Prevalence of vitamin K deficiency in children with mild to moderate chronic liver disease.
OBJECTIVES: Children with chronic liver disease are at risk for vitamin K deficiency because of fat malabsorption and inadequate dietary intake. The objective of this study was to determine the prevalence of vitamin K deficiency in children with mild to moderate chronic cholestatic and noncholestatic liver disease. METHODS: Vitamin K status was examined in 43 children (0.25-15.9 years) with mild to moderate chronic cholestatic liver disease, 29 children (0.9-16.9 years) with chronic mild to moderate noncholestatic liver disease, and in 44 healthy children (1-18 years). Vitamin K status was assessed by the plasma PIVKA-II (protein induced in vitamin K absence) assay (enzymelinked immunosorbent assay). Plasma PIVKA-II values greater than 3 ng/mL are indicative of vitamin K deficiency. RESULTS: The mean plasma PIVKA-II (+/-SD) in cholestatic, noncholestatic, and healthy children was 61.9 +/-144, 1.2 +/- 3, and 2.1 +/- ng/mL, respectively (P < 0.002). Fifty-four percent of the children supplemented with vitamin K had plasma PIVKA-II greater than 3 ng/mL. Plasma conjugated bilirubin, total bile acids, and severity of liver disease were positively correlated with plasma PIVKA-II levels (P < 0.05). CONCLUSIONS: Vitamin K deficiency is prevalent in children with mild to moderate chronic cholestatic liver disease, even with vitamin K supplementation. Elevated PIVKA-II levels occurred in children with a normal prothrombin, indicating that more sensitive markers of vitamin K status should be used in children with chronic liver disease. Vitamin K deficiency was related to degree of cholestasis and severity of liver disease in children. Children without cholestasis did not exhibit vitamin K deficiency.
J Pediatr Gastroenterol Nutr. 2006 Jan;42(1):71-76
Positive feedbacks of coagulation: their role in threshold regulation.
Tissue factor (TF), the initiator of coagulation, continuously circulates in the plasma, and the clotting system “idles,” generating very low levels of active clotting enzymes, clotting products, and by-products. Given the enormous amplification potential of the clotting cascade, rigorous control is required to ensure that such low-level stimulation does not cause massive system amplification and response. We propose that among the various mechanisms of regulation, activation thresholds may play a major role. These arise when positive-feedback reactions, of which there are several in the clotting system, are regulated by inhibitors. Such thresholds act like switches, so that small stimuli and/ or nonproductive local conditions will generate no response, whereas larger stimuli or the existence of local prothrombotic conditions will produce a full, explosive response. We review here the evidence for system idling, the structures of the various feedback mechanisms of clotting, the mechanisms by which they can produce threshold behavior, and the possible role of thresholds in system regulation.
Arterioscler Thromb Vasc Biol. 2005 Dec;25(12):2463-9
The multifunctional protein C system.
The protein C pathway is a major regulator of blood coagulation, since it controls the conversion of prothrombin to thrombin through a feedback inhibition mechanism. Protein C circulates in plasma as an inactive zymogen and is activated on the surface of endothelial cells by the thrombin-thrombomodulin complex, a process that can be further enhanced when protein C binds to its membrane receptor, the endothelial-cell protein C receptor. Activated protein C (APC) is then released from the complex, binds protein S and inhibits thrombin formation by inactivating coagulation factors Va and VIIIa. The importance of the protein C anticoagulant pathway is emphasized by the increased risk of venous thromboembolism (VTE) associated with protein C and protein S deficiencies, the factor V Leiden mutation, and reduced circulating APC levels. The protein C pathway also plays a significant role in inflammatory processes, since it prevents the lethal effects of E. coli-associated sepsis in animal models and improves the outcome of patients with severe sepsis. APC seems to display anti-apoptotic and neuroprotective activities. Thus, it reduces organ damage in animal models of sepsis, ischemic injury, endothelial cell injury, or stroke. Further research will hopefully widen the current therapeutic perspectives in all these illnesses, where these effects might play a crucial role in their treatment. This review will summarize the mechanisms that contribute to these biological activities of the protein C pathway.
Curr Med Chem Cardiovasc Hematol Agents. 2005 Apr;3(2):119-31
The anticoagulant protein C pathway.
The anticoagulant protein C system regulates the activity of coagulation factors VIIIa and Va, cofactors in the activation of factor X and prothrombin, respectively. Protein C is activated on endothelium by the thrombin-thrombomodulin-EPCR (endothelial protein C receptor) complex. Activated protein C (APC)- mediated cleavages of factors VIIIa and Va occur on negatively charged phospholipid membranes and involve protein cofactors, protein S and factor V. APC also has antiinflammatory and anti-apoptotic activities that involve binding of APC to EPCR and cleavage of PAR- 1 (protease-activated receptor-1). Genetic defects affecting the protein C system are the most common risk factors of venous thrombosis. The protein C system contains multidomain proteins, the molecular recognition of which will be reviewed.
FEBS Lett. 2005 Jun 13;579(15):3310-6
Coagulation inhibitors in inflammation.
Coagulation is triggered by in- flammatory mediators in a number of ways. However, to prevent unwanted clot formation, several natural anticoagulant mechanisms exist, such as the antithrombinheparin mechanism, the tissue factor pathway inhibitor mechanism and the protein C anticoagulant pathway. This review examines the ways in which these pathways are down-regulated by inflammation, thus limiting clot formation and decreasing the natural anti-inflammatory mechanisms that these pathways possess.
Biochem Soc Trans. 2005 Apr;33(Pt 2):401-5
Vitamin D, K, and bone mineral density.
Both vitamin D and vitamin K are essential nutrients for bone health. It is believed that vitamin D defi- ciency is responsible for rickets in infants and osteomalacia in adults, and chronic vitamin D insufficiency induces hyperparathyroidism and reduces bone mineral density, resulting in an increased risk of osteoporosis. Vitamin K deficiency is thought to cause impaired activation of bone matrix protein osteocalcin, and reduction of osteoblast function, resulting in impaired bone formation. Recently, we reported that a high prevalence of low vitamin D status (low serum 25-hydroxyvitamin D concentration), low bone mineral density, and a high prevalence of low vitamin K status (high serum undercarboxylated osteocalcin concentration), high frequency of bone fracture in elderly women in Japan. However, no correlation between low vitamin K status and low bone mineral density was observed in this subjects.
Clin Calcium. 2005 Sep;15(9):1489-94
Vitamin K2 as a protector of bone health and beyond.
Several lives of evidence indicate a protective effect of vitamin K against osteoporosis. Epidemiological studies showed that low vitamin K intake is associated with the increased risk of osteoporosis. Vitamin K2 (menatetrenone, MK-4) has been clinically used in the treatment of patients with osteoporosis in Japan, Korea, and Thailand. Previous studies demonstrated the efficacy of vitamin K2 (45 mg/day) to prevent bone loss and reduce the rate of vertebral fractures, although a large, randomized intervention study is anticipated to provide more detailed evidence. Recently, vitamin K2 has been shown to reduce the progression of hepatocarcinoma. Moreover, it has been proposed that vitamin K may also have beneficial effects to prevent atherogenesis. The clarifi- cation of molecular mechanisms by which vitamin K2 exerts these salutary effects deserve further investigations.
Clin Calcium. 2005 Apr;15(4):605-10
Atherosclerosis and matrix dystrophy.
Atherosclerosis is characterized by inflammatory metabolic change with lipid accumulation in the artery. Atherosclerotic plaque occurs at discrete locations in the arterial system and involves the proliferation of smooth muscle cells (SMCs) together with imbalance of the extracellular matrix elements, elastic fiber in particular. The role of elastin in arterial development and disease was confirmed by generating mice that lack elastin. Thus, elastin is a critical regulatory molecule that regulates the phenotypic modulation, proliferation and migration of SMCs. We estimated that elastin expression and SMC proliferation are coupled inversely: potent stimulators of cell proliferation may potentially inhibit elastin expression and potent inhibitors of cell proliferation can stimulate elastin expression. Moreover, elastin was found to be expressed maximally at the G(0) and minimally at the G(2)/ M phase during the cell cycle, suggesting that its expression is regulated by the cell growth state. The elastin peptide VPGVG enhanced SMC proliferation, resulting in the reduction of elastin expression. The inhibition of elastin expression by elastin fragments may be reflected in the negative feedback regulatory mechanism. The relationship between cell proliferation and elastin expression may be changed in atherosclerosis. Areas of atherosclerotic plaque show abnormality of elasticity and permeability from the viewpoint of the physiological function of the arterial wall. The etiology was estimated to be that cholesterol and calcium are deposited on the elastic fiber, resulting in decreased elastin synthesis and cross-linking formation. In addition, these dysfunctions of elastin fiber are also associated, in that the down-regulation of elastin and its related components (fibrillin-1 and lysyl oxidase) are directly related to calcification in SMCs. The denatured arterial elastin by cholesterol and calcium accumulation was also susceptible to proteolytic enzymes such as elastase and matrix metalloproteinase (MMP). Therefore, metabolic change in elastic fiber induces decreased elasticity and is associated with essential hypertension. Vitamin K(2) is used in drug therapy against atherosclerosis, or calcification in diabetes mellitus or dialysis, due to its promotion of the carboxylation of the matrix Gla protein.
J Atheroscler Thromb. 2004;11(5):236-45