Platelet function analyser (PFA)-100^® closure time in the evaluation of non-steroidal anti-inflammatory drug-induced platelet dysfunction in children with bleeding symptoms

Dear Sir,

Non-steroidal anti-inflammatory drugs (NSAID), particularly ibuprofen, are commonly prescribed for children to treat inflammation, pain, and fever, as these drugs decrease prostaglandin synthesis through blockade of the cyclo-oxygenase enzyme. One of the main risks in children taking NSAID is an antiplatelet effect¹.

Closure time (CT), measured by a platelet function analyser (PFA-100^®, Dade-Behring, Marburg, Germany), is a parameter that can now be determined in a clinical laboratory as a possible alternative or supplement to the bleeding time. Two test cartridges are available: collagen/adenosine diphosphate (C/ADP) and collagen/epinephrine (C/Epi). Although the results provided by the PFA-100^® are not specific for any particular disorder, the device has the strengths of simplicity and excellent sensitivity for demonstrating particular haemostatic disturbances such as von Willebrand’s disease, platelet disorders, and platelet-affecting medication². In addition, the PFA-100^® CT is cheap: the cost of each test (using a C/Epi or C/ADP test cartridge) is approximately US$ 12.

The ability of the PFA-100^® CT to evaluate platelet dysfunction in children with bleeding symptoms who are taking a NSAID has not been thoroughly studied thus far. The aim of the present study was, therefore, to determine whether the CT can reveal platelet dysfunction in children with bleeding symptoms who are taking ibuprofen, naproxen or flurbiprofen.

Twenty-seven children with bleeding (epistaxis, ecchymosis and subconjunctival bleeding) were admitted to the Paediatric Haematology Department of Denizli State Hospital. Eight male and six female children between the ages of 2 and 8 years were administered ibuprofen for the treatment of fever and three male and ten female children between the ages of 8 and 15 years were administered naproxen or flurbiprofen for the treatment of fever, headache or dysmenorrhoea. These drugs were administered by the parents, not prescribed by a doctor. Records were made of the doses and how many times the three drugs had been administered. The CT was studied at first admission of the patients and 48 hours after cessation of drug intake.

The PFA-100^® CT was evaluated using both C/Epi and C/ADP cartridges in all patients, together with platelet counts and routine coagulation tests (i.e., activated partial thromboplastin time [APTT] and prothrombin time [PT]). The PFA-100^® CT is prolonged in patients with significant reductions in platelet count or haematocrit. The blood samples from our patients contained >150×10⁹ platelets/L and had a haemoglobin concentration of >11 g/dL. The manufacturer advises that each laboratory establishes its own PFA-100^® CT reference ranges by using buffered 0.109 M (3.2%) or 0.129 M (3.8%) citrate anticoagulated blood. Before our study, normal CT values for PFA-100^® CT were <110 seconds for the C/ADP cartridge and <150 seconds for the C/Epi cartridge.

The theoretical maximum C/Epi CT is 300 seconds, but for practical purposes any value >250 seconds can be considered a “maximally” prolonged; values between 200–250 seconds are moderately prolonged and a CT between 165–200 seconds is considered slightly prolonged.

The effects of ibuprofen, naproxen and flurbiprofen drugs on PFA-100^® CT in our patients are summarised in Table I. All cases had prolonged CT measured with the C/Epi cartridge and normal CT measured with the C/ADP cartridge. Patients who had taken ibuprofen had slightly prolonged C/Epi CT with a normal C/ADP CT, whereas patients who had taken naproxen or flurbiprofen had moderately to maximally prolonged C/Epi CT with a normal C/ADP CT.

Table I.

Effects of NSAID on the PFA-100^® CT.

Drugs	Dosage (mg/kg/dose) mean (min-max)	Times/total (times/a week)+ mean (min-max)	C/EPI sec* mean (min-max)	C/EPI sec** mean (min-max)
Ibuprofen (n=14)	8.6 (7.1–10.7)	4.6 (3–7)	184 (174–198)	95 (78–112)
Naproxen (n=7)	6.5 (5.6–7.6)	4.5 (3–6)	248 (224–300s<)	101 (88–112)
Flurbiprofen (n=6)	2.5 (2–2.8)	3.6 (2–5)	250 (228–300s<)	110 (88–110)

Legend:

^*first admission of the patients;

^**48 hours after cessation of drug intake;

⁺how many times the drug was used during the week before admission.

The prolonged C/Epi CT returned to normal (C/Epi CT <150s) 48 hours after cessation of the three drugs. Because the doses and number of administrations were different for each of the three drugs, the antiplatelet effect of these three drugs could not be compared precisely. However, our results showed that naproxen and flurbiprofen caused more prolonged C/Epi CT than did ibuprofen.

The PFA-100^® CT can provide rapid results and an early indication of a patient’s potential platelet dysfunction³. NSAID prolong the C/EPI CT in about 95% of healthy individuals, but have little or no effect on C/ADP CT. In the present study, all children had prolonged C/Epi CT with normal C/ADP CT. The antiplatelet effect of these drugs indicate appropriate doses and only a few administrations.

The effect of NSAID on platelets is temporary. According to the literature, when NSAID are discontinued, abnormally prolonged C/Epi CT values return to normal within 36 hours to 2 days following cessation of naproxen⁴ and within 24 hours following cessation of ibuprofen⁵. In our study, prolonged C/Epi CT normalised 48 hours after the last dose of ibuprofen, naproxen or flurbiprofen.

In conclusion, children with bleeding symptoms and a history of NSAID use can be assessed using the PFA-100^® CT. Paediatricians should prescribe NSAID to children with extreme caution according to the children’s bleeding symptoms.