During the initial phase or during treatment with oral anticoagulants, hypersensitivity or resistance may be observed, requiring significant changes in prescribed dosage.
A thorough knowledge of the mode of action of vitamin K and its antagonists is useful to improve understanding of unexpected response to oral anticoagulant therapy. These abnormal responses may be due to poor compliance to treatment by the patient, insufficient or excessive vitamin K intake, interference with other drugs or abnormalities of the hepatic enzymes which are the target of oral anticoagulant drugs.
The search for a cause is justified by the risks associated with these abnormal responses. It must be rigorously undertaken with an accurate interrogation, use of an anticoagulation monitoring leaflet and, if necessary, measurement of plasma concentrations and pharmacokinetics of the anticoagulant drug.
[Hypersensitivity and resistance to antivitamins K] Kereveur-A; Trossaert-M; Horellou-MH; Conard-J; Dupeyron-JP; Samama-M. Arch-Mal-Coeur-Vaiss. 1995 Apr; 88(4): 487-95.
Atherosclerosis & Vitamin K
Protein-bound gamma-carboxyglutamate (Gla) has been demonstrated in calcified atherosclerotic plaques. Vitamin K is required for the formation of Gla-residues.
Vitamin K status may be an important factor in the development and progression of atherosclerotic calcifications.
Women with aortic atherosclerosis have an impaired vitamin K status as reflected by a lower nutritional vitamin K intake; which is compatible with the view that vitamin K or Gla-containing proteins are involved in the development of calcification of the vessel wall.
Vitamin K intake and osteocalcin levels in women with and without aortic atherosclerosis: a population-based study. Jie-KS; Bots-ML; Vermeer-C; Witteman-JC; Grobbee-DE. Atherosclerosis. 1995 Jul; 116(1): 117-23.
Concepts and controversies
Concepts and controversies
Vitamin K is a fat-soluble vitamin crucial to the production of many proteins involved with the coagulation process. It is integral in the synthesis of coagulants (factors II, VII, IX and X) and anticoagulants (proteins C and S). It is generally recognised that routine administration of vitamin K (phytomenadione) shortly after birth will prevent major neonatal morbidity and mortality related to haemorrhage. Vitamin K supplementation during pregnancy is also recommended if mothers are on anticonvulsant therapy or prolonged treatment with certain antibiotics. These medications, if ingested by pregnant women, predispose the neonate to a bleeding tendency caused by vitamin K deficiency. Vitamin K treatment of pregnant mothers before premature delivery has also been suggested to reduce the incidence of severe intracranial haemorrhage (ICH) in premature neonates. Although further studies are pending, the data to date do not support using antenatal vitamin K for preventing ICH.
Current concepts and controversies in the use of vitamin K. Thorp-JA; Gaston-L; Caspers-DR; Pal-ML. Drugs. 1995 Mar; 49(3): 376-87.
Deficiency in Infants
Deficiency in Infants
Single or multiple vitamin K doses may effectively treat Vitamin K Deficiency Bleeding (VKDB) that occurs in infants, according to this study. VKDB as defined is a rare but serious bleeding disorder (high incidence of intracranial bleeding). Protection against bleeding should be achievable with lower peak vitamin K levels by using repeated (daily or weekly) small oral doses rather than by using one intramuscular dose.
Sutor AH, von Kries R, Cornelissen EA, McNinch AW, Andrew M: Vitamin K deficiency bleeding (VKDB) in infancy. ISTH Pediatric/Perinatal Subcommittee. International Society on Thrombosis and Haemostasis, Thromb Haemost 1999 Mar;81(3):456-61
Dietary factors & Vitamin K
Enough information exists on the vitamin K content of foods and the quantity of vitamin K that alters coagulation status from the therapeutic range to provide the patient with advice concerning a group of foods to avoid and a group of foods to limit to one serving per day. With respect to other dietary factors that may interact with oral anticoagulants, the patient should be cautioned concerning supplements of vitamins A, E, and C and alcohol used chronically or ingested in large quantities.
Interaction of dietary factors with oral anticoagulants: review and applications. Harris-JE. J-Am-Diet-Assoc. 1995 May; 95(5): 580-4.
Energy transfer provides an arrow in the metabolism of living systems. Direct energetic coupling of chemical transformations, such that the free energy generated in one reaction is channeled to another, is the essence of energy transfer. Vitamin K provides a particularly instructive example: A key principle can be termed "base strength amplification" - the free energy of oxygenation of vitamin K hydroquinone (vitamin KH2) is used to transform a weak base to a strong base in order to effect proton removal from selected glutamate (Glu) residues in the blood-clotting proteins.
Vitamin K and energy transduction: a base strength amplification mechanism. Dowd-P; Hershline-R; Ham-SW; Naganathan-S. Science. 1995 Sep 22; 269(5231): 1684-91.
Young female athletes may benefit from vitamin K supplementation, according to this study conducted on 8 female athletes - 4 of whom had been amenorrhoeic for more than one year, and the rest of which were using oral contraceptives. All participants received daily vitamin K supplementation for one month, and various bone markers were measured before and after treatment. After treatment, all subjects exhibited an increased calcium-binding capacity of osteocalcin. In the low-estrogen group, vitamin K supplementation induced a 15-20% increase of bone formation markers and a parallel 20-25% decrease of bone resorption markers. These results indicate that vitamin K aids in bone formation and resorption in young female athletes.
Craciun AM, Wolf J, Knapen MH, Brouns F, Vermeer C: Improved bone metabolism in female elite athletes after vitamin K supplementation, Int J Sports Med 1998 Oct;19(7):479-84
The efficacy and side effects of oral vitamin K2 therapy were examined in 20 children and adults with probable secondary osteoporosis who had been hospitalized for a long period, due to severe mental and/or physical handicaps. Vitamin K2 was given for 12 months. Bone mineral density significantly increased 4 months after starting oral vitamin K2 therapy and it retained the elevated level after 12 months of treatment. Serum total protein levels significantly decreased following the start of this therapy. The reasons of this decrease are unknown and should be investigated further.
Tsuji H, Honke K, Hasui M: Effects of a vitamin K2 preparation in severely handicapped patients complicated by osteopenia, No To Hattatsu 1998 Nov;30(6):477-82
Vitamin K, found in iceburg lettuce, may lower the risk of hip fracture in middle-aged and older women, according to this study conducted on 12,700 women. About 20% of women who consumed less than 109 mcg of vitamin K a day had a 43% higher risk of hip fracture. The majority of women had the same fracture risk, regardless of vitamin intake. Those women who ate lettuce every day experienced a 55% less risk of hip fracture than those who only ate lettuce once a week.
Feshkanish, Diane MD: American Journal of Clinical Nutrition, 1999 Jan; 69:74-9
Interleukin 6 (IL-6)
Interleukin 6 (IL-6)
Naphthoquinone vitamins (vitamins K) are widely recognized for their role in the gamma-carboxylation of specific glutamyl residues in coagulation, anti-coagulation and extra-hepatic proteins. Recent reports found these compounds can exert actions other than those normally associated with protein gamma-carboxylation. Naphthoquinones may have effects on the production of inflammatory mediators including cytokines. Fibroblasts are now recognized as a rich source of cytokines and we have examined the effect of various naphthoquinones on the production of interleukin 6 (IL-6) by lipopolysaccharide-stimulated human gingival fibroblasts.
Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds. Reddi-K; Henderson-B; Meghji-S; Wilson-M; Poole-S; Hopper-C; Harris-M; Hodges-SJ. Cytokine. 1995 Apr; 7(3): 287-90.
The use of perioperative vitamin K may reduce nonsurgical bleeding in left ventricular assist device (LVAD) recipients, according to this study conducted on 66 LVAD patients. Patients receiving the LVAD design often suffer from intense bleeding complications. Seven of 27 patients (25.9%) not treated with vitamin K bled, while only 2 of 39 (5.1%) patients treated with vitamin K required re-exploration for bleeding. These results indicate that supplementation with vitamin K reduces the probability of bleeding complications from implantation of a LVAD.
Kaplon RJ, Gillinov AM, Smedira NG, Kottke-Marchant K, Wang IW, Goormastic M, McCarthy PM: Vitamin K reduces bleeding in left ventricular assist device recipients, J Heart Lung Transplant 1999 Apr;18(4):346-50
Healthy term infants born at the University of Missouri have received vitamin K prophylaxis as a single oral dose since 1967. A retrospective study was undertaken to determine whether either hemorrhagic disease of the newborn or any unexplained intracranial hemorrhage occurred in an infant who received orally administered vitamin K, but none could be found in three separate databases.
Twenty-seven years of experience with oral vitamin K1 therapy in neonates. Clark-FI; James-EJ. J-Pediatr. 1995 Aug; 127(2): 301-4.
Osteoporosis & Vitamin K
The effect of vitamin supplements on bone metabolism indices in patients with osteoporosis has received scant attention in the literature.
Vitamin K corrected the carboxylation defect in osteocalcin and while less marked 4 weeks later, the improvement was still detectable.
Carboxylation of osteocalcin in post-menopausal osteoporotic women following vitamin K and D supplementation. Douglas-AS; Robins-SP; Hutchison-JD; Porter-RW; Stewart-A; Reid-DM. Bone. 1995 Jul; 17(1): 15-20.
This review summarizes current knowledge regarding a possible role of vitamin K insufficiency in the pathogenesis of osteoporosis.
Although the abundance of vitamin K-dependent proteins in bone suggests an important function, the precise role of vitamin K in skeletal health remains to be determined. Serum concentrations of vitamin K are reportedly reduced in older individuals and persons with osteoporotic fracture.
The effect of vitamin K antagonists (oral anticoagulants) on both renal calcium excretion and bone density is controversial. Thus, many of the reports implicating a role for vitamin K insufficiency in the development of osteoporosis are conflicting.
Vitamin K nutrition and osteoporosis. Binkley-NC; Suttie-JW. J-Nutr. 1995 Jul; 125(7): 1812-21.
Oral administration of vitamin K was reported to increase bone mineral density. However, the possible role of vitamin K in the pathogenesis of osteoporosis still remains unclear.
Results suggest the possibility that deficiency of vitamin K, particularly that of menaquinone-7, is one of the risk factors for developing osteoporosis.
[Serum concentration of vitamin K in elderly women with involutional osteoporosis] Kaneki-M; Mizuno-Y; Hosoi-T; Inoue-S; Hoshino-S; Akishita-M; Akedo-Y; Horiki-K; Nakamura-T; Shiraki-M; et-al: Nippon-Ronen-Igakkai-Zasshi. 1995 Mar; 32(3): 195-200.
Between 1964 and 1994, at least 52 patients with cutaneous adverse effects of vitamin K have been described in the European and North American literature.
Cutaneous hypersensitivity reactions to vitamin K: 2 case reports and a review of the literature.
Bruynzeel-I; Hebeda-CL; Folkers-E; Bruynzeel-DP. Contact-Dermatitis. 1995 Feb; 32(2): 78-82.
Vitamin K intake may reduce sensitivity to warfarin under usual dietary conditions, according to this study conducted on 50 patients using warfarin during an 8-week period. A one-week recall dietary questionnaire was completed at weeks 2 and 8. Warfarin sensitivity index (WSI) was defined as final INR/final warfarin dose (mg/day/m2 of body surface area). Vitamin K intake was 17-974 (median: 179) microg/day. Participants who consumed large amounts of vitamin K were found to require more warfarin. The researchers concluded that warfarin sensitivity is reduced by vitamin K intake.
Lubetsky A, Dekel-Stern E, Chetrit A, Lubin F, Halkin H: Vitamin K intake and sensitivity to warfarin in patients consuming regular diets, Thromb Haemost 1999 Mar;81(3):396-9
Crohn's Disease and Osteoporosis
Crohn's Disease and Osteoporosis
People with Crohn's disease may have increased rates of osteoporosis due to low levels of vitamin K, a fat soluble vitamin that helps to synthesize the osteocalcin protein, which in turn binds calcium to bone. Researchers measured the bone mineral density and blood levels of several markers (vitamins D and K, triglycerides, total immunoreactive osteocalcin, and "free" osteocalcin) from 32 Crohn's patients and healthy, age-matched controls. Patients with Crohn's disease exhibited significantly lower levels of vitamin K, and higher "free" osteocalcin than healthy subjects. It was also found that high levels of "free" osteocalcin were associated with low lumbar spine bone mineral density.
Schoon EJ, et al: Low serum and bone vitamin K status in patients with longstanding Crohn's disease: another pathogenetic factor of osteoporosis in Crohn's disease?, Gut 2001 Apr;48(4):473-7
Bone mineral density & Vitamin K
Bone mineral density
Vitamin K deficiency may cause reduced bone mineral density in vitamin D-deficient women with Parkinson's disease, according to this study. This cross-sectional study involved 62 women with Parkinson's who were vitamin D-deficient and 62 age-matched controls (average age was 70.7 years). The Parkinson's patients were divided into two groups based on their functional capabilities: group A, which included independent patients, and group B, which included dependent patients. Measurements of vitamin K concentrations in blood sera and bone mineral density (BMD) using computed radiograph densitometry were taken to assess the relationship between BMD and vitamin K levels.
Compared to Group A, Group B had lower concentrations of vitamin K, lower metacarpal BMD, and lower levels of vitamin D. The concentration of vitamin K did show a positive correlation with vitamin D levels. Statistical analysis revealed that vitamin K, vitamin D, functional capabilities of the patient, and undercarboxylated osteocalcin were independent determinants of BMD. The vitamin K deficiency seen in the patients may reduce production of fully carboxylated osteocalcin and therefore cause reduced BMD.
Sato Y, Kaji M, Tsuru T, Satoh K, Kondo I: Vitamin K deficiency and osteopenia in vitamin D-deficient elderly women with Parkinson's disease, Arch Phys Med Rehabil 2002 Jan;83(1):86-91
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