrombosis of small vessels, it is worthwhile to notice that increased thrombin generation may also contribute to vascular inflammation ( 75 ).…”

Section: Scd Pathophysiology: a Complex Schema And Interrelated Pathwaysmentioning

confidence: 99%

Extracellular Vesicles in Sickle Cell Disease: Plasma Concentration, Blood Cell Types Origin Distribution and Biological Properties

et al. 2021

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Prototype of monogenic disorder, sickle cell disease (SCD) is caused by a unique single mutation in the β-globin gene, leading to the production of the abnormal hemoglobin S (HbS). HbS polymerization in deoxygenated condition induces the sickling of red blood cells (RBCs), which become less deformable and more fragile, and thus prone to lysis. In addition to anemia, SCD patients may exhibit a plethora of clinical manifestations ranging from acute complications such as the frequent and debilitating painful vaso-occlusive crisis to chronic end organ damages. Several interrelated pathophysiological processes have been described, including impaired blood rheology, increased blood cell adhesion, coagulation, inflammation and enhanced oxidative stress among others. During the last two decades, it has been shown that extracellular vesicles (EVs), defined as cell-derived anucleated particles delimited by a lipid bilayer, and comprising small EVs (sEVs) and medium/large EVs (m/lEVs); are not only biomarkers but also subcellular actors in SCD pathophysiology. Plasma concentration of m/lEVs, originated mainly from RBCs and platelets (PLTs) but also from the other blood cell types, is higher in SCD patients than in healthy controls. The concentration and the density of externalized phosphatidylserine of those released from RBCs may vary according to clinical status (crisis vs. steady state) and treatment (hydroxyurea). Besides their procoagulant properties initially described, RBC-m/lEVs may promote inflammation through their effects on monocytes/macrophages and endothelial cells. Although less intensely studied, sEVs plasma concentration is increased in SCD and these EVs may cause endothelial damages. In addition, sEVs released from activated PLTs trigger PLT-neutrophil aggregation involved in lung vaso-occlusion in sickle mice. Altogether, these data clearly indicate that EVs are both biomarkers and bio-effectors in SCD, which deserve further studies.

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The molecular basis for the prothrombotic state in sickle cell disease

Cited by 45 publications

References 138 publications

Linking Labile Heme with Thrombosis

Linking Labile Heme with Thrombosis

P-Selectin Blockade in the Treatment of Painful Vaso-Occlusive Crises in Sickle Cell Disease: A Spotlight on Crizanlizumab

Extracellular Vesicles in Sickle Cell Disease: Plasma Concentration, Blood Cell Types Origin Distribution and Biological Properties

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