Clinical evaluation of thrombotic microangiopathy: identification of patients with suspected atypical hemolytic uremic syndrome

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a rare genetic disorder caused by defective complement regulation resulting in thrombotic microangiopathy (TMA). Patients can present as children or adults. The syndrome consists of hemolytic anemia with schistocytosis, thrombocytopenia, significant renal damage, and/or other organ system dysfunction(s). Patients with aHUS may succumb to the complications of the disease with the very first manifestation; surviving patients often suffer from progressive organ dysfunction with significant morbidity and mortality despite plasma infusion or plasma exchange. Eculizumab, a humanized monoclonal antibody to C5, was approved for treatment of aHUS in 2011. This is an expensive but highly effective therapy changing the lives and improving the outcome of patients with aHUS. Making timely and accurate diagnosis of aHUS can be life-saving if eculizumab treatment is begun promptly. Finding a genetic mutation in a complement regulatory protein is diagnostic with the appropriate clinical syndrome, but at least 30 % of patients do not have defined or reported mutations. Thus the diagnosis rests on the clinical acumen of the physician. However, the clinical manifestations of aHUS are shared by other etiologies of thrombotic microangiopathy. While laboratory finding of undetectable ADAMTS13 activity defines TTP, distinguishing aHUS from the other causes of TMA remains an art. In addition, aHUS can be unmasked by conditions with enhanced complement activation, such as systemic lupus erythematosus, pregnancy, malignant hypertension, and hematopoietic stem cell transplantation. Thus if TMA occurs in the setting of enhanced complement activation, one must consider aHUS as an underlying etiology, especially if treatment of the condition does not resolve the TMA.

Keywords: Atypical hemolytic uremic syndrome; Complement dysregulation; Thrombotic microangiopathy; Thrombotic thrombocytopenic purpura.

Fig. 1

Complement system in the pathogenesis of thrombotic microangiopathies. SLE: systemic lupus erythematosus; APS: antiphospholipid syndrome; HTN: hypertension; HSCT: hematopoietic stem cell transplantation; CFH: complement factor H; CFI: complement factor I; MCP: membrane cofactor protein; TM: thrombomodulin

Fig. 2

Diagnostic algorithm for patients with thrombotic microangiopathies (TMA). MAHA: microangiopathic hemolytic anemia; TTP: thrombotic thrombocytopenic purpura; HUS: hemolytic uremic syndrome