A 4-Week-Old Female Infant with Type 3 von Willebrand Disease Presenting with Nosebleeds and Uncontrolled Bleeding Following Surgical Frenectomy: A Clinical Case

Abstract

Patient

Female, 4-week-old

Final Diagnosis

von Willebrand type 3

Symptoms

Bleeding

Clinical Procedure

—

Specialty

Pediatrics and Neonatology

Objective

Rare disease

Background

Congenital von Willebrand disease can be autosomal recessive or dominant and is classified into types 1, 2, and 3, based on laboratory findings. Severe von Willebrand factor deficiency (type 3 von Willebrand disease) is a rare, congenital deficiency of plasma coagulation factor, the symptoms of which can manifest as early as during the first weeks of a child’s life.

This report describes the case of a 4-week-old female infant with congenital von Willebrand disease presenting with nosebleeds and uncontrolled bleeding following surgical frenectomy.

Case Report

A 4-week-old female newborn experienced prolonged bleeding episodes, repeated nosebleeds, and gastrointestinal bleeding following the procedure of inferior labial frenulum cutting (frenectomy). During hematology diagnostics at the neonatal ward, the cause of the described manifestations was identified. In the tested parameters of the coagulation system, the activity of von Willebrand factor in the patient was <1% (below detectable levels). In addition, a secondary decrease in the child’s serum FVIII activity (2.1%) was observed. We confirmed type 3 von Willebrand disease.

Conclusions

Although type 3 of the disease is an extremely rare disorder within the coagulation cascade, it is important to be aware of the symptoms that can signal a bleeding diathesis, also in children in the first weeks of life. In every patient, regardless of age, in the presence of bleeding and abnormalities in the results of hemostasis system tests, plasma coagulation disorders should be investigated.

Introduction

Affecting approximately 1% of the population, von Willebrand disease (VWD) is the most common congenital plasma defect of hemostasis [1]. However, symptomatic patients are encountered much less commonly, with an estimated frequency of 0.1% to 0.01% [1].

VWD is a diverse group of disorders with a variety of clinical manifestations. The underlying cause of the disease is a deficiency or dysfunction of von Willebrand factor (VWF), one of the plasma coagulation factors. This protein has a dual function in the coagulation system. On the one hand, it stabilizes coagulation factor VIII in the plasma and, on the other hand, it is responsible for the process of platelet adhesion at the site of blood vessel damage [2,3].

VWF is synthesized in vascular endothelial cells and in bone marrow megakaryocytes. VWD is inherited both in an autosomal recessive and dominant manner, depending on the type of disease. The VWF gene is located on the shorter arm of chromosome 12, and the location of the mutation within the gene is relatively well correlated with VWD subtype [4,5].

According to the current classification based on the criteria of the International Society on Thrombosis and Haemostasis (modification as of 2006), there are 3 main types of VWD: type 1, partial VWF deficiency; type 2, qualitative VWF dysfunction, divided into 4 subtypes; and type 3, complete VWF deficiency, the so-called severe type [5].

Type 1 VWD is the most common and mildest disorder. It can be asymptomatic for many years [6,7]. Some patients affected by this type experience excessive bleeding after tooth extractions or surgery, prolonged and excessive menstrual bleeding in girls, excessive and recurrent nosebleeds and gum bleeding, and easy bruising [8].

Type 2 VWD is less common. It is caused not by a quantitative, but by a qualitative VWF disorder, namely dysfunction and abnormal protein synthesis. Four subtypes can be distinguished in type 2. They differ in the nature of VWF dysfunction. Type 2 accounts for a total of 20% to 35% of VWD cases [7].

Type 3 VWD is the least common, with a frequency of 1: 250 000 to 1: 1 000 000 people in the general population [4]. It is estimated that it accounts for only 1% of all cases of the disease [5,7], and it is inherited in an autosomal recessive manner [6]. This type of VWD is associated with complete VWF deficiency and, secondarily, with a significant decrease in the patient’s serum activity of factor VIII (FVIII; most often <10 IU/dL) [5].

Patients with types 2 and 3 VWD are particularly predisposed to gastrointestinal bleeding. In such patients, concomitant disorders of the structure of small blood vessel walls in the small intestine (so-called intestinal angiodysplasia) are commonly observed [9,10]. The secondary decrease in the activity of FVIII in the blood serum of patients with type 3 of the disease contributes to bleeding similar to that observed in patients diagnosed with hemophilia, such as spontaneous bleeding into the joints or muscles [5].

In patients with type 3 VWD, bleeding time and closure time on a platelet function analyzer device are prolonged. Due to the decrease in FVIII activity below 30 IU/dL, the activated partial thromboplastin (aPTT) time is also prolonged. VWF activity does not affect the remaining values of the hemostasis tests prothrombin time, thrombin time, or fibrinogen concentration [5]. The diagnosis of each of the types is based on the evaluation of specific hemostasis tests of the patient’s serum. In type 1, a fairly uniform deficiency of VWF can be determined in regards to its concentration (VWF antigen [VWF: Ag]) and activity (VWF ristocetin cofactor activity assay [VWF: RCo]), with the VWF: RCo/VWF: Ag ratio exceeding 0.6 (usually about 1).

In subtypes 2A, 2B, 2M of VWD, the VWF: RCo/VWF: Ag ratio is generally lower than 0.6. It is related to a defect in the function of this protein. In the 2N subtype, a marked decrease in FVIII activity is observed, with normal or only slightly reduced VWF activity. In this case, FVIII: C/vWF: Ag is lower than 0.5.

In type 3, the lack of VWF is noted, which is expressed in almost indeterminate values of VWF: RCo and VWF: Ag. At the same time, the FVIII serum level is very low [5].

This report describes the case of a 4-week-old female infant with type 3 VWD presenting with nosebleeds and uncontrolled bleeding following surgical frenectomy.

Laboratory tests performed in the child revealed an isolated prolongation of aPTT; prothrombin time was in the normal range. Complete blood count revealed a normal platelet count. Due to the prolonged aPTT time, detailed hemostasis tests were performed in a hematology laboratory. We obtained markedly diminished levels of vWF and FVIII; VWF: Ag was undetectable, VWF: RCo was undetectable, and serum FVIII activity was decreased (2.1%). Based on the obtained test results, type 3 VWD was diagnosed in our patient.

Case Report

We describe a case of a 4-week-old female newborn, born to unrelated parents. It was the second pregnancy and second childbirth in the mother. The girl was delivered vaginally in the week 38 of pregnancy, with a birth weight of 3310 g, and 10 points on the APGAR scale. The postpartum period was uncomplicated, and the waters broke several hours before delivery. Intragestationally, the mother had been treated for hypothyroidism. Several weeks prior to delivery, she had also received a preparation of low-molecular-weight heparin as prescribed by the gynecologist, due to a slightly elevated concentration of D-dimers.

On day 3 of life, the child was vaccinated in accordance with the current Polish vaccination calendar. No adverse post-vaccination reactions were observed. The girl was breastfed and periodically supplemented with the first infant formula.

The child was admitted to the hospital on day 28 of life due to a suspected upper respiratory tract infection. In the medical history obtained on admission, the parents described an episode of prolonged several-hour bleeding that occurred in the patient during the second week of life, after frenectomy. No diagnostic work-up was performed for disorders of hemostasis at that time. Starting on the day before admission to the hospital, nasal bleeding had been observed. At the time of admission to the ward, on physical examination, a small amount of dried blood was visible in the right nasal passage. The child was in a relatively good general condition, with normal cardiopulmonary efficiency. In the ward, the girl vomited once, and the vomit contained a trace of fresh blood. Apart from this incident, no other disturbing abnormalities were observed. The basic vital signs were normal.

After admission, laboratory tests were extended by the basic parameters of the coagulation system. Inflammation indices remained low. Laboratory tests revealed an isolated prolongation of aPTT. Prothrombin time was within the reference range. Complete blood count revealed a normal platelet count. Also, hemoglobin concentration was normal for age. The results are presented in Table 1.

Table 1.

Laboratory tests performed on day 28 of life.

Blood component	Result	Reference range
White blood cells	14.31×109/L	8.36–14.42×109/L
Red blood cells	3,43×1012/L	3.32–4.80×1012/L
Hemoglobin	11.7 g/dL	10.80–14.60 g/dL
Hematocrit	31.90%	32.00–44.50%
Mean corpuscular volume	93.00 fL	90.10–103.00 fL
Platelets	538.00×109/L	279.00–571.00×109/L
C-reactive protein	<5 mg/L	0.00–10.00 mg/L
Procalcitonin	0.07 ng/mL	<0.5 ng/mL
APTT	85.3 s	26.0–36.0 s
INR	1.11	0.90–1.20
Fibrinogen	2.3 g/L	1.8–3.5 g/L

APTT – activated partial thromboplastin time; INR – international normalized ratio.

Due to the occurrence of bleeding and prolonged aPTT time, detailed hemostasis tests were performed in a hematology laboratory. We obtained the following results: VWF: Ag was undetectable, VWF: RCo was undetectable, and serum FVIII activity was decreased (2.1%). The results are presented in Table 2.

Table 2.

Results of coagulation tests on day 29 of life.

Coagulation parameter	Result	Reference range
Prothrombin time	13.3 s	10.4–13.0 s
INR	1.20	0.85–1.15
APTT	59.0 s	25.0–33.5 s
Thrombin time	21.0 s	14.0–21.0 s
Fibrinogen	2.4 g/L	1.8–3.5 g/L
Factor VIII	2.1%	50.00–150.00%
Factor IX	38.1%	50.00–150.00%
Factor XI	51.8%	50.00–150.00%
Factor XII	58.4%	50.00–150.00%
Factor XIII	109.1%	50.00–150.00%
Von Willebrand factor (ristocetin cofactor activity assay)	<1.0%	50.00–150.00%
Von Willebrand factor (antigen)	<1.0%	50.00–150.00%

APTT – activated partial thromboplastin time; INR – international normalized ratio.

Based on the obtained test results, type 3 VWD was diagnosed (undetectable VWF: Ag and VWF: RCo). In addition, a secondary decrease in the child’s serum FVIII activity (2.1%) was observed, which is characteristic of this type of disease. The reduced activity of factor IX was associated with the age of the girl. Due to the immaturity of the liver, lower activity of coagulation factors produced in this organ is observed in newborns and infants up to 6 months of age [11].

VWF is an acute phase protein, and its plasma content increases in situations such as stress or infections. Its concentration can be overestimated in children in the first weeks of life [5,11]. In the present newborn, despite factors that might naturally increase the concentration of this protein in the blood serum, VWF activity was below detectable levels, which clearly indicated type 3 VWD.

During the stay in the ward, the newborn was administered FVIII concentrate containing VWF (Fanhdi, Grifols) for 5 days. Drug tolerance was good. No recurrence of bleeding was observed. The ultrasound imaging of the lungs, encephalon, and abdominal cavity revealed no abnormalities. It was recommended to use tranexamic acid at home for 5 days.

In the following months, the girl returned several times to the pediatric Emergency Department, most often due to increased nosebleeds. Each time, she required the administration of a coagulation factor. Moreover, twice during the hospital stay, she needed transfusion of the red blood cell concentrate, due to increasing anemia. In the fourth year of life, due to numerous spontaneous episodes of bleeding from the nose and gastrointestinal tract, the girl started prophylaxis. Therefore, the number of bleeding episodes could be minimized and the number of hospitalizations was significantly reduced.

Discussion

VWF deficiency was first described in the inhabitants of the Åland Islands by a Finnish physician, Erik von Willebrand, in 1924. In later years, thanks to increasingly accurate diagnostic methods, various types of the disease and various mechanisms of inheritance were distinguished. In recent years, cases of acquired von Willebrand syndrome, which can be due to immune system disorders, have also been described.

Severe VWF deficiency (type 3 VWD) is a rare blood clotting disorder. However, it should be considered in every newborn with symptoms of bleeding diathesis, regardless of the sex or family history, especially if the described symptoms are accompanied by isolated prolongations of aPTT and normal platelet counts.

An early diagnosis of a potentially severe clinical hemorrhagic diathesis is critical for prognosis.

During the first month of life, the present girl experienced a number of symptoms that might indicate disorders in the hemostasis system, namely prolonged bleeding after minor surgery, nosebleeds, and gastrointestinal bleeding. The patient’s age supported the congenital basis of the described symptoms. Isolated aPTT prolongation suggested a pathology within the intrinsic coagulation pathway. Making a diagnosis was possible after performing detailed hemostasis tests that confirmed severe VWF deficiency.

The family history was contributory as regards to bleeding: the father and the 4-year-old sister of the patient manifested a mild decrease in VWF activity in the absence of significant bleeding, apart from nosebleeds in the father. The mother experienced postpartum hemorrhage, requiring the ligation of the iliac arteries and bleeding in the first trimester of pregnancy. Her third-trimester VWF activity was inadequate for gestational age (62%), which strongly suggested mild VWD. A significant hemorrhagic history was also presented by the girl’s maternal grandmother. The family was referred to the genetic counseling clinic; however, they did not attend to the scheduled tests. According to current medical knowledge, type 3 VWD is inherited only in an autosomal recessive manner. Patients with type 3 VWD can develop bleeding within the locomotor system (into the joints and muscles) which, if left untreated or if the treatment is delayed, can lead to advanced secondary arthropathy.

Because type 3 VWD is an extremely rare condition, there are not many reports in the literature regarding symptomatic pediatric patients. In the article “Bleeding spectrum in children with moderate or severe VWD: Relevance of pediatric-specific bleeding”, Sanders et al describe individual cases of pediatric patients with different types of VWD. The clinical symptoms of patients with type 3 VWD described in this article are very similar to those presented by our patient. In both cases, attention is drawn to the isolated prolongation of APTT and abnormalities in the detailed hemostasis tests. Of note, severe VWD often manifests at the very early stage of life [12].

Type 3 VWD carriers are usually asymptomatic. However, they can have a mild form of the disease. Therefore, it was recommended to diagnose first-degree relatives for VWD, as well as all further relatives who develop hemorrhagic symptoms. The diagnosis of mild forms of VWD is more difficult than that of type 3 because aPTT remains normal in most cases (factor VIII activity remains normal or is decreased to a degree that does not affect aPTT values).

The treatment of bleeding in the course of VWD consists in the therapeutic and prophylactic use of tranexamic acid, intravenous or subcutaneous desmopressin, and FVIII concentrates containing VWF and recombinant VWF concentrate (intravenous preparations). In Poland, clotting agent concentrates and desmopressin are available 24 hours a day at regional blood banks.

In mild disease, tranexamic acid for mucosal bleeding and minor procedures or desmopressin perioperatively is usually sufficient. A clotting factor concentrate is necessary in individuals who are intolerant to desmopressin, who have not achieved a hemostatic response in the desmopressin trial, or in whom desmopressin is contraindicated.

Desmopressin is ineffective in patients with type 3 VWD. Coagulation factor concentrates should be administered in case of bleeding into muscles and joints, mucosal bleeding not responding to tranexamic acid, and perioperatively. Some patients require treatment at home that allows the early self-administration of factor concentrate in case of bleeding. They undergo training in the administration of such preparations intravenously in hemophilia treatment centers. In addition, some patients with severe disease (rarely in mild types) who experience frequent, clinically significant bleeding or who have had life-threatening bleeding require prophylactic treatment. The prophylaxis involves regular injections of factor concentrate, usually 2 to 3 times a week, to prevent bleeding within the locomotor system, to inhibit mucosal bleeding, or to prevent the recurrence of serious bleeding (usually from the gastrointestinal tract).

Conclusions

Making a diagnosis in the neonatal period made it possible to include the child in early multidisciplinary treatment, including bleeding prevention. Congenital VWD can be autosomal recessive or dominant and is classified into types 1, 2, and 3, based on the laboratory findings. Severe VWF deficiency (type 3 VWD) is an extremely rare disorder within the coagulation cascade. However, it should be considered in every newborn with symptoms of severe bleeding diathesis. In the diagnostic process, we should exclude thrombocytopenia, while simultaneously performing hemostasis system tests (APTT, prothrombin time, fibrinogen concentration). In this case report, we described the case of a 4-week-old female infant with congenital type 3 VWD presenting with nosebleeds and uncontrolled bleeding following surgical frenectomy.

Immediate hematological diagnostics in the neonatal period revealed laboratory abnormalities typical of the severe type of VWD. Timely diagnosis of patients with bleeding diathesis symptoms allows for an accurate diagnosis and the initiation of appropriate treatment.