Drug-associated thrombocytopenia is often unrecognized. We report a 76-year-old female with lymphoma who presented with easy bruising and oral bleeding. She had undergone screening for hepatitis B virus (HBV) prior to starting rituximab and was found to have hepatitis B core serum antibody (IgG anti-HBc). She was therefore treated with prophylactic entecavir 0.5 mg daily to prevent reactivation of HBV. Her initial platelet count was 136,000/mm3. Five days after starting entecavir, she presented with bruising and oral bleeding and was found to have a platelet count of 7,000/mm3. A coagulation profile and the rest of the blood parameters (RBC and WBC counts) were normal. Entecavir was stopped, and she was given 3 units of apheresed platelets followed by intravenous immunoglobulin (1 g/kg) for 5 consecutive days. Her platelet counts improved and normalized in one week. She was diagnosed with entecavir-induced thrombocytopenia based on the temporal relationship and after carefully excluding alternate causes of thrombocytopenia. This case highlights the importance of recognizing drug-induced thrombocytopenia (DITP) as a reversible cause of thrombocytopenia.
The most common side effects of entecavir therapy for hepatitis B virus (HBV) include headache, fatigue, dizziness, nausea, and vomiting. Very rarely, patients can develop lactic acidosis and hepatic steatosis. Although other nucleoside analogues with activity against HBV such as lamivudine [
A 76-year-old female presented with a 2-day history of easy bruising and bleeding from her mouth. She denied epistaxis, melena, hematochezia, hematuria, or other bleeding manifestations. She had estrogen receptor positive stage 1 breast cancer 24 years ago for which she underwent lumpectomy followed by tamoxifen for 5 years. She has had regular mammograms since then, and there has been no evidence of local disease recurrence. Fourteen years ago, she was diagnosed with Waldenstrom’s macroglobulinemia for which she was treated with chlorambucil and prednisone for 3 months with significant improvement. Her plasma cell dyscrasia has been quiescent. M-spike on serum protein electrophoresis was minimal. She had intermittent hospitalizations for pneumonia, thought to be related to functional immunoglobulin deficiency. She was on intravenous immunoglobulin replacement for 6 months, but it was discontinued later. Three years ago, she presented with pleural and pericardial effusions, and pleural biopsy showed activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL). A PET scan showed uptake in the pleural space with no lymphadenopathy. A bone marrow biopsy showed no evidence of DLBCL, and she was treated with rituximab and bendamustine for 3 months and remained in remission for the next three years. Four weeks prior to the current admission, she presented with fatigue, night sweats, and 10-pound weight loss and was found to have retroperitoneal lymphadenopathy. She underwent CT-guided core biopsy of the retroperitoneal nodes that confirmed recurrence of her DLBCL. A repeat bone marrow biopsy showed normocellular bone marrow with progressive trilineage hematopoiesis, but no evidence of DLBCL. She was scheduled to start salvage therapy for DLBCL with rituximab and lenalidomide. Viral hepatitis serologies were performed prior to initiation of rituximab, showing evidence of prior hepatitis B infection (IgG anti-HBc antibody). She was therefore started on prophylactic entecavir 0.5 mg daily 5 days prior to the current admission. Other medical problems included diabetes mellitus, hypertension, atrial fibrillation, gout, hypothyroidism, hyperlipidemia, and osteoporosis. Her other medications besides entecavir included allopurinol, amiodarone, rosuvastatin, diltiazem, pantoprazole, dabigatran, ramipril, and levothyroxine. No recent change in these medications had occurred.
On physical examination, her temperature was 98.3°F with blood pressure 100/68 mmHg, pulse 90 beats per min, and respiratory rate 18 per minute. She looked tired but had no pallor, icterus, or generalized lymphadenopathy. The anterior nares were clear without epistaxis. Mucous membranes were moist, and the oropharynx revealed two scabs in the buccal mucosa with dried blood. She had normal S1 and S2 without any rubs, murmurs or gallops, and normal vesicular breath sounds. Her abdomen was soft and nontender without hepatosplenomegaly or ascites. Skin was warm and dry without petechia, purpura, or ecchymosis. The rest of the physical exam was unremarkable. Complete blood count showed thrombocytopenia with a platelet count of 7000/mm3. Peripheral blood smear showed no evidence of platelet clumping. The hemoglobin and white blood cell counts were normal. Thyroid function tests and a coagulation profile were essentially normal. Her last recorded platelet count 10 days prior to starting entecavir was 136,000/mm3. Her baseline platelet count range is between 120,000 and 150,000/mm3. Entecavir was discontinued, but her other drugs were continued. She received 3 units of platelets followed by intravenous immunoglobulin (1 g/kg) for 5 consecutive days. Her platelet counts improved and normalized in one week (Figure
Course of drug-induced immune thrombocytopenia in a patient treated with entecavir. Entecavir was prescribed for prophylaxis to prevent HBV reactivation before initiating rituximab therapy. Starting from day 5 of treatment, the patient reported having easy bruising and bleeding from the oral cavity. She came to the office on day 7, and her platelet count was 7000 per cubic millimeter. Entecavir was discontinued immediately, and 3 units of apheresed platelets and IV immunoglobulin were given (days 7–11). The platelet counts improved and normalized in a week.
Patients with chronic hepatitis B or serological evidence of past infection are at risk for viral reactivation when treated with immunosuppressive therapy. B-cell depleting agents such as rituximab have the highest risk of HBV reactivation [
Clinicians should elicit a detailed drug exposure history to establish the diagnosis of DITP, specifically enquiring about prescription drugs, over the counterdrugs, herbal preparations, certain foods, and beverages [
Clinical criteria and levels of evidence for evaluation of patients with suspected drug-induced thrombocytopenia.
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(1) Drug administration preceded thrombocytopenia; complete and sustained recovery from thrombocytopenia is noted after drug discontinuation |
(2) Other drugs administered prior to thrombocytopenia were continued or reintroduced after discontinuation of the suspected drug |
(3) Other etiologies of thrombocytopenia excluded |
(4) Reexposure to the drug resulted in recurrent thrombocytopenia |
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(1) Definite: all 4 criteria met |
(2) Probable: criteria 1–3 met |
(3) Possible: criterion 1 met |
(4) Unlikely: criterion 1 not met |
Adapted from
The clinical presentation of DITP can vary from asymptomatic thrombocytopenia to life-threatening hemorrhage. Patients may have epistaxis, gum bleeding, oral mucous membrane blood blisters, melena, hematochezia, and hematuria when the platelet count drops below 20,000/mm3, and deaths from bleeding have been reported [
Once drug sensitivity is documented, autoantibodies persist for life, and patients should be advised to avoid the drug in future, and this should be documented in their medical records as a serious “allergy.”
Entecavir-induced thrombocytopenia is a reversible cause of thrombocytopenia potentially mediated via numerous immune and nonimmune mechanisms. Clinicians should maintain a high index of clinical suspicion for DITP in the patient presenting with severe thrombocytopenia soon after starting entecavir and quick resolution after discontinuing the drug. Early recognition and prompt discontinuation of entecavir is critical to avoid life-threatening hemorrhage.
The authors declare that they have no conflicts of interest.