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Vitamin K is essential for the synthesis of few coagulation factors. Infants can easily develop vitamin K deficiency owing to poor placental transfer, low vitamin K content in breast milk, and poor intestinal absorption due to immature gut flora and malabsorption. Vitamin K deficiency bleeding (VKDB) in infancy is classified according to the time of presentation: early (within 24 h), classic (within 1 week after birth), and late (between 2 week and 6 months of age). VKDB in infancy, particularly late-onset VKDB, can be life-threatening. Therefore, all infants, including newborn infants, should receive vitamin K prophylaxis. Exclusive breastfeeding and cholestasis are closely associated with this deficiency and result in late-onset VKDB. Intramuscular prophylactic injections reduce the incidence of early-onset, classic, and late-onset VKDB. However, the prophylaxis strategy has recently been inclined toward oral administration because it is easier, safer, and cheaper to administer than intramuscular injection. Several epidemiological studies have shown that vitamin K oral administration is effective in the prevention of VKDB in infancy; however, the success of oral prophylaxis depends on the protocol regimen and parent compliance. Further national surveillance and studies are warranted to reveal the optimal prophylaxis regimen in term and preterm infants.

Vitamin K is required for the ɣ-carboxylation of specific glutamic acid residues within the Gla domain of the 17 vitamin K-dependent proteins (VKDPs). The timely detection and correction of vitamin K deficiency can protect against bleeding. Vitamin K also plays a role in bone metabolism and vascular calcification. Patients at increased risk of vitamin K deficiency include those with a restricted diet or malnutrition, lipid malabsorption, cancer, renal disease, neonates and the elderly. Coagulation assays such as the prothrombin time have been used erroneously as indicators of vitamin K status, lacking sufficient sensitivity and specificity for this application. The measurement of phylloquinone (K 1 ) in serum is the most commonly used marker of vitamin K status and reflects abundance of the vitamin. Concentrations <0.15 µg/L are indicative of deficiency. Disadvantages of this approach include exclusion of the other vitamin K homologues and interference from recent dietary intake. The cellular utilisation of vitamin K is determined through measurement of the prevalence of undercarboxylated VKDPs. Most commonly, undercarboxylated prothrombin (Protein Induced by Vitamin K Absence/antagonism, PIVKA-II) is used (reference range 17.4-50.9 mAU/mL (Abbott Architect), providing a retrospective indicator of hepatic vitamin K status. Current clinical applications of PIVKA-II include supporting the diagnosis of vitamin K deficiency bleeding of the newborn, monitoring exposure to vitamin K antagonists, and when used in combination with α-fetoprotein, as a diagnostic marker of hepatocellular carcinoma. Using K 1 and PIVKA-II in tandem is an approach that can be used successfully for many patient cohorts, providing insight into both abundance and utilisation of the vitamin., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Four-factor prothrombin complex concentrate is approved for use of life-threatening bleeding secondary to vitamin K antagonism in adults. We describe the use of four-factor prothrombin complex concentrate for hemostasis in a 6-week-old child with life-threatening vitamin K dependent-bleeding who never received vitamin K prophylaxis at birth., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Vitamin K deficiency bleeding (VKDB) in infancy is a serious but preventable cause of mortality or permanent disability. Lack of epidemiologic data for VKDB in sub-Saharan Africa hinders development and implementation of effective prevention strategies. We used convenience sampling to consecutively enroll mothers delivering in a southwestern Uganda Hospital. We collected socio-demographic and dietary information, and paired samples of maternal venous and neonatal cord blood for the immunoassay of undercarboxylated prothrombin (PIVKA-II), a sensitive marker of functional vitamin K (VK) insufficiency. We used univariable and multivariable logistic regression models to identify predictors of VK insufficiency. We detected PIVKA-II of ≥0.2 AU (Arbitrary Units per mL)/mL (indicative of VK insufficiency) in 33.3% (47/141) of mothers and 66% (93/141) of newborns. Importantly, 22% of babies had PIVKA-II concentrations ≥5.0 AU/mL, likely to be associated with abnormal coagulation indices. We found no significant predictors of newborn VK insufficiency, including infant weight (AOR (adjusted odds ratio) 1.85, 95% CI (confidence interval) 0.15-22.49), gender (AOR 0.54, 95% CI 0.26-1.11), term birth (AOR 0.72, 95% CI 0.20-2.62), maternal VK-rich diet (AOR 1.13, 95% CI 0.55-2.35) or maternal VK insufficiency (AOR 0.99, 95% CI 0.47-2.10). VK insufficiency is common among mothers and newborn babies in southwestern Uganda, which in one fifth of babies nears overt deficiency. Lack of identifiable predictors of newborn VK insufficiency support strategies for universal VK prophylaxis to newborns to prevent VKDB.

Introduction: Late vitamin K deficiency bleeding in young infants is a rare disorder which occurs almost exclusively in breast-fed infants who did not receive proper vitamin K prophylaxis at birth and who might additionally suffer from cholestasis. Its impact on morbidity is high since in 50% of the cases it presents with intracranial hemorrhage with a mortality rate of 20% and life-long neurologic sequelae in 30% of the affected infants., Case Reports: 2 male infants were both admitted to our unit at the age of 5 weeks with subdural hematoma with midline shift due to late vitamin K deficiency bleeding. Both infants did not receive the recommended Vitamin K prophylaxis in Germany. One patient presented with cholestatic jaundice on admission as an additional risk factor., Discussion: Parents who in the apparent best interest for their children refuse the recommended and well established vitamin K prophylaxis at birth leading to the reappearance of late vitamin K deficiency bleeding. These parents also tend to refuse routine immunizations of childhood in later life, which not only have an impact on their own child but might bear a risk for the whole community., Conclusion: It is the responsibility of health-care takers to show increased awareness to the growing number of parents refusing vitamin K prophylaxis at birth and educate them properly about the devastating consequences of late vitamin K deficiency bleeding., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Pathogenesis of intraventricular hemorrhage (IVH) in premature infants is multifactorial. Little is known about the impact of genetic variants in the vitamin K-dependent coagulation system on the development of IVH., Methods: Polymorphisms in the genes encoding vitamin K epoxide reductase complex 1 (VKORC1 -1639G>A) and coagulation factor 7 (F7 -323Ins10) were examined prospectively in 90 preterm infants <32 weeks gestational age with respect to coagulation profile and IVH risk., Results: F7-323Ins10 was associated with lower factor VII levels, but not with individual IVH risk. In VKORC1-wildtype infants, logistic regression analysis revealed a higher IVH risk compared to carriers of the -1639A allele. Levels of the vitamin K-dependent coagulation parameters assessed in the first hour after birth did not differ between VKORC1-wildtype infants and those carrying -1639A alleles., Conclusions: Our data support the assumption that genetic variants in the vitamin K-dependent coagulation system influence the coagulation profile and the IVH risk in preterm infants. Further studies focussing on short-term changes in vitamin K-kinetics and the coagulation profile during the first days of life are required to further understand a possible link between development of IVH and genetic variants affecting the vitamin K-metabolism.

Background: Neonates routinely receive vitamin K to prevent vitamin K deficiency bleeding, which is associated with a high mortality rate and a high frequency of neurological sequelae. A coagulation screening test might be necessary to detect prophylactic failure or incomplete prophylaxis. However, venous access and the volume of blood required for such testing can be problematic. CoaguChek XS is a portable device designed to monitor prothrombin time while only drawing a small volume of blood. Although the device is used in adults and children, studies have not been performed to evaluate its clinical utility in neonates, and the reference value is unknown in this population. The objectives of the present study were to determine the reference intervals (RIs) for international normalized ratio (INR) using the CoaguChek XS by capillary puncture in healthy term neonates, to evaluate factors that correlate with INR, and to evaluate the device by assessing its ease of use in clinical practice., Methods: This study included 488 healthy term neonates born at a perinatal center between July 2012 and June 2013. The INRs determined by CoaguChek XS were measured in 4-day-old neonates., Results: The enrolled neonates were orally administered vitamin K 6-12 h after birth. A RI for INRs in 4-day-old neonates was established using the CoaguChek XS with a median value of 1.10 and a range of 0.90-1.30. A significant difference in the INR was noted between male (median value, 1.10; RI, 0.90-1.30) and female (median value, 1.10; RI, 0.90-1.24) neonates (p = 0.049). The INR was found to correlate with gestational age, birth weight, and hematocrit value., Conclusions: The CoaguChek XS device is safe, fast, and convenient for performing INR assays in neonates. Our study is the first to establish a RI for INRs that were measured using the CoaguChek XS in healthy term neonates.

Background/aims: Recently, many cases of vitamin K-dependent coagulopathy of unknown origin have been reported. Such patients lack any relevant family history and have no systemic disease, raising suspicion of superwarfarin intoxication. We evaluated individual risk factors causing coagulopathy and hemorrhagic symptoms in patients with suspected superwarfarin intoxication. In addition, we determined how to effectively treat vitamin K-dependent coagulopathy caused by suspected superwarfarin intoxication., Methods: Seven patients with suspected superwarfarin intoxication who lacked any definitive history of rodenticide ingestion were included. Thirty-one patients initially diagnosed with rodenticide poisoning were also included. We performed a retrospective chart review of all subjects and examined clinical data including patient demographics and medical histories., Results: Patients initially diagnosed with rodenticide poisoning were divided into two groups, one of which had a laboratory abnormality (prothrombin time [PT] > 13 seconds) and another group with PTs in the normal range. There was no significant difference between the two groups in any of age, gender, the extent of chronic alcohol consumption, the causative rodenticide, psychiatric problems, ingestion of drugs interacting with warfarin, the extent of intoxication, or the type of ingestion attempt. The albumin level of the former group was significantly lower than that of the latter group (p = 0.014). Furthermore, a significant difference between the two groups was evident in terms of simultaneous ingestion of rodenticide and alcohol (p = 0.023)., Conclusions: Most patients with superwarfarin poisoning did not exhibit any complication. When such complications were evident, they were associated with serum albumin level and coingestion of rodenticide and alcohol.

We report the case of late vitamin K deficiency bleeding (VLDB), with appropriate but insufficient prophylaxis, secondary to extrahepatic cholestasis. Late VKDB is rare today but serious, with a risk of intracranial hemorrhage in more than half of the cases. The diagnosis, causes and prevention of this disease are discussed., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background: Vitamin K deficiency bleeding (VKDB) in infants is a rare but serious worldwide problem, particularly in Southeast Asia. Apart from exclusive breast feeding, little is known of the maternofetal risk factors that predispose infants to VKDB., Objectives: To assess (a) the relationships between functional vitamin K insufficiency in a large cohort of Thai mothers to that of their newborn infants and (b) the importance of delivery risk factors and maternal intakes of vitamin K as determinants of neonatal vitamin K status., Methods: Vitamin K status was assessed by measuring undercarboxylated prothrombin (protein induced by vitamin K absence/antagonist-II (PIVKA-II)) in 683 mothers and in the cord blood of their babies by sensitive immunoassay. Dietary phylloquinone (vitamin K(1); K(1)) intakes were assessed in 106 of these mothers by food frequency questionnaire., Results: Babies were categorised as 'normal' (n=590) or 'high risk' (n=93) according to birth weight and delivery type. PIVKA-II was detectable (>0.15 arbitrary units (AU)/ml) in 85 mothers (12.4%) and 109 babies (16.0%) with median levels of 0.78 and 1.04 AU/ml in mothers and babies, respectively. 'High-risk' babies had a higher median detectable PIVKA-II concentration than 'normal-risk' babies (3.1 vs 1.0 AU/ml, p=0.02) and a higher prevalence of clinically relevant (>5.0 AU/ml) concentrations (p=0.006). Mothers with K(1) intakes below the US recommended 'adequate intake' for pregnancy (<90 microg/day) had a higher prevalence of detectable PIVKA-II (18.8%) than those with adequate intakes (3.3%) (p=0.01)., Conclusions: Functional, clinically relevant, vitamin K insufficiency was more common in 'high-risk' than 'normal-risk' newborns. Vitamin K insufficiency in mothers was linked to lower dietary K(1) intakes during pregnancy.

Introduction: This review summarizes current knowledge on vitamin K for the paediatrician. Vitamin K is a fat-soluble vitamin, present in plants as phylloquinone and produced by bacteria as menaquinone. It is acting as a co-factor for gamma-glutamyl carboxylase. This enzyme is responsible for post-translational modification of some glutamate side chains to gamma-carboxyglutamate. The majority of gamma-carboxylated proteins function in blood coagulation; others play a role in calcium homeostasis., Data: Newborn babies are at particular risk of vitamin K deficiency, as placental transfer is limited and human milk is a poor source. Vitamin K prophylaxis at birth effectively prevents vitamin K deficiency bleeding (VKDB), formerly known as "haemorrhagic disease of the newborn". Recent epidemiological studies provide data on the effectiveness of different administration routes and dosing schemes. Infants of mothers taking drugs that inhibit vitamin K are at risk of early VKDB and should receive 1 mg intramuscular (i.m.) as soon as possible after birth. Classic VKDB is prevented by intramuscular as well as by oral administration of 1 mg vitamin K. In exclusively breast-fed infants, single i.m. administration at birth is also effectively preventing (rare) late VKDB but single oral administration is not. If given orally, prophylaxis should be continued by either weekly administration of 1 mg till 12 weeks or repeating 2 mg at weeks 1 and 4. Daily administration of 25 microg offers insufficient protection. The only infants not fully protected in this way are those with yet unrecognised liver disease., Conclusions: Further work is needed before firm recommendations can be made regarding dose in preterm infants and in patients with fat malabsorption/cholestasis or regarding the role of vitamin K in the prevention of osteoporosis.

Coagulation factors do not cross the placental barrier but are synthesized independently by the conceptus. At birth, activities of the vitamin K dependent factors II, VII, IX, and X and the concentrations of the contact factors XI and XII are reduced to about 50% of normal adult values. The levels of the factors V, VIII, XIII, and fibrinogen are similar to adult values. Plasma concentrations of the naturally occurring anticoagulant proteins (antithrombin, protein C, and protein S) are significantly lower at birth than during the adult years. Plasminogen is reduced by approximately 50%. Platelet counts are within the normal range, regarding function, however, neonatal platelets seem to be hyporeactive. The von Willebrand factor contains large multimers and its concentration is increased. Properties and functions of vitamin K as well as requirement and plasma concentrations in newborns are reviewed. Regarding vitamin K deficiency bleeding (VKDB), the classical nomenclature is used: "early" (presenting within the first 24 h of life), "classical" (day 1-7 after birth), and "late" (8 days to 6 months). After the presentation of the history of vitamin K prophylaxis, vitamin K levels are described as can be expected after the administration of prophylactic doses at various routes. Subsequently, the actual schedule of vitamin K prophylaxis as recommended by the "Osterreichische Gesellschaft für Kinder- und Jugendheilkunde" is given as follows: i) the oral treatment of healthy full-term babies and orally fed preterm babies, ii) the parenteral treatment of small preterm and sick full-term babies, and iii) the treatment of mothers under medication with enzyme-inducing drugs with vitamin K during the last 15-30 days of pregnancy. The regimes of prophylactic vitamin K treatment of different countries are also given. Finally, the therapeutic use of vitamin K is addressed; the potential use of fresh-frozen plasma, prothrombin complex preparations, and recombinant factor VIIa is discussed.

Disorders of coagulation in children often prove challenging to the medical care team. The aims of this study were to assess the spectrum and prevalence of coagulation disorders among children attending Mansoura University Children Hospital (MUCH), Mansoura, Egypt. A total of 105 pediatric patients were referred to MUCH. They were divided into two groups: congenital coagulation disorders (75 cases, age 45.36 +/- 48.59 months), and acquired coagulation disorders (30 cases, age 56.13 +/- 61.61 months). All patients were subjected to thorough history taking including the nature of bleeding, family, past history, mode of inheritance, and detailed physical findings. Hemostatic tests included: platelet count, bleeding time (BT), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT). Specific tests in the congenital group include assay of coagulation factors according to each disorder, Von Willebrand factor assay, ristocetin aggregation test, APTT mixing study for detection of inhibitors in complicated hemophilia cases, F VIII C to VWAg ratio with cut off 0.7 for detection of carriers in some hemophilia A families. Congenital disorders constituted 71.4% of the studied cases vs. 28.6% for acquired disorders. Hemophilia A (42.85%), hemophilia B (14.28%) and liver diseases (14.28%) represented the majority of the studied cases. Mild and moderate cases of hemophilia A and B are more frequent than severe cases in both types. Male sex is more frequent than female in the congenital group (94.7 vs. 5.3%, P < 0.001). Direct correlation existed between factor level assay and severity of hemophilia (r = 0.73, P = 0.006). Three mothers and one sister were identified as carrier out of four families. Anti-clotting factors inhibitor was detected in 18.2% of patients with hemophilia A and in 9.1% with hemophilia B. In conclusion, our study found that hemophilias are the most prevalent congenital coagulation disorders among children. Attention must be given for detection of hemophilia carriers and inhibitors of clotting factors.

Antibodies, such as anti-Rh18 (Hr/Hr(S)), that react with the common products of RHCE can cause HDN as well as severe hemolytic transfusion reactions. Individuals with anti-Rh18 antibodies can have different RHCE genetic backgrounds; therefore, sera and RBCs from these individuals may cross-react. In these situations, genotyping may be the best method to determine compatibility. We report a 26-year-old pregnant Puerto Rican woman who presented at 31 weeks' gestation with anti-E and anti-Rh18 in her serum. No potential donors were identified among family members or within the American Rare Donor Program; therefore, a unit of the patient's RBCs was collected one week before her planned caesarian section. To improve our ability to supply blood for this patient in the future, molecular testing was performed. The patient was found to be homozygous for an RH haplotype in which a variant RHD*DAR, is linked to a variant RHCE*ceAR. The DAR-ceAR haplotype has been described in Dutch-African populations, but this is the first report of an individual self-identified of Hispanic ethnicity. This case report demonstrates the clinical importance of molecular testing of patients with rare Rh phenotypes.

A 24-year old female, gravida III, para III, delivered a full-term infant by cesarean section. A maternal blood sample at the time of admission showed antibody in her serum that had apparent anti-e specificity and that her RBCs were e+. Further studies determined that the antibody was anti-hrS. Cord RBCs had a negative DAT and a normal Hb level. There was no clinical evidence for increased hemolysis in the infant. We describe an hrS+ infant with no evidence of HDN due to anti-hrS.

We studied babies (22 to 32 weeks gestational age) of mothers wishing to breast-feed. Group 1 received 1 mg of vitamin K and Group 2 received 0.5 mg of vitamin K. The Day 2 plasma levels of vitamin K were 1900 to 2600 times higher on average, and the Day 10 vitamin K levels 550 to 600 times higher on average, relative to normal adult plasma values, whether an initial prophylaxis dose of 0.5 mg or 1 mg was used. We conclude that 0.5 mg as the initial dose of vitamin K intramuscularly or intravenously would likely be more than adequate to prevent hemorrhagic disease of the newborn, and that 0.3 mg/per kg may be used for babies with birth weights below 1000 g. To decrease vitamin K intakes in this population, new preparations of total parenteral nutrition multivitamins are needed.

Background: The Colton blood group system (CO, ISBT 015) is composed of three antigens, of which Co3 (ISBT 015.003) is carried by almost all persons, except those of the extremely rare Co(a-b-) phenotype. The Colton blood group antigens are expressed by the water channel aquaporin 1 (aqp1; also known as channel-forming integral protein, CHIP-28), which is a highly conserved RBC integral membrane protein. The two most frequent alleles, CO1 and CO2, encode the antigens Co(a) and Co(b), respectively. Four null alleles have been described for the AQP1 gene to date., Case Report: An Indian woman had an alloimmune antibody to an high-frequency antigen associated with mild HDN. Her RBCs were typed Co(a--b-), and the antibody was an anti-Co3. She typed CO1-positive and CO2-negative in a new genotyping method, using PCR with sequence-specific priming, for CO1 and CO2. A method for nucleotide sequencing of the four AQP1 exons from genomic DNA was developed. The patient was shown to be homozygous for a nonfunctional allele AQP1(232delG) that also carried the CO1-specific polymorphism., Conclusion: The kindred presented a fifth example of an AQP1 null allele, which was caused by a single nucleotide deletion leading to a shift in the reading frame beyond codon 78. A method of genotyping CO for Co(a) and Co(b) antigen phenotype prediction was presented.

Newborn babies are born vitamin K deficient; however, the deficiency is not sufficiently severe to cause a vitamin K deficiency coagulopathy and haemorrhagic disease of the newborn (HDN). Severe vitamin K deficiency can develop quickly in breast-fed newborns and can result in the appearance of classic HDN during the first week of life or late HDN during the first 2 months of life. Both forms of the disease can be severe, causing brain damage and death. Classic and late HDN are prevented by the intramuscular administration of vitamin K at birth. Oral prophylaxis prevents classic HDN but is ineffective in preventing late HDN. Despite proven effectiveness of intramuscular vitamin K prophylaxis there have been concerns about the need for, and safety of, this therapy. This review provides evidence that there is need for intramuscular vitamin K prophylaxis for all babies in order to eradicate haemorrhagic disease of the newborn and concludes that there is no evidence that this therapy is harmful.

Hemorrhagic disease of the newborn (HDN) is usually a self-limiting hemorrhagic disorder of childhood that occurs as a result of vitamin K deficiency. It may be defined as early or late form depending on the time of onset related to birth. HDN is recognized as one of several bleeding disorders that can mimic the findings of nonaccidental head injury and may lead to a mistaken diagnosis of child abuse. We present a single fatal case of late-onset HDN with illustration of hematologic assays that can be performed to assist the pathologist in making the correct diagnosis of HDN.

Background: The evaluation of the disease of vitamin K deficiency bleeding (VKDB)., Method: 108 reported cases between 1980 and 1990 from Germany., Results: VKDB occurs preferentially (90%) in fully breastfed infants, males are affected nearly twice as often as females. The peak age is four weeks; the majority (79%) of the infants are between three and seven weeks old. 58% of the patients suffer from intracranial bleeding, which results in a total mortality rate of 19% and in neurological damage in 21%. Generally the VKDB occurred suddenly as no warning signs were noticed or they were so insignificant as not to be heeded. In at least 37% of the patients cholestasis was detected. The Quick value was pathologically low in every case. Vitamin K dependent factors were low and PIVKA was detectable, whereas vitamin K independent hemostatic parameters were normal or even elevated. The combination of low Quick value and normal fibrinogen as well as platelet level is a good diagnostic indicator which can be confirmed by administration of vitamin K, after which the Quick value will rise within 30 minutes. Vitamin K prophylaxis reduces the incidence of VKDB from 5.13 per 100,000 births to a tenth of that; single dose oral prophylaxis reduces the risk by a factor of 3.3 and a single parenteral dose by 14.3. Parenteral prophylaxis is more effective in patients with hepatobiliary disorders. Patients who suffered VKDB despite having received vitamin K prophylaxis are older at onset (without prophylaxis 32 days, with oral prophylaxis 37 days, and with parenteral prophylaxis 63 days) and have less intracranial bleeding (35%) than patients who received none (62%)., Conclusion: Late form of VKDB is a rare but serious disease which can be prevented by VK-prophylaxis.

alpha-Aminoadipic acid (alpha AA) is an intermediate in lysine metabolism. We report a new case with alpha AA excess in urine and plasma, without alpha-ketoadipic acid, in a full-term male child born to unrelated parents; he presented at 24h of life with seizures that failed to respond to phenobarbital, clonazepam, and Vigabatrin and death occurred on the 38th day of life. Brain imaging suggested antenatal haemorrhage. Small quantities of alpha AA were also detected in the blood and urine of both parents and a healthy brother, all three of whom exhibited the same defect in platelet aggregation as the deceased child. Both parents had decreased levels of plasma neopterin, a finding that might be related to the immunodeficiency described in other cases.

This is a retrospective study of the epidemiology, clinical features, laboratory findings, treatment and outcome of haemorrhagic disease in 42 Kelantanese infants who were admitted to Hospital Universiti Sains Malaysia during a 2-year period (1987-1988). Classical haemorrhagic disease of the newborn was the commonest presentation (48%), followed by early onset (29%) and late onset (24%) disease. Home deliveries accounted for 81% of the affected infants. Most of these babies were not given vitamin K at birth in contrast to those delivered in hospitals. All except one infant were breastfed. The six commonest presenting clinical features were pallor, jaundice, umbilical cord bleeding, tense fontanelle, convulsions and hepatomegaly. All the infants had prolonged prothrombin and partial thromboplastin times which were corrected by administration of vitamin K. Subdural haemorrhage was the commonest form of intracranial haemorrhage, followed by subarachnoid haemorrhage. The overall case fatality rate was 14%. The results of this study once again emphasize the value of vitamin K prophylaxis in the newborn.

Vitamin K prophylaxis has been developed to prevent classic haemorrhagic disease of the newborn. Single vitamin K administration after birth has been reported to fail, resulting in late haemorrhagic disease of the newborn. The preventive effect of oral administration of vitamin K1 1 mg, repeated weekly during the first three months of life, was studied in 48 healthy breast-fed infants, by determination of thrombotest, PIVKA-II and vitamin K1 concentrations at the age of 4, 8 and 12 weeks. All infants showed normal thrombotest values and PIVKA-II was not detectable. Vitamin K1 concentrations were negatively correlated with the number of days elapsed since the most recent vitamin K administration. Six to seven days after the latest application, mean levels were 1223, 927 and 748 pg/ml at ages 4, 8 and 12 weeks, respectively. In conclusion, weekly administration of vitamin K1 1 mg offers complete protection against vitamin K deficiency and does not result in an accumulation of vitamin K1 in the blood.

The prevalence of vitamin K deficiency in the newborns delivered at Siriraj Hospital was studied. The prolongation of one stage prothrombin time and the presence of PIVKA-II (non carboxylated prothrombin antigen) in cord blood were interpreted as the secondary change from vitamin K deficiency state. The most reliable method to diagnose vitamin K deficiency is the detection of vitamin K level in plasma which is not yet available in Thailand. Although the prevalence of vitamin K deficiency in the newborns from our data is not high, only 0.6%, it is shown that some of the apparently normal newborn infants may have bleeding problem from vitamin K deficiency in both newborn and early infancy periods. So, the correction of this deficiency by administration of vitamin K to all newborns is appropriate and reasonable decision.

The authors describe a two months aged patient affected by cow's milk protein intolerance (CMPI) with serious haemorrhagic manifestations. As blood coagulative laboratory findings demonstrated a prolongation of P.T. and P.T.T. with a marked reduction of vitamin K-dependent factors only, the authors believe these bleeding manifestations secondary to a case of late haemorrhagic disease of the newborn. Vitamin K treatment determined a rapid normalization of haemorrhagic symptoms and laboratory clotting tests, without any alteration of these ones during the patient's follow-up too. The authors suggest that blood coagulative pattern must be investigated in all CMPI cases, especially in the ones with a precocious onset of clinical symptoms. In the cases with vitamin K-dependent factors deficiency the treatment is immediately necessary, while in other cases a daily dietary supplementation or a vitamin K weekly or monthly injection could be enough in order to prevent any further vitamin K-dependent factors deficiency.

The correlation between the appearance of functionally-atypical factor VII and perinatal complications was investigated in 66 newborn infants. The presence of an abnormal clotting factor was assumed if the ratio between clotting activity and antigen-related factor VII material exceeded the normal range for adult plasma. The newborns were divided into a risk group of infants threatened by adverse conditions of labour or post-natal adaptation, and a control group of newborns without perinatal complications. The findings were as follows: The incidence of atypical factor VII was significantly higher in the risk group. There was no difference between prenatal and postnatal complications in this respect. Infants born by caesarian section or with cord complications, as well as those with delayed respiratory adaptation, showed a higher incidence of atypical factor VII than the risk group as a whole. Atypical factor VII was not detected until the third day of life, irrespective of the prenatal or postnatal complications. These findings suggest that perinatal risk factors are associated with an alteration of factor VII synthesis.

The aim of this study is the behavior of Normotest (NT) values in newborns in the first 4 days of life. The study has been carried out between January, 1982, and December, 1984, at the Department of Child Health and Neonatal Medicine - School of Medicine - University of Genoa. The number of infants tested was 1320. 694 were males and 626 females, 529 preterm (G.A. less than 37 weeks) and 791 full term babies. Infants have been tested from one to five times in the first four days of life, with the first evaluation within 12 hours of life. 1215 newborns (92%) presented NT values greater than 20%, 105 babies (8%) had NT below 20% in at least one evaluation, and received Vitamin K1 (0.5 mg/kg i.m.) as prophylaxis, being thereafter excluded from this study. Among the neonate with NT greater than 20%, 426 babies have been considered, who had, at least, three evaluations in the first four days of life. 288 (68%) of the 426 newborns, had not important disease, while 138 (32%) were sick neonates; of these babies 88 (64%) had respiratory distress syndrome and 50 (36%) had an infectious condition. The mean of NT values of the 426 newborns decreased from the first (33.84%) to the 2nd day (32.72%), with a following increment in 3rd (35.29%) and 4th day of life (39.01%). Newborns with gestational age (G.A.) less than 34 weeks showed significantly lower values than newborns with G.A. between 34-37 weeks and those with G.A. greater than 37 weeks. No newborn with NT values greater than 20% either received vitamin K or showed symptoms of haemorrhagic disease in early or later neonatal period.

Factors II, IX, and X in the plasmas of 10 patients with 'hemorrhagic disease of the newborn' were investigated by means of electroimmunoassay and crossed immunoelectrophoresis (CIE). The biological activity was within 4.2-30 U/dl for factor II, 5.1-20 U/dl for factor IX, and 5.2-24 U/dl for factor X, whereas the immunological antigen was within 33-58, 25-50, and 35-60 U/dl, respectively. Thus, for all factors, 1.7 times more antigen than activity was present. The CIE pattern of factors II and IX in the presence of Ca++ ions clearly showed a biphasic precipitin arc, and in the absence of Ca++ ions, only one precipitin arc was observed. These results implied the presence of precursor proteins PIVKA-II and -IX in the plasma. However, even in the presence of Ca++ ions the CIE pattern of factor X antigen in the patient plasmas only showed a single precipitin arc with a slightly faster than normal electrophoretic mobility. PIVKA-II, -IX, and the abnormal factor X antigen (PIVKA-X) disappeared within 24 h after the patients were treated with vitamin K.

A new class of proteins has emerged, the so-called vitamin K-dependent calcium binding proteins, which are uniquely characterized by the presence of alpha-carboxyglutamic acid residues. These proteins have been identified in a variety of tissues and body fluids. The specialized nature of calcium binding by Gla residues promotes protein phospholipid interaction, which is important not only in blood coagulation but in many tissue processes involving calcium metabolism. What role other than the blood coagulation mechanism the vitamin K reaction may play in diseases in children is still unclear.

Discussion about vitamin K prophylaxis has again become a matter of major concern since cases of life threatening bleeding due to late onset vitamin K deficiency have been observed in Germany. This review tries to summarize present knowledge about the clinical presentation, pathogenesis and the potential prevention of vitamin K deficiency caused bleeding in the neonatal period and infancy.

Protein in vitamin K absence (PIVKA) is the prothrombin precursor found in plasma when carboxylation to prothrombin is impaired. We report on two cases in which mother-infant PIVKA concentrations were measured at birth after chronic anticonvulsant therapy during pregnancy. Maternal values were 2.4 and 4%, and infant values 20.0 and 18% in cases 1 and 2, respectively. This demonstrates that, despite the normal coagulation profiles previously described, mothers on chronic anticonvulsant therapy may have a subclinical carboxylation defect, while their infants are at risk for hemorrhagic disease. Estimation of maternal PIVKA levels may be of value for predicting risk of hemorrhage in the neonate.

In order to evaluate the specificity of hemostatic mechanism in premature Infants, the following examinations of coagulation and fibrinolytic parameters have been done: platelet number, concentrations of fibrinogen prothrombin, factors V, VII X, X, VIII, IX and XIII, antithrombin III, plasminogen, euglobulin lysis time, fibrin degradation products, alpha-1 antiplasmin and alpha-2 macroglobulin. The examinations have been done in the whole of 18 premature infants of both sexes. The obtained results show that lowered level of coagulant activity was not exclusively the consequence of low activity of vitamin-K dependent factors, but the result of more complex disorders partly connected with the transient reduction of factors VIII, XIII and fibrinogen. The total fibrinolytic activity, in the meantime, was of the normal intensivity. The established disorder of coagulation-fibrinolytic balance probably represents the certain contributing factor in more frequent occurrence of haemorrhagic syndrome in premature infants.

In a prospective study of blood coagulation status in small-for-dates and postmature infants there was often evidence of intravascular coagulation. Abnormal coagulation findings correlated with the degree of growth retardation and with the degree of postmaturity. Macroscopical placental infarction and neonatal polycythaemia were associated with coagulation abnormalities; asphyxia, however, was not. Intravascular coagulation may be an additional hazard to small-for-dates and postmature infants.

The role of Vit. K prophylaxis in preventing haemorrhagic disease of newborn has been well established for many years. Although the opinions differ on a general prophylaxis and selective prophylaxis i.e. prophylaxis only for newborn at risk. In our hospital only the selective Vit. K prophylaxis was administered to newborns during the last 20 years. We observed a marked reduction in the incidence of haemorrhagic disease of newborn, particularly after the availability of neonatal intensive care unit. This could be attributed to the effectiveness of Vit. K prophylaxis and better neonatal care and observation. Hence, the present study, reinforced by the experience of the past emphasise the efficacy and safety of Vit. K prophylaxis in the prevention of haemorrhagic disease of newborn.

A case of early neonatal severe bleeding and persistent hypoglycemia with a fatal outcome is reported. The autopsy examination revealed the features of neonatal hepatic necrosis. Further study by the electron microscopy indicated the presence of herpes type particles in the nucleus and cytoplasm of the remaining liver cells. Serological study of the maternal blood, post partum, revelaed positive reaction to Herpes simplex virus type 2 at low titer. It is believed that intrauterine herpes infection was responsible for the severe hepatic damage manifesting in complex clinical findings.

Vitamin K is required for the synthesis of active forms of some coagulation factors. Bleeding due to low levels of the vitamin K dependent coagulation factors (classic hemorrhagic disease of the newborn) is most frequently seen in newborns with a low intake of breast milk, who are not fed supplemental formula, since transplacental transfer of vitamin K seems to be small and breast milk is relatively deficient in vitamin K. Severe bleeding due to vitamin K deficiency is also observed in 4-12 weeks old infants. The reason for the deficiency in otherwise healthy infants of this age is unclear. Classic hemorrhagic disease of the newborn is not existent in infants given vitamin K intramuscularly at birth. Also, the late manifestation of vitamin K deficiency has been observed virtually exclusively in infants, who had not been given vitamin K parenterally at birth. Since most newborns will be breast fed and supplemental formula feeding will not be required in most healthy full term newborns, all newborns should be given a dose of vitamin K intramuscularly immediately after birth. Whether it is safe to administer vitamin K to the mother or orally to the child requires further investigation.