Thrombotic microangiopathy in pregnancy: when you hear hoofbeats, consider the zebras?

Thrombotic microangiopathy (TMA) refers to a set of conditions marked by an underlying pathologic alteration of the microvasculature, characterised by endothelial engorgement and platelet aggregation resulting in damage to the microcirculation.1 Clinically, TMA manifests through microangiopathic hemolytic anaemia (MAHA) with evidence of red blood cell fragmentation, thrombocytopenia and micro-thrombotic end-organ ischemic injury.1, 2 The presence of TMA in the context of pregnancy should prompt consideration of three entities: (i) Pre-eclampsia/HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome; (ii) thrombotic thrombocytopenia purpura (TTP); and (iii) pregnancy-associated aHUS (p-aHUS), a complement-mediated microangiopathy.3 Pre-eclampsia/HELLP is the most common TMA encountered in pregnancy, complicating 2–7% and 0·2–0·6% of gestations, respectively.1, 4 It is thought to be driven by abnormal placentation, endothelial dysfunction and imbalance of antiangiogenic factors present as early as the first trimester, yet its phenotypic variability remains poorly understood.1 Moreover, recent studies have linked upregulation of the complement alternative pathway to the pathogenesis of HELLP.5, 6 Some degree of renal compromise and acute kidney injury (AKI) can be seen in 15–20% of women with pre-eclampsia/HELLP, and its risk is higher in early-onset disease.4 AKI has also been noted in 20% of HELLP syndrome cases presenting postpartum, wherein dialysis is often required.7 TTP, a life-threatening disorder, has been defined broadly as a TMA in the setting of ADAMTS13 (A Disintegrin And Metalloprotease ThromboSpondin type 1 motif member 13) level below 10%, which can be congenital (owing to genetic mutations) or acquired (due to antibodies against ADAMTS13).2 A reduction of this cleaving enzyme promotes the accumulation of large von Willebrand factor multimers which bind to platelets, resulting in the formation of fibrin strands and precipitating intravascular hemolysis and ischemic damage.2 The incidence of TTP in pregnancy is estimated to be less than 1 in 100,000 pregnancies.1 While classically the clinical presentation was thought to consist of a pentad of manifestations (fever, MAHA, thrombocytopenia, renal involvement and neurologic symptoms), a later study found this pentad to occur in only 5–40% of cases.8 If untreated, the reported mortality rate can reach 90%,9 while treatment consisting of plasma exchange can reduce mortality to 20%.2 In contrast, HUS is a complement-mediated TMA in which ADAMTS13 levels are typically normal.1, 2 While the classic form presents with bloody diarrhea secondary to Shiga toxin-producing E. Coli,2 atypical HUS (aHUS) has a genetic origin, with mutations in genes regulating the alternative complement pathway.1 aHUS presents with MAHA, thrombocytopenia and renal dysfunction or failure.10 Pregnancy and the postpartum period are known triggers of aHUS, leading to the recognition of p-aHUS as a distinct entity.11 The incidence of p-aHUS has been estimated at 1:25,000 pregnancies,12 and 70–80% of cases occur postpartum.13 Initial treatment typically consists of plasma exchange, particularly if TTP has not been excluded conclusively.2 Once the diagnosis of p-aHUS is certain, management with a complement inhibitor should be considered, if accessible.2 At present, eculizumab, a humanised monoclonal anti-C5 antibody against the terminal complement component,2 which acts to block complement-mediated inflammation and endothelial damage, has been approved for treatment of aHUS.1 Data on its use in p-aHUS continue to accumulate, and thus far results have been reassuring, with absence of the drug in breast milk and levels in cord blood samples insufficient to affect the concentration of complement in the neonate.14 To date, in addition to case reports, outcomes of pregnancies in women with p-aHUS have been described in three case-series, with a sample size of 87, seven and 22, respectively.13, 15, 16 Complement gene abnormalities were identified in 32–71%, while 73–100% of patients presented in the postpartum period. In the larger studies, live births occurred in 86–95% of pregnancies, while in the smaller study, the live birth rate was 57%. Plasmapheresis was used in ~78% of patients in the larger studies, while eculizumab was used in 5% in the Bruel et al. study and in 46% in the Huerta et al. series. Approximately half of the patients progressed to ESRD and a third required a renal transplant. Hemodialysis was initiated in 41%. Relapse was noted in 20–30%.11 In the current report, Timmermans et al. 17 present data on p-aHUS from two registries: the Limburg Renal Registry in the Netherlands and the Cliniques Universitaires Saint-Luc registry in Belgium, which includes cases with primary aHUS defined as thrombotic microangiopathy (TMA), ADAMTS13 activity at or above 10% and proven complement defects. For the study, TMA was considered in presence of (i) typical morphologic features of TMA on kidney biopsy, or (ii) microangiopathic hemolytic anemia (MAHA) (hematocrit <30%, hemoglobin <10 g/l, lactate dehydrogenase >500 u/l and schistocytes on peripheral blood smear), thrombocytopenia (platelets <150 g/l) and acute kidney injury in absence of pathologic evidence of TMA. Complement gene abnormalities were demonstrated in 47% of women with primary HUS. Additionally, pathogenic variants were present in two asymptomatic female relatives who were also tested. All 39 pregnancies were managed without prophylactic intervention. P-aHUS evolved in seven (18%) pregnancies [peripartum in four (57%) and postpartum in three (43%)]. Severe kidney failure was the pathognomonic manifestation, with six (15%) requiring dialysis. Thrombocytopenia and MAHA were observed in 5/7. Similarly, pre-eclampsia/HELLP was the initial diagnosis in 5/7 eventually diagnosed with P-aHUS, and was present in an additional 5/32 pregnancies unaffected by P-aHUS. Twenty-six (6%) pregnancies had no maternal complications. Caesarean section was performed in 4/8 pregnancies with P-aHUS. Overall, 90% of pregnancies ended in live birth and, of those, 10 (29%) were pre-term. There were two neonatal deaths (one in an infant born at 26 weeks’ gestation, and another in a term well-grown infant born by elective Caesarean section who died of asphyxia). Of the pregnancies with P-aHUS, three (38%) infants were small for gestational age. Plasma exchange was offered in six pregnancies, with normalisation of kidney function in two. Eculizumab was initiated in three patients refractory to plasma exchange. With a median follow-up of 3 years from onset of primary aHUS, the rate of end-stage kidney disease was 3·72 (95% CI, 2·8–7·2) per 100 person-years. The description of p-aHUS provided by Timmermans et al. 17, and based on data from Belgian and Dutch registries, provides further insight into a rare, potentially life-threatening condition for which sparse data are available. Diagnosis of p-aHUS or, for that matter, TTP, can be elusive in pregnancy, as their clinical presentation can mimic pre-eclampsia/HELLP,11 a spectrum of conditions much more prevalent in pregnancy and with which clinicians in general and obstetricians in particular are exceedingly familiar. Consideration of several features may prove of benefit when establishing the diagnosis. Pre-eclampsia/HELLP are typically associated with a relatively swift recovery postpartum. Thus, when thrombocytopenia or renal derangements continue to progress beyond 48–72 h postpartum, the possibility of TTP or p-aHUS should be entertained.1 In this regard, ADAMTS-13 levels below 10%, or focal neurologic deficits (including paresis, paresthesias or aphasia), would be in keeping with TTP.1, 3 In contrast, progressive AKI with creatinine above 2 mg/dl, need for dialysis or lactate dehydrogenase levels above 1,000 u/l would be more consistent with p-aHUS3, 18 Adding complexity to the subject, accumulating data suggest that alternative complement pathway dysregulation may be the basis of pregnancy complications for disorders other than p-aHUS, linking alterations in the alternative complement pathway to manifestations of lupus and antiphospholipid syndrome.4 Furthermore, some authors have proposed that a substantial portion of HELLP syndrome occurs as a result of genetic mutations resulting in an impaired ability to regulate the alternative complement pathway, analogous to aHUS.6 Worth pondering is whether this is indeed the case, or whether the instances of what was considered to be HELLP syndrome but demonstrated to have an associated complement genetic mutation may have in fact represented an undiagnosed p-aHUS. Perhaps when we hear the hoofbeats of the herds of horses, it may be worthwhile to also consider the zebras.

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