Sudden Bleedings Caused by a Severe Acquired Coagulopathy in an infant – A Diagnostic and Therapeutic Challenge

Introduction

The differential diagnosis of bleedings in infancy includes, besides child abuse and trauma, a severe inherited or acquired haemorrhagic diatheses. Therefore, a detailed bleeding history, a careful physical examination and an extended coagulation diagnostic is crucial to clarify the underlying reason for the bleeding symptoms.

We report on an infant who presented with multiple haematomas suspicious for a severe coagulopathy or child abuse. Diagnostics revealed the ingestion of a single dose of phenprocoumon leading to a transient severe coagulation disorder due to a genetically determined increased sensitivity to vitamin K antagonists (VKA).

Case presentation

An 11 months old boy of consanguineous parents was transferred to our centre from a municipal hospital due to the sudden appearance of multilocular haematomas since one week with a suspected diagnosis of a severe haemophilia. The skin bleeding tendency had appeared for the first time 1 week ago after multiple minor traumas in the mobile child. Taking the family history was challenging because of the family’s foreign background but was considered unremarkable besides an older sister (8 yrs.) with a complex congenital heart disease and a daily intake of phenprocoumon.

The physical examination revealed multiple haematomas of different age spread over the whole body and minor oral mucosal bleedings. Otherwise the patient was in good general condition, with normal age-appropriate development and without any dysmorphic signs ([Fig. 1]).

Fig. 1 Clinical appearance of the patient on time of admission presenting with multilocular large haematomas.

Imaging methods, including ultrasound of the abdomen, cranial CT and X-ray of the most affected left lower limb were all unremarkable, therefore excluding internal bleedings, heavy trauma and child abuse.

The laboratory results on admission are presented in [Table 1].

Table 1 Laboratory results on admission.

Parameters	Pat.’s values	Age-matched reference range
activated partial thromboplastin time (APTT)	>180 sec	24–36 sec
prothrombin time (PT)	<2%	70–120%
International normalized ratio (INR)	not measurable	0.9–1.2
thrombin clotting time	16.2 sec	16.3–17.6 sec1
clotting factors II, VII, XI, X	2–4%	>50%
haemoglobin	8.5 g/dl	10.5–12.9 g/dl
white cell count	26 200/µl	6 000–17 500/µl
platelet count	513 000/µl	150 000–400 000/µl

Normal values for: fibrinogen, activities of clotting factors V and VIII, C-reactive protein, transaminases, bilirubin, erythrocyte indices, iron, transferrin, transferrin saturation, ferritin, urine analysis, faecal occult blood testing; 1 reference range from: Monagle P et al., Thromb Haemost 2006; 95: 362–72

Laboratory coagulation parameters allowed exclusion of haemophilia as well as a- or hypofibrinogenaemia but a disorder of vitamin K dependent coagulation factors was suspected ([Table 1]). We immediately administered 10 mg vitamin K i. v. and 600 IE of prothrombin complex concentrate (PPSB). 5 h later PT and APTT normalized. During the following days we repeatedly observed prolongation of the PT and therefore vitamin K was administered another 3 times p.o. until a permanent normalization of the clotting factors was achieved on day 7 after admission ([Fig. 2]).

Fig. 2 Course of prothrombin time (PT) following admission to our hospital (day 0) and dependence on the administration of vitamin K and PPSB (prothrombin complex concentrate).

After questioning the parents again with the help of a translator we learned that one week before admission the child had a non-recurring access to a maximal dose of 3 mg phenprocoumon taken once daily by the older sister. Due to the recurrent droppings of the PT despite of repeated vitamin K applications we primarily suspected a continuation of phenprocoumon intake provided by the parents during the hospital stay. Therefore, we measured phenprocoumon plasma levels in specimen kept stored starting from the day of admission. In the first sample, collected on admission one week after the assumed drug intake, the plasma level of phenprocoumon was still within the therapeutic range (1.0–3.0 mg/dl, Medical laboratory Bremen). Over the following period of 17 days we measured the plasma phenprocoumon levels additionally 5 times showing a normal pharmacological half-life of approximately 110–130 h (Verhoef T I et al., Br J Clin Pharmacol 2014; 77(4): 626–641) ([Fig. 3]). Based on these data additional phenprocoumon applications were excluded.

Fig. 3 Course of the phenprocoumon plasma level of the patient in comparison to a person with a normal vitamin K antagonist sensitivity in days since the assumed drug intake.

The course of the phenprocoumon plasma levels was suggestive of an increased sensitivity to VKAs. This was confirmed by genetic testing in leukocytes (Centre for Human Genetics, Martinsried, Germany) showing a homozygosity for two vitamin K epoxide reductase complex subunit 1 alleles (VKORC1 gene on position g.1173 C>T).