von Willebrand disease (VWD) is a genetic bleeding disorder caused by quantitative and/or qualitative deficiencies of von Willebrand factor (VWF), and is the most common coagulation disorder, with prevalence varying from 0.1% to 0.8% depending upon the criteria used for diagnosis [1,2]. Patients with VWD usually have minor bleeding symptoms, but often have mucocutaneous bleed-ing, including menorrhagia, easy bruising, epistaxis, and unexpected bleeding problems that can occur in situations, such as surgery or delivery. Menorrhagia is the most common bleeding symptom in women with VWD and affects over 70% of patients [3-5].

The main cause of anemia in premenopausal women is blood loss due to menstruation, and iron deficiency anemia (IDA) occurs in 5-10% of patients with menstrual disorders [6]. However, the specific cause of menorrhagia has been identified in less than half of the cases in affected women.

According to the Korean Hemophilia Foundation’s annual report that was published in 2019, 146 patients with VWD are registered, and in Korea, VWD is considered to have lower disease registration rules than the actual prevalence rate [7]. This suggests that there could be some patients who have not been diagnosed correctly, and there is a possibility that doctors have not diagnosed these cases because of their low awareness of VWD.

In addition, studies focused on VWD in Korea have been very limited. Therefore, we investigated the clinical characteristics of VWD in premenopausal women with menorrhagia and IDA to understand the importance of VWD diagnosis in these patients.

1) Study design and patients

The study was conducted retrospectively using the medical records of 193 premenopausal women who came to the departments of internal medicine and pediatrics at a University hospital in Korea with anemia and were diagnosed with both IDA and menorrhagia between January 2009 and March 2020. Among them, 44 patients with inaccurate medical records or insufficient blood test results were excluded. Patients with underlying diseases, including idiopathic thrombocytopenic purpura, aplastic anemia, chronic kidney disease, and patients exposed to drugs that could impair coagulation were also excluded. A total of 120 patients were enrolled in the study.

2) Study methods

For all patients with both IDA and menorrhagia, medical records were used to investigate age at the time of diagnosis, bleeding history other than menorrhagia, family history, treatment method, treatment duration, and frequency of recurrence of IDA. The data on laboratory tests, including complete blood count, ferritin, serum iron, total iron-binding capacity, transferrin saturation, VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), factor VIII coagulant activity (FVIII:C), bleeding time, prothrombin time, and activated partial thromboplastin time (aPTT) were collected.

3) Diagnostic criteria for IDA and menorrhagia

IDA was diagnosed by anemia (hemoglobin <12 g/dL in females over 12 years old) with either low ferritin (≤15 ng/mL) or low transferrin saturation (serum iron/total iron-binding capacity <16%) [8-10]. Menorrhagia is defined as heavy menstrual bleeding with a total menstrual blood loss of 80 mL or more in each menstruation cycle and/or bleeding lasting for more than 7 days [11]. The presence of menorrhagia was based on the medical records obtained from a gynecologist.

4) Diagnostic criteria for VWD

Type 1 VWD was diagnosed according to the Hospital for Sick Children (HSC) criteria [12,13]. Type 1 VWD was defined as a case in which both VWF:Ag (<50%) and VWF:RCo (<50%) were low, and there was significant mucosal bleeding or a family history of VWD. When either VWF:Ag or VWF:RCo was below the recommended standard, it was defined as a possible type 1 VWD. In cases where the ratio of VWF:RCo and VWF:Ag was <0.6, it was further classified into types 2A, 2B, 2M, and 2N VWD. Type 3 VWD was diagnosed when VWF:RCo and VWF:Ag were <3 IU/dL each, FVIII:C was <10 IU/dL, and there was a total loss of von Willebrand multimer [14-16].

5) Statistical analyses

Two-sample t-tests and the Wilcoxon rank-sum tests were used to analyze continuous data. A P-value of <0.05 was considered statistically significant. Statistical analyses were performed using SPSS software (version 20.0, Chicago, IL, USA).

1) Demographics of patients

A total of 120 patients were included in this study, of whom 19 were aged <20 years, and 101 adults were identified. The hemostatic test results of all patients are shown in Table 1. The median age of patients who were diagnosed with both IDA and menorrhagia was 39 years (range 12-55 years) and the median hemoglobin level of the patients was 8.6 g/dL (range 3.9-11.8 g/dL). Among all the patients, only 12 underwent a test to diagnose VWD, all of whom were pediatric patients; of these 12 patients, 4 were diagnosed with VWD. In total 4 of the 120 (3.3%) patients with IDA and menorrhagia were diagnosed with VWD. Table 2 shows the differences in clinical and laboratory features between the pediatric patients tested for VWD, with and without VWD. Although there was no statistical significance, there was a tendency towards younger patients in the disease group (13.25 vs. 15.00 years). A trend was also observed in the frequency of recurrence of IDA between the 2 groups, but there were no significant differences between the groups for any of the parameters.

Table 1 . Laboratory data of the 120 patients with iron deficiency anemia and menorrhagia.

	Median	Range
Age at diagnosis (years)	39	12-55
Hemoglobin (g/dL)	8.6	3.9-11.8
Hematocrit (%)	28.8	15.2-36.7
RBC count (×1012/L)	4.16	1.93-5.33
MCV (fL)	70.95	24.6-97.6
MCH (pg)	21.6	12.2-33.5
MCHC (g/dL)	30.1	16.2-34.3
Platelet count (×109/L)	296	134-816
Ferritin (ng/mL)	4.4	1.23-50.76
Transferrin saturation (%)	4.27	1.31-60.82

RBC, red blood cell; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemo-globin concentration..

Table 2 . Comparison between pediatric patients tested for von Willebrand disease.

	Patients with VWD (N=4) Mean±SD	Patients without VWD (N=8) Mean±SD	P-value
Age at diagnosis (years)	13.25±1.5	15.00±2.0	0.1563
Hemoglobin (g/dL)	8.15±2.38	7.99±1.62	0.8907
Hematocrit (%)	28.88±5.14	27.18±4.89	0.5883
RBC count (×1012/L)	4.55±0.32	4.04±0.80	0.2577
MCV (fL)	63.38±9.49	68.11±7.39	0.3605
MCH (pg)	17.90±4.94	20.18±3.28	0.3579
MCHC (g/dL)	27.88±3.2	29.35±1.88	0.4608
Platelet count (×109/L)	450.00±260.09	390.75±67.66	0.6827
Ferritin (ng/mL)	4.11±3.12	4.47±3.86	0.9339
Transferrin saturation (%)	5.10±4.23	3.17±1.73	0.4370
Recurrence of IDA (times)	1.25±1.50	0.38±1.06	0.2874
Duration of normalized lab (months)	4.0±2.83	3.5±4.38	0.4016
Treatment duration (months)	38.50±43.96	12.75±11.39	0.4600

VWD, von Willebrand disease; RBC, red blood cell; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; IDA, iron deficiency anemia; SD, standard deviation..

2) Cases of patients with VWD

The hemostatic test results and clinical features, including bleeding symptoms and recurrence rate, found in the 4 patients with VWD are shown in Table 3. Patient 1 had repeated epistaxis (1-2 times/week) for 3-4 years from the age of 8 years and was screened for hemorrhagic disease when the patient visited our pediatric hematologic outpatient clinic. At that time, VWF:Ag and VWF:RCo were found to be 38% and 41%, respectively. After menarche at the age of 11 years, due to menorrhagia she again underwent VWD tests at the age of 13 years. VWF:Ag, VWF:RCo, and FVIII:C were found to be 30%, 26%, and 72.5%, respectively, and definite type 1 VWD was diagnosed. After being prescribed ferrous sulfate for 3 months, IDA was overcome, and there was no recurrence of anemia.

Table 3 . Baseline clinical characteristics of the 4 patients with von Willebrand disease.

Patient no.	Age (years)	Blood group	Bleeding symptoms other than menorrhagia	Family history	Hb (g/dL)	VWF: RCo (%)	VWF: Ag (%)	FVIII: C (%)	VWD type	aPTT (s)	Recurrence of IDA (times)
1	12	B+	Epistaxis	None	11.5	26	30	72.5	Definite type 1	37.0	0
2	12	O+	None	None	5.9	32	31	95.3	Definite type 1	39.7	2
3	14	A+	None	None	7.8	38	41	62.7	Definite type 1	39.5	0
4	15	O+	Tooth extraction bleeding	None	7.4	48	50	45.2	Possible type 1	57.0	3

VWF:RCo, von Willebrand factor ristocetin cofactor activity; VWF:Ag, von Willebrandfactor antigen; FVIII:C, factor VIII coagulant activity; aPTT, activated partial thromboplastin time; Hb, hemoglobin; IDA, iron deficiency anemia..

Patient 2 had tetralogy of Fallot and had undergone heart surgery twice in our hospital at the ages of 10 and 14 months. There was no surgery-related bleeding. After visiting the pediatric hematologic outpatient clinic, she was diagnosed with IDA and started on ferrous sulfate treatment. At the age of 12 years, after menarche, she was found to have menorrhagia and a VWD screening test was performed. VWF:Ag and VWF:RCo were found to be 46% and 46%, respectively. The patient was prescribed ferrous sulfate for 32 months. As she did not visit the outpatient clinic regularly, there were 2 recurrences of anemia. The first VWD test was normal at the time according to the International Society on Thrombosis and Hemostasis consensus guidelines [13]. However, IDA and menorrhagia recurred, and the VWD screening test was repeated 4 times; VWF:Ag, VWF:RCo, and FVIII:C were found to be 31%, 32%, and 95.3%, respectively, and definite type 1 VWD was diagnosed according to the HSC criteria. Therefore, she was prescribed tranexamic acid during menstruation, and the symptoms related to menorrhagia improved thereafter.

Patient 3 was diagnosed with anemia (hemoglobin, 5.8 g/dL) at a local clinic with symptoms of enteritis and a common cold around the age of 14 years. She was referred to our outpatient clinic of the pediatric hematologic department from the gynecologic department because of anemia and menorrhagia after menarche at the age of 11 years. The patient was diagnosed with IDA, and the VWD screening showed that VWF:Ag, VWF:RCo, and FVIII:C were 41%, 38%, and 62.7%, respectively, and definite type 1 VWD was diagnosed. She was prescribed iron acetyl transferrin for 8 months, and there was no recurrence of anemia. Currently, she is being treated with hormonal medication in the local clinic of the gynecology department, and the symptoms of menorrhagia are under control.

Patient 4 was diagnosed with neurofibromatosis and regularly visited our pediatric neurology department for follow-up. Due to IDA and menorrhagia, she was transferred to our pediatric hematologic outpatient clinic. Initial VWD screening of VWF:Ag and VWF:RCo were found to be 62% and 45%, respectively. At the age of 21 years, due to uncontrolled bleeding after undergoing a dental procedure at the local dental clinic, she visited the pediatric hematologic clinic. At that time, aPTT was prolonged to 57.0 seconds. VWD screening tests were repeated 8 times, the lowest values of VWF:Ag, VWF:RCo, and FVIII:C were found to be 50%, 48%, and 45.2%, respectively.

VWD is a hereditary hemorrhagic disease with heterogeneous patterns caused by quantitative or qualitative abnormalities in the glycoprotein termed as VWF and is considered the most common genetic hemorrhagic disorder [1]. Although epidemiological studies estimate a prevalence of up to 1% of the general population, based on clinical symptoms of patients, the more conservative prevalence rate would be approximately 0.01% of the general population [17,18].

In Korea, there are only 146 registered patients with VWD, which is significantly lower when compared to 1,746 registered patients with hemophilia A [7]. Accord-ing to the 2018 survey of the World Federation of Hemophilia, in the United States, 13,616 hemophilia A patients were registered and 11,805 VWD patients were reported. In Asian countries, 1,325 patients with VWD are registered compared to 5,301 hemophilia A patients in Japan [19]. Compared to other countries, the number of registered VWD patients in Korea is significantly low. In a recent study, 775 patients with hemophilia A and 517 patients with VWD were reported in data from the Korean Health Insurance Review and Assessment Service database from 2010 to 2015 [20]. This result is contrary to a previous study including the Korean Hemophilia Foundation annual report. This means that VWD patients are not being properly diagnosed in Korea or nationwide statistics are not being conducted [13]. In particular, due to the nature of the disease, a few patients are expected to register with the Korean Hemophilia Foundation because they usually show few clinical symptoms.

There is no difference in prevalence between the sexes, as VWD is caused by autosomal dominant inheritance. However, it is thought that women with symptoms, such as menorrhagia, have a higher diagnosis rate than men because the clinical symptoms are generally not clear [3,21]. However, a multi-center study on VWD showed that there was not much difference in prevalence between the sexes [2,13]. The misconception regarding VWD prevalence is believed to be due to a lack of awareness of VWD, which often causes female patients to fail to suspect VWD even if they have bleeding symptoms, such as menorrhagia [3,22]. Therefore, in this study, the subjects of the study were women with menorrhagia and IDA.

Out of the 120 patients who were diagnosed with menorrhagia and IDA and were enrolled in this study, treatment started in adulthood for 101 patients. Only 12 out of the 120 patients underwent the VWD screening test, and all were pediatric patients. Four of the 12 patients who underwent the test were diagnosed with VWD, which was significantly higher than the known prevalence of VWD. VWD can be diagnosed at any age. Considering the various factors that affect diagnosis, it is difficult to determine whether VWD is more likely to be diagnosed at a certain time either in children or adults [23,24]. Further studies on the prevalence of VWD disease in the adult group with significant bleeding symptoms are necessary.

In addition, considering the case histories of the 4 patients in this study, although the initial VWD screening test was confirmed as normal, most of the patients were diagnosed with VWD after repeated tests. Even in patients with VWD, the activity of the VWF in stress, exercise, or pregnancy may be increased. VWF is an acute phase reactant that has been reported to increase up to 3 times higher than the normal level in acute infectious diseases caused by bacteria, viruses, and other parasites, and also to increase and decrease significantly according to the progress and improvement of infection [25]. Therefore, in cases of suspected VWD symptoms, repeated VWD screening tests are necessary [5].

Compared with the patient group without VWD, the patient group with VWD tended to be younger in age at the time of diagnosis of VWD and with a higher frequency of recurrence of IDA. Therefore, accurate diagnosis and appropriate treatment of VWD in the patient group with significant bleeding tendency will help reduce the worsening of symptoms. In particular, it is essential to differentiate VWD in women with symptoms, such as menorrhagia and IDA. Although the effective therapy for menorrhagia with VWD is unclear, a study has revealed that the most common therapies for menorrhagia with VWD are combined oral contraceptives, tranexamic acid, and desmopressin [26].

The limitation of the study is that a small number of patients were included as the study was conducted at a single center. In addition, the number of patients who underwent VWD tests was very small compared to the total patient group who had IDA and menorrhagia; thus the prevalence of actually diagnosed VWD may not be accurately predicted. All of the researchers who conducted this study were pediatricians, but VWD can be diagnosed at any age; therefore, the study was conducted on patients of all ages. However, evaluation of VWD was not performed efficiently in adult patients. It was difficult to involve other departments due to the retrospective nature of the research, which also did not reflect the subjective indicators available to patients. Since this research institute is a tertiary medical institution, only a group of patients with severe symptoms may have been referred to our hospital and this could have resulted in a selection bias.

Most of the studies focused on VWD have been reported in the West, and there are few reported studies of the disease in Asia, which is an important strength of this study. The study also points out the need for further research on VWD. According to our study results, there was a much higher prevalence of patients with anemia accompanied by hemorrhagic symptoms, which can help create the necessary care guidelines for diagnosing VWD in clinical care.

In conclusion, VWD should be considered as an important causative factor in patients with IDA and unexplained menorrhagia. In addition to menorrhagia, patients with anemia who exhibit other bleeding symptoms should also be examined for VWD. As there is a low diagnosis rate for VWD in Korea, more attention is needed for this disease in the future. Further studies on the prevalence of VWD disease in adults with significant bleeding symptoms are needed.

The authors have no conflict of interest to declare.