Sickle cell disease (SCD) caused by a mutation in the β-globin

Sickle cell disease (SCD) caused by a mutation in the β-globin gene intergenic region and the gene correlate with Hb F levels in individuals of African descent with SCD (53-57). of SCD (59) and polymorphisms in the gene and gene may contribute to the variability in Hb F response to hydroxyurea (60 61 Sickle cell disease genotype and cardiopulmonary complications of sickle cell disease Clinical phenotypes and laboratory values vary among the Hb SS SC and Sβ+-thalassemia sickle cell genotypes. Patients with Hb SS have higher markers of hemolysis and lower hemoglobin values compared to those with Hb SC or Sβ+-thalassemia. Correspondingly the prevalence of leg ulcers and priapisms VER-49009 which are sickle phenotypes related to higher hemolytic rates are more prevalent in individuals with Hb SS disease (62 63 Other complications of SCD including stroke vaso-occlusive pain episodes and early mortality are also higher in Hb SS versus Hb SC or Sβ+-thalassemia (10 64 65 Avascular necrosis occurs at comparable prevalences between the major sickle cell genotypes although it typically presents at an earlier age in individuals with Hb SS disease (66). Conversely the prevalence of proliferative retinopathy is usually highest in those with Hb SC disease followed by individuals with Sβ+-thalassemia and SS genotype (67). Comparison of the cardiopulmonary complications by sickle cell genotype suggest that individuals with Hb SS or Sβ0-thalassemia are at higher risk for acute chest syndrome pulmonary hypertension and low steady-state oxyhemoglobin saturations at rest compared to individuals with Hb SC or Sβ+-thalassemia (44 68 69 Here we report new analyses of the PUSH and Walk-PHaSST cohorts for the relationship between three major sickle cell genotypes Hb SS SC and Sβ+-thalassemia and certain pulmonary and cardiac complications of SCD. In particular we have focused on acute chest syndrome history oxygen desaturation tricuspid regurgitation velocity (TRV) elevation left ventricular (LV) size and LV function as determined by echocardiography and N-terminal probrain natriuretic peptide Rabbit Polyclonal to ARFGEF2. (NT-proBNP) elevation. Acute chest syndrome which includes VER-49009 pneumonia is usually a frequent pulmonary complication of SCD (44). It is second only to vaso-occlusive crisis as a cause of hospitalization and recurrent episodes may cause debilitating chronic pulmonary disease (70). It is also a leading cause of death in VER-49009 SCD accounting for approximately 25% of deaths (64 71 The cause of acute chest syndrome is known in only about a third of cases and is related to pulmonary infections pulmonary infarction and excess fat embolism (44 72 Acute chest syndrome seems to be associated with a personal or family history of asthma increased inflammatory markers and increased phospholipase A2 levels. A physician diagnosis of asthma VER-49009 has been associated with increased incidence of acute chest syndrome pain and early death (75). In a cohort of 291 infants in the Cooperative Study of Sickle Cell Disease who were prospectively followed for 11 years acute chest syndrome was twice VER-49009 as common in those diagnosed with asthma (44). Debate continues as to whether the airway hyper-reactivity reported in almost 80% of children with SCD is usually a distinct entity or overlaps with the approximately 20% of children diagnosed with SCD and asthma as comorbidities. A positive family history of asthma predicts increased risk of acute chest syndrome (76). Both asthma and SCD are inflammatory diseases whose severity has been associated with increases in inflammatory markers for airway and vascular inflammation respectively. Arachidonic acid released from cell membranes by phospholipase A2 produces leukotriene B4 and cysteinyl leukotrienes. Leukotriene B4 promotes neutrophil activation and chemotaxis. Cysteinyl leukotrienes promote bronchoconstriction mucus production airway edema and easy muscle proliferation in the lung and also results in vascular vasoconstriction vascular leakage and up-regulation of cellular adhesion molecules (75). The role of ventilation perfusion (VQ) mismatch in the connection between acute chest syndrome and asthma has also been a source of speculation as has the role of nitric oxide. An increase in exhaled nitric oxide correlates with increased asthma severity but NO bioavailability decreases with more severe hemolysis higher plasma free hemoglobin levels and higher TRV. Oxygen desaturation has an impartial association with left ventricular hypertrophy and diastolic dysfunction in patients with SCD (77). TRV reflects systolic pulmonary artery pressure and right ventricular systolic pressure (78). A TRV of > 3.0 m/sec in adults carries a substantial.