March 2020 Case Cedars-Sinai Skip to content Close Select your preferred language English عربى 简体中文 繁體中文 فارسي עִברִית 日本語 한국어 Русский Español Tagalog English English عربى 简体中文 繁體中文 فارسي עִברִית 日本語 한국어 Русский Español Tagalog Translation is unavailable for Internet Explorer Cedars-Sinai Home 1-800-CEDARS-1 1-800-CEDARS-1 Close Find a Doctor Locations Programs & Services Health Library Patient & Visitors Community My CS-Link Education clear Go Close Academics Academics Faculty Development Community Engagement Calendar Research Research Areas Research Labs Departments & Institutes Find Clinical Trials Research Cores Research Administration Basic Science Research Clinical & Translational Research Center (CTRC) Technology & Innovations News & Breakthroughs Education Graduate Medical Education Continuing Medical Education Graduate School of Biomedical Sciences Professional Training Programs Medical Students Campus Life Office of the Dean Simulation Center Medical Library Program in the History of Medicine About Us All Education Programs Departments & Institutes Faculty Directory Anatomic and Clinical Pathology Residency Back to Anatomic and Clinical Pathology Residency Application Information Explore the Residency Training Curriculum Autopsy Pathology Rotation Bone and Soft Tissue Head and Neck Pathology Rotation Breast Pathology Rotation Cardiovascular Pathology Rotation Clinical Chemistry Rotation Coagulation Rotation Cytopathology Rotation Dermatopathology Rotation Forensic Pathology Rotation Frozen Section Rotation Gastrointestinal and Liver Pathology Genitourinary Pathology Rotation Genomic Pathology Rotation Gynecologic Pathology Rotation Hematopathology Rotation Laboratory Management Rotation Microbiology Rotation Neuropathology Rotation Pulmonary and Mediastinal Pathology Rotation Renal Pathology Rotation Transfusion Medicine Rotation Surgical Pathology Pathology Physician Scientist Training Program Residents Graduates Case of the Month Archive Publications Leadership Frequently Asked Questions March 2020 Case Authors Chelsea Halprin, DO (Fellow), Chelsea Hayes, MD (Faculty) Subject Transfusion Medicine Clinical History A multiparous female patient in her 30s presented to an outside institution at 10 weeks gestation with headache, gross hematuria, hypertension, and thrombocytopenia (7K). Further work up demonstrated proteinuria (300 mg/dl) and thrombotic microangiopathy (TMA). An ADAMTS13 resulted at 11% and an inhibitor study was negative. The patient was started on Solumedrol and therapeutic plasma exchange (TPE). After 6 TPE procedures, her thrombocytopenia resolved (297K). However, the patient experienced a sudden relapse when TPE was held on hospital day 7. TPE was resumed and she was transferred to CSMC for a higher level of care. In the setting of an ADAMTS13 activity >10%, hypocomplementemia (C3: 70, C4: 6), acute kidney injury (creatinine 1.3 from 0.6) proteinuria, and a variant of unknown significance identified within an aHUS genetic panel, complement-mediated TMA was diagnosed. The patient received Eculizumab every two weeks as an outpatient and remained in remission until she presented at 35 weeks with recurrent thrombocytopenia (7K). She tolerated C-section with transfusion support and was treated with Eculizumab without response. After an ADAMTS13 resulted <5% with an elevated ADAMTS13 IgG Ab (30), the diagnosis of complement-mediated TMA was changed to thrombotic thrombocytopenic purpura (TTP). Eculizumab was discontinued and TPE was initiated. Her hospital course was complicated by refractory thrombocytopenia that ultimately required 14 TPE procedures and Rituximab before she achieved a sustained response. Figures Figure 1: First Hospitalization- Clinical Course Figure 2: Second Hospitalization- Clinical Course Figure 3: ADAMTS13 Testing- First Hospitalization (Reference Laboratory #1) Figure 4: ADAMTS13 Testing- Second Hospitalization (Reference Laboratory #2) Diagnosis Refractory TTP, initially misdiagnosed as complement-mediated TMA Discussion Thrombotic microangiopathy (TMA) describes a pathologic lesion characterized by abnormalities in the vessel wall of arterioles and capillaries that lead to microvascular thrombosis. The primary TMA syndromes include thrombotic thrombocytopenic purpura (TTP), Shiga toxin-mediated hemolytic uremic syndrome (ST-HUS), drug-induced TMA, and complement-mediated TMA (CM-TMA). Differentiating between these entities based upon clinical findings alone can be extremely difficult, especially when laboratory results are not available. Ultimately, it is important to take a global approach and consider clinical presentation, laboratory evidence, and history to avoid misinterpretation of borderline laboratory results and to initiate timely treatment. In the case presented above, the patient had several clinical features suggestive of CM-TMA including renal injury with proteinuria, hypocomplementemia, and a variant of unknown significance within an aHUS genetic panel. When the ADAMTS13 activity resulted as a borderline value (11%) and the reflex inhibitor testing was negative, complement mediated TMA seemed like the most accurate diagnosis. Additionally, the patient appeared to respond well to Eculizumab- though in reality she had likely achieved remission due to the 10 plasma exchange procedures she received prior to Eculizumab administration. When the patient relapsed later in pregnancy, however, she was hospitalized at our institution which utilized a different reference laboratory. This time, the ADAMTS13 activity resulted less than 10%, which was essentially diagnostic of TTP. However, the inhibitor testing again resulted negative. This prompted the second reference laboratory to conduct reflex ADAMTS13 antibody testing. While the inhibitor test utilizes a mixing study, the antibody test utilizes an ELISA method and increases sensitivity. The ADAMTS13 antibody resulted positive, confirming the diagnosis of acquired TTP. If the first reference laboratory utilized an algorithm that reflexed to an ADAMTS13 antibody test when the ADAMTS13 activity was borderline and the ADAMTS13 inhibitor testing was negative, the patient may have been properly diagnosed with TTP and avoided exposure to Eculizumab during pregnancy. Ultimately, it is important for clinicians to maintain a comprehensive understanding of ADAMTS13 testing, including differences in reflex algorithms, to accurately interpret borderline results and differentiate CM-TMA from TTP. References George, James N, and Carla Nestor. "Approach to the Patient with Suspected TTP, HUS, or Other Thrombotic Microangiopathy (TMA)." UpToDate, 11 Sept. 2019, www-uptodate-com.mlprox.csmc.edu/contents/approach-to-the-patient-with-suspected-ttp-hus-or-other-thrombotic-microangiopathy-tma. George, James N., and Carla M. Nester. "Syndromes of Thrombotic Microangiopathy." New England Journal of Medicine, vol. 371, no. 7, 2014, pp. 654–666., doi:10.1056/nejmra1312353. Tsai, Han-Mou, et al. "ADAMTS13-Binding IgG Are Present in Patients with Thrombotic Thrombocytopenic Purpura." The Journal of Thrombosis and Haemostasis, vol. 95, no. 5, 2006, pp. 886–892. Sadler, J. Evan. "Von Willebrand Factor, ADAMTS13, and Thrombotic Thrombocytopenic Purpura." Blood, vol. 112, no. 1, 2008, pp. 11–18., doi:10.1182/blood-2008-02-078170. Have Questions or Need Help If you have questions or would like to learn more about the Anatomic and Clinical Pathology Residency Program at Cedars-Sinai, please call or send a message to Academic Program Coordinator, LeeTanya Marion-Murray. Department of Pathology and Laboratory Medicine 8700 Beverly Blvd., Room 8709 Los Angeles, CA 90048-1804 310-423-6941 send a message Please ensure Javascript is enabled for purposes of website accessibility