Recurrent acute thrombocytopenia in the hospitalized patient: sepsis, DIC, HIT, or antibiotic-induced thrombocytopenia.

Our patient, a 30-year-old man with end-stage renal disease attributed to congenital dysplastic kidneys who had been on hemodialysis for 3.5 years, was admitted to the hospital with severe hypertension, hyperkalemia, and an infected arm arterio-venous graft after missing his regular dialysis treatment. Previously, he had been hospitalized on multiple occasions for hypertension, peptic ulcer disease, seizures, peripheral neuropathy, venous thrombosis, and failure to maintain his dialysis schedule. His blood pressure was 211/139 and his arterio-venous graft was erythematous and indurated. Serum potassium was 7.4 meq/L, hemoglobin was 9.9 gm/dL, platelet count was 217,000/µL, and white blood cell count was 9,400/µL with a normal differential. He improved with dialysis and was initially treated with piperacillin/tazobactam, gentamicin, and vancomycin for the graft infection. Blood cultures were negative. He left the hospital against medical advice on the 3rd day but returned on the 6th day, when antibiotic treatment was resumed with piperacillin/tazobactam, vancomycin, and ciprofloxacin. On Day 11, his platelet count decreased to 70,000/µL from 201,000/µL the previous day (Fig. 1). His vital signs were normal and his clinical status was stable. Hemoglobin was 8.4 gm/dL and white blood cell count was 8,000/µL, similar to previous measurements. The peripheral blood smear confirmed the decreased platelet count; red cell and white cell morphology were normal; serum lactate dehydrogenase (LDH) was 112 U/L; coagulation studies were normal. Figure 1 Platelet counts and piperacillin administration in the patient presented in this report. The bars at the top represent administration of piperacillin on Days 1–3, 6–10, and 19–21. Acute, unexpected thrombocytopenia in a patient hospitalized for multiple medical problems has multiple potential etiologies. In a patient being treated for infection and at risk for additional infectious complications, sepsis must be the initial consideration because of the risk for sudden, critical deterioration. In a patient on multiple medications, drug-induced thrombocytopenia (DITP) is the other principal consideration. The patient had isolated thrombocytopenia, without evidence for microangiopathic hemolysis, consistent with both of these etiologies. The absence of evidence for microangiopathic hemolysis (no schistocytes [fragmented red blood cells] were seen on examination of the peripheral blood smear, serum LDH was normal) excluded consideration of thrombotic thrombocytopenic purpura. His medications on Day 11 were piperacillin/tazobactam, phenytoin, gabapentin, pantoprazole, sertraline, aliskerin, amlodipine, isosorbide mononitrate, labetalol, clonidine, hydralazine, lisinopril, kayexalate, vitamin B12 complex, calcium acetate, erythropoietin, morphine, hydromorphone, quetiapine, diphenhydramine, ondansetron, promethazine, bacitracin ointment, and heparin (given as prophylaxis, 5,000 U every 8 h and also for dialysis). Heparin-dependent platelet-reactive antibody ELISA assay was negative. Also on Day 11, blood cultures were reported as positive for vancomycin-resistant Enterococcus faecium; piperacillin/tazobactam was stopped and quinupristin/dalfopristin was started; 3 days later, quinupristin/dalfopristin was changed to daptomycin. On Day 13, the platelet count began to recover after reaching a nadir of 33,000/µL, becoming normal on Day 16 (Fig. 1). All medications other than piperacillin/tazobactam had been continued. The list of medications was extensive, but this is similar to many patients hospitalized for multiple medical problems. Although heparin may be the most common cause of DITP, and although half of patients with heparin-induced thrombocytopenia may not have thrombotic complications recognized at the time of diagnosis, heparin does not typically cause sudden and severe thrombocytopenia [1]. The negative test for heparin-dependent antibodies was evidence against heparin as the cause of the thrombocytopenia. The recovery of his platelet count while continuing heparin confirmed that heparin was not the etiology of the thrombocytopenia. Among the other medications, there have been reports of thrombocytopenia, with varying levels of evidence, caused by piperacillin, phenytoin, pantoprazole, amlodipine, hydralazine, morphine, quetiapine, and ondansetron (www.ouhsc.edu/platelets). However, all medications except piperacillin/taxobactam were continued while the platelet count recovered to normal, excluding them from consideration of the etiology of the thrombocytopenia. At this time, Enterococcus faecium bacteremia was considered to be the etiology of the thrombocytopenia. On Day 20, blood cultures were reported as positive for Klebsiella oxytoca and piperacillin/tazobactam was restarted. The platelet count decreased from 377,000/µL on Day 20 to 91,000/µL on Day 21 and to 18,000/µL on Day 22 at which time the patient developed hematemesis, hematochezia, and hemoptysis for which he received two units of red cells and one unit of single donor platelets. On Day 22, piperacillin/tazobactam was stopped when it was recognized that both episodes of thrombocytopenia had occurred while piperacillin/tazobactam was being administered and that all other medications had been continued during the intervening platelet count recovery. The patient’s platelet count recovered to normal 3 days after piperacillin/tazobactam was stopped (Fig. 1). Although recurrent bacteremia remained a potential etiology of thrombocytopenia, the onset of thrombocytopenia within 1 day of resuming piperacillin/tazobactam and the recovery of the platelet count to normal within 3 days after piperacillin/tazobactam was stopped provided strong evidence that it was the cause of the thrombocytopenia. Using previously established clinical criteria [2], there appeared to be definite evidence for piperacillin/tazobactam as the etiology of the thrombocytopenia (Table I). However, some doubt persisted because of the recurrent bacteremia with multiple organisms; bacterial sepsis remained a possible though unlikely etiology of the thrombocytopenia. TABLE I Clinical Criteria and Levels of Evidence for Evaluation of Patients with Suspected Drug-Induced Thrombocytopenia Hospital records documented that our patient had received five courses of piperacillin/tazobactam of 3–10 days each between July 2006 and September 2008 with no occurrence of thrombocytopenia documented by daily platelet counts. DITP typically occurs within 1–2 weeks after beginning daily treatment with a new drug, or after intermittent use for a longer time. The absence of thrombocytopenia during five previous treatment courses with piperacillin/tazobactam added uncertainty to the etiology of the thrombocytopenia. Also, if piperacillin/tazobactam was the etiology, it was important to determine which antibiotic of this combination was responsible. Review of the database for published reports of drug-induced thrombocytopenia (www.ouhsc.edu/platelets) documented that there have been two previous reports of thrombocytopenia caused by piperacillin. One report described thrombocytopenia related to piperacillin/tazobactam; this report documented drug-dependent, platelet-reactive antibodies with piperacillin but not with tazobactam [3]. An additional report described piperacillin-induced thrombocytopenia, providing definite evidence defined by recurrent thrombocytopenia with repeated piperacillin administration [4]. Piperacillin as the etiology of the thrombocytopenia in our patient was confirmed by documentation of piperacillin-dependent platelet-reactive antibodies and by the absence of tazobactam-dependent platelet-reactive antibodies (Fig. 2) [5]. Our patient’s platelet count has been normal for the following 6 months. Figure 2 Demonstration of a piperacillin-dependent, platelet-reactive antibody in the patient presented in this report (left) and absence of a detectable tazobactam-dependent, platelet-reactive antibody (right). Results shown are representative of three independent ...