Treatment of Epistaxes in Hereditary Haemorrhagic Telangiectasia (Rendu-Osler-Weber Disease) With Tranexamic Acid

ORIGINAL ARTICLES

Treatment of Epistaxes in Hereditary Haemorrhagic Telangiectasia (Rendu-OslerWeber Disease) With Tranexamic Acid Carmelo Morales-Angulo,a Alfonso Pérez del Molino,a Roberto Zarrabeitia,a África Fernández,b Francisco Sanz-Rodríguez,b and Luisa María Botellab a

Unidad de THH, Hospital Sierrallana, Torrelavega, Cantabria, Spain Unidad de Genética Molecular, CIB, Madrid, Spain

b

Objective: Recurrent epistaxis is the most frequent clinical manifestation of hereditary haemorrhagic telangiectasia (HHT). Its treatment occasionally presents difficulties as there is no consensus on the appropriate therapeutic protocol. Our objective was to explore the utility of oral tranexamic acid for the treatment of epistaxes in HHT patients. Patients and method: A 3-year prospective study was carried on HHT patients with epistaxis treated with oral tranexamic acid in the HHT unit at our hospital. Results: Ten patients with HHT were treated with oral tranexamic acid during the study. Most of them improved both the frequency and severity of their epistaxis and were satisfied with the treatment. No treatment-related complications were recorded. Two patients needed more aggressive treatments to control epistaxis. Conclusions: Oral tranexamic acid is useful for achieving significant reductions in epistaxis frequency and intensity in selected patients with HHT. In those presenting severe epistaxis, however, it may need to be combined with more aggressive therapies.

Tratamiento de las epistaxis en la telangiectasia hemorrágica hereditaria (enfermedad de RenduOsler-Weber) con ácido tranexámico

Key words: Hereditary haemorrhagic telangiectasia. Epistaxis. Treatment. Tranexamic acid.

Palabras clave: Telangiectasia hemorrágica hereditaria. Epistaxis. Tratamiento. Ácido tranexámico.

Introducción: Las epistaxis son la manifestación clínica más frecuente en los enfermos con telangiectasia hemorrágica hereditaria (HHT). Su tratamiento es en ocasiones muy complejo, y no hay consenso sobre el protocolo terapéutico que se ha de aplicar. El objetivo de nuestro estudio fue valorar la utilidad del ácido tranexámico oral en las epistaxis secundarias a HHT. Pacientes y método: Se realizó un estudio prospectivo de pacientes con HHT tratados por epistaxis en la unidad de HHT de nuestro hospital mediante ácido tranexámico durante 3 años. Resultados: Se trató a 10 pacientes con HHT mediante ácido tranexámico oral durante el período de estudio. Todos ellos presentaron una disminución tanto en la intensidad como la frecuencia de las epistaxis. En su mayoría estaban satisfechos con los resultados del tratamiento. Ninguno presentó complicaciones relacionadas con él y 2 pacientes siguieron precisando otros tratamientos para control de las epistaxis. Conclusiones: El ácido tranexámico oral es útil en el tratamiento de las epistaxis en algunos pacientes con HHT, pues reduce de forma significativa tanto la intensidad como la frecuencia. Sin embargo, en los que presentan epistaxis severas no impide la necesidad de seguir realizando otros tratamientos agresivos.

INTRODUCTION Correspondence: Dr. C. Morales-Angulo. Alto de Veneras, 8. 39478 Puente Arce. Cantabria. España. E-mail: [email protected] Received February 5, 2007. Accepted for publication February 12, 2007.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder involving the blood vessels of incomplete penetrance. Its prevalence in Cantabria is approximately 1/12 000.1 There are 2 types of HHT, type 1 and type 2, caused by mutations in the endoglin gene and Acta Otorrinolaringol Esp. 2007;58(4):129-32

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Morales-Angulo C et al. Treatment of Epistaxes in Hereditary Haemorrhagic Telangiectasia (Rendu-Osler-Weber Disease) With Tranexamic Acid

in the ALK-1 gene, respectively.2,3 A new mutation in a third gene located on chromosome 5 (HHT type 3) has recently been described.4 These genes code for proteins that are involved in the proper development of blood vessels. The most common clinical manifestations in HHT are epistaxis, generally mild or moderate.5-7 Nevertheless, some patients present severe nose bleeds that markedly interfere with their quality of life.8 These epistaxic episodes appear as a result of the formation of telangiectasias in the nasal mucosa. They are focal dilatations of the postcapillary venules, which in advanced stages present excessive layers of smooth muscle without elastic fibres and often connect directly with dilated arterioles.9 As a result of the structural alterations named, these telangiectasias are very sensitive to slight trauma and even friction from the air inhaled, giving rise to nosebleeds. There is no optimal treatment for epistaxis in patients with HHT. Several treatments are used, all of them without very satisfactory results.10-13 The use of systemic antifibrinolytic agents in patients with HHT was described for the first time by Saba et al,14 who used oral aminocaproic acid in 2 patients, with improvement in the epistaxis and secondary anaemia. Other authors have subsequently used tranexamic acid and have reported good outcomes with the use of oral and topical administration,15-18 albeit there are also studies that demonstrate the contrary.19 The objective of our study was to confirm whether the use of oral tranexamic acid is effective in moderate or severe epistaxis in patients with HHT.

2001 and December 31, 2004. The Curação diagnostic criteria were used to diagnose HHT20 (Table 1). Our work included patients seeking care for epistaxis that interfered with their quality of life and did not present contraindications for the use of oral tranexamic acid. Contraindications included having had thromboembolic phenomena. The dose of tranexamic acid used was 500 mg/8 h per os; the dose was adjusted according to kidney function. The analyses performed for all patients included haemogram, plasma biochemistry, coagulation study and genetic study to determine the causative mutation of the disorder. Moreover, an otorhinolaryngologist involved in HHT patient evaluation carried out a head and neck examination. In order to assess treatment efficacy, transfusion needs and the frequency and intensity of the epistaxis were quantified according to the scale by Sadick et al21 both before and after. Thus, on the basis of frequency, the following degrees were established: degree I, bleeding less than once a week; degree II, several times per week; degree III, more than once a day; and according to intensity: degree I, drops of blood on a handkerchief; degree II, handkerchief covered with blood; degree III, a container of some kind is needed to collect the blood. A scale from I (very satisfied) to IV (very dissatisfied) was used to measure patient satisfaction.

RESULTS PATIENTS AND METHOD A prospective study was conducted on all the patients seen at the HHT unit of our hospital between January 1, TABLE 1. The Curação Criteria20*

Diagnosis of hereditary haemorrhagic telangiectasia Definitive: if 3 criteria are present Possible or suspected: if 2 criteria are present Unlikely: if fewer than 2 criteria are present

Criteria 1. Epistaxis: spontaneous, recurring 2. Multiple telangiectasias, located in characteristic places Lips Oral cavity Fingers Nose 3. Visceral lesions Gastrointestinal telangiectasias Pulmonary AVF Hepatic AVF Cerebral AVF Spinal AVF 4. First degree relative with a history of these criteria *AVF indicates arteriovenous fistula.

130 Acta Otorrinolaringol Esp. 2007;58(4):129-32

Eighty patients with HHT were seen at our hospital during the course of the study; the subjects belonged to 23 different families, all Spanish; 10 patients presented epistaxis that interfered with their quality of life; they presented no contraindications for oral tranexamic acid, and they were willing to participate in the study. Patient characteristics and prior treatments for nose bleeds are presented in Table 2. As regards tranexamic acid (Table 3), treatment duration varied between 3 and 25 months, with a mean of 14 months. All the patients presented a reduction of both intensity and frequency of epistaxis (Table 3); 8 patients are satisfied or very satisfied with the treatment, 1 patient is moderately satisfied, and 1 dissatisfied with the treatment. These latter 2 patients have required several treatments despite the medication, albeit significantly fewer treatments than before taking tranexamic acid. At present, 9 continue to take oral tranexamic acid either continuously or intermittently. None have presented drug-related complications.

DISCUSSION More than 90% of HHT patients suffer nose bleeds that typically appear before the third decade of life, get worse with age and become very severe in 18% of cases, to the point where they represent a tremendous limit on patients’ quality of life.8.

Morales-Angulo C et al. Treatment of Epistaxes in Hereditary Haemorrhagic Telangiectasia (Rendu-Osler-Weber Disease) With Tranexamic Acid

haemoglobin figures. None of the patients presented any side effects during administration of the medication and did not require any blood transfusion. Pérez del Molino et al18 were able to control a massive, life-threatening bout of epistaxis in one patient with HHT by initiating treatment with oral tranexamic acid. Klepfish et al17 used topic tranexamic acid in drops, 5 drops (approximately 0.5 mL) of 100 mg/mL, following the onset of nosebleed episodes in one patient with severe epistaxis and anaemia, who achieved good control of epistaxis and normalized haemoglobin levels with hardly any iron supplements and with no medication-related side effects during the 3 year follow-up period. The 10 patients included in our study presented epistaxis that significantly interfered with their quality of life; 4 of them had already undergone several treatments. Almost all of them presented significant improvement of epistaxis, with improved haemoglobin values and decreased needs for blood transfusions in the 4 patients who had been anaemic prior to treatment.

Many different treatments have been used, such as cauterization, treatment with oestrogens and/or progesterone, septal dermoplasty, embolization or radiotherapy among others, all with limited and temporary efficacy.6,22 Kwann et al23 and subsequently Watanabe et al24 observed increases fibrinolytic activity in telangiectasic tissue mediated by an increase in plasminogen activator levels. With these findings as a starting point, several authors began to use antifibrinolytic agents, such as aminocaproic acid initially and tranexamic acid later on, in patients with HHT.14-17 Tranexamic acid is an antifibrinolytic agent that is some 10 times more potent than aminocaproic acid and has a longer half-life. It is a by-product of the synthesis of the amino acid lysine, 4-aminomethyl-cyclohexanecarboxylic acid.25 Like aminocaproic acid, it binds reversibly to plasminogen, preventing plasminogen from binding to fibrin and hence its activation and transformation into plasmin.26,27 It is used in the treatment of various hemorrhagic diatheses and is effective even when the bleeding is not associated with signs of excessive fibrinolysis.28 As it enters the extravascular space and accumulates in the tissues,29 it is believed that the basis of its efficacy is the inhibition of fibrinolysis in the tissues and hence, the clots are stabilized.25 Its side effects depend on dosage and generally involve the gastrointestinal tract (nausea, vomiting, abdominal pain, and diarrhoea).25 The greatest risk associated with its use is the thrombotic complications resulting from the inhibition of fibrinolysis, which is the natural mechanism controlling thrombi formation.25 Tranexamic acid would act in patients with HHT by inhibiting fibrinolysis in the wall of the telangiectasic vessels, where, as we have said, there is an increase in the fibrinolytic activity allowing the deposits of fibrin to seal the bleeding sites effectively.23,24 Sabba et al16 treated 3 patients with HHT presenting severe epistaxis with oral tranexamic acid at doses of 1 g/6 h in 2 of them and 500 mg/2 h to the third, and there was a very significant decrease in the nosebleed and an increase in the

TABLE 2. Patient Characteristics*

No./Age/Gender

Mutation

Prior Treatments

1/47/M

Unknown

No

2/80/M

HHT1

Cauterization, A/P packing

3/69/M

ALK1

Cauterization, A/P packing

4/42/M

ALK1

No

5/49/F

ALK1

Cauterization, A/P packing

6/47/F

ALK1

No

7/59/M

HHT1

Cauterization, A/P packing

8/45/F

ALK1

No

9/78/F

ALK1

No

10/41/F

ALK1

No

*A/P indicates anterior/posterior; F, female; M, male.

TABLE 3. Treatment With Tranexamic Acid and its Efficacy*

No.

Dose

Period of Use, Months

Previous Transfusions

Transfusions Following Treatment

Prior Epistaxis, I/F

Epistaxis Following Treatment

Satisfaction

1

500 mg/12 h

2

No

No

III/II

I/I

II

2

500 mg/8 h

24

>5

<5

III/III

II/II

II

3

500 mg/8 h

25

<5

0

III/III

I/I

II

4

500 mg/8 h

2

No

No

II/II

I/I

II

5

1000 mg/8 h

16

<5

<5

III/II

II/II

III

6

500 mg/8 h

11

<5

0

III/II

I/I

II

7

500 mg/8 h

12

<5

<5

III/III

II/II

III

8

500 mg/12 h

4

No

No

II/II

I/I

I

9

500 mg/12 h

6

No

No

II/II

I/I

II

10

500 mg/8 h

4

No

No

II/II

I/I

I

21

*I/F indicates intensity/frequency, both according to the scale devised by Sadick et al.

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In 2 patients, despite the significant improvement in nosebleeds and anaemia and in spite of the decrease in needs for transfusion, prior nasal packing had been required on several occasions. No patients presented oral tranexamic acid treatmentrelated complications; it would therefore seem that it is a safe medication at the doses generally used (500 mg/ 8-12 h). Oral tranexamic acid is useful for treating epistaxis in some patients with HHT because it significantly reduces both their intensity as well as the frequency. Nevertheless, it does not preclude the need to follow other treatments in patients with severe epistaxis.

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