Vitamin K Deficiency Bleeding
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Previously, the term “hemorrhagic disease of the newborn” was used to describe bleeding disorders in neonates associated with a traumatic birth or hemophilia. [1] The current proper diagnostic term that has been adopted is “vitamin K deficiency bleeding” (VKDB), because vitamin K deficiency is not the sole cause of hemorrhagic disorders in preterm and term infants. [2]
Vitamin K represents a group of lipophilic and hydrophobic vitamins.
Although some controversy surrounds the postnatal timing of the initial hemorrhage, vitamin K deficiency bleeding is usually classified by three distinct time periods after birth, as discussed below. [3]
Early-onset vitamin K deficiency bleeding usually occurs during first 24 hours after birth. It is seen in infants born to mothers taking anticonvulsant (eg, phenytoin, barbiturates, carbamazepine) or antituberculosis medication (eg, rifampin, isoniazid). Serious hemorrhagic complications can occur in this type of hemorrhage.
The mechanisms by which anticonvulsant and antituberculosis medications cause vitamin K deficiency bleeding in neonates is not clearly understood, but limited studies suggest that this disorder is a result of vitamin K deficiency and can be prevented by administration of vitamin K to the mother during the last 2-4 weeks of pregnancy. When vitamin K supplementation is given after the birth for early-onset vitamin K deficiency bleeding, it may be too late to prevent this disease, especially if vitamin K supplementation was not provided during pregnancy.
Numerous other maternal medications and/or exposure to toxins during pregnancy are lalso associated with vitamin K deficiency bleeding in neonates, including but not limited to vitamin K antagonists (eg, warfarin, phenprocoumon). [3]
Classic vitamin K deficiency bleeding usually occurs after 24 hours after birth but may present as late as the first week of life. It usually occurs from the second day of life to the end of the first week; however, it can occur during first month and sometimes overlaps with late-onset vitamin K deficiency bleeding.
Classic vitamin K deficiency bleeding is observed in infants who have not received prophylactic vitamin K at birth, with an incidence ranging from 0.25 to 1.7 cases per 100 births. Infants who have this disease are often ill, have delayed feeding, or both. Bleeding commonly occurs in the umbilicus, gastrointestinal (GI) tract (ie, melena), skin, nose, surgical sites (ie, circumcision) and, uncommonly, in the brain. [3]
Late-onset vitamin K deficiency bleeding usually occurs between age 2-12 weeks; however, it can be seen as long as 6 months after birth.
This disease is most common in breastfed infants who did not receive vitamin K prophylaxis at birth. Vitamin K content is low in mature human milk, with a range of 1-4 μg/L. Industrial contaminants in breast milk have also been implicated in promoting vitamin K deficiency bleeding.
More than half of these infants present with acute intracranial hemorrhages. [3]
The following three forms of vitamin K are known:
K1: Phylloquinone is predominantly found in green leafy vegetables, vegetable oils, and dairy products. The vitamin K given to neonates as a prophylactic agent is an aqueous, colloidal solution of vitamin K1.
K2: Menaquinone is synthesized by gut flora.
K3: Menadione is a synthetic, water soluble form that is no longer used medically because of its ability to produce hemolytic anemia.
Vitamin K is an essential cofactor for γ-glutamyl carboxylase enzymatic activity that catalyses the γ-carboxylation of specific glutamic acid residues in a subclass of proteins. [4] These vitamin K–dependent proteins are known as Gla-proteins; the role of Gla proteins is not completely understood. [5] The image below outlines the vitamin K cycle.
Coagulation factors II, VII, IX, and X as well as other Gla-proteins (eg, protein C, protein S, protein Z) also depend on the presence of vitamin K for their activity. Vitamin K deficiency gives rise to abnormal prothrombin levels; thus, prothrombin does not effectively participate in blood clot formation. As noted above, vitamin K undergoes posttranslational carboxylation of glutamic acid residues on the amino-terminal part of the vitamin K-dependent proteins.
In vitamin K deficiency, des-carboxylated proteins are formed that are functionally defective because they cannot bind calcium and phospholipid. These abnormal coagulation factors are called protein-induced by vitamin K absence (PIVKA). PIVKA-II is a des-carboxylated prothrombin. [6]
The following is a brief history of vitamin K’s use in medicine.
The following is a brief history of vitamin K’s use in medicine.
In 1894, Charles Townsend described a self-limited bleeding condition that usually occurs 1-5 days after birth in patients with nonclassic hemophilia. [4, 7, 8] The term “vitamin K” originated from the German koagulations-vitamin. [4] Henrik Dam and Edward Doisy won the 1943 Nobel Prize for the discovery and functions of vitamin K. Subsequent research has provided significant contributions to the current knowledge of vitamin K and its association with coagulation factors, namely the vitamin K–dependent coagulation factors VII, IX, and X. [9]
Clarke and Shearer wrote a brief but excellent history of vitamin K deficiency bleeding in neonates, including discussion of the following [10] :
Discovery and rediscovery of vitamin K deficiency bleeding by medical science
Historic toxicology-related issues related to an older vitamin K preparation given to neonates
Unproven assumption that older preparations of vitamin K were associated with cancer or leukemia in later life (ie, phenol-containing preparations)
Problems with administering vitamin K to infants with cholestasis
Use of oral preparations of vitamin K to prevent vitamin K deficiency bleeding in neonates and the residual risk of vitamin K deficiency bleeding thereafter
Administration of excess intramuscular (IM) vitamin K in very preterm infants (ie, hepatic storage)
Measurements of vitamin K antagonist II (PIVKA-II) to provide early detection of vitamin K deficiency (ie, uncarboxylated or abnormal coagulation factor II is released into the blood before changes in the prothrombin time [PT])
Continued occurrence of serious vitamin K deficiency bleeding associated with parental refusal of vitamin K prophylaxis immediately after birth
Newborn infants are at risk of developing vitamin K deficiency, and this coagulation abnormality leads to serious bleeding. Transplacental transfer of vitamin K is very limited during pregnancy, as is the storage of vitamin K in the neonatal liver, all of which makes the newborn infant uniquely vulnerable to hemorrhagic disorders unless exogenous vitamin K is given for the prevention of bleeding immediately after birth.
Once the infantile gut is colonized with bacterial flora, the microbial production of vitamin K results in a lower risk of infantile vitamin K deficiency bleeding (VKDB). [11] A gut-related microbial source of vitamin K is particularly important if dietary phylloquinone (vitamin K1) is restricted. [12]
The most common sites of hemorrhage or bleeding are the umbilicus, mucous membrane, the gastrointestinal (GI) tract, circumcision site, and venipuncture sites. Hematomas frequently occur at the sites of trauma (ie, large cephalohematomas, scalp bruising related to instrumentation used at delivery and, rarely, intracranial hemorrhage). Neonatal mortality and long-term neurologic morbidity are severe consequences of vitamin K deficiency bleeding.
Placental transfer of vitamin K is very limited, [13] and phylloquinone levels in umbilical cord blood is very low. [14] The newborn infant’s intestinal tract is relatively sterile and takes some time to colonize with bacteria, which may have a role in synthesizing vitamin K2 (menaquinone). Because Bacteroides species are among the most common bacteria that inhabit the human intestinal tract, and because strains such as B fragilis synthesize vitamin K, Bacteroides species are more significant in producing human vitamin K in the intestine than Escherichia coli. [15]
As noted earlier, breast milk is a poor source of vitamin K (breast milk levels are 1-4 μ g/L). The recommended dietary intake of vitamin K is 1 μg/kg/day. [16] Exclusively breastfed infants have intestinal colonization with lactobacilli that do not synthesize vitamin K; thus, reduced production of menaquinone increases the neonatal risk of developing a hemorrhagic disorder if not supplemented with vitamin K. Formula-fed infants have higher fecal concentrations of vitamin K1 because of dietary intake, as well as significant quantities of fecal menaquinone, reflecting the gut’s microflora. [17]
Preterm infants who are receiving total parenteral nutrition (TPN) are not at such bleeding risk because they are receiving vitamin K via the multivitamin additive in the TPN. However, special consideration is needed for very low birth weight infants whose intestinal tract bacterial flora is altered because of multiple courses of broad-spectrum antimicrobials. Once preterm infants are weaned off TPN, they may develop vitamin K deficiency if they are exclusively fed breast milk.
Vitamin K deficiency in the newborn can be present for various reasons (see Pathophysiology).
Maternal medications that interfere with vitamin K stores or function (eg, carbamazepine, phenytoin, barbiturates, some cephalosporins, rifampin, isoniazid, warfarin or warfarinlike drugs) can result in vitamin K deficiency bleeding (VKDB) in the infant.
In addition to breastfeeding, clinical states that are risk factors for late-onset vitamin K deficiency bleeding include the following:
Hepatitis
Intestinal bacterial overgrowth
Chronic exposure to broad spectrum antimicrobial agents
In the United States, routine intramuscular (IM) administration of vitamin K immediately after birth has made vitamin K deficiency bleeding (VKDB) an uncommon occurrence. The frequency of vitamin K deficiency bleeding varies from 0.25% to 1.7% in the first week of life in infants not receiving vitamin K prophylaxis. The risk of such bleeding is 1,700 per 100,000 infants (1 of 59) if vitamin K is not given; when IM vitamin K is provided, the risk of vitamin K deficiency bleeding falls to 1 per 100,000 infants. [18] Late vitamin K deficiency bleeding (2-12 weeks after birth) appears to be reduced or prevented with parenteral administration of vitamin K at birth.
The frequency of vitamin K deficiency bleeding (VKDB) in countries outside the United States varies with the use of vitamin K prophylaxis, the efficacy of prophylaxis programs, frequency of breastfeeding, and the vitamin K content of locally available formulas.
Late vitamin K deficiency bleeding has fallen from 4.4-7.2 cases per 100,000 births to 1.4-6.4 cases per 100,000 births in reports from Asia and Europe after regimens for prophylaxis were instituted. [19, 20, 21] Interest is growing for requiring mandatory vitamin K prophylaxis in India and China, as well as in other countries with a high burden of neonatal deaths, to reduce the long-term morbidity and mortality related to vitamin K deficiency bleeding. [22]
No racial predilection is noted, but breastfeeding practices can result in apparent racial disparities.
No predilection to vitamin K deficiency bleeding based on sex is apparent.
Vitamin K deficiency bleeding is primarily a disease of the newborn, but such hemorrhage can occur beyond the neonatal period, especially if conditions such as short gut syndrome, intestinal bacterial overgrowth, and certain genetic conditions are present.
Prognosis is based on the amount of blood loss, bleeding site, and gestational age of the newborn. It can range form mild to severe complications, and even death can occur.
In the absence of intracranial hemorrhage, the prognosis for vitamin K deficiency bleeding (VKDB) in an otherwise healthy infant is excellent. Prognosis after intracranial hemorrhage depends on the extent and location of the hemorrhage. Long-term sequelae of intracranial hemorrhage may include motor and intellectual deficits.
Intracranial hemorrhage is the primary serious complication of vitamin K deficiency bleeding. Intracranial hemorrhage is uncommon in classic vitamin K deficiency bleeding, but it can be observed in more than 50% of infants with late-onset vitamin K deficiency bleeding. Intracranial hemorrhage is responsible for nearly all mortality and long-term sequelae due to vitamin K deficiency bleeding.
Hepatic or adrenal gland bleeding may also be a complication. [23]
Complications of treatment include anaphylactoidlike reactions during intravenous vitamin K administration, hyperbilirubinemia or hemolytic anemia after high doses of vitamin K, and hematomas at the site of injection, if administered intramuscularly.
In the era of internet and social media widespread information regarding vitamin K deficiency bleeding (VKDB) is available—but such information may not be accurate, peer-reviewed, and scientifically evaluated. It is highly advisable that clinicians address this issue during visits in the antenatal period. By providing parents with factual information and education, acceptance of Vitamin K has been shown to increased. [18, 24, 25]
The following may be useful resources from various governments and educational organizations:
American Academy of Pediatrics policy statement on vitamin K (2003; most recent, as of December 2017)
Australian government publication on vitamin K (2010; most recent, as of December 2017)
Canadian Pediatric Society statement on vitamin K (1997; reaffirmed 2016)
European Society for Paediatric Gastroenterology Hepatology and Nutrition position paper (2016)
Vitamin K prophylaxis guidelines from Stanford University (2006; most recent, as of December 2017)
Victora C. Vitamin K deficiency and haemorrhagic disease of the newborn: a public health problem in less developed countries?. Evaluation, Policy and Planning Series. No. EVL-97-005. New York, NY: UNICEF; February 1997. [Full Text].
Sutor AH, von Kries R, Cornelissen EA, McNinch AW, Andrew M. Vitamin K deficiency bleeding (VKDB) in infancy. ISTH Pediatric/Perinatal Subcommittee. International Society on Thrombosis and Haemostasis. Thromb Haemost. 1999 Mar. 81 (3):456-61. [Medline].
Pichler E, Pichler L. The neonatal coagulation system and the vitamin K deficiency bleeding – a mini review. Wien Med Wochenschr. 2008. 158 (13-14):385-95. [Medline].
Bandyopadhyay PK. Vitamin K‐dependent γ‐glutamylcarboxylation: an ancient posttranslational modification. In: Litwack G, ed. Vitamins and Hormones. London, UK: Academic Press; 2008. Vol 78: 157-84. [Full Text].
Oldenburg J, Marinova M, Muller-Reible C, Watzka M. The vitamin K cycle. Vitam Horm. 2008. 78:35-62. [Medline].
Widdershoven J, van Munster P, De Abreu R, et al. Four methods compared for measuring des-carboxy-prothrombin (PIVKA-II). Clin Chem. 1987 Nov. 33 (11):2074-8. [Medline].
Brinkhous KM, Smith HP, Warner ED. Plasma plasma prothrombin level in normal infancy and in hemorrhagic disease of the newborn. Am J Med Sci. April 1937. 193:475-81.
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Hougie C, Barrow EM, Graham JB. Stuart clotting defect. I. Segregation of an hereditary hemorrhagic state from the heterogeneous group heretofore called stable factor (SPCA, proconvertin, factor VII) deficiency. J Clin Invest. 1957 Mar. 36 (3):485-96. [Medline].
Clarke P, Shearer MJ. Vitamin K deficiency bleeding: the readiness is all. Arch Dis Child. 2007 Sep. 92 (9):741-3. [Medline].
Benno Y, Sawada K, Mitsuoka T. The intestinal microflora of infants: fecal flora of infants with vitamin K deficiency. Microbiol Immunol. 1985. 29 (3):243-50. [Medline].
Paiva SA, Sepe TE, Booth SL, et al. Interaction between vitamin K nutriture and bacterial overgrowth in hypochlorhydria induced by omeprazole. Am J Clin Nutr. 1998 Sep. 68 (3):699-704. [Medline].
Greer FR. Vitamin K status of lactating mothers and their infants. Acta Paediatr Suppl. 1999 Aug. 88 (430):95-103. [Medline].
von Kries R, Shearer MJ, Widdershoven J, Motohara K, Umbach G, Gobel U. Des-gamma-carboxyprothrombin (PIVKA II) and plasma vitamin K1 in newborns and their mothers. Thromb Haemost. 1992 Oct 5. 68 (4):383-7. [Medline].
Gibbons RJ, Engle LP. Vitamin K compounds in bacteria that are obligate anaerobes. Science. 1964 Dec 4. 146 (3649):1307-9. [Medline].
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Greer FR, Mummah-Schendel LL, Marshall S, Suttie JW. Vitamin K1 (phylloquinone) and vitamin K2 (menaquinone) status in newborns during the first week of life. Pediatrics. 1988 Jan. 81 (1):137-40. [Medline].
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Takahashi D, Shirahata A, Itoh S, Takahashi Y, Nishiguchi T, Matsuda Y. Vitamin K prophylaxis and late vitamin K deficiency bleeding in infants: fifth nationwide survey in Japan. Pediatr Int. 2011 Dec. 53 (6):897-901. [Medline].
Darlow BA, Phillips AA, Dickson NP. New Zealand surveillance of neonatal vitamin K deficiency bleeding (VKDB): 1998-2008. J Paediatr Child Health. 2011 Jul. 47 (7):460-4. [Medline].
Rai RK, Luo J, Tulchinsky TH. Vitamin K supplementation to prevent hemorrhagic morbidity and mortality of newborns in India and China. World J Pediatr. 2017 Feb. 13 (1):15-9. [Medline].
Hascoet JM, Picaud JC, Lapillonne A, Boithias-Guerot C, Bolot P, Saliba E, et al. [Vitamin K in the neonate: recommendations update] [French]. Arch Pediatr. 2017 Sep. 24 (9):902-5. [Medline].
Hamrick HJ, Gable EK, Freeman EH, et al. Reasons for refusal of newborn vitamin K prophylaxis: implications for management and education. Hosp Pediatr. 2016 Jan. 6(1):15-21. [Medline]. [Full Text].
Marcewicz LH, Clayton J, Maenner M, et al. Parental refusal of vitamin K and neonatal preventive services: a need for surveillance. Matern Child Health J. 2017 May. 21 (5):1079-84. [Medline].
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Witt M, Kvist N, Jorgensen MH, Hulscher JB, Verkade HJ, and the Netherlands Study Group of Biliary Atresia Registry (NeSBAR). Prophylactic dosing of vitamin K to prevent bleeding. Pediatrics. 2016 May. 137(5):[Medline]. [Full Text].
Hauschner H, Rosenberg N, Seligsohn U, et al. Persistent neonatal thrombocytopenia can be caused by IgA antiplatelet antibodies in breast milk of immune thrombocytopenic mothers. Blood. 2015 Jul 30. 126 (5):661-4. [Medline].
Mitsiakos G, Pana ZD, Chatziioannidis I, et al. Platelet mass predicts intracranial hemorrhage in neonates with gram-negative sepsis. J Pediatr Hematol Oncol. 2015 Oct. 37 (7):519-23. [Medline].
American Academy of Pediatrics Committee on Fetus and Newborn. Policy statement: Controversies concerning vitamin K and the newborn. Pediatrics. 2003 Jul. 112 (1 pt 1):191-2. [Medline]. [Full Text].
[Guideline] American Academy of Pediatrics Committee on Nutrition. Vitamin K compounds and the water-soluble analogues: use in therapy and prophylaxis in pediatrics. Pediatrics. 1961 Sept. 28:501-7. [Full Text].
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Dharmendra J Nimavat, MD, FAAP Associate Professor of Clinical Pediatrics, Department of Pediatrics, Division of Neonatology, Southern Illinois University School of Medicine; Staff Neonatologist, Clinical Director, NICU Regional Perinatal Center, HSHS St John’s Children’s Hospital
Dharmendra J Nimavat, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association of Physicians of Indian Origin
Disclosure: Nothing to disclose.
Michael P Sherman, MD, FAAP Professor, Department of Child Health, University of Missouri-Columbia School of Medicine; Neonatologist, Women’s and Children’s Hospital; Professor Emeritus, Department of Pediatrics, University of California, Davis, School of Medicine
Michael P Sherman, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, American Thoracic Society, European Society for Paediatric Research, Pediatric Infectious Diseases Society, Perinatal Research Society, Society for Pediatric Research, Western Society for Pediatric Research
Disclosure: Nothing to disclose.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
David A Clark, MD Professor and Martha Lepow Chairman of Pediatrics, Professor of Obstetrics and Gynecology, Albany Medical College; Director, Children’s Hospital at Albany Medical Center
David A Clark, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Forestry Association, American Pediatric Society, Capital District Pediatric Society, Christian Medical and Dental Associations, European Society for Paediatric Research, Eastern Society for Pediatric Research, Floyd W Denny Pediatric Alumni Society, Medical Society of the State of New York, New York Academy of Sciences, Society for Pediatric Research
Disclosure: Nothing to disclose.
Santina A Zanelli, MD Associate Professor, Department of Pediatrics, Division of Neonatology, University of Virginia Health System
Santina A Zanelli, MD is a member of the following medical societies: American Academy of Pediatrics, American Epilepsy Society, Society for Neuroscience, Society for Pediatric Research
Disclosure: Nothing to disclose.
Oussama Itani, MD, FAAP, FACN Clinical Associate Professor of Pediatrics and Human Development, Michigan State University; Medical Director, Department of Neonatology, Borgess Medical Center
Oussama Itani, MD, FAAP, FACN is a member of the following medical societies: American Academy of Pediatrics, American Association for Physician Leadership, American Heart Association, American College of Nutrition
Disclosure: Nothing to disclose.
The authors appreciate the review of this article and helpful suggestions for improvement from Professor Daniel Batton, the Director of the Neonatology Division at Southern Illinois University School of Medicine.
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