Abstract
To the Editor:
A
Case Report
A 9-year-old girl was referred to our clinic with complaints of inattentiveness, concentration problems, and learning difficulties, which had resulted in low school grades. According to the psychiatric assessment, she was diagnosed with ADHD—inattentive type with normal intellectual capacity. There was nothing remarkable in the prenatal, postnatal, early developmental, or family history, and no other associated medical comorbidity. Routine blood test results were all within normal ranges. Treatment of OROS-MPH 18 mg was initiated. This was generally well tolerated with some level of decreased appetite but no significant change in weight. The dose of OROS-MPH was increased to 27 mg/day 3 weeks later. During their second visit to our clinic 5 weeks later, the patient's mother reported that on the 10th day of OROS-MPH 27 mg/day treatment, her daughter had experienced nasal bleeding and this had occurred everyday when the dose of OROS-MPH was increased to 27 mg/day. The patient was referred to the pediatric clinic because of the nasal bleeding. A detailed evaluation was made. There was no history of hypertension, no bleeding disorder; or recent intake of nonsteriod anti-inflammatory drugs (NSAIDs), warfarin, or any antiplatelet agents. The patient was not taking any medication other than MPH. No other physical cause, such as excessive sneezing, coughing, nasal trauma, recent surgery, or infection, which could explain nasal bleeding, could be found. The coagulation profile, hemogram, and renal and liver function test results were within normal range. Otorhinological referral did not reveal any local cause of the bleeding. Therefore, the nasal bleeding was considered by the physician to be a possible adverse effect of OROS-MPH, and the medication was discontinued. After the cessation of OROS-MPH, the bleeding did not reoccur. It was decided to initiate atomoxetine for the ADHD symptoms. The patient experienced no bleeding during this treatment and tolerated the medication well.
Discussion
For children and adolescents with ADHD, MPH is a first-line psychopharmacological treatment and has been reported to result in significant improvement in 70%–80% of cases (Green 2007). There are several well-known potential adverse effects of MPH (Ahmann 1993; Storebø et al. 2015). However, there have been few reports of adverse hematological effects and bleeding, and a definitive causal relationship has not been established (McEvoy 2002). A few case reports have suggested a possible relationship between MPH and thrombocytopenia (Grossman and Grossman 1985; Kuperman et al. 2003). In a case report by Coskun and Adak (2017), an adolescent girl with ADHD experienced excessive and frequent menstrual bleeding while taking OROS-MPH.
To the best of our knowledge, there have been no reports of MPH-related nasal bleeding in pediatric cases with ADHD and, therefore, this is the first reported case of OROS-MPH-related nasal bleeding. It could be argued that the epistaxis occurred spontaneously and without any obvious cause, but as the timing coincided with the OROS-MPH treatment and did not recur after decreasing the dose, OROS-MPH would appear to be the likely causative agent.
In respect of possible mechanisms of MPH-associated bleeding, one possible mechanism could be that OROS-MPH could have caused or triggered nasal bleeding in this case by causing a kind of bleeding diathesis such as thrombocytopenia. The patient had no history of abnormal bleeding, and the bleeding tests and platelet counts were normal. Therefore, it could not have been a consequence of MPH-induced thrombocytopenia. MPH is known to facilitate dopaminergic transmission by blocking dopamine transporters (Volkow et al. 1998; Greenhill 2001). Several different effects of dopamine on platelet aggregation have been previously described. In the micromolar range, these include dopamine-induced platelet aggregation, enhanced adenosine diphosphate (ADP)-induced platelet aggregation, and inhibited epinephrine-induced aggregation (Braunstein et al. 1977). In the nanomolar range, the enhancing effect of dopamine on ADP-induced platelet aggregation has also been observed (Anfossi et al. 1992). Dopamine at high concentrations (5 mM) has been reported to completely inhibit ADP-induced platelet aggregation (Braunstein et al. 1977). In a study of 35 healthy individuals, the platelet aggregatory response to catecholamines was investigated and only one subject showed a response to dopamine (100 μM) alone (Pyo et al. 2003). To date, there has been no investigation of the ADP-dependent effects of dopamine. In a study by Schedel et al. (2008), dopamine was seen to be a coagonist for ADP-induced platelet microaggregate formation and adhesion to collagen. This effect was observed at physiological concentrations of dopamine. Therefore, it could be speculated that the effect of MPH on increasing dopamine may have had an antithrombotic effect in microcirculation and thus caused the bleeding in the nasal mucosal surface, which may be more sensitive to drug effects and bleeding.
Despite these possible explanations, it cannot be said with certainty that MPH was the cause of the bleeding in this case. However, the chronological sequence and response to drug discontinuation in the absence of identifiable medical causes are suggestive of possible causality. Further studies are warranted on this area.
Since this rarely reported adverse event may strongly affect patient compliance, it is necessary for clinicians to be aware of the possibility.
Footnotes
Ethical Disclosures
Protection of human and animal subjects: The author declares that no experiments were performed on humans or animals for this investigation.
Disclosures
No competing financial interests exist.