Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults

Abstract

Transplant-associated thrombotic microangiopathy (TMA) leads to generalized endothelial dysfunction that can progress to multiorgan injury, and severe cases are associated with poor outcomes after hematopoietic stem cell transplantation (HSCT). Identifying patients at highest risk for severe disease is challenging. We prospectively evaluated 100 consecutive HSCT recipients to determine the incidence of moderate and severe TMA and factors associated with poor overall outcomes. Thirty-nine subjects (39%) met previously published criteria for TMA. Subjects with TMA had a significantly higher nonrelapse mortality (43.6% vs 7.8%, P < .0001) at 1 year post-HSCT compared with those without TMA. Elevated lactate dehydrogenase, proteinuria on routine urinalysis, and hypertension were the earliest markers of TMA. Proteinuria (>30 mg/dL) and evidence of terminal complement activation (elevated sC5b-9) in the blood at the time of TMA diagnosis were associated with very poor survival (<20% at 1 year), whereas all TMA subjects without proteinuria and a normal sC5b-9 serum concentration survived (P < .01). Based on these prospective observations, we conclude that severe TMA occurred in 18% of HSCT recipients in our cohort and propose an algorithm to identify the highest-risk patients who might benefit from prompt clinical interventions.

Figure 1

Time course of clinical and laboratory markers in relation to date of TMA diagnosis. The date of TMA diagnosis is marked as day 0 (black vertical line) and represents the posttransplant day when study diagnostic criteria for TMA were fulfilled, including elevated LDH and schistocytosis. We additionally included the timing of proteinuria (≥30 mg/dL on random urinalysis), hypertension (defined as a systolic blood pressure >95th percentile for age, sex, and height), AKI (doubling of the pretransplant serum creatinine), and a haptoglobin less than the lower limit of normal. For each variable, the white vertical lines represent the median day the criterion became positive and the gray area the IQR. Hypertension (day −14) and an elevated LDH (day −13) were the first markers of TMA, followed by proteinuria (day −10). Schistocytosis occurred on day 0, because this was typically the last criterion to turn positive and thus defined the TMA diagnosis date. A decreased haptoglobin lagged the first elevation in LDH by almost 2 weeks. AKI, defined using serum creatinine, occurred a median of almost 28 days after TMA was diagnosed.

Figure 2

NRM among study subjects with and without TMA at 1 year after HSCT. Gray’s competing risk method was used to obtain the cumulative incidence of NRM. The 1-year NRM was 43.6% ± 8% in subjects with TMA and 7.8% ± 3.8% in HSCT subjects without TMA (P < .0001).

Figure 3

Association between markers at the time of TMA diagnosis and death by 1 year after HSCT. At the time of TMA diagnosis, a hemoglobin ≤8 g/dL, proteinuria (defined either as ≥30 mg/dL of protein on a random urinalysis or a random urine protein/creatinine [Ur prot/creat] ratio >2 mg/mg), and a soluble membrane attack complex (sC5b-9) concentration above the upper limit of normal were all significantly associated with an increased risk of death. Haptoglobin was higher in patients who died, likely representing an acute inflammatory state.

Figure 4

TMA risk stratification. The figure displays Kaplan-Meier survival curves for subjects with TMA (n = 39) examining proteinuria ≥30 mg/dL and serum sC5b-9 concentrations at the time of TMA diagnosis in (A) subjects with proteinuria of ≥30 mg/dL vs no proteinuria, (B) subjects with elevated serum sC5b-9 concentration vs normal sC5b-9 concentration, and (C) subjects with no proteinuria and normal sC5b-9, proteinuria ≥30 mg/dL and normal sC5b-9, no proteinuria, and elevated sC5b-9 and both proteinuria ≥30 mg/dL and elevated sC5b-9 at the time of TMA diagnosis.

Figure 5

Algorithm for the evaluation of TMA after HSCT. Screening for TMA includes monitoring LDH, complete blood count, and routine urinalyses. TMA should be suspected in HSCT recipients with an acute elevation of LDH, proteinuria >30 mg/dL, and hypertension more severe than expected with calcineurin or steroid therapy, usually requiring >2 antihypertensive medications. Clinical interventions should be considered for patients with both proteinuria >30 mg/dL and elevated sC5b-9.