Pulmonary hypertension in sickle cell disease.

Sickle cell disease (SCD) is a complex genetic disorder that has long challenged both patients and healthcare professionals. One of its chronic and debilitating complications is pulmonary hypertension (PH). SCD-associated PH is often post-capillary, secondary to left heart disease. It can also sometimes be pre-capillary with multiple and often interrelated mechanisms including obstructive remodeling of the pulmonary vascular bed secondary to hemolysis, endothelial dysfunction, thrombosis, hypoxia, or associated risk factors like portal hypertension. Screening symptomatic patients with echocardiographic signs of PH is crucial to determine those who should undergo right heart catheterization, the cornerstone exam to diagnose and categorize patients with PH. The workup following the diagnosis relies on identifying the cause of PH to personalize treatment. Ongoing efforts are made to treat this complex condition, starting with treating the underlying disease with hydroxyurea or chronic blood exchange transfusion. Robust data on the efficacy of PAH-specific therapies are lacking in this specific population. Initiation of such therapies must be made by an expert center after a case-by-case assessment of the benefit-risk ratio according to the phenotype and the mechanisms involved in the development of PH. Efforts are also poured into studying the interventional and medical therapies used on chronic thromboembolic PH for patients presenting with a thrombotic form. The management of those patients requires a multidisciplinary approach, with conjoint efforts from PH and SCD specialists.

Clinical phenotypes and outcomes of precapillary pulmonary hypertension of sickle cell disease.

RATIONALE: Precapillary pulmonary hypertension (PH) is a devastating complication of sickle cell disease (SCD). Little is known about the influence of the SCD genotype on PH characteristics. OBJECTIVES: To describe clinical phenotypes and outcomes of precapillary PH due to SCD according to disease genotype. METHODS: A nationwide multicentre retrospective study including all patients with SCD-related precapillary PH from the French PH Registry was conducted. Clinical characteristics and outcomes according to SCD genotype were analysed. RESULTS: 58 consecutive SCD patients with precapillary PH were identified, of whom 41 had homozygous for haemoglobin S (SS) SCD, three had S-ß0 thalassaemia (S-ß0 thal) and 14 had haemoglobin SC disease (SC). Compared to SC patients, SS/S-ß0 thal patients were characterised by lower 6-min walk distance (p=0.01) and lower pulmonary vascular resistance (p=0.04). Mismatched segmental perfusion defects on lung scintigraphy were detected in 85% of SC patients and 9% of SS/S-ß0 thal patients, respectively, and 50% of SS/S-ß0 thal patients had heterogeneous lung perfusion without segmental defects. After PH diagnosis, 31 patients (53%) received medical therapies approved for pulmonary arterial hypertension, and chronic red blood cell exchange was initiated in 23 patients (40%). Four patients were managed for chronic thromboembolic PH by pulmonary endarterectomy (n=1) or balloon pulmonary angioplasty (n=3). Overall survival was 91%, 80% and 60% at 1, 3 and 5 years, respectively, without influence of genotype on prognosis. CONCLUSIONS: Patients with precapillary PH related to SCD have a poor prognosis. Thrombotic lesions appear as a major component of PH related to SCD, more frequently in SC patients.

Chronic blood exchange transfusions in the management of pre-capillary pulmonary hypertension complicating sickle cell disease.

The long-term effects of chronic blood exchange transfusions (BETs) on pre-capillary pulmonary hypertension complicating sickle cell disease (SCD) are unknown.13 homozygous SS SCD patients suffering from pre-capillary pulmonary hypertension and treated by chronic BETs were evaluated retrospectively. Assessments included haemodynamics, New York Heart Association Functional Class (NYHA FC), 6-min walk distance (6MWD) and blood tests.Before initiating BETs, all patients were NYHA FC III or IV, median (range) 6MWD was 223 (0-501) m and median (range) pulmonary vascular resistance (PVR) was 3.7 (2-12.5) Wood Units. After a median number of 4 BET sessions, all patients had improved to NYHA FC II or III. Significant improvements in haemodynamics were observed, including a decrease in PVR (p=0.01). There was a trend to higher 6MWD (p=0.09). Median (range) follow-up time after initiation of BETs was 25 (6-53) months. During this period, two patients decided to stop BETs. One of them died from acute right heart failure and the other experienced worsening pulmonary hypertension. Two other patients died during follow-up at 25 and 54 months after BET initiation.Chronic BETs may be a potential therapeutic option in pre-capillary pulmonary hypertension complicating SCD, leading to significant clinical and haemodynamic improvements. These data must be confirmed in a prospective study.

Arterio-venous fistula for automated red blood cells exchange in patients with sickle cell disease: Complications and outcomes.

Erythrocytapheresis (ER) can improve outcome in patients with sickle cell disease (SCD). A good vascular access is required but frequently it can be difficult to obtain for sickle cell patients. Arterio-venous fistulas (AVFs) have been suggested for ER in SCD supported by limited evidence. We report the largest cohort of ER performed with AVFs from three French SCD reference centers. Data of SCD patients undergoing ER with AVFs in the French SCD reference center were retrospectively collected. The inclusion criteria were: SS or Sß-Thalassemia and AVF surgery for ER. SCD-related complications, transfusion history, details about AVF surgical procedure, echocardiographic data before and after AVF, AVF-related surgical and hemodynamical complications were collected. Twenty-six patients (mean age 20.5 years, mean follow-up 68 months [11-279]) were included. Twenty-three patients (88.5%) required central vascular access before AVF. Fifteen AVFs (58%) were created on the forearm and 11 (42%) on the arm. Nineteen patients (73%) had stenotic, thrombotic or infectious AVF complications. A total of 0.36 stenosis per 1,000 AVF days, 0.37 thrombosis per 1,000 AVF days and 0.078 infections per 1.000 AVF days were observed. The mean AVF lifespan was 51 months [13-218]. One patient with severe pulmonary hypertension worsened after AVF creation and died. We report the first series of SCD patients with AVF for ER, demonstrating that AVFs could be considered as a potential vascular access for ER. Patients with increased risk for hemodynamic intolerance of AVFs must be carefully identified, so that alternative vascular accesses can be considered. Am. J. Hematol. 92:136-140, 2017. © 2016 Wiley Periodicals, Inc.

Immunohematologic tolerance of chronic transfusion exchanges with erythrocytapheresis in sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) has become a major public health issue. Hydroxyurea and red blood cell (RBC) transfusion are the cornerstone treatments. Erythrocytapheresis (ECP) is an automated method for transfusion exchange. Given that ECP requires more blood than conventional transfusion, there is concern about alloimmunization and hemolytic transfusion reactions. We evaluate the incidence of hemolytic transfusion reactions and alloimmunization rates in patients receiving conventional blood transfusions and in patients participating in long-term blood exchange programs with ECP. STUDY DESIGN AND METHODS: All hemolytic transfusion reactions and alloimmunizations in SCD patients were recorded over the period 2006 to 2011. Conventional transfusions and ECP were compared. RESULTS: The cohort consisted of 188 SCD patients. The median (±SD) age was 23 (±14) years. The ECP and conventional transfusion groups comprised 49 and 139 patients, respectively. The prevalence of alloimmunization was 33% in the ECP group and 22% in the conventional transfusion group (p = 0.1797). The alloimmunization/RBC unit (RBCU) ratio was lower in the ECP group than in the conventional transfusion group (1.6 and 11.6 per 1000, respectively; p < 0.0001). Although patients in the ECP group received more than 10 times more RBCUs than patients in the conventional transfusion group (206 vs. 19 RBCUs per patient, respectively; p < 0.0001), none of the four recorded hemolytic transfusion reactions (n = 4) occurred. CONCLUSION: Regarding alloimmunization, ECP exhibits a good immunohematologic safety profile relative to conventional transfusion in a large SCD mainly adult cohort.

Blood oxidative stress status in patients with macrophagic myofasciitis.

The study aimed at determining the presence of an oxidative stress in patients with macrophagic myofasciitis (MMF), a new inflammatory myopathy with suspected toxic etiology related to aluminium hydroxide-containing vaccines. A total of 30 MMF patients (nine males, 21 females; aged 42+/-14 years), whose diagnosis was confirmed by deltoid biopsy, have been included and compared to 38 sex- and age-matched healthy control subjects (10 males, 28 females; aged 43+/-8 years). The blood oxidative stress status has been evaluated by assaying six parameters: plasma lipid peroxidation products (thiobarbituric acid-reactive substances: TBARS) and antioxidant defense systems: plasma vitamin E and glutathione peroxidase (GSH-Px) activity, erythrocyte GSH-Px and Cu,Zn-superoxide dismutase (SOD) activities. Plasma selenium was also determined as a trace element essential to the activity of GSH-Px. Statistical significance was evaluated by the Mann-Whitney test. Plasma GSH-Px activity, selenium and vitamin E concentration were significantly lower in MMF group than in controls (P=0.004, P=0.003 and P=0.009, respectively), with a positive correlation in MMF patients between plasma GSH-Px activity and selenium concentration (rho=0.0001). The other parameters of oxidative stress did not significantly differ between both groups. A macrophage activation could occur in MMF, consequently to chronic stimulation by aluminium-containing vaccines, and could participate to the lower values of selenium and vitamin E observed in comparison with controls. Nevertheless, since no deficiency in these elements has been observed, no supplementation is to be considered.