Free plasma Hb has been recently implicated in the genesis of pulmonary hypertension in sickle cell disorders (SCD) through a putative NO scavenging mechanism. We have recently reported that free plasma Hb is correlated with increased plasma red cell derived vesicles (RBVes) in sickle cell and thalassemia disorders (

Westerman, Blood 2004; 104:1671
). Since high levels of HbF have been associated with decreased elevation of RBVes in children with SCD (
Setty Blood 2000;96:1119–1124
), we hypothesized that patients treated with hydroxyurea (HU) might show a similar normalisation of RBVes. Given our finding of an association between RBVes and free plasma Hb, such treatment might also be predicted to correct increments in free plasma Hb. In this study we have examined whether sickle cell patients treated with HU show evidence of a decrease in free plasma Hb and RBVes compared to untreated SCD patients. RBVes, free plasma Hb, and markers of activation of thrombolysis were quantitated. 35 adult SCD patients, 27 in steady state, untransfused and not receiving HU and 7 patients on long term HU at a dose of 10–30 mg/kg/day. These parameters were also measured in 27 healthy control subjects without SCD. RBVes were significantly higher in untreated SCD (15.59±3.07 x 103/μL of blood) than in control subjects (2.13 ± 0.5)(p=0.001). In HU-treated SCD patients, vesicles were significantly lower (3.97±0.83)(p=0.0371). than in untreated patients and approached levels found in healthy controls. Free plasma Hb was significaly increased in untreated SCD (16.74±3.87) compared with healthy controls (1.77±0.2)(p=0.001); these levels were also corrected in HU treated SCD patients (13.42±4.48). The proportion of RBVes expressing phosphatadyl serine was also lower in HU-treated SCD (37.25± 9.79) than in untreated SCD (52.52±4.74). This was paralleled by a decrease in red cells expressing PS in HU treated patients (11.83± 3.95) compared with untreated patients (42.71±8.45)(p=0.011). This decrease in both RBVes and RBCs expressing PS in HU-treated patients might in principle decrease activation of coagulation. Indeed, plasma Ddimers, which are increased in untreated SCD (480 ±60.14) compared with healthy controls (117.43±38)(p=0.018). are normalised in HU treated patients (190±28.69). These data provide evidence of a link between RBVes and plasma Hb and suggest that PS expression on RBVes and red cells plays a role in the prothrombotic state seen in SCD. As HU treatment appears to correct plasma Hb, long term treatment may be associated with a decreased scavenging of NO and hence the risk of pulmonary hypertension. The correction of the prothrombotic tendency may also be beneficial in this regard. Prospective trials are indicated to confirm whether HU treated patients have evidence of decreased risk of pulmonary hypertension.

Topics:
erythrocytes, hydroxyurea, plasma, thrombolytic therapy, vesicle, pulmonary hypertension, fetal hemoglobin, long-term treatment, serine, sickle cell anemia

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2005, The American Society of Hematology
2005
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