British Journal of Haematology, 2002, 119, 295–309

Guideline

THE INVESTIGATION AND MANAGEMENT OF NEONATAL HAEMOSTASIS AND THROMBOSIS*

and postnatal age of the infant and are shown in SUMMARY Tables I–VI (Andrew et al, 1987, 1988). An understanding These guidelines address developmental aspects of neonatal of these age-related ranges is essential to the interpretation haemostasis and thrombosis, the laboratory investigation of of neonatal investigations. the neonate, and the diagnosis and clinical management of haemostatic and thrombotic conditions occurring in this 1. INDICATIONS FOR HAEMOSTATIC period (defined as the first 4 weeks of life following birth). OR THROMBOTIC TESTING OF THE NEONATE Relevant scientific papers were identified by a systematic literature review from Medline 1975–2000 using index Haemostasis terms which incorporated the various component subjects The majority of bleeding problems in the neonatal period are of these guidelines. Further publications were obtained from acquired but inherited coagulation disorders may also the references cited and from reviews known to the mem- present at this time, particularly following iatragenic chal- bers of the working party and to the Haemostasis and lenges. Generally, testing for defects of haemostasis is Thrombosis Task Force. Evidence and graded recommen- indicated in all sick neonates, which would include all dations presented in these guidelines are in accordance with admissions to the neonatal intensive care unit. More the US Agency for Health Care Policy and Research, as specifically, screening is carried out in the following circum- described in the Appendix. It will be noted that there is a lack stances: of a strong evidence base for many of the recommendations • Any haemorrhagic neonate suggested, as the appropriate clinical and laboratory trials • A family history of an inherited bleeding disorder have not been and perhaps never will be undertaken in (dependent on the coagulation factor defect, the severity neonates. Most of the recommendations are therefore of of the deficiency and the likelihood of an accurate Grade C evidence levels IV: higher levels are mentioned diagnosis in the neonate) specifically throughout the document when relevant. • Severe metabolic disease, severe respiratory distress syndrome, liver dysfunction or other predisposing factors for disseminated intravascular coagulation (DIC) INTRODUCTION • Babies whose mothers were taking anticonvulsants, The human haemostatic system is dynamic and is pro- warfarin or antituberculous drugs at the time of delivery foundly influenced by age. Although considered immature • All neonates undergoing surgery or tissue biopsy who in the newborn, it is a physiological system which results in have had previous bleeding problems. few problems for the healthy term neonate, but may contribute to morbidity in the sick and preterm infant Thrombosis when additional acquired abnormalities may be present. Congenital thrombophilia should be considered in: Many of the procoagulants, anticoagulants and proteins • Any child with a clinically significant thrombosis, includ- involved in fibrinolysis are gestation dependent. The new- ing spontaneous thrombotic events, unanticipated or born’s haemostatic system matures during the early weeks extensive venous thrombosis, ischaemic skin lesions or and months of life with most haemostatic parameters purpura fulminans reaching adult values by 6 months of age. In addition, there • A positive family history of neonatal purpura fulminans. is evidence of an accelerated maturation pattern in the Asymptomatic neonates should not be investigated unless premature infant with preterms showing similar levels of there is a significant medical history such as previous coagulation proteins to term infants by 6 months of age. neonatal purpura fulminans or thrombosis. Parents need Values for coagulation parameters in the infant are there- counselling before any investigations are performed either fore dependent to a varying extent on both the gestational on themselves or their children so that the consequences of testing asymptomatic individuals can be fully explained.

Correspondence: Michael D. Williams, Department of Haematology, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 2. LABORATORY INVESTIGATION OF NEONATAL 6NH, UK. E-mail: [email protected] HAEMOSTASIS, THROMBOSIS AND FIBRINOLYSIS *Although the advice and information contained in these guidelines is believed to be true and accurate at the time of going to press, Laboratory investigation should identify neonates with neither the authors nor the publishers can accept any legal inherited or acquired disorders of coagulation. The physi- responsibility or liability for any errors or omissions. ological deficiencies of procoagulant and anticoagulant

Ó 2002 Blackwell Publishing Ltd 295 296 Guideline Table I. Reference values for coagulation tests in the healthy full-term infant during the first 6 months of life.

Tests Day 1 (n) Day 5 (n) Day 30 (n) Day 90 (n) Day 180 (n) Adult (n)

PT(s) 13Æ0±1Æ43 (61)* 12Æ4±1Æ46 (77)* 11Æ8±1Æ25 (67)* 11Æ9±1Æ15 (62)* 12Æ3±0Æ79 (47)* 12Æ4±0Æ78 (29) APTT(s) 42Æ9±5Æ80 (61) 42Æ6±8Æ62 (76) 40Æ4±7Æ42 (67) 37Æ1±6Æ52 (62)* 35Æ5±3Æ71 (47)* 33Æ5±3Æ44 (29) TCT(s) 23Æ5±2Æ38 (58)* 23Æ1±3Æ07 (64) 24Æ3±2Æ44 (53)* 25Æ1±2Æ32 (52)* 25Æ5±2Æ86 (41)* 25Æ0±2Æ66 (19) Fibrinogen (g ⁄ l) 2Æ83 ± 0Æ58 (61)* 3Æ12 ± 0Æ75 (77)* 2Æ70 ± 0Æ54 (67)* 2Æ43 ± 0Æ68 (47)* 2Æ51 ± 0Æ68 (47)* 2Æ78 ± 0Æ61 (29) II(U ⁄ ml) 0Æ48 ± 0Æ11 (61) 0Æ63 ± 0Æ15 (76) 0Æ68 ± 0Æ17 (67) 0Æ75 ± 0Æ15 (62) 0Æ88 ± 0Æ14 (47) 1Æ08 ± 0Æ19 (29) V(U⁄ ml) 0Æ72 ± 0Æ18 (61) 0Æ95 ± 0Æ25 (76) 0Æ98 ± 0Æ18 (67) 0Æ90 ± 0Æ21 (62) 0Æ91 ± 0Æ18 (47) 1Æ06 ± 0Æ22 (29) VII (U ⁄ ml) 0Æ66 ± 0Æ19 (60) 0Æ89 ± 0Æ27 (75) 0Æ90 ± 0Æ24 (67) 0Æ91 ± 0Æ26 (62) 0Æ87 ± 0Æ20 (47) 1Æ05 ± 0Æ19 (29) VIII (U ⁄ ml) 1Æ00 ± 0Æ39 (60)* 0Æ88 ± 0Æ33 (75)* 0Æ91 ± 0Æ33 (67)* 0Æ79 ± 0Æ23 (62)* 0Æ73 ± 0Æ18 (47) 0Æ99 ± 0Æ25 (29) VWF (U ⁄ ml) 1Æ53 ± 0Æ67 (40) 1Æ40 ± 0Æ57 (43) 1Æ28 ± 0Æ59 (40) 1Æ18 ± 0Æ44 (40) 1Æ07 ± 0Æ45 (46) 0Æ92 ± 0Æ33 (29) IX (U ⁄ ml) 0Æ53 ± 0Æ19 (59) 0Æ53 ± 0Æ19 (75) 0Æ51 ± 0Æ15 (67) 0Æ67 ± 0Æ23 (62) 0Æ86 ± 0Æ25 (47) 1Æ09 ± 0Æ27 (29) X(U⁄ ml) 0Æ40 ± 0Æ14 (60) 0Æ49 ± 0Æ15 (76) 0Æ59 ± 0Æ14 (67) 0Æ71 ± 0Æ18 (62) 0Æ78 ± 0Æ20 (47) 1Æ06 ± 0Æ23 (29) XI (U ⁄ ml) 0Æ38 ± 0Æ14 (60) 0Æ55 ± 0Æ16 (74) 0Æ53 ± 0Æ13 (67) 0Æ69 ± 0Æ14 (62) 0Æ86 ± 0Æ24 (47) 0Æ97 ± 0Æ15 (29) XII (U ⁄ ml) 0Æ53 ± 0Æ20 (60) 0Æ47 ± 0Æ18 (75) 0Æ49 ± 0Æ16 (67) 0Æ67 ± 0Æ21 (62) 0Æ77 ± 0Æ19 (47) 1Æ08 ± 0Æ28 (29) PK (U ⁄ ml) 0Æ37 ± 0Æ16 (45) 0Æ48 ± 0Æ14 (51) 0Æ57 ± 0Æ17 (48) 0Æ73 ± 0Æ16 (46) 0Æ86 ± 0Æ15 (43) 1Æ12 ± 0Æ25 (29) HMW-K (U ⁄ ml) 0Æ54 ± 0Æ24 (47) 0Æ74 ± 0Æ28 (63) 0Æ77 ± 0Æ22 (50)* 0Æ82 ± 0Æ32 (46)* 0Æ82 ± 0Æ23 (48)* 0Æ92 ± 0Æ22 (29) XIIIa (U ⁄ ml) 0Æ79 ± 0Æ26 (44) 0Æ94 ± 0Æ25 (49)* 0Æ93 ± 0Æ27 (44)* 1Æ04 ± 0Æ34 (44)* 1Æ04 ± 0Æ29 (41)* 1Æ05 ± 0Æ25 (29) XIIIb (U ⁄ ml) 0Æ76 ± 0Æ23 (44) 1Æ06 ± 0Æ37 (47)* 1Æ11 ± 0Æ35 (45)* 1Æ16 ± 0Æ34 (44)* 1Æ10 ± 0Æ30 (41)* 0Æ97 ± 0Æ20 (29)

*Values that do not differ statistically from the adult values. These measurements are skewed because of a disproportionate number of high values. All values expressed as mean ± 1 SD. (n) ¼ numbers studied. All factors except fibrinogen are expressed as U ⁄ ml where pooled plasma contains 1Æ0U⁄ ml. PK, Prekallikrein; HMW-K, high-molecular-weight kininogen. From Andrew et al (1987), Copyright American Society of Hematology, used by permission.

Table II. Reference values for the inhibition of coagulation in the healthy full-term infant during the first 6 months of life.

Inhibitors Day 1 (n) Day 5 (n) Day 30 (n) Day 90 (n) Day 180 (n) Adult (n)

AT 0Æ63 ± 0Æ12 (58) 0Æ67 ± 0Æ13 (74) 0Æ78 ± 0Æ15 (66) 0Æ97 ± 0Æ12 (60)* 1Æ04 ± 0Æ10 (56)* 1Æ05 ± 0Æ13 (28) a2-M 1Æ39 ± 0Æ22 (54) 1Æ48 ± 0Æ25 (73) 1Æ50 ± 0Æ22 (61) 1Æ76 ± 0Æ25 (55) 1Æ91 ± 0Æ21 (55) 0Æ86 ± 0Æ17 (29) C1E-INH 0Æ72 ± 0Æ18 (59) 0Æ90 ± 0Æ15 (76)* 0Æ89 ± 0Æ21 (63) 1Æ15 ± 0Æ22 (55) 1Æ41 ± 0Æ26 (55) 1Æ01 ± 0Æ15 (29) a1-AT 0Æ93 ± 0Æ22 (57)* 0Æ89 ± 0Æ20 (75)* 0Æ62 ± 0Æ13 (51) 0Æ72 ± 0Æ15 (56) 0Æ77 ± 0Æ15 (55) 0Æ93 ± 0Æ19 (29) HCII 0Æ43 ± 0Æ25 (56) 0Æ48 ± 0Æ24 (72) 0Æ47 ± 0Æ20 (58) 0Æ72 ± 0Æ37 (58) 1Æ20 ± 0Æ35 (55) 0Æ96 ± 0Æ15 (29) Protein C 0Æ35 ± 0Æ09 (41) 0Æ42 ± 0Æ11 (44) 0Æ43 ± 0Æ11 (43) 0Æ54 ± 0Æ13 (44) 0Æ59 ± 0Æ11 (52) 0Æ96 ± 0Æ16 (28) Protein S 0Æ36 ± 0Æ12 (40) 0Æ50 ± 0Æ14 (48) 0Æ63 ± 0Æ15 (41) 0Æ86 ± 0Æ16 (46)* 0Æ87 ± 0Æ16 (49)* 0Æ92 ± 0Æ16 (29)

*Values that do not differ statistically from the adult values.

All values expressed as mean ± 1 SD. (n) ¼ numbers studied. AT, antithrombin; a2-M, a2-macroglobulin; C1E-INH, C1esterase inhibitor; a1-AT, a1-antithrombin; HC-II, Heparin Cofactor II. From Andrew et al (1987), Copyright American Society of Hematology, used by permission. proteins can make distinguishing the pathological from the newborn’s coagulation system in the early weeks and physiological difficult and the correct interpretation of such months of life, necessitate sequential reference ranges which investigations is dependent on an awareness of the normal reflect the effects of gestational and postnatal age. As levels of these proteins in the neonate and how these are screening tests and factor assays are influenced by a influenced by gestational age, postnatal age and by external number of variables including test methodology, reagents factors such as sepsis or vitamin K deficiency. In particular, and instrumentation, laboratories should, wherever possi- the diagnosis of the majority of mild congenital factor ble, establish their own normal ranges for neonates of deficiencies will need to be confirmed by repeat testing later different gestational ages (Hathaway & Corrigan, 1991): in infancy: there is seldom any clinical indication to test for practically, the difficulty of recruiting suitable cohorts of a mild deficiency in children less than 6 months old and neonates can preclude this approach, with laboratory investigation can therefore usually be deferred beyond this reference ranges then being based on literature-derived age. The gestation-dependent differences between neonates data. The most frequently quoted data are those of Andrew and adults, together with the evolving state of the et al (1987, 1988, 1990a) who used a standardized

Ó 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 295–309 Ó 02BakelPbihn Ltd, Publishing Blackwell 2002

Table III. Reference values for coagulation tests in healthy premature infants (30–36 weeks gestation) during first 6 months of life. rts ora fHaematology of Journal British

Day 1 Day 5 Day 30 Day 90 Day 180 Adult

Tests MB MB MB MB MB MB

PT(s) 13Æ0 (10Æ6–16Æ2)* 12Æ5 (10Æ0–15Æ3)* 11Æ8 (10Æ0–13Æ6)* 12Æ3 (10Æ0–14Æ6)* 12Æ5 (10Æ0–15Æ0)* 12Æ4 (10Æ8–13Æ9) APTT(s)_ 53Æ6 (27Æ5–79Æ4) 50Æ5 (26Æ9–74Æ1) 44Æ7 (26Æ9–62Æ5) 39Æ5 (28Æ3–50Æ7) 37Æ5 (21Æ7–53Æ3)* 33Æ5 (26Æ6–40Æ3) TCT(s) 24Æ8 (19Æ2–30Æ4)* 24Æ1 (18Æ8–29Æ4)* 24Æ4 (18Æ8–29Æ9)* 25Æ1 (19Æ4–30Æ8)* 25Æ2 (18Æ9–31Æ5)* 25Æ0 (19Æ7–30Æ3) Fibrinogen (g ⁄ l) 2Æ43 (1Æ50–3Æ73)* 2Æ80 (1Æ60–4Æ18)* 2Æ54 (1Æ50–4Æ14)* 2Æ46 (1Æ50–3Æ52)* 2Æ28 (1Æ50 ¼ 3Æ60) 2Æ78 (1Æ56–4Æ00) II (U ⁄ ml) 0Æ45 (0Æ20–0Æ77) 0Æ57 (0Æ29–0Æ85) 0Æ57 (0Æ36–0Æ95) 0Æ68 (0Æ30–1Æ06) 0Æ87 (0Æ51–1Æ23) 1Æ08 (0Æ70–1Æ46) 119 V(U⁄ ml) 0Æ88 (0Æ41–1Æ44)* 1Æ00 (0Æ46–1Æ54) 1Æ02 (0Æ48–1Æ56) 0Æ99 (0Æ59–1Æ39) 1Æ02 (0Æ58–1Æ46) 1Æ06 (0Æ62–1Æ50)

295–309 : VII (U ⁄ ml) 0Æ67 (0Æ21–1Æ13) 0Æ84 (0Æ30–1Æ38) 0Æ83 (0Æ21–1Æ45) 0Æ87 (0Æ31–1Æ43) 0Æ99 (0Æ47–1Æ51)* 1Æ05 (0Æ67–1Æ43) VIII (U ⁄ ml) 1Æ11 (0Æ50–2Æ13)* 1Æ15 (0Æ53–2Æ05)* 1Æ11 (0Æ50–1Æ99)* 1Æ06 (0Æ58–1Æ88)* 0Æ99 (0Æ50–1Æ87)* 0Æ99 (0Æ50–1Æ49) VWF (U ⁄ ml) 1Æ36 (0Æ78–2Æ10) 1Æ33 (0Æ72–2Æ19) 1Æ36 (0Æ66–2Æ16) 1Æ12 (0Æ75–1Æ84)* 0Æ98 (0Æ54–1Æ58)* 0Æ92 (0Æ50–1Æ58) IX (U ⁄ ml) 0Æ35 (0Æ19–0Æ65) 0Æ42 (0Æ14–0Æ74) 0Æ44 (0Æ13–0Æ80) 0Æ59 (0Æ25–0Æ93) 0Æ81 (0Æ50–1Æ20) 1Æ09 (0Æ55–1Æ63) X(U⁄ ml) 0Æ41 (0Æ11–0Æ71) 0Æ51 (0Æ19–0Æ83) 0Æ56 (0Æ20–0Æ92) 0Æ67 (0Æ35–0Æ59) 0Æ77 (0Æ35–1Æ19) 1Æ06 (0Æ70–1Æ52) XI (U ⁄ ml) 0Æ30 (0Æ08–0Æ52) 0Æ41 (0Æ13–0Æ69) 0Æ43 (0Æ15–0Æ71) 0Æ59 (0Æ25–0Æ93) 0Æ78 (0Æ46–1Æ10) 0Æ97 (0Æ67–1Æ27) XII (U ⁄ ml) 0Æ38 (0Æ10–0Æ66) 0Æ39 (0Æ09–0Æ69) 0Æ43 (0Æ11–0Æ75) 0Æ61 (0Æ15–1Æ07) 0Æ82 (0Æ22–1Æ42) 1Æ08 (0Æ52–1Æ64) PK (U ⁄ ml) 0Æ33 (0Æ09–0Æ57) 0Æ45 (0Æ26–0Æ75) 0Æ59 (0Æ31–0Æ87) 0Æ79 (0Æ37–1Æ21) 0Æ78 (0Æ40–1Æ15) 1Æ12 (0Æ62–1Æ62) HMWK (U ⁄ ml) 0Æ49 (0Æ09–0Æ89) 0Æ62 (0Æ24–1Æ00) 0Æ64 (0Æ16–1Æ12) 0Æ78 (0Æ32–1Æ24) 0Æ83 (0Æ41–1Æ25)* 0Æ92 (0Æ50–1Æ36) XIIIa (U ⁄ ml) 0Æ70 (0Æ32–1Æ08) 1Æ01 (0Æ57–1Æ45)* 0Æ99 (0Æ51–1Æ47)* 1Æ13 (0Æ71–1Æ55)* 1Æ13 (0Æ65–1Æ61)* 1Æ05 (0Æ55–1Æ55) XIIIb (U ⁄ ml) 0Æ81 (0Æ35–1Æ27) 1Æ10 (0Æ68–1Æ58)* 1Æ07 (0Æ57–1Æ57)* 1Æ21 (0Æ75–1Æ67) 1Æ15 (0Æ67–1Æ63) 0Æ97 (0Æ57–1Æ37)

*Values indistinguishable from those of adults. Measurements are skewed owing to a disproportionate number of high values. Values different from those of full-term infants.

All factors except fibrinogen are expressed as U ⁄ ml, where pooled plasma contains 1Æ0U⁄ ml. All values are given as a mean (M) followed by lower and upper boundary encompassing 95% of Guideline the population (B). Between 40 and 96 samples were assayed for each value for newborns. From Andrew et al (1988), Copyright American Society of Hematology, used by permission. 297 298 Guideline Table IV. Reference values for inhibitors of coagulation in healthy premature infants during first 6 months of life.

Day 1 Day 5 Day 30 Day 90 Day 180 Adult

Tests MB MB M B MB MB MB

AT 0Æ38 (0Æ14–0Æ62) 0Æ56 (0Æ30–0Æ82)* 0Æ59 (0Æ37–0Æ81) 0Æ83 (0Æ45–1Æ21) 0Æ90 (0Æ52–1Æ28) 1Æ05 (0Æ79–1Æ31) a2-M 1Æ10 (0Æ56–1Æ82) 1Æ25 (0Æ71–1Æ77)* 1Æ38 (0Æ72–2Æ04) 1Æ80 (1Æ20–2.6) 2Æ09 (1Æ10–3Æ21) 0Æ86 (0Æ52–1Æ20) C1E-INH 0Æ65 (0Æ31–0Æ99) 0Æ83 (0Æ45–1Æ21) 0Æ74 (0Æ40–1Æ24) 1Æ14 (0Æ60–1Æ68)* 1Æ40 (0Æ96–2Æ04) 1Æ01 (0Æ71–1Æ31) a1AT 0Æ90 (0Æ36–1Æ44)* 0Æ94 (0Æ42–1Æ46) 0Æ76 (0Æ38–1Æ12) 0Æ81 (0Æ49–1Æ13)* 0Æ82 (0Æ48–1Æ16)* 0Æ93 (0Æ55–1Æ31) HCII 0Æ32 (0Æ00–0Æ60) 0Æ34 (0Æ00–0Æ69)* 0Æ43 (0Æ15–0Æ71) 0Æ61 (0Æ20–1Æ11) 0Æ89 (0Æ45–1Æ40)* 0Æ96 (0Æ66–1Æ26) Protein C 0Æ28 (0Æ12–0Æ44)* 0Æ31 (0Æ11–0Æ51)* 0Æ37 (0Æ15–0Æ59) 0Æ45 (0Æ23–0Æ67) 0Æ57 (0Æ31–0Æ83) 0Æ96 (0Æ64–1Æ28) Protein S 0Æ26 (0Æ14–0Æ38) 0Æ37 (0Æ13–0Æ61)* 0Æ56 (0Æ22–0Æ90) 0Æ76 (0Æ40–1Æ12) 0Æ82 (0Æ44–1Æ20) 0Æ92 (0Æ60–1Æ24)

*Values indistinguishable from those of adults. Measurements are skewed owing to a disproportionate number of high values. Lower limit which excludes the lower 2Æ5% of the population is given (B). Values different from those of full-term infants. All values are expressed in U ⁄ ml, where pooled plasma contains 1Æ0U⁄ ml. All values are given as a mean (M) followed by lower and upper boundary encompassing 95% of the population (B). Between 40 and 75 samples were assayed for each value for the newborn. From Andrew et al (1988), Copyright American Society of Hematology, used by permission.

Table V. Reference values for the components of the fibrinolytic system in healthy full-term infants during the first 6 months of life, compared with those in adults.

Fibrinolytic Day 1 Day 5 Day 30 Day 90 Day 180 Adults component mean (boundary) mean (boundary) mean (boundary) mean (boundary) mean (boundary) mean (boundary)

Plasminogen (U ⁄ ml) 1Æ95 (1Æ25–2Æ65) 2Æ17 (1Æ41–2Æ93) 1Æ98 (1Æ26–2Æ70) 2Æ48 (1Æ74–3Æ22) 3Æ01 (2Æ21–3Æ81) 3Æ36 (2Æ48–4Æ24) TPA (ng ⁄ ml) 9Æ60 (5Æ0–18Æ9) 5Æ60 (4Æ0–10Æ0)* 4Æ10 (1Æ00–6Æ00)* 2Æ1(1Æ0–5Æ0)* 2Æ8(1Æ0–6Æ0)* 4Æ9(1Æ4–8Æ4) a2AP (U ⁄ ml) 0Æ85 (0Æ55–1Æ15) 1Æ00 (0Æ70–1Æ30)* 1Æ00 (0Æ76–1Æ40)* 1Æ08 (0Æ76–1Æ40)* 1Æ11 (0Æ83–1Æ39)* 1Æ02 (0Æ63–1Æ35) PAI (U ⁄ ml) 6Æ40 (2Æ0–15Æ1) 2Æ30 (0Æ0–8Æ10)* 3Æ40 (0Æ0–8Æ80)* 7Æ2(1Æ0–15Æ3) 8Æ1(6Æ0–13Æ0) 3Æ6(0Æ0–11Æ0)

*Values indistinguishable from those of adults.

TPA, tissue plasminogen activator; a2AP, a2-antiplasmin; PAI, plasminogen activator inhibitor. For a2AP, values are expressed as U ⁄ ml, where pooled plasma contains 1Æ0U⁄ ml. Plasminogen units are those recommended by the Committee on Thrombolytic Agents. Values for TPA are given as ng ⁄ ml. Values for PAI are given as U ⁄ ml, where one unit of PAI activity is defined as the amount of PAI that inhibits 1 international unit of human single-chain TPA. All values are given as a mean followed by the lower and upper boundary encompassing 95% of the population (boundary). From Andrew et al (1990a), by permission of The American Journal of Pediatric Hematology ⁄ Oncology.

Table VI. Reference values for the components of the fibrinolytic system in healthy premature infants during the first 6 months of life, compared with those in adults.

Fibrinolytic Day 1 Day 5 Day 30 Day 90 Day 180 Adults component mean (boundary) mean (boundary) mean (boundary) mean (boundary) mean (boundary) mean (boundary)

Plasminogen (U ⁄ ml) 1Æ70 (1Æ12–2Æ48) 1Æ91 (1Æ21–2Æ61) 1Æ81 (1Æ09–2Æ53) 2Æ38 (1Æ58–3Æ18) 2Æ75 (1Æ91–3Æ59) 3Æ36 (2Æ48–4Æ24) TPA (ng ⁄ ml) 8Æ48 (3Æ00–16Æ70) 3Æ97 (2Æ00–6Æ93)* 4Æ13 (2Æ00–7Æ79)* 3Æ31 (2Æ00–5Æ07)* 3Æ48 (2Æ00–5Æ85)* 4Æ96 (1Æ46–8Æ46) a2AP (U ⁄ ml) 0Æ78 (0Æ40–1Æ16) 0Æ81 (0Æ49–1Æ13) 0Æ89 (0Æ55–1Æ23) 1Æ06 (0Æ64–1Æ48)* 1Æ15 (0Æ77–1Æ53) 1Æ02 (0Æ68–1Æ36) PAI (U ⁄ ml) 5Æ40 (0Æ0–12Æ2)* 2Æ50 (0Æ0–7Æ1)* 4Æ30 (0Æ0–10Æ9)* 4Æ80 (1Æ0–11Æ8)* 4Æ90 (1Æ0–10Æ2)* 3Æ60 (0Æ0–11Æ0)

*Values indistinguishable from those of adults. Values that are different from those of the full-term infant. All values are given as a mean followed by the lower and upper boundary encompassing 95% of the population (boundary). From Andrew et al (1990a), by permission of The American Journal of Pediatric Hematology ⁄ Oncology.

Ó 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 295–309 Guideline 299 protocol and venous blood samples from healthy term and increased neonatal haematocrit in order to avoid dilution preterm infants who had received 1 mg of Vitamin K at of coagulation factors and this is particularly pertinent for least 12 h prior to the first blood sample being drawn (see neonates with very high haematocrits (Corrigan, 1989). Tables I–VI). Laboratories and neonatal units usually take a more pragmatic approach to this problem and accept a degree of artefactual prolongation of the coagulation times. Blood is INVESTIGATION OF THE NEONATE therefore usually taken into 3Æ2% buffered sodium citrate, 2A. Sampling one part citrate to nine parts blood (National Committee Sample collection. Present day automated coagulometers for Clinical Laboratory Standards, 1998, Grade C recom- have reduced the need for laboratories to establish manual mendation based on level IV evidence) and the normal values microtechniques for coagulation screening. One millilitre of detailed in Tables I–VI have been obtained using this blood is sufficient to perform a coagulation screen and an methodology. additional 1 ml will be necessary for subsequent procoag- Overfilled or underfilled samples should not be analysed. ulant or anticoagulant assays. Sample processing. Twenty-four-hour access to laboratory Blood sampling from a neonate should avoid contamina- support is essential, and this will include availability of tion with intravenous fluids, particularly heparin, and factor assays. should also avoid activation of the coagulation process. Neonatal units should have established their own blood 2B. Laboratory investigation discard procedures to minimize the risk of contamination; i) Haemostasis. Screening tests of neonatal haemostasis activation is likely if sampling is slow through plastic tubing and their interpretation are described in Table VII. The and will result in a shortening of the prothrombin time (PT), investigation and management of neonatal thrombocytope- activated partial thromboplastin time (APTT) and thrombin nia are not within the remit of these guidelines but have time (TT). Platelet clumping is common in such samples, recently been the subject of Practice Guidelines (Letsky & resulting in spurious thrombocytopenia. All neonatal sam- Greaves, 1996) and of extensive review (Roberts & Murray, ples should be inspected for fibrin strands and platelet 1999). clumps to help interpretation of results. Abnormal results require more specific testing of the Sample anticoagulant. Sample tubes (1 ml) should be various components of the haemostatic system and should readily available to the Neonatal Unit. Ideally, the volume include: of anticoagulant in the sample tube should be based on the • Specific factor assays. Prolongation of the PT, APTT or TT volume of plasma and not on the total volume of blood which corrects in a 1:1 mix with normal plasma is taken. It should therefore be reduced in proportion to the indicative of either a single factor or multiple factor

Table VII. Screening tests of neonatal haemostasis.

Investigation Result Comment

1. Platelet count and < 150 · 109 ⁄ lis Platelet clumping secondary to activation is common. Always look for fibrin strands morphology abnormal, see text in sample. Morphology important for congenital platelet disorders such as Bernard Soulier, grey platelet syndrome 2. Prothrombin time (PT) See text Establish in-house normal range* if possible. Prolonged by deficiencies of some Vitamin K-dependent factors. 3. Activated partial See text Establish in-house normal range* if possible. Prolonged in healthy neonate thromboplastin time (APTT) because of relatively reduced levels of vitamin K-dependent factors and contact factors. 4. Thrombin clotting time (TCT) See text Prolonged compared with adult TCT because of fetal fibrinogen. Addition of calcium to the buffering system shortens time to adult range and increases sensitivity. 5. Fibrinogen See text Equivalent to adult normal range but levels rise in the first week of life (NB: when screening for DIC). Discrepancies between functional and immune assays helpful in diagnosis of dysfibrinogenaemias. 6. Bleeding time (BT) See text Infrequently performed. Shorter than adult range. Modified template device for use in neonates.

*Results obtained are dependent on reagents and coagulometer used. It is therefore preferable to establish in-house normal ranges rather than rely on published data (see text). Will be sensitive to hypofibrinogenaemias, dysfibrinogenaemias and the presence of heparin but not to the effects of fetal fibrinogen (Ockelford & Carter, 1982). Andrew et al (1990b).

Ó 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 295–309 300 Guideline deficiencies. The gestational age, postnatal age, vitamin K the natural history of the thrombotic event remain uncer- status and general well being of the neonate should all be tain. Thrombophilic defects have also been reported in considered in the interpretation of factor assays (see later). neonates with ischaemic stroke (Gunther et al, 2000), a • Factor XIII screen. Factor XIII deficiency does not prolong condition which often accompanies perinatal asphyxia and, any of the routine screening tests and requires specific less commonly, hypertension and polycythaemia: again, investigation. Screening for this deficiency involves the the contributory role of such defects in these settings is use of calcium or thrombin to produce a fibrin clot and uncertain. In order to justify the routine investigation of assessing the solubility of the clot in either 5 mol ⁄ l urea such defects, their demonstration should be shown to or 1% monochloracetic acid. The results of such screening influence the treatment of an affected individual. At the tests can be variable with thrombin-based screens more present time this is not the case and so extensive thromb- sensitive to reductions in factor XIII (Jennings et al, ophilic screening of the neonate with venous thrombosis or 2000); factor XIII assays are not widely used in the UK cerebral infarction cannot be recommended as part of but are more sensitive to lower levels of this protein (UK evidence-based guidelines. It is not possible, however, to NEQAS for blood coagulation 1998, Survey 112, unpub- make the assumption that the aetiology of thrombosis in lished observation). children and adults is similar or that the response to • Platelet function. The neonate’s bleeding time is shorter treatment and long-term complications of thrombosis are than that of adults and of older children (Andrew et al, the same in these two age groups. Clinicians should be aware 1990b), and may be influenced by a number of variables: that there are ongoing International and National Registries testing must therefore be standardized [Grade B recom- for Paediatric Thrombosis which will, in time, accumulate mendations based on level IIa,b evidence (Sutor, 1998)]. It is data and thereby inform the investigation and treatment of seldom indicated in the neonate and usually only childhood thrombosis: the provision of thrombophilic infor- performed when other more specific tests of haemostasis mation is likely to form an important component of such have failed to establish a cause of bleeding. Other global registries. tests of platelet function using instruments such as the The normal ranges of anticoagulant proteins in the Platelet Function Analyser (PFA)100 may provide an neonate are wide and can make interpretation of results alternative to the bleeding time and are currently being difficult. With the provisos mentioned above, laboratory evaluated in neonates. Formal platelet aggregation testing investigations may include the following, test methodology in the neonate requires significant amounts of platelet- having been addressed in the British Society for Standards rich plasma (> 150 ll). Variable results have been in Haematology (BCSH) guidelines for the investigation of reported in otherwise healthy neonates, making interpre- thrombophilia (Walker et al, 2001). tation of results difficult and, in most cases, of little • Protein C activity. Protein C is a Vitamin K-dependent clinical significance. protein and levels are physiologically reduced in the • Platelet glycoprotein expression is fully developed in term newborn. Homozygous protein C deficiency is usually and premature neonates and flow cytometry can establish easily diagnosed in the neonate with levels often unde- the diagnosis of the congenital disorders Bernard Soulier tectable at presentation. In contrast, the wide range of disease and Glanzmann’s Thrombasthenia using minimal protein C levels seen in the normal neonate can make amounts of blood. heterozygous protein C deficiency difficult to diagnose and • Investigation of the parents’ platelet function may be assays may have to be repeated after 6 months to confirm a helpful in selected cases. deficiency. Assays of other vitamin K-dependent coagula- • D-dimer. D-dimer estimation is a specific test of fibrin lysis tion proteins for comparison can be of help in the diagnosis, by plasmin and is a sensitive marker of coagulation as can the measurement of parental levels of protein C activation, including disseminated intravascular coagu- • Protein S. Total protein S levels in the neonate are low lation. There are very few data on normal D-dimer levels when compared with adult ranges but the protein is present in the neonate, but these have been reported to be almost totally in its free form due to the low levels of C4 b increased in cord blood samples even in the absence of binding protein (Schwarz et al, 1988). Free protein S levels, DIC because of the activation of coagulation which occurs however, are low when compared with adult values and during delivery (Hudson et al, 1990). increase to the adult range by 4 months of age, total protein ii) Thrombosis. The causative role of congenital deficien- S increasing similarly in the first 10 months of life. As with cies of anticoagulants in neonatal thrombosis is clear only in protein C, homozygous protein S deficiency is usually the homozygous ⁄ double heterozygous deficiencies of Protein associated with low or undetectable levels of protein S in C and Protein S which result in neonatal purpura fulminans: this age group and again, the heterozygous state can be replacement of these proteins forms the basis of treatment for difficult to diagnose definitively until a later age these conditions and the measurement of these proteins • Anti-thrombin (AT). Functional AT levels are reduced in should be undertaken in all neonates who develop this the term neonate and more so in the premature infant: they condition. It is becoming increasingly recognized that there will remain reduced for at least the first 3 months of life is a high prevalence of other thrombophilic defects in • Resistance to activated Protein C. The wide variations in children who develop venous thrombosis (Junker et al, neonatal factor VIII levels make this an inappropriate test 1999; Lawson et al, 1999; Heller et al, 2000), although in this age group and the Factor V Leiden genotype the causative nature of these defects and their influence on should be looked for directly

Ó 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 295–309 Guideline 301 • Factor V Leiden decarboxyprothrombin (PIVKA II), the Echis Prothrombin • Prothrombin20210A. time ratio and measurement of vitamin K concentrations, Each of these single point mutations is associated with an but these assays are rarely available for routine laboratory increased risk of venous thrombosis in adults and children use (Solano et al, 1990). and is identified using polymerase chain reaction (PCR) The use of vitamin K prophylaxis. i) In an attempt to reduce techniques (Bertina et al, 1994; Poort et al, 1996). Approx- early VKDB, guidelines have been published on the man- imately 4% and 2%, respectively, of Caucasians are hetero- agement of pregnant women with epilepsy (Delgado-Escueta zygous for these gene defects. Their causative role in & Janz, 1992). In addition to giving advice about the choice neonatal thrombosis is unknown but they may have a of anti-convulsant, intramuscular vitamin K (1 mg) is contributory role in the pathogenesis of thrombosis in this recommended for all neonates together with antenatal particular age group. administration of oral vitamin K (20 mg ⁄ d) during the last Abnormalities of the fibrinolytic system. Plasminogen levels 4 weeks of pregnancy. The latter recommendation is based at birth are approximately 50% of adult values but on the finding of absent PIVKA II in the cord blood of homozygous plasminogen deficiency does not appear to be women who received antenatal oral prophylaxis (Cornelis- associated with thrombosis (Mingers et al, 1998) and it sen et al, 1993; Grade B recommendation based on level IIa would therefore not seem justified to include this investiga- evidence). tion in thrombophilia testing. ii) Vitamin K requirements in a neonate are estimated to Other investigations of thrombophilia. Babies of women be around 1 lg ⁄ kg ⁄ d. Classical VKDB can be prevented by with systemic lupus erythematosus and ⁄ or antiphospholipid the postnatal administration of a single dose of vitamin K syndromes may infrequently develop thrombosis in the (1 mg) given orally or by intramuscular (i.m.) injection presence of associated autoantibodies (lupus anticoagulant, (Cornelissen et al, 1997). One i.m. dose of vitamin K, with anticardiolipin antibodies). Testing thrombotic neonates for rare exceptions, will also prevent late VKDB but the same is these disorders in the absence of a maternal history is not not true following a single oral dose, particularly in high- justified because of the rarity of such findings. risk infants (McNinch & Tripp, 1991). Routine prophylaxis Associations of neonatal thrombosis and other thromb- using parenteral vitamin K remains controversial following ophilic defects such as the methylenetetrahydrofolate the report of an association between i.m. vitamin K and reductase (MTHFR) T677T genotype and increased serum childhood cancer (Golding et al, 1992); a number of levels of lipoprotein a have recently been reported (Heller subsequent studies have failed to confirm this association et al, 2000). and the current evidence has been reviewed recently (Zipursky, 1999). Despite the absence of clear supporting data, the contro- 3. THE MANAGEMENT OF SPECIFIC ACQUIRED versy surrounding i.m. vitamin K and the risk of childhood DEFECTS OF HAEMOSTASIS cancer seems unlikely to be resolved in the short term. This Vitamin K deficiency and disseminated intravascular coag- has resulted in the continued use of parenteral vitamin K ulation (DIC) remain the major acquired haemostatic and to the development of alternative oral regimens, leading problems encountered in the neonate. The occurrence of to a wide variation in prophylaxis policy both in the UK and intracranial and intraventricular haemorrhage in this age worldwide. group has resulted in various prophylactic interventions Currently, it is recommended that all neonates receive being proposed but the lack of large controlled trials has postnatal vitamin K prophylaxis for the prevention of VKDB made treatment recommendations difficult and a number of (Grade B recommendation based on level III evidence, McNinch areas of controversy need to be resolved. & Tripp, 1991). It is not possible at this time to make a firm recommendation on the optimal route or regimen to be 3A. Vitamin K deficiency used: however, in well babies vitamin K 1 mg by i.m. Levels of the vitamin K-dependent coagulation proteins injection or oral vitamin K 1 mg at birth with an additional (factor II, VII, IX, X) and the naturally occurring inhibitors 25 lg ⁄ d thereafter for 3 months in infants who continue to protein C and protein S are physiologically low at birth and be breast fed appear to be associated with the lowest risk of these proteins are functionally inactive in the absence of VKDB (Grade B recommendation based on level III evidence, vitamin K. Cornelissen et al, 1997). Alternative oral regimes have also Haemorrhagic disease of the newborn or, in current been shown to be effective, such as vitamin K 2 mg at birth terminology, vitamin K deficiency bleeding (VKDB) can be followed by 1 mg weekly for 3 months in breast-fed babies classified as early, classical and late depending on the timing (Grade B recommendation based on level III evidence, Hansen & of presentation and the associated features (Sutor et al, Ebbesen, 1996). 1999). Management of vitamin K deficiency bleeding. Any infant Diagnosis. Isolated prolongation of the PT is the earliest suspected of VKDB should receive immediate intravenous laboratory evidence of vitamin K deficiency followed by vitamin K replacement: it is standard practice to administer prolongation of the APTT. The diagnosis is confirmed by a dose of 1 mg which will usually result in correction within correction of these parameters by vitamin K1 or by assay of a few hours (Grade C recommendation based on level IV the specific factors and comparing with age-adjusted normal evidence). Intravenous vitamin K can be associated with ranges. Other confirmatory tests include measurement of anaphylactoid reactions and should be administered by slow

Ó 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 295–309 302 Guideline intravenous injection; if venous access cannot be estab- performed for diagnostic purposes, reduced levels of proco- lished it can be given subcutaneously, the intramuscular agulant proteins and anticoagulants are also present, route being avoided in the presence of a coagulopathy reflecting ongoing consumption. It should, however, be (Grade C recommendations based on level IV evidence, Sutor emphasized that the laboratory assessment of DIC can be et al, 1999). difficult in the neonate and young infant because of the In infants who are bleeding, fresh-frozen plasma (FFP) physiological coagulation changes which occur during this 10–15 ml ⁄ kg should be administered in addition to vitamin period. The use of selected factor assays (FV and FVIII) can K(Grade C recommendation based on level IV evidence). This be useful in differentiating DIC from other acquired coag- will raise the vitamin K clotting factors by 10–20 iu ⁄ dl: care ulopathies in this age group. should be taken to avoid increases in blood pressure Management of DIC. The most important aspect of man- secondary to rapid volume expansion. The use of Pro- agement is reversal of the underlying disease process. thrombin Complex Concentrate (PCC) should be considered Acidosis should be corrected, tissue perfusion maintained in the presence of life-threatening haemorrhage or intra- and the neonate well oxygenated. Beyond this there are no cranial haemorrhage when it is necessary to normalize the clear guidelines on the optimal management of neonatal levels of the depleted coagulation factors. Whereas extrap- DIC and a virtual absence of recent randomized controlled olation of adult studies would suggest a dose of 50 u ⁄ kg, it trials addressing the available treatment options. should be noted that there is no direct data available for the All recommendations on the management of neonatal DIC are use of these concentrates in the neonate. grade C based on level IV evidence. Blood product replacement is indicated for the treatment 3B. Disseminated intravascular coagulation (DIC) of clinical bleeding in the presence of laboratory confirma- DIC always occurs as a secondary event to another disease tion of DIC. FFP (10–15 ml ⁄ kg) provides procoagulant entity (Table VIII). The incidence is particularly high during proteins and the naturally occurring inhibitors, AT, Protein the neonatal period, especially in preterm infants. The C (PC) and Protein S. Cryoprecipitate 10 ml ⁄ kg contains a clinical spectrum of neonatal DIC varies greatly from higher concentration of FVIII and fibrinogen per unit apparently asymptomatic cases of low-grade compensated volume than FFP and is particularly useful in the presence DIC to fulminant DIC characterized by bleeding and of hypofibrinogenaemia. Platelet concentrates (10– thrombosis. Intrapulmonary and intraventricular haemor- 15 ml ⁄ kg) may be necessary to maintain a platelet count rhage may be exacerbated in preterm infants by thromb- of > 50 · 109 ⁄ l. Paediatric platelet packs contain 60 ml of ocytopenia and an uncompensated coagulopathy. concentrate and are therefore ideal for most neonatal Laboratory diagnosis of DIC. DIC is characterized by transfusions: if such packs are not available an adult pack procoagulant activation, fibrinolytic activation and the should be used. Volume reduction of adult packs may be consumption of anticoagulants together with biochemical clinically indicated but this process can result in platelet evidence of end organ damage (Bick, 1995). Laboratory activation and aggregation, thereby reducing the in vivo abnormalities may therefore include a prolongation of the efficacy of the platelets. Red cell concentrates may be routine coagulation screening tests [PT, APTT, thrombin required and exchange transfusion may be necessary to clotting time (TCT)], a reduced plasma fibrinogen level, avoid volume overload. thrombocytopenia and increased D-dimers or fibrin ⁄ fibrino- Thrombosis can be as problematic as bleeding in DIC and gen degradation products. Although not routinely heparin should be given in obvious thrombotic DIC. The administration of naturally occurring coagulation inhibitors such as AT and PC has been shown to be of benefit in Table VIII. Disorders associated with neonatal disseminated intra- specific cases of adult DIC associated with multi organ vascular coagulation. failure (Smith et al, 1997; Eisele et al, 1998), although it is not known if this is applicable to similarly affected neonates: (a) Fetal ⁄ neonatal disorders (b) Maternal ⁄ obstetric disorders in the absence of clinical trials heparin, AT or PC either Hypoxia – acidosis; Dead twin alone or in combination cannot currently be recommended birth asphyxia, RDS for the routine treatment of neonatal DIC. Infection – bacterial, viral, Placental abruption fungal, protozoal, parasitic 3C. Intraventricular (IVH) ⁄ intracranial (ICH) haemorrhage Necrotizing enterocolitis Severe pre-eclampsia Periventricular-intraventricular haemorrhage is the most Meconium aspiration common form of ICH in preterm infants of low birth weight Aspiration of amniotic fluid with an incidence of around 15–20% for infants less than Brain injury 32 weeks gestation (Oh et al, 1996). The aetiology is Hypothermia multifactorial with alterations in cerebral blood flow, Haemolysis fragility of the immature germinal matrix vessels and Giant haemangioma (Kasabach–Merrit syndrome) endothelial ischaemia being more significant than impaired Homozygous ProteinC ⁄ S haemostasis. deficiency Various therapeutic modalities have been used in an Malignancy attempt to reduce the incidence of IVH, including measures to improve haemostasis. There has been no consistent

Ó 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 295–309 Guideline 303 benefit achieved by the prophylactic use of FFP or platelets Clinical features. In the absence of a positive family in high-risk infants (Northern Neonatal Nursing Initiative history, the diagnosis may be suspected by the presence of (NNNI) Trial Group, 1996a, b; Andrew et al, 1993) and abnormal bleeding, which usually occurs in the context of these blood products should not therefore be routinely an otherwise healthy infant. The haemophilias are the administered to such children (Grade A recommendations commonest inherited bleeding disorders to present in the based on level Ib evidence). It is, however, common practice to neonatal period. The pattern of bleeding observed in transfuse platelets prophylactically when the platelet count neonates is often iatrogenic in origin and can be charac- falls below 30 · 109 ⁄ l in an otherwise well infant or below terized by continued oozing or excessive haematoma 50 · 109 ⁄ l in the sick preterm neonate. formation following venepuncture, heel stab sampling or Information is also limited on the optimal management of the administration of intramuscular vitamin K. Significant a neonates with a pre-existing IVH: it would, however, seem haemorrhage can occur following circumcision. Umbilical appropriate to correct a coagulation abnormality and bleeding is relatively uncommon in haemophilia and is maintain a platelet count of > 50 · 109 ⁄ l in order to typically associated with severe hypofibrinogenaemia and prevent extension of the bleed (Grade C recommendation based homozygous factor XIII deficiency. Likewise, ICH occurs on level IV evidence). An inherited coagulation disorder infrequently in haemophiliacs but is a significant cause of should always be excluded in any neonate with an morbidity and mortality in the severe forms of factor VII, apparently spontaneous ICH (Grade C recommendation based factor X and factor XIII deficiency (Girolami et al, 1985). on level IV evidence). Diagnosis. Factor VIII levels are within the normal adult range in both term and preterm infants and it is therefore possible to confirm a diagnosis of haemophilia A in the 4. THE MANAGEMENT OF INHERITED neonatal period regardless of gestational age and severity. COAGULATION DEFICIENCIES This also applies to deficiencies of fibrinogen and factor V. The vast majority of bleeding problems seen during the The diagnosis of severe (< 2 iu ⁄ dl) and moderate neonatal period are due to acquired haemostatic disorders. (2–5 iu ⁄ dl) haemophilia B can also be confirmed in the However, inherited coagulation disorders can present in the neonatal period. However, confirmation of mildly neonatal period and there may be no preceding family (> 5 iu ⁄ dl) affected cases is problematic due to overlap with history to suggest the diagnosis. the normal range necessitating repeat testing at around Perinatal management. In the presence of a positive family 6 months of age. history of an inherited coagulation deficiency, pregnancy von Willebrand disease (VWD) is caused by quantitative and delivery should be managed in such a way as to reduce or qualitative defects of von Willebrand factor (VWF) the potential risk of bleeding in both the mother and baby to (Sadler, 1994). This factor is an acute phase protein and a minimum. This should entail the close liaison of the physiological increases make the diagnosis of type 1 VWD Obstetric and Neonatal Units and the local Haemophilia difficult in the neonate. Type 2 VWD can be suspected from Centre so that a management plan exists for the delivery discrepancies in the plasma levels of VWF antigen and and for the subsequent investigation and treatment of the activity and some subtypes may be confirmed by analysis of neonate. The management of such women has been the VWF multimers, although the relative lack of VWF-cleaving subject of recent guidelines (Haemostasis and Thrombosis protease in the neonate can make such analysis difficult. Task Force, 1994). Type 3 von Willebrand disease can be diagnosed in Rarely, factor replacement therapy may be required neonates who have essentially a total deficiency of von urgently following delivery and access to appropriate Willebrand factor. Knowledge of the particular molecular treatment should be arranged prior to delivery. At birth a defect occurring in the family will also be of value where the cord blood sample should be obtained for the relevant diagnosis is in doubt. coagulation factor investigations. Homozygous deficiencies of factors II, VII, X and XI can Historically the risk of intracranial haemorrhage in be diagnosed in the neonatal period, whereas levels in neonatal haemophilia A or B has appeared to be low. heterozygotes may overlap with the normal range preclud- However, a recent literature review has described a cumu- ing confident identification at this stage. Exclusion of Factor lative incidence for intracranial and extracranial haemor- XIII deficiency should be carried out in neonates having rhage of 3Æ58% (Kulkarni & Lusher, 1999). Prophylactic characteristic bleeding patterns accompanied by normal administration of factor VIII concentrate to the neonate coagulation screening tests. may reduce this incidence or modify the bleed (Buchanan, Management. Where there is clinically significant ongo- 1999), although no evidence currently exists to support this ing haemorrhage and a congenital factor deficiency is as routine practice. Whereas cranial ultrasound findings suspected but not confirmed, fresh-frozen plasma (10– from large prospective series are lacking, scanning of the 15 ml ⁄ kg) may be administered while the results of head should at the least be undertaken in the first hours laboratory investigations are awaited (Grade C recommenda- after delivery if there has been any trauma during delivery tion based on level IV evidence). Guidelines for the treatment of and in other congenital deficiency states where the risk of hereditary coagulation disorders have recently been pub- ICH is higher, e.g. FXIII, FVII, FX, deficiency [Grade C lished by the UK Haemophilia Centres Doctors’ Organization recommendation based on level IV evidence (Girolami et al, (UKHCDO, 1997) and management of these disorders 1985, Anwar & Miloszewski, 1999). should always be undertaken in conjunction with the local

Ó 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 295–309 304 Guideline Haemophilia Centre or Comprehensive Care Centre. Recom- sick term and preterm infants: the most important risk binant factor VIII and recombinant factor IX concentrates factor for the development of thrombosis during the carry the lowest risk of transmitting viral infection and neonatal period is the presence of an indwelling central should therefore be given to neonates with haemophilia A line and consequently the vessels involved tend to be those or B who require factor replacement [Grade B recommenda- most frequently used for catheterization. Other documented tion based on level III evidence (UKHCDO, 1997)]. If recom- risk factors for the development of neonatal thrombosis binant products are not available, a high purity, viricidally include asphyxia, septicaemia, dehydration, maternal dia- inactivated plasma-derived concentrate should be used betes and cardiac disease. [Grade B recommendation based on level III evidence (UKHCDO, Spontaneous, non-catheter-related thrombotic events are 1997)]. There is little information available on the phar- uncommon in the neonatal period and most frequently macokinetics of replacement therapy in neonates and involve the renal vein. The majority of cases of renal vein dosing is therefore based on schedules used in older children thrombosis present during the first few days of life and, in and adults (Rickard, 1995). approximately a quarter of these, the thrombosis is bilateral Due to the risks of hyponatraemia and water intoxica- with a smaller proportion also developing extension into the tion, desmopressin (DDAVP) should not be used in the inferior vena cava. treatment of neonatal VWD. A viricidally treated interme- Predisposing factors. Acquired deficiencies of protein C diate purity factor VIII concentrate containing the high- and protein S, particularly in sick, preterm infants, may molecular-weight multimers of von Willebrand factor increase the risk of thrombosis (Manco-Johnson et al, remains the treatment of choice [Grade C recommendation 1991). At present, the impact of inherited prothrombotic based on level IV evidence (UKHCDO, 1997)]. defects on both catheter-related and spontaneous throm- The treatment of bleeding secondary to other inherited botic events in the neonatal period remains poorly defined, deficiency disorders should be with specific high purity although it seems likely that these will become increasingly factor concentrates where these products exist (fibrinogen, recognized as contributory factors in this setting (Heller factor VII, factor XI, factor XIII) or, alternatively, with PCC et al, 2000). for deficiencies of factor II or factor X and fresh-frozen Neonatal thrombotic events have occasionally been plasma for factor V deficiency (Grade C recommendation based reported in association with maternal systemic lupus on level IV evidence). Although specific concentrates are erythematosus due to the transplacental passage of anti- usually plasma derived, recombinant factor VIIa may phospholipid antibodies (Tabbutt et al, 1994). provide an alternative to plasma-derived factor VII for the Diagnosis of neonatal thrombosis. Thrombosis must be treatment of inherited factor VII deficiency (Billio et al, confirmed objectively before undertaking thrombolytic 1997). Factor XI concentrate and PCCs should be used with treatment or anticoagulation given the significant risks of care in the neonatal period because of the potential risk of such treatment in this age group. thrombosis: there are few data available on the use of Doppler ultrasound methods are the most frequently used these products in neonates and FFP may provide a safer scanning techniques and provide readily available, non- alternative. Neonates found to have homozygous factor XIII invasive imaging giving valuable diagnostic information. deficiency are at significant risk of ICH and are likely to Reliance on Doppler can fail to diagnose thrombosis in benefit from routine prophylaxis that maintains plasma particular sites such as the aorta, right atrium and inferior factor XIII levels above 3 iu ⁄ dl. Current regimens utilize a vena cava in neonates with umbilical artery or venous dose of 30 iu ⁄ kg administered once monthly. If factor XIII catheters when compared with the use of contrast angiogra- concentrate is not available, FFP 5–10 ml ⁄ kg can be used. phy (Vailas et al, 1986; Roy et al, 1997). Similar problems are Prophylaxis during the neonatal period should also be likely to exist with imaging of the upper limb venous system considered in severe homozygous FVII and FX deficiency and the most recent recommendation of the Scientific and although even with appropriate replacement therapy sig- Standardization Subcommittee on Neonatal Haemostasis is nificant haemorrhage may still occur (Grade C recommenda- that contrast angiography remains the gold standard tion based on level IV evidence). imaging technique for the confirmation of thrombotic vessel All infants who may require treatment with factor occlusion, particularly when thrombolytic therapy or surgery concentrates should be vaccinated against hepatitis B is planned [Grade B recommendation based on level III evidence (Grade C recommendation based on level IV evidence). This (Schmidt & Andrew, 1992)]. Linograms, when dye is injected should be administered subcutaneously with pressure via a central venous line, are not a substitute for venography applied over the injection site for 5 min. Hepatitis A and may fail to demonstrate extensive thrombosis. vaccination should not be administered until the child is Computerized tomography (CT) and magnetic resonance at least 1 year old. imaging (MRI) scanning are indicated for thrombosis- related problems of the central nervous system (CNS). Management of neonatal thrombosis. The management of 5. NEONATAL THROMBOSIS arterial and venous thromboembolic events in the neonatal Neonates and infants less than 1 year of age account for the period remains controversial and it is generally acknowl- largest proportion of thrombotic events seen in the paedi- edged that there is an urgent need for large multicentre atric population (Andrew et al, 1994a). These events, studies on which to base recommendations. Treatment however, remain relatively uncommon and often occur in options include supportive care only, anticoagulant therapy

Ó 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 295–309 Guideline 305 with heparin or low-molecular-weight heparin (LMWH), The optimal duration of anticoagulation remains unde- thrombolytic therapy and surgery. Warfarin is not indicated fined but short-term therapy (e.g. 10–14 d) is commonly in the neonatal period because of the difficulties in estab- used, with objective radiological monitoring performed both lishing consistent levels of anticoagulation. during and after completion of anticoagulant therapy. If All recommendations on the management of neonatal throm- there is evidence of a new or extending thrombus following bosis are Grade C, based on level IV evidence, unless otherwise completion of initial therapy, heparin should be recom- stated. menced. Supportive therapy. In the absence of controlled studies Low molecular weight heparin is becoming increasingly indicating the efficacy of more aggressive therapy, support- used in the treatment of neonatal thrombosis. Dose-finding ive care alone may be appropriate management for clini- studies have been published and indicate that, as with cally silent thrombosis, which will therefore include the standard heparin, dose requirements in the neonate are majority of small, asymptomatic catheter-related events higher than in older children (Massicotte et al, 1996; Nohe (Schmidt & Andrew, 1992). Regular objective monitoring et al, 1999). For example, the recommended dose of should be performed to detect extension of the original enoxaparin is 1Æ5mg⁄ kg ⁄ dose administered subcuta- thrombus and in the case of catheter-related events, neously twice per day which should result in a therapeutic catheter removal is recommended. anti-Xa level of between 0Æ5 and 1Æ0 units ⁄ ml by chrom- Anticoagulant therapy. In the presence of more extensive, ogenic assay at 4 h post dose [Grade B recommendation based clinically significant thrombosis, particularly when there is on level IIb evidence (Massicotte et al, 1996)]. evidence of organ or limb dysfunction, consideration should Thrombolytic therapy. Thrombolytic therapy should be be given to the use of anticoagulant therapy. Unfractionated considered in the presence of extensive thrombosis with heparin remains the most frequently used anticoagulant, organ dysfunction or when limb viability is threatened. although there is increasing experience with LMWH in this Such therapy should not be used within 10 d of surgery or age group. in the presence of pre-existing bleeding problems. The use of heparin in the neonatal period is complicated Streptokinase, urokinase and tissue plasminogen activa- by the physiological immaturity of the haemostatic system, tor (t-PA) have all been used in neonates but overall with reduced levels of antithrombin resulting in relative experience is relatively limited and results conflicting heparin resistance (Schmidt et al, 1988). (Chalmers & Gibson, 1999). As with heparin, the response A dosage regimen for unfractionated heparin has been to thrombolytic agents in the neonate is significantly suggested by Andrew et al (1994b) and is shown in different from that seen in older children, reflecting Table IX [Grade B recommendation based on level IIb evidence physiologically reduced levels of plasminogen. In vitro (Andrew et al, 1994b)]. studies have demonstrated that t-PA is more effective than In the absence of a validated therapeutic range for the use streptokinase and similar to urokinase at lysing thrombi in of heparin in neonates, the APTT should be prolonged to a plasmas with decreased concentrations of plasminogen. therapeutic range corresponding to an anti-Xa level of t-PA and urokinase are therefore the preferred agents for 0Æ35–0Æ7 units ⁄ ml, although the limitations of the anti-Xa thrombolytic therapy in neonates. Recommended dosing level should be noted (it provides a guide to the pharmoki- regimens are shown in Table X [Grade B recommendation netics of heparin and only limited information on the based on evidence level IIB (Leaker et al, 1996)]. anticoagulant and prohaemorrhagic effects in vivo of this There is no laboratory therapeutic range for thrombolytic drug. Also, standard anti Xa assays will tend to underes- agents and successful lysis is confirmed on clinical and timate heparin unless the neonatal antithrombin deficiency radiological changes: monitoring should therefore be per- is fully corrected in the test system). formed during thrombolytic therapy to assess the response Nomograms are available for dose adjustment (Andrew to treatment and the duration of therapy will vary depend- et al, 1994b), and can be modified by individual laboratories ing on this response. Failure to induce lysis of the thrombus in order to achieve their own therapeutic APTT range. may indicate the need for plasminogen supplementation Thrombocytopenia is common in the sick neonate and with FFP. every attempt should be made to maintain a platelet count In order to reduce the risk of bleeding in the neonate above 50 · 109 ⁄ l during heparin therapy. receiving fibrinolytics, it is recommended that fibrinogen is maintained at > 1 g ⁄ l using cryoprecipitate and the platelet count at > 50 · 109 ⁄ l by transfusion (Grade C, level IV evidence). Table IX. Heparinization of neonates and dose adjustment.

Loading dose of heparin : 75 iu ⁄ kg, then Table X. Thrombolytic regimes in the neonate. Continuous infusion : 28 iu ⁄ kg ⁄ h Monitor using an APTT or heparin assay, Drug Bolus Maintenance Duration taking first blood sample 4 h after loading dose. Urokinase 4400 u ⁄ kg 4400 u ⁄ kg ⁄ h 6–12 h Use nomogram for dose adjustment. t-PA None 0Æ1–0Æ6mg⁄ kg ⁄ h6h

Ó 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 295–309 306 Guideline The use of heparin either during or after completion of ment therapy when DIC is ongoing, the half-life of the thrombolytic therapy is controversial: if given, a dose of infused protein C may be as short as 2–3 h, necessitating 28 iu ⁄ kg ⁄ h is appropriate in the neonate. frequent dosing. This usually improves to about 10 h once Prophylactic anticoagulation. Heparin prophylaxis is rec- the DIC is controlled, enabling a single daily treatment to ommended for neonates with indwelling umbilical artery be given (Dreyfus et al, 1995). Protein C levels should catheters and those undergoing cardiac catheterization. remain in excess of 0Æ25 U ⁄ ml to prevent further throm- Umbilical artery patency can be prolonged by the use of low- bosis (Muller et al, 1996). Replacement therapy is required dose heparin (3–5 u ⁄ h) by continuous infusion [Grade B for an initial period of at least 6–8 weeks to facilitate recommendation based on level IIb evidence (Sutor et al, 1997)]. resolution of clinical lesions. Whether the incidence of clinically significant thrombi is There is no currently available protein S concentrate and also reduced is not clear. Thrombotic complications associ- FFP is therefore used for replacement therapy (10–20 ml ⁄ kg ated with cardiac catheterization can be reduced by the every 8–12 h) (Grade C recommendation based on level IV administration of a bolus of heparin (100–150 units ⁄ kg) as evidence). the femoral artery is catheterized (Freed et al, 1974). A Long-term management remains controversial but cur- second bolus may be required for prolonged procedures. rent regimens utilize oral anticoagulants with or without concomitant replacement therapy. It is difficult to warfar- inize infants until their vitamin K-dependent factors have 6. CONGENITAL HOMOZYGOUS PROTHROMBOTIC physiologically increased and affected babies should prefer- DISORDERS ably receive replacement therapy. Older children receiving Protein C and Protein S deficiencies warfarin seem to require an International Normalized Ratio Homozygous (or compound heterozygous) deficiencies of (INR) at the upper end of the therapeutic range (3Æ0–4Æ5) to protein C and protein S (plasma activities < 0Æ01 U ⁄ ml) are prevent recurrent skin necrosis (Grade C recommendation rare conditions and usually present as life-threatening based on level IV evidence) and therefore require careful disorders in the neonatal period (Marlar & Neumann, monitoring. Where possible, dosing should be individualized 1990). A less severe form of protein C deficiency in which to identify the minimum dose required to remain symptom the level of protein C, although reduced, remains detectable free. In the event of recurrent problems during warfarin (0Æ02–0Æ23 U ⁄ ml), may present in the neonatal period, therapy, temporary or longer term reintroduction of protein although does so more commonly in later life (Sharon et al, C replacement may be required. 1986). Similar problems have been reported in the management Clinical features. Onset is usually within the first few days of homozygous protein S deficiency where, again, intermit- of life and can occur within hours of birth. The microcir- tent replacement with FFP may be required in addition to culation is characteristically affected first with the develop- oral anticoagulants (Mahasandana et al, 1996). ment of purpura fulminans associated with laboratory Low-molecular-weight heparin may be a useful thera- evidence of DIC. Cerebral and renal vein thrombosis are peutic option in the long term treatment of homozygous common and can be presenting features. Ocular manifes- protein C deficiency in which plasma levels remain detect- tations are also characteristic and it is likely that cerebral able but its place in the management of cases with and ophthalmic thrombosis often occur as intrauterine undetectable levels has not been determined (Monagle et al, events. Although purpura fulminans is almost always a 1998). feature, major vessel thrombosis occasionally occurs in isolation. Other homozygous defects Diagnosis. In the acute untreated phase, baseline labora- Homozygous AT deficiency has been recorded very infre- tory results are frequently indicative of DIC. The definitive quently. Type I defects are probably incompatible with life diagnosis can be difficult in the neonate. Protein C and and the majority of reports relate to type II HBS defects protein S levels are physiologically reduced at birth and are (Chouwdury et al, 1994). Long-term anticoagulation has further reduced in the presence of DIC, during which protein been successfully used in this disorder. C in particular can reach very low levels. The diagnosis is Homozygosity for the Factor V Leiden mutation rarely therefore based on finding undetectable protein C (or presents in childhood and a significant number of adults protein S) activity (< 0Æ01 U ⁄ ml) with heterozygous levels with this mutation also remain symptom free throughout in the parents. When the molecular defect is known, their lives, the same being true for individuals homozygous prenatal diagnosis can be offered to families when there is a for the PT20210A mutation. prior history of neonatal purpura fulminans. Management. The most important aspect of management 1Birmingham Children’s Michael D. Williams1 in the acute phase is the immediate and adequate Hospital, Birmingham, and Elizabeth A. Chalmers2 replacement of the deficient inhibitor. Protein C deficient 2Royal Hospital for Brenda E. S. Gibson2 neonates should receive Protein C concentrate at a starting Sick Children, Yorkhill, dose of 40 IU ⁄ kg, subsequent dosage being based on Glasgow, UK on behalf of the protein C recovery data. If concentrate is not immedi- Haemostasis and Thrombosis ately available, FFP 10–20 ml ⁄ kg should be used as a Task Force, British Committee temporary measure. During the early stages of replace- for Standards in Haematology

Ó 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 295–309 Guideline 307 ACKNOWLEDGMENTS Buchanan, G.B. (1999) Factor concentrate prophylaxis for neo- nates with haemophilia. Journal of Paediatric Haematology ⁄ On- The authors and the Haemostasis and Thrombosis Task cology, 21, 254–256. Force wish to acknowledge the helpful, constructive Chalmers, E.A. & Gibson, B.E.S. (1999) Thrombolytic therapy in the comments made on this document by British Society of management of paediatric thromboembolic disease. British Jour- Haematology members and by other representatives of nal of Haematology, 104, 14–21. professional bodies including the Royal College of Paedi- Chouwdury, V., Lane, D.A., Mille, B., Auberger, K., Gandenberger- atrics and Child Health, the British Association for Bachem, S., Pabinger, I., Olds, R.J. & Thein, S.L. (1994) Homo- Paediatric Medicine and the Paediatric Haematology zygous antithrombin deficiency: Report of two new cases (99Leu Forum. to Phe) associated with venous and arterial thrombosis. Throm- bosis and Haemostasis, 72, 198–202. Cornelissen, M., Steegers-Theunissen, R., Kollee, L., Eskes, T., RECOMMENDED REVIEW AND EXPIRY DATE Vogels-Mentik, G., Motohara, K., De Abreu, R. & Monnens, L. OF THIS GUIDELINE (1993) Increased incidence of neonatal vitamin K deficiency resulting from maternal anti convulsant therapy. American 1. Review date: 5 years from publication Journal of Obstetrics and Gynaecology, 168, 923–928. 2. Expiry date: 6 months after review date. Cornelissen, M., von Kries, R., Loughnan, P. & Schubiger, G. (1997) Prevention of vitamin K deficiency bleeding: efficacy of different multiple oral dose schedules of vitamin K. European Journal of REFERENCES Paediatrics, 156, 126–130. Andrew, M., Paes, B., Milner, R., Johnson, M., Mitchell, L., Tollef- Corrigan, J.J. 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Ó 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 295–309 Guideline 309 Solano, C., Cobcroft, R.G. & Scott, D.C. (1990) Prediction of vitamin APPENDIX. GRADED RECOMMENDATIONS K response using the Echis time and the Echis-prothrombin time (US Department of Health & Human Services, 1992) ratio. Thrombosis and Haemostasis, 64, 353–357. Sutor, A.H. (1998) The bleeding time in paediatrics. Seminars in Grade of recommendation Thrombosis and Haemostasis, 24, 531–543. Sutor, A.H., Massicotte, P., Leaker, M. & Andrew, M. (1997) Heparin therapy in paediatric patients. Seminars in Thrombosis A. (Evidence levels Ia, Ib) Requires at least one randomized and Haemostasis, 23, 303–319. controlled trial as part of the body Sutor, A.H., von Kries, R., Cornelissen, E.A.M., McNinch, A.W. & of literature of overall good qual- Andrew, M. on behalf of the ISTH Paediatric ⁄ Perinatal Sub- ity and consistency addressing committee (1999) Vitamin K Deficiency Bleeding (VKDB) in the specific recommendation. Infancy. Thrombosis and Haemostasis, 81, 456–461. B. (Evidence levels IIa, IIb, III) Requires availability of well-con- Tabbutt, S., Griswold, W.R., Ogino, M.T., Mendoza, A.E., Allen, J.B. ducted clinical studies but no & Reznik, V.M. (1994) Multiple thromboses in a premature randomized clinical trials on the infant associated with maternal phospholipid antibody topic of recommendation syndrome. Journal of Perinatology, 14, 66–70. C. (Evidence level IV) Requires evidence from expert United Kingdom Haemophilia Centre Directors Organisation Exec- committee reports or opinions utive Committee (1997) Guidelines on therapeutic products to and ⁄ or clinical experience of treat haemophilia and other hereditary coagulation disorders. respected authorities; indicates Haemophilia, 3, 63–77. absence of directly applicable US Department of Health and Human Services, Public Health Ser- studies of good quality vice and Agency Care Policy and Research (1992) Acute Pain Management: Operative or Medical Procedures and Trauma. Report AHCPR Pub. 92–0038, Agency for Health Care Policy and Levels of evidence Research Publications. Vailas, G.N., Brouillette, R.T., Scott, J.P., Shkolnik, A., Conway, J. & Wiringa, K. (1986) Neonatal aortic thrombosis: recent experi- Ia. Meta-analysis of randomized controlled trials. ence. Journal of Pediatrics, 10, 101–108. Ib. At least one randomized controlled trial. Walker, I.D., Greaves, M. & Preston, F.E. on behalf of the Hae- IIa. At least one well-designed controlled study without random- mostasis and Thrombosis Task Force, British Committee for ization. Standards in Haematology (2001) Investigation and manage- IIb. At least one other type of well-designed quasi-experimental ment of heritable thrombophilia. British Journal of Haematology, study. 114, 512–528. III. Well-designed nonexperimental descriptive studies, such as Zipursky, A. (1999) Prevention of vitamin K deficiency in new- comparative studies, correlation studies and case–control studies. borns. British Journal of Haematology, 104, 430–437. IV. Expert committee reports or opinions and ⁄ or clinical evidence of respected authorities. Keywords: neonate, developmental haemostasis, throm- bosis, bleeding disorders, anticoagulation.

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