|
|
Blood, 15 September 2007, Vol. 110, No. 6, pp. 2166-2172.
Prepublished online as a Blood First Edition Paper on May 29, 2007; DOI 10.1182/blood-2006-12-061697.
 Previous Article | Next Article 
Submitted December 13, 2006
Accepted May 24, 2007
Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension and nitric oxide scavenging by cell-free hemoglobin
Jose Villagra, Sruti Shiva, Lori A. Hunter, Roberto F. Machado, Mark T. Gladwin, and Gregory J. Kato*
Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC, United States
Vascular Medicine Branch, National Heart, Lung and Blood Institute, Bethesda, MD, United States
Critical Care Medicine Department & Department of Nursing, NIH Clinical Center, Bethesda, MD, United States
Johns Hopkins University School of Medicine, Baltimore, MD, United States
* Corresponding author; email: gkato{at}mail.nih.gov.
Increased platelet activation is recognized in patients with sickle cell disease (SCD), but its pathogenesis and clinical relevance remain uncertain. Pulmonary arterial hypertension (PAH), an important complication of SCD, is characterized by a proliferative pulmonary vasculopathy, in situ thrombosis, and vascular dysfunction related to scavenging of nitric oxide (NO) by hemoglobin released into blood plasma during intravascular hemolysis. We investigated links between platelet activation, PAH and NO scavenging in patients with SCD. Platelet activation marked by activated fibrinogen receptor correlated to the severity of PAH (r = 0.58, p < 0.001), and to laboratory markers of intravascular hemolysis, such as reticulocyte count (r = 0.44, p = 0.02). In vitro exposure of platelets to pathologically relevant concentrations of cell-free hemoglobin promoted basal and agonist-stimulated activation and blocked the inhibitory effects on platelet activation by an NO donor. In patients with SCD, administration of sildenafil, a phosphodiesterase-5 inhibitor that potentiates NO-dependent signaling, reduced platelet activation (p = 0.01). These findings suggest a possible interaction between hemolysis, decreased NO bioavailability and pathological platelet activation that might contribute to thrombosis and pulmonary hypertension in SCD, and potentially other disorders of intravascular hemolysis. This supports a role for NO-based therapeutics for SCD vasculopathy. This trial was registered at www.clinicaltrials.gov as #NCT00352430.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
K. I. Ataga
Hypercoagulability and thrombotic complications in hemolytic anemias
Haematologica,
November 1, 2009;
94(11):
1481 - 1484.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Yuditskaya, A. Tumblin, G. T. Hoehn, G. Wang, S. K. Drake, X. Xu, S. Ying, A. H. Chi, A. T. Remaley, R.-F. Shen, et al.
Proteomic identification of altered apolipoprotein patterns in pulmonary hypertension and vasculopathy of sickle cell disease
Blood,
January 29, 2009;
113(5):
1122 - 1128.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. J. Kato and M. T. Gladwin
Evolution of Novel Small-Molecule Therapeutics Targeting Sickle Cell Vasculopathy
JAMA,
December 10, 2008;
300(22):
2638 - 2646.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. T. Gladwin and E. Vichinsky
Pulmonary Complications of Sickle Cell Disease
N. Engl. J. Med.,
November 20, 2008;
359(21):
2254 - 2265.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. C. Minneci, K. J. Deans, S. Shiva, H. Zhi, S. M. Banks, S. Kern, C. Natanson, S. B. Solomon, and M. T. Gladwin
Nitrite reductase activity of hemoglobin as a systemic nitric oxide generator mechanism to detoxify plasma hemoglobin produced during hemolysis
Am J Physiol Heart Circ Physiol,
August 1, 2008;
295(2):
H743 - H754.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. C. Frei, Y. Guo, D. W. Jones, K. A. Pritchard Jr, K. A. Fagan, N. Hogg, and N. J. Wandersee
Vascular dysfunction in a murine model of severe hemolysis
Blood,
July 15, 2008;
112(2):
398 - 405.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. De Franceschi, O. S. Platt, G. Malpeli, A. Janin, A. Scarpa, C. Leboeuf, Y. Beuzard, E. Payen, and C. Brugnara
Protective effects of phosphodiesterase-4 (PDE-4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice
FASEB J,
June 1, 2008;
22(6):
1849 - 1860.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. F. Barnett, P. Y. Hsue, and R. F. Machado
Pulmonary Hypertension: An Increasingly Recognized Complication of Hereditary Hemolytic Anemias and HIV Infection
JAMA,
January 23, 2008;
299(3):
324 - 331.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. T. Gladwin and G. J. Kato
Hemolysis-associated hypercoagulability in sickle cell disease: the plot (and blood) thickens!
Haematologica,
January 1, 2008;
93(1):
1 - 3.
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. I. Ataga, C. G. Moore, C. A. Hillery, S. Jones, H. C. Whinna, D. Strayhorn, C. Sohier, A. Hinderliter, L. V. Parise, and E. P. Orringer
Coagulation activation and inflammation in sickle cell disease-associated pulmonary hypertension
Haematologica,
January 1, 2008;
93(1):
20 - 26.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. R. Morris
Mechanisms of Vasculopathy in Sickle Cell Disease and Thalassemia
Hematology,
January 1, 2008;
2008(1):
177 - 185.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
