Leg Ulcer in Hereditary Spherocytosis

Giraldi, Susana; Abbage, Kerstin Taniguchi; Marinoni, Leide Parolin; Oliveira, Vânia de; Pianowski, Mara; Lehmkuhl, Adelina E.; Neto, José Fillus

doi:10.1046/j.1525-1470.2003.20512.x

Cited by 30 publications

(16 citation statements)

References 4 publications

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“…1 These clinical features have also been reported in thalassemia intermedia, hereditary spherocytosis, and other forms of severe hemolytic anemia. [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] This suggests that sickling is not required for this subphenotype and instead implicates the severe hemolysis of sickle cell disease in its pathobiology. Consistent with this model, the Jamaican sickle cell population, characterized by severe hemolysis, has a much higher prevalence of leg ulcers and priapism than those in Greece and India, who have less severe hemolysis, but comparable rates of VOC pain crisis.…”

Section: Discussionmentioning

confidence: 99%

Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease

Kato

McGowan

Machado

et al. 2006

Blood

563

346

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Pulmonary hypertension is prevalent in adult patients with sickle cell disease and is strongly associated with early mortality and markers of hemolysis, in particular, serum lactate dehydrogenase (LDH). Intravascular hemolysis leads to impaired bioavailability of nitric oxide (NO), mediated by NO scavenging by plasma oxyhemoglobin and by arginine degradation by plasma arginase. We hypothesized that serum LDH may represent a convenient biomarker of intravascular hemolysis and NO bioavailability, characterizing a clinical subphenotype of hemolysisassociated vasculopathy. In a cohort of 213 patients with sickle cell disease, we found statistically significant associations of steady-state LDH with low levels of hemoglobin and haptoglobin and high levels of reticulocytes, bilirubin, plasma hemoglobin, aspartate aminotransferase, arginase, and soluble adhesion molecules. LDH isoenzyme fractionation confirmed predominance of LD1 and LD2, the principal isoforms within erythrocytes. In a subgroup, LDH levels closely correlated with plasma cell-free hemoglobin, accelerated NO consumption by plasma, and impaired vasodilatory responses to an NO donor. Remarkably, this simple biomarker was associated with a clinical subphenotype of pulmonary hypertension, leg ulceration, priapism, and risk of death in patients with sickle cell disease. We propose that LDH elevation identifies patients with a syndrome of hemolysisassociated NO resistance, endothelial dysfunction, and end-organ vasculopathy. IntroductionPulmonary hypertension is an increasingly recognized complication of sickle cell disease and other chronic hereditary and acquired hemolytic anemias. Doppler echocardiography screening reveals a tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or greater in 33% of adults with sickle cell disease, indicative of pulmonary hypertension. 1 Pulmonary hypertension in these patients is associated with a 10-fold increased risk for early mortality. Elevated pulmonary artery pressures in patients with sickle cell disease have been associated with low hemoglobin concentration, high levels of serum lactate dehydrogenase (LDH), elevated systolic systemic blood pressure, history of priapism, renal insufficiency, and markers of iron overload. Of the several independent epidemiologic factors associated with pulmonary hypertension, an elevated level of serum LDH has drawn particular interest and controversy. In addition to a link with pulmonary hypertension, we and others have observed a link between LDH and a generalized state of endothelial activation, reflected by elevated blood plasma levels of soluble adhesion molecules, especially vascular cell adhesion molecule (VCAM-1). 2-10 Both pathologic endothelial activation and pulmonary hypertension are associated with more severe hemolytic anemia, reflected by low hemoglobin levels and high reticulocyte counts. 1,2,8 These data begin to suggest that LDH elevation may be a marker of hemolysis-associated endothelial dysfunction and pulmonary hypertension.LDH has long been considered a useful c...

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Section: Discussionmentioning

confidence: 99%

Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease

Kato

McGowan

Machado

et al. 2006

Blood

563

346

View full text Add to dashboard Cite

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“…SCD patients are not the only patients with congenital hemolytic anemia to develop skin ulcerations, and they have been reported in thalassemia intermedia [18], hereditary spherocytosis [19], pyruvate kinase deficiency [20], and congenital dyserythropoietic anemia [21]. Ulcer prevalence in other types of congenital hemolytic anemias is not known, but their occurrence suggests that sickling is not a conditio sine qua non for ulcer formation, while chronic anemia and hemolysis appear to be common factors.…”

Section: Epidemiologymentioning

confidence: 99%

Critical Reviews: How we treat sickle cell patients with leg ulcers

Minniti

Kato

2015

American J Hematol

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The past five decades have seen an improvement in the mortality and morbidity of sickle cell disease (SCD) because of prophylaxis against infectious complications, improved and expanded red cell transfusions, implementation of hydroxyurea therapy, and advances in supportive care. Now that the majority of patients in the western hemisphere reaches adulthood, end organ diseases are frequent, which include vasculopathic complications such as chronic leg ulcers. The management of patients with leg ulcers requires the hematologist to lead a team of health care professionals, and investigates the presence of associated, but potentially still occult signs of vasculopathy, such as pulmonary hypertension, renal disease, priapism and retinopathy. These complications may be asynchronous, and long term careful screening is indicated, in order to ensure early diagnosis and intervention. It is crucial to address both the immediate consequences of pain, infection and disability, and long term effects on quality of life, employment and stigma associated with chronic ulceration. Recent insights into their pathophysiology may have practical implications. We propose a holistic approach to the management of patients' physical and emotional problems and mechanisms of ulcers formation and delayed healing. An overview of topical and systemic therapies for chronic ulcers is given, with the understanding that wound care therapy is best left to the wound specialists, medical and surgical, with whom the hematologist must keep an open line of communication. In the absence of evidence-based guidelines, our opinion is based on both a critical review of the literature and our personal clinical and research experience. Am. J. Hematol. 91:22-30, 2016. V C 2015 Wiley Periodicals, Inc. Clinical CasesCase 1. A 49 year old African American woman with sickle cell anemia, bilateral hip replacements for avascular necrosis of the femoral head, pulmonary arterial hypertension documented by pulmonary artery catheterization, and history of laser treatment and vitrectomy for proliferative retinopathy and vitreous hemorrhage, presented with a very painful ulcer at the right malleolus. She has had three previous ulcers, on both legs, the first at age 32 years, attributed to excessive standing at her job, no trauma, which had responded to topical care and healed within few months of presentation. At that time she was not taking hydroxyurea, but has been taking it now for longer than 10 years with good fetal hemoglobin response: 17%. This current ulcer developed while she was experiencing high personal stress but no physical trauma. She rarely experiences vaso-occlusive pain crisis and has very infrequent hospitalizations. She was referred to the wound care service and after 7 months of unfruitful therapies, including surgical debridement, MIST ultrasound therapy, antibiotics, and compressions, she was started on monthly transfusions and her ulcer healed 5 months later. She has had consistently elevated serum lactate dehydrogenase (LDH) (>600 IU/L), serum dire...

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“…Such localized hemolysis has been shown within and outside of capillaries by electron microscopy in the vicinity of leg ulcers of a patient with spherocytosis. 10 Although 2% of patients with spherocytosis develop leg ulcers, 12 the clinical finding of recurrent pseudoerysipelas as seen in our patient has not been reported thus far. Because our patient had mild spherocytosis based on hematologic and serologic findings, 1 we hypothesize that his family carries an unknown mutation for a mild autosomal dominant phenotype.…”

Section: Discussionmentioning

confidence: 48%

“…1 The most frequently reported dermatologic complication of hereditary spherocytosis, reported in fewer than 2% of the patients, are leg ulcers at atypical locations, such as the back of the feet in patients withouth splenectomy. [10][11][12][13] Healing of refractory leg ulcers was reported after splenectomy. 11,14 The pathogenesis of the more commonly described leg ulcers in congenital spherocytosis is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…It is intruiging to speculate that a clinical or subclinical venous insufficiency might be a necessary contributing factor to stasis hemolysis in patients with spherocytosis, explaining the rarity of the finding in contrast to the relative frequency of leg ulceration in patients with congenital spherocytosis. 12 Future studies in larger groups of patients with congenital spherocytosis who develop leg ulceration will have to determine whether these symptoms can be found in patients before leg ulceration, in single families, or only in patients with concomitant subclinical or clinical venous insufficiency. The dermal inflammatory reaction, clinically observed as pseudoerysipelas in our patient, might be a consequence of such stasis-induced lysis of the more fragile spherocytes.…”

Section: Discussionmentioning

confidence: 99%

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