March 2020 Case

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.

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)

Refractory TTP, initially misdiagnosed as complement-mediated TMA

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.

1. 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.
2. 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.
3. 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.
4. 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.