ABSTRACT
It has long been considered that a severe coagulation deficiency in premature newborns
could be a major contributing factor in the occurrence of intraventricular hemorrhage
(IVH). High-grade IVH has also been shown to coincide with severe derangement of coagulation
in extremely low birth weight infants. This review focuses on the relevance of the
physiologically developing immature hemostatic system to IVH, and the potential benefit
of agents affecting hemostasis for IVH therapy or prevention in preterm infants. The
findings of small, open-label interventional studies on the effect of ethamsylate,
vitamin K, fresh frozen plasma, recombinant activated factor VII, and prothrombin
complex concentrate on the premature coagulation system will be reviewed.
KEYWORDS
Intraventricular hemorrhage - prematurity - vitamin K - recombinant factor VIIa -
thrombin
REFERENCES
- 1
Fanaroff A A, Stoll B J, Wright L L NICHD Neonatal Research Network et al.
Trends in neonatal morbidity and mortality for very low birthweight infants.
Am J Obstet Gynecol.
2007;
196
(2)
147, e1-e8
- 2
Vohr B R, Garcia-Coll C, Mayfield S, Brann B, Shaul P, Oh W.
Neurologic and developmental status related to the evolution of visual-motor abnormalities
from birth to 2 years of age in preterm infants with intraventricular hemorrhage.
J Pediatr.
1989;
115
(2)
296-302
- 3 Volpe J J. Neurology of the Newborn. 3rd ed. Philadelphia: Saunders; 1995
- 4
Hambleton G, Wigglesworth J S.
Origin of intraventricular haemorrhage in the preterm infant.
Arch Dis Child.
1976;
51
(9)
651-659
- 5
Gould S J, Howard S.
An immunohistochemical study of the germinal layer in the late gestation human fetal
brain.
Neuropathol Appl Neurobiol.
1987;
13
(6)
421-437
- 6
Perlman J M, McMenamin J B, Volpe J J.
Fluctuating cerebral blood-flow velocity in respiratory-distress syndrome. Relation
to the development of intraventricular hemorrhage.
N Engl J Med.
1983;
309
(4)
204-209
- 7
Nakamura Y, Okudera T, Fukuda S, Hashimoto T.
Germinal matrix hemorrhage of venous origin in preterm neonates.
Hum Pathol.
1990;
21
(10)
1059-1062
- 8
Reeder J D, Kaude J V, Setzer E S.
Choroid plexus hemorrhage in premature neonates: recognition by sonography.
AJNR Am J Neuroradiol.
1982;
3
(6)
619-622
- 9
Papile L A, Burstein J, Burstein R, Koffler H.
Incidence and evolution of subependymal and intraventricular hemorrhage: a study of
infants with birth weights less than 1,500 gm.
J Pediatr.
1978;
92
(4)
529-534
- 10
Leviton A, Kuban K, Paneth N.
Intraventricular haemorrhage grading scheme: time to abandon?.
Acta Paediatr.
2007;
96
(9)
1254-1256
- 11
Vasileiadis G T.
Grading intraventricular hemorrhage with no grades.
Pediatrics.
2004;
113
(4)
930-931, author reply 930–931
- 12
Hope P L, Gould S J, Howard S, Hamilton P A, Costello A M, Reynolds E O.
Precision of ultrasound diagnosis of pathologically verified lesions in the brains
of very preterm infants.
Dev Med Child Neurol.
1988;
30
(4)
457-471
- 13
Amato M, Konrad D, Hüppi P, Donati F.
Impact of prematurity and intrauterine growth retardation on neonatal hemorrhagic
and ischemic brain damage.
Eur Neurol.
1993;
33
(4)
299-303
- 14
Linder N, Haskin O, Levit O et al..
Risk factors for intraventricular hemorrhage in very low birth weight premature infants:
a retrospective case-control study.
Pediatrics.
2003;
111
(5 Pt 1)
e590-e595
- 15
Lemons J A, Bauer C R, Oh W NICHD Neonatal Research Network et al.
Very low birth weight outcomes of the National Institute of Child health and human
development neonatal research network, January 1995 through December 1996.
Pediatrics.
2001;
107
(1)
E1
- 16 Horbar J D. Vermont-Oxford Network 1997 Database Summary. Burlington, VT: Vermont-Oxford
Network; 1997
- 17
Levene M I, Fawer C L, Lamont R F.
Risk factors in the development of intraventricular haemorrhage in the preterm neonate.
Arch Dis Child.
1982;
57
(6)
410-417
- 18
McCrea H J, Ment L R.
The diagnosis, management, and postnatal prevention of intraventricular hemorrhage
in the preterm neonate.
Clin Perinatol.
2008;
35
(4)
777-792, vii
- 19
Whitelaw A.
Intraventricular haemorrhage and posthaemorrhagic hydrocephalus: pathogenesis, prevention
and future interventions.
Semin Neonatol.
2001;
6
(2)
135-146
- 20
Krishnamoorthy K S, Shannon D C, DeLong G R, Todres I D, Davis K R.
Neurologic sequelae in the survivors of neonatal intraventricular hemorrhage.
Pediatrics.
1979;
64
(2)
233-237
- 21
Pinto-Martin J A, Whitaker A H, Feldman J F, Van Rossem R, Paneth N.
Relation of cranial ultrasound abnormalities in low-birthweight infants to motor or
cognitive performance at ages 2, 6, and 9 years.
Dev Med Child Neurol.
1999;
41
(12)
826-833
- 22
Vohr B, Garcia Coll C, Flanagan P, Oh W.
Effects of intraventricular hemorrhage and socioeconomic status on perceptual, cognitive,
and neurologic status of low birth weight infants at 5 years of age.
J Pediatr.
1992;
121
(2)
280-285
- 23
Vohr B R, Allan W C, Westerveld M et al..
School-age outcomes of very low birth weight infants in the indomethacin intraventricular
hemorrhage prevention trial.
Pediatrics.
2003;
111
(4 Pt 1)
e340-e346
- 24
Ment L R, Bada H S, Barnes P D et al..
Practice parameter: neuroimaging of the neonate: report of the Quality Standards Subcommittee
of the American Academy of Neurology and the Practice Committee of the Child Neurology
Society.
Neurology.
2002;
58
(12)
1726-1738
- 25
Andrew M, Paes B, Milner R et al..
Development of the human coagulation system in the healthy premature infant.
Blood.
1988;
72
(5)
1651-1657
- 26
Andrew M, Paes B, Milner R et al..
Development of the human coagulation system in the full-term infant.
Blood.
1987;
70
(1)
165-172
- 27
Reverdiau-Moalic P, Delahousse B, Body G, Bardos P, Leroy J, Gruel Y.
Evolution of blood coagulation activators and inhibitors in the healthy human fetus.
Blood.
1996;
88
(3)
900-906
- 28
Salonvaara M, Riikonen P, Kekomäki R et al..
Effects of gestational age and prenatal and perinatal events on the coagulation status
in premature infants.
Arch Dis Child Fetal Neonatal Ed.
2003;
88
(4)
F319-F323
- 29
Cvirn G, Gallistl S, Leschnik B, Muntean W.
Low tissue factor pathway inhibitor (TFPI) together with low antithrombin allows sufficient
thrombin generation in neonates.
J Thromb Haemost.
2003;
1
(2)
263-268
- 30
Cvirn G, Gallistl S, Kutschera J et al..
Clot strength: a comparison between cord and adult blood by means of thrombelastometry.
J Pediatr Hematol Oncol.
2008;
30
(3)
210-213
- 31
Kisker C T, Perlman S, Bohlken D, Wicklund B.
Measurement of prothrombin mRNA during gestation and early neonatal development.
J Lab Clin Med.
1988;
112
(4)
407-412
- 32
Feusner J H, Slichter S J, Harker L A.
Acquired haemostatic defects in the ill newborn.
Br J Haematol.
1983;
53
(1)
73-84
- 33
Schmidt B, Wais U, Pringsheim W, Kunzer W.
Plasma elimination of antithrombin III is accelerated in term newborn infants.
Eur J Pediatr.
1984;
141
225-227
- 34
Corrigan Jr J J, Sleeth J J, Jeter M, Lox C D.
Newborn's fibrinolytic mechanism: components and plasmin generation.
Am J Hematol.
1989;
32
(4)
273-278
- 35
Gray O P, Ackerman A, Fraser A J.
Intracranial haemorrhage and clotting defects in low-birth-weight infants.
Lancet.
1968;
1
(7542)
545-548
- 36
Cade J F, Hirsh J, Martin M.
Placental barrier to coagulation factors: its relevance to the coagulation defect
at birth and to haemorrhage in the newborn.
BMJ.
1969;
2
(5652)
281-283
- 37
Piotrowski A, Dabrowska-Wojciak I, Mikinka M et al..
Coagulation abnormalities and severe intraventricular hemorrhage in extremely low
birth weight infants.
J Matern Fetal Neonatal Med.
2010;
23
(7)
601-606
- 38
Fowlie P W, Davis P G.
Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm
infants.
Cochrane Database Syst Rev.
2002;
(3)
CD000174
- 39
Fowlie P W, Davis P G, McGuire W.
Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm
infants.
Cochrane Database Syst Rev.
2010;
(7)
CD000174
- 40
Ment L R, Vohr B, Allan W et al..
Outcome of children in the indomethacin intraventricular hemorrhage prevention trial.
Pediatrics.
2000;
105
(3 Pt 1)
485-491
- 41
Ojala R, Ikonen S, Tammela O.
Perinatal indomethacin treatment and neonatal complications in preterm infants.
Eur J Pediatr.
2000;
159
(3)
153-155
- 42
Dani C, Bertini G, Pezzati M IntraVentricular Ibuprofen Study Group et al.
Prophylactic ibuprofen for the prevention of intraventricular hemorrhage among preterm
infants: a multicenter, randomized study.
Pediatrics.
2005;
115
(6)
1529-1535
- 43
Van Overmeire B, Allegaert K, Casaer A et al..
Prophylactic ibuprofen in premature infants: a multicentre, randomised, double-blind,
placebo-controlled trial.
Lancet.
2004;
364
(9449)
1945-1949
- 44
Whitelaw A, Odd D.
Postnatal phenobarbital for the prevention of intraventricular hemorrhage in preterm
infants.
Cochrane Database Syst Rev.
2007;
(4)
CD001691
- 45
Chiswick M L, Johnson M, Woodhall C et al..
Protective effect of vitamin E (DL-alpha-tocopherol) against intraventricular haemorrhage
in premature babies.
Br Med J (Clin Res Ed).
1983;
287
(6385)
81-84
- 46
Phelps D L, Rosenbaum A L, Isenberg S J, Leake R D, Dorey F J.
Tocopherol efficacy and safety for preventing retinopathy of prematurity: a randomized,
controlled, double-masked trial.
Pediatrics.
1987;
79
(4)
489-500
- 47
Brion L P, Bell E F, Raghuveer T S.
Vitamin E supplementation for prevention of morbidity and mortality in preterm infants.
Cochrane Database Syst Rev.
2003;
(4)
CD003665
- 48
Cools F, Offringa M.
Neuromuscular paralysis for newborn infants receiving mechanical ventilation.
Cochrane Database Syst Rev.
2000;
(4)
CD002773
- 49
Hunt R, Hey E.
Ethamsylate for the prevention of morbidity and mortality in preterm or very low birth
weight infants.
Cochrane Database Syst Rev.
2010;
(1)
CD004343
- 50
Hubbard D, Tobias J D.
Intracerebral hemorrhage due to hemorrhagic disease of the newborn and failure to
administer vitamin K at birth.
South Med J.
2006;
99
(11)
1216-1220
- 51
Andrew M.
The relevance of developmental hemostasis to hemorrhagic disorders of newborns.
Semin Perinatol.
1997;
21
(1)
70-85
- 52
Hey E.
Vitamin K—what, why, and when.
Arch Dis Child Fetal Neonatal Ed.
2003;
88
(2)
F80-F83
- 53
Clarke P, Mitchell S.
Vitamin K prophylaxis in preterm infants: current practices.
J Thromb Haemost.
2003;
1
(2)
384-386
- 54
Costakos D T, Greer F R, Love L A, Dahlen L R, Suttie J W.
Vitamin K prophylaxis for premature infants: 1 mg versus 0.5 mg.
Am J Perinatol.
2003;
20
(8)
485-490
- 55
Clarke P, Mitchell S J, Wynn R et al..
Vitamin K prophylaxis for preterm infants: a randomized, controlled trial of 3 regimens.
Pediatrics.
2006;
118
(6)
e1657-e1666
- 56 American Academy of Pediatrics, Committee on Nutrition .Nutritional needs of preterm
infants. In: Pediatric Nutrition Handbook. 5th ed. Elk Grove Village, IL: American
Academy of Pediatrics; 2004: 350-351
- 57
Crowther C A, Crosby D D, Henderson-Smart D J.
Vitamin K prior to preterm birth for preventing neonatal periventricular haemorrhage.
Cochrane Database Syst Rev.
2010;
(1)
CD000229
- 58
Beverley D W, Pitts-Tucker T J, Congdon P J, Arthur R J, Tate G.
Prevention of intraventricular haemorrhage by fresh frozen plasma.
Arch Dis Child.
1985;
60
(8)
710-713
- 59
Dani C, Poggi C, Ceciarini F, Bertini G, Pratesi S, Rubaltelli F F.
Coagulopathy screening and early plasma treatment for the prevention of intraventricular
hemorrhage in preterm infants.
Transfusion.
2009;
49
(12)
2637-2644
- 60
Veldman A, Josef J, Fischer D, Volk W R.
A prospective pilot study of prophylactic treatment of preterm neonates with recombinant
activated factor VII during the first 72 hours of life.
Pediatr Crit Care Med.
2006;
7
(1)
34-39
- 61
Waltl H, Födisch H J, Kurz R, Hohenauer L, Mitterstieler G, Rössler H.
Intracranial haemorrhage in low-birth-weight infants and prophylactic administration
of coagulation-factor concentrate.
Lancet.
1973;
1
(7815)
1284-1286
- 62
Thomas D B, Burnard E D.
Prevention of intravascular haemorrhage in low-birthweight babies.
Lancet.
1973;
2
(7828)
562
- 63
Thomas D B, Burnard E D.
Prevention of intraventricular haemorrhage in babies receiving artificial ventilation.
Med J Aust.
1973;
1
(19)
933-936
- 64
Gupta J M, Starr H, Fincher P, Lam-Po-Tang P R.
Intraventricular haemorrhage in the newborn.
Med J Aust.
1976;
2
(9)
338-340
- 65
Turner T, Prowse C V, Prescott R J, Cash J D.
A clinical trial on the early detection and correction of haemostatic defects in selected
high-risk neonates.
Br J Haematol.
1981;
47
(1)
65-75
Gili KenetM.D.
Professor - Hematology, Thrombosis Unit, National Hemophilia Center
Sheba Medical Center, Tel Hashomer 52621, Israel
eMail: Gili.kenet@sheba.health.gov.il
