Cholangiocarcinoma Presenting with Acquired Thrombotic Thrombocytopenic Purpura Confirmed by Positive Autoantibodies of ADAMTS13
Thrombotic thrombocytopenic purpura (TTP) is a severe and life-threatening form of thrombotic microangiopathy (TMA). It is characterized by a triad of symptoms: severe thrombocytopenia, microangiopathic hemolytic anemia, and signs of regional ischemia or infarction, such as neurological dysfunction and renal insufficiency. The diagnosis of TTP is confirmed by identifying a low activity of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), a protease that cleaves von Willebrand factor (vWF). Additionally, the presence of inhibitory autoantibodies against ADAMTS13 further supports the diagnosis. While TTP is often secondary to conditions such as infections, autoimmune diseases, pregnancy, or drug reactions, it is exceedingly rare for TTP to be the initial manifestation of a solid tumor. This report details a unique case of acquired TTP associated with underlying cholangiocarcinoma in an elderly woman treated with bortezomib.
The patient, a 66-year-old woman, presented with a 10-day history of fatigue and dull headache. Laboratory tests revealed a dramatic reduction in her blood platelet count to 2 x 10^9/L, a hemoglobin level of 77 g/L, and the presence of schistocytes in her peripheral blood smear. Further testing showed an elevated lactate dehydrogenase (LDH) level of 721 U/L and a serum creatinine level of 104 mmol/L, which is above the reference range of 45–84 mmol/L. The Coombs test was negative. Based on these findings, TTP was suspected and subsequently confirmed by a severe reduction in plasma ADAMTS13 activity to 6%, along with detectable ADAMTS13 autoantibodies.
The measurement of ADAMTS13 activity was performed using a fluorescence resonance energy transfer assay, with the vWF86 peptide (a region from Q1599 to P1611C of vWF) as the substrate. The presence of ADAMTS13 autoantibodies was determined through a mixing test, where equal volumes of the patient’s plasma and negative control plasma were mixed with normal pooled plasma and incubated at 37°C. The test was considered positive if the ADAMTS13 activity of the mixture containing the patient’s plasma was between 25% and 75% of that of the mixture containing the negative control plasma.
Upon diagnosis, the patient was immediately treated with total plasma exchange and methylprednisolone. Due to her persistently low platelet count, subcutaneous bortezomib (1.3 mg/m^2, twice a week) was added four days later, in conjunction with continued plasma exchange. This treatment was administered four times. Following this regimen, her platelet levels returned to 127 x 10^9/L, her LDH levels decreased to 262 U/L, and her plasma ADAMTS13 activity normalized to 119%. The inhibitory autoantibodies in her plasma became undetectable. Additional tests, including blood cytomegalovirus virus-DNA, blood Epstein-Barr virus-DNA, and serum antinuclear antibodies, were all negative.
Imaging studies, including computed tomography and magnetic resonance cholangiopancreatography, revealed a mass with nearby intrahepatic cholangiectasis. A left hepatectomy was performed, and the final histopathology confirmed the diagnosis of cholangiocarcinoma (T1aM0N0). Despite the successful management of TTP, the patient succumbed to tumor recurrence four months later, although her platelet count remained normal throughout this period.
This case highlights the diagnostic challenges in distinguishing TTP from other forms of secondary TMA in patients with solid tumors. The authors recommend testing for ADAMTS13 activity and the presence of inhibitory autoantibodies to confirm the diagnosis of acquired TTP. This approach is particularly important in cases where TTP may be the initial manifestation of an underlying malignancy, as seen in this patient.
The pathogenesis of tumor-associated TTP remains poorly understood. However, evidence suggests that cytokines such as interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, which inhibit ADAMTS13 activity, are elevated in human tumor samples. Additionally, a significant reduction in serum ADAMTS13 activity has been observed in tumor patients, which may contribute to the onset of TTP. This case report underscores the importance of considering solid tumors as a potential underlying cause of TTP, particularly in patients with no other apparent risk factors.
In conclusion, this case of cholangiocarcinoma presenting with acquired TTP, confirmed by positive ADAMTS13 autoantibodies, illustrates the complex interplay between malignancy and thrombotic microangiopathy. The successful management of TTP in this patient involved a combination of plasma exchange, corticosteroids, and bortezomib, highlighting the need for a multidisciplinary approach in such cases. Further research is needed to elucidate the mechanisms underlying tumor-associated TTP and to optimize treatment strategies for this rare but serious condition.
doi.org/10.1097/CM9.0000000000000727
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