Thrombotic microangiopathy (TMA) is a serious complication that may occur in patients with systemic lupus erythematosus (SLE), adversely affecting the prognosis and increasing mortality. The pathogenesis of TMA in these patients may be multifactorial and overlap between different entities may exist. We present a case of a 24-year-old man, previously diagnosed with SLE, class IV lupus nephritis, and antiphospholipid antibody syndrome, who was admitted with acute kidney injury, severe pancytopenia, and other features consistent with lupus flare. A clinical TMA diagnosis was made and the patient was treated with plasmapheresis, rituximab and immunoglobulin endovenous (EV) infusions. Hemodialysis was initiated during hospitalization and, despite the hematological recovery, the patient remained dialysis dependent. The complementary study revealed high levels of anti-factor H (fH) autoantibodies with no pathogenic mutations on complement genes (namely CFHR1 and CFHR3). Initially, the most likely cause of TMA seemed to be secondary to SLE, but the presence of anti-fH antibodies in our patient may suggest a concomitant complement-mediated TMA.