Clinica Chimica Acta 287 (1999) 45–57 www.elsevier.

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Interdependence of serum concentrations of vitamin K 1 , vitamin E, lipids, apolipoprotein A 1 , and apolipoprotein B: importance in assessing vitamin status
a, b c Bill E. Cham *, Jeffery L. Smith , David M. Colquhoun
a

The Curacel Institute of Medical Research, 14 /1645 Ipswich Road, Rocklea, Queensland 4106, Australia b Lipid Metabolism Laboratory, Department of Surgery, The University of Queensland, Royal Brisbane Hospital, Herston, Queensland 4029, Australia c Wesley Medical Centre, Auchenflower, Queensland 4066, Australia Received 10 March 1999; received in revised form 13 May 1999; accepted 22 May 1999

Abstract Vitamin E (a-tocopherol) and vitamin K 1 (phylloquinone) are fat-soluble vitamins and are important nutrients in health and disease. In this study serum concentrations of vitamin E and vitamin K 1 , lipids and apolipoproteins A 1 and B were measured in neonates, normal and hyperlipidaemic individuals in an attempt to establish their interrelationships. A high degree of correlation was observed between the concentrations of the vitamins and those of lipids and apolipoproteins (r ranged from 0.42 to 0.92; p , 0.001). Stepwise linear regression methods determined that serum concentrations of both vitamin E and vitamin K 1 could best be predicted by using equations excluding lipids but containing only apolipoprotein A 1 and B concentrations. Correlation coefficients between predicted and measured values were 0.89 for serum vitamin E, and 0.83 for serum vitamin K 1 concentrations. To test the validity of the derived formulae, measured and estimated vitamin K 1 and vitamin E concentrations in serum were determined in another group of neonates, normal adults and hypercholesterolemic adults and the comparisons were shown to be very good. These results indicate that the serum levels of both vitamins depend critically on the concentration of the lipoprotein carriers, apolipoproteins A 1 and B. Hence, in order to identify variations in serum vitamin K 1 and vitamin E concentrations, which are independent of variations in carrier concentration, it will be necessary to express these serum vitamins as ratios of vitamins to apolipoprotein A 1 and B carriers. © 1999 Elsevier Science B.V. All rights reserved.

*Corresponding author. Tel.: 161-732-744-452; fax: 161-732-744-453. 0009-8981 / 99 / $ – see front matter © 1999 Elsevier Science B.V. All rights reserved. PII: S0009-8981( 99 )00117-5

E. Apolipoprotein A 1 . assessed the vitamin K nutritional status of individuals in different age groups [11]. Cham et al. Cholesterol 1. the use of a relative measure of plasma vitamin E (ratio of tocopherol to total lipids or to cholesterol) has become essential in evaluating vitamin E nutritional status in individuals or in populations [6. Vitamin K 1 . Thus. As for LDL. Vitamin E is secreted from the liver in VLDL and is delivered to cells chiefly via the high affinity receptor for LDL [4].1. aged 23–49 (mean 42 years). Further studies in neonates found that a series of very low absolute concentrations of vitamin K 1 in serum did not reflect the vitamin K status [12]. cells may also take up the vitamin via a route. For example in a hyperlipidaemic state the absolute value of serum vitamin E concentration may be normal and the subject still found to be vitamin E nutritionally deficient [7] Thus. despite the limited evidence. Sadowski et al. The authors noted that they obtained different results when they used a ratio of vitamin to lipid rather than absolute concentrations of serum vitamin as the index of nutritional adequacy [11]. The relation between vitamin K 1 and serum lipids is less clear. it seemed probable that the interpretation of serum vitamin K 1 levels might require similar qualifications to those applying to vitamin E [10]. 2.8–10]. .46 B. Serum concentrations of vitamin E are dependent on plasma lipid concentrations [6]. There are strong similarities and links between the metabolism of LDL and that of vitamin E.5]. Subjects and methods 2. Introduction The fat-soluble vitamins K 1 and E do not have specific physiological carriers in plasma. namely. chylomicrons. very-low-density lipoproteins (VLDLs). / Clinica Chimica Acta 287 (1999) 45 – 57 Keywords: Vitamin E. Apolipoprotein B. which is independent of the LDL receptor [4. The present study has examined the interrelation between the concentration of serum vitamins K 1 and E and some of their carrier lipoprotein components using vitamin E as a currently established marker. Subjects Blood samples (10 ml) were taken from an antecubital vein from 34 normal adult subjects: twenty males. fourteen females. serum lipid values were however not considered. They are transported by the plasma lipoproteins and are present in all lipoprotein fractions. low-density lipoproteins (LDLs) and high-density lipoproteins (HDLs) [1–3].

No chylomicrons were present in any of the specimens. 5. Twelve male and seventeen female hypercholesterolemic patients were on hypolipidemic (Zocor) drug therapy. Brisbane. Serum concentrations of vitamin K 1 and vitamin E [13]. normal adults and hypercholesterolemic individuals). 5. HDL-cholesterol and LDL-cholesterol. An additional set of multiple regression analyses was carried out to determine the extent to which the equations relating vitamin K 1 and vitamin E to the other variable might differ between the three subject groups (neonates. / Clinica Chimica Acta 287 (1999) 45 – 57 47 aged 25–53 (mean 45 years). of total cholesterol. HDL-cholesterol and triglycerides [14]. Stepwise linear regression methods were used to determine the subsets of variables with greatest predictive power and the best fitting models based on these variables. aged 37–68 (mean 53 years) who had fasted for 12 h. Serum samples were extracted immediately or stored at 2 708C in disposable polystyrene tubes with polyethylene stoppers. were measured according to established published methods. or from the umbilical cord vein from 32 neonates supplied by the Royal Women’s Hospital. Cham et al. 2.3.5 mmol / l. VLDL-cholesterol was calculated from the difference of total cholesterol.2.E. The resulting derived models were then simplified by ‘rounding off’ the values of estimated regression coefficients (without loss of predictive power) and expressed on the scale of the original measurements rather than in terms of their logarithmic values. 2. HDL-cholesterol and triglycerides using the Friedewald formula [16]. These analyses included a nominal . The procedures used were in accord with the Helsinki Declaration of 1975 as revised in 1983. The concentration of LDL-cholesterol was calculated from the values for total cholesterol. Statistical methods Preliminary inspection of the data of 20 neonates. aged 30–62 (mean 51 years).B. twenty females.5 mmol / l) subjects: twenty males. Measurements The blood samples were protected from the light and were centrifuged at 48C. and 40 hypercholesterolemic (serum cholesterol . and of apolipoproteins A 1 and B [15]. 22 normal adults and 28 hypercholesterolemic subjects indicated that all the measured variables were highly correlated with one another and that not all variables would be required in models to describe the relationships between vitamin K 1 and vitamin E and the other variables. The patterns of variability in the data indicated that the regression analyses should be based on the logarithmic values of measured variables. The rational for including neonates was to establish whether the observations were limited or more generalized over a wide range of lipoprotein constituents. whose serum total cholesterol concentrations were .

Apo A 1 and in Apo B in sera of neonates.48 B. These results were also expressed as ratios of individual measured vitamin E / estimated vitamin E and individual measured vitamin K 1 / estimated vitamin K 1 values. In contrast.2. and the hypercholesterolemic patients had a mean level which was four-fold that of neonates. total triglyceride. VLDL-cholesterol. The mean concentration of total cholesterol in serum of normal adults was three-fold that of neonates. except for HDL-cholesterol and Apo A 1 which were found to be similar in concentrations in normal adults and in hypercholesterolemic subjects. cholesterol standardised individual values for vitamins E and K 1 are not significantly different in the three groups. Samples of a further 12 neonates. and the calculated concentrations of VLDLcholesterol and LDL-cholesterol in serum from neonates. The measured values of these vitamins were then compared with the estimated values (derived from the models) using linear regression analysis. vitamin K 1 . Apo A 1 . standard deviation (SD) and range of total cholesterol. . individual cholesterol standardised vitamin E and vitamin K 1 levels in serum are presented. Linear correlation coefficients Table 2 shows the linear correlation coefficients of vitamin K 1 and vitamin E with total cholesterol. Range of serum lipids and apolipoproteins Table 1 shows the measured concentrations of the mean. HDL-cholesterol. normolipidemic adults and hypercholesterolemic patients. Results 3. / Clinica Chimica Acta 287 (1999) 45 – 57 variable in the regression models. A similar pattern was seen for most of the other parameters in serum (Table 1). total triglyceride.E. When compared. normal adults and hypercholesterolemic subjects. Apo B. normal adults and hypercholesterolemic subjects (Table 1). The results of Table 2 lead to the following models for best predicting the concentrations of vitamins K 1 and E as described in the methods. LDL-cholesterol. Cham et al. 3. In addition. the differences in concentrations of the other parameters were highly significant in sera of neonates. 12 normal adults and 12 hypercholesterolemic patients were randomly chosen and the serum vitamins K 1 and E were measured. vitamin E. HDL-cholesterol.1. 3. The variable took one of three values and represented the subject groups.

18–0. and range of serum lipids and apolipoproteins Neonates n520 VLDL-cholesterol mmol / l LDL-cholesterol mmol / l HDL-cholesterol mmol / l Total cholesterol mmol / l Total triglyceride mmol / l Apo B g / l Apo A 1 g / l Vitamin K 1 ng / l Vitamin E mg / l Vitamin K 1 nmol / l ]]]]]]] Total cholesterol mmol / l Vitamin E mmol / l ]]]]]]] Total cholesterol mmol / l 0.33 b (0.6260.52–7.77) 0. Values with similar superscripts in the different columns for that particular parameter are not significantly different from each other.73 c (0.B.6660.7–5.5–11.3860.06 a (0.28) 1.884(0.2) 1.3160 08 a (0.41–0.001) from each other for that particular parameter as determined by Students’ t test. Values in brackets are parameter standard errors.42 b (0.3360.960.5) 0.11 a (0.01) 0.1860.35) 0.1660.6 a (3.96–2.9061.39 b (1. with R 2 5 0.1360.09–0.10–1 33) 4.15 b (0.50 b (5.79–1.86120.38 b (0.20) 5416197 c (204–910) 11.2) 0.3761.3.19–1.5460.4 a (0.624(0.2160.06 a (0.25 a (0.46–2.0–17.E.34 a (0.45–0.51 b (2.7660.85) 3.7) 0.05) 4.10) 6.5260. Model for vitamin K1 The best fitting stepwise regression model was: Log e vitamin K 1 (ng / l) 5 5.88) 1. 3.35) 4.99) 1.42–0.4–6.5–9.01–2.04–0.14 a (0.3161.1960.9 a (2.33) 3.1) Values with different superscripts in the different columns are significantly different ( p.7260.6760.12 a (0. standard deviation.7660.3 a (24–571) 2.14 b (0.18–0.3–5.89) 82.56 b (3.07–3.85) 3. / Clinica Chimica Acta 287 (1999) 45 – 57 49 Table 1 Mean.68–2. The equation may be simplified to: .39–1.18 a (0.160.4560.5–7.7660 36 c (0.1263.66–2.69) 1.861.7) 0.01 a (0.07 c (5.0760.2) Normal adults n522 0.07 c (2.8260.150) 1 2.0660.02–0.0.0) Hypercholesterolemic patients n528 0.84) 1.35 b (0.178) log e (Apo B /Apo A 1 ).21–0.86) 0.10–0.89) 1.08 a (0.697.124(0.0–5.6360.19 c (0.5161. Cham et al.00 c (6.3) 0.193) log e Apo A 1 (g / l) 1 0.15) 3436155 b (49–590) 7.8–2.48) 0.

/ Clinica Chimica Acta 287 (1999) 45 – 57 Table 2 Linear correlation coefficients between vitamin K 1 and vitamin E concentrations in serum and the concentrations of lipids and apolipoproteins in serum of neonates (n520). Predicted vitamin K 1 (ng / l) 5 369 3 Apo B (g / l) 3 Apo A 1 (g / l) with R 5 0.346) 1 0.50 B.253* 0. with equally good fits.795 respectively.429(0.168(0. Cham et al.916(0.745 0.0 in Eq.680 0.673 predicted vitamin K 1 . Models for vitamin E Two models.695 * P50. These equations were: Log e vitamin E (mg / l) 5 1.107) log e Apo B (g / l) with an R of 0. R 2 for the modified equations were 0.495 0.802 and Log e vitamin E (mg / l) 5 2.049.001 for all other values. P.920 0.423 0.145) log e Apo A 1 (g / l) 1 0.535(0. (1) and rounding the coefficients of log e Apo A 1 to 0.090) 1 0.5 in Eq.416 0. (2).695 Vitamin E Variable VLDL-Ch LDL-Ch HDL-Ch Total-Ch Triglycerides Apo A 1 Apo B Vitamin K 1 r 0. 2 3.208) log e Apo B (g / l).744 0. .683 and an approximate standard error for a predicted vitamin K 1 level of 0.4.798.785 and 0.084(0.916 0.749 0.866 0. and log e Apo B to 1.184) log e cholesterol (mmol / l) 1 0.589 0. 2 2 (1) (2) These equations may be simplified with very little loss of fit by rounding the coefficients of both log e cholesterol and log e Apo B to 0.5.654 0. with an R of 0.173(0. resulted from the stepwise regression analyses.0.451 0. Normal adults (n522) and hypercholesterolemic patients (n528) Vitamin K 1 Variable VLDL-Ch LDL-Ch HDL-Ch Total-Ch Triglycerides Apo A 1 Apo B Vitamin E r 0.E.

44) for normal adults 5 5.236) (Apo B /Apo A 1 ) 1 0.363predicted vitamin E.5.25) for neonates 5 4. For example.684 (0.353) log e Apo A 1 (g / l) 1 0.722. allowing for subject differences the model for log e vitamin K 1 becomes: Log e vitamin K 1 (ng / l) 5 C 1 0. 3. with an R 2 of 0.444) 1 1. In its simplified form the above equation becomes: Predicted vitamin K 1 (ng / l) 5 115 3 Apo A 1 (g / l) 3 Apo B 3 vitamin E 0.722) for the equivalent model without subject group effects (see section on . (2) may be expressed as: Predicted vitamin E (mg / l) 5 9.741 which is only a small increase on the R 2 (50.343) log e Apo A 1 (g / l) 1 0.78 3 Apo B (g / l) 3 Apo A 0.697(0.67(0.E.461(0. Model for vitamin K1 with vitamin E included in the set of explanatory variables A slightly better fitting model is derived if vitamin E is one of the explanatory variables.50) for hyperlipidemics This model has an R 2 of 0.706 and an approximate standard error for predicted vitamin K 1 50.200) log e vitamin E (mg / l) where: C 5 4.446(0.354(0. / Clinica Chimica Acta 287 (1999) 45 – 57 51 The simplified version of Eq.529 (0.13(0. 2 3.B.3 (g / l) 1 The standard error of a predicted vitamin E determination using the above equation is 0. with R 5 0.01(0.201) log e vitamin E (mg / l). Subject group differences There were small but statistically significant improvements in best fitting regression models when differences between subject groups were considered.5 (g / l).6453vitamin K 1 .6. Log e vitamin K 1 (ng / l) 5 4. Cham et al.

9]. Calculation of serum concentrations of vitamins K1 and E To confirm the reliability of the equations for vitamins K 1 and E. / Clinica Chimica Acta 287 (1999) 45 – 57 Model for vitamin K 1 with vitamin E included in the set of explanatory variables). independent of the influence of cholesterol itself. and Vitamin E (mg / l) 5 9. 4.7. and the capacity for storage and batch analysis.E.52 B. viz. However. The evaluation of such individual patients relies less on serum vitamin E levels but rather on functional assessments of vitamin E activity. it should be noted that the above model no longer contains a term in log e Apo B. Cham et al.8. It is now established that the most valuable measurement of vitamin E nutritional status is the lipid-standardised serum vitamin E (mmol / l tocopherol / mmol / l cholesterol) [6. such as peroxidative haemolysis tests [7]. associated with neurological sequelae [7] is uncommon and confined to a small number of subjects with major disturbances of vitamin E absorption or distribution [17. Discussion True deficiency of vitamin E. The utility of this index has been well demonstrated by Gey in his evaluation of vitamin E as a risk factor in ischaemic heart disease (IHD) [9]. such cumbersome tests to assess vitamin E nutrition are unsuitable. Vitamin K 1 (ng / l) 5 369 3 Apo B (g / l) 3 Apo A 1 (g / l).18]. however the present study indicates that a combined function of Apo A 1 and B may be more accurate. The results expressed as the ratios of measured vitamin E / estimated vitamin E and the ratios of measured vitamin K 1 / estimated vitamin K 1 of each individual are shown in Table 3 and they confirm the reliability of the above equations. The study demonstrated an inverse correlation between lipid-standardised vitamin E and survival from IHD.3 (g / l) 1 we calculated the concentrations of these two vitamins of another set of subjects consisting of 12 neonates. 3. The values of vitamin E involved were within the accepted . In this measurement cholesterol serves as a simple marker of lipoprotein concentration. For population studies. Serum assays of vitamin E have the advantage of simplicity. 12 normolipidemic adults and 12 hypercholesterolemic subjects and compared the individual predicted values to the measured individual values. Similar small improvements in degree of fit and changes in model structure occurred with other models when subject group effects were included.78 3 Apo B (g / l) 3 Apo A 0.

997 Vitamin E a b Range of Vitamin K 1 concentrations as measured by an HPLC procedure.954 Hypercholesterolemic adults (n512) 336–2180 358–2591 1.4–5.001 for all correlations. r-Values were obtained by comparing individual measured values with the corresponding estimated value using a linear regression analysis.0860.10 0.E.5–51.8–47. The three groups of subjects examined had highly significantly different serum levels of lipids.9–9.0. The means and ranges for lipid-standardised vitamin E of the two adult groups encompassed those published by Gey for a number of regional European populations [9]. the statistical observations of the study have underlined the necessity of quoting serum vitamin E and K 1 levels adjusted for not only lipids but apolipoprotein concentrations.0060. Ratios of corresponding individual measured / estimated values of vitamin K 1 in serum. In consequence.998 9. p.0060 10 0. 1 g Ratios of corresponding individual measured / estimated values of vitamin E in serum.B.0 1.10 0. / Clinica Chimica Acta 287 (1999) 45 – 57 53 Table 3 Comparisons of measured and estimated vitamin K 1 and vitamin E concentrations in serum Neonates (n512) Vitamin K 1 Measured ng / l a Estimated ng / l b Ratio measured / estimated c r-value d Measured mg / l e Estimated mg / l f Ratio measured / estimated g r-value d 51–199 38–244 1. e Range of vitamin E concentrations as measured by an HPLC method. even though the mechanisms involved in the pathogenesis remain unclear.989 5. f Range of vitamin E concentrations as estimated according to the formula: d c Vitamin E (mg / l) 5 9. Thus.8 5.3 1.78 3 Apo B (g / l) 3 Apo A 0.0360.8–10. the interpretation of absolute levels of vitamin K 1 in serum is also problematical. apolipoproteins and vitamins but these differences disappeared when vitamin E and vitamin K 1 levels were related to total cholesterol (Table 1) or to apolipoproteins (data not shown). Although the overall sample size of the various sera in the present study is relatively small. the concept of a ‘relative’ vitamin E deficiency with adverse pathological and clinical consequences has emerged.944 Normal adults (n512) 296–572 281–561 1.5–5. Cham et al.9].0460.9 10.9960. Quite low serum concentrations of the vitamin K 1 have been .981 1. Range of vitamin K 1 concentrations as estimated according to the formula: Vitamin K 1 (ng / l) 5 369 3 Apo B (g / l) 3 Apo A 1 (g / l).5 1.0 0.10 0.3 (g / l). reference range and well above those identified as indicating vitamin E deficiency [8. The present work has identified a degree of correlation between serum vitamin K 1 and lipid parameters which is similar to that for vitamin E.04 0.10 0.

31% of patients with chronic bowel disease had mild vitamin K deficiency. without overt clotting defects. It is not possible to conclude whether the observed changes in vitamin K 1 were a consequence of changes in lipoprotein metabolism. Using this technique.54 B. These serum concentrations were considered pathological because they were significantly lower than age-matched control values. However. before and after vitamin K administration. The association of vitamin K and elevated lipid serum levels could lead to a synergistic development of the atheromatous plaque and acute coronary syndromes [28]. Osteocalcin or bone-Gla-protein (BGP) is a well-studied vitamin K-dependent protein secreted by osteoblasts [23]. Cham et al. measurable effects on calcium metabolism. has proved to be a much more sensitive index of subclinical vitamin K deficiency [22]. an early step in plaque evolution. and will be manifested by the failure of these proteins to function normally [21]. reversible on treatment with vitamin K 1 were noted. but it should be noted that they do not differ from absolute values in healthy neonates (Table 1). No defects in nutrition or bowel function were identified in these women.E. / Clinica Chimica Acta 287 (1999) 45 – 57 reported to occur in patients with fractures. Such Gla-proteins are found in atherosclerotic plaques and are associated with calcification. the prothrombin time has been used as an index of function of vitamin K dependent clotting proteins but it is known to be a crude and very insensitive measure [21]. A previous study has suggested that post-menopausal women may develop a vitamin K deficient state which is manifested by sub-optimal gamma-carboxylation of BGP. Radioimmunoassay of decarboxylated prothrombin. Deficiency of vitamin K will result in defective gamma-carboxylation of vitamin K dependent proteins. detected by calcium binding studies [24]. The formation of other Gla-proteins is also vitamin K dependent. These results. and 98 pg / ml (mean) for those with osteoporosis and fractures [20]. with or without osteoporosis. These proteins do not interfere with normal calcium homeostasis and paradoxically may inhibit precipitation of calcium salts. have raised the question of a possible role of vitamin K in the pathogenesis of post-menopausal or senile osteoporosis. viewed in the light of the low absolute serum vitamin K 1 levels in osteoporotic subjects with hip fractures. The data in Table 1 also indicates that a 6. vitamin K metabolism or both.5 fold difference in mean serum vitamin K 1 concentrations between subject groups attenuate markedly when normalized for serum cholesterol concentration. but neither serum vitamin K nor lipids were monitored in this study [22]. Lipid and calcium are co-localised in plaques and rupture of plaques that precipitates acute events tends to occur at . Traditionally.27]. Values quoted were 113 pg / ml (mean) for individuals with traumatic fractures [19]. The Gla-proteins only known function is to bind calcium and do so with very high affinity [26. Calcium phosphate (hydroxyapatite) precipitates by a mechanism similar to active bone formation and is vitamin K dependent [25].

Cham et al. apolipoprotein A 1 and apolipoprotein B will be affected by induced acute changes in lipid removal with retention of apolipoproteins in serum. Kamst and Mr N. vitamin K and vitamin E. At this stage it is unknown how the interdependence of serum concentrations of vitamin K 1 . Mr T. This work was supported by grants from the National Health and Medical Research Council of Australia and from Curacel International. In neither case has the deficiency state been correlated with absolute or lipoprotein-standardised levels of serum vitamin K 1 . both being non-lipid components of lipoprotein fractions. Two relative deficiency states of vitamin K have been identified by assays that detect reduced gamma-carboxylation of vitamin K dependent proteins. The present study has provided a range for lipoprotein standardised serum vitamin K 1 and vitamin E levels in 50 adults and 22 neonates. lipids. as is the case for the lipid apheresis procedure currently being investigated as a possible treatment for atherosclerosis in our laboratory [31–36]. It is clear that further groups of both healthy and diseased subjects need to be studied to define reference ranges and to identify abnormalities linked to disease processes. Caterer. / Clinica Chimica Acta 287 (1999) 45 – 57 55 sites of calcium deposition [29. Acknowledgements The authors acknowledge the excellent technical work provided by Mr John Saville. Thus in the context of atherosclerosis there is a nexus with lipoproteins. Previous studies with haemodialysis patients have shown that vitamin K 1 was related to apolipoprotein E and strongly modulated by the apo E genotype [37. vitamin E. There is a clear need to relate lipid-standardised serum vitamin K 1 concentrations to other indices of bone metabolism in both post-menopausal women and in individuals with chronic bowel disease in the hope of identifying those at high risk of osteoporotic fractures.30]. We also thank Annette Miles for her secretarial assistance. this communication indicates that the use of apolipoprotein levels appear to yield information beyond simple lipid sub-fractions to the extent that the atherogenic apolipoprotein B and antiatherogenic apolipoprotein A 1 .E.B. The assistance with the statistical methods by Dr Anthony Barnes and the collaboration of Dr Peter Roeser are gratefully acknowledged. The observed correlation between serum vitamin K 1 with serum cholesterol followed a similar pattern as has previously been shown for serum vitamin E and serum cholesterol. . best described ‘the relative’ status of vitamins E and K 1 in such a manner that reliable equations using concentrations of such apolipoprotein components of lipoproteins could be used to calculate the serum concentrations of these vitamins. and in patients with atherosclerosis with a view to preventive intervention.38]. correctable by vitamin K administration [24]. Importantly.

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