Complement-Mediated Thrombotic Microangiopathy: A Murky Presentation of a Rare Disease Entity

Abstract Complement-mediated thrombotic microangiopathy (TMA), also known as atypical hemolytic uremic syndrome (aHUS) is a rare, hereditary, progressive, life-threatening disorder caused by a disruption in regulation of the alternative pathway of the complement system. Eculizumab, a terminal complement inhibitor, has emerged as a first-line therapy, however data are limited to small case series (Brocklebank et al., 2017). Here, we present a diagnostically challenging case of complement-mediated TMA, who received eculizumab therapy with excellent hematologic response. A 68-year-old female with history of possible Sjogren's syndrome, migraine disorder, chronic fatigue syndrome, inflammatory colitis, hypertension, and poor medical follow up presented with 6-day history of severe fatigue, hematochezia, decreased urine output, dyspnea with exertion and anginal chest pain. 2 weeks prior, patient endorsed “flu-like” illness and had diffuse myalgias without fevers. Further history revealed ibuprofen usage of 800-1200 mg/day for several years. Shortly after admission, patient became severely agitated and confused with an attempt to elope from hospital. During diagnostic workup, labs were significant for hemoglobin 5.6 g/dL, platelets 57,000/uL, serum creatinine 6.6 mg/dL, BUN 101 mg/dL. Peripheral smear showed schistocytes and tear drop cells, low platelets without clumping, and hypochromic normocytic red cells. LDH of 2152 U/L, haptoglobin Patient was subsequently transferred to tertiary care center for initiation of eculizumab. Genetic testing was completed, notable for decreased Factor H and a heterozygous missense mutation in complement factor H of uncertain significance, only having been previously reported in a single patient with aHUS (Fremeaux-Bacci et al., 2013). She achieved excellent hematologic response with eculizumab evidenced by improved platelet count, haptoglobin, decreased LDH, however she unfortunately remained dialysis-dependent. Thrombotic microangiopathy (TMA) syndromes are overlapping entities which can be categorized by primary vs secondary etiology. Primary syndromes include TTP (hereditary or acquired), Shiga-toxin mediated HUS, drug-induced TMA and complement mediated TMA. Secondary causes include pregnancy-associated (pre-eclampsia/HEELP syndrome), malignancy, systemic infection, severe hypertension, autoimmune disorders like SLE, and complications from organ transplantation. When evaluating a patient with suspected TMA, it is important to correctly categorize their disease to guide appropriate treatment. Complement-mediated TMA results from a hereditary deficiency of regulatory proteins that restrict activation of alternative complement pathway. These proteins include complement factor H (CFG) and its related proteins (CFHRs), membrane cofactor protein (MCP), CFI. Instead, it may result from an autoantibody inhibiting CFH of CFI. The consequence of this up-regulation is uncontrolled damage to vascular endothelium and renal cells, which manifests as a characteristic pentad. In our case, a CFH gene mutation was identified and history revealed a flu-like illness preceding her hospitalization. It is plausible that this illness may have served as a “second-hit” via complement-amplification. (Asif et al., 2017). Alternatively, in this patient with history of inflammatory colitis and reported Sjogren's syndrome, subclinical autoimmune disorder may also have served as a trigger. This case presentation serves as a reminder to not overlook the “zebra” that is complement-mediated TMA, to allow for prompt initiation of eculizumab therapy. Disclosures No relevant conflicts of interest to declare.