Prothrombin Complex Concentrate for Intracerebral Hemorrhage Secondary to Vitamin K Deficiency Bleeding in a 6-Week-Old Child.

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.

Late Vitamin K Deficient Bleeding in 2 Young Infants--Renaissance of a Preventable Disease.

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.

International normalized ratio testing with point-of-care coagulometer in healthy term neonates.

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.

Genetic variants of the vitamin K dependent coagulation system and intraventricular hemorrhage in preterm infants.

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.

Vitamin K Deficiency Bleeding in Infancy.

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.

Laboratory assessment of vitamin K status.

Vitamin K is required for the É£-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 (K1) 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 K1 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.

Vitamin K, an update for the paediatrician.

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.

Serologic and molecular genetic management of a pregnancy complicated by anti-Rh18.

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.

Prevalence and Predictors of Functional Vitamin K Insufficiency in Mothers and Newborns in Uganda.

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.

Maternal alloanti-hrS--an absence of HDN.

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.

Haemorrhage in neonatal hepatic necrosis due to herpes infection.

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.

Evidence of vitamin K deficiency in cord 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 vitamin K-dependent proteins.

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.

[Normotest in the early neonatal period]. / Ii normotest nel periodo neonatale precoce.

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.

[A case of late neonatal hemorrhagic disease associated with intolerance for cow's milk proteins]. / Su un caso di malattia emorragica neonatale tardiva associata ad intolleranza alle proteine del latte vaccino.

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.

Evaluation of risk factors in patients with vitamin K-dependent coagulopathy presumed to be caused by exposure to brodifacoum.

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.

[Vitamin K deficiency bleeding: a case secondary to transient neonatal cholestasis]. / Maladie hémorragique par déficit en vitamine K : à propos d'un cas secondaire à une cholestase néonatale transitoire.

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.

Prevalence of subclinical vitamin K deficiency in Thai newborns: relationship to maternal phylloquinone intakes and delivery risk.

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.