The Pharmacokinetics and Lipoprotein Fraction Distribution of Intramuscular vs. Oral Vitamin K1Supplementation in Women of Childbearing Age: Effects on Hemostasis

J Nathan Hagstrom; Edwin G Bovill; Roger F Soll; Kenneth W Davidson; James A Sadowski

doi:10.1055/s-0038-1649970

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1995; 74(06): 1486-1490
DOI: 10.1055/s-0038-1649970

Original Articles

Coagulation

Schattauer GmbH Stuttgart

The Pharmacokinetics and Lipoprotein Fraction Distribution of Intramuscular vs. Oral Vitamin K₁Supplementation in Women of Childbearing Age: Effects on Hemostasis

J Nathan Hagstrom

¹The Department of Pathology, University of Vermont, Burlington, Vermont, USA

,

Edwin G Bovill

¹The Department of Pathology, University of Vermont, Burlington, Vermont, USA

,

Roger F Soll

²The Department of Pediatrics, University of Vermont, Burlington, Vermont, USA

,

Kenneth W Davidson

³The Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA

,

James A Sadowski

³The Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA

› Author Affiliations

Abstract

PDF Download

Summary

Prenatal maternal vitamin K₁ supplementation to improve the hemostatic status of the fetus may depend upon the route of administration and subsequent presentation at the placental barrier. We investigated intramuscular (IM) vs oral (PO) vitamin K₁ supplementation in eight healthy, nonpregnant women of childbearing age. Pharmacokinetics were studied in each subject after a 5 mg IM dose and after a 5 mg oral dose of vitamin K₁ approximately one month later. Plasma collected at the peak vitamin K level for each treatment was separated into very low density lipoproteins (VLDL), low density lipoprotein (LDL), high density lipoprotein (HDL) and lipoprotein-free fractions by density gradient ultracentrifugation. Vitamin K₁ was measured in the plasma and lipoprotein fractions using HPLC. The concentration of vitamin K₁, in plasma reached a peak 2 h after an IM dose and remained high throughout the 30 h course of the study. In contrast, the oral dose of vitamin K₁ peaked at 4 h and rapidly decreased to near baseline by 18 to 30 h. The distribution of vitamin K₁ in the lipid fractions was different for IM compared to PO. The percentage of vitamin K₁ in the VLDL fraction at the peak for an oral dose was significantly higher than for an IM dose (80.8% ± 3.5 vs 10.8% ± 6.5, p <0.0001). After the oral absorption stage, the subjects took 5 mg of vitamin K₁ orally, once a day, for 12 days. No significant differences were observed for the following coagulation proteins and hemostatic markers measured immediately before and after long-term oral vitamin K supplementation: factor II, factor VII, protein C, and thrombin-antithrombin III complex. In conclusion, physiological processing of supplemented vitamin K₁ differs in the IM vs PO routes of administration and 12 days of oral vitamin K₁does not alter the concentration of selected vitamin Independent coagulation proteins or thrombin-antithrombin complex generation

PDF (1479 kb)

References

References
1 Shearer MJ, Rahim S, Barkhan P, Stimmler L. Plasma vitamin K₁ in mothers and their newborn babies. Lancet 1982; 2: 460-463
2 Sann L, Leclercq M, Troncy J, Guillaumond M, Berland M, Coeur P. Serum vitamin K₁ concentration and vitamin K-dependent clotting factor activity in maternal and fetal cord blood. Am J Obstet Gynec 1985; 153: 771-774
3 McCarthy PT, Shearer MJ, Gau G, Crampton OE, Barkhan P. Vitamin K content in human liver at different ages. Haemostasis 1986; 16 Suppl (Suppl. 05) 83 abstr
4 Greer FR, Mummah-Schendel LL, Marshall S, Suttie JW. Vitamin K₁ (phylloquinone) and vitamin K₂ menaquinone status in newborns during the first week of life. Pediatrics 1988; 81: 137-140
5 Bovill EG, Soll RF, Lynch M, Bhushan F, Landesman Freije M, Church W, McAuliffe T, Davidson K, Sadowski J. Vitamin K₁ metabolism and the production of des-carboxy prothrombin and protein C in the term and premature neonate. Blood 1993; 81: 77-83
6 Bleyer WA, Hakami N, Shepard TH. The development of hemostasis in the human fetus and newborn infant. J Pediatr 1971; 79: 838-853
7 Hathaway WE, Bonnar J. Perinatal Coagulation. New York: Grime & Stratton; 1978
8 Andrew M, Paes B, Johnston M. Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hem Oncol 190 (12) 95-104
9 Motohara K, Kuroki Y, Kan H, Endo F, Matsuda I. Detection of vitamin K deficiency by use of an enzyme-linked immunosorbent assay for circulating abnormal prothrombin. Pediatr Res 1985; 19: 354-357
10 Shapiro AD, Jacobson LJ, Armon ME, Manco-Johnson MJ, Hulae P, Lane PA, Hathaway WE. Vitamin K deficiency in the newborn infant: prevalence and perinatal risk factors. J Pediatr 1986; 109: 675-680
11 Motohara K, Endo F, Matsuda I. Screening for late neonatal vitamin K defieiency by acarboxyprothrombin in dried blood spots. Arch Dis Child 1987; 62: 370-375
12 Widdershoven J, Lambert W, Motohara K, Monnens L, de Leenheer A, Matsuda I, Endo F. Plasma concentrations of vitamin K₁ and PIVKA-II in bottle fed infants with and without vitamin K prophylaxis at birth. Eur J Pediatr 1988; 148: 139-142
13 Kries RV, Becjer A, Göbel U. Vitamin K in the newborn: Influence of nutritional factors on acarboxy-prothrombin detectability and factor II and VII clotting activity. Eur J Pediatr 1987; 146: 123-127
14 Salmonsen L. On the prevention of haemorrhagic disease of the newborn by the administration of cow’s milk during the first two days of life. Acta Paediatr Scand 1940; 28: 1
15 Dam H, Dyggve H, Larsen H, Plum P. The relation of vitamin K deficiency to hemorrhagic disease of the newborn. Adv Pediatr 1952; 5: 129-153
16 Sutherland JM, Glueck HI, Gleser G. Hemorrhagic disease of the newborn: Breast feeding as a necessary factor in the pathogenesis. Am J Dis Child 1967; 113: 524-533
17 McNinch AW, Orme RL, Tripp JH. Haemorrhagic disease of the newborn returns. Lancet 1983; 1: 1089-1090
18 Lane PA, Hathaway WE. Vitamin K in infancy. J Pediatr 1985; 106: 351-359
19 Committee on Nutrition, American Academy of Pediatrics. Vitamin K compounds and the water soluble analogues: use in therapy and prophylaxis in pediatrics. Pediatrics 1961; 28: 501-507
20 Mandelbrot L, Guillaumont M, Leclercq M, Lefrère JJ, Gozin D, Daffos F, Forestier F. Placental transfer of vitamin K₁ and its implications in fetal hemostasis. Thromb Haemost 1988; 60: 39-43
21 Hamulyák K, de Boer-van den Berg MA G, Thijssen HH W, Hemker HC, Vermeer C. The placental transport of [³H| vitamin K₁ in rats. Brit J Haem 1987; 65: 335
22 Hiraike H, Kimura M, Itokawa Y. Distribution of K vitamins (phylloquinone and menaquinones) in human placenta and maternal and umbilical cord plasma. Am J Obstet Gynecol 1988; 158: 564-569
23 Yang Y-M, Simon N, Maertens P, Brigham S, Liu P. Maternal-fetal transport of vitamin K₁ and its effects on coagulation in premature infants. J Pediatr 1989; 115: 1009-1013
24 Kazzi NJ, Ilagan NB, Liang K-C, Kazzi GM, Grietsell LA, Brans YW. Placental transfer of vitamin K₁ in preterm pregnancy. Obstet Gynecol 1990; 75: 334-337
25 Pomerance JJ, Teal JG, Gogolok JF, Brown S, Stewart ME. Maternally administered antenatal vitamin K₁: effect on neonatal prothrombin activity, partial thromboplastin time, and intraventricular hemorrhage. Obstet Gynecol 1987; 70: 235-241
26 Morales WJ, Angel JL, O’Brien WF, Knuppel RA, Marsalisi F. The use of antenatal vitamin K in the prevention of early neonatal intraventricular hemorrhage. Am J Obstet Gynecol 1988; 159: 774-779
27 Kazzi NJ, Ilagan NB, Liang K-C, Kazzi GM, Poland RL, Grietsell LA, Fuji Y, Brans YW. Maternal administration of vitamin K does not improve the coagulation profile of preterm infants. Pediatrics 1989; 84: 1045-1050
28 Motohara K, Takagi S, Endo F, Kiyota Y, Matsuda I. Oral supplementation of vitamin K for pregnant women effects on levels of plasma vitamin K and PIVKA-II in the neonate. J Pediatr Gastroenterol Nutr 1990; 11: 32-36
29 Sadowski JA, Bacon DS, Hood S, Davidson KW, Ganter CM, Haroon Y, Shepard DC. The application of methods used for the evaluation of vitamin K nutritional status in human and animal studies. In: Current Advances in Vitamin K Research, Steenbock Symposium. Suttie JW. ed New York, NY: Elsevier Science; 1988. pp 453-463
30 Mulhare PE, Tracy PB, Golden EA, Brnada RF, Bovill EG. A case of acquired factor X deficiency with in vivo and in vitro evidence of inhibitor activity directed against factor X. Am J Clin Pathol 1991; 96: 196-200
31 Lindgren FT, Jensen LC, Hatch FT. The isolation and quantitative analysis of serum lipoproteins. In: Blood Lipids and Lipoproteins: Quantitation, Composition and Metabolism. Nelson GS. ed New York: John Wiley and Sons, Inc; 1972. p 181
32 Haroon Y, Bacon DS, Sadowski JA. Liquid-chromatographic determination of vitamin K₁ in plasma, with fluorometric detection. Clin Chem 1986; 32: 1925-1929
33 Shearer MJ, Barkham P, Webster GR. Absorption and excretion of an oral dose of tritiated vitamin K₁ in man. Brit J Haem 1970; 18: 297-308
34 McNinch AW, Upton C, Samuels M, Shearer MJ, McCarthy P, Tripp JH, Orme RL E. Plasma concentrations after oral or intramuscular vitamin K₁ in neonates. Arch Dis Child 1985; 60: 814-818
35 Shinzawa T, Mura T, Tsune M, Shiraki K. Vitamin K absorption capacity and its association with Vitamin K deficiency. Am J Dia Child 1989; 143: 686-689
36 Wittmaack FM, Gafvels ME, Bronner M, Matsuo H, McCrae KR, Tomaszewski JE, Robinson SL, Strickland DK, Strauss JF. Localization and regulation of the human very low density lipoprotein/apolipoprotein-E receptor: Trophoblast expression predicts a role for the receptor in placental lipid transport. Endocrinology 1995; 136: 340-348
37 Naoum HG, De-Chazal RC, Eaton BM, Contractor SF. Characterization and specificity of lipoprotein binding to term human placental membranes. Biochem Biophys Acta 1987; 902: 193-199
38 Saupe J, Shearer MJ, Kohlmeier M. Phylloquinone transport and its influence on γ-carboxyglutamate residues of osteocalcin in patients on maintenance hemodialysis. Am J Clin Nutr 1993; 58: 204-208
39 Israels LG, Friesen E, Jansen AH, Israels ED. Vitamin K₁ increases sister chromatid exchange in vitro in human leukocytes and in vivo in fetal sheep cells: a possible role for “vitamin K deficiency” in the fetus. Pediatr Res 1987; 22: 405-408
40 Freeman BA, Tanswll AK, Cunningham MK. Vitamin K₁ stimulates endothelial free radical production. Am Rev Respir Dis 1987; 135: A98 abstr
41 Cornelissen M, Smeets D, Merkx G, DeAbreu R, Kollee L, Monnens L. Analysis of chromosome aberrations and sister chromatid exchanges in peripheral blood lymphocytes of newborns after vitamin K prophylaxis at birth. Pediatr Res 1991; 30: 550-553