Case 18 – A 60-year-old man with significant bleeding

A 60-year-old man presents to the emergency department complaining of a persistent nosebleed. His nose began bleeding spontaneously about 3 hours ago, and he has not been able to get it to stop despite direct pressure and ice packs. He denies trauma, blood disorders, cancer, or a family history of hematologic or oncologic problems. He has gastroesophageal reflux disease, for which he recently increased his dose of cimetidine, and atrial fibrillation, for which he takes metoprolol and warfarin. His temperature is 37.0°C (98.6°F), blood pressure is 120/80 mm Hg, heart rate is 90/min, and respiratory rate is 10/min. Physical examination is notable for crusted blood around his left nasal ala and slowly oozing bright red blood from his left nostril. He also has small conjunctival hemorrhages and a large bruise on his knee. The remainder of his physical examination is unremarkable, including a regular heart rate and rhythm and normal chest, abdominal, and neurologic examinations. Laboratory tests show:

WBC count: 6000/mm³
Hemoglobin: 13.5 g/dL
Hematocrit: 40%
Platelet count: 350,000/mm³
International Normalized Ratio: 12.5
Prothrombin time: Normal

What conditions should be included in the differential diagnosis?

The differential diagnosis of clinically significant hemorrhage includes trauma and disorders of hemostasis, specifically problems with platelet quantity (thrombocytopenia) and quality or clotting factor deficiency. Inherited (hemophilia, von Willebrand’s disease) and acquired (hematologic malignancy, bone marrow dysfunction, liver disease, medication, autoimmune) diseases may have identical clinical presentations, albeit frequently in different patient populations.

What is the most likely diagnosis?

This patient has clinically significant, persistent bleeding (epistaxis and other hemorrhagic phenomena) in the context of an International Normalized Ratio (INR) of 12.5 while receiving warfarin therapy. Although he may have an underlying malignancy or inherited bleeding disorder, his entire clinical presentation can be explained by his medications. Cimetidine inhibits the cytochrome P450 (CYP450) system of drug metabolism (a hepatic enzymatic system that metabolizes drugs for excretion), and warfarin is metabolized by this system. Thus, a recent increase in cimetidine dosage in a patient who takes warfarin could easily lead to dangerously high warfarin levels, evidenced in this patient by severe bleeding and a high INR.

What other risk factors are associated with this condition?

Medications and other compounds that induce the CYP45 system include:

1. Alcohol
2. Barbiturates
3. Carbamazepine
4. Dexamethasone
5. Griseofulvin
6. Phenytoin
7. Quinidine
8. Rifampin

Medications and other compounds that inhibit the CYP45 system include:

1. Cimetidine
2. Clarithromycin
3. Erythromycin
4. Grapefruit juice
5. Isoniazid
6. Ketoconazole
7. Ritonavir

What is the most appropriate management for this patient?

In patients with either severe bleeding or an INR >20 (risk factor for intracranial hemorrhage), immediate cessation of warfarin and CYP450 inhibitors is crucial. This patient should also receive nasal packing, as well as admission for observation and serial neurologic exams (for intracranial hemorrhage monitoring), INR assessments, and hemoglobin levels. Finally, this patient should be counseled to use a different histamine blocker for his gastroesophageal reflux disease, such as ranitidine, to avoid this complication in the future.

By Brian Ash, MD, Resident in Anesthesia and Perioperative Care, University of California, San Francisco Medical Center; in association with Le TT, Schabelman E, Shivaram A, and Klein J, eds: First Aid Cases for the USMLE Step 2 CK. New York: McGraw-Hill, 2007.

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