NeoQuest March 2024: Intracranial Hemorrhage in a Term Newborn

A two-day-old male infant is delivered by normal spontaneous vaginal delivery at 38 weeks’ gestational age. He received vitamin K immediately after birth. On the exam, he is well-appearing but has an elevated temperature of 38.5°C. Blood and cerebrospinal fluid (CSF) cultures are obtained, and a complete blood count is normal. He is started on ampicillin, gentamicin, and acyclovir. He continues to have recurrent fevers despite no growth on cultures and negative HSV PCRs from blood and CSF after 48 hours. Brain magnetic resonance imaging is obtained on postnatal day 6 (Figure 1). A hematologic profile reveals a hemoglobin level of 15 g/dL, a platelet count of 320 x 10⁹/L, a prothrombin time of 13 seconds, a partial thromboplastin time of 31 seconds, and a fibrinogen level of 310 mg/dL.

 
Figure 1. Brain magnetic resonance imaging (axial proton density and T2-weighted) of the infant in the vignette reveals bilateral intraventricular layering and subependymal hypointense signal consistent with hemorrhage (blue arrows). Image from: Kluge MC, Vachharajani A, Mazuru D, Gruner B, Severance T, Intracranial Bleeding in a Neonate. Neoreviews. 2024;25(3):e159–e162.¹

Of the following, the most likely laboratory finding in this infant would be?

1. Low concentration of antithrombin
2. Low concentration of factor VII
3. Low concentration of factor XIII
4. Low concentration of protein S
5. von Willebrand factor deficiency

Answer: C. Low concentration of factor XIII

Explanation:

Bleeding disorders in the newborn are rare, although they can be life-threatening. Neonatal bleeding syndromes can be classified into those affecting primary hemostasis (blood vessels, von Willebrand factor, and platelets), secondary hemostasis (coagulation proteins), or tertiary hemostasis (fibrinolytic system). The infant in the vignette presents with brain magnetic resonance imaging (MRI) findings consistent with bilateral intraventricular layering and subependymal hypointense signal consistent with hemorrhage (Figure 1), in addition to a normal platelet count as well as normal prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen levels.¹ This constellation of findings should raise suspicion for factor XIII deficiency, an autosomal recessive disorder of fibrin clot formation (Option C).^1–3 Factor XIII is known as the “fibrin stabilizing factor” due to its role in the final step of the coagulation cascade by cross-linking fibrin polymers for stable clot formation.^1–4 Infants with a factor XIII activity level of <5% may have symptomatic bleeding, with umbilical stump bleeding occurring in 80% of cases and neonatal intracranial hemorrhage occurring in 25-30% of cases.^1–3 Other classic features of factor XIII deficiency include hemarthroses, bruising, poor wound healing, delayed postoperative bleeding, and a maternal history of recurrent spontaneous miscarriages.^2–4 Infants with factor XIII deficiency are managed with infusions of recombinant or plasma-derived factor concentrate. Fresh frozen plasma and cryoprecipitate may be used if factor product is unavailable.^1–5

Antithrombin is the most important physiologic inhibitor of thrombin and activated serine protease factors IXa, Xa, and XIa.⁶ The concentrations of most anticoagulant proteins, such as antithrombin, are decreased in the neonate relative to normal adult values (Figure 2).⁶ A deficiency in antithrombin leads to an increased risk of developing thromboemboli, which is not consistent with the presentation of intracranial hemorrhage in the infant in the vignette (Option A).^5,6

 
Figure 2. Characterization of neonatal coagulation compared with adults and their overall impact on the maintenance of hemostasis. Abbreviations: AT = antithrombin, α2M = α₂-macroglobulin, F = factor, vWF = von Willebrand factor, PC = protein C, PS = protein S, t-PA = tissue plasminogen activator. Image from: Guzman, et al. Thrombosis in the neonatal intensive care unit. Neoreviews. 2023;24(6):e356-e369.⁸

Factor VII is among the vitamin K-dependent coagulation proteins. A deficiency in factor VII may be observed in infants with vitamin K deficiency or liver dysfunction, or it may be inherited in an autosomal recessive pattern.^5,7 Factor VII deficiency is often associated with prolonged PT due to its involvement in the extrinsic pathway (Figure 3) and decreased levels of fibrinogen (Option B).^5,7

Figure 3. Overview of the coagulation cascade. Image from: Kluge MC, Vachharajani A, Mazuru D, Gruner B, Severance T, Intracranial Bleeding in a Neonate. Neoreviews. 2024;25(3):e159–e162.¹

Protein S is an anticoagulant protein, with values in the neonate that are more than 50% of adult normal values (Figure 2).⁸ Deficiency of protein S is a rare inherited thrombophilia and thus is a risk factor for the development of thrombosis (Option D).⁸

Most infants have elevated von Willebrand factor at birth, which contributes to normal hemostasis (Figure 2).⁸ Von Willebrand disease (vWD) is a disorder inherited in an autosomal dominant or recessive pattern.^2,3,5,8,9 It is characterized by a deficiency in von Willebrand factor, which functions as an adhesive protein that binds platelets to injured vascular walls and augments aggregation of platelets.^3,5,9 Most infants with vWD exhibit a mild phenotype and are not likely to present with bleeding in the newborn period but may present with mucocutaneous bleeding, easy bruising, bleeding after circumcision, or umbilical stump bleeding.^2,3,5 Patients with vWD usually have a normal PT and aPTT. However, the aPTT may be prolonged if concentrations of factor VIII are sufficiently low (Table 1), which is not consistent with the infant in this vignette (Option E).^3,5

Table 1.

Typical Patterns of Coagulation Screening Tests in Newborns

PTT=partial thromboplastin time, PT=prothrombin time, PFA=platelet function analyzer, one arrow=mild, two arrows=moderate, three arrows=severe. Table from: Manco-Johnson M. Bleeding disorders in the neonate. Neoreviews. 2008;9(4):e162-e169.⁹

Did you know?
Coagulation factors and proteins do not cross the placenta and are thus generated by the fetus. The fetal hemostatic system and production of associated coagulation proteins begins in the liver, as early as 5 weeks of gestation, and fetal blood can form clots beginning at 11 weeks of gestation.⁵

Which inherited bleeding disorders have an X-linked recessive inheritance pattern?
For a summary of neonatal bleeding disorders and their inheritance patterns, refer to the table in: Guzzardo G and Regling K. Developmental hemostasis: the evolution of our coagulation system. Neoreviews. 2022;23(2):e82-e95.⁵

Which procoagulant and anticoagulant factors are vitamin K-dependent?
For a review of the clinical manifestations and laboratory abnormalities in vitamin K-dependent bleeding, refer to: Davila J. Coagulation disorders in the newborn. Neoreviews. 2018;19(1):e11-e21.³

NeoQuest March 2024 Author:

Lila S. Nolan, MD, FAAP, Washington University School of Medicine

References:

1. Kluge MC, Vachharajani A, Mazuru D, Gruner B, Severance T. Intracranial Bleeding in a Neonate. Neoreviews. 2024;25(3):e159–e162.
2. Nuss R, Manco-Johnson M. Bleeding disorders in the neonate. Neoreviews. 2000;1(10):e196–e200
3. Davila J. Coagulation disorders in the newborn. Neoreviews. 2018;19(1):e11–e21
4. Singh A, Singh SN. Case 1: neonate with generalized scalp swelling and severe pallor. Neoreviews. 2016;17(8):e478–e480
5. Guzzardo GM, Regling K. Developmental hemostasis: the evolution of our coagulation system. Neoreviews. 2022;23(2):e82–e95
6. Manco-Johnson M, Nuss R. Hemostasis in the neonate. Neoreviews. 2000;1(10):e191–e195
7. Letterio J, Pateva I, Petrosiute A, Ahuja S. Chapter 79. Hematologic and oncologic problems in the fetus and neonate. Fanaroff and Martin’s Neonatal-Perinatal Medicine. 2019, 11^th Edition
8. Guzman RE, Hughes A, Kiskaddon A, Fort P, Betensky M. Thrombosis in the neonatal intensive care unit. Neoreviews. 2023;24(6):e356–e369
9. Manco-Johnson MJ. Bleeding disorders in the neonate. Neoreviews. 2008;9(4):e162–e169