the bleeding newborn

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Seminar in Paediatrics : The Bleeding Newborn

The Bleeding NewbornPatr ick M . P. Yuen

Paediatricians w ho care fo r newborn babies arefrequently confronted with neonates suffering from seriousand life-threatening haemorrhages. In this article, a practicalclinical approach to the rapid diagnosis and management ofthese neonates based on a few simple laboratory tests isdescribed together with the t reatment of various bleedingdisorders.HAEMOSTASIS I N THE N E W B O R NFor a complete review of haemostasis in the normalnewborn , th e reade rs ar e urged to re f e r to the excellentmonograph on perinata l coagulation (1).CLOTTING FACTORSAlmost all the clotting factors are produced in the liverand they are pr esent in reduced concentrations in terminfants, as compared in older children and adults. The levelsare even lower in the premature infants (Table 1). Onlyfactors V , VIIIc an d XIII are present in concentrationsapproaching those of adult levels.

P L A T E L E T SAlthough pla telet numbers ar e similar in prematu re ,term infants an d adults, their function may be somewh a timpaired (2, 3).FI BRI NOL YTI C SYSTEMWhile antithrombin III and plasminogen are low in theneonates, especially in the premature, the ^ 2 antiplasminlevel is normal.PROTEIN C SYSTEMProtein C is a potent anticoagulant as w e l l as aprofibrinolytic agent (4).Mean protein C antigen level infull-term neonates is about one third of normal adults' meanlevel, th e more premature th e infant, th e lower th e proteinC level (5).While reduced levels Vit K dependent factors (II, VII,IX and X) and contact factors (XI, XII, pre-kallikrein an dhigh molecular weight kininogen), especially in thepremature, predispose th e newborn infants to bleeding

FactorI

(fibrinogen)II(p ro t h ro mb i n )V

VI IVII IcIX

XXIXIIXII I

Normaladult range% or mg %175-450%

60-150%50-150%50-120%50-200%50-150%50-150%60-120%60-120%80-120%

Site ofproductionL i v er

LiverLiverLive r

E ndoth e l iu m?LiverLive r

pp

? Live r

In vivo1/2life(hrs or days)

4- 7 days

2 - 3 da y s12-30 hr

4-6hr1 2 h r2 4 hr

40-48 hr72 h r48 hr

4- 6 days

Vit. Kdependent

noyesnoyesnoye syesnonono

Levels inneonatesreduced

reducednormalreducedn o rmalreducedreducedr e d u c e dreducednor m a l

Lab testsPT/PTT/TT

PT/PTTPT/PTT

PTPT TPT T

PT/PTTPT TPTT

solubilitytest in 5Mu r eaTable 1 Clotting factors in newborn

Department of Paediatrics, The Chinese University of H ong Kong, Shatin NTPatrick M.P.Yuen , M.D. (C), F.R.C.P. (C), Senior LecturerCorrespondence to : Dr. P at r ick M.P. Yuen

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CLINICAL APPROACH TO THE BLEEDINGNEONATEA t h o r o u g h h i s t o r y a n d p h y s i c a l e x a m i n a t i o n will givet h e c l in i c a n s a c l u e a s t o t h e c a u s e o f th e b l e e d i n g ( 6 ) .H i s t o r y t a k i n g s h o u l d i n c l u d e t h e f o l l o w i n g q u e s t i o n s .I ) I s the i n f an t "sick" o r " w e l l " at the o n s e t o f b l e e d i n g ?

Well infants (usua l ly f u l l - t e r m w i t h n o r m a l b i r t h w e i g h tan d w i t h o u t a n o b v i o u s u n d e r l y i n g d i s o r d e r a n d a r e a ls oalert a n d v i g o u r o u s ) g e n e r a l ly h a v e i m m u n e t h r o m b o -c y t o p a e n i a , v i t a m i n K d e f i c i e n c y , i s o l a t e d c l o t t i n g f a c t o rd e f i c i e n c i e s , m a t e r n a l l y d e r i v e d d r u g p r o b l e m o r a l o ca li se dvascu la r l es ion such as an u l c e r o r h a e m a n g i o m a . "Sick"i n f a n t s ( b a b i e s o f t e n w i t h p e r i n a t a l i n f e c t i o n , t i s s u e n e c r o s i s ,h y p o g l y c a e m i a , h y p o x i a , a c i d o s i s o r p r o b l e m s r e l a t e d top r e m a t u r i t y o r d y s m a t u r i t y ) h a v e D I G o r c o n s u m p t i v et h r o m b o c y t o p a e n i a . I n f a n t s w i t h c o n g e n i t a l p r o t e i n Cde f ic ie ncy c a n present i n t h e n e o n a t a l p e r i o d w i t h e i t h e r

F i g . 1 Purpura fulminans in a C hinese b o y homozygousfo r p r o t e i n C d e f i ci e n c yII ) Is there a family history of bleeding disorder?B l e e d i n g i n t h e n e o n a t a l p e r i o d c a n o c c u r i n h a e m o p h i l i aA (severe fac tor V I I I c d e f i c i e n c y , < 1 % a c t i v i t y ) ,h a e m o p h i l i a B ( fac tor IX d e f i c i e n c y ) , f a c t o r X I I I d e f i c i e n c ya n d a f i b r i n o g e a a e m i a . B l e e d i n g f r o m t h e umbi l ica l s t u m p a n d84

t h e o c c u r r e n c e o f a n u n u s a l l y large c e p h a h a e m a t o m a ,s u b g a l e a l a n d i n t r a c r a n i a l haemorrhage f o l l o w i n g t h er e l a t i v e l y u n c o m p l i c a t e d b i r t h o f a n i n f a n t c a n b e t h epresenting s i g n s . T h e w e l l k n o w n muscle a n d j o i n thaemorrhages seen in older c h i l d r e n w i t h th e a b o v ed i s o r d e r s d o n o t u s u a l l y b e g i n u n t i l i n f a n t s start to c r a w l a n dw a l k . A n y i n f a n t w h o h a s p r o l o n g e d bleeding f o l l o w i n g aheel p r i c k , n e e d l e p u n c t u r e fo r b l o o d t a k i n g o r c i rcumcis ions h o u l d b e suspected o f h a v i n g a b l e e d i n g disorder. N e o n a t a lb l e e d i n g secondary t o v o n W i l l e b r a n d ' s disease is rare, i f i toccur s a t a l l .HI ) H a s V i t a m i n K b e e n given t o t h e i n fa n t?H e m o r r h a g i c disease of the newborn occurs p r i m a r i l y inb r e a s t - f e d i n f a n t s because h u m a n breast milk contains lesst h a n o n e f o u r t h th e a m o u n t o f V i t am i n K o f cow's m i l k .B l e e d i n g c h a r a c t e r i s t i c a l l y occurs between th e second a n df o u r t h day of life. These consist of G-I bleeding, expistaxis,s u b g a l e a l a n d i n t r a c r a n i a l haemorrhages. A s ingle parenteraldose of 0.5 to 1.0 mg or oral dose of 1.0 to 2.0 mg V i t a m i nK , i s recommended fo r p r o p h y l a x i s ( 8 ) .IV ) I s the b l e e d i n g generalised o r l oca l i sed?Loca l i sed b l ee ding e .g . subg a lea l haemorrhage orbleeding f r o m u m b i l i c a l s t u m p is u s u a l l y n o t a generalisedc o a g u l a t i o n a b n o r m a l i t y b u t i t ma y b e . I t u s u a l l y denotes asingle fac tor de f i c i ency as in severe Haemoph i l i a A pat i ent .Generalised b l e e d i n g is a l m o s t a l w a y s a coagulat iona b n o r m a l i t y , th e cause o f w h i c h is usua l ly compl ica t ed an dm u l t if a c e t e d e . g . D I C , V i t a m i n K d e f i c i e n c y o r severe l iverdisease.V ) History o f materna l i l l ness .

Does the mother have l u p u s erythematosus? Has sheh ad or does she now h a v e ITP? Has she had ec lamps ia?V I) History o f maternal i nfec t ion.Is there an y evidence o f maternal o r fetal infect ion withG M V , rube l l a , toxoplasma, coxsackie virus, herpes simplexan d syph i l i s?V II) H i s t o r y o f maternal d r u g intake e .g . drugs g i v e n to

mother that ca n af fec t i n f a n t ' s haemostasis.B a r b i t u r a t e sC o u m a r i nM e t h o r b i t a lM e t h u s u x i m i d eP h e n y l h y d a n t o i nP r i m i d o n eD i p y r i d a m o l eA SAQuin id ineQu i n i n eS e d o mi dT o l b u t a m i d e

D e p r e s s i o n o f V'i t K d e p e n d e n t f a c t o r sD e p r e s s i o n of Vit K d e p e n d e n t f a c t o r sD e p r e s s i o n of Vit K d e p e n d e n t f a c t o r sD e p r e s s i o n of Vi t K d e p e n d e n t f a c t o r sD e p r e s s i o n of Vi t K d e p e n d e n t f a c t o r sD e p r e s s i o n of Vi t K d e p e n d e n t f a c t o r sPla te le t d y s f u n c t i o nP l a t e l e t d y s f u n c t i o nT h r o m b o c y t o p a e n i aT h r o m b o c y t o p a e n i aT h r o m b o c y t o p a e n i aT h r o m b o c y t o p a e n i a

Table 2 M aternal drug intake that ca n affect infant'shaemostasis

V I I I ) A g e o f onset o f bleeding.Bleeding c lue to Vi t K d e f i c i e n c y occurs u s u a l l y at 2n d to4 t h d a y o f a g e . I m m u n e thrombocytopaenia causes b l e e d i n g


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Seminar in Paediatrics: The Bleeding Newbornusual ly within 24 hrs of age whi l e that due to p ro te in Cdef ic iency t im e of o n s e t of p urp u ra v a r ie s f rom 2 hrs (9) to6 d a y s of age (10) .P H Y S I C A L E X A M I N A T I O NIn phys ical examinat ion , th e paed iatr ic ian shouldd e t e r m i n e w h e t h e r th e infant is "sick" or "well", an d alsow h e t h e r th e bleed ing i s genera l ised or localised. Theseobservat ions to be corre la ted with the h is to ry w i l l help todefine th e pathophys io logy under ly ing th e h e m o r rh a g e .In the phys ical examinat ion , one should also look fo rlocal ised c lues such as the p resence o f a g ian t hemangioma(p late le t t rapp ing can occur , accomp anied in some ins tancesby a p icture of D IC ) ske le ta l anomalies such as b i la te ra la b s e n c e of rad i i in so -cal led TAR ( thrombocytopaen ia andabsen t radii) syndrome character ised b y c o n g e n i ta lh yp o m e g a k a ryo c y t ic t h ro m b o c y to p a e n ia a n d b i l a t e ra labsence of ra d ius an d e v id e n c e of i n t ra u te r in e infect ion s uc ha s h e p a to s p le n o m e g a ly , s e p si s -l i k e p ic tu re , e n c e p h a l i t i s ,m i c r o c e p h a l y and genera l ised petechiae .L A B O R A T O R Y TESTSScreening tests s h o u ld include th e fol lowing:i ) Co m p le t e b lo o d c o un t (H b , wbc & d if f e re n t ia l , p la t e l e t )inc lud ing m o s t im p o r ta n t ly a b lood smear .i i ) P ro th ro m b in t im e (P T ) and part ial t h r o m b o p l a s t i n t i m e(FIT).D e p e n d i n g on the clincial p ic tu re an d r e s u l t s o fscreen ing t e s t s , o th e r l a b o ra to ry t e s t s m a y b e o f v a l u e inarr iv ing at a diagnosis. T h e s e include:i ) Indiv idua l factor a ssa ysi i ) Fib r in d e g re d a t io n p ro d u c t s (FD P )i i i ) P ro te in C assay

Platelet count is a sensitive indicator of m a n y diseaseprocesses. N orm al counts sugges t inh er i ted facto rdef ic iency, Vitamin K def ic iency, some ins tances of m a te rn a ld rug in g e s t io n o r local causes such as p u lm o n a ry o rin t ravent r icu la r h a e m o r rh a g e a s seen i n p re t e rm in f a n t s .Lo w cou nts sugges t a p rocess o f e i ther excess ivec o n s um p t io n (e.g DIC) which is more common o r poorproduct ion ( rare) .E v e r y pract is ing doctor should b e ab le to in t e rp re t ablood sme a r . T h e p r e s e n c e of p la te le t c lumps in low powerfield would indicate platelet count is adequate . A roughes t imate o f the p la te le t co unt can be achieved by count ingth e n u m b e r of p la t e l e t s in 10 oil fields and mul t ip ly thatnumber by 2000. T h e y would give the number o f p la te le tpe r mm3. Also the p r e s e n c e of giant pla telets on s m e a rind icates h ype rut i l iz at ion ra the r than poor p ro duct ion . M orethan 1 0% schisocytes ( f ragmented rbc) sugges t sm ic ro a n g io p a th y such as DIG. Gra n u lo p a e n ia sugges t ssepsis .C O A G U L A T I O N S C R E E N I N G TESTS (PT, PTT)A word o f caut ion concern ing the in te rp re ta t ion o f t h e s etests m u s t b e made. Firstly th e paediatrician must e n s u r et h e r e is a p roper d i lu t ion o f the in fan t ' s b lood with anant icoagulan t . T h e standard ratio o f 1 part 3.8% t r isod iumci t rate to 9 parts o f b lood w ithout tak ing in to cons iderat ionof the Hct leve l would resul t in excess of ci t ra te . When th eH ct i s > 55% the ant icoagulan t must b e reduced i . e . theant icoagulan t ra t io m u s t be based on plasma vo lume ra th erthan the vo lum e of whole b lood (11). Secondly , normalvalues vary from o ne laborato ry to another . Genera l lyspeaking, t e rm in fan ts have more p ro longed P T & P T Tthan o lder ch i ld ren and adul ts . Such p ro longat ion o f PT &P T T i s e v e n m ore pronounc e d in the p re - t e rm infants.

T he PT and PT T a r e global t e s t s of the en t i re b loodcoagula t ion m e c h a n i s m . T h e P T m e a s u r e s th e ex tr ins iccoagulation p a t h w a y & P T T assesses th e in t r ins ic clo t t ings ys t e m . An y P T g r e a t e r t han 17 sec in a n e o n a t e of anyges tat ional a g e & a P T T g re a t e r t han 45 to 50 sec in a termi n f a n t should b e c o n s id e re d a b n o rm a l . In the p re t e rminfants, PTT is gen era l ly no t regarde d as a useful screen ingtest because of the wide range o f n o rm a l values (12) . PT Tis i n f lue n c e d b y mi n u t e quant i ty o f h e p a r in . T h e re f o re b lo o df o r coagulat ion s tud ies should not be t a k e n via an i n d w e l l in gveno us o r ar te r ia l catheter con ta in in g hepar in e ven i f i t hasbeen f lushed w i t h normal sa l ine . Indiv idua l factor assays e.g.factor V I I I , IX can be m e a s u r e d b y o n e -s ta g e p ro th ro m b int ime t e s t us ing p lasmas congen i ta l ly def ic i ent in there s p e c t iv e f a c to r s as s ub s t ra t e s . A usefu l s c re e n in g test fo rfacto r X I I I deficiency is by d e m o n s t r a t i n g th e infant 's f i b r i nclot is so lub le in 5 M u r e a .F I B R I N D E G R A D A T I O N PR O D UC T S ( F D P )Since f ib r ino lys is is an i n t e g r a l p a r t o f blood coagu lat ion ,w i t h excess ive c l o t f o r m a t i o n t h e re is an i n c re a s e in clotlysis i.e. activation of f ibr inolyt ic s y s t e m . A rise in fibrind e g r a d a t i o n products occurs .P R O T E I N C ASSAYP ro te in C l eve l can be m e a s u r e d by the m e t h o d o fe n z y me - l i n k e d i m m u n o s o r b e n t a s sa y ( E L I SA ) . C o m m e r c i a lkits are now avai lable in (he m a r k e t .D I F F E R E N T I A L D I A G N O S I S (Tab le 3)C B C wi th pla t e l e t c o u n t , s m e a r , P T & P T T a re usefult e s t s to be d o n e .S I C K I N F A N T SI ) Decreased p la te le ts , increased P T & P T T

T h i s can be the re s u l t o f DIG s e c o n d a ry to i nfec t ion ,h y p o x i a , shock o r t issue necros is . Pro te in G deficiency ca ne i ther p resen t as mass ive thrombos is o f blood v e s s e l s orp u r p u r a f u lminans . T h e l a t t e r is a m a n i f e s ta t io n ofDIG.Serious genera l ised b leed ing can occur in DIG. T h i s inc ludesoozing from n e e d le p un c tu re si tes and GI b leed ing .T h e ra p y i s a im e d a t t r e a t in g th e un d e r ly in g d is o rd e r(e .g . in fect ion) . In s ym p to m a t ic p a t i e n t s , f r e s h p la t e l e tconcentra tes (1 u n i t usua l ly has 30 cc) can be g iv e n e v e ry12 t o 24 h o urs . O ne unit should raise th e platelet count to100,000/mm3. Less r i se than th is sugges t s e i th e r im p ro p e rcollection o f plate le ts , outdated p la te le ts o r h yp e ru t i l i z a t io n .Be c a use of the re la t ive ly large vo lume of f resh p lasmap r e s e n t , 1 uni t of f resh p la te le ts w i l l also ra ise the var iousclo t ting facto rs by 20% of n o rm a l .Fresh f ro z e n p la s m a (FFP) 10-15 m l/k i lo /1 2 h r . w i l lreplace al l clo t t ing facto rs ( including p ro te in G) and al lowsa d j u s t m e n t o f blood (butn o t rbc)v o l u m e . In p a t i e n t s w h ocont inu e to bleed in sp i te o f in tens ive rep lacement therapy,"2 v o lum e e x c h a n g e " t r a n s f us io n w i th f r e s h b lo o d i.e. 1 70cc/kilo m a y b e helpful. T h e r e is less t e n d e n c y to usehepar in in the t r e a tm e n t of DIG now un le s s t h e r e isev idence o f large ve sse l th rombos is .In pat ien ts with homozygous p ro te in C def ic iency, 10ml/ki lo of f resh f ro zen p lasma, once o r twice a day, ar esufficient to eliminate thrombotic complications. Thisapproach is obvious ly not a practical long t e rm t h e ra pe u t i cregime as it will even tual ly lead to hyperpro te inaemia.Al t e rna t e methods include the use of I.V. Factor IXc onc e nt ra t e (which is r ich in p ro te in C) o r Warfarin po. Ith as been found e ve ry o t h e r day infusions of 50-75 units/kiloo f pro te in C a re sufficient to stop th e thrombotic e p i sode s .In the neonates , 0.25 to 0 .5 mg Warfarin/day p.o.

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Seminar in Paediatrics : The Bleeding Newborn

Disorder- Qual i tat iveplateletab n o rmal i t y- SepsisAfibringenaemia

Haemophilia AModerate bleedingSevere bleedingVon WillebrandHaemophilia BModerate bleedingSevere bleedingLife-threateningOther factordeficiencies

DIC

Protein C deficiency

Vit K d e f .

ProductPlatelet

C ryo p rec i p i t a t e

C ryo p rec i p i t a t eCryoprecip i tateC ryo p rec i p i t a t e

FFPFFPF IX concent rateF F P

FFPFresh w ho l e b lo o d

Hep ar i n

FFPF IX co n cWarfar in

Vit K 1

Concentration7-8 x 1010platelets/u

200-300 mg/bagFibrinogen75-100 u V IIIc / b ag75-100 u V II Ic / b ag75-100 u V IIIc / b ag

1 F IX u / ml1 F IX u / ml2 0 F I X u / m l

15-30 Protein C u/ml

Dose1 u/5 kiloq 12-24 hrs

1 bag/3 kilo

20 u/kilo50 u/ki lo20 u/kilo

10-15 u/kilo20-25 u/kilo50-75 u/kilo10-15 ml/kilo

10-15 ml/kilo2 - v o l u m e exchange(170ml/kg)50 u/kg loading dose,fo l lowed b y 20-25u / kg / h r

10-15 ml/kgq 1 2 h r50-75 u/kilo0.25 to 0.5 m g / d a y po^0.25 mg / d to k eep P .T.2-3x above n o r m a l

1 m g I. V . & w e e k l y until P.T.r e t u r n s to n o r m a l

Table 4 Haemostatic therapy in N . B.vo n Willebrand 's disease. F or specif ic diagnosis, assay o fspecific factor must be obtained.

In the case of moderate h a e m o r rh a g e , FFP may beused. In severe haem orrhage in haemoph i l ia A (Factor VII Idef ic iency) , Cryoprecip i ta te m a y b e used and in haemophi l iaB (F IX def ic iency) in the presence of l i f e - threaten inghaemorrhage F IX concentrate should be us e d .IV ) Normal p la te le ts , PT & PTTTh e above f ind ings can be seen in pat ien ts with localtraum a, local vascular lesions such as an ulcer , Factor X II Idef ic iency or a qual i ta t ive p la te le t disorder such as maternalAspirin ingestion. Platelet aggregat ion s tud ies will confirmth e diagnosis.

Bleeding as a result of qual i ta t ive p la te le t abnormali t iesgenerally responds to platelet transfusions.In the treatment o f bleed ing neonate, therapy shouldalways be aimed at the primary disorder. Blood products(Table 4) should on ly b e used w h e n t h e y are abso lute lynecessary because o f t h e d a n g e r o f i n t ro d uc in g CM V ,hepatitis and AIDS.

REFERENCES1. Hathaw ay W E Bonnar J . : Per inatal coagulat ion . Grune & St rat ton 1978.2. Stuart M J: Plate le t function in the n e o n at e . A. J. Ped. Hem./Onc. 1979; 1 :227-

234.3. Stuart M J, Allen JB : Arachidonic acid metabol ism in the neonatal p late le t .Pediatrics 1982; 69:714-718.4. Clouse LH, Com p PC: The regulat ion of haem ostasis: The p ro te in C system.N .E.J. M . 1986; 314, 20:1298-1303.5. M al ar R A : Protein C in thromboem bol ic d isease. Semin . Thromb. & Haemostas1985; 11, 4:387-393.6. Glader BE, Buchanan GR: Th e b lee d ing neona te . Ped iat r ics 1976; 58, 4:548-555.7. Y u e n P et al : P u r p u r a fu lminans in a Chinese bo y with congenital pro te in Cdef iciency. Pedia trics 1986; 77, 5:670-676.8. H a t h a w a y W E: 1CTH Subcommit tee on neonatal hemostasis . Thromb. &

Haemostas. 1986; 55, 1:145.9. Estelles A et al : Severe inher i t ed "homozygous" protein C deficiency in a newb ornin fan t . Thromb. & Haemostas. 1984; 52, 1:53-56.10. Sills RH et al : Severe pro te in C def ic iency. J. of Ped. 1964; 105, 3:409-413.11 . Hel lem A J: Scand. J. Clin. Lab. Invest. Suppl. 1960; 51:1-117.12 . B u c h a n a n GR : Coagulat ion d isorders in the neonate . Ped . Clin. of N .A . 1986; 33 ,1:203-220.13 . An d r e w M , Ke l t o n J: Neonatal thrombocytopaen ia: Cl in ics in perinatology 1984;11, 2:359-391.14. Colv in BT: Throm bocytopen ia: Cl in ics in haemato logy 1985; 14, 3:661-681.

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