The following case on methotrexate and thrombocytopenia was donated by Kirk Seale, M.S., PharmD, BCGP.
Kirk received his Master’s degree in Drug regulatory affairs from the University of Florida and received his PharmD from the University of Mississippi. He has also been appointed to serve on the Government Affairs Committee with The American Society of Consultant Pharmacist for 2019-2020. He currently works at Heartland Behavioral Health Facility and also serves as a long-term-care Consultant Pharmacist in Missouri.
LinkedIn profile: https://www.linkedin.com/in/kirk-seale-212b4920
He has no financial disclosures in relation to the content provided.
If you are a pharmacist and interested in donating a case study like this methotrexate and thrombocytopenia case, or a clinical pearl, feel free to shoot me an email!
OB is an 83 y/o female with a diagnosis of rheumatoid arthritis (RA), osteoporosis, hypertension, Type II Diabetes Mellitus, edema, allergies, and periodic muscle spasms. The following medications are listed on her profile:
- Potassium Chloride 20 MEq daily
- Lasix (furosemide) 40mg daily
- Methotrexate 15 mg weekly (for approximately 3 years)
- Vitamin D3 (cholecalciferol) 2,000 units daily
- Folic acid 1 mg daily
- Allegra (fexofenadine) 180 mg daily
- Cyanocobalamin (B 12) 1,000 mg daily
- Calcium 600 D (calcium / vitamin d) 1 PO BID
- Coreg (carvedilol) 3.125mg BID
- Metformin 1000 MG BID
- Singulair (montelukast) 10 mg daily
- Zanaflex (tizanidine) 2 mg HS PRN
- Prolia (denosumab) 60mg q 6 months
CBC with Differential was obtained and was unremarkable except a decrease in platelet count to 80 × 103/µL (3 months ago platelets were reported as 209 × 103/µL). The patient’s complete metabolic panel was unremarkable except for an increase in serum creatinine from 0.9 mg/dL to 1.3mg/dL. Her calculated Creatinine Clearance (CrCl) was estimated as 26 ml/min.
Thrombocytopenia
Normal lab values for platelets usually range 150,000 – 400,000 × 103/µL. It is when platelets fall below 150,000 that thrombocytopenia may be considered. A fall in platelets can be caused by an increase in platelet destruction or a decrease in platelet production. In spite of stringent regulations associated with laboratories and lab test, errors can and do occur. Minor fluctuations in lab values can be due to several factors including errors in reporting, however, this patient’s platelets were fairly constant over the previous 12-month period. A sudden drop in a patient’s platelets from 209 × 103/µL to 80 × 103/µL should alert the practitioner that further investigation needed.
Methotrexate and Thrombocytopenia
What would cause this patient’s platelets to fall so dramatically? A sudden drop in platelets can be from immune-mediated mechanisms or drug-induced thrombocytopenia (DIT). There are hundreds of drugs implicated in the pathogenesis of DIT. Some of the most common drugs are listed in Table 1. Having RA and taking several medications that can cause thrombocytopenia, are risk factors for this patient developing a decrease in platelets. In addition, the elderly are at a significantly greater risk of myelosuppression while taking low dose oral methotrexate which is one of the most recognized adverse effects of chemotherapeutic agents. Reviewing the patient’s medication profile, the most obvious choice would be DIT caused by methotrexate.
Drug-Induced Thrombocytopenia – Table 1:
| Common Drugs that cause Thrombocytopenia: | |
| Heparin | Quinine |
| Chemotherapeutic agents | ranitidine |
| Antirheumatic drugs | Diuretics |
| Gold salts | Sulfonamides |
| Oral antidiabetic drugs | Numerous antibiotics |
| Anticonvulsants | NSAIDs |
| Quinidine |
Methotrexate, classified as a disease-modifying anti-rheumatic drug (DMARD), is one of the most widely used and most effective drugs in the treatment of rheumatoid arthritis (RA). Patients taking methotrexate to treat inflammatory arthritis are usually prescribed between 10-25 mg each week. The entire prescribed dose is usually taken on one day each week.
It’s important to keep in mind the black box warnings and contraindications for methotrexate listed in the manufacturer package insert. Side effects experienced by a patient will be different when using methotrexate for inflammatory diseases versus using methotrexate to treat leukemia or other cancers. In the treatment of RA, contraindications include preexisting renal dysfunction, preexisting blood dyscrasias, liver disease, and active infectious disease (including immunosuppression). Pregnancy and breastfeeding are also contraindications for the use of methotrexate, however, this would not be of concern for this elderly patient. Major toxic effects of methotrexate include hepatic, renal, pulmonary and bone marrow disorders, although these major toxicities are experienced less frequently when using low dose (oral) therapy. When they do occur, they can be life-threatening.
Renal Considerations
80-90% of methotrexate is excreted via the kidneys depending on the dose and how the medication is given (i.e. IV, or PO). With renal compromise there can be a delay in drug elimination from the body and subsequently an increase in drug serum levels leading to toxic side effects. There are several studies demonstrating the decreased elimination with increased renal impairment in low dose (oral) methotrexate dosing. In addition, there have been case studies reviewing the fatal consequences that can occur with low dose (oral) methotrexate toxicity and renal insufficiency. Although the manufacturer package insert recommends a dose reduction for renal impairment, unfortunately, there is no specific guideline for dose adjustment provided by the manufacturer labeling. Recommendations for reducing the dose of methotrexate use in renal insufficiency (i.e. Aronoff 2007, Kintzel 1995) have been published, however, these recommendations pertain to high dose cancer therapies and do not address low dose oral therapies seen commonly in long-term care. For adults, Aronoff recommended administering 50% of the methotrexate dose with a CrCl between 10-50 ml/min and avoiding methotrexate use in those patients with CrCl < 10 ml/min. Kintzel recommended a reduction of the dose by 65% with CrCl 46-60 ml/ min, using 50% of the dose with CrCl between 31-45 ml/min, and avoiding methotrexate use if the CrCL was < 30 ml/min.
Myelosuppression, including thrombocytopenia, can occur abruptly at any time during methotrexate treatment. This patient had several risk factors that could lead to thrombocytopenia including renal insufficiency that may have impaired methotrexate excretion with consequent accumulation of its metabolites. Although the package insert does suggest dosing adjustment in renal insufficiency, there is no specific adjustment recommendation for decreased renal function. Since potentially fatal toxicities with this drug can occur, liver function test, complete blood counts with differential, as well as evaluations of renal function including CrCl estimation, should be performed regularly along with medication dose adjustments as needed.
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