Pulmonary Hypertension in Paroxysmal Nocturnal Hemoglobinuria

Heller, Paula G.; Grinberg, Alejandro R.; Lencioni, Melisa; Molina-Molina, María; Aj, Roncoroni

doi:10.1378/chest.102.2.642

Cited by 63 publications

(30 citation statements)

References 4 publications

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“…These observations confirm those of previous studies of patients with thalassemia and paroxysmal nocturnal hemoglobinuria, pointing towards a direct relation between hemolytic anemia and hypercoagulability. 3,21 Using ex vivo experiments with hemolysates others showed that erythrocytederived microparticles enhance coagulation activation. 22 Furthermore, in splenectomized patients with idiopathic thrombocytopenic purpura, erythrocyte-derived microparticles are correlated with shortening of activated partial thromboplastin time and increased factor XI activity.…”

Section: Discussionmentioning

confidence: 99%

Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease

Beers¹,

Schaap²,

Berckmans³

et al. 2009

Haematologica

239

221

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BackgroundSickle cell disease is characterized by a hypercoagulable state as a result of multiple factors, including chronic hemolysis and circulating cell-derived microparticles. There is still no consensus on the cellular origin of such microparticles and the exact mechanism by which they may enhance coagulation activation in sickle cell disease. Design and MethodsIn the present study, we analyzed the origin of circulating microparticles and their procoagulant phenotype during painful crises and steady state in 25 consecutive patients with sickle cell disease. ResultsThe majority of microparticles originated from platelets (GPIIIa,CD61) and erythrocytes (glycophorin A,CD235), and their numbers did not differ significantly between crisis and steady state. Erythrocyte-derived microparticles strongly correlated with plasma levels of markers of hemolysis, i.e. hemoglobin (r=-0.58, p<0.001) and lactate dehydrogenase (r=0.59, p<0.001), von Willebrand factor as a marker of platelet/endothelial activation (r=0.44, p<0.001), and D-dimer and prothrombin fragment F1+2 (r=0.52, p<0.001 and r=0.59, p<0.001, respectively) as markers of fibrinolysis and coagulation activation. Thrombin generation depended on the total number of microparticles (r=0.63, p<0.001). Anti-human factor XI inhibited thrombin generation by about 50% (p<0.001), whereas anti-human factor VII was ineffective (p>0.05). The extent of factor XI inhibition was associated with erythrocyte-derived microparticles (r=0.50, p=0.023). ConclusionsWe conclude that the procoagulant state in sickle cell disease is partially explained by the factor XI-dependent procoagulant properties of circulating erythrocyte-derived microparticles.Key words: microparticles, sickle cell disease, coagulation activation, hemolysis. Citation

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Section: Discussionmentioning

confidence: 99%

Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease

Beers¹,

Schaap²,

Berckmans³

et al. 2009

Haematologica

239

221

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“…Multiple mechanisms directly and indirectly attributable to hemolysis reduce NO bioavailability in SCD and thalassemia. A similar mechanism also may pertain in malaria and paroxysmal nocturnal hemoglobinuria [40,41]. …”

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confidence: 95%

PULMONARY HYPERTENSION IN SICKLE CELL DISEASE: Relevance to Children

Kato

Onyekwere

Gladwin

2007

Pediatric Hematology and Oncology

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Pulmonary arterial hypertension (PAH), once considered a rare complication of sickle cell disease (SCD) and thalassemia, appears to be more common in adults with hemoglobinopathy than previously appreciated. On prospective screening of adults with SCD, approximately one-third of adults are found on echocardiography to have a tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or higher, many of whom are asymptomatic. Dyspnea on exertion is the most common presenting symptom. This TRV abnormality is a marker for approximately 40% 3-year mortality in adults, and it is associated with laboratory values suggestive of more severe intravascular hemolysis. Release of hemoglobin and arginase from lysed red cells causes scavenging of nitric oxide (NO) and catabolism of L-arginine, the obligate substrate for NO synthase. The resulting impairment in NO bioavailability is associated with pulmonary vasoconstriction, endothelial dysfunction, thrombosis, and eventual development of plexogenic arterial lesions, the histological hallmark of all forms of PAH. Undoubtedly, additional pathophysiological mechanisms will also play a role in its multifactorial pathogenesis. Early data from children with SCD indicate a similar prevalence of elevated TRV, but the prognostic implications of this remain to be established. Individual patient diagnosis of PAH requires confirmation by right heart catheterization studies and individualized management. Hemolysis-associated PAH with impairments in NO bioavailability is being identified in thalassemia and other hemolytic disorders, and may be a general consequence of long-standing, severe intravascular hemolytic anemia.Keywords sickle cell; thalassemia; pulmonary hypertension; nitric oxide; arginase Pulmonary hypertension is a complication of sickle cell disease (SCD) and thalassemia gaining considerable attention in the past 4 years. Cor pulmonale, the clinical syndrome of right ventricular failure, has been considered for decades to be a rare, but well-known, terminal complication in adults with both hemoglobinopathies [1,2]. As the survival of patients with hemoglobinopathies has improved dramatically in the last forty years, the prevalence of such chronic complications has increased. Well-documented studies of pulmonary arterial hypertension (PAH) have drawn the attention of the hematology community to its frequent occurrence and poor prognosis [3][4][5][6][7]. This article will review the current understanding of hemoglobinopathy-associated pulmonary hypertension, with special attention to the most recently developing data in children. PREVALENCE AND PROGNOSISIn the last few years, echocardiographic screening studies have suggested that the prevalence of hemoglobinopathy-associated PAH is much higher than previously known. In SCD, approximately one-third of adult patients have an elevated tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or higher, a threshold that correlates in right heart catheterization studies to a pulmonary artery systolic pressure of at least 30 mm Hg [8][9]...

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“…Pulmonary hypertension may develop in most forms of hereditary and chronic hemolytic anemia [7][8][9][10] suggesting that there is a clinical syndrome of hemolysis-associated pulmonary hypertension. Nevertheless, an association between hemolysis and pulmonary hypertension in sickle cell disease has been questioned because, in most studies thus far, not all markers of hemolysis have had significant associations with estimated pulmonary artery pressure.…”

Section: Introductionmentioning

confidence: 99%

Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation

Minniti¹,

Sable²,

Campbell³

et al. 2009

Haematologica

165

144

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BackgroundElevation of echocardiography-determined tricuspid regurgitant jet velocity predicts high systolic pulmonary artery pressure and early mortality in adults with sickle cell disease. The definition, prevalence and clinical correlates of elevated jet velocity have not been established in pediatric patients. The present study tested the hypotheses that elevated jet velocity affects 10% of pediatric patients, is associated with both hemolysis and hypoxia, and has clinical correlates with acute chest syndrome, stroke, transfusion requirement and abnormal 6-minute walk test results. Design and MethodsA prospective multicenter study of 310 patients aged 3-20 years old with sickle cell disease under basal conditions and 54 matched controls was conducted. A hemolytic index was generated by principal component analysis of the levels of lactate dehydrogenase, aspartate aminotransferase and bilirubin and reticulocyte count. ResultsElevated jet velocity (defined as ≥2.60 m/sec based on the mean±2 SD in controls) occurred in 32 patients (11.0%) including one child of 3 years old. After adjustment for hemoglobin concentration, systolic blood pressure and left ventricular diastolic function, a 2 SD increase in the hemolytic index was associated with a 4.5-fold increase in the odds of elevated jet velocity (p=0.009) and oxygen saturation ≤98% with a 3.2-fold increase (p=0.028). Two or more episodes of acute chest syndrome had occurred in 28% of children with elevated jet velocity compared to in 13% of other children (p=0.012), more than ten units of blood had been transfused in 39% versus 18% (p=0.017) and stroke had occurred in 19% versus 11% (p=0.2). The distance walked in 6-minute walk tests did not differ significantly, but oxygen saturation declined during the tests in 68% of children with elevated jet velocity compared to in 32% of other children (p=0.0002). ConclusionsAccording to a pediatric-specific definition the prevalence of elevated jet velocity in this population of young patients with sickle cell disease was 11%. The study provides evidence for independent associations of elevated jet velocity with hemolysis and oxygen desaturation. Further investigations should address whether elevated jet velocity may indicate future complications and whether early intervention is beneficial.Key words: sickle cell disease, pulmonary hypertension, hemolysis, oxygen saturation, tricuspid regurgitant jet velocity, children.Citation: Minniti CP, Sable C, Campbell A, Rana S, Ensing G, Dham N, Onyekwere O, Nouraie M, Kato GJ, Gladwin MT, Castro OL, and Gordeuk VR. Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation. Haematologica 2009; 94:340-347. doi:10.3324/haematol.13812 ©2009 Ferrata Storti Foundation.

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Pulmonary Hypertension in Paroxysmal Nocturnal Hemoglobinuria

Cited by 63 publications

References 4 publications

Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease

Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease

PULMONARY HYPERTENSION IN SICKLE CELL DISEASE: Relevance to Children

Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation

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