A 1-day-old female newborn was transferred to our hospital because of recurrent apnea (Fig. 1). The baby was born vaginally at 39 weeks of gestation with a birth weight of 2.7 kg and 1- and 5- minute Apgar scores of 9 and 10, respectively. Her mother had experienced three first-trimester miscarriages prior to the present pregnancy. Her protein C and protein S (PS) levels were relatively low (51% and 70%, compared with reference values of 64-150% and 64-146%, respectively). There was no family history of bleeding or thrombotic disorders.

The newborn had normal vital signs and physical examination showed no remarkable findings, including abdominal distension, or skin lesions. Initial evaluations, including a complete blood count with differential, chest-abdominal X-rays and echocardiography, revealed no abnormality. Her apnea events improved over time, and she took her mother’s milk every 3 hours. On day 3, she suddenly became lethargic. A brain computed tomography scan showed subarachnoid and posterior fossa subdural hemorrhages. And she experienced repeated bilious vomiting and her abdominal distention progressively worsened. An abdominal X-ray on day 4 showed pneumoperitoneum, suggesting intestinal perforation. Surgical exploration revealed ischemic changes with multiple perforations in the distal transverse colon near the splenic flexure in the anti-mesenteric border. The colon proximal and distal to the area appeared normal, without any features suggestive of necrotizing enterocolitis or Hirschsprung disease. The affected colon was resected, followed by end-to-end anastomosis. A biopsy sample showed normal ganglion cells, with venous congestion and neutrophil infiltration of the mucosa. These findings were compatible with ischemic colitis.

Further examination on day 3 showed plasma protein C activity below detectable limits (<10%), whereas plasma protein S activity was within normal limits for her age (35%). The patient was started on 600 U/kg/day activated PC (aPC) concentrate (Anact C, Teijin/Chemo-Sero-Therapeutic Research Institute, Tokyo, Japan), for a total of 6 days. She was subsequently switched to fresh frozen plasma with low molecular heparin. Her post-operative course was uneventful and oral feeding was initiated on day 7. Ophthalmological examination on day 9 revealed no bleeding. Anti-coagulation therapy was continued until day 21, when serum concentrations of fibrin degradation products normalized. Follow-up brain magnetic resonance imaging on day 25 showed no evidence of ventriculomegaly, ischemic changes or vascular malformations. Her growth and development were appropriate at follow-up at 3 months. The clinical and diagnostic profile of the patients is depicted in Fig. 1.

Fig. 1. Clinical course of the neonate with hereditary Protein C deficiency.

After obtaining informed consent from her parents, genomic DNA was extracted from the newborn’s peripheral blood leukocytes. The coding region of PROC (exons 1-9) was amplified by polymerase chain reaction (PCR), followed by direct sequencing of the PCR products. A heterozygous missense mutation was observed in exon 9 (c.1015G>A, p.Val339Met). This mutation was previously reported in Japanese families with PC deficiency [1]. These two vascular events viz. intracranial hemorrhage and focal colonic ischemia, were attributed to a decreased level of plasma protein C activity. After starting aPC replacement, followed by anticoagulant therapy, the patient did not develop any other complications.

The initial manifestations of severe protein C deficiency include intracranial thrombosis and hemorrhage and/or purpura fulminans, occurring during the first two weeks of life. An increased risk of thrombosis in the fine blood vessels within the germinal matrix is probably associated with a risk of neonatal intracranial hemorrhage. In our patient, intracranial hemorrhage along with the recurrent miscarriage history of her mother strongly suggested the possibility of a thrombotic disorder.

Neonatal colonic perforation is extremely rare. A state of increased coagulability may be a significant factor in the pathogenesis of colonic ischemia [2]. Ischemic perforation in the colon has been reported in an adult patient with antiphospholipid syndrome [3]. Perioperative management of the patient was challenging because of the competing risks of bleeding and recurrent thrombosis. Administration of aPC concentrate seems appropriate for both the treatment and prophylaxis of thrombosis, without increasing the risk of bleeding [4].

It is challenging to screen for inherited protein C deficiency in neonates because their levels are lower than reference levels in adults. It may be useful to compare protein C and protein S levels, a low protein C and protein S ratio may be more diagnostic than low levels alone [5].

In conclusion, this case highlights the importance of recognizing congenital protein C deficiency in early neonates who experience intracranial hemorrhage or colonic perforation.

Acknowledgements: Ms Hotta, Dr Ishimura and Prof Ohga for valuable clinical suggestions and genetic analysis.

Contributors: HM: drafted the manuscript; MK, DH: critically revised the manuscript for important intellectual content. All authors approved the final version of the manuscript.

Funding: None; Competing Interest: None stated.

1. Miyata T, Sakata T, Zheng YZ, Tsukamoto H, Umeyama H, Uchiyama S, et al. Genetic characterization of protein C deficiency in Japanese subjects using a rapid and nonradioactive method for single-stand conformational polymorphism analysis and a model building. Thromb Haemost. 1996;76:302-11.

2. Theodoropoulou A, Koutroubakis IE. Ischemic colitis: clinical practice in diagnosis and treatment. World J Gastroenterol. 2008;14:7302-8.

3. Ahmed K, Darakhshan A, Au E, Khamashta MA, Katsoulis IE. Postpartum spontaneous colonic perforation due to antiphospholipid syndrome. World J Gastroenterol. 2009;15:502-5.

4. Kumagai K, Nishiwaki K, Sato K, Kitamura H, Yano K, Komatsu T, et al. Perioperative management of a patient with purpura fulminans syndrome due to protein C deficiency. Can J Anaesth. 2001;48:1070-4.