Myotonic dystrophy type 1 and pulmonary embolism: successful thrombus resolution with dabigatran etexilate therapy.

Myotonic dystrophy type 1 (DM1) is the most common form of adult muscular dystrophy. It is an autosomal dominant inherited disease with multisystemic involvement. Respiratory function is often affected and respiratory failure is the most common cause of death. Pulmonary embolism is a rare cause of respiratory failure in DM1 patients, so that the best anticoagulation strategy in these patients is still unclear. We describe the case of pulmonary embolism in a DM1 patient, in which pulmonary thrombus was completely resolved with oral dabigatran etexilate therapy.

Introduction

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults, affecting approximately 1 in 8000 people worldwide. It is a multisystem disorder with autosomal dominant inheritance. Clinical manifestations may vary from muscle symptoms such as myotonia, muscle weakness/atrophy and fatigue to cardiac arrhythmias, early cataracts, central/obstructive apnea, respiratory failure, insulin resistance, dysphagia and gastrointestinal dysmotility (1). Cardiac involvement is quite common, as in other muscular dystrophies (2), affecting about 80% of patients, and often precedes the skeletal muscle one. Cardiac involvement may include arrhythmias (3-6) atrioventricular block (7), ventricular premature contractions, atrial fibrillation (8-10), atrial flutter (11), right/left bundle branch block and non-sustained ventricular tachycardia (12) which often lead to needs of cardiac devices such as pacemakers or implantable cardiac defibrillator (13-16). Left ventricular systolic dysfunction has also been reported (17-22). Respiratory failure is a common feature in almost all muscular dystrophies and, together with cardiac involvement is the main cause of death (23-24). Respiratory failure in DM1 patients is often the consequence of a combination of respiratory muscle weakness and degeneration, and lung elastic properties alterations (25). Pulmonary embolism is a rare event in DM1 patients (26). Moreover, the best antithrombotic strategy in this subset of patients is still debated, and novel oral anticoagulants (NOAC) have never been systematically tested in DM1 patients (27). We described the case of a pulmonary embolism in a DM1 patient treated for the first time with dabigatran etexilate, obtaining a complete resolution of the pulmonary thrombus.

Case report

We report the case of a 62-year-old female patient affected by DM1. She had no other cardiovascular risk factors excepted for systemic arterial hypertension. She was admitted to the Emergency Department because of dyspnea arising 7 days before and worsening in the last 6 hours. The recent clinical history was not relevant, as only an unilateral knee pain was reported which limited her daily activities. At admission the patient was conscious; physical examination showed heart rate (HR) 124 bpm, blood pressure (BP) 110/60 mmHg, breathing rate (BR) 23/min, SpO2 85% (FiO2 21%). The ECG showed a new-onset incomplete right bundle branch block with S wave in DI, Q wave and inverted T wave in DIII (a combination known as S1Q3T3 pattern, suggestive for pulmonary embolism). The arterial blood gas analysis revealed hypoxemia with hypocapnia and respiratory alkalosis; the blood exams showed high levels of I-troponin and D-dimer. The echocardiogram showed normal structure and function of the left ventricle, while the right ventricle presented a reduced longitudinal contractile function (Tricuspid Annulus Plane Systolic Excursion, TAPSE 14 mm), with abnormal function of mid-basal free wall and apical hyper-contractility (Mc Connell’s sign). The systolic pulmonary artery pressure – derived from the echocardiographic measurement of the tricuspid regurgitant jet velocity – was 60 mmHg. The Wells score was 6. A parasternal short axis view revealed the presence of a large thrombus inside pulmonary artery just on the level of main pulmonary artery bifurcation (Fig. 1). As the suspicious for pulmonary embolism (PE) was high, Computed Thomography Pulmonary Angiography (CTPA) was performed. CTPA images, acquired with the maximum intensity of radio-opaque contrast in the pulmonary arteries, showed the presence of a large thrombus on the pulmonary artery bifurcation extended to the central part of the lumen of both branches (Fig. 2). In the absence of hemodynamic instability, the patient – according to the current ESC guidelines on acute pulmonary embolism management (28) – was treated with fondaparinux 7.5 mg, subcutaneously once daily. As after 5 days of medical therapy, the echocardiographic re-evaluation still showed the thrombus in pulmonary artery, the treatment was stopped and dabigatran (a direct thrombin inhibitor, DTI) was administered at a dosage according to the patient’s age and renal function (150 mg/bid). Seven days after, the cardiac ultrasound examination showed the complete resolution of the thrombus (Fig. 3). At the same time, the clinical and biochemical parameters returned within the normal ranges. Dabigatran was then prescribed as the long-life therapy according to the high thrombotic risk of the patient.

Figure 1.

Parasternal short axis view of the pulmonary artery. The stars indicate the right and left pulmonary artery. The white arrow indicates the thrombus lying on the bifurcation of the pulmonary artery.

Figure 2.

Computed thomography pulmonary angiography (CTPA) demonstrating saddle pulmonary embolism partially obstructing both main pulmonary arteries; the white area above the center is the pulmonary artery, opacified by radiocontrast; the black arrow indicates the pulmonary thrombus.

Figure 3.

Parasternal short axis view of the pulmonary artery showing the complete resolution of the thrombus on the bifurcation of the pulmonary artery.

Discussion

Myotonic dystrophy type 1 is mainly characterized by skeletal muscle involvement, anyway cardiac involvement is quite common (29-31). Respiratory system is also affected with diaphragmatic weakness and/or recurrent pulmonary infections, which can lead to respiratory failure.

Recently it has been observed that dystrophic patients may have high thrombotic risk due to some predisposing factors. Firstly, they are affected by a myopathy that leads to mobility restriction and a sedentary lifestyle, which may increase their thromboembolic risk. The increasing age and a personal history of venous thrombo-embolism seem to be other predisposing factors. Compared with other inherited myopathies, patients with DM1 have a higher thromboembolic risk (32). Moreover, muscle degeneration can enhance coagulation and fibrinolysis processes as described in other forms of muscular dystrophies such as Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and Fukuyama congenital muscular dystrophy (FCMD). Hyper-coagulability state could be another predisposing factor for recurrent thrombotic events; however little is still known about the mechanisms underlying hypercoagulability state in these patients (33). In DMD and BMD a protein known as utrophin (a dystrophin-related protein), could play a role in hypercoagulability and recurrent thrombosis events. It seems that the upregulation of utrophin observed in these patients, leads to a lower expression of thrombomodulin, resulting in hypercoagulability state (34). However, none of these evidences is quite strong and referred to DM1. New perspective about incidence of venous thromboembolism and predicting factors of recurrent thrombosis specifically in the subset of DM1 patients may will rise from the results of a retrospective cohort study by Whabi et al. (NCT number: NCT03141749). What could be the best anticoagulation strategy in these patients is still debated. To date, Warfarin is still considered the first line treatment and the standard of care for DM1 patients requiring anticoagulation, as its safety and effectiveness has been established over the last decades (35). However, the difficulties in achieving an optimal anticoagulation with conventional warfarin therapy, likely related to several factors such as the slow onset of action, the variable pharmacologic effects, the interaction with several food and drug and the needs of periodic closely target INR monitoring, make the therapeutic management in clinical practice it difficult and reduce the real-life DM1 patient’s compliance. All these challenges have prompted an extensive research on the use of NOACs in a subset of patients (36, 37). Unfortunately, none of the trials evaluating the use of NOACs (38) in clinical practice, included DM1 patients (39-41). Dabigatran etexilato is a thrombin direct inhibitor whose safety and effectiveness in the treatment of venous thrombo-embolism and pulmonary embolism (PE) was tested in RE-COVER (42) and RE-COVER II (43) trials. Its efficacy was non-inferior to warfarin, with no significant differences in minor and major bleedings. No data are available about the use of this drug for the management of PE in DM1 patients. This case report is the first to report the use of Dabigatran etexilato for PE in a DM1 patient; using this drug the complete resolution of the pulmonary thrombus after an episode of pulmonary embolism was achieved. No major or minor bleedings were observed during treatment, and clinical and biochemical parameters returned within normal range 7 days after therapy.

Oral anticoagulation is an important issue in this subset of patients because they present a high prevalence of atrial fibrillation (44-47) requiring long-term anticoagulation to reduce the risk of thromboembolic events (48, 49).

Conclusions

The present case is the first to report the complete resolution of a pulmonary thrombus in a DM1 patient with pulmonary embolism, by using dabigatran etexilato. The use of dabigatran etexilate as anticoagulation treatment could be particularly useful in this subset of patients, for their variable cognitive impairment and consequent poor compliance with periodic INR monitoring.