Efficacy and Safety of Direct Oral Anti‐Coagulants in Painful Venous Malformations in Children

ABSTRACT

Direct oral anticoagulants (DOAC), including dabigatran, apixaban, and rivaroxaban, are increasingly used in adults for painful venous malformations (VMs) instead of subcutaneous drugs such as low molecular weight heparins or fondaparinux. However, these medications are poorly studied in children. In seven children with painful VMs and chronic intravascular consumptive coagulopathy, DOACs allowed for successful pain control and improvement in coagulopathy, with no adverse effects. DOACs appear to be an effective alternative in childhood VM associated with intravascular coagulopathy.

1. Introduction

Low molecular weight heparins (LMWH) and fondaparinux, a synthetic inhibitor of factor Xa, improve the chronic consumptive coagulopathy and related symptoms such as pain and bleeding associated with venous malformations (VMs) [1, 2]. Subcutaneous injections, the only available mode of administration for these agents, are a source of discomfort, especially in children. Direct oral anti‐coagulants (DOAC), including dabigatran, apixaban, and rivaroxaban, appear to be an efficient and safe alternative in adults [3, 4, 5, 6, 7]. Among them, dabigatran is favored because of the availability of a specific reversing agent in the event of over‐anticoagulation [7]. Several DOACs are approved for use in children for the treatment and prevention of thromboembolic events, but their use for VMs in this age group has been rarely reported, with concerns raised regarding the theoretical risk of hemorrhage. We describe the use of DOAC in children and adolescents with VMs treated at the Necker Hospital, Paris.

2. Methods

A retrospective review was undertaken of patients under the age of 18 years who were treated with a DOAC for a painful VM. Age, sex, VM location and characteristics, platelet count, D‐dimer and fibrinogen levels, molecular findings, and anticoagulant types were collected. Patients received written information about the publication of their case details. The study registration number is 20241223143303.

Successful pain control and normalization or improvement of biological parameters were initially established with LMWH or fondaparinux in all but one patient (Patient 5). Pain control was assessed during examinations by evaluating functional normalization and the discontinuation of pain reliever use. Biological parameters to assess and follow the degree of coagulopathy included platelet count, fibrinogen, and D‐dimer levels. Improvement in pain and coagulopathy was used to confirm that the pain was specifically related to the chronic coagulopathy and that anticoagulant treatment was the appropriate management. Upon achieving this outcome, switching to an oral medication was proposed to improve patient comfort and cooperation.

Based on our experience in adults, for whom dabigatran etexilate was the most effective DOAC, this drug was chosen for the treatment of patients 12 years and older and weighing over 50 kg (patients 1 and 2) [8]. The starting dosage was 110 mg twice daily, increased to 150 mg twice a day if the D‐dimer level was not normalized. Rivaroxaban has been studied more extensively in children and can be taken once daily, so it was chosen for patients under 12 years old and weighing less than 50 kg (patients 3–7).

3. Results

Four females and 3 males aged 7–17 years were included. In all patients, the VM was located on a limb. Molecular diagnosis was performed in two patients (patients 1 and 6), confirming a somatic pathogenic variant of the PIK3CA gene in patient 1, while no mutation was identified in patient 6. In patients 1 and 2, the VMs included deep phlebectasias, putting them at risk for pulmonary thromboembolism, although this did not occur. Patient characteristics and specifics of treatments are detailed in Table 1.

TABLE 1.

Patient characteristics and treatment.

Patient number, sex, age, weight	VM location, characteristics	Symptoms	Plt (G/L), D‐dimer (ng/ml), Fg (g/L) levels at baseline	LMWH type and dosage	Plt, D‐dimer/Fg levels once pain relief obtained with LMWH	DOAC type, dosage; ttt duration at last follow‐up	Plt (G/L), D‐dimer/Fg levels with DOAC
1. F, 17 years, 54 kg	Segmental, left lower limb, deep phlebectasia	Chronic pain, risk of PTE	NA/3000/2.2	Tinzaparin	NA/310/NA	Dabigatran: 110 mg BID 12 months	222/270/2.42
2. F, 12 years, 52 kg	Segmental right lower limb with knee involvement deep phlebectasia	Chronic pain, joint limitation, risk of PTE	174/6100/1.5	Fondaparinux 5 mg/day	145/970/3.79	Dabigatran: 150 mg BID 12 months	217/430/3.38
3. M, 10 years, 39 kg	Foot	Chronic pain, limping, sport limitation	304/8683/2.17	Enoxaparin 0.2 mL 1*/day	314/2261/4.07	Rivaroxaban: 10 mg/day 6 months	310/874/2.82
4. M, 12 years, 50 kg	Foot, ankle, leg	Chronic pain, limping, sport limitation	291/3430/2.40	Fondaparinux 2.5 mg/day	248/670/2.40	Rivaroxaban: 10 mg/day 24 months	225/650/2.01
5. M, 11.5 years, 45 kg	Upper left limb with hand involvement	Chronic pain	182/14727/1.8		—	Rivaroxaban: 10 mg/day 16 months Rivaroxaban:10 mg/day 24 months	192/594/3.5
6. F, 10 years, 34 kg	Cervico‐facial, upper limbs (bilateral)	Chronic pain	286/21002/1.76	Enoxaparin 0.4 mL 1*/day	283/1100/2.09	Rivaroxaban 7.5 mg 12 months	283/4013/2.18
7. F, 7 years, 27 kg	Right inferior limb	Chronic pain, joint limitation, walking limitation	165/> 4000/1.3	Enoxaparin 0.2 mL 1*/day	259/> 4000/2.0	Rivaroxaban: 10 mg 12 months	278/> 4000/1.6

Abbreviations: BID: bis in die; DOAC: direct oral anticoagulant; F: female; Fg: fibrinogen; LMWH: low molecular weight heparin; NA: non‐available; Plt: platelet; PTE: pulmonary thromboembolism; ttt: treatment.

Before anticoagulants were introduced, all patients had refractory pain that led to functional limitation despite management with compression garments, pain relievers, anti‐inflammatory agents, or aspirin. In all patients, the clinical improvement (resolution of functional impairment) achieved with LMWH was maintained while on DOAC treatment.

At baseline, platelet count (normal range: 200–500 G/L) and fibrinogen levels (normal range: 2–4 g/L) were low in Patient 7 and normalized with anticoagulant treatment. D‐dimer levels (normal level < 500 ng/mL) were elevated in all patients ranging from 3000 to 21,000 ng/mL, mean level: 8706 ng/mL. Upon treatment with DOACs, D‐dimer level normalized in patients 1 and 2, and improved just above normal in patients 3, 4, and 5. Patients 6 and 7 achieved a stable significant decrease in D‐dimer level, comparable to levels on LMWH, though still above normal.

4. Discussion

In all patients, successful pain control, along with the resolution of functional impairment, was maintained with DOACs, without adverse effects. In patients with deep phlebectasias, for whom thromboembolic prevention is mandatory and requires maintaining D‐dimer levels within the normal range, the increased dosage of dabigatran did not lead to bleeding complications. We showed that increasing the dosage of dabigatran may correlate with better biological and clinical efficacy, while in the current literature, D‐dimer reduction appeared more variable with dabigatran than with LMWH; however, in those reports, dabigatran was mostly used at low dosages [6].

For patients 3–7, the treatment goal was to achieve pain relief, while persistently elevated D‐dimer levels, similar to those observed under LMWH, were tolerated as long as there was no pain or functional impairment. Therefore, a 10 mg/day dosage was chosen, lowered to 7.5 mg/day in younger patients with lower weight if it was enough to obtain pain relief. Patients 6 and 7 had the highest D‐dimer levels at baseline, with low fibrinogen and platelet count in Patient 7. Although less impressive, as D‐dimer levels remained significantly elevated, biological improvement (D‐dimer level lowering in Patient 6, platelet count and fibrinogen normalization in Patient 7) correlated with dramatic improvement in the clinical condition. The correlation between clinical and biological severity and the response to treatment was previously observed in a recent adult cohort [6].

Until now, no bleeding manifestations have been observed, confirming previous reports that in this context, DOACs, while improving the coagulopathy comparably to LMWH and fondaparinux, may introduce a lower risk for bleeding. However, none of our patients had invasive procedures while on DOACs, and the current recommended protocol is that children needing a surgical procedure should be switched to LMWH.

In conclusion, this small series of children with VMs and chronic intravascular coagulopathy showed that DOACs may achieve excellent pain control as well as thromboembolic prevention without adverse effects. Such results need to be confirmed in larger trials.

Consent

In accordance with our local regulations regarding monocentric retrospective observational studies, patients and their parents were informed about the conduct of a study using their medical data, including a clause of non‐opposition. The study registration number is 20241223143303.

Conflicts of Interest

The authors declare no conflicts of interest.

Boccara O., Bonigen J., Soupre V., Puzenat E., Bisdorff A., and Drouet L., “Efficacy and Safety of Direct Oral Anti‐Coagulants in Painful Venous Malformations in Children,” Pediatric Dermatology 42, no. 5 (2025): 1020–1023, 10.1111/pde.15930.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.