Plasma levels of TNF-alpha in sickle cell patients receiving hydroxyurea.

Hydroxyurea (HU), a chemotherapeutic agent, used increasingly in the treatment of sickle cell disease (SCD) stimulates the release of a tumor necrosis factor (TNF-alpha) from human macrophages in vitro and the concentration of TNF-alpha is greater than normal in subjects affected by SCD. It is widely accepted that HU may inhibit vaso-occlusive crisis (VOC) by stimulating the production of fetal hemoglobin (HbF) and nitric oxide (NO) in SCD; however, the beneficial effects of HU in vivo may be counteracted by the release of TNF-alpha and, in turn, the expression of a vascular cell adhesion molecule (VCAM-1) on leukocytes. Previous studies have shown that the severity of SCD increases with the leukocyte count. Therefore, we examined the relationship between plasma levels of TNF-alpha and HbF in SCD patients during steady-state (StSt) conditions (in the absence of VOC) and during VOC conditions after the acute administration of HU. Venous blood was collected in SCD patients over 6 h after administering a single dose of HU. Plasma TNF-alpha was found to be greater in SCD subjects than in reported normal adult controls (p<0.05). TNF-alpha in the StSt group was not significantly different than in the VOC group; however, the plasma TNF-alpha tended to greater in the VOC group (p>0.1). An increase in the HbF concentration after acute administration of HU (p<0.01) was not associated with a significant change in plasma TNF-alpha (p>0.1). Contrary to the results of in vitro studies, HU did not increase the plasma concentration of TNF-alpha. These findings suggest that a HU-induced increase in TNF-alpha does not contribute to VOC and sickle cell patients can be counseled that the HU-induced increase in TNF-alpha does not counteract the beneficial effects of HU in SCD.

Arterialization of venous blood for differentiation of sickle cell subjects in vaso-occlusive crisis.

These studies were designed as two experiments. Experiment 1 was performed to validate the hypothesis that oxygen saturation of the venous blood may be a marker for vaso-occlusive crisis (VOC) in sickle cell patients undergoing hydroxyurea (HU) treatments. Experiment 2 was performed to test the hypothesis that an acute increase in the blood nitric oxide (NO) concentration by administering HU modulates the perception of pain in sickle cell subjects in VOC. The percent saturations of oxyhemoglobin (%O

Long-term outcomes in patients with sickle cell disease and frequent vaso-occlusive crises.

BACKGROUND: The frequency of vaso-occlusive crises correlates with mortality in patients with sickle cell disease (SCD). We examined the degree to which a high number of hospitalization days for these events affected survival. PATIENTS AND METHODS: We reviewed data for 58 adult patients with SCD (mean age, 29.9 +/- 7.3 years) treated at our hospital between 1986 and 1994 who had at least 100 hospitalization days during any of these years. Their mean follow up period was 6.65 years (median, 6.84 years; range, 0.15-14.51 years). RESULTS: Thirty-five patients (60.3%) died during follow-up. In multivariate analysis that included age, gender, and numbers of transfusions and hospitalization days, only age was significantly associated with mortality. The National Cooperative Study of Sickle Cell Disease (CSSCD) estimates the 10-year mortality at 15% for all 20-year old SS patients and also for all 30-year-old women. For 30-year-old men, the CSSCD estimated a 10-year mortality of about 28%. Thus, the 60.3% mortality of our patients after a median follow-up of only 6.84 years was substantially higher. Fifty-one patients were still alive after 1992, when hydroxyurea became available for SCD. The median survival of 15 hydroxyurea-treated patients was 7.3 years, compared with 4.3 years in 36 patients who did not take the drug. CONCLUSIONS: Mortality for patients with SCD with a high number of hospitalization days was much higher than that expected for patients with SCD in general. There was a (nonsignificant) trend for longer survival in these severely ill patients if they took hydroxyurea.

Nitric oxide and cyclic GMP levels in sickle cell patients receiving hydroxyurea.

Recent studies suggest that nitric oxide (NO) may partly be responsible for the beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) patients. NO stimulates cyclic guanosine monophosphate (cGMP) production, which mediates vasodilatation. We investigated the association between NO, cGMP and fetal haemoglobin (HbF) levels after HU administration. Our data showed that chronic HU significantly increased NO, cGMP, and HbF levels in SCD. Recently it was shown that HbF production was stimulated by cGMP-dependent protein kinase. Our results suggest that NO stimulates cGMP production, which then activates a protein kinase and increases the production of HbF.

Arterialization of peripheral venous blood in sickle cell disease.

Arterialization of the venous blood is thought to be indicative of cutaneous shunting, and occurs in patients with sickle cell disease (SCD) during vaso-occlusive crisis (VOC). We performed the present study to quantify the amount of shunting that occurs in sickle cell patients presenting at the Howard University Sickle Cell Center, Washington, D.C., as outpatients and for hospitalizations associated with sickle cell crisis. Peripheral venous blood was drawn anaerobically into heparinized syringes from 9 normal control subjects (NC), 24 outpatients (steady-state group), and 14 inpatients during crisis (VOC group). Spectrophotometric measurements were made for the following species of hemoglobin (Hb): oxy-Hb (O2Hb), reduced Hb (RHb), carboxy-Hb (COHb), and met-Hb (MHb). In addition, fetal hemoglobin (HbF) was measured by high-pressure liquid chromatography (HPLC). The O2Hb saturations of the steady state group were not significantly different than those of the NC group (55 +/- 4% vs. 40 +/- 6%). However, the O2Hb saturations of the VOC group were 73 +/- 3%, and this value was found to be significantly greater than those of both the steady-state and the NC groups (p < 0.05). Reduced hemoglobin saturations were inversely related to the O2Hb values, as expected. Compared to the NC group, the steady-state, and VOC groups had greater dyshemoglobin (COHb and MHb) levels (p < 0.05). These findings suggest that the percentages of venous O2Hb and dyshemoglobins may be increased in sickle cell disease even in the absence of VOC. Therefore, the venous O2Hb saturation may be a useful biochemical marker for the arteriovenous shunting and hemodynamic adaptations associated with sickle cell disease.

Nitric Oxide Metabolites in Sickle Cell Anemia Patients after Oral Administration of Hydroxyurea; Hemoglobinopathy.

The mechanism of action of hydroxyurea (HU) in decreasing the frequency of pain crisis in sickle cell disease (SCD) has not been fully elucidated. In vitro and in vivo studies suggest that nitric oxide (NO), a potent vasodilator, may partly be responsible for the beneficial effect of HU. This study was designed to determine the effect of oral administration of HU on plasma levels of NO metabolites (NO(x) ) in sickle cell patients (SCP). The results indicate that during steady-state plasma levels of NO(x) were significantly higher in HU-treated patients compared to non HU-treated patients or normal controls (p <.05). In five inpatients in mild pain plasma levels of NO(x) increased significantly after 2 h of HU administration (p <.05); however, in three inpatients in persistent pain with significantly lower baseline NO(x) there was a minimal NO(x) response to HU at 2 h (p <.01). These observations indicate that HU administration is associated with the production of NO in some SCP, but that further study of the pharmacodynamics of this effect is necessary.