Biopsy‐proven thrombotic microangiopathy without schistocytosis on peripheral blood smear: A cautionary tale
Authors: Catherine R. Murphree, Nga N. Nguyen, Joseph J. Shatzel, Sven R. Olson, Paul D. Chung, Joseph B. Lockridge, Nicole K. Andeen, Thomas G. DeLoughery
Journal: American Journal of Hematology (2019)

The presence of schistocytes is considered the sine qua non of thrombotic microangiopathy (TMA), itself often a harbinger of medically urgent diseases including thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and atypical HUS.1 Published diagnostic criteria suggest that the presence of thrombocytopenia and schistocytosis alone should prompt immediate workup and consideration for empiric therapy for any of the various TMA diagnoses.2 Accordingly, major trials examining therapeutic interventions for TTP and HUS have required the presence of microangiopathic hemolytic anemia as represented by schistocytes for subject inclusion3; the absence of schistocytes on the peripheral blood smear is often reassuring and considered sufficient to rule out TMA. Recently, we encountered a unique series of patients with TMA confirmed via renal biopsy but without schistocytes evident in the peripheral blood, leading to delays both in the diagnosis and initiation of appropriate therapy. This finding challenges the classically held diagnostic paradigm surrounding TMA and suggests clinicians maintain a high index of suspicion for this collection of diseases when seeing patients with other characteristic TMA findings such as acute renal failure, thrombocytopenia, and biomarkers of hemolysis. Institutional Review Board approval was obtained at Oregon Health & Science University to retrospectively review the electronic medical record for TMA cases treated at our center from January 2015 to the present. The medical record for each identified patient was reviewed for demographic and laboratory data including peripheral blood smear findings, as well as clinical outcomes. We identified six patients treated for TMA who lacked schistocytes on review of the peripheral blood smear. Patient demographics are outlined in Table 1. Four patients received a diagnosis of biopsy-proven acute TMA postrenal transplant. Patient 1 was a 59-year-old female patient who underwent transplant for cryptogenic renal failure. She had a maximum lactate dehydrogenase (LDH) of 1171 U/L, with a platelet count as low as 56 × 109/L. Despite the absence of schistocytes, she underwent renal biopsy which was consistent with TMA. She was started on complement-inhibition therapy with eculizumab, and genetic testing subsequently revealed a mutation in complement factor B. Patient 2, a 63-year-old male patient, was also postrenal transplant for end-stage-renal disease secondary to hypertension and type 2 diabetes. His LDH rose to 928 U/L, creatinine rose to 8.7 g/dl, and platelets decreased to 46 × 109/L before a diagnosis of TMA was made. Renal biopsy performed 7 days after transplant similarly revealed pathologic findings of TMA, although genetic testing was negative for complement mutations. Patient 3 was a 56-year-old female patient who received a renal biopsy for declining renal function postrenal transplant. Her LDH rose to 980 U/L and platelets nadired at 79 × 109/L. Renal biopsy confirmed TMA on postoperative day 5, and she was empirically started on eculizumab. Complement genetic panel is still pending at time of this article. Patient 4, a 29-year-old female patient, underwent renal transplant due to end-stage-renal disease from lupus nephropathy. Following transplant, her LDH levels climbed to 1140 U/L, with her platelets dropping to 48 × 109/L. Renal biopsy was performed on postoperative day 17, which demonstrated pathologic evidence of TMA (Figure S1) and was then treated with plasmapheresis, hemodialysis, and intravenous immunoglobulin. Genetic testing was not performed on this patient. Tacrolimus MMF Patients 1, 2, 3, and 4 had received immunosuppressive therapy with the calcineurin inhibitor (CNI) tacrolimus after their renal transplants as per our institution's transplant protocol; although controversial, CNIs have commonly been implicated as causative agents contributing to development of post-transplant TMA. Patient 5 was a 34-year-old female patient who, 6 weeks postpartum, developed renal failure requiring hemodialysis with an LDH of 328 U/L and platelets of 66 × 109/L; renal biopsy confirmed TMA with genetic testing ultimately showing a CFHR3-CFHR1 deletion. She was started on eculizumab with eventual renal and hematologic recovery. Patient 6 was a 43-year-old female patient who presented with a prodrome of diarrhea and acute renal failure in the absence of schistocytes. She received a renal biopsy leading to a diagnosis of TMA 4 days after presentation. She was ultimately found to have Escherichia coli-associated typical HUS and was treated with supportive care alone. Her maximum creatinine was 6.3 g/dl, maximum LDH 1140 U/L, with platelet nadir of 85 × 109/L. These six cases illustrate that biopsy-proven TMA can be seen in patients with acute renal failure and elevated LDH in the absence of peripheral blood schistocytes. Given the often grave prognosis associated with untreated TMA, with the potential for permanent renal failure or death, this unique presentation without schistocytes is noteworthy and should stimulate careful re-evaluation of commonly-accepted diagnostic criteria for TMA. At least one case similar to those presented here has been reported in the literature describing a patient who was status postallogeneic bone marrow transplant with TMA discovered on intestinal biopsy, also in the absence of peripheral blood schistocytes.4 Similarly, in one retrospective series, 80 out of 886 postallogeneic stem cell transplant patients with diarrhea were found to have histologic evidence of intestinal TMA, with only 46% of those patients reportedly showing greater than two schistocytes per high-powered field in the peripheral blood.4, 5 Lastly, recurrence of acquired TTP in the absence of schistocytes has also been reported.6 We acknowledge several limitations to our report, including the difficulty in retrospectively quantifying the number of schistocytes present on individual blood smears and that interpretation of the blood smear might have changed with serial evaluation. In each of our included patients, however, an attending hematologist thoroughly reviewed the blood smear, limiting the possibility for missing schistocytes. Second, it is unclear if biopsy-proven TMA in the absence of schistocytes shares the same underlying pathophysiology, proceeds with a similar clinical course, and carries the same prognosis as the more traditional TMA presentation with schistocytes. Also pertinent is whether this atypical presentation responds to traditional therapies considered for each specific TMA subtype. In conclusion, this case series adds to the literature describing biopsy-proven organ damage secondary to TMA in the absence of some, but not all, of the characteristic peripheral blood findings. Although elevated LDH, thrombocytopenia, and renal injury were present in each case, there was no evidence of schistocytosis on review of peripheral blood. Based on these cases, medical providers encountering patients with a constellation of hemolytic anemia, thrombocytopenia, and renal failure may wish to give more careful consideration of TMA even in the absence of schistocytes, particularly in the appropriate clinical contexts such as postsolid organ or hematopoietic stem cell transplants. The authors declare no potential conflict of interest. C.R.M. contributed with primary manuscript composition and data collection. N.N.N. contributed with manuscript composition and data collection. J.J.S. supervised overall research and initiated project conception. P.D.C. contributed with manuscript composition. N.K.A. contributed with data collection. S.R.O., J.B.L., and T.G.D. provided critical edits. 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.