Rapid onset vancomycin-induced thrombocytopenia confirmed by vancomycin antibody test

Abstract

We report a case of vancomycin-induced thrombocytopenia (VIT) with rapid onset after re-exposure to vancomycin. A 58-year-old man with cellulitis was initiated on vancomycin. Approximately 1 hour into the vancomycin infusion, the patient developed an infusion-related reaction. Vancomycin infusion was stopped. A complete blood count obtained 4 hours after discontinuation of the vancomycin infusion revealed a platelet count of 31 ×10­⁹/L. Investigations ruled out likely causes of thrombocytopenia. VIT was diagnosed based on clinical symptoms and confirmed with drug-dependent platelet antibody testing. Without complications, platelet counts recovered within 7 days after discontinuation of vancomycin. No correlation between vancomycin level and VIT was observed.

Background

Vancomycin is a glycopeptide antibiotic frequently used as first-line empiric therapy for gram-positive bacterial infections, including infections associated with methicillin-resistant Staphylococcus aureus. A rare, dangerous, and often overlooked adverse event that can occur with vancomycin is thrombocytopenia. Two retrospective studies reported the incidence of vancomycin-induced thrombocytopenia (VIT) as high as 5.9%–7.1%.^{1 2} However, these studies did not report on confirmation of the adverse event with antiplatelet antibody-specific testing. Thus, the true incidence of VIT remains unknown. Here, we describe a case of VIT developing within 4 hours post infusion of a single dose of vancomycin.

Case presentation

A 58-year-old man with a medical history of mild factor VII (FVII) deficiency without associated bleeding diatheses (baseline FVII 50%), controlled type 2 diabetes mellitus (haemoglobin A1c of 6.5), and ischaemic cardiomyopathy with reduced left ventricular ejection was admitted to the hospital for elective implantation of an implantable cardioverter defibrillator for primary prevention of sudden cardiac death. Shortly thereafter, the patient was noted to have cellulitis of his right lower leg. A basic metabolic panel and complete blood count (CBC) were unremarkable. Blood cultures were collected after antibiotics were given and remained negative. Intravenous vancomycin and cefepime were started. Other medications at the time of the event included aspirin, bumetanide, enoxaparin, fluoxetine, gabapentin, insulin aspart, lisinopril, metoprolol succinate, nicotine patch and trazodone. Approximately 1 hour into the vancomycin infusion, the patient developed rigours, respiratory distress with hypoxia, tachycardia and chest pain. Physical examination was unremarkable for rash. The vancomycin infusion was stopped and the patient’s clinical status improved with supportive care. A CBC obtained 4 hours after the vancomycin infusion was discontinued and revealed a platelet count of ×10­⁹/L.

Investigations

Immediate evaluation for pulmonary embolism, acute myocardial infarction, bacteraemia and SARS-CoV-2 was unremarkable. Repeat CBC confirmed significant thrombocytopenia with the nadir platelet count of 27×10⁹/L (figure 1). A peripheral blood smear was reviewed and did not reveal platelet clumping, schistocytes or other significant abnormalities. Laboratory evaluation revealed a negative heparin-platelet antibody, lactate dehydrogenase 242 IU/L, haptoglobin 96 mg/dL, corrected reticulocyte count 1.5%, partial thromboplastin time 28 s, prothrombin time 16.4 s (slightly prolonged, but consistent with previous values and known history of mild FVII deficiency), fibrinogen 298 mg/dL, D-dimer 2.32 ug/mL, normal vitamin B₁₂ and folate levels, negative viral hepatitis panel and negative HIV antigen/antibody testing. Review of recent imaging revealed a normal appearing liver and spleen. Other than the aforementioned antibiotics, the medication list did not include agents concerning for contribution to thrombocytopenia. On retrospective review of the patient’s medical record, similar significant and abrupt decreases in the platelet count within 36 hours of vancomycin administration were noted on multiple hospital encounters within the previous 3 years. However, during those encounters, VIT did not appear to be suspected and no results of vancomycin drug-dependent platelet antibody testing were found in the patient’s medical record. Drug-dependent platelet antibody testing was ordered.

Figure 1.

A graph shows the association between platelet counts and vancomycin exposure. The hospital day and time are displayed on the x-axis, while the platelet counts are displayed on the y-axis. The graph depicts platelet counts rapidly falling after vancomycin administration on hospital day 3. After vancomycin discontinuation, platelet counts recovered back to baseline on hospital days 9–10.

Differential diagnosis

New-onset acute thrombocytopenia in hospitalised patients has a limited differential diagnosis, which led our initial investigations. Pseudothrombocytopenia was ruled out with the review of a peripheral blood smear. No findings of an uncontrolled infection were discovered and laboratory evaluation was not consistent with disseminated intravascular coagulation given the lack of abnormal haemolysis markers, normal coagulation studies and the lack of shistocytes on the peripheral blood smear. Similarly, a thrombotic microangiopathy was also deemed unlikely given the lack of haemolysis and unremarkable peripheral blood smear. At this point, the investigation shifted towards iatrogenic aetiologies. The patient was exposed to enoxaparin during the hospitalisation; therefore, heparin-induced thrombocytopenia was ruled out with appropriate testing. Other drug-induced thrombocytopenias were then thought to be the most likely cause with VIT being the suspected culprit.

Outcome and follow-up

Vancomycin therapy was discontinued after a single dose and the patient’s platelet count subsequently improved without further intervention after a period of 7 days (figure 1). Drug-dependent platelet antibody testing was completed and positive for vancomycin IgM and IgG (Versiti, Wisconsin, USA), confirming suspicion of VIT. Moreover, the Naranjo adverse drug reaction probability scale (table 1) was used and found vancomycin to be a probable cause of the thrombocytopenia in this case.³ The patient’s medical record was updated to list vancomycin as an allergy, described as thrombocytopenia with positive antibody test results, to avoid any future administrations and adverse events from vancomycin.

Table 1.

Naranjo algorithm adverse drug reaction probability scale

Question	Yes	No	Do not know/not tested	Score
1. Are there previous conclusive reports on this reaction?	+1	0	0	+1
2. Did the adverse event appear after the suspected drug was administered?	+2	−1	0	+2
3. Did the adverse event improve when the drug was discontinued or a specific antagonist was administered?	+1	0	0	+1
4. Did the adverse event reappear when the drug was readministered?	+2	−1	0	0
5. Are there alternative causes that could on their own have caused the reaction?	−1	+2	0	+2
6. Did the reaction reappear when a placebo was given?	−1	+1	0	0
7. Was the drug detected in blood or other fluids in concentrations known to be toxic?	+1	0	0	0
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0	0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0	+1
10. Was the adverse event confirmed by any objective evidence?	+1	0	0	+1
Total score probability interpretation: ≥9 = definite; 5–8=probable; 1–4=possible; <0=doubtful	Total score:			8

Discussion

Vancomycin is often overlooked as a cause for thrombocytopenia and its aetiology is not well understood. We presented a case of rapid VIT, which occurred 4 hours post vancomycin infusion, confirmed by a drug-dependent platelet antibody test. Drug-induced immune thrombocytopenia (DITP) is a challenging clinical diagnosis. Various mechanisms of VIT have been proposed. One of the most supported theories is that vancomycin causes DITP via a drug-dependent antibody reaction, also known as a ‘Quinine-type reaction’.⁴ A vancomycin-induced antibody preferentially binds to the GPIIb/IIIa complex on the platelet membrane resulting in clearance of platelets and thus thrombocytopenia. More recent research has shown that the binding between vancomycin and the antibody is the first step inducing structural change.⁵ This effect increases affinity and specificity of the activated antibody to platelets resulting in thrombocytopenia.

The diagnosis of DITP is, moreover, established based on clinical criteria, including re-exposure to the drug, which could risk potentiating the reaction.⁶ Recently, a recommendation on DITP laboratory testing was published by The International Society on Thrombosis and Haemostasis (ISTH).⁷ The aim of the ISTH recommendation is to standardise laboratory testing for drug-dependent platelet-associated antibodies with the most frequently implicated prescription drugs, including vancomycin. There are two testing methods that have been recommended: flow cytometry and enzyme immunoassay.⁸ A positive result has high specificity for DITP and the suspected drug should be avoided in those patients with a positive result. However, a negative result does not rule out DITP due to low sensitivity of the test.⁷ In our patient, the confirmation test was performed via flow cytometry, which is one of the recommended standard tests for DITP.

While a prior study found platelet count reaching its nadir an average of 8.3 days after vancomycin initiation (range 3–27 days), nadir platelet count in our patient was reached within 12 hours after exposure, which can be explained with patient’s prior exposures to vancomycin.⁸ On chart review, a relationship between prior episodes of thrombocytopenia and vancomycin administration in our patient was elucidated. The severity of thrombocytopenia varied and ranged between 60% and 85% decrease in platelet count. In the current episode, an 83% platelet count reduction was observed within 4 hours post infusion of a single dose of vancomycin and other possible causes of thrombocytopenia were ruled out. While the degree of platelet count decrease was consistent with previous reports, the onset of thrombocytopenia was faster than previously reported.^{8 9} We suspected that this rapid onset of thrombocytopenia could be attributed to the repeated prior exposures to vancomycin in our patient. Getzan Packer and Ruggero et al each reported a case of rapid VIT occurring 1 day post vancomycin dose.^{10 11} Like our patient, both cases report a previous exposure to vancomycin prior to event that led to the VIT diagnosis. In contrast to our patient, suspicion of VIT was based on the Naranjo Adverse Drug Reaction Probability Scale for both cases, without confirmation of drug-dependent antibody test.^{10 11} One case report describes a rapid VIT that was confirmed with antibody testing on the second exposure to vancomycin.¹² This case report supported our suspicion that repeated vancomycin exposure may be associated with rapid onset of VIT. However, unlike our case, that patient experienced two rapid VIT episodes, the second taking place when vancomycin was rechallenged 3 days after its discontinuation.¹² In our case, the patient’s last known exposure to vancomycin was about 9 months prior to the single vancomycin dose that resulted in rapid VIT. Our patient’s recovery time to baseline platelet count was consistent with previous reports, which was around 7 days.^8–11

We also investigated the correlation between vancomycin serum concentration and thrombocytopenia from the patient’s history. No correlation was found between vancomycin serum concentration and the severity of thrombocytopenia (r²=23%). Currently, published studies showing a clinical correlation between vancomycin serum levels and VIT are lacking.

Learning points.

• Rapid onset of vancomycin-induced thrombocytopenia (VIT) may occur in patients with a history of vancomycin exposure and does not appear to correlate with vancomycin serum levels.

• Platelet counts usually recover to baseline within 1 week after vancomycin discontinuation.

• Monitoring during vancomycin therapy should include platelet count to ensure prompt recognition of VIT to avoid bleeding complications associated with low platelet counts.

• In addition to clinical criteria, drug-dependent platelet antibody testing is useful for confirmation of VIT and for documenting the adverse drug reaction to avoid future vancomycin administration.

Ethics statements

Patient consent for publication

Next of kin consent obtained.