Abstract
This study was undertaken to determine whether simultaneous activation of clotting, fibrinolysis, and kinin-kallikrein is associated with disease severity in preterm infants with neonatal respiratory distress syndrome (RDS), during the first 5 d of life. In the infants with severe RDS, we found activation of clotting, fibrinolysis, and kinin-kallikrein within 6-12 h of birth, indicated by increased thrombin-antithrombin III complex formation[22.5 ng/ml versus 1.4 ng/ml (median values) in the mild/moderate RDS infants, p < 0.001], increased tissue-type plasminogen activator plasma concentrations [5.1 ng/ml versus 2.6 ng/ml (median values) in the mild/moderate RDS infants, p < 0.01], and increased plasma kallikrein activity [198% versus 189% of maximal activated human plasma (median values) in the mild/moderate infants,p < 0.01], respectively. Thrombin generation, tissue-type plasminogen activator release, and kallikrein activity did not change significantly in the severe RDS group throughout the study. In these infants, kallikrein activity was accompanied by lower values of plasma kallikrein inhibitory activity. Activation of clotting, fibrinolysis, and kinin-kallikrein was accompanied with a transient decrease of the neutrophil count and a steady decrease of the platelet count in the severe RDS group. The studied parameters of clotting and fibrinolytic and kinin-kallikrein activation were significantly correlated with continuous measures of RDS severity. We, therefore, suggest that this activation process likely contributes to respiratory insufficiency in neonatal RDS.
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Abbreviations
- RDS:
-
respiratory distress syndrome
- ARDS:
-
acute respiratory distress syndrome
- T-AT III:
-
thrombin-antithrombin III
- t-PA:
-
tissue-type plasminogen activator
- PKKI:
-
plasma kallikrein inhibitory activity
- Fio2:
-
fraction of inspired oxygen
- PIP:
-
peak inspiratory pressure
- VEI:
-
ventilator efficiency index
- a/APo2:
-
arterial/alveolar oxygen tension ratio
- HELLP:
-
hemolysis elevated liver enzymes, and low platelet count
- CPAP:
-
continuous positive airway pressure
- CPP:
-
cryoglobulin poor plasma
References
Jefferies AL, Coates G, O'Brodovich H 1984 Pulmonary epithelial permeability in hyaline membrane disease. N Eng J Med 311: 1075–1080.
O'Brodovich HM, Coates G 1988 Pulmonary edema in respiratory distress syndrome and bronchopulmonary dysplasia. In: Merritt TA, Northway WH, Boynton BR (eds) Bronchopulmonary Dysplasia, Blackwell Scientific Publications, Boston, pp 143–159.
Jobe A, Jacobs H, Ikegami M, Berry D 1985 Lung protein leaks in ventilated lambs: effect of gestational age. J Appl Physiol 58: 1246–1251.
Nilsson R, Grossmann G, Robertson B 1978 Lung surfactant and the pathogenesis of neonatal bronchiolar lesions induced by artificial ventilation. Pediatr Res 12: 249–255.
Berry D, Jobe A, Ikegami M 1991 Leakage of macromolecules in ventilated and unventilated segments of preterm lamb lungs. J Appl Physiol 70: 423–429.
Brus F, van Oeveren W, Okken A, Bambang Oetomo S 1994 Activation of the plasma clotting, fibrinolytic and kinin-kallikrein system in preterm infants with severe idiopathic respiratory distress syndrome. Pediatr Res 36: 647–653.
Peters M, Ten Cate JW, Breederveld C, De Leeuw R, Emeis J, Koppe J 1984 Low antithrombin III levels in neonates with idiopathic respiratory distress syndrome: poor prognosis. Pediatr Res 18: 273–276.
Schmidt B, Vegh P, Weitz J, Johnston M, Caco C, Roberts R 1992 Thrombin/antithrombin III complex formation in the neonatal respiratory distress syndrome. Am Rev Respir Dis 145: 767–770.
Saugstad OD, Buo L, Johansen HT, Roise O, Aasen AO 1992 Activation of the plasma kallikrein-kinin system in respiratory distress syndrome. Pediatr Res 32: 431–435.
Saugstad OD, Harvie A, Langslet A 1982 Activation of the kallikrein-kinin system in premature infants with respiratory distress syndrome (RDS). Acta Paediatr Scand 71: 965–968.
Stark CR, Abramson D, Erkan V 1968 Intravascular coagulation and hyaline membrane disease of the newborn. Lancet 2: 1180–1181.
Corrigan JJ, Jeter MA 1992 Tissue-type plasminogen activator, plasminogen activator inhibitor, and histidine-rich glycoproteins in stressed human newborns. Pediatrics 89: 43–46.
Malik AB, Horgan MJ 1987 Mechanisms of thrombin-induced lung vascular injury and edema. Am Rev Respir Dis 136: 467–470.
Haynes JB, Hyers TM, Giclas PC, Franks JJ, Petty TL 1988 Elevated fibrin degradation products in ARDS. Am Rev Respir Dis 122: 841–847.
Stewart JM 1993 The kinin system in inflammation. Agents Actions Suppl 42: 145–157.
Giedion A, Haefliger H, Dangel P 1973 Acute pulmonary x-ray changes in hyaline membrane disease treated with artificial ventilation and positive end expiratory pressure. Pediatr Radiol 1: 145–152.
Koenig JM, Christensen RD 1991 Incidence, neutrophil kinetics, and natural history of neonatal neutropenia associated with maternal hypertension. N Eng J Med 321: 557–562.
Brazy JE, Grimm JK, Little VA 1982 Neonatal manifestations of severe maternal hypertension occurring before the thirty-sixth week of pregnancy. J Pediatr 100: 265–271.
Jansen NJG, van Oeveren W, van Vliet M, Stoutenbeek CP, Eysman L, Wildevuur Ch RH 1991 The role of different types of corticosteroids in the inflammatory mediators in cardiopulmonary bypass. Eur J Cardiothorac Surg 5: 211–217.
Levene MI, Williams JL, Fawer CL 1985 Ultrasound of the infant brain. Clin Dev Med 92: 000–000.
Gu YJ, Obster R, de Haan J, Gallandat Huet RCG, van Oeveren W 1992 Biocompatibility of leukocyte removal filters during bedside leukocyte filtration of red cell concentrates. Transfus Sci 13: 467–472.
van Lingen RA, Hofhuis WDJ, Dekker I, Baerts W, Hählen K, Sauer PJJ 1992 The effect of heparin in arterial catheters on the coagulation in preterm infants. J Perinat Med 20: 39–46.
Notter RH, Egan EA, Kwong MS, Holm BA, Shapiro DL 1985 Lung surfactant replacement in premature lambs with extracted lipid from bovine lung lavage: effects of dose, dispersion technique and gestational age. Pediatr Res 19: 569–577.
Redmond CR, Loe WA, Bartlett RH, Arensman RM 1988 Extracorporeal membrane oxygenation. In: Goldsmith JP, Karotkin EH, Barker S(eds) Assisted Ventilation of the Neonate. WB Saunders, Philadelphia, pp 200–212.
van der Kamp KWHJ, van Oeveren W 1994 Beta-factor XII a and kallikrein generation in plasma during incubation with biomaterials. J Biomed Mater Res 28: 349–352.
Saugstad OD, Aasen AO, Guldvog I, Lium B, Lyngaas K, Amundsen E 1982 Changes of components of the plasma kallikrein-kinin system during experimental lung insufficiency in dogs. Acta Chir Scand Suppl 509P: 61–67.
Guldvog I, Saugstad OD, Aasen AO, Dale J, Lium B, Larsbraaten M, Lyngaas K, Amundsen E 1980 Blood cells and coagulation during experimental lung insufficiency in dogs. Acta Chir Scand Suppl 499P: 131–139.
Aasen AO, Saugstad OD, Lium B, Guldvog I, Lyngaas K, Larsbraaten M, Amundsen E 1980 Plasma antiplasmin activities in experimental lung insufficiency. Acta Chir Scand Suppl 499P: 113–121.
Sarnaik AP, Lieh-Lai M 1994 Adult respiratory distress syndrome in children. Pediatr Clin North Am 41: 337–364.
Palta M, Gabbert D, Fryback D, Widjaja I, Peters ME, Farrell P, Johnson J 1990 Development and validation of an index for scoring baseline respiratory disease in the very low birth weight neonate. Pediatrics 86: 714–721.
Cooper JA, Feustel PJ, Line BR, Malik AB 1986 Pulmonary epithelial clearance of 99mTc-DTPA after thrombin-induced pulmonary microembolism. Am Rev Respir Dis 134: 734–738.
Busing CM, Bleyl U 1974 Oxygen induced pulmonary hyaline membranes (PHM) and disseminated intravascular coagulation (DIC). Virchows Arch 363: 113–122.
Fuchimukai T, Fujiwara T, Takahashi A, Enhorning G 1987 Artificial pulmonary surfactant inhibited by proteins. J Appl Physiol 62: 429–437.
Ueda T, Ikegami M, Jobe A 1994 Surfactant subtypes. In vitro conversion, in vivo function, and effects of serum proteins. Am J Respir Crit Care Med 149: 1254–1259.
Corrigan JJ 1992 Normal hemostasis in the fetus and newborn coagulation: In: Polin RA, Fox WW (eds) Fetal and Neonatal Physiology, Vol 2. WB Saunders, Philadelphia, pp 1368–1371.
Liu J, Gurewich V 1993 Substrate inhibition of fibrin-dependent plasminogen activation by tissue-type plasminogen activatory. J Biol Chem 268: 12257–12259.
Viscardi RM, Broderick K, Sun CJ, Yale-Loehr AJ, Hessamfar A, Taciak V, Burke KC, Koenig KB, Idell S 1992 Disordered pathways of fibrin turnover in lung lavage of premature infants with respiratory distress syndrome. Am Rev Respir Dis 146: 492–499.
Idell S, Kumar A, Koenig KB, Coalson JJ 1994 Pathways of fibrin turnover in lavage of premature baboons with hyperoxic lung injury. Am J Repir Crit Care Med 149: 767–775.
Gao XP, Mayan WG, Conlon JM, Rennard SI, Rubinstein I 1993 Mechanisms of T-kinin-induced increases in macromolecule extravasation in vivo. J Appl Physiol 74: 2896–2903.
Frantz E, Soifer SJ, Clyman RI, Heyman MA 1989 Bradykinin produces pulmonary vasodilatation in fetal lambs: role of prostaglandin production. J Appl Physiol 67: 1512–1517.
Pitt BR, Lister G 1984 Kinetics of pulmonary angiotensin-converting enzyme activity in concious developing lambs. J Appl Physiol 57: 1158–1166.
Merritt TA, Cochrane CG, Holcomb K, Bohl B, Hallman M, Strayer D, Edwards DK 1983 Elastase and α-1-proteinase inhibitor activity in tracheal aspirates during respiratory distress syndrome. J Clin Invest 72: 656–666.
Speer CP, Ruess D, Harms K, Herting E, Gefeller O 1993 Neutrophil elastase and acute pulmonary damage in neonates with severe respiratory distress syndrome. Pediatrics 91: 794–799.
Groneck P, Götze-Speer B, Oppermann M, Eiffert H, Speer CP 1994 Association of pulmonary inflammation and increased microvascular permeability during the development of bronchopulmonary dysplasia: a sequential analysis of inflammatory mediators in respiratory fluids of high-risk preterm neonates. Pediatrics 93: 712–718.
Kohelet D, Perlman M, Hanna G, Ballin A 1990 Reduced platelet counts in neonatal respiratory distress syndrome. Biol Neonate 57: 334–342.
Heffner JE, Sahn SA, Repine JE 1987 The role of platelets in the adult respiratory distress syndrome. Culprits or bystanders? Am Rev Respir Dis 135; 482–492
Renesto P, Chignard M 1993 Enhancement of cathepsin G-induced platelet activation by leukocyte elastase: consequence for neutrophil-mediated platelet activation. Blood 82: 139–144.
Le Guennec JC, Lauziere M, Black R, Sirois P 1991 Effects of indomethacin on prostaglandin E2 and thromboxane B2 contents of tracheal lavage fluids in premature infants. Inflammation 15: 55–59.
Nemerson Y 1992 The tissue factor pathway of blood coagulation. Semin Hematol 29: 170–176.
Collen D 1980 On the regulation and control of fibrinolysis. Thromb Haemostas 43: 77–89.
Kaplan AP, Silverberg M 1987 The coagulation-kinin pathway of human plasma. Blood 70: 1–15.
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The authors thank Johan Haan for his excellent technical assistance and Miep Helfrich for correction of the manuscript.
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Brus, F., Van Oeveren, W., Okken, A. et al. Disease Severity Is Correlated with Plasma Clotting and Fibrinolytic and Kinin-Kallikrein Activity in Neonatal Respiratory Distress Syndrome. Pediatr Res 41, 120–127 (1997). https://doi.org/10.1203/00006450-199701000-00019
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DOI: https://doi.org/10.1203/00006450-199701000-00019
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