Keywords

Platelets; Thrombocytopenia; Vancomycin; Immunofluorescence

Introduction

The differential diagnosis for isolated thrombocytopenia in critically ill patients is broad and includes sepsis, disseminated intravascular coagulation, and thrombotic and medication effects [1,2]. Vancomycin, a commonly used antibiotic for hospital-acquired infections, can cause severe, refractory thrombocytopenia due to antibody-mediated platelet destruction. We describe a unique case of severe vancomycin induced thrombocytopenia with a lower nadir and longer effect duration than previously described.

Case Presentation

A 70-year-old man presented with a fall, altered mental status and an upper respiratory infection, found to have a subarachnoid and intraventricular hemorrhage. He was not a candidate for neurosurgical intervention and was transferred to the medical intensive care unit for management of respiratory failure. Initially, he was diagnosed with influenza A and pneumonia for which he was treated empirically with a 7 day course of intravenous vancomycin and piperacillin/ tazobactam. His hospital course was complicated by ischemic acute tubular necrosis requiring continuous renal replacement therapy with transition to intermittent hemodialysis. Twelve days after completing antibiotics, he developed septic shock requiring vasopressors and was started empirically on vancomycin, meropenem, and micafungin. Within 6 hours of receiving vancomycin, the patient’s platelet count decreased from 197,000/μL to 1,000/μL, confirmed by a citrated platelet count and lack of platelet clumping. Heparin-induced thrombocytopenia antibody was negative. Lab tests were not consistent with disseminated intravascular coagulation, and our suspicion for immune thrombocytopenic purpura was low. Antibiotics were subsequently deescalated to cefepime.

With the drop in the platelet count, the patient developed coffee-ground secretions from his gastric tube associated with a decrease in hemoglobin from 7.5 g/dL to 6.3 g/dL. He was transfused a total of twelve units of platelets and 3 units of packed red blood cells over the following 4 days. A vancomycin-dependent platelet antibody test was obtained after the patient received his sixth unit of platelets. He remained refractory to platelet transfusions, and the platelet count recovered to >150,000/μL after eleven days. The vancomycin-dependent antibody test (performed by Blood Center of Wisconsin) returned positive for IgG platelet antibody in the patient’s serum without the drug. Both the IgM and IgG platelet antibody in the patient’s serum with vancomycin were negative. The test result returned 8 days after sending the blood sample, and vancomycin was subsequently added to the patient’s list of medication allergies.

Discussion

Vancomycin is a widely used glycopeptide antibiotic. It is an established cause of immune-mediated thrombocytopenia, first reported in 1985. Features of drug-induced immune thrombocytopenia include a platelet nadir <20,000/μL, bleeding complications, and onset 5-10 days after beginning daily drug exposure or within hours of subsequent exposure [3]. A platelet-specific drug-dependent antibody formation results in platelet destruction [4]. Blood samples should be tested for the antibodies using immunofluorescence by flow cytometry, the most sensitive method for detecting drug-dependent antibodies [2]. A positive lab test demonstrating the antibodies can confirm the diagnosis, but a negative test does not rule it out [3]. In the largest available case series, about 55% of patients had only IgG antibodies, 10% had only IgM, and 35% had both classes present [1]. The targets of the antibodies are often on platelet GPIIb/IIIA or GPIb/IX [3,5].

A drug re-challenge resulting in thrombocytopenia recurrence is also diagnostic but impractical [3]. In one case, vancomycin-dependent antibodies were not detected due to the timing of the serum sampling after massive platelet transfusions [6]. Although the antibody testing is not useful in the acute management, it can be helpful in pinpointing a specific drug as the cause of thrombocytopenia as the drug sensitivity can persist for many years to indefinitely; therefore, it is important to counsel patients on drug avoidance [2,3,5].

In a case series of patients with vancomycin-dependent antibodies, the nadir platelet count, a mean of 13,600/μL, was reached about 8 days after initiation of vancomycin. The median time required for the platelet level to return to at least 150,000/μL after vancomycin was stopped was 7.5 days. Severe thrombocytopenia (platelet count <20,000/μL) persisted for 7-8 days after vancomycin was discontinued in 2 dialysis patients. Ten of the 29 patients (34%) had severe bleeding-gross hematuria, gastrointestinal hemorrhages requiring transfusion, intrapulmonary hemorrhages, and excessive bleeding from venipuncture sites [1].

Acute vancomycin-induced thrombocytopenia can occur rapidly as an amnestic response, especially in patients with pre-existing IgG class vancomycin-dependent antibodies from prior exposure, such as our patient [1,2,4,7]. The thrombocytopenia is also refractory to platelet transfusions [4,5] patients received 10 units of platelets in some cases [7-8]. Management consists of stopping the medication, and the platelet count usually returns to normal within a week [2]. Treatment with intravenous immunoglobulin and/or steroids can be considered in some cases of severe thrombocytopenia or significant mucosal bleeding [1-3,5,7,8].

Conclusion

Critically ill patients may have several reasons for thrombocytopenia, but physicians must have a high index of clinical suspicion for immune-mediated thrombocytopenia. Vancomycin antibody induced thrombocytopenia is a severe disease that is refractory to treatment. It can increase the risk of bleeding and does not respond to platelet transfusions. Testing for drug-dependent antibodies takes time; thus, it is imperative to avoid susceptible medication exposure during the work-up. Vancomycin is a widely used antibiotic and can cause significant morbidity through this mechanism if left unrecognized.

References

1. Drygalski AV, Curtis BR, Bougie DW, McFarland JG, Ahl S, et al. (2007) Vancomycin-induced immune thrombocytopenia. N Engl J Med 356: 904-910.
2. Anand A, Chauhan H (2011) Piperacillin and vancomycin induced severe thrombocytopenia in a hospitalized patient. Platelets 22: 294-301.
3. Arnold DM, Nazi I, Warkentin TE, Smith JW, Toltl LJ, et al. (2013) Approach to the diagnosis and management of drug-induced immune thrombocytopenia. Trans Med Rev 27: 137-145.
4. Kenney B, Tormey CA (2008) Acute vancomycin-dependent immune thrombocytopenia as an amnestic response. Platelets 19: 379-383.
5. Christie DJ, Van Buren N, Lennon SS, Putnam JL (1990) Vancomycin-dependent antibodies associated with thrombocytopenia and refractoriness to platelet transfusion in patients with leukemia. Blood 75: 518-523.
6. Mizon P, Kiefel V, Mannessier L, Mueller-Eckhardt C, Goudemand J (1997) Thrombocytopenia induced by vancomycin-dependent platelet antibody. Vox Sang 73: 49-51.
7. Marraffa J, Guharoy R, Duggan D, Rose F, Nazeer S (2003) Vancomycin-induced thrombocytopenia: a case proven with rechallenge. Pharmacotherapy 23: 1195-1198.
8. Zenon GJ, Cadle RM, Hamill RJ (1991) Vancomycin-induced thrombocytopenia. Arch Intern Med 151: 995-996.