Antithrombin III deficiency in neonatal respiratory distress syndrome.
Neonatal respiratory distress syndrome (RDS) is an acute lung injury believed to result primarily from surfactant deficiency in the immature lung. Although surfactant replacement therapy has improved the outcome of this disease, RDS remains a major cause of neonatal mortality and morbidity. Preliminary experimental evidence suggests that unopposed intravascular thrombin activity may contribute to the progression of RDS by promoting high permeability pulmonary oedema and pulmonary hypertension. In the extravascular lung compartment, polymerizing fibrin may inhibit surfactant function. In addition, interstitial and alveolar thrombin formation and resulting fibrin deposition may contribute to the development of chronic lung disease through amplification of inflammation and fibrosis. There is good evidence that extravascular coagulation occurs during the course of RDS. Fibrin is a major component of the hyaline membranes, which are a hallmark of acute lung injury, and which can be regarded as locally produced clots. It has been less certain whether neonatal RDS is also associated with intravascular activation of the coagulation system. Although low levels of antithrombin III (AT III) have been reported in infants with RDS, direct evidence of increased intravascular thrombin formation has been lacking. However, recently, plasma concentrations of thrombin-antithrombin III (TAT) complexes have been measured in infants with RDS and correlated with RDS severity. TAT formation was significantly increased in severe neonatal RDS, while free AT III activity was decreased. These data are consistent with increased thrombin generation and resulting AT III consumption. Therefore, to regulate thrombin activity, infants with severe RDS may benefit from replacement therapy with AT III concentrate. This hypothesis has been strengthened by experiments that have demonstrated the efficacy of thrombin inhibition in several animal models of acute lung injury. However, controlled clinical trials will be required to determine whether thrombin is just a coincidental marker of neonatal RDS, or whether unopposed thrombin activity exacerbates the disease process.
Schmidt
B K
BK
Department of Paediatrics, McMaster University, Hamilton, Ontario, Canada.
D000818:Animals; D000990:Antithrombin III / Q000235:genetics; D020152:Antithrombin III Deficiency; D002986:Clinical Trials as Topic; D005337:Fibrin / Q000502:physiology; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology; D007231:Infant, Newborn; D011654:Pulmonary Edema / Q000209:etiology / Q000503:physiopathology; D012127:Respiratory Distress Syndrome, Newborn; D013917:Thrombin / Q000502:physiology
D005343:Fibrinolytic Agents; D000990:Antithrombin III; D005337:Fibrin; D013917:Thrombin