The clinical picture of thrombotic microangiopathy in patients older than 60 years of age

Field: Medicine (Health Sciences)

Thrombotic microangiopathy (TMA), a rare and life-threatening syndrome, encompasses a wide spectrum of pathologies, including thrombotic thrombocytopenic purpura (TTP), shigatoxin-mediated haemolytic and uremic syndrome (ST-HUS), complement mediated TMA, formerly described as atypical haemolytic and uremic syndrome (aHUS), and secondary TMAs.1, 2 Ageing of the population along with an increased suspicion index from intensive-care unit (ICU) physicians have led to more frequent diagnoses of TMA in older patients. Patients over 60 years of age seem to be at higher risk of mortality and complications,3, 4 as borne out in recent, dedicated studies focusing on elderly-onset TTP.5, 6 However, data concerning all TMA subtypes are lacking. To better assess the peculiar features of TMA among older patients, we investigated traditional parameters in all patients admitted to Saint-Louis University Hospital ICU between January 2006 and June 2017 for TMA. Patients were diagnosed with TMA if they presented with thrombocytopenia, microangiopathic haemolytic anaemia and signs of visceral ischaemia. There were no exclusion criteria. Clinical, biological and follow-up data were retrieved from the patients' medical charts. Presenting symptoms were classified as renal involvement (serum creatinine elevation), neurological involvement (altered mental state, seizure, stroke, headache), cardiac involvement (increased troponin-T, T-wave alterations), bleeding, venous thrombosis, and shock. TMA syndromes were classified according to the following criteria: (i) TTP if ADAMTS13 activity was <10% of normal; (ii) ST-HUS when ADAMTS13 activity was >10%, with documentation of ST; (iii) aHUS when ADAMT13 activity was >10%, without any feature compatible with secondary TMA, nor ST; (iv) secondary TMAs encompassing drug-related TMAs, pregnancy-related TMAs, cancer-related TMAs, post-transplantation TMAs, malignant hypertension, and renal scleroderma crisis, all with ADAMTS13 >10%. Plasma exchange (PEX) therapy along with corticosteroids was initiated as soon as possible after ICU admission. If an obvious case of secondary TMA, known to be unresponsive to PEX, was found, only supportive care was provided. Further treatments were initiated depending on final diagnosis. Data are presented as numbers (%) and medians (interquartile range); older patients (≥60 years old) were compared to younger patients (<60 years old) using non-parametric statistical tests (chi-square test or Mann–Whitney); P < 0·05 was considered significant. Statistics were performed using StatView software (SAS Institute, Cary, NC, USA). Among 154 TMA patients requiring ICU admission, 26 (17%) were ≥60 years old and 128 (83%) were <60 years old. Their comorbid conditions, onset manifestations and biological features are detailed in Table I. Older patients presented more frequently with cardiovascular risk factors. Stroke and altered mental state occurred more frequently among older patients (8% vs. 1%, P = 0·02; 46% vs. 21%, P = 0·007) as did gastro-intestinal bleeding (19% vs. 5%, P = 0·009). Elevated troponin rate was more frequent among older patients (83% vs. 59%, P = 0·025), and urea rate was also higher [21·6 (11·6–27.4) vs. 9·7 (5·9–16.6), P < 0·001]. Time from first abnormal biological parameter to diagnosis was longer in older patients (two vs. one days, P = 0·0428). TMA subgroups and underlying diseases are shown in Fig 1. No differences were found concerning TMA subgroups between younger and older patients. Ongoing cancer and imputable drugs (non-steroidal anti-inflammatory agents, tacrolimus, ciclosporin, rifampicin, revlimid) were more frequent among older patients (respectively 39% vs. 8%, P < 0·0001 and 23% vs. 6%, P = 0·0065). HIV infection was not observed in older patients (0% vs. 13%, P = 0·0488). There were no differences concerning PEX, initiated in 20 older (77%) and 107 younger patients (84%). Total number of PEX, requirement for additional specific treatments (corticosteroids, vincristine, rituximab or splenectomy), and length of stay did not differ. Older patients underwent renal replacement therapy (RRT) more frequently (46% vs. 27%, P = 0·0466); requirement for other organ support therapies (vasoactive drugs and mechanical ventilation), antibiotics or transfusions did not differ statistically. Secondary bleedings occurred more often in older patients (35% vs. 16%, P = 0·0239) but other complications, such as hypertension, venous thrombosis, nosocomial infection, neurological or cardiovascular event, were similar between groups. ICU mortality was higher in older patients (19% vs. 7%, P = 0·0485). Our data highlight the atypical starting characteristics of older patients with TMA. In this population, altered mental state and strokes are more frequent, as well as renal involvement and higher rate of troponin; time from first abnormal biological parameter to diagnosis is also longer. Some of these results are similar to those described in older patients with TTP.5, 6 At onset, gastro-intestinal bleeding also occurs more often among older patients, suggesting a larger proportion of patients with pre-existing gastro-intestinal lesions. Moreover, these events can be challenging in the context of potential TMA-targeted therapies increasing the risk of haemorrhage (such as caplacizumab), and venous thromboembolism prevention management. Secondary TMAs occurred more often in older patients, especially drug- and cancer-related, the latter either associated with a genuine TTP, or with multimetastatic cancer including bone marrow involvement.7-9 The number of refractory TTP was similar between groups, and congruent with the literature.3 Complications were similar in both groups, except for bleeding, which occurred more frequently among older patients. Within our cohort, ICU mortality was consistent with the rest of the literature.3-6 The more frequent requirement for RRT and the higher ICU mortality among older patients could be explained by the higher rate of comorbidities and resulting frailty. The delayed diagnosis of TMA due to atypical features may also account for this difference, as well as the higher rate of cancer-related TMA, most of the time beyond all therapeutic resource.9 Anyhow, ICU mortality among older and younger patients with TTP did not differ, highlighting the efficiency of PEX and other therapies,10, 11 even in older patients with comorbidities.6 Overall mortality of older patients with TMA may be underestimated, as patients who felt too frail to receive TMA treatments were not admitted in the ICU. In conclusion, older patients with TMA present with atypical neurological features and more frequent renal involvement. In these patients, delayed diagnosis, renal involvement, increased troponin, association with cancer, and overall frailty may account for the higher ICU mortality. Increasing awareness of TMA-related complications may improve outcomes, and the potential benefit of early treatment of the TMA and of the associated condition in this population deserves to be evaluated. JS and EN had full access to all data and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: JS, EM, EA. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: JS. Critical revision of manuscript for intellectual content: all authors. Final approval of the manuscript: JS, EM, EA. The authors declare that they have no conflict of interest. The collection and use of data was approved by the institutional review board (CIC Clermont-Ferrand — IRB no. 5891; Ref: 2007–16), which waived the need for signed informed consent of the participants, in accordance with French legislation on non-interventional studies. The authors received no financial support for the research, authorship, and/or publication of this article.