Diagnosis and management of thromboses in the perinatal period.
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Humans↗
Biomedical subjects
M J Manco-Johnson
Publications and source records attributed to M J Manco-Johnson.
Molecular forms of human protein C: comparison and distribution in human adult plasma.
Protein C (PC) is a vitamin K-dependent protein which functions as both an anticoagulant and profibrinolytic. It is synthesized as a single chain protein (SC-PC) and post-translationally modified into a two chain form (2C-PC). Two chain PC consists of a light chain (LC) and a heavy chain (HC). The present study was undertaken to determine the composition of the molecular forms of PC in plasma. PC was immunoprecipitated, subjected to SDS-PAGE and Western blotting. The blots were scanned by densitometry to determine the distribution of the various forms. The percentage of SC-PC and 2C-PC was found to be 10% and 90% respectively. This is in agreement with previous work. SC-PC and the heavy chain of 2C-PC consisted of three molecular forms ("alpha", "beta", and "gamma"). The "alpha" form of HC is the standard 2C form with a MW of 40 Kd. The "beta" form of HC has also been described and has MW which is 4 Kd less than the "alpha" form. The "gamma" species of the SC and 2C-PC has not been previously described. However, its 3 Kd difference from the "beta" form could be due to modification of the "beta" species or to a separate modification of the alpha-HC. The LC of PC was shown to exist in two forms (termed form 1 and form 2). The difference between these two forms is unknown. The molecular forms of PC are most likely due to a post-translational modification (either loss of a carbohydrate or a peptide) rather than from plasma derived degradation.
Aged↗
Neonatal protein C: molecular composition and distribution in normal term infants.
Protein C (PC) is a vitamin K-dependent serine protease which functions as the central regulatory protein with both anticoagulant and profibrinolytic properties. The PC levels in healthy term newborns are approximately one third of adult levels. Severely decreased levels of PC are seen in sick term and preterm infants. These neonates appear to have an increased incidence of thrombosis. Undetectable levels of PC are found in homozygous PC deficient infants with DIC and purpura fulminans symptoms. In this present study we report the composition and distribution of PC in term newborn and compare the results with adult values. Plasma was obtained from placental cord blood of 20 healthy term (38-42 weeks gestation) infants. PC was immunopurified, run on SDS-PAGE, and immuno-blotted. The composition of the PC molecule in neonatal plasma is identical to that seen in adults. Using densitometry to determine the distribution of the PC components, we observed a 2-fold increase in single chain PC in the neonate as compared to the adult. In the neonate, there was an inverse correlation between the level of total PC antigen and the amount of single chain. These findings suggest the possibility that the processing of PC may be developmentally influenced.
Female↗
Neonatal antithrombin III deficiency.
Hemorrhagic and thrombotic complications are common in sick preterm infants and may reflect inadequate regulation of coagulation. All neonates have low levels of the pivotal regulator antithrombin III (ATIII) compared with adults. Plasma levels of ATIII are very low in preterm infants and are further diminished in infants with respiratory distress, necrotizing enterocolitis, sepsis, or disseminated intravascular coagulation. Babies with lower levels of ATIII in the cord blood have been shown to have a worse outcome than neonates with levels appropriate for gestational age, including higher mortality and increased incidence of intracranial hemorrhages and catheter-related thromboses. The origin of severe ATIII deficiency is unknown. Therapies with plasma replacement or anticoagulation have decreased the incidence and severity of hemorrhagic and thrombotic complications in high-risk infants in several clinical trials. These data lay the groundwork and rationale for potential use of ATIII replacement in deficient preterm infants.
Antithrombin III↗
Heparin cofactor II in adults and infants with thrombosis and DIC.
Heparin cofactor II (HC II) was measured by a chromogenic activity assay in normal preterm infants (gestational age, 28-36 weeks; n = 17; 29% +/- 11.5 [mean +/- 1 SD], range 11-51), normal full-term infants (n = 18; 49% +/- 6.6 [mean +/- 1 SD], range 36-58), and normal adults (n = 38; 101% +/- 14 [mean +/- 1 SD], range 73-130). Normal children attained adult levels at approximately 5 to 7 months of age. The lower values in preterm and term infants most likely reflect immature liver function. Neither adults and children with a history of thrombosis with prior negative evaluation (n = 74), patients with documented protein C and protein S deficiency (n = 4), nor sick infants without evidence of consumptive coagulopathy (n = 15) had significantly lower levels of HC II activity. Infants with disseminated intravascular coagulation (n = 2) had strikingly lower levels of HC II activity.
Disseminated Intravascular Coagulation↗
Severe protein C deficiency in newborn infants.
Eleven infants initially seen in the neonatal period had levels of protein C suggestive of homozygous protein C deficiency but as an apparently acquired condition. Family studies failed to document parental carrier status, the clinical course was not typical of that reported with homozygous protein C deficiency, and protein C levels increased in all restudied infants, six of whom received heparin anticoagulation. No infant had evidence of vitamin K deficiency. Care is advised in the evaluation of infants with low levels of protein C. Parental blood studies, delayed testing, and serial assays can help to establish the correct diagnosis.
Female↗
Vitamin K deficiency in the newborn infant: prevalence and perinatal risk factors.
The prevalence of vitamin K deficiency in newborn infants and the influence of perinatal risk factors were studied prospectively in 934 infants. A noncarboxylated prothrombin assay to detect proteins induced in vitamin K absence (PIVKA-II) was used to determine the presence of vitamin K deficiency; of 934 cord blood samples assayed, 2.9% were positive for PIVKA-II (0.015 to 0.15 U/ml). All infants found to have detectable PIVKA-II were born at term. The number of infants positive for PIVKA-II was greater in the group small for gestational age (7.4%) than in those appropriate (2.7%) or large (3.1%) for gestational age. Nine categories of perinatal risk groups were defined: however, the majority of infants who were PIVKA-II positive (63%) were normal. All infants received prophylactic vitamin K, and no infant with PIVKA-II in the cord sample subsequently had clinical bleeding. In two patients the rate of 50% disappearance of PIVKA-II after vitamin K administration approximated 70 hours. Two PIVKA-II positive patients with active bleeding or disseminated intravascular coagulation had an accelerated disappearance of 20 to 40 hours. The long disappearance time of PIVKA-II in a steady state may allow detection of vitamin K deficiency despite administration of vitamin K. The majority of cases of neonatal vitamin K deficiency occurred in normal newborn infants. Therefore, all infants should receive prophylactic vitamin K at birth.
Biomarkers↗
Abnormal antithrombin III with defective serine protease binding (antithrombin III "Denver").
A hereditary (three family members) deficiency of antithrombin III (AT-III) in which AT-III antigen (AT-III ag) is normal in spite of low heparin cofactor and antithrombin activity is described. Plasma levels were: AT-III ag, 0.92-0.96 U/ml; AT-III heparin cofactor activity, 0.54-0.62 U/ml; progressive antithrombin activity index, 0.13-0.18; anti-Xa activity, 0.50-0.56 U/ml. Plasma crossed immunoelectrophoresis (CIE) patterns performed with and without added heparin were normal, but serum CIE revealed a decreased complex peak. Purification of the patient's plasma AT-III by heparin-sepharose affinity chromatography showed a normal protein recovery and elution profile, but the purified AT-III fraction showed only 50% of the normal progressive thrombin neutralization and anti-Xa activity. When thrombin-antithrombin (TAT) complexes were formed by incubating with excess thrombin, SDS-polyacrylamide gel electrophoresis (PAGE) analysis revealed that half the patient AT-III formed TAT complexes while the remainder migrated as free AT-III. All the control AT-III formed TAT complexes. The patient's nonreacting AT-III (AT-III "Denver"), isolated by affinity chromatography, showed CIE and SDS-PAGE migration patterns characteristic of normal AT-III but failed to bind thrombin or Xa. Calculations from turnover studies in one patient and normal subjects with autologous 131I-AT-III suggested that AT-III "Denver" is removed from the plasma slightly more rapidly than normal. These studies indicate that the patients' variant AT-III molecule was characterized by normal heparin interaction but defective binding and inhibition of thrombin and Xa. These characteristics allow isolation of the nonreactive variant molecule by heparin-sepharose affinity chromatography.
Antithrombin III↗
Timing and course of neonatal intracranial hemorrhage using real-time ultrasound.
Knowledge of the timing and course of neonatal intracranial hemorrhage is essential in determining the etiology of hemorrhage, since the key to preventing neurologic damage in newborns is to define preventable causes and to treat the complications of hemorrhage. In an intensive study of 49 neonates delivered less than or equal to 32 weeks gestation, the initial hemorrhage typically occurred in the first three days of life, with 36% occurring on day 1, 32% on day 2, and 18% on day 3. Most of the major hemorrhages (Grades III and IV) occurred on day 1, although ventricular enlargement occurred at a variable time after the initial insult. By the sixth day, 91% of all intracranial hemorrhage had occurred.
Cerebral Hemorrhage↗