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PMID: 17536019 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural

Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin.

Blood ·Vol. 110 ·No. 6 ·2007-09-15 ·Pages 2166-72

Villagra J, Shiva S, Hunter LA, Machado RF, Gladwin MT, Kato GJ

Abstract

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 < .001) and to laboratory markers of intravascular hemolysis, such as reticulocyte count (r = 0.44, P = .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 = .01). These findings suggest a possible interaction between hemolysis, decreased NO bioavailability, and pathologic 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 no. NCT00352430.

MeSH Terms
3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors Adult Anemia, Sickle Cell/complications,physiopathology Female Flow Cytometry Hemoglobins/metabolism Hemolysis Humans Hypertension, Pulmonary/etiology,physiopathology Male Nitric Oxide/metabolism Phosphodiesterase Inhibitors/pharmacology Piperazines/pharmacology Platelet Activation Purines/pharmacology Sildenafil Citrate Sulfones/pharmacology Thrombosis/etiology,physiopathology
Chemicals
Hemoglobins Phosphodiesterase Inhibitors Piperazines Purines Sulfones Nitric Oxide Sildenafil Citrate 3',5'-Cyclic-GMP Phosphodiesterases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Villagra José
Vascular Medicine Branch of National Heart, Lung, and Blood Institute, Clinical Center, National Institutes of Health, Bethesda, MD 20892-1476, USA.
Shiva Sruti
Hunter Lori A
Machado Roberto F
Gladwin Mark T
Kato Gregory J
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2006-12-061697
Published
2007-09-15
Epub
2007-00-29
Pages
2166-72
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC1976348
Subset
IM
Grants
NICHD NIH HHS · 5K12HD001399 · United States
NCI NIH HHS · T32CA60441 · United States
Intramural NIH HHS · Z99 HL999999 · United States
NICHD NIH HHS · K12 HD001399 · United States
NCI NIH HHS · T32 CA060441 · United States
Intramural NIH HHS · ZIA HL006014-02 · United States
Databases
ClinicalTrials.gov
NCT00352430
External Links
PubMed source DOI: 10.1182/blood-2006-12-061697 PMC Full Text View journal details
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