Anoosha Habibi

A Hemodynamic Study of Pulmonary Hypertension in Sickle Cell Disease

BACKGROUND The prevalence and characteristics of pulmonary hypertension in adults with sickle cell disease have not been clearly established. METHODS In this prospective study, we evaluated 398 outpatients with sickle cell disease (mean age, 34 years) at referral centers in France. All patients underwent Doppler echocardiography, with measurement of tricuspid-valve regurgitant jet velocity. Right heart catheterization was performed in 96 patients in whom pulmonary hypertension was suspected on the basis of a tricuspid regurgitant jet velocity of at least 2.5 m per second. Pulmonary hypertension was defined as a mean pulmonary arterial pressure of at least 25 mm Hg. RESULTS The prevalence of a tricuspid regurgitant jet velocity of at least 2.5 m per second was 27%. In contrast, the prevalence of pulmonary hypertension as confirmed on catheterization was 6%. The positive predictive value of echocardiography for the detection of pulmonary hypertension was 25%. Among the 24 patients with confirmed pulmonary hypertension, the pulmonary-capillary wedge pressure was 15 mm Hg or less (indicating precapillary pulmonary hypertension) in 11 patients. Patients with confirmed pulmonary hypertension were older and had poorer functional capacity and higher levels of N-terminal pro-brain natriuretic peptide than other patients. In contrast, patients who had a tricuspid regurgitant jet velocity of at least 2.5 m per second without pulmonary hypertension and patients with a tricuspid regurgitant jet velocity of less than 2.5 m per second had similar clinical characteristics. CONCLUSIONS In this study of adults with sickle cell disease, the prevalence of pulmonary hypertension as confirmed on right heart catheterization was 6%. Echocardiographic evaluation alone had a low positive predictive value for pulmonary hypertension. (Funded by the French Ministry of Health and Assistance Publique-Hôpitaux de Paris; ClinicalTrials.gov number, NCT00434902.).

Pulmonary Hypertension and Cor Pulmonale during Severe Acute Chest Syndrome in Sickle Cell Disease

RATIONALE Steady-state mild pulmonary hypertension is a risk factor for death in adults with sickle cell disease. Acute pulmonary hypertension has been reported during exercise and vasoocclusive pain crisis in these patients. OBJECTIVES The aim of the present study was to evaluate changes in pulmonary pressures and cardiac biomarkers during severe acute chest syndrome and their associations with mortality. METHODS We prospectively evaluated 70 consecutive adults who received standardized treatment in our intensive care unit for a total of 84 episodes. At admission, cardiac biomarkers were measured. Transthoracic echocardiography was performed for pulmonary hypertension assessment via measurement of tricuspid regurgitant jet velocity and was repeated when possible after resolution. MEASUREMENTS AND MAIN RESULTS Tricuspid jet velocity was less than 2.5 m/second in 34 (40%) of the 84 episodes, 2.5 to 2.9 m/second in 19 (23%), and 3 m/second or greater in 31 episodes (37%). Cor pulmonale occurred in 11 (13%) episodes. Tricuspid jet velocity showed significant positive correlations with B-type natriuretic peptide (rho = 0.54, P < 0.01) and cardiac troponin I (rho = 0.42, P < 0.01). Pulmonary pressures increased compared with steady state then decreased after resolution. All five patients who required invasive ventilation and all four patients who died during the immediate hospital course had jet velocity values of 3 m/second or greater. Overall mortality was 12.9% (9 patients) and survival was significantly lower in patients whose jet velocity was 3 m/second or greater during at least one episode, compared with the other patients (P < 0.01). CONCLUSIONS Pulmonary pressures increase during severe acute chest syndrome, and pulmonary hypertension is associated with cardiac biomarker elevation and a higher risk of death.

Delayed hemolytic transfusion reaction in sickle cell disease patients: evidence of an emerging syndrome with suicidal red blood cell death

BACKGROUND: Delayed hemolytic transfusion reaction (DHTR) is a life‐threatening complication in sickle cell disease (SCD) characterized by recurrence of disease complications, recipient red blood cell (RBC) destruction, and frequently no detectable antibody. Phosphatidylserine (PS) exposure signs suicidal RBC death or eryptosis and is involved in vasoocclusive crisis (VOC).

Pulmonary Artery Thrombosis during Acute Chest Syndrome in Sickle Cell Disease

RATIONALE The pathophysiology of acute chest syndrome (ACS) in patients with sickle cell disease is complex, and pulmonary artery thrombosis (PT) may contribute to this complication. OBJECTIVES To evaluate the prevalence of PT during ACS using multidetector computed tomography (MDCT). METHODS We screened 125 consecutive patients during 144 ACS episodes. One hundred twenty-one MDCTs (in 103 consecutive patients) were included in the study. MEASUREMENTS AND MAIN RESULTS Twenty MDCTs were positive for PT, determining a prevalence of 17% (95% confidence interval, 10-23%). Revised Geneva clinical probability score was similar between patients with PT and those without. D-dimer testing was very often positive (95%) during ACS. A precipitating factor for ACS was less frequently found in patients with PT as compared with those without. Patients with PT exhibited significantly higher platelet counts (517 [273-729] vs. 307 [228-412] 10(9)/L, P < 0.01) and lower bilirubin (28 [19-43] vs. 44 [31-71] μmol/L, P < 0.01) levels at the onset of ACS as compared with others. In addition, patients with PT had a higher platelet count peak (537 [345-785] vs. 417 [330-555] 10(9)/L, P = 0.048) and smaller bilirubin peak (36 [18-51] vs. 46 [32-83] μmol/L, P = 0.048)and lactate dehydrogenase peak (357 [320-704] vs. 604 [442-788] IU/L, P = 0.01) during hospital stay as compared with others. CONCLUSIONS PT is not a rare event in the context of ACS and seems more likely in patients with higher platelet counts and lower hemolytic rate during ACS. Patients with sickle cell disease presenting with respiratory symptoms suggestive of ACS may benefit from evaluation for PT.

A randomized, controlled clinical trial of ketoprofen for sickle-cell disease vaso-occlusive crises in adults

Vaso-occlusive crisis (VOC) is the primary cause of hospitalization of patients with sickle-cell disease. Treatment mainly consists of intravenous morphine, which has many dose-related side effects. Nonsteroidal antiinflammatory drugs have been proposed to provide pain relief and decrease the need for opioids. Nevertheless, only a few underpowered trials of nonsteroidal antiinflammatory drugs for sickle-cell VOC have been conducted, and conflicting results were reported. We conducted a phase 3, double-blind, randomized, placebo-controlled trial with ketoprofen (300 mg/day for 5 days), a nonselective cyclooxygenase inhibitor, for severe VOC in adults. A total of 66 VOC episodes were included. The primary efficacy outcome was VOC duration. The secondary end points were morphine consumption, pain relief, and treatment failure. Seven VOC episodes in each group were excluded from the analysis because of treatment failures. No significant between-group differences were observed for the primary outcome or the secondary end points. Thus, although ketoprofen was well-tolerated, it had no significant efficacy as treatment of VOC requiring hospitalization. These findings argue against its systematic use in this setting.

Decreased sickle red blood cell adhesion to laminin by hydroxyurea is associated with inhibition of Lu/BCAM protein phosphorylation

Sickle cell disease is characterized by painful vaso-occlusive crises during which abnormal interactions between erythroid adhesion molecules and vessel-wall proteins are thought to play a critical role. Hydroxyurea, the only drug with proven benefit in sickle cell disease, diminishes these interactions, but its mechanism of action is not fully understood. We report that, under hydroxyurea, expression of the unique erythroid laminin receptor Lu/BCAM was increased, but red blood cell adhesion to laminin decreased. Because Lu/BCAM phosphorylation is known to activate cell adhesion to laminin, it was evaluated and found to be dramatically lower in hydroxyurea-treated patients. Analysis of the protein kinase A pathway showed decreased intracellular levels of the upstream effector cyclic adenosine monophosphate during hydroxyurea treatment. Using a cellular model expressing recombinant Lu/BCAM, we showed that hydroxyurea led to decreased intracellular cyclic adenosine monophosphate levels and diminished Lu/BCAM phosphorylation and cell adhesion. We provide evidence that hydroxyurea could reduce abnormal sickle red blood cell adhesion to the vascular wall by regulating the activation state of adhesion molecules independently of their expression level.

Pregnancy in sickle cell disease: maternal and fetal outcomes in a population receiving prophylactic partial exchange transfusions

OBJECTIVE To describe pregnancy outcomes for pregnant women with sickle cell disease (SCD) receiving prophylactic transfusions. STUDY DESIGN This retrospective case-control study compared pregnancy outcomes among women with SCD receiving prophylactic transfusions and women without any hemoglobinopathy, matched for ethnicity, parity, age and hospital. RESULTS The study included two groups of pregnancies: 128 in women with SCD (95 with SS phenotype and 33 with SC) and 128 in women with AA phenotype. No woman died. Two perinatal deaths (2.1%) and five alloimmunizations (5.3%) occurred, all in the SS group. Compared with the control group, HbSS disease was more often associated with pre-eclampsia (9.4% versus 2.3%, p=.03), preterm delivery (15.8% versus 6.2%, p=.01), birth weight <10th percentile (13.7% versus 3.9%, p=.008) and caesarean delivery (73.6% versus 26.4%, p<.01). CONCLUSION Despite prophylactic blood transfusions, SCD remains a severe complicating factor in pregnancy. The policy of systematic transfusions should be analyzed in a sufficiently large randomized trial.

Recommandations pratiques de prise en charge de la drépanocytose de l’adulte

Sickle cell disease is a systemic disease that can potentially involve all organs. As the prevalence of patients with sickle cell disease increases gradually in France, every physician can be potentially involved in the care of these patients. Complications of sickle cell disease can be acute or chronic. Pain is the main symptom and should be treated quickly and aggressively. Acute chest syndrome is the leading cause of acute death and must be prevented, detected, and treated without delay. Chronic complications are one of the main concerns in adults and should be identified as early as possible in order to prevent sequels. Many organs can be involved, including the bones, kidneys, eyes, lungs... The indications for a specific treatment (blood transfusion or hydroxyurea) should be discussed. Health care should be carefully organized to allow both a regular follow-up near the living place and access to specialized departments. We present in this article the French guidelines for the sickle cell disease management in adulthood.

Acute kidney injury in sickle patients with painful crisis or acute chest syndrome and its relation to pulmonary hypertension

BACKGROUND The association between chronic kidney involvement and sickle cell disease (SCD) has been well characterized, but our knowledge on acute kidney injury (AKI) in relation to SCD remains limited. METHODS We retrospectively assessed 254 episodes of vaso-occlusive complication in 161 SCD patients who were admitted to our hospital: these included 174 episodes of painful crisis (PC), 58 episodes of moderate acute chest syndrome (ACS) and 22 episodes of severe ACS. RESULTS The overall incidence of AKI [defined according to Acute Kidney Injury Network (AKIN) criteria] during vaso-occlusive complications was low (4.3%) but seemed to be related to its severity: 2.3% for PC vs 6.9% for moderate ACS and 13.6% for severe ACS (P = 0.03). This finding led us prospectively to look at specific risk factors for AKI occurrence in SCD patients admitted to our intensive care unit for severe ACS and, in particular, the possible link between AKI and haemodynamic status (transthoracic echocardiography). Among patients with severe ACS, those with AKI displayed significantly greater aminotransferases, bilirubin and lactate dehydrogenase levels than patients without AKI. Echocardiography identified higher systolic pulmonary artery pressure in patients with AKI than in those without, whereas the cardiac index was similar between groups. CONCLUSIONS AKI incidence during vaso-occlusive complications of SCD is relatively low (<5%) and appears to be confined to patients with ACS and pulmonary hypertension. These findings suggest a pathophysiological process involving right ventricular dysfunction and venous congestion.

Six Months of Hydroxyurea Reduces Albuminuria in Patients with Sickle Cell Disease

The earliest symptom of glomerular injury in patients with sickle cell disease (SCD) is microalbuminuria. The effect of hydroxyurea (HU) on urine albumin-to-creatinine ratio (ACR) is unclear and should be determined, because increasing numbers of patients with SCD take this drug to improve red blood cell function. In this cohort study of 58 SS-homozygous adults with SCD who initiated HU therapy, we evaluated ACR changes and relationships of these changes with demographic, clinical, and biologic parameters at HU initiation (baseline) and 6 months later (follow-up). Between baseline and follow-up, ACR declined significantly for the entire population (3.0-1.7 mg/mmol; P<0.01), but this was primarily driven by the ACR reduction in the microalbuminuria subgroup (8.1-2.3 mg/mmol; P=0.03; n=23). According to bivariate analyses on 39 patients who did not receive a blood transfusion during the study period, the baseline to follow-up ACR decline was strongly associated with decreases in levels of hemolysis markers, percentage of dense red blood cells, and systolic BP. Bivariate analysis also revealed a close association between the ACR decrease and high baseline levels of hemolysis markers and percentage of dense red blood cells. These results show that urine ACR decreased significantly after 6 months of HU and confirm a close relationship between ACR and hemolysis evolution in patients with SCD.