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Protein C and Protein S) in Neonatal Vitamin K Deficiency

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Protein C and Protein S) in Neonatal Vitamin K Deficiency Archives ofDisease in Childhood 1993; 68: 297-302 297 Relationship between vitamin K dependent Arch Dis Child: first published as 10.1136/adc.68.3_Spec_No.297 on 1 March 1993. Downloaded from coagulation factors and anticoagulants (protein C and protein S) in neonatal vitamin K deficiency Tetsuo Matsuzaka, Hiroya Tanaka, Masafumi Fukuda, Mikihiro Aoki, Yoshiro Tsuji, Hisayoshi Kondoh Abstract which are functionally defective. Dysfunction To determine the relationship between of these coagulation factors and inhibitors are vitamin K dependent coagulation factors clinically well known and seen in such dis- and natural anticoagulants, namely pro- eases as haemorrhagic disease of the new- tein C and protein S, in various degrees born8-10 and thromboembolic disorders of vitamin K deficiency, plasma values including neonatal purpura fulminans.1 1-5 As for clotting activity, protein induced by vitamin K deficiency in the early neonatal vitamin K absence (PIVKA-II), protein C period causes haemorrhagic diseases rather antigen, gammacarboxy protein C anti- than thromboembolic disorders, vitamin K gen, and protein S antigen including total deficiency has been viewed exclusively from and free fractions and activity of protein its relevance to coagulation factors. C were measured in 66 full term and We report our study of the changes of pro- healthy breast fed neonates who did not tein C and protein S as well as of coagulation receive vitamin K supplement at birth. factors from the occurrence of vitamin K The 66 neonates were divided into a con- deficiency to its correction with vitamin K trol group (17 cases) and a low group administration. Furthermore, the relation- (49 cases) according to their values for ship between the breast milk intake and clotting activity-that is, 220% or <20% vitamin K deficiency in neonates was also during the first six days of life-and vita- investigated. min K was immediately given when the neonates showed values <20%. In the low group clotting activity gammacarboxy Subjects and methods protein C, free protein S, and protein C SUBJECTS activity was significantly decreased to a Sixty six healthy, full term (range 38-41 minimum on day 2 or 3, and increased in weeks) neonates with a normal birth weight parallel after vitamin K administration. (range 2755-3970 g) aged 0 to 6 days were http://adc.bmj.com/ Furthermore, they were positively corre- studied. There was no history of maternal lated with one another and inversely cor- anticonvulsant or anticoagulation treatment. correlated with the PIVKA-II concen- They fed exclusively on breast milk except for trations. These findings suggest that supplements of 5% glucose solution, and did simultaneous gammacarboxylation of not receive vitamin K prophylaxis at birth. coagulation factors and proteins C and S Informed consent was obtained from all par- acts to maintain both coagulation and ticipating parents. on October 1, 2021 by guest. Protected copyright. anticoagulation activities in parallel at various concentrations of vitamin K. The breast milk intake in the group with low SCREENING FOR HYPOPROTHROMBINAEMIA AND Nagasaki University values of clotting activity was significant- VITAMIN K ADMINISTRATION School ofMedicine, ly lower than that in the control group A test for clotting activity (Normotest, Nagasaki, Japan, during the first three days of life. Nyegaard and Co) was used as the screening Department of Paediatrics Therefore, mothers should be advised to test for hypoprothrombinaemia because this Tetsuo Matsuzaka try to increase the breast milk secretion, test accurately reflects total coagulant activity Hiroya Tanaka for example, by providing frequent suck- of factors II, VII, and X and requires only Masafumi Fukuda lings to infants in the first days oflife. 0 01 ml whole blood. The test was Mikihiro Aoki capillary Yoshiro Tsuji performed every day from 0 to 6 days of age. (Arch Dis Child 1993;68:297-302) As the values for clotting activity in patients Scientific Data Centre with vitamin K deficiency haemorrhage were for the A-Bomb Disaster Vitamin K is required for the post-transla- less than 10%,16 we regarded values <20% as Hisoyoshi Kondoh tional gammacarboxylation of glutamic an indication of being at risk of haemorrhagic acid residues in the vitamin K dependent disease of the newborn and immediately gave Correspondence to: Dr Tetsuo Matsuzaka, proteins,' including not only coagulation fac- 2 mg of vitamin K2 syrup (Eisai Ltd).Sixty six Department of Paediatrics, tors II, VII, IX, and X but also protein C2 neonates were divided into a low (49 cases) Nagasaki University School of Medicine, and protein S,3 which are the important and a control group (17 cases) according to 7-1 Sakamoto-machi, inhibitors of coagulation.4-7 Vitamin K defi- whether their values were <20% or .20%. Nagasaki 852, Japan. ciency results in the biosynthesis of abnormal The low group was further divided into three Accepted 18 September 1992 non-gammacarboxy forms of these proteins subgroups: low-1 (12 cases), low-2 (19 298 Matsuzaka, Tanaka, Fukuda, Aoki, Tsuji, Kondoh cases), and low-3 (18 cases) showing values were discarded, and the samples in the low-I <20% on day 1, 2, and 3 of life, respectively. group were excluded from the following Arch Dis Child: first published as 10.1136/adc.68.3_Spec_No.297 on 1 March 1993. Downloaded from In order to overcome the effect ofpacked cell measurements because the number of samples volume on coagulation activity, the clotting on day 1 was only 1. factor value was corrected using a correction factor: (100-Hn)/(100-Hs), where Hn is the ASSAY METHODS normal mean packed cell volume (haemato- Protein induced in vitamin K absence crit) value (0-45 is used here) and Hs, the (PIVKA-II) was measured by enzyme linked packed cell volume ofa sample. We use the cor- immunosorbent assay (ELISA) using mono- rected value of the clotting activity throughout clonal antibody against PIVKA-II (Eitest the study except for the screening test. monoP-II; Eisai Ltd).'7 The lowest limit of plasma PIVKA-II is 0-06 arbitrary units (AU)/ml (1 AU corresponds to 1 gg of puri- PREPARATION OF PLASMA SAMPLES fied prothrombin). Blood sampling for the following assays was Total protein C antigen was quantitated by performed on days 0, 3, 4, and 6 in the con- sandwich ELISA (Asserachrom protein C, trol group, whereas in the three low groups it Boehringer Mannheim Yamanouchi). The was performed on day 0, immediately before lowest limit of this assay is 0 1% of the normal (on day 1 in low-i, on day 2 in low-2, and on adult concentration. day 3 in low-3 group) and one day after vita- Gammacarboxy protein C was also mea- min K administration, and on day 6 of life. sured by one step sandwich ELISA (TD-82; Venous blood was collected into siliconised Teijin Ltd)18 using two monoclonal anti- tubes containing 1/10th the volume of 3-8% protein C antibodies, one of which recognised sodium citrate, centrifuged at 2500 g for 20 a gammacarboxyglutamic acid domain related minutes at 4°C, and the supernatant plasma conformational change induced by metal ions, was stored at -70°C. The clotted samples and the other was directed against the activa- tion peptide. Briefly, diluted plasma samples, peroxidase-conjugated antibody against gam- 80 macarboxyglutamic acid domain and anti- body (against the activation peptide) coated 70 polystyrene beads were mixed and incubated. After washing, the beads were immersed in a 60 substrate solution containing hydrogen 50 peroxide. Then, the reaction was stopped by addition of acetic acid, and absorbance of g 40 650 nm was read using a spectrophotometer (Shimadzu). The lowest limit of this assay is 30 10% of the normal adult concentration. Protein C activity was measured by an 20 activated partial thromboplastin time method (Staclot protein C; Diagnostica http://adc.bmj.com/ 10 Stago) using Protac, an activator of protein C. 0 The lowest limit is 50/o of the normal adult 0 2 3 4 5 6 value. Total protein S antigen was determined by conventional Laurell rocket immunelec- trophoresis using antiprotein S antibody as pre- 16 Free S was viously reported.'9 protein antigen on October 1, 2021 by guest. Protected copyright. 14 measured by one step sandwich ELISA (TD- 84; Teijin Ltd),20 using polyclonal antiprotein 12 S antibody and peroxidase-conjugated mono- clonal antiprotein S antibody that recognised 10 the C4bp binding site. The lowest limit of this assay is 5% of the normal adult value. E 8 MEASUREMENT OF BREAST MILK INTAKE IN 6 NEONATES The volume of breast milk intake was mea- 4 sured every day from 0 to 6 days after birth by 2 weighing neonates before and after feeding and a 1 g gain in weight was assumed to be 0I 1 ml of milk intake. 0 1 2 3 4 5 6 STATISTICAL ANALYSIS Days All data analyses were performed using IBM Figure 1 Serial clotting activity and PIVKA-IIfor the control group and two groups 9377 and SAS Statistical Software. Student's t shown to have low values for clotting activity on day 2 or 3 (low-2 group and low-3 group test and Wilcoxon's rank sum test were used respectively); results are mean (SE). Note the rise in clotting activity andfall in PIVKA-II to analyse normally distributed and non- in the groups with low values after vitamin K administration. The control group had no vitamin K, whereas low-2 and low-3 groups had it on day 2 and 3, respectively; normally distributed data, respectively. Re- **p<OO1, ***p<OOO1 as compared with the value on day 0 within the same group. gression analysis was performed by the Vitamin K dependent proteins in neonates 299 method of least squares, and the correlation increased to the maximum on day 2 (mean coefficient (r) was calculated.
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