A new onset of thrombocytopenia and microangiopathic hemolytic anemia in the healthcare setting: A challenge for diagnosis
Authors: Mengyang Di, Jessica Bian, James N. Butera
Journal: American Journal of Hematology (2018)

A 43-year-old African American man with history of untreated chronic hepatitis C infection, insulin dependent diabetes mellitus (IDDM), intravenous (IV) polysubstance abuse complicated by recent necrotizing fasciitis, and peripheral inserted central catheter associated deep vein thrombosis (DVT), was transferred from a community hospital for thrombocytopenia and microangiopathic hemolytic anemia (MAHA). He was initially admitted to the community hospital for a soft tissue abscess in the left upper extremity. He underwent incision and drainage (I&D) on hospital day 7 and skin grafting on hospital day 14. He developed thrombocytopenia (platelets decreased to 54 × 109 /L from a baseline level of 400 × 109 /L) and was found to have MAHA on hospital day 18. He was subsequently transferred to our hospital on day 21 with a creatinine level of 1.8 mg/dL (baseline around 1.1 mg/dL). Upon transfer, he endorsed mild headache with no other complaints. He denied any pertinent family history. The differential diagnosis for the concurrence of thrombocytopenia and MAHA is relatively broad, including primary thrombotic microangiopathy (TMA) syndromes and other systemic disorders (Table 1). For this patient, thrombocytopenia and MAHA occurred acutely in the setting of infection. Potential causes include thrombotic thrombocytopenia purpura (TTP) (also considering the creatinine level at transfer1), systemic infection, infective endocarditis, disseminated intravascular coagulopathy (DIC), the introduction of new medications during hospitalization, and scleroderma renal crisis. The patient underwent successful infectious source control (I&D) in the outside hospital, thus on-going bacteremia or DIC seemed less likely the cause. Other causes including Shiga toxin-mediated hemolytic-uremic syndrome (HUS), systemic malignancies, complement-, metabolism-, or coagulation-mediated TMA syndromes are unlikely, given the absence of diarrhea, recent weight loss or any other red flag signs for cancer, as well as the negative family history of inherited platelet disorders or atypical HUS. The patient's home medications prior to admission included gabapentin for diabetic neuropathy, warfarin for DVT, and long-acting insulin for IDDM. Upon arrival to the outside hospital, he received one dose of sulfamethoxazole/trimethoprim for the soft tissue infection. He was subsequently started on clindamycin and piperacillin/tazobactam after admission. He received subcutaneous heparin for DVT prophylaxis from hospital day 2 to day 17, acetaminophen per os (po), long-acting oxycodone po and hydromorphone IV as needed throughout his stay. The patient also received packed red blood cells and fresh frozen plasma prior to transfer. Clindamycin, piperacillin/tazobactam, and sulfamethoxazole/trimethoprim can all lead to thrombocytopenia, while hemolytic anemia is rare with the use of clindamycin. Anemia associated with piperacillin/tazobactam (mainly piperacillin) is through a different mechanism (autoimmune) from MAHA.2, 3 Although the use of sulfamethoxazole/trimethoprim has been reported to cause MAHA,4 the patient did not develop thrombocytopenia and MAHA until 14 days after the use, which would be atypical timing. Heparin-induced thrombocytopenia (HIT) was another possibility, however, the timing of thrombocytopenia and other possible alternative diagnosis resulted in a low HIT score.5 His other medications were extensively reviewed and found to rarely cause thrombocytopenia or anemia. The patient was not in acute distress. He was afebrile and normotensive with a normal pulse and respiratory rate. He was alert and awake, and was oriented to self, place, and time. He responded appropriately to questions during the interview. Cardiovascular and pulmonary examinations were normal. Abdomen was soft, non-distended, and non-tender, with normal bowel sounds. He had no skin rash. Left forearm wound was healing appropriately. Physical exam for this patient was mostly unremarkable. The absence of fever, heart murmur, rash, and the overall well appearance made the diagnosis of endocarditis less likely. Although no fever, purpura, petechia, or altered mental status were noted on exam, this does not rule out TTP; the presentation of the complete “pentad” is very rare. His laboratory results on admission were significant for thrombocytopenia (8 × 109/L), anemia (7.4 g/dL), and leukocytosis (12.7 × 109 /L) with elevated reticulocytes of 12.5%. Peripheral blood smear review showed 8 schistocytes and 0-1 platelet per high-power field. He also had indirect hyperbilirubinemia (total bilirubin 3.7 mg/dL, direct bilirubin 0.5 mg/dL), elevated lactate dehydrogenate (LDH) (1489 IU/L), and low haptoglobin level (<8 mg/dL), with a negative direct antiglobulin test. The results above confirmed the lab findings of thrombocytopenia and MAHA from the outside hospital. Creatinine was elevated to 1.80 mg/dL from the baseline level of 1.1-1.2 mg/dL. Folate and vitamin B12 were normal. D-dimer was elevated to 1100 ng/mL, PT (13.3 seconds) was mildly prolonged, PTT, INR, and fibrinogen were all normal. Autoimmune lab results showed a mildly elevated ANA titer (1:40), and negative anti-SCL and double-stranded DNA antibody. Hepatitis C viral load (1 179 034 IU/mL) was markedly elevated, which was consistent with the history of untreated hepatitis C infection. The other infectious disease work-ups were negative including blood culture (obtained at admission), hepatitis B, HIV, blood parasite smear, as well as echocardiogram. ADAMTS13 activity was pending. The above results supported the initial low suspicion of autoimmune, metabolic or nutritional etiologies. The current coagulation profile excluded DIC as a differential diagnosis. Infections, such as bacteremia and endocarditis, were unlikely given the negative blood culture and negative echocardiogram. The patient had three (thrombocytopenia, MAHA, and acute kidney injury) of the pentad manifestations for TTP. Although a definitive diagnosis of TTP is typically confirmed with a low ADAMTS13 level, given the clinical course consistent with TTP and low likelihood of other common etiologies, TTP was diagnosed presumptively. Therapeutic plasma exchange (PEX) was started on hospital day 21 (the day of transfer). Prednisone 60 mg daily and folic acid 3 mg daily were also administered since hospital day 22. Oral long-acting oxycodone and IV hydromorphone were continued for pain management. The patient had finished the full course of antibiotics for soft tissue infection prior to transfer. Heparin was held in the setting of severe thrombocytopenia. ADAMTS13 activity6 was back on hospital day 22, which was 98%. Although the clinical picture was mostly consistent with TTP, a normal ADAMTS13 level basically excluded the diagnosis of TTP; TTP diagnosed in the setting of normal or near normal ADAMTS13 level was only very rarely reported in the literature.7, 8 The proposed interpretations for the normal ADAMTS13 levels were the dissociation of ADAMTS13 autoantibodies from ADAMTS13 during the incubation phase of testing,7, 8 or frequent previous transfusions.8 Nevertheless, since there was still lacking of alternative diagnoses, PEX was continued.9 Efforts were made meanwhile to look for other possible explanations, such as TMA occurring after surgery,10 complement-induced or drug-induced TMA. While the patient was receiving PEX, his platelet level was improved to 75 × 109/L on hospital day 24 and was stable at 64-70 × 109/L during hospital days 25-27. However, it dropped to 35 × 109/L on hospital day 28. On the day the platelet level decreased abruptly, the patient was witnessed by his nurse to be crushing long-acting oxycodone pills in his bed that he had placed in his mouth to partially liquefy. He admitted to placing the pills in his mouth and not swallowing them when the nurses dispensed medications. There was concern that patient was self-injecting crushed long-acting oxycodone into his IV, although this was never witnessed. His platelets decreased to 16 × 109/L on hospital day 29. IV injection of crushed long-acting oxycodone or oxymorphone (Opana ER) has been reported to cause TTP-like disease. Upon witnessed discovery that the patient crushed long-acting oxycodone pills, his platelets dropped. The concurrence of the two events highly suggested drug-induced TMA with long-acting oxycodone as the offending drug. Long-acting oxycodone was discontinued, and plasma exchange was held since hospital day 29. Platelet level increased to 74 × 109/L on hospital day 30, was 141 × 109/L on hospital day 31, and stayed above 150 × 109/L throughout his remaining hospital stay. The quick resolution of thrombocytopenia and MAHA after the discontinuation of long-acting oxycodone further supported the diagnostic hypothesis of drug-induced TMA by IV use of crushed long-acting oxycodone (Figure 1 and Supporting Information Appendix S1). Oxymorphine (Opana-ER) was the first opioid reported to cause TMA (the CDC report).11 The mechanism has been studied and accurately defined as an effect of polyethylene oxide, a polymer included in the formulation of oxymorphine to deter IV misuse.12 Three case studies from Australia subsequently described TMA induced by IV injection of long-acting oxycodone,13-15 which has the same polymer; the etiology is presumably similar. TMA caused by IV injection of narcotics presenting as an outpatient to the Emergency room has been reported. However, hospital acquired TMA is rare, and to the best of our knowledge, this is the first case report of TMA induced by IV misuse of oral narcotics occurring in the hospital setting. An updated systematic review summarized 31 cases with TMA induced by oxymorphine or long-acting oxycodone.16 We identified additional 20 cases through a complementary literature search (a total of 51 cases from 18 case reports or case series; search strategy in Supporting Information Appendix S2, study selection in Supporting Information Appendix S3, references of the 18 studies in Supporting Information Appendix S5). The misuse of oral narcotics in all 51 patients took place outside the hospital. Our case shared similar characteristics with the ones reported in the literature (Supporting Information Appendix S4). Most patients were young adults (median [range], years: 34 [22, 49] in the CDC report11 which did not provide individual patient data, 28 [22, 61] in the remaining 36 patients), and 59% were female. The development of TMA does not seem associated with the dose or duration of the IV drug use. A total of 22 patients presented with abdominal pain, six with chest pain, five with visual disturbances, three with altered mental status, 16 with fatigue, and eight with fever (not all studies reported presenting symptoms). Most patients (71.7% if a threshold level of 1.1 mg/dL is applied) had kidney injury. Significant variations were noted in the kidney function (0.4-14.4 mg/dL), platelet counts (8-172 × 109/L), hemoglobin (4.8-12.5 g/dL) and LDH (131-4473 U/L) levels. All the patients (with the lab data available) had a low haptoglobin level and a normal ADAMTS13 activity. It is more challenging to make the diagnosis when TMA develops acutely in a hospitalized patient. One would assume IV drug use is much less common in the hospital, which is a frequently monitored setting. This may decrease the clinical suspicion of drug-induced TMA as a potential cause. On the other hand, it may be difficult to obtain a reliable history in the cases where this diagnosis is suspected, given the stigmatization of the IV drug use behavior. Moreover, in the hospital, there are usually multiple potential causes for thrombocytopenia and MAHA. In this case, recent surgery, antibiotics exposures, and infection were all confounding factors. To avoid this diagnostic pitfall, one needs to pay close attention to the time course of inciting events, as well as taking careful consideration of all confounding factors. In our case, although infection is a common trigger for acquired TTP, the time course did not fit, as his infection was improved at the time thrombocytopenia and MAHA developed (both episodes). TMA occurring after surgery was considered as an alternative explanation before the final diagnosis was reached. However, per careful literature review, this condition is usually caused by major and aggressive procedures such as bowel resection and repair of aortic aneurysm, as opposed to a simple I&D as in our patient.10 Based on this reasoning process, the first episode of TMA in our patient was likely secondary to the IV misuse of long-acting oxycodone as well. The timely availability of ADAMTS13 testing in house can help to make the right diagnosis early during the hospital course. The result was back the day after transfer in our patient, and the normal result prompted rethinking of TTP, although it did not lead immediately to the final diagnosis. In addition, being familiar with the clinical manifestations of drug-induced TMA as summarized from the literature above would help physicians consider this as a potential diagnosis, even in the inpatient setting. If the clinical picture does not completely fit any of the most likely or common diagnoses, TMA induced by IV drug use should be considered, even in hospitalized patients, especially in those with known history of IV drug use and/or taking oral narcotics during hospitalization. Healthcare providers should be aware of signs suggestive of IV drug use, such as pretending to swallow medications, crushing narcotic pills, unexplained frequent departures from the floor or room, and unexplained visitors. As in our case, it was the incidental finding from the nurse of the patient crushing long-acting oxycodone pills that led eventually to the final diagnosis. Careful and continual patient observation remains a critically important part of patient care even in the era when medical technologies and diagnostic tests have never been such advanced; medicine is never merely based on lab evaluations. And nursing staffs who have extensive interactions with patients play an essential role in providing such additional information. The platelet and hemoglobin levels normalized quickly after the discontinuation of long-acting oxycodone in our patient. Similarly, most cases reported in literature experienced complete recovery of hematologic abnormalities (in 3-12 days) after discontinuation of the offending drugs and supportive care. In contrast, most patients (with follow-up data available) with acute kidney injury had prolonged impaired kidney function or even became dialysis dependent, despite early and aggressive therapeutic PEX (Supporting Information Appendix S4). However, this high percentage is likely due to reporting bias. In summary, IV misuse of oral narcotics in healthcare settings, although thought be rare, should be considered as a cause of new thrombocytopenia and MAHA in hospitalized patients, especially when the clinical manifestations or courses are atypical for all other alternative diagnoses. Increased awareness and familiarity with this specific disease condition is essential for making the diagnosis early in the disease course. The most important management is to discontinue the offending oral narcotics and appropriate patient education, as most patients can be managed supportively. Where available, rapid ADAMTS13 activity measurement would allow physicians to determine the necessity of PEX, as a normal level mostly excludes TTP, for which PEX is a key treatment to decrease mortality. Also, more data is required to help identify patients who might progress to chronic kidney disease or become dialysis dependent, with explorations on potential early treatments to reverse kidney injury. The authors thank Dr. Kwame Dapaah-Afriyie, MD, MBA, from the Department of Medicine of the Miriam Hospital, The Warren Alpert Medical School of Brown University, for his insights and suggestions on clinical analysis and interpretation of the case. Appendix 1. Key parameters of the presented case over time Appendix 2. Search strategy Appendix 3. Flow diagram of study selection Appendix 4. Included studies and patient characteristics Appendix 5. References of included case reports or case series Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.