Vitamin K deficiency bleeding after missed prophylaxis: rapid synergistic effect of vitamin K therapy on hemostasis.

To the Editor: We thank Drs. Hubbard and Tobias for their fascinating report of two infants with devastating intracerebral bleeding, (1) and Dr. Waseem for his accompanying editorial. (2) These cases of hemorrhagic disease of the newborn, now better termed vitamin K deficiency bleeding (VKDB), (3) are tragic but most instructive. The series of four warning bleeds suffered by Patient 1 in the weeks leading up to its catastrophic intracranial bleed was startling. Warning bleeds are frequent harbingers of late VKDB (3,4) but presumably went unrecognised in this patient because of the rarity of VKDB in the US. Appreciation of warning bleeds and prompt action could prevent significant morbidity and mortality.

The report omitted the crucial information that vitamin K was administered to both infants as part of their emergency treatment at presentation with intracranial hemorrhage. We are grateful to the authors for clarifying that each infant was given vitamin K (phytomenadione) 1 mg intravenously for a total of three days (Dr. J Tobias, written communication). Given this, it is relevant to consider in more detail the temporal aspects of vitamin K efficacy and its potential synergy with recombinant factor VIIa (rFVIIa) in reversal of coagulopathy. As the authors state, administration of rFVIIa allowed surgical intervention in Patient 1 after approximately 20 minutes. Assuming that vitamin K was administered in close proximity to rFVIIa, we consider that it too would have exerted a rapid and synergistic hemostatic effect. As would be expected from the rarity of VKDB, there are few detailed coagulation studies of the response to vitamin K given as the sole therapy for the disorder. Sutor and Kunzer (5) reported on the time interval between vitamin K administration and effective hemostasis in four infants with severe VKDB from various sites (none, however, with intracerebral bleeding) and in whom the PT at presentation ranged from <1 to 4% of normal. In all infants, the PT recovered to 30 to 50% of normal within one hour of receiving intravenous vitamin K (1-3 mg), with clinically significantly reduced bleeding by as early as 20 minutes. The accompanying rapid burst in synthesis of all the vitamin K-dependent proteins, also observed by Sutor and Kunzer as early as 20 to 30 minutes following administration, is entirely explainable by the known mechanism of vitamin K in conversion of precursor des-[gamma]-carboxy proteins to active coagulation factors. In vitamin K deficiency, there is probably a readily available microsomal pool of these precursors that can be immediately transformed to active factors without protein synthesis. Thus, in the two cases reported, the immediate localized effect of rFVIIa at the bleeding site combined with the rapid effect of vitamin K on systemic coagulation can be considered to have been complimentary therapeutic strategies.

The authors also kindly clarified the reasons for missed prophylaxis in their cases: Patient 1 was born to Mennonite parents (Amish branch) as a rural home delivery by a midwife, and vitamin K was not offered; Patient 2 was an elective home delivery and the parents declined vitamin K (Dr. J. Tobias, written communication). Although home births are rare in the US, they are on the increase in the United Kingdom. In 2005, the home confinement rate for England and Wales was 2.57% (6); home deliveries are attended by a community midwife who also has the responsibility for administration of either oral or IM vitamin K to the newborn, depending upon parental preference and consent.

Between 7 and 32 cases of VKDB occurred in each of the three 2-year long surveys undertaken in Britain and Ireland in the past 2 decades (7); 31 to 70% of cases received no prophylaxis, and parental refusal of vitamin K prophylaxis has become the main explanation for late cases of VKDB. We completely agree with Drs. Hubbard and Tobias that vitamin K prophylaxis should be mandatory for all infants.

Paul Clarke, MB, FRCPCH

Neonatal Unit

Norfolk & Norwich University Hospital

Norwich, United Kingdom

Martin J. Shearer, PhD, MRCPath

Centre for Haemostasis & Thrombosis

St Thomas's Hospital

London, United Kingdom

References

1. Hubbard D, Tobias JD. Intracerebral hemorrhage due to hemorrhagic disease of the newborn and failure to administer vitamin K at birth. South Med J 2006;99:1216-1220.

2. Waseem M. Vitamin K and hemorrhagic disease of newborns. South Med J 2006;99:1199.

3. Sutor AH, von Kries R, Cornelissen EA, et al. Vitamin K deficiency bleeding (VKDB) in infancy. ISTH Pediatric/Perinatal Subcommittee. International Society on Thrombosis and Haemostasis. Thromb Haemost 1999;81:456-461.

4. McNinch AW, Tripp JH. Haemorrhagic disease of the newborn in the British Isles: two year prospective study. BMJ 1991;303:1105-1109.

5. Sutor AH, Kunzer W. Time interval between vitamin K administration and effective hemostasis. In: Suzuki S, Hathaway WE, Bonnar J, et al (eds). Perinatal Thrombosis and Hemostasis. Tokyo, Springer-Verlag, 1991, pp 257-262.

6. Office for National Statistics (2006). Birth Statistics. Review of the Registrar General on births and patterns of family building in England and Wales, 2005, series FM1 no. 34. London: HMSO. Available at: http://www.statistics.gov.uk/downloads/theme_population/FM1_34/FM1_no34_2005.pdf. Accessed January 29, 2007.

7. McNinch AW, Tripp JH. Vitamin K deficiency bleeding. London: British Paediatric Surveillance Unit, 17th Annual Report, 2002-2003, pp 31-32. Available at: http://www.bpsu.inopsu.com/publications/annual_reports/annual-report_2003.pdf. Accessed January 29, 2007.