Naproxen-induced thrombocytopenia

Abstract

Thrombocytopenia has many mechanisms with broad differentials. A detailed history and physical, with timely diagnostic testing, is necessary to parse out the underlying etiology. Clinicians should maintain a high suspicion for drug-induced thrombocytopenia when there is an acute drop in the platelet level after exposure to commonly implicated drugs. Drug-induced thrombocytopenia is not well defined, as reporting is voluntary and not critically reviewed. Oftentimes, the culprit is not the drug itself, but a drug metabolite, which is difficult to prove with drug-dependent antibody testing. Here we present a case where naproxen led to hemarthrosis secondary to drug-induced thrombocytopenia.

Thrombocytopenia is a very common problem encountered in both inpatient and outpatient settings. It is often noted when the platelet count drops below 150 × 10³/μL. Many etiologies may be responsible, including a falsely low count, immune-mediated platelet destruction, drug-induced, infections, nutritional deficiencies, pregnancy, chronic liver disease, and malignancies. Thrombocytopenia can cause both bleeding and thrombosis, each requiring different treatments and considerations. ¹ Here, we present a case of a healthy middle-aged man who used multiple days of naproxen, a nonsteroidal anti-inflammatory drug (NSAID), that led to hemarthrosis secondary to drug-induced thrombocytopenia.

CASE DESCRIPTION

A 41-year-old previously healthy man with a recent left anterior cruciate ligament injury and left meniscal injury treated with left meniscal repair presented with worsening left lower extremity pain. The patient was placed on naproxen as needed for postoperative pain. He was evaluated a few days prior to presentation in an ambulatory orthopedic clinic for worsening left knee pain and underwent arthrocentesis of the left knee that demonstrated hemarthrosis but without a septic joint. The patient was scheduled for outpatient orthopedic follow-up but presented to the hospital for worsening pain, in addition to hematuria, frequent bloody gums when brushing, and periods of epistaxis when blowing his nose. He was noted to be afebrile with normal vital signs.

On exam, he was in no distress and had no findings of splenomegaly or active bleeding, but had multiple areas of petechiae across his body, most notable in the lower extremities. He had a platelet count of 2000/μL on confirmation, without any further cell line abnormalities. He was noted to have baseline platelets of 209,000/μL 2 years prior and denied any recent antiplatelet use. He was given multiple platelet transfusions with no response. All testing, including bilateral venous duplex ultrasonography for deep vein thrombosis, heparin-induced thrombocytopenia (HIT) antibody, viral serologies for human immunodeficiency virus and hepatitis C virus, as well as serum levels of thyroid-stimulating hormone, vitamin B12, and folate were all unremarkable. His immature platelet fraction was 11.6%. Naproxen was discontinued and dexamethasone was initiated for 4 days for a suspected immune-mediated etiology. After 48 h, the patient’s platelets subsequently increased to 9000/μL and then 25,000/μL, and he was ultimately discharged with a platelet count of 111,000/μL (Figure 1).

Figure 1.

Platelet count trend from admission to discharge. The star indicates when dexamethasone was initiated.

DISCUSSION

Thrombocytopenia has many etiologies, and prompt diagnosis is critical, as complications include life-threatening bleeding or thrombosis. Drug-induced thrombocytopenia is caused by drug-induced antibodies, but this is often difficult to prove with laboratory testing. Therefore, it is easily overlooked, except in the case of HIT given the presence of heparin antibodies. Testing for other medications is not widely available and may still be falsely negative. Additionally, drug metabolites may be the etiology and are even more difficult to identify due to lack of drug metabolite antibody testing. ² Given known limitations in laboratory testing, certain criteria were developed to help in diagnosis: 1) use of the drug preceded development of thrombocytopenia and platelet recovery was sustained following drug discontinuation; 2) no other drugs were used prior to development; 3) other etiologies were eliminated; and 4) reexposure to the candidate drug caused recurrent thrombocytopenia or drug-dependent antiplatelet antibodies. ³ The presence of severe thrombocytopenia (<20,000/μL) increases the likelihood for drug-induced thrombocytopenia, as seen in our patient. The most common medications include abciximab, acetaminophen, beta-lactams, carbamazepine, gold compounds, heparin, ibuprofen, linezolid, naproxen, phenytoin, piperacillin, ranitidine, quinidine, quinine, rifampin, sulfonamides, trimethoprim-sulfamethoxazole, valproic acid, and vancomycin. ^{4 , 5} Treatment generally involves discontinuing the drug. In severe thrombocytopenia, corticosteroids are often given, but there is no clear evidence that they are helpful.