Features of Postpartum Hemorrhage-Associated Thrombotic Microangiopathy and Role of Short-Term Complement Inhibition

Abstract

Introduction: In pregnancy-related atypical hemolytic uremic syndrome (p-aHUS), transferring recommendations for treatment decisions from nonpregnant cohorts with thrombotic microangiopathy (TMA) is difficult. Although potential causes of p-aHUS may be unrelated to inherent complement defects, peripartal complications such as postpartum hemorrhage (PPH) or (pre)eclampsia or Hemolysis, Elevated Liver enzymes and Low Platelets (HELLP) syndrome may be unrecognized drivers of complement activation.

Methods: To evaluate diagnostic and therapeutic decisions in the practical real-life setting, we conducted an analysis of a cohort of 40 patients from 3 German academic hospitals with a diagnosis of p-aHUS, stratified by the presence (n = 25) or absence (n = 15) of PPH.

Results: Histological signs of TMA were observed in 84.2% of all patients (100% vs. 72.7% in patients without or with PPH, respectively). Patients without PPH had a higher likelihood (20% vs. 0%) of pathogenic genetic abnormalities in the complement system although notably less than in other published cohorts. Four of 5 patients with observed renal cortical necrosis (RCN) after PPH received complement inhibition and experienced partially recovered kidney function. Patients on complement inhibition with or without PPH had an increased need for kidney replacement therapy (KRT) and plasma exchange (PEX). Because renal recovery was comparable among all patients treated with complement inhibition, a potential beneficial effect in this group of pregnancy-associated TMAs and p-aHUS is presumed.

Conclusion: Based on our findings, we suggest a pragmatic approach toward limited and short-term anticomplement therapy for patients with a clinical diagnosis of p-aHUS, which should be stopped once causes of TMA other than genetic complement abnormalities emerge.

Keywords: complement inhibition; genetic kidney disease; p-aHUS; postpartum hemorrhage; pregnancy; renal cortical necrosis.

Graphical abstract

Figure 1

Temporal correlation of the thrombotic microangiopathic (TMA) event before and after delivery (day 0). Red symbols indicate individuals, in whom a pathogenic mutation of a complement regulatory gene could be identified. Patients without postpartum hemorrhage are represented by a solid rhombus. Patients with postpartum hemorrhage are depicted in circles. Most TMAs occurred at the time of delivery or shortly thereafter. In 7 patients, the exact onset of event could not be determined especially when (pre)eclampsia was documented and in 1 patient onset was 10 weeks before delivery.

Figure 2

Pragmatic treatment algorithm for patients with p-aHUS and postpartum hemorrhage. ¹In countries with no access to CIT, an initial treatment trial with plasma exchange should be considered in women requiring hemodialysis. All patients should be planned for genetic testing to search for aHUS susceptibility variants. ²Considering the extent of RCN, kidney function parameters and histopathologic findings, CIT should be continued for 1 to 3 months as per clinical judgment. ³In patients with a detectable susceptibility variant for aHUS, treatment may be continued depending on kidney function and individual risk for relapse (genetics, trigger factors). ∗Other causes of TMA may emerge after turn-around of diagnostic tests (e.g., aTTP, autoimmune disorders, infections). CIT, complement inhibitor treatment; p-aHUS, pregnancy-induced atypical hemolytic syndrome; PPH, postpartum hemorrhage; RCN, renal cortical necrosis; TMA, thrombotic microangiopathy; TTP, acquired thrombotic thrombocytopenic purpura.