Hemorrhagic Disease of the Newborn

Dr. Bambang Mulyawan SpA FK UMM

Pendahuluan

Hemorrhagic Diseases of the Newborn (HDN) : perdarahan pada hari-hari pertama kehidupan akibat kekurangan vitamin K yang ditandai dengan menurunnya faktor II, VII, IX, X Towsend (1894) :perdarahan pada bayi sehat tanpa trauma, asfiksia, infeksi Dam ( 1929 ): perdarahan spontan karena defisiensi vit K (ayam) Brinkhous (1937) : hubungan antara defisiensi vit K dengan HDN

Definisi

American Academy of Pediatric (AAP) : penyakit perdarahan pada hari-hari I kehidupan karena kekurangan vit K, ditandai oleh kekurangan protrombin, prokonvertin, dan mungki juga faktor faktor lain. HDN : mencakup perdarahan karena faktor lain. VKDB ( vitamin K dependent bleeding) atau PDVK ( perdarahan akibat defisiensi vitamin K ) Istilah yang dipakai tetap : HDN Bentuk HDN : dini, klasik, lambat. Manifestasinya nonspesifik: memar ringan ekimosis generalisata, perdarahan saluran cerna, perdarahan intrakranial

Beberapa penyebab perdarahan

Aetiology VKDB Hemophilia ITP DIC Chronic liver diseases Afibrinogenemia OthersALL,MDS Percentage 40 15 13 12 04 01 15

Conditions associated with Vit K Bleeding

Hemorrhagic deficiency of newborn & infants(VKDB) Chronic diarrhoeas & malabsorption Liver disorders-hepatitis Warfarin and other drugs Prolonged antibiotics

Dr Rajesh Kumar, MD (PGI, Chandigarh), DM (Neonatology, PGI, Chandigarh)

07/03/07

Macam perdarahan

Bleeding in the
gastrointestinal
urinary

tract

tract umbilical stump nose scalp intracranial hemorrhage Shock death

Permasalahan : BBL cendrung memiliki kadar VIT K dan cadangan VIT K dalam hati yang relatif lebih rendah dibanding bayi yang lebih besar Asupan VIT K dalam ASI belum mencukupi ( 0,5 mg/L) sedangkan VIT K dari makanan tambahan dan sayuran belum dimulai Negara ASIA angka kesakitan bayi karena PDVK berkisar antara 1 :1200 -1 : 1400 KH angka tersebut dapat turun menjadi 1 :10000 dengan pemberian profilaksis VIT K pada BBL

Akibat PDVK adalah terjadi perdarahan otak dengan angka kematian 10 -50 % yang umumnya terjadi pada bayi dalam rentang umur 2 minggu sapai 6 bulan dengan angka kecacatan 30 50 % Secara nasional belum ada angka PDVK sedangkan dari RSCM bagian Anak ( 1990-2000) menunjukan terdapatnya 21 kasus diantaranya 17 (81%) mengalami komplikasi perdarahan intrakranial Selain itu akibat PDVK terlihat kejadian KIPI berupa perdarahan yang timbul 2 jam sampai 8 hari pasca imunisasi Data KIPI tahun 2003 -2006 sebanyak 42 kasus dimana 27 kasus (65%) diantaranya meninggal

Secara fisiologis kadar faktor koagulasi yang tergantung VIT K dalam tali pusat sekitar 50 % dan akan menurun dengan cepat mencapai titik terendah dala 48-72 jam setelah kelahiran VIT K 1 Selain sedian injeksi terdapat pula sedian oral tab 2 mg tetapi absorpsi VIK K1 oral tidak sebaik VIT K 1 injeksi terutama bayi yang menderita diare Pemberian VIK K1 oral pemberiannya memerlukan beberapa minggu (3 x dosis oral, masing-masing 2 mg yang diberikan pada waktu lahir, umur 3-5 hari, dan umur 4-6 minggu) Sebagai konsekuensinya maka tingkat kepatuhan ortu merupakan suatu masalah tersendiri

10

PENGERTIAN

VIT K vitamin larut dalam lemak, merupakan suatu naftokuinon yang berperan dalam modifikasi dan aktivitas beberapa protein yang berperan dalam pembekuan darah sep protrombin atau faktor II,VII,IX,Xdan anti koagulan protein C dan S dll yang belum banyak diketahui

11

Epidemiologi
Pemberian profilaksis vit.K pada bayi baru lahir : menurunkan angka kesakitan/ kejadian HDN ( AS, Jepang, Thailand ) Bayi dengan ASI cenderung HDN. Vit. K ASI < susu sapi

Faktor resiko

Obat yg mengganggu metabolisme vit K yg diminm ibu selama hamil : antikoagulan ( warfarin ), antikonvulsan ( fenobarbital, fenitoin ), antituberkulosa ( INH, Rifampisin) Sintesis vit K yg kurang oleh bakteri usus : antibiotika, khususnya bayi prematur Gangguan fungsi hati ( kolestasis) ASI eksklusif Sindroma malabsorpsi Diare kronis

Kasus

3 day old term female presents to your office for first check up. Mom had prenatal care and decided to have the baby at home with a midwife. Uncomplicated pregnancy and delivery. Mom doesnt believe in immunizations and didnt want her baby to get any medicines at birth. Baby has been having some mild bleeding around her gums with feeding and mom noticed a small amount of blood in the diaper this morning.

What is her diagnosis ?

Hemorrhagic

Disease of the Newborn

How could this have been avoided ?

0.5

to 1 mg IM of vitamin K

Hemorrhagic Disease of the Newborn

Why are Newborns deficient in Vit K ?
Placental transfer is poor Breast milk is a poor source GI tract is sterile at birth

What lab values are associated ?

Platelet Count Normal Fibrinogen Normal PT prolonged

Gambaran kklinis dan laboratorium

Umumnya : perdarahan, pucat, hepatomegali Perdarahan : spontan, trauma ( hematom sefal) Kebanyakan : kulit, mata , hidung, sal.cerna Kulit : purpura, ekimosis, bekas tusukan jarum Lain : umbilikus, sirkumsisi Komplikasi tersering : perdarahan intrakranial ( subdural, subaraknoid) peningkatan intrakranial / kadang tidak bergejala dan tanda. Sakit kepala, muntah, cengeng, uub menonjol, pucat, kejang fokal/umum, fotopobi edema papil, kesadarn<, perubahan tek.nadi, pupil anisokor, kelainan neurologis fokal

Perdarahan Akibat Defisiensi VIT K (PDVK)

PDVK dapat terjadi spontan atau perdarahan karena proses lain seperti pengambilan darah vena atau pada operasi disebabkan karena berkurangnya faktor pembekuan darah (koagulasi) yang tergantung pada VIT K yaitu faktor II,VII,IX.X sedangkan faktor kuagulasi lainya , kadar fibrinogen dan jumlah trombosit dalam batas normal Manifestasi klinis yang sering ditemukan adalah perdarahan, pucat dan hepatomegali ringan Perdarahan dapat terjadi spontan atau akibat trauma, terutama trauma lahir

22

Pada kebanyakan kasus perdarahan terjadi dikulit, mata, hidung dan saluran cerna (muntah atau berak darah) Perdarahan kulit sering berupa purpura, ekimosis, atau perdarahan melalui bekas tusukan jarum suntik Tempat perdarahan yang utama adalah umbilikus, membran mukosa, saluran cerna, sirkumsisi dan dan pungsi vena Perdarahan juga berupa hematoma pada tempat trauma seperti cepal hematoma akibat lebih lanjut adalah timbulnya perdarahan intrakranial yang menyebabkan mortalitas dan morbilitas yang menetap

24

Perdarahan intrakranial merupakan komplikasi tersering 63 % dimana 80 -100 % berupa perdarahan subdural dan subaraknoid Pada perdarahan intrakranial didapatkan gejala peningkatan tekanan intrakranial (TIK) bahkan tidak menunjukan gejala ataupun tanda Pada sebagian kasus 60 % didapatkan sakit kepala, anak menjadi iritabel, ubun2 besar menonjol, pucat dan kejang, kejang bersifat lokal dan umum Gejala yang paling mudah dikenali adalah tangisan bayi yamelengking ng dengan nada tinggi (high pitch cry) yang tidak bisa dihentikan walaupun bayi tersebut sudah ditenangkan dan diletakan dipundak sambil dielus-elus punggungnya

27

3 Types of HD of N

Early Disease 1st 24 hours Maternal use of anticoagulant/anticonvulsant Severe bleeding/intracranial hemorrhage Classic Disease 1-7 days Cutaneous, GI or circumcision site bleeding
Late-onset Beyond 1 week

Associated with exclusively breast-fed

VKDB Characteristics
Type Early Onset Within 24 hrs Details
h/o drug intake in mother Anticonv;antiTB,coumarins, salicylates , Poor nutrition:: Scalp,GI,ICH Usually in breast fed babies::GI,Skin,nasal Common in breast fed rare in top fed and vit K rcd at birth..50%ICH,GI

Classical

2-7 days

Late

1-6 months

07/03/07

Dr Rajesh Kumar, MD (PGI, Chandigarh), DM (Neonatology, PGI, Chandigarh)

Age distribution of VKDB patients

Age 0-1 day 1-3 days 3-6 days 6-30 days 1-3 mths 3-6 mths 6-9 mths 9-12 mths >12 mths Percentage 7.5 5.0 27.5 32.5 7.5 10.5 7.5 2.5

Aetiology of ICH
VKD ITP Hemophilia

Mortality in VKDB
Total mortality was 30% Only in cases with ICH

Mortality in ICH cases

87.5% .due to VKDB 12.5%..due to ITP

Why is newborn Vit K deficient?

Maternal:cord blood ratio30:1 Hepatic content in neonate-25% of adult Human milk content(2-15ug/l)-25% cowmilk Colostrum rich in Vit K not given Sterile gut Plasma half-life-72 hrs

07/03/07

Dr Rajesh Kumar, MD (PGI, Chandigarh), DM (Neonatology, PGI, Chandigarh)

Limited placental transfer of Vit K; 30-60 % of adult value at birth Breast fed will have adult value by 6 weeks Formula fed has much higher value; 10 fold Lipid soluble Phytonadion (1 mg) injection at birth: Vit K level at 6 wks 1.5 times higher than breast fed babies

07/03/07

Dr Rajesh Kumar, MD (PGI, Chandigarh), DM (Neonatology, PGI, Chandigarh)

Case selection criteria

1. 2.

3.

4.

Age 2 days to 12 months Prolonged PT(>1.5 times) & PTTK Which normalised within 24 hrs of Vit K Absence of liver disease and/or septicemia
07/03/07
Dr Rajesh Kumar, MD (PGI, Chandigarh), DM (Neonatology, PGI, Chandigarh)

Patofisiologi HDN

Neonatus dlm 48 72 jam secara fisiologis mengalami penurunan faktor koagulasi yg bergantung vit K (faktor II, VII, IX, dan X ) sekitar 50%, yg segera normal kembali berangsur-angsur dlm usia 7 10 hari. Penyebab : vit K ibu <, flora normal usus utk sintesis vit K <, cadangan vit K bayi < Lebih sering pd bayi prematur, ringan___berat Mekanisme hemostasis fase plasma terganggu perdarahan spontan ( gambar : skema proses pembekuan )

Role in the Mechanism

http://www.frca.co.uk/images/clotting_cascade.gif

In blood clotting, vitamin K is needed as a cofactor to activate clotting factors:

Clotting factor II
(prothrombin)

Clotting factor VII

(proconvertin)

Clotting factor IX
(thromboplastin)

Clotting factor X
(Stuart factor)

Vitamin K Deficiency
Incomplete carboxylation of coagulation proteins that do not form appropriate complexes with Ca&phospholip

Qualitative deficiency of Factors II,VII,IX,X

BLEEDING

VITAMIN KS METABOLIC/BIOCHEMICAL FUNCTIONS

Aids in blood clotting (primary function)

Assist body in the absorption of calcium Prevents atherosclerosis-hardening of arteries which inhibits the flow of blood around the body Lowers risk of Alzheimers and kidney stones

AIDS IN BLOOD CLOTTING

Primary function of Vitamin K Initiates the healing process by slowing and stopping the bleeding Given to patients before surgery to prevent excessive bleeding Vitamin K is the coenzyme to Vitamin Kdependent coagulation proteins in the blood coagulation cascade known as factors II, VII, IX, and X

Diagnosis

Anamnesis, pemeriksaan fisik, laboratorium Anamnesis : awitan, lokasi, pemberian ASI/ susu formula, riwayat ibu minum obat-obatan antokoagulan antikonvulsan, lokasi fisik perdarahan Laboratorium : waktu pembekuan >, penurunan aktivitas faktor II, VII, IX, X tanpa trombositopeni atau kelainan faktor pembekuan lain. PT dan PTT memanjang bervariasi, TT normal. Masa peradarahan dan jumlah lekosit normal, anemi normokrom normositik Perdarahan intrakranial : USG kepala, CT Scan, MRI Respon yang baik terhadap pemberian vit K

Diagnosis banding
Gangguan hemostatis yang didapat Bedakan dengan gangguan hemostatis lain, atau yg bersifat kongenital Gangguan fungsi hati hati tidak mampu sintesis faktor-faktor pembekuan DIC akibat koagulopati konsumtif

Penatalaksanaan

Antenatal : mencegah terjadinya perdarahan, pemberian vit K oral tu.untuk bentuk klasik, untuk bentuk lambat diberikan IM Postnatal / setelah bayi lahir : mencegah dan mengobati AAP ( 2003 ) : vit K harus diberikan pada semua bayi baru lahir 0,5 1 mg IM dosis tunggal

3 Bentuk VIK yang Diketahui

1.

2.

3.

VIT K 1 (Phytomenadione) terdapat pada sayuran hijau, sedian yang ada saat ini adalah cremophor dan VIT K mixed micelles (KMK) VIK K2 (Menaquinone) disintesis oleh flora usus normal seperti bacteriodes fragilis dan beberpa strain E.coli VIT K 3 (Menadione) yang sering dipakai sekarang merupakan VIT K sintetik tetapi jarang diberikan lagi pada neonatus karena dapat menyebabkan anemia hemolitik

51

Secara fisiologis kadar faktor koagulasi yang tergantung VIT K dalam tali pusat sekitar 50 % dan akan menurun dengan cepat mencapai titik terendah dala 48-72 jam setelah kelahiran VIT K 1 Selain sedian injeksi terdapat pula sedian oral tab 2 mg tetapi absorpsi VIK K1 oral tidak sebaik VIT K 1 injeksi terutama bayi yang menderita diare Pemberian VIK K1 oral pemberiannya memerlukan beberapa minggu (3 x dosis oral, masing-masing 2 mg yang diberikan pada waktu lahir, umur 3-5 hari, dan umur 4-6 minggu) Sebagai konsekuensinya maka tingkat kepatuhan ortu merupakan suatu masalah tersendiri

53

Recommendations to improve Vit K status

Admn of Vit K to 1. All pregnant mothers 2. ALL NEWBORNS( healthy or high risk) s 3. All infants with diarrhoea or antibiotics 4. Routinely to all infants once a month

Pregnant mothers
Tablets of vit k 20mg/day in the last month of pregnancy--Improve blood levels of newborn Improve Vit K content of breast milk Esp. in mothers taking medications Must be given routinely

Ibu hamil yang mendapat pengobatan antikonvulsan harus mendapat vit K profilaksis 5 mg sehari selama trimester III atau 24 jam sebelum melahirkan diberi vit K 10 mg IM. Kemudian kepada bayinya diberikan vit K 1 mg dan diulang 24 jam kemudian

ALL NEWBORNS Healthy and high-risk

Vit K 0.5mg 1mg IM 1-4 mg PO Born at homePO At the first contact IM /PO

American Academy of Pediatrics 1961

Prophylactic use of Vit K recommended by the American Academy of Pediatrics, and by the American College of Obstetricians and Gynecologists since 1961. Up until 1987, administration of vit K at birth was mandatory in only five states in the US AAP recommendation renewed in 1993 and remains current

Vit K should be administered subcutaneously or intravenously but not intramuscularly to avoid hematoma formation at the site of injection Plasma should be administered to infants with serious bleeding manifestations.

07/03/07

Dr Rajesh Kumar, MD (PGI, Chandigarh), DM (Neonatology, PGI, Chandigarh)

Vit K prophylaxis
I.M. Vit K at birth Oral mixed miclellar Vit K (Konakion): 2 mg at birth, 7 days, 30 days ( many failures) Weekly oral Vit K (2 mg) for 3 months Oral 2 mg at birth, 25 mcg daily from 7 days to 3 months

07/03/07
Dr Rajesh Kumar, MD (PGI, Chandigarh), DM (Neonatology, PGI, Chandigarh)

Oral Vit K1
Efficacy in oral administration is uncertain Oral administration contraindicated in

Premature,

sick neonate, on antibiotic Cholestasis, diarrhea

07/03/07

Dr Rajesh Kumar, MD (PGI, Chandigarh), DM (Neonatology, PGI, Chandigarh)

Renewed Interest in Vit K

Since the 1980s attention UK, Europe, Japan, Canada, Australasia and Middle East HDN and vit K deficiency reported in both developed and developing countries where it is not routinely used, or where use may be waning Controversy re oral versus parenteral use of routine Vit K largely resolved Intramuscular administration within the first 6 hours after birth more effective in preventing both early and late HDN

Rekomendasi DepKes RI (2003)

Semua bayi baru lahir harus mendapat profilaksi vit K Jenis vit K adalah vit K1 Cara pemberian adalah secara IM atau per oral Dosis IM, 1 mg dosis tunggal Dosis oral, 3 x@ 2 mg, diberikan pd waktu bayi lahir, umur 3-7 hari, dan pd saat bayi berumur 1 2 tahun Untuk bayi lahir yang ditolong dukun bayi maka diwajibkan pemberian profilaksis vit K1 secara oral Kebijakan ini harus dikoordinasikan bersama Dir Pelayanan Farmasi dan Peralatan dlm penyediaan vit K1 dosis injeksi 2 mg/ml/ampul, vit K1 dosis 2 mg/tabyg dikemas dlm bentuk strip 3 tab atau kelipatannya Profilaksis vit K1 pada bayi baru lahir dijadikan sebagai program nasional

Prognosis

HDN ringan prognosisnya baik, biasanya sembuh sendiri atau membaik setelah mendapat vit K1 dlm waktu lebih kurang 24 jam HDN dengan manifestasi perdarahan intrakranial, intratorakal dan intra abdominal dapat mengancam jiwa, 27% kasus HDN dengan manifestasi perdarahan intrakranial meninggal

SUMMARY
Vitamin K is a fat-soluble vitamin that is found in green leafy vegetables

and is involved in blood coagulation Two natural subtypes: K1 (phylloquinone) and K2 (menaquinone) A coagulation cascade produces fibrin to clot blood Vitamin K is involved in the activation of clotting factors Vitamin K is a cofactor in the carboxylation of glutamate residues in clotting factors, leading to Ca2+ binding and clotting factor activation Vitamin K deficiency can cause hemorrhage symptoms Vitamin K deficiency is rare in adults, but is a risk in newborns Oral anticoagulants inhibit the effects of vitamin K and vice versa

Summary

Deficiency of Vit K remains a significant worldwide cause of neonatal morbidity and mortality Routine prophylactic use of vitamin K should always be used to prevent HDN (good public health practice) Administration by intramuscular injection (0.5-1.0 mgm) within 6 hours of birth is preferable May be given orally as 3 doses spread over the first 4 weeks of life Vit K showing up in literature on osetoporosis A safe, inexpensive preventive procedure that should be mandatory component of newborn care.

COOMBS TEST

Indirect Coombs test (Indirect Antiglobulin test):

This test is performed to detect presence of Rh-antibodies or other antibodies in patients serum in case of the following: 1. To check whether an Rh-negative women (married to Rhpositive husband) has developed Anti Rh-antibodies

2. Anti D may be produced in the blood of any Rh-negative person by exposure to D antigen by

Transfusion of Rh positive blood Pregnancy, if infant is Rh positive (if father is Rh-positive) Abortion of Rh-positive fetus.

Requirements:

Test tubes: (10x75 mm) Pasteur pipettes Incubator Centrifuge

Specimen: Serum (need not be fasting) Reagents: 1. Antihuman serum 2. Anti-D serum Additional Requirements: Coombs control cells
A. Make a pooled O Rho (D) positive cells from at least three different O positive blood samples. B. Wash these cells three times in normal saline (these cells should be completely free from serum with no free antibodies). Make 5 % saline suspension of these cells

Procedure:
1.

Label three test tubes as T (test serum) PC (Positive control) and NC (negative control). In the tube labelled as T, add two drops of Anti-D serum

2.

3.
4.

In the tube PC add one drop of saline

Add one drop of 5 % saline suspension of the pooled O Rho (D) positive cells in each tube. Incubate all the three tubes for one hour at 37C

5.

Procedure: (cont.)

Wash the cells three times in normal saline to remove excess serum with no free antibodies, (in the case of inadequate washings of the red cells, negative results may be obtained). Add two drops of Coombs serum (anti human serum) to each tube. Keep for 5 minutes and then centrifuge at 1,500 RPM for one minute. Resuspend the cells and examine macroscopically as well as microscopically

Test Interpretation:
Observations 1 Positive Control (PC)
(A)

Conclusions Correctly performed test procedure. Coombs serum may not be proper. Repeat the test again.

Agglutination

(B)

No Agglutination

Negative control (NC)

Test (Serum) (T)

It should show no agglutination, since saline does not contain Anti-D or any other antibodies.
(A)

Agglutination (and if PC results are correct) No Agglutination

Patients serum contains Anti-D.

(B)

Patients serum does not contain Anti-D.

Direct Coombs test (direct antiglobulin test):

This test is performed to detect anti-D antibody or other antibodies attached to the red cell surface within the blood stream. This occurs in the following circumstances:

When there is a Rh-positive baby in the womb of a sensitized Rhnegative women; the antibodies produced in the mothers serum cross the placenta and after entering the baby's blood stream, these antibodies will attach to the baby's Rh-positive red blood cells. These coated (or sensitized) cells are clumped and removed from the circulation, causing hemolytic anemia (Hemolytic Disease of the Newborn: Erythroblastosis Fetalis). When the baby is born, the baby's blood is collected (or cord blood is collected from umbilical cord) and tested by the anti globulin Coombs test (direct) to detect anti D antibodies coated on red blood cells. Transfusion reactions Drug induced red cells sensitization Autoimmune hemolytic anemia

Requirements: (same as that for Indirect Coombs test)

Test tubes: (10x75 mm) Pasteur pipettes Incubator Centrifuge

Specimen: Blood drawn into EDTA is preferred but oxalateed, or clotted, citrated whole blood may be used (specimen need not be fasting sample)

Procedure:
1.

Prepare a 5 % suspension in isotonic saline of the red blood cells to be tested.

2.

With clean Pasture pipette add one drop of the prepared cell suspension to a small tube.
Wash three times with normal saline to remove all the traces of serum.

3.

4.
5. 6. 7.

Decant completely after the last washing

Add two drops of Antihuman serum. Mix well and centrifuge for one minute at 1500 RPM. Resuspend the cells by gentle agitation and examine macroscopically and microscopically for agglutination.