Vitamin K Deficiency in Infants

Vitamin K Deficiency in InfantsParttraporn Isarangkura and Ampaiwan ChuansumritHistoryVitamin K (VK) is an essential fat-soluble vitamin or mi- cronutrient. 1895 Charles Towsend (Boston, USA) first described syn-drome of “Hemorrhagic Disease of the Newborn(HDN)”. 1929 VK was discovered by Henrick Dam, the Danish bio-chemist. K stands for “Koagulation”. 1939 VK was synthesized for clinical use. 1974 Definite action of VK in carboxylation process wasknown. 1995 One hundred year celebration of Dam’s birth: Inter-national Symposium on “Vitamin K in Infancy” in Basel, Switzerland by Sutor, Hathaway et al(1).Physiology and Metabolism of VKTypes of natural VK: 1. K1 Phyloquinone from plant, fat-soluble. 2. K2 Menaquinone from GI flora, water-soluble.K2 has longer half-life in the liver storage than K1. Adults receive VK half from diet and half from gastrointestinal (GI) flora. For newborn and infants the main source of VK comes from diet (milk) and small amounts from GI flora.Metabolism.Vitamin K is an essential fat-soluble vitamin that is required for the post-translational gamma carboxylation of the coagulation factors II, VII, IX, X and Proteins C and S. These proteins contain the unique amino acid, gamma carboxyl glutamic acid, which is necessary for calcium binding and essential for their function. The process occurs in the liver cells. The enzymes necessary for the vitamin K epoxide cycle are vitamin K epoxide reductase and vitamin K quinone reductase. Undercarboxylated vitamin K dependent proteins which are produced and released in the absence of VK are named protein induced by VK absence or PIVKA II.Vitamin K dependent proteins:1. Clotting factors II, VII, IX, X or prothrombin complex (PC).2. Protein C inhibits Vlla, Va and increases fibrinolysis. 3. Protein S, cofactor of protein C. 4. Osteocalcin for calcium metabolism: increases calciumdeposition in bone, tissue and increases renal tubular reabsorption and etc.Physiologic deficiency of prothrombin complex in newborn babies. Newborn babies received VK in small amounts from the mother at birth. PC levels will decrease at 1-2 weeks of age and becomes normal at 6 week to 6 month of age.Bangkok, ThailandOctober 24–28, 19991541.2. 3. 4.Etiology of physiologic PC deficiency in infants: Low vitamin K level in the newborn babies. 1.1 low plasma K1 level and K1 has short half-life dur-ing storage in the liver. 1.2 low K1 concentration in the liver tissue. 1.3 low K intake from breast milk (low VK content inbreast milk). 1.4 low VK producing bacteria from GI tract. Prematurity of liver function which decreases production of prothrombin Ag. Low liver enzyme K epoxide reductase for vitamin K metabolism. Placental barrier to the transport of VK from mother to neonate. VK administered to mother does not effect the level of coagulation factors in cord blood(2).Laboratory test for VKP deficiency:1. Blood coagulation test: - Prothrombin time (Quick’s method) is the most usefuland practical test. - Thrombotest. - Assay for VK dependent coagulation factors II, VII,IX, X. 2. Direct test using 2 markers: descarboxy prothrombin, descarboxy osteocalcin. Noncarboxylated prothrombin or descarboxy prothrombin (PIVKA II) by- - - - -latex agglutination. EIA electroimmunoassay. CIE closed immune electrophoresis. RIA radioimmunoassay. ELISA enzyme-linked immunosorbant assay.3. Vitamin K assay: high performance liquid chromatography fluorometric detection.Vitamin K Deficiency Bleeding (VKDB) in infants.Definition of VKDB(1). Hemorrhage in infants due to VK deficiency shown by low activity of VK dependent coagulation factors (II, VII, IX, X), normal activity of VK inde- pendent coagulation factors (I, V, VIII, XI, XII, XIII) and the presence of PIVKA II. Administration of VK is followed by shortening of the prothrombin time after 30-60 minutes and corrects the coagulation abnormalities.

Classification of VKDB in infants.VKDB can be classified by etiology and by the age at onset into four groups (see Table 1):1. Early HDN. 2. Classic HDN. 3. Late HDN or Acquired PC deficiency (APCD) in infants. 4. Secondary PC deficiency. A series of patients seen in Thailand including classic HDN, late HDN and secondary VKDB of the authors’ report is shown in Table 2.1. Early HDN.Etiology. Baby born of mother who has been on certain drugs:- anticonvulsant: barbiturate, phenytoin. - antituberculous drug: rifampin, isoniazide. - antibiotics. - VK antagonist anticoagulant.Clinical manifestation: Bleeding usually occurs within 2 days and not more than 5 days of life.Organs of bleeding are reported to be gastrointestinal, liver, intracranial, etc.Mortality is rather high. Deblay et al(3) reported 8 out of 111 neonates born to epileptic women treated with anticonvulsants develop early HDN (7%) and three cases died (37% mortality).Management. VK parenterally can correct coagulation defect and stop bleeding.Prevention. The mechanism of production of VK deficiency is not known but it can be prevented by administra-tion of VK to the mother antepartum for 2 weeks. VK given to the infant immediately after delivery may be too late.2. Classic HDN.Occurs during 2 to 7 day of life when the prothrombin complex is low.Etiology. VK deficiency from low intake and low storage at birth. It was found in babies who do not received VKP or VK supplemented.The incidence is thought to be 0.4-1.7/100 birth in babies not receiving VKP at birth(4).Clinical manifestation. Among 75 cases of the author’s series, bleeding was found in GI tract in 70%, skin in 27%, intracranial in 19% and the mortality rate was 1-2% (5).Management. VK and plasma infusion.Prevention. VKP at birth intramuscularly or by oral route can prevent classic HDN.3. VKDB from secondary causes.Etiology. Definite etiology inducing VKP is found in association with bleeding: 1) Malabsorption of VK ie gut resection. 2) Biliary atresia.3) Severe liver disease-induced intrahepatic biliary obstruc- tion, chlolestatic disease. etc.Clinical manifestations: The age onset of bleeding is varied from 2 weeks to over 1 year according to the primary disease. Intracranial bleeding was found in 65%, mortality rate was 26% and permanent neurological handicap 28% (see Table 2) (5,6).Management. Plasma and VK will correct coagulation defect. Removal of primary cause is the most important treat- ment. In chronic cases in which primary disease could not be treated i.e. permanent gut resection, total parental nutrition; long term VK administration is recommended.Prognosis depends on the primary disease.4. Late HDN.Synonyms. - Acquired prothrombin complex deficiency (APCD) syndrome in infants is common in Southeast Asia. It was named by Bhanchetin 1966(7). - Idiopathic vitamin K deficiency in infants(IVKDI) is named in Japan(8-11).Definition. Late HDN is an acquired bleeding disorder in the 2 week to 6 month age infant caused by reduced vitamin K dependent clotting factor (II, VII, IX, X) with a high incidence of intracranial hemorrhage and responds to VK.History. It was first reported in 23 Thai babies by Bhanchet et al in 1966(7). Cases were reported by Chan and Wong in Singapore(12) and Lovric in Australia in 1967(13) and both papers referred to Bhanchet’s first report from Thai- land(7). Nammacher et al reported 4 cases in USA in 1970(14). APCD or late HDN was described in detail in 93 reported cases by Bhanchet-Isarangkura in 1977 and 1975 (15-

16). Since then attention has been drawn to this disease as one of major health problems in infants in Southeast Asian countries because of the high prevalence (30-80 per 100,000 births), high incidence of intracranial bleeding (80%), high mortality (25%) and permanent neurological handicap (50-65%)(17).In early 1980s it apparently became a major problem in Europe and Japan.(8-11,18) VKDB and VKP were described and disscussed in detail in the “International Sym- posium of VK in Infancy” in Basel, Switzerland 1994 for the cerebration on the “100th birthday of Henrik dam” who discovered VK(1). Prevention of VKDB in infants was thor- oughly review by Zipursky in 1999(19).The incidence, risk factors, clinical manifestations andoutcome are shown in Table 3(6,15,20). The incidence of lateHDN is most commonly found in 2 week to 2 month oldinfants (75% (15). It may range between 2 weeks to 11 monthsfor babies receiving late additional food which is the main

source of VK. The disease occurs in male more than femaleat a ratio of about 2:1(6,15). Almost all of them received breastfeeding (90-95%) and did not receive VKP at birth (80- 96%)(6,20).Pathogenesis of late HDN(9,21,22).Infants have very limited VK reserve at birth, depending largely on milk for their supply. The supply from intestinal bacteria is limited particularly in breast fed infants. Low VK content in breast milk from some mothers and no additional VKP are important causes of VK deficiency in late HDN. 1. Low vitamin K in plasma and liver storage at birth (see Table 4). K level of cord blood is below 0.01 ng/mL or undetectable while adult K level is 0.26 ng/mL(23). Main source of VK in infant is K1

from diet which has shorter half life than K2 from GI flora(19).2. Low vitamin K intake in breast-fed infant (see Table 5). VK content in breast milk is below 5 mg/mL while formula milk has 50-60 mg/mL(24). Breast milk of mothers with late HDN contains lower vitamin K1 and K2 level than that of the control mothers(25,26).3. In formula fed infants, the bowel contains Bacteriodes fragillis which can produce vitamin K2

whereas in breast- fed babies, the bowel contains Lactobacillus which can not produce K2. The endogenous bowel production of VK in formula fed infants can correct the VK deficiency in the newborn(21).Risk factors: 1. Low intake from low K content in breast milk. 2. No VKP giving at birth for supplementation.Prevalence of late HDN and its health problem.It should be noted that the incidence of late HDN in the eastern world is 25-80 per 100,000 births(6,8,27,28)

which is higher than that in the western world (4-25 per 100,000 births(18)) as shown in Table 6.The observation in England and Japan, summer tem- perature were associated with a doubling in incidence.It should be noted that VKDB in infant in the first year of life manifested with a high incidence of intracranial hemorrhage(ICH), as observed in late HDN and secondary prothrombin complex deficiency (65%) as shown in Table 2. Late HDN has the highest incidence of ICH (80-90%) among any bleeding disorders. The reason could not be definitely explained. It is hypothesized that during the first year of life, the brain develops rapidly while the bony and supportive tissue structures cannot expand accordingly. ICH is found in subdural, subarachnoid and intracerebral space in 100, 80, 30 percent respectively(20)of cases.Late HDN is one of the important health problems in infant morbidity, mortality and socio-economic problem of the country. More attention should be drawn to physicians and health authorities to prevent this serious disease.Management of late HDN:1. Vitamin K1 1-2 mg iv daily for 1-3 days. 2. FFP 10 mL/kg/dose in severe bleeding. 3. PRC transfusion in moderate to severe anemia. 4. Treat intracranial bleeding : anticonvulsant, dexamethasone iv, subdural tap daily-until no obtainable fluid, lumbar puncture when neurological symptoms improved. 5. Follow up neurological complications and early stimula- tion for neurological handicap.Prevention of classic and late HDN by vitamin K prophylaxis. VKP to all newborn babies was started from 1961 in USA and from 1960-1970 in Europe. At the beginning, the intramuscular route was routinely practiced by giving 1 mg i.m. to all newborn babies.For developing countries such as Thailand about 30 to 40 years ago (1960-1970), around half of the deliveries were carried out by traditional birth attendants or midwives. Parenteral injection could not be caried out by midwives. The first author asked a pharmaceutical company to pro- vide VK pediatric drops (Konakion, Roche, Basel, Swit- zerland) and conducted research studies of VKP by the oral route, 2 mg single dose which can be practiced routinely. The high efficacy, low toxicity, low cost, the long expira- tion date, the simple way of storage and administration of VK pediatric drops made it practical for developing countries at that time(17). VKP 2 mg oral route for normal newborn and 0.5-1 mg intramuscular route for unwell babies has been routinely practice in Thailand since 1988 and has been compulsorily practiced all over the country from 1994 until 1998. The incidence of late HDN decreased from 30- 70 to 4-7 per 100,000(6) birth. Since 1999, VKP 1 mg intramuscularly is mandatory to all newborn babies while most deliveries are carried out in the hospitals. VKP i.m. route is given together with routine vaccination ie. Hepatitis B, BCG.In the developed world, VKP has changed from time to time. In 1992 Jean Golding(29) reported an unexpected association between childhood cancer and neonatal VKP intramusculary but not by oral route. Intramuscular VKP doubled the incidence of leukemia in children under 10 years of age. Since then VKP by oral route has became more and more practiced in Europe in different dosages. The result shows that the VKP intramuscular route gives the most promising results in protecting late HDN(19) (as shown in Table 7). It should be noted that following several studies there was no evidence of an

increased incidence of childhood cancer after the administration of VK i.m. at birth (19).VKP by the intramuscular route:Advantages: 1. Produces higher and more sustained plasma VK levels than oral administration(30,31). 2. Giving a “depot” effect with delay release of VK for week after injection(32). 3. More reliability in term of intake and absorption. 4. Only single dose is required.Disadvantages: It may induce bleeding, infection, injur vessels and nerves at the injection site rarely.VKP by oral route.Advantages : 1. Simple way of administration but it is costly and trouble- some to give many doses repeatedly. 2. No bleeding, infection, injured vessels and nerves at the injection site. 3. Parental request.Disadvantages: 1. Less reliable in term of intake. 2. Unpredictable absorption. 3. Unnoticed regurgitation. 4. Danger of lipid aspiration. 5. Requires skilled person for drug administrationVitamin K mixed micelles (KMM) is a new form of K1. It has been used for intramuscular and oral route. The composition of K1 and KMM is shown in Table 8. KMM has no cremophor which may induce anaphylactic shock for intravenous injection. Glycocholic acid and lecithin are added in KMM to enhance absorption despite biliary ob- struction.It is now clear that the administration of VK 1 mg i.m. immediately after birth will prevent both classic and late HDN. Oral VKP given at birth and supplemented during the neonatal period for 1-5 month did not entirely prevent late HDN (see Table 7).Cost effectiveness of VKP in preventing late HDN.Most infants affected by late HDN are fully or exclusively breast-fed. However, breast feeding should be continuously and strongly promoted together with the promotion of giving VKP to all newborn babies at birth.The expense of VKP 1 mg i.m. single dose would cost US$ 0.5-1 per dose per newborn baby. The World Bank classifies intervention of disability-adjusted life years (DALY) below US$ 100 is most effective(33).Conclusion.It can be concluded that there is need for a single dose of VKP 1 mg intramuscularly at birth for all newborn babies in order to eradicate classic and late HDN and there is no evidence that this therapy is harmful. For developing countries, VKP must be given 1 mg i.m. as early as possible if it cannot be given at birth because of home delivery. VKP given within 2 weeks of delivery will prevent late HDN.AcknowledgementsThe authors are grateful to the physicians, scientists, nurses, patients and parents who have contributed their knowledge, experience, assistance in taking care of patients, advice and support to the first author throughout the entire work on late HDN and VKP for over 30 years since 1963. The authors would like to thank Prof. William E Hathaway who always gives advice and moral support.References1. Sutor AH, Hathaway WE eds. Vitamin K in Infancy, International Symposium 1994. New York : Schattauer : Ed Roche, 1995.2. Kazzi N J, Ilagan NB, Liang KC, Kazzi GM, Poland RL, Grietsell LA, Fujii Y and Brans YW. Maternal administration of vitamin K does not improve the coagulation profileof preterm infants. Pediatrics 1989;84:1045-50. 3. Deblay MF, Vert P, Andre M and Marchal F. Transplacentalvitamin K prevents haemorrhagic disease of infant ofepileptic mother. Lancet 1982;1:1247. 4. Merenstein K, Hathaway WE, Miller RW, Paulson JA andRowley DL. Controversies concerning vitamin K and thenewborn. Pediatrics 1993;91:1001 5. Isarangkura P. Prothrombin complex and vitamin K In :Hathirat P, Chuansurit A, Isarangkura P, eds. Text Book ofPediatrics Hematology. Bangkok : Chaijareon 1995:256-85. 6. Chuansumrit A, Isarangkura P, Hathirat P and Vitamin Kstudy Group. Vitamin K deficiency bleeding in Thailand: A 32-year history. Southeast Asian J Trop Med Pub Hlth 1998;29:649-54.7. Bhanchet P, Bhamarapravati N, Bukkaves S, Tuchinda S. A new bleeding syndrome in Thai infants (Acquired prothrombin complex deficiency). XI Congress of International Society of Hematology, Australia, Abstract book 1966:20.8. Nakayama K, Ikeda I, Shirahata A. Hemorrhagic disease due to vitamin K deficiency in infancy. Nihon Iji Shinpo 1981;2996:22-8.9. Nagao T, Nakayama K. Vitamin K deficiency in Japan. Pediatr 1984;74:315-6.10. Hanawa I, Maki M, Murata B, et al. The second nation-wide survey in Japan of vitamin K deficiency in infancy. Eur J Pediatr 1988;147:472-7.11. Hanawa Y, Maki M, Matsuyama E, et al. The third nationwide survey in Japan of vitamin K deficiency in infancy. Acta Paediatr Jpn 1990;32:51-9.12. Chan MCK, Wong HB. Late hemorrhagic disease of Singapore infants. J. Singapore Pediatr Soc 1967;9:72.13. Lovric VA, Jones RF. The hemorrhagic syndrome of early childhood. Aust Ann Med 1967;16:173.14. Nammacher MA, Willemin M, Hartmann JR, Gaston LW. Vitamin K deficiency in infants beyond the neonatal

period. J Pediatr 1970;4:549.15. Bhanchet–Isarangkura P, Tuchinda S, Bhamaraphavati N, Visudhiphan P, Hathirat P, Bukkaaves S. A bleeding syndrome in infants due to acquired prothrombin complex deficiency, a survey of 93 affected infants. Clin Pediatr 1977;16:992–8.16. Bhanchet–Isarangkura P, Kashemsant C. A bleeding syndromes in infants : Acquired prothrombin complex deficiency of unknown etiology. Southeast Asian J Trop Med Pub Hlth 1975;6:592–8.17. Isarangkura PB, Pintadit P, Tejavej A, Siripoonya P, Chulajata C, Green GM. Vitamin K prophylaxis in the neonate by the oral route and its significance in reducing infant mortality and morbidity. J Med Assoc Thai 1986;69:56-61.18. Von Kries R. Neonatal Vitamin K Prophylaxis: the Gordian Knot still awaits untying. BMJ 1998;316:161-2.19. Zipursky A. Prevention of vitamin K deficiency bleeding in newborn. Brit J Hemato 1999;104:430-7. 20. Isarangkura PB. Idiopathic vitamin K deficiency in infancy(Acquired prothrombin complex deficiency syndrome). JPediatr Obstet Gynaecol 1984;10:5-11. 21. Lane PA, Hathaway WE, Vitamin K in infancy. J Pediatr1985;106:351-9. 22. Bhanchet–Isarangkura P. The pathogenesis of acquiredprothrombin complex deficiency (APCD Syndrome) ininfants. Southeast Asian J Trop Med Pub Hlth 1979;10:350-2. 23. Shearer MJ, Rahim S, Barkhan P, Stimuler L. Plasma vitamin K1 in mother and the newborn babies. Lancet1982;2:460-3. 24. Haroon Y, Shearer MJ, Rahim S, et al. The content ofphylloquinone (vitamin K1) in human 25. milk, Cow’s milk and infant formula foods determined byhigh performance liquid chomatography. J Nutr1982;112:1105-12. 26. Isarangkura PB, Mahasandana C, Panstienkul B, NagayamaK, Tsijkimoto I, Yamamoto Y. Vitamin K level in maternal breast milk of infants with acquired prothrombin complex deficiency syndrome. Southeast Asian J Trop Med Pub Hlth 1983;14:575-6.27. Isarangkura PB, Mahasandana C, Panstienkul B, Nakayama K, Tsikimoto I, Yamamoto Y, Yonekubo A. The different levels of vitamin K1 and K2 in the maternal breast-milk of infants with acquired prothrombin complex deficiency syndrome. Southeast Asian J Trop Med Pub Hlth 1987;18:568-9.28. Ungchusak K, Tishyadhigama S, Choprapawon C, et al. Incidence of idiopathic vitamin K deficiency in infants: a national hospital-based survey in Thailand, 1983. J Med Assoc Thai 1988;71:417-21.29. Khanjanathiti P, Nanna P, Chairsamee H. Reduction of infant morbidity and mortality. Rama Med J 1987;10:155- 61.30. Golding J, Paterson M, Kinlen LJ. Factors associated with childhood cancer in a national cohort tudy. Br J Cancer 1990;62:304-8.31. Schubiger G, Tonz O, Gruter J, Shearer MJ. Vitamin K concentration in breast-fed neonates after oral or intramuscular administration of a single dose of a new mixed- micellar preparation of phylloquinone. Pediatr Gastroentero and Nutrition 1993;16:435-9.32. McNinch AW, Upton C, Samuels M, Shearer MJ, McCarthy P, Tripp JH, Orme RLE. Plasma concentrations after oral or intramuscular vitamin K1 in neonates. Arch Dis Child 1985;60:814-8.33. Loughnan PM, McDougall PN. Does intramuscular vitamin K1 act as an unintended depot preparation? Paediatr 1996;32:251-4.34. World Bank. World Development Report 1993. Investing in Health. New York, NY : Oxford University Press Inc; 1993.

Risk Factors of Acquired Prothrombin Complex Deficiency Syndrome: A Case-Control StudyBoonchian Pansatiankul MD*, Sutthichai Jitapunkul MD*** Queen Sirikit National Institute of Child Health, Department of Medical Services; MOPH, College of Medicine, Rangsit University, Bangkok ** Department of Medicine, Faculty of Medicine, Chulalongkorn University, BangkokBackground: Idiopathic vitamin K deficiency in infancy or acquired prothrombin complex deficiency (APCD) is a serious bleeding disorders in infants. It leads to a high mortality rate and permanent neurological sequele among the survivors. A low vitamin K intake by infants is suggested to have a major role in the pathogenesis. To reduce the incidence of this syndrome, its risk factors have to be identified.Objective: To determine the risk factors of the acquired prothrombin complex deficiency syndrome in the early infantile period. Material and Method: A case-control study was conducted in 20 cases and 60 age- and sex-matched controls who were admitted to the Queen Sirikit National Institute of Child

Health in Bangkok during August 1991 to August 1993. Feeding type, maternal history of herb-liquor extracts (herbal medicine) use and no history of vitamin K1 prophylactics at birth were identified to be risk factors of the syndrome. All subjects were fed by breast milk with or without formula milk. None of the subjects fed by formula milk were in the case group (Chi- square for trend = 14.77, p = 0.001).Rusults: The rate of a maternal history of herb-liquor extracts use in the case group was significantly higher than that of the control group (p = 0.03). Vitamin K2MK4 level in breast milk obtained from the mothers of the infants with maternal history of herb-liquor extracts use was lower than that obtained from the mothers of the infants without maternal history of herb-liquor extracts use (p = 0.03). No infant with history of intramuscular K1 prophylactics was in the case group. Three out of eight infants with history of oral vitamin K1 regimen were cases. Although vitamin K1 and K2MK4 level in breast milk obtained from the cases’ mothers were significantly lower than that obtained from the controls’ mothers (p = 0.015 and p = 0.003 respectively), there was an overlapping of vitamin K levels among these two groups.Conclusion: This study demonstrated that vitamin K in breast milk has a main role in the pathogenesis of this disease. Herb-liquor extracts may be a cause of the APCD syndrome. Intramuscular vitamin K1 prophylactics should be routinely given to all newborn babies who will receive breast feeding. Effectiveness of oral vitamin K1 prophylactics regimen must be studied urgently.Keywords: Acquired prothrombin complex deficiency syndrome, Vitamin K, Risk factors, ThailandJ Med Assoc Thai 2008; 91 (Suppl 3): S1-8 Full text. e-Journal: http://www.medassocthai.org/journal

Idiopathic vitamin K deficiency in infancy or acquired prothrombin complex deficiency (APCD) syndrome is a serious bleeding disorder in the early infantile period that was first described in 1966(1). Since 1966, this bleeding disorder has been reported from many parts of the world including North America, Europe, Australia and Asia(2-20). The majority of the cases reported in literature have been in Japan and Thailand. The APCD syndrome is one of the most serious diseases affecting infants. It leads to a high mortality rate and permanent neurological sequelae among the survivors(1-20). A high incidence of this syndrome in Thailand (35.5 per 100,000 live births) makes this disorder a public health problem for the nation(2).Available data at present suggests that a low vitamin K intake by infants is responsible for the disorder(21,22). However, some patients who had been given vitamin K prophylactics at birth were reported(3,7,16,17). Infant fed with breast milk that was found to have a much lower level of vitamin K than formula milk(8,23-26), had a higher risk of APCD syndrome(3-5,8,20,27). A high percentage of having a maternal history of herb-liquor extracts (herbal medicine) intake and diet restrictions among patients with APCD syndrome were reported from Thailand(2,3,5,20,28). Coumarin was found in some herb-liquor extracts and has been hypothesized as a possible causative factor in this disorder(5,28,29). However, coumarin could not be detected in plasma or breast milk obtained from mothers who took herb- liquor extracts(28).Although low vitamin K is considered to have a major role in the pathogenesis of the APCD syndrome, we know little about other factors involved in the pathogenesis. Moreover, to reduce the incidence of this syndrome, its risk factors have to be identified. Therefore, we conducted a case-control study to determine risk factors of the APCD syndrome among Thai infants admitted to the Queen Sirikit National Institute of Child Health in Bangkok.Material and MethodTwenty infants aged between 2 weeks and 3 months, who were admitted to the Queen Sirikit National Institute of Child Health from August 1991 to August 1993 and diagnosed as having acquired prothrombin complex deficiency syndrome (APCD), were recruited for the study. These cases were diagnosed as having APCD by evidence of having bleeding disorder, venous clotting time longer than 15 minutes(30), abnormal prothrombin time (PT) (31), abnormal partial thromboplastin time (PTT)(32), normal thrombin time (TT)(33), the low activities of factors II, VII, IX, X(34-36) and normal platelet number. Seasonal pattern of admission, clinical manifestation and outcome of these patients was collected. Coagulogram on admission including PT(31), PTT(32), TT(33) and the activities of factors II, VII, IX, X(34, 35) were studied. For each case, three infants who were admitted during the same period and were age- (+ 2 weeks) and sex- matched were recruited as controls. Subjects with any evidence of liver impairment, diarrhea for more than three days or having received antibiotics in the last seven days were excluded from the study.Information on the subjects and their mothers was obtained to identify risk factors of the APCD syndrome in this population including types of feeding (breast feeding only, breast plus formula milk

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feeding or formula milk feeding only), a history of vitamin K prophylactics, nutritional status of infants and their body weight, a history of blood transfusion, a history of drug use, a history of herb-liquor extracts intake by mothers, a history of maternal diet restriction, a history of abnormality during pregnancy and a family history of bleeding disorders.Breast milk samples, obtained from the mothers who were breast feeding the subjects, were deep frozen (below -20 Celsius), kept in a pack of dried ice and sent to the University of Occupational and Environmental Health in Japan for analysis. Vitamin K1, K2MK4 and K2MK7 levels in the milk were analyzed by the method reported by Shino(36).Chi-square test, Chi square for trend(37) and Student’s unpaired t-test were used for statistical analysis. Odds ratio and its 95% confidence intervals(38) of risk factors were calculated. SPSS-PC+ program was used for statistical analysis.ResultsTwenty cases and 60 age- and sex-matched controls were recruited. Mean age of cases and controls were 43.6 + 13.5 days (range 21-73) and 46.8 + 14.5 days (range 26-82) days respectively. Seventy percent of subjects were male. (Table 1) No seasonal variation of admitted cases was found (6, 7 and 7 cases were admitted in summer, rainy season and winter respectively). Common clinical manifestations on admission of these APCD cases were convulsion and drowsiness (95%), anemia (85%) and fever (50%). Nineteen cases (95%) had intracranial bleeding including subdural hematoma, intracerebral hemorrhage, intraventricular hemorrhage and subarachnoid hemorrhage. Two cases (10%) had gastrointestinal tract bleeding. Only 10% of the cases had cutaneous bleeding (skin and oral cavity) (45%) had completely recovered. Permanent neurological handicaps including hemiparesis, micro- cephaly, convulsive disorders, spasticity and hydro- cephalus were found in nine cases (45%). Two cases were intrahospital dead. Prothrombin time, partial thromboplastin time, thrombin time and the activities of factors II, VII, IX, X on admission were abnormal in cases only (Table 2). The cases had slightly lower weight on admission than the controls. Eleven cases (55%) and twenty-six controls (43%) were classified as having malnutrition. (Table 1) There was no evidence of malnutrition in all of the subjects’ mothers. There was no history of blood transfusion, history of abnormality during pregnancy or family history of bleeding disorders in all of the subjects. Common drugs used during pregnancy were paracetamol, vitamins and antihistamines. Apart from vitamin K1 prophylactics, 32% of cases and 28% of controls received some common cold remedies before admission. No evidence of medication, which could affect coagulation such as warfarin, phenytoin, phenobarbital or aspirin, was found.Cases had higher rate of maternal history of postpartum herb-liquor extracts intake than controls (Chi-square = 4.69, p = 0.03). The difference in a history of maternal diet restriction between cases and controls was not statistically significant. Seventy percent of cases (n =14) were fed by breast milk only, 30% (n = 6) by both breast and formula milk and none by formula milk only. Thirty percent of controls (n = 18) were fed by breast milk only, 25% (n = 15) by both breast and formula milk and 45% (n = 27) by formula milk only. Chi- square about trend and chi square for trend on types of feeding were 15.14 (p = 0.0005) and 14.77 (p < 0.001) respectively. Five cases (25%) had been given oral vitamin K1 at birth. None of the cases received intramuscular vitamin K1. Three cases (5%) and thirty-four infants (57%) in the control group received received oral and intramuscular vitamin K1 prophylactics at birth respectively. There was a statistically significant difference in the history of vitamin K1 prophylactics between the cases and controls (Chi-square = 21.58, p = 0.0000). Odds ratios and their 95% confidential interval of these factors are shown in Table 3.Vitamin K1 level in breast milk obtained from the mothers of cases and controls were 0.89 + 0.8 and 1.62 + 1.3 nanogram/mL respectively. Vitamin K2MK4 level in breast milk obtained from the mothers of cases and controls were 0.53 + 0.5 and 1.09 + 0.8 nanogram/ mL respectively. The difference of vitamin level between cases and controls was statistically significant (p = 0.015 for vitamin K1; p = 0.003 for vitamin K2MK4) (Table 1). Vitamin K2MK7 levels in all samples were lower than 0.1. Vitamin K2MK4 levels in breast milk obtained from subjects with a history of maternal herb-liquor extracts use were lower than those obtained from subjects without a history maternal herb-liquor extracts use (p = 0.03). There was no statistical difference in vitamin K1 levels among these two groups. There was no significant effect from maternal diet restriction on vitamin level in breast milk. When 1 and 0.5 nanograms per milliliter of vitamin K1 and K2MK4 level respectively were used as cut-off levels, the odds ratios for having APCD among those having low vitamin level were DiscussionInfants with APCD syndrome in the present study had typically clinical manifestations and out- comes(1-19). All of them had abnormal coagulogram which confirmed the diagnosis of the APCD syndrome. None of the controls had abnormal coagulogram (Table 2). Therefore, there were no misclassified cases in the present study.

This case-control study demonstrated some univariate factors including feeding type, vitamin K1 prophylactics, maternal history of herb-liquor extracts intake, vitamin K1 and vitamin K2MK4 level in breast milk. Feeding type is a strong risk factor suggested by the fact that none of the cases took formula milk. Moreover, linear trend of relation between types of feeding and disease is demonstrated by the chi square for trend analysis. It implies that the main cause of the disease should relate to breast milk.Although there were some infants in the case group who had a history of vitamin K1 prophylactics at birth, all of them received the oral regimen. Three out of five subjects who had been given oral vitamin K1 prophylactics were cases while none of subjects who had been given intramuscular regimen were. The oral regimen has been used in Thailand since 1984(39). Efficacy of this regimen was tested both in Thailand and aboard(39-43). However, there were reports of sixteen infants who had been given oral vitamin K1 prophylactics at birth and developed the APCD syndrome(44). Although there were reports of unrecognized bile duct paucity and liver diseases as causes of late vitamin K-deficiency bleeding after oral vitamin K prophylaxis(45,46), our study suggested an ineffectiveness of the oral route regimen. This might partly explain the finding of Pansatiankul BJ and colleague that the incidence of the APCD syndrome increasedsignificantly high (Table 3).after routine use of oral vitamin K1 prophylactic was implicated by the Ministry of Public Health of Thailand(19). Regurgitation of oral vitamin K1 solution after administration, improper storage or improper administration may be responsible factors in its ineffectiveness. Further study about effectiveness of the oral prophylactic regimen must be urgently done(47). Meanwhile, routine prophylactics by the intramuscular prophylactic regimen should be recommended. Findings from this study suggested that, at least, newborns who take breast milk (with or without formula milk) should be given prophylactics routinely.Use of herb-liquor extracts and restriction on diet during postpartum period are common practice in Thailand. It is believed that herb-liquor extracts are useful for the health of mothers during early postpartum period. There are reports about high prevalence of using herb-liquor extracts and diet restriction among mothers of infants with the APCD syndrome in Thailand(2-5). From this study, association of these two factors and the syndrome was demonstrated. This finding confirmed previous finding of Pansatiankul BJ and colleague(20). Vitamin K2MK4 levels in breast milk obtained from mothers who had used herb-liquor extracts were lower than vitamin K2MK4 levels in breast milk obtained from mothers who had not used herb-liquor extracts. Moreover, dicumarol, one of the coumarin anticoagulant, has been found in alcoholic herb elixirs(29). Thus, herb-liquor extracts may have a role in the pathogenesis of the disease. Coumarin, alcohol or other substances in herb-liquor extracts may affect the level of vitamin K2MK4 in breast milk(5). The responsible substance and the mechanism should be investigated further.The vitamin K2MK7 in all samples obtained either from cases or controls were lower than 0.1 suggests that it may not be a factor in pathogenesis. The vitamin K1 and K2MK4 levels in breast milk obtained from the mothers of the controls were significantly higher than that of cases. Infants who were only fed by formula milk, which contains much higher vitamin K than breast milk(48), were free from disease. This supports the key role of low vitamin K level in breast milk in pathogenesis of the APCD syndrome(49,50).ConclusionThe type of feeding, intramuscular vitamin K1 prophylactics, use of herb-liquor extracts and level of vitamin K (K1 and K2MK4) in breast milk are all factors relating to the APCD syndrome. Low levels of vitamin K1 and K2MK4 in breast milk are the key factor in the pathogenesis. Intramuscular vitamin K1 prophylactics should be recommended for routine use in the newborn who will be fed with breast milk instead of an oral regimen. Effectiveness of oral vitamin K1 prophylactics must be urgently studied. Herb-liquor extracts may have a role in the pathogenesis of this syndrome. Avoiding the use of these extracts may reduce the incidence of the APCD syndrome among Thai infants.AcknowledgementsWe are grateful to Dr. Akira Shirahata, Depart- ment of Pediatrics, University of Occupational and Environmental Health, Japan for their valuable co- operation. We also thank Associate Professor Dr. Somchai Jitapunkul and Mr. Preecha Vichitthammaros for their statistical analytical assistance.References1. Bhanchet P, Bhamarapravati N, Bukkavesa S, Tuchinda S. A new bleeding syndrome in Thai infants. Acquired prothrombin complex sufficiency. The XI Congress of the International Society of Haematology; Sydney, Australia, August 1966:20.2. Ungchusak K, Tishyadhigama S, Choprapawon C, Sawadiwutipong W, Varintarawat S. Incidence of idiopathic vitamin K deficiency in infants: a national, hospital based, survey in Thailand, 1983. J Med Assoc Thai 1988; 71: 417-21.

3. Pansationkul BJ, Ratnasiri B. Acquired prothrombin complex deficiency syndrome: 10 years experience at Children’s hospital. Bull Dept Med Serv 1992; 17: 485-92.4. Bhanchet P, Tuchinda S, Hathirat P, Visudhiphan P, Bhamaraphavati N, Bukkavesa S. A bleeding syndrome in infants due to acquired prothrombin complex deficiency: a survey of 93 affected infants. Clin Pediatr 1977; 16: 992-8.5. Mitrakul C, Tinakorn P, Rodpengsangkaha P. Spontaneous subdural hemorrhage in infants beyond the neonatal period. J Trop Pediatr Environ Child Health 1977; 23: 226-35.6. Chan MC, Boon WH. Late haemorrhagic disease of Singapore infants. J Singapore Paediatr Soc 1967; 9: 72-81.7. Chaou WT, Chou ML, Eitzman DV. Intracranial hemorrhage and vitamin K deficiency in early infancy. J Pediatr 1984; 105: 880-4.8. Motohara K, Matsukura M, Matsuda I, Iribe K, Ikeda T, Kondo Y, et al. Severe vitamin K deficiency in breast-fed infants. J Pediatr 1984; 105: 943-5.Lovric VA, Jones RF. The haemorrhagic syndrome of early childhood. Australas Ann Med 1967; 16: 173-5.10. Nammacher MA, Willemin M, Hartmann JR, Gaston LW. Vitamin K deficiency in infants beyond the neonatal period. J Pediatr 1970; 76: 549-54.11. Taj-Eldin S, al Nouri L, Fakri O. Haemorrhagic diathesis in children associated with vitamin K deficiency. J Clin Pathol 1967; 20: 252-6.12. Forbes D. Delayed presentation of haemorrhagic disease of the newborn. Med J Aust 1983; 2: 136-8. 13. Dremsek PA, Sacher M. Life-threatening hemorrhage caused by vitamin K deficiency in breast-fedinfants. Wien Klin Wochenschr 1987; 99: 314-6. 14. Deberdt P, Courpotin C, Papouin M, Lasfargues G. Acute anemia caused by hemoperitoneum disclos- ing hemorrhagic disease of the newborn. Arch FrPediatr 1988; 45: 47-8. 15. Behrmann BA, Chan WK, Finer NN. Resurgenceof hemorrhagic disease of the newborn: a report ofthree cases. CMAJ 1985; 133: 884-5. 16. Vitamin K deficiency causing infantile intracranial haemorrhage after the neonatal period. Lancet1983; 1: 1439-40. 17. Hanawa Y, Maki M, Murata B, Matsuyama E,Yamamoto Y, Nagao T, et al. The second nationwide survey in Japan of vitamin K deficiency in infancy. Eur J Pediatr 1988; 147: 472-7.18. Nakayama K, Ikeda I, Shirahata S, et al. Bleeding due to vitamin K deficiency. Iji-shimpo 1981; 2996: 22. (in Japanese)19. Pansatiankul BJ, Isranurug S, Ungchusak K, Thanasophon Y, Sunakorn P. Incidence of acquired prothrombin complex deficiency and the status of vitamin K administration in infants in Thailand. Bull Dept Med Serv 1989; 14: 761-70.20. Pansatiankul BJ, Ruengsuwan S, Lektrakul J. Risk factors of bleeding diathesis secondary to low prothrombin complex level in infants: a preliminary report. Southeast Asian J Trop Med Public Health 1993; 24(Suppl 1): 121-6.21. Bhanchet-Isarangkura P. The pathogenesis of acquired prothrombin complex deficiency syndrome (APCD syndrome) in infants. Southeast Asian J Trop Med Public Health 1979; 10: 350-2.22. Isarangkura PB. Idiopathic vitamin K deficiency in infancy (acquired prothrombin complex deficiency syndrome). J Pediatr Obstet Gynaecol 1984; 10: 5-11.23. Haroon Y, Shearer MJ, Rahim S, Gunn WG, McEnery G, Barkhan P. The content of phylloquinone (vitamin K1) in human milk, cows’ milk and infant formula foods determined by high-performance liquid chromatography. J Nutr 1982; 112: 1105-17. Fournier B, Sann L, Guillaumont M, Leclercq M. Variations of phylloquinone concentration in human milk at various stages of lactation and in cow’s milk at various seasons. Am J Clin Nutr 1987; 45: 551-8.Canfield LM, Martin GS, Sugimoto K. Vitamin K in human milk. In: Suttie JW, editor. Current advances in vitamin K research. New York: Elsevier; 1988: 499-504.von Kries R, Shearer M, McCarthy PT, Haug M, Harzer G, Gobel U. Vitamin K1 content of maternal milk: influence of the stage of lactation, lipid composition, and vitamin K1 supplements given to the mother. Pediatr Res 1987; 22: 513-7. Isarangkura PB, Mahadandana C, Panstienkul B, Nakayama K, Tsijkimoto I, Yamamoto Y, et al. Vitamin K level in maternal breast milk of infants with acquired prothrombin complex deficiency syndrome. Southeast Asian J Trop Med Public Health 1983; 14: 275-6.Santawanpas S, Bhanchet-Isarangkura P, Tontisirin K, Mahasandana C. The possibility of the native alcoholic drugs as etiological factor of the acquired prothrombin complex deficiency syndrome. Southeast Asian J Trop Med Public Health 1980; 11: 367-70.

Pansatiankul BJ, Mekmanee R. Dicumarol content in alcoholic herb elixirs: one of the factors at risk induced IVKD-I. Southeast Asian J Trop Med Public Health 1993; 24 Suppl 1: 201-3.Lee RI, White PD. A clinical study of the coagulation time of blood. Am J Med Sci 1913; 145: 503. Tocantins LM. Estimation of prothrombin by the one stage method of Quick. In: Tocantins LM, editor. The coagulation of blood. New York: Grune and Stratton; 1955: 98-100.Proctor RR, Rapaport SI. The partial thromboplastin time with kaolin: a simple screening test for first stage plasma clotting factor deficiencies. Am J Clin Path 1961; 36: 212-9.Jim RTS. A case study of the plasma thrombin time. J Lab Clin Med 1975; 50: 45-60. Bachman F, Duckert F, Koller F. The Stuart-Prower assay and its clinical significance. Diath Haemorrh 1958; 2: 24-38.Biggs R, Eveling J, Richard G. The assay of anti- haemophilic globulin activity. Br J Haematol 1955; 1: 20-6.36. Shino M. Determination of endogenous vitamin K (phylloquinone and menaquinone-n) in plasma by high-performance liquid chromatography using platinum oxide catalyst reduction and fluorescence detection. Analyst 1988; 113: 393-7.37. Bland M. An introduction to medical statistics. Oxford: Oxford Medical Publications; 1990: 248-51.38. Schlesselman JJ. Case-control studies: design, conduct, analysis. New York: Oxford University Press; 1982.39. Isarangkura PB, Bintadish P, Tejavej A, Siripoonya P, Chulajata R, Green GM, et al. Vitamin K prophylaxis in the neonate by the oral route and its significance in reducing infant mortality and morbidity. J Med Assoc Thai 1986; 69(Suppl 2): 56-61.40. Motohara K, Endo F, Matsuda I. Vitamin K deficiency in breast-fed infants at one month of age. J Pediatr Gastroenterol Nutr 1986; 5: 931-3.41. O’Connor ME, Addiego JE Jr. Use of oral vitamin K1 to prevent hemorrhagic disease of the newborn infant. J Pediatr 1986; 108: 616-9.42. von Kries R, Kreppel S, Becker A, Tangermann R, Gobel U. Acarboxyprothrombin concentration [corrected] after oral prophylactic vitamin K. Arch Dis Child 1987; 62: 938-40.43. McNinch AW, Upton C, Samuels M, Shearer MJ, McCarthy P, Tripp JH, et al. Plasma concentrations after oral or intramuscular vitamin K1 inneonates. Arch Dis Child 1985; 60: 814-8. 44. Chuansumrit A, Mahasandana C. Situation of acquired prothronbin complex deficiency in Thailand.Bangkok: Chaicharoen LTD.; 1990: 13. (in Thai) 45. Humpl T, Bruhl K, Brzezinska R, Hafner G, Coerdt W, Shearer MJ. Fatal late vitamin K-deficiency bleeding after oral vitamin K prophylaxis secondary to unrecognized bile duct paucity. JPediatr Gastroenterol Nutr 1999; 29: 594-7. 46. Wariyar U, Hilton S, Pagan J, Tin W, Hey E. Six years’ experience of prophylactic oral vitamin K. Arch Dis Child Fetal Neonatal Ed 2000; 82: F64-8. 47. von Kries R. Oral versus intramuscular phytome- nadione: safety and efficacy compared. Drug Saf1999; 21: 1-6. 48. Haroon Y, Shearer MJ, Rahim S, Gunn WG, McEneryG, Barkhan P. The content of phylloquinone (vitamin K1) in human milk, cows’ milk and infant formula foods determined by high-performance liquid chromatography. J Nutr 1982; 112: 1105-17.49. Shearer MJ, Rahim S, Barkhan P, Stimmler L. Plasma vitamin K1 in mothers and their newborn babies. Lancet 1982; 2: 460-3.50. Greer FR, Marshall S, Cherry J, Suttie JW. Vitamin K status of lactating mothers, human milk, and breast-feeding infants. Pediatrics 1991; 88: 751-6.

Intracranial hemorrhage in hemorrhagic disease of the newbornIrawan Mangunatmadja, MD; Rina W Sundariningrum, MD; Hardiono D Pusponegoro, MD; Endang Windiastuti, MDABSTRACT

Background Hemorrhagic disease of the newborn (HDN) represents a special case of vitamin K deficiency because the four vitamin K-coagulation factors (factors II,VII,IX,X) are already at physiologically low levels in the newborn. It responds to vitamin K therapy.

Objective The aim of this study was to review the incidence, clinical manifestation, and outcome of HDN.

Methods This was a retrospective cross sectional study on 22 patients hospitalized for HDN in the Department of Child Health, Cipto Mangunkusumo Hospital from January 1997 until Decem- ber 2001. Data were obtained from medical records.Results The commonest age group (17 out of 22) was 1–3 month- old. Normal delivery was found in 19 patients and only 3 patients received prophylaxis vitamin K. Almost all of them (20 out of 22) were exclusively breastfed. Seizure, pallor, decreased consciousness, and bulging of the anterior fontanel were significant clinical manifestations found in 21, 21, 13, and 9 patients respectively. Based on brain USG and/or CT scan, intracranial hemorrhage was found in 19 patients. Six out of 22 patients died and 7 patients survived with handicapConclusion Intracranial hemorrhage due to vitamin K mostly oc- curred at the age of 1 to 3 month-old. The commonest clinical manifestations were seizure, pallor, decreased consciousness, and bulging of the anterior fontanel. Prevention by giving vitamin K routinely to all newborn babies is recommended [Paediatr Indones 2003;43:82-84].

Hemorrhagic disease of the newborn (HDN) represents a special case of vitamin K

deficiency because the four vitamin K-coagulation factors (factors II,VII,IX,X) are already at physiologically low levels in the newborn.1 HDN is classified 1-3 into: (1) early HDN which is confined to the first 24 hours of life; (2) classical HDN which occurs in the first 2 weeks of life; (3) late HDN which is observed predominantly in infants aged 2 weeks to 6 months, and (4) secondary vitamin K deficiency that occurs in the presence of underlying diseases such as liver disease, chronic diarrhea, and biliary atresia.Late onset disease also known as acquired prothrombin complex deficiency (APCD) is associated with high incidence of central nervous system hemorrhage and mortality.1,2

Exclusive breast-feeding without vitamin K supplementation and failure to administer parenteral vitamin K at birth appear to be at least contributing factors in classic and late disease.1 The aim of this study was to review the incidence, clinical manifestations of HDN, and the outcome of the patients.MethodsThis was a retrospective cross sectional study done by reviewing the medical records of vitamin K deficiency bleeding in infants without history of head trauma who were hospitalized in the Department of Child Health, Cipto Mangunkusumo Hospital from January 1997 until December 2001. Diagnosis of HDN was based on bleeding symptoms with an acquired prolongation of the PT and PTT.1 The data of age, gender, clinical manifestations, peripheral blood examinations, PT, PTT, brain ultrasonography and /or CT scan, management, and outcome were collected.ResultsDuring the period of January 1997 until December 2001 there were 22 patients with age ranged from 1 month–9 months consisting of 12 males and 10 females. There were 20 patients of late HDN and 2 patients of secondary vitamin K deficiency. The commonest age group (17 out of 22) was 1–3 month- old. Most patients (19 out of 22) had gestational age of 37–42 weeks. Normal delivery was found in 19 patients and only 3 patients received vitamin K prophylaxis. Almost all of them (20 out of 22) were exclusively breastfed (Table 1).

Seizure, pallor, decreased consciousness, and bulging of the anterior fontanel were significant clinical manifestations found in 21, 21, 13 and 9 patients respectively. Most of patients had hemoglobin level <10 g/ dl (17 out of 22 patients). Based on brain USG and/or CT scan, intracranial hemorrhage (ICH) was found in 16 patients. Six out of 22 patients died and 7 patients survived with handicap (Table 2).

DiscussionThe commonest classification of HDN found in this study was late HDN (20 out of 22 patients), which was comparable with the commonest age group of 1– 3 month-old (17 out of 22). Late HDN is observed mostly in infants with age of 1-3 months during which breast milk

is the main source of food.1Most patients (19 out of 22) had gestational age of 37-42 weeks. Normal delivery was found in 19 out of 22 patients, but only 3 patients received vitamin K prophylaxis. Almost all of them (20 out of 22) were exclusively breastfed. The vitamin K content in breast milk is very low (2.5 mg/L), only one-tenth from that in formula milk (33 mg/L).2 Newborns require 0.3 mg/ kg/day or 1 mg/day of vitamin K and take about 500 ml of milk daily. Thus, the amount of vitamin K in breast milk may be insufficient to meet daily require- ments, particularly from mothers with low milk se- cretion.2The presenting symptoms and signs of ICH were seizure, focal neurologic signs, or evidence of increased intracranial pressure (ICP).4 Seizure, pallor, decreased consciousness, and bulging of the anterior fontanel were significant clinical manifestations found in 21, 21, 13, and 9 patients respectively. These symptoms were considered of ICH. This condition was supported by brain USG or CT scan that showed ICH in 16 patients. The definitive diagnosis of ICH is achieved by non-contrast CT Scan.5The management of all patients with anemia and prolongation of the PT and PTT were packed red cell transfusion, fresh frozen plasma, and vitamin K3 1 mg IM for 3 days. Vitamin K3 (menadione) is a synthetic compound with properties similar to those of vitamin K1. 6 The correction of prolonged PT can be achieved by the use of intravenous vitamin K1

(5–25 mg), but the need for immediate nor- malization of this parameter often requires the use of fresh-frozen plasma (10-20 mL/kg) or prothrombin complex concentrate.5

To decrease intracranial pressure due to intracranial hemorrhage, dexamethasone intravenous was given with or without furosemide intravenous or mannitol drip. Osmotic diuretics, particularly mannitol, are most helpful for the control of elevated ICP. It was given in a dose of 0.75–1 g/kg, followed by 0.25-0.50 g/kg every 3-5 hour. This effect can be enhanced by the concomitant use of loop diuretics (furosemide).5 Corticosteroids are controversial in the management of increased ICP owing to ICH.5

In this study, the incidence of ICH was 16 out of 22. Mortality rate was high, 6 out of 22 patients and 7 patients survived with handicap. In late HDN, the incidence of intracranial bleeding is strikingly high (80%) which results in high mortality rate (10-50%) and neurological sequaele (30-50%).2 In this study, only 3 out of 22 patients received vitamin K prophylaxis. The American Academy of Pediatrics recommended a routine administration of vitamin K prophylaxis (2 mg orally or 1 mg intramuscularly) to all newborn babies.2,7

In conclusion, ICH due to vitamin K deficiency most often occurs at the age of 1 to 3 months old with seizure, pallor, decreased consciousness, and bulging of the anterior fontanel as the commonest symptoms. We recommended prevention for this condition by giving of vitamin K routinely to all newborn babies.References1. Casella JF, Pelidis MA. Disorders of coagulation factors. In: McMillan JA, DeAngelis CD, Feigen RD, Warshaw JB, editors. Oski’s pediatrics: principle and practice. 3rd ed. Philadelphia: Lippincott Williams &Wilkins; 1999. p. 1481-90.2. Isarangkura PB. Vitamin K prophylaxis in newborn babies. J Paediatr Obstet Gynecol 1991;17:5-9.3. Chuansumrit A, Isarangkura PB, Hathirat P. Vita- min K deficiency bleeding in Thailand: a 32-year history. Southeast Asian J Trop Med Pub Hlth 1998;29:649-54.4. Komberg AJ, Prensky AL. Cerebrovascular disease. In: McMillan JA, DeAngelis CD, Feigen RD, Warshaw JB, editors. Oski’s pediatrics: principle and practice. 3rd ed. Philadelphia: Lippincott Williams &Wilkins; 1999. p. 1928-36.5. Steig PE, Kase CS. Intracranial hemorrhage: diagnosis and emergency management. Neurol Clin 1998;16:373-90.6. Frank J, Aswal S. Neurologic disorders associated with gastrointestinal diseases, nutritional deficiencies, and fluid-electrolyte disorders. In: Swiman KE, Ashwal S, editors. Pediatric neurology: principles & practice. 3rd ed. St Louis: Mosby; 1999. p. 1438-69.7. Vitamin K Ad Hoc Task Force. American Academy of Pediatrics. Controversies concerning vitamin K and the newborn. Pediatrics 1993;91:1001-3.

PERDARAHAN YANG TERJADI AKIBATDEFISIENSI KOMPLEKS PROTROMBIN (Bleeding Caused by Acquired Prothrombin Complex Deficiency) Bambang P, Mia RA, IDG Ugrasena Divisi Hematologi Onkologi Bagian Ilmu Kesehatan Anak RSU Dr.Soetomo FK UNAIR SurabayaKorespondensi:Prof. Dr. Bambang P, dr, SpA(K) Divisi Hematologi Onkologi Bagian Ilmu Kesehatan Anak FK Unair RSU Dr. Soetomo Jl. Mayjen Prof. Moestopo 6-8 Surabaya Telp 031-5501681, 031-5501693 Fax 031-5501748 E mail: [email protected] composed of 4 phase, vascular, platelet, plasma and fibrinolysis phase. Disturbance of one phase will lead to coagulation disorders with bleeding manifestation, eg. Prothrombin complex deficiency (factor II, VII, IX and X). Prothrombin complex deficiency can be due to vitamin K deficiency dan liver disease. Incidence of Vitamin K deficiency bleeding (VKDB) account 1 in 200 – 400 birth in neonates without vitamin K prophylaxis.Risk factors of VKDB are mother’s drug (eg. anticonvulsant, antibiotic, antituberculostatic), low vitamin K producing bacteria from GIT, low vitamin K intake, liver disorder and malabsorbsion syndrome. VKDB can be classified into 4 type: early VKDB, classic VKDB, late VKDB or acquired prothrombin complex deficiency (APCD) and Secondary prothrombin complex (PC) deficiency. To prevent VKDB, vitamin K1 prophylaxis is needed to all newborn babies per orally or intramuscularly. Vitamin K1 and fresh frozen plasma (FFP) may be indicated in the management of VKDB. Coagulation disorder in liver disease can be caused by coagulation protein synthesis disturbance, include protein induced by vitamin K. Primary management of this disorder is for the liver disease. FFP, cryoprecipitate and prothrombin complex consentrate (consist of factor II,VII,IX and X) may be considered in special condition. Keywords : Prothrombin complex deficiency, vitamin K deficiency, liver disease.AbstrakProses hemostasis terdiri dari fase vaskular, fase trombosit, fase plasma dan fase fibrinolisis. Apabila salah satu fase ini terganggu maka timbul gangguan hemostasis dengan manifestasi klinis perdarahan, misalnya pada defisiensi kompleks protrombin (faktor II,VII, IX dan X). Defisiensi kompleks protrombin dapat disebabkan oleh defisiensi vitamin K dan penyakit hati. Angka kejadian gangguan koagulasi pada defisiensi vitamin K (dikenal sebagai VKDB) berkisar antara 1:200 sampai 1:400 kelahiran bayi yang tidak mendapat profilaksis vitamin K. Faktor resiko timbulnya VKDB adalah obat yang diminum ibu hamil (antikonvulsan, antibiotika, antituberkulostatik, antikoagulan), kurangnya sintesis vitamin K oleh bakteri usus, kurangnya asupan vitamin K, gangguan fungsi hati serta sindroma malabsorbsi. VKDB dibagi menjadi 4 yaitu VKDB dini, VKDB klasik, VKDB lambat atau acquired prothrombin complex deficiency (APCD) dan defisiensi kompleks protrombin sekunder. Pencegahan VKDB dilakukan dengan pemberian profilaksis vitamin K1 pada semua bayi baru lahir baik secara per oral maupun intramuskular. Penatalaksanaan penderita VKDB meliputi pemberian vitamin K1 dan fresh frozen plasma (FFP). Gangguan koagulasi pada penyakit hati disebabkan oleh gangguan sintesis protein faktor koagulasi, termasuk protein yang tergantung vitamin K. Penatalaksanaan utama adalah untuk penyakit primer yang mendasarinya, sedangkan pemberian FFP, Kriopresipitat dan konsentrat kompleks protrombin yang mengandung faktor II, VII, IX dan X dapat dipertimbangkan pada kondisi tertentu. Kata

kunci : defisiensi kompleks protrombin, defisiensi vitamin K, penyakit hati PENDAHULUANProses hemostasis merupakan mekanisme yang kompleks, terdiri dari empat fase yaitu fase vaskular (terjadi reaksi lokal pembuluh darah), fase trombosit (timbul aktifitas trombosit), fase plasma (terjadi interaksi beberapa faktor koagulasi spesifik yang beredar di dalam darah) dan fase fibrinolisis (proses lisis bekuan darah). Bila salah satu dari keempat proses ini terganggu, maka akan timbul gangguan pada proses hemostasis yang manifestasi klinisnya adalah perdarahan.1,2

Gangguan pada proses pembekuan darah, dapat berupa kelainan yang diturunkan secara genetik atau kelainan yang didapat. Gangguan pembekuan yang didapat bisa disebabkan oleh adanya gangguan faktor koagulasi karena kekurangan faktor pembekuan yang tergantung vitamin K, penyakit hati, percepatan penghancuran faktor koagulasi dan inhibitor koagulasi.1-3 Salah satu diantaranya adalah defisiensi kompleks protrombin yaitu kekurangan faktor-faktor koagulasi faktor II, VII, IX dan X.1,3,4

PROSES KOAGULASIProses koagulasi atau kaskade pembekuan darah terdiri dari jalur intrinsik dan jalur ekstrinsik. Jalur intrinsik dimulai saat darah mengenai permukaan sel endotelial, sedangkan jalur ekstrinsik dimulai dengan pelepasan tissue factor (Faktor III) pada tempat terjadinya luka.1Jalur pembekuan darah intrinsik memerlukan faktor VIII, IX, X, XI dan XII, dibantu dengan protein prekalikrein, high-molecular weight kininogen (HMWK), ion kalsium dan fosfolipid dari trombosit. Jalur ini dimulai ketika prekalikrein, HMWK, faktor XI dan faktor XII bersentuhan dengan permukaan sel endotelial, yang disebut dengan fase kontak. Adanya fase kontak ini menyebabkan konversi dari prekalikrein menjadi kalikrein, yang kemudian mengaktifkan faktor XII menjadi faktor XIIa. Faktor XIIa memacu proses pembekuan melalui aktivasi faktor XI, IX, X dan II (protrombin) secara berurutan (Gambar 1).1,5

Aktifasi faktor Xa memerlukan bantuan dari tenase complex, terdiri dari ion Ca, faktor VIIIa, IXa dan X, yang terdapat pada permukaan sel trombosit. Faktor VIIIa pada proses koagulasi bersifat seperti reseptor terhadap faktor IXa dan X. Aktifasi faktor VIII menjadi faktor VIIIa dipicu oleh terbentuknya trombin, akan tetapi makin tinggi kadar trombin, malah akan memecah faktor VIIIa menjadi bentuk inaktif.1,5

Jalur ekstrinsik dimulai pada tempat terjadinya luka dengan melepaskan tissue factor (TF). TF merupakan suatu lipoprotein yang terdapat pada permukaan sel, adanya kontak dengan plasma akan memulai terjadinya proses koagulasi. TF akan berikatan dengan faktor VIIa akan mempercepat aktifasi faktor X menjadi faktor Xa sama seperti proses pada jalur intrinsik. Aktifasi faktor VII terjadi melalui kerja dari trombin dan faktor Xa. Faktor VIIa dan TF ternyata juga mampu mengaktifkan faktor IX, sehingga membentuk hubungan antara jalur ekstrinsik dan intrinsik.1,5

Selanjutnya faktor Xa akan mengaktifkan protombin (faktor II) menjadi trombin (faktor IIa). Trombin akan mengubah fibrinogen menjadi fibrin monomer dengan bantuan kompleks protrombinase yang terdiri dari fosfolipid sel trombosit, ion Ca, faktor V dan Xa. Faktor V merupakan kofaktor dalam pembentukan kompleks protrombinase. Seperti faktor VIII, Faktor V teraktifasi menjadi faktor Va dipicu oleh adanya trombin. Selain itu trombin juga mengubah faktor XIII menjadi faktor XIIIa yang akan membantu pembentukan cross-linked fibrin polymer yang lebih kuat.1,3,5

PERKEMBANGAN HEMOSTASIS SELAMA MASA ANAK

Sistem koagulasi pada neonatus masih imatur sehingga pada saat lahir kadar protein koagulasi lebih rendah. Kadar dari sistem prokoagulasi seperti protein prekalikrein, HMWK, faktor V, XI dan XII serta faktor koagulasi yang tergantung vitamin K (II, VII, IX, X) pada bayi cukup bulan lebih rendah 15 – 20% dibandingkan dewasa dan lebih rendah lagi pada bayi kurang bulan. Kadar inhibitor koagulasi seperti antitrombin, protein C dan S juga lebih rendah 50% dari normal. Sedangkan kadar faktor VIII, faktor von Willebrand dan fibrinogen setara dengan dewasa.2,6

Kadar protein prokoagulasi ini secara bertahap akan meningkat dan dapat mencapai kadar yang sama dengan dewasa pada usia 6 bulan. Kadar faktor koagulasi yang tergantung vitamin K berangsur kembali ke normal pada usia 7-10 hari. Cadangan vitamin K pada bayi baru lahir rendah mungkin disebabkan oleh kurangnya vitamin K ibu serta tidak adanya cadangan flora normal usus yang mampu mensintesis vitamin K.2,6,8

Selain itu kadar inhibitor koagulasi juga meningkat dalam 3 – 6 bulan pertama kehidupan kecuali protein C yang masih rendah sampai usia belasan tahun.2 Meskipun kadar beberapa protein koagulasi lebih rendah, pemeriksaan prothrombin time (PT) dan activated partial thromboplastin time (aPTT) tidak jauh berbeda dibandingkan dengan anak dan dewasa. Namun didapatkan pemanjangan pemeriksaan bleeding time terutama pada usia < 10 tahun, sehingga interpretasi hasil pemeriksaan laboratorium harus dilakukan secara hati-hati.2,6

Secara umum gangguan pembekuan darah masa anak disebabkan oleh beberapa keadaan seperti pada tabel 1.

DEFISIENSI VITAMIN KVitamin K merupakan salah satu vitamin larut dalam lemak, yang diperlukan dalam sintesis protein tergantung vitamin K (Vitamin K – dependent protein ) atau GIa. Vitamin K diperlukan sintesis prokoagulan faktor II, VII, IX dan X (kompleks protrombin) serta protein C dan S yang berperan sebagai antikoagulan (menghambat proses pembekuan). Molekul-molekul faktor II, VII, IX dan X pertama kali disintesis dalam sel hati dan disimpan dalam bentuk prekursor tidak aktif. Vitamin K diperlukan untuk konversi prekursor tidak aktif menjadi faktor pembekuan yang aktif.2,10

Kekurangan vitamin K dapat menimbulkan gangguan dari proses koagulasi sehingga menyebabkan kecenderungan terjadinya perdarahan atau dikenal dengan Vitamin K Deficiency Bleeding (VKDB).6,10-12

Gambar 2 menunjukkan terjadinya fase karbosilaksi dalam siklus metabolisme vitamin K. Pada kondisi defisiensi vitamin K, rantai polipeptida dari faktor koagulasitergantung vitamin K tetap terbentuk normal, namun fase karboksilasi (proses gamma karboksilasi dari amino terminal glutamic acid) tidak terjadi. Sehingga bentuk akarboksi dari faktor II, VII, IX dan X tidak mampu berikatan dengan ion kalsium dan tidak dapat berubah menjadi bentuk aktif yang diperlukan dalam proses koagulasi.10,12-14

Angka kejadian VKDB berkisar antara 1:200 sampai 1:400 kelahiran bayi yangtidak mendapat vitamin K profilaksis. Di Amerika Serikat, frekuensi VKDB dilaporkan bervariasi antara 0,25-1,5% pada tahun 1961, dan menurun menjadi 0-0,44% pada 10 tahun terakhir dengan adanya program pemberian profilaksis vitamin K.7,13,15 Di Jepang, insidens VKDB mencapai 20 – 25 per 100.000 kelahiran.16

Danielsson pada tahun 2004 melaporkan bahwa insidens VKDB di Hanoi Vietnam sangat tinggi, sebesar 116 per 100.000 kelahiran.17 Angka kematian akibat VKDB di Asia mencapai 1:1200 sampai 1:1400 kelahiran.2,18 Angka kejadian tersebut ditemukan lebih tinggi, mencapai 1:500 kelahiran, di daerah-daerah yang tidak

memberikan profilaksis vitamin K secara rutin pada bayi baru lahir.3

Di Indonesia, data mengenai VKDB secara nasional belum tersedia. Hingga tahun 2004 didapatkan 21 kasus di RSCM Jakarta, 6 kasus di RS Dr Sardjito Yogyakarta dan 8 kasus di RSU Dr Soetomo Surabaya.18

Faktor resiko yang dapat menyebabkan timbulnya VKDB antara lain obat-obatan yang mengganggu metabolisme vitamin K, yang diminum ibu selama kehamilan, seperti antikonvulsan (karbamasepin, fenitoin, fenobarbital), antibiotika (sefalosporin), antituberkulostatik (INH, rifampicin) dan antikoagulan (warfarin). Faktor resiko lain adalah kurangnya sintesis vitamin K oleh bakteri usus karena pemakaian antibiotika berlebihan, gangguan fungsi hati (kolestasis), kurangnya asupan vitamin K pada bayi yang mendapatkan ASI eksklusif, serta malabsorbsi vitamin K akibat kelainan usus maupun akibat diare.2,7,10,16

Kadar vitamin K pada ASI < 5 mg/ml, jauh lebih rendah dibandingkan dengan susu formula yaitu sekitar 50 - 60 mg/ml. Selain itu pada usus bayi yang mendapat susu formula, mengandung bakteri bacteriodes fragilis yang mampu memproduksi vitamin K. Sedangkan pada bayi dengan ASI eksklusif, ususnya mengandung bakteri Lactobacillus yang tidak dapat memproduksi vitamin K.11

Tabel 2 menunjukkan klasifikasi VKDB pada anak berdasarkan etiologi dan onset terjadinya menjadi 4 kelompok yaitu VKDB dini, VKDB klasik, VKDB lambat atau acquired prothrombin complex deficiency (APCD) dan Secondary prothrombin complex (PC) deficiency.Pendekatan diagnosis VKDB melalui anamnesis, pemeriksaan fisik dan laboratorium. Anamnesis dilakukan untuk mencari informasi tentang onset perdarahan, lokasi perdarahan, pola pemberian makanan, serta riwayat pemberian obat-obatan pada ibu selama kehamilan. Pemeriksaan fisik ditujukan untuk melihat keadaan umum bayi dan lokasi perdarahan pada tempat-tempat tertentu seperti GIT, umbilikus, hidung, bekas sirkumsisi dan lain sebagainya.2,7

Pemeriksaan laboratorium menunjukkan penurunan aktifitas faktor II, VII, IX, dan X sedangkan faktor koagulasi lain normal sesuai dengan usia. Terdapat pemanjangan waktu pembekuan, Prothrombin Time (PT) dan Partial Thromboplastin Time (PTT), sedangkan Thrombin Time (TT) dan masa perdarahan normal. Pemeriksaan lain seperti USG, CT Scan atau MRI dapat dilakukan untuk melihat lokasi perdarahan misalnya jika dicurigai adanya perdarahan intrakranial. Selain itu respon yang baik terhadap pemberian vitamin K memperkuat diagnosis VKDB.3,7,8

VKDB harus dibedakan dengan gangguan hemostasis lain baik yang didapat maupun yang bersifat kongenital. Diantaranya gangguan fungsi hati juga dapat menyebabkan gangguan sintesis faktor-faktor pembekuan darah, sehingga memberikan manifestasi klinis perdarahan. Tabel dibawah memperlihatkan gambaran laboratorium kedua kelainan tersebut.8Penatalaksanaan VKDB terdiri dari penatalaksanaan untuk pencegahan dan penatalaksaan untuk mengobati kelainan ini.Pencegahan VKDBDapat dilakukan dengan pemberian vitamin K Profilaksis. Ada tiga bentuk vitamin K, yaitu :1. Vitamin K1 (phylloquinone), terdapat dalam sayuran hijau 2. Vitamin K2 (menaquinone), disintesis oleh flora usus normal 3. Vitamin K3 (menadione), vitamin K sintetis yang sekarang jarang diberikankarena dilaporkan dapat menyebabkan anemia hemolitik.2,6

Pemberian vitamin K per oral sama efektifnya dibandingkan pemberian intramuskular

dalam mencegah terjadinya VKDB klasik, namun tidak efektif dalam mencegah timbulnya VKDB lambat.2 Amerika Serikat merekomendasikan penggunaan phytonadione, suatu sintesis analog vitamin K1 yang larut dalam lemak, diberikan secara i.m.13 Thailand sejak tahun 1988 merekomendasikan pemberian vitamin K 2 mg per oral untuk bayi normal dan 0,5 – 1 mg i.m untuk bayi prematur atau tidak sehat. Ternyata mampu menurunkan angka kejadian VKDB dari 30 – 70 menjadi 4 – 7 per 100.000 kelahiran. Sejak tahun 1999 Vitamin K 1 mg i.m harus diberikan pada semua bayi baru lahir dan diberikan bersama imunisasi rutin.11

Kanada sejak tahun 1997 merekomendasikan pemberian vitamin K1 intramuskular 0,5 mg (untuk bayi < 1500 g) dan 1 mg (untuk bayi > 1500 g) diberikan dalam waktu 6 jam setelah lahir. Untuk orang tua yang menolak pemberian secara i.m, vitamin K1 diberikan per oral dengan dosis 2 mg segera setelah minum, diulang pada usia 2 – 4 minggu dan 6-8 minggu.20 AAP pada tahun 2003 merekomendasikan pemberian vitamin K pada semua bayi baru lahir dengan dosis tunggal 0,5 – 1 mg i.m.15

Departemen Kesehatan RI pada tahun 2003 mengajukan rekomendasi untuk pemberian vitamin K1 pada semua bayi baru lahir dengan dosis 1 mg i.m (dosis tunggal) atau secara per oral 3 kali @ 2 mg pada waktu bayi baru lahir, umur 3 – 7 hari dan umur 1 – 2 tahun.21

Untuk ibu hamil yang mendapat pengobatan antikonvulsan harus mendapat profilaksis vitamin K1 5 mg/hari selama trimester ketiga atau 10 mg i.m pada 24 jam sebelum melahirkan. Selanjutnya bayinya diberi vitamin K1 1 mg i.m dan diulang 24 jam kemudian.2,22

Meskipun ada penelitian yang melaporkan hubungan antara pemberian vitamin K i.m dengan meningkatnya angka kejadian kanker pada anak, namun penelitian terbaru yang dilakukan oleh McKinney pada tahun 1998 tidak membuktikan adanya peningkatan resiko terjadinya kanker pada anak yang mendapatkan profilaksis vitamin K i.m.7,23

Pengobatan defisiensi vitamin KBayi yang dicurigai mengalami VKDB harus segera mendapat pengobatan vitamin K1 dengan dosis 1 – 2 mg/hari selama 1 – 3 hari.2,11 Vitamin K1 tidak boleh diberikan secara intramuskular karena akan membentuk hematoma yang besar, sebaiknya pemberian dilakukan secara subkutan karena absorbsinya cepat. Pemberian secara intravena harus diperti.mbangkan dengan seksama karena dapat memberikan reaksi anafilaksis, meskipun jarang terjadi.2,6

Selain itu pemberian fresh frozen plasma (FFP) dapat dipertimbangkan pada bayi dengan perdarahan yang luas dengan dosis 10 – 15 ml/kg, mampu meningkatkan kadar faktor koagulasi tergantung vitamin K sampai 0,1 – 0,2 unit/ml.6,11,12,22 Respon pengobatan diharapkan terjadi dalam waktu 4 – 6 jam, ditandai dengan berhentinya perdarahan dan pemeriksaan faal hemostasis yang membaik. Pada bayi cukup bulan, jika tidak didapatkan perbaikan dalam 24 jam maka harus dipikirkan kelainan yang lain misalnya penyakit hati.2,12

Prognosis VKDB ringan pada umumnya baik, setelah mendapat vitamin K1 akan membaik dalam waktu 24 jam. Angka kematian pada VKDB dengan manifestasi perdarahan berat seperti intrakranial, intratorakal dan intraabdominal sangat tinggi. Pada perdarahan intrakranial angka kematian dapat mencapai 25% dan kecacatan permanen mencapai 50 – 65%.2,11,24

GANGGUAN KOAGULASI PADA PENYAKIT HATIMeskipun kelainan hati yang mendasari berbeda, patofisiologi terjadinya abnormalitas hemostasis pada penyakit hati hampir sama baik pada neonatus, anak maupun dewasa. Hati adalah organ yang penting untuk sintesis faktor-faktor koagulasi (fibrinogen,

prekalikrein, HMWK, II, V, VII, IX,X, XI, XII dan XIII), sintesis plasminogen, regulator koagulasi (antitrombin III, protein C dan S) dan inhibitor fibrinolisis. Hati juga berperan dalam pemecahan faktor – faktor koagulasi maupun fibrinolisis yang aktif dari sirkulasi. Gangguan fungsi hati dapat menyebabkan gangguan sintesis protein faktor koagulasi. Selain itu hati merupakan tempat reaksi karboksilasi post ribosom dari protein yang tergantung vitamin K sehingga pada gangguan fungsi hepar penggunaan vitamin K akan terganggu pula.6,12

Gangguan fungsi hati dapat disebabkan oleh imaturitas, infeksi, hipoksia, sindrom Reye, sirosis dan lain-lain.2Manifestasi perdarahan dan gambaran laboratorium tergantung pada berat ringannya kerusakan hati. Perdarahan spontan jarang terjadi, pada umumnya terjadi perdarahan di bawah kulit yang timbul akibat prosedur yang invasif. Pada sirosis hepatis dapat terjadi perdarahan dari gaster dan varises esofagus yang dapat mengancam jiwa.Pemeriksaan PT memanjang pertama kali dikarenakan kadar faktor VII menurun paling awal, jika kerusakan hepar terus berlanjut akan diikuti dengan pemanjangan PTT. 2,6,12

Penatalaksanaan utama adalah untuk penyakit primer yang mendasarinya. Penanganan abnormalitas koagulasi pada penyakit hati tergantung pada gejala klinis yang terjadi serta tempat timbulnya perdarahan (misalnya perdarahan GIT, perdarahan tempat bekas biopsi). FFP dapat diberikan dengan dosis 10 – 15 ml/kg berat badan karena mengandung semua faktor - faktor koagulasi yang dibutuhkan. Kriopresipitat 1 kantung / 5 kg berat badan diberikan untuk mengatasi hipofibrinogenemia. Pemberian konsentrat kompleks protrombin yang mengandung faktor II, VII, IX dan X dengan konsentrasi tinggi, dapat dipertimbangkan pada kondisi tertentu misalnya untuk persiapan biopsi hati atau pada keadaan dimana perdarahan sudah tidak dapat diatasi dengan terapi di atas.2,6,12

Pada penyakit hati juga terjadi defisiensi faktor – faktor koagulasi tergantung vitamin K, maka pemberian vitamin K mampu mengoreksi koagulopati yang terjadi. Vitamin K1 diberikan secara oral, subkutan atau intravena (tidak secara intramuskular) dengan dosis 1 mg (untuk bayi), 2 – 3 mg (untuk anak) dan 5 – 10 mg (untuk dewasa).2,6,12

Prognosis kelainan ini tergantung pada penyakit primer yang mendasarinya dan pemberian terapi yang adekuat dalam mengatasi perdarahannya.2,6

REFERENSI1. King MW. 2004. Blood Coagulation. Didapat dari : http://www.med.unibs.it/~marchesi/blood.html. (Diakses tanggal 8 Agustus 2004).2. Respati H, Reniarti L, Susanah S. Gangguan Pembekuan Darah. Didapat: Defisiensi Vitamin K. Dalam: Permono B, Sutaryo, Ugrasena IDG, Windiastuti E, Abdulsalam M, Eds. Buku Ajar Hematologi-onkologi Anak. Jakarta: Badan Penerbit IDAI, 2005:182-96.3. Hagstrom JN. 2003. Hypoprothrombinemia. Didapat dari: http://www.emedicine.com. (Diakses tanggal 10 Agustus 1005).4. Willoughby MLN. Pediatric Haematology. Edinburg: London, 1977:327-9.5. Anonym. 2004. Blood coagulation. Didapat dari: http://www.tollefsen.wustl.edu/projects/coagulation/coagulation.html. (Diakses tanggal 9 Agustus 2005).6. Chalmers EA, Gibson BE. Acquired disorders of hemostasis during childhood. Dalam: Lilleyman J, Hann I, Blanchette V, Eds. Pediatric Hematology. Edisi ke-2. London: Churchill Livingstone, 2000:629-49.7. Sutor AH, von Kries R, Cornelissen M, McNinch AW, Andrew M. Vitamin K Deficiency Bleeding (VKDB) in infancy. Thromb Haemost 1999;81:456- 61.

8. Respati H, Reniarti L, Susanah S. Hemorrhagic Disease of the Newborn. Dalam: Permono B, Sutaryo, Ugrasena IDG, Windiastuti E, Abdulsalam M, Eds. Buku Ajar Hematologi-onkologi Anak. Jakarta: Badan Penerbit IDAI, 2005:182-96.9. Grosset AB. Acquired coagulation disorder. Dalam: Lee GR, Foerster J, Paraskevas F, Greer JP, Eds. Wintrobe’s Clinical Hematology. Edisi ke-10. Philadelphia: Lippincot Williams & Wilkins, 1999:1733-7.10. World Health Organization, Food and Agriculture Organization of United Nations. 2002. Vitamin K. Didapat dari: http://www.fao.org/documents/show_cdr.asp?url_file=/DOCREP/004/Y2809 E/y2809e00.htm. (Diakses tanggal 8 Agustus 2005).11. Isarangkura P, Chuansumrit A. 1999. Vitamin K Deficiency in Infant. 1999. Didapat dari: http://www.ishapd.org/1999/43.pdf. (Diakses tanggal 10 Agustus 2005).12. Lusher JM. Disease of Coagulation: The Fluid Phase. Dalam Nathan DG, Oski FA, Eds. Hematology of Infancy and Childhood. Edisi ke-3. Philadelphia: WB Saunders co, 1987:1293-1342.13. Buck ML. 2001. Vitamin K for the Prevention of Bleeding in Newborns. Didapat dari:http://www.heatlhsystem.virginia.edu/internet/pediatrics/pharma- news/v7no10.pdf. (Diakses tanggal 22 Agustus 2005).14. Canadian Paediatric Society, Fetus and Newborn Committee. Routine Administration of Vitamin K to Newborns. Pediatrics & Child Health 1997;2(6):429-3115. American Academy of ediatrics, Committee on Fetus and Newborn. Controversies Concerning Vitamin K and the Newborn. Pediatrics 2003;112:191-2.16. Wariyar U, Hilton S, Pagan J, et al. Six Years’ Experience of Prophylactic Oral Vitamin K. Arch Dis Child Fetal Neonatal Ed 2000;82:F64-8.17. Danielsson N, Hoa DP, Thang NV, Vos T, Loughnan PM. Intracranial Hemorrhage Due to Late Onset Vitamin K Deficiency Bleeding in Hanoi Province, Vietnam. Arch Dis Child Fetal Neonatal Ed 2004;89:F546-550.18. Windiastuti E. Epidemiology of Vitamin K Deficiency. Disampaikan dalam KONIKA XIV di Bandung, Juli 2005.19. Lanzkowsky P. Manual of Pediatric Hematology and Oncology. Edisi ke-2. New York: Churchill Livingstone, 1995:239-54.20. Anonym. 2003. Vitamin K Deficiency. Didapat dari: http://www.merck.com/mrkshared/mmanual/section1/chapter3/3h.jsp. (Diakses tanggal 19 Agustus 2005).21. Departemen Kesehatan RI. Konvensi HTA Perdana Indonesia, 2003. 22.

Goorin AM, Cloherty JP. Bledding. Dalam: Cloherty JP, Stark AR, Eds. Manual of Neonatal Care. Edisi ke-4. Philadelphia: Lippincott-Raven,1998:460-5. 23. McKinney PA, Juszcak F, Findlay E, Smith K. Case–control Study ofChildhood Leukaemia and Cancer in Scotland: Findings for NeonatalIntramuscular Vitamin K. BMJ 1998;316:173-7. 24. Pooni PA, Singh D, Singh H, Jain BK. Intracranial Hemorrheage in LateHemorrhagic Disease of the Newborn. Indian Pediatr 2003;40:243-248.

Pertanyaan :1. Bagaimana peran vitamin K pada proses koagulasi ? 2. Mengapa kadar vitamin K pada bayi baru lahir rendah ? Bagaimana cara mencegah VKDB? 3. Bagaimana cara menegakkan diagnosis VKDA? 4. Bagaimana penatalaksanaan vitamin K defisiensi

bleeding dan VKDB? 5. Mengapa penyakit hati dapat menyebabkan gangguan koagulasi ? Faktor-faktor apa saja yang terganggu?

Documents

Vitamin K Deficiency in Infants