Thrombotic microangiopathy (TMA) represents a serious pathological condition, characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and various organ dysfunctions(1), which refers to a pattern of endothelial cell injury of variable severity that preferentially affects the central nervous system (altered consciousness, seizures), the kidneys (acute kidney injury [AKI]), and the heart (raised serum troponin level, ischemia, sudden death)(2). Acute thrombotic thrombocytopenic purpura (TTP) was almost universally fatal until the introduction of plasma therapy, which improved the survival from below 10% to 80-90%. Patients who survive an acute episode are at high risk of relapse and of long-term morbidity(3).
Pregnant patients most often present with symptoms of severe preeclampsia/HELLP syndrome (e.g., hypertension, upper abdominal pain, nausea, vomiting, malaise, neurological complications/eclampsia)(1,4) but, rarely, TMA is due to thrombotic thrombocytopenic purpura (TTP) or to atypical hemolytic uremic syndrome (aHUS). Due to overlapping clinical and laboratory features, TTP and aHUS are often mistaken for preeclampsia or HELLP(4). Taking into consideration that the etiology of maternal TMAs is diverse during pregnancy, and that it could have severe maternal and fetal complications, this review outlines the differential diagnosis of pregnancy-associated microangiopathic conditions, with a focus on the distinction between TTP, aHUS and severe preeclampsia or HELLP syndrome, in order to avoid unnecessary and potentially harmful treatments.
Pregnancy-specific TMAs: preeclampsia and HELLP syndrome
Preeclampsia (PE), a disorder that complicates 2-8% of pregnancies, is a leading cause of maternal and neonatal morbidity and mortality. Especially the early-onset PE (i.e., PE requiring delivery before 34 weeks of gestation) is associated with an increased risk of both short- and long-term maternal complications and perinatal mortality and morbidity(5). Impaired placentation with abnormal blood-flow velocity and resistance in placental vessels(6), endothelial dysfunction, abnormal angiogenesis, and exaggerated inflammatory response with resultant generalized vasospasm, activation of platelets and abnormal hemostasis(7) are associated with preeclampsia and fetal growth restriction(6,7).
The individual risk of pregnant patients for developing preeclampsia is calculated based on parameters such as maternal characteristics, sonographic measurements, physiological markers and biochemical determination of maternal serum markers. The screening test for the first trimester should be a combination of maternal risk factors, measurements of mean arterial pressure (MAP), serum placental growth factor (PLGF), maternal serum pregnancy-associated plasma protein A (PAPP-A), and uterine artery pulsatility index (UTPI)(8). In pregnancies that develop PE, the values of uterine artery pulsatility index and MAP are increased and the values of serum PAPP-A and PlGF are decreased(9).
The clinical application of first-trimester screening is the identification of patients at high risk for PE, and could potentially improve the pregnancy outcome using low-dose aspirin before 16 weeks of pregnancy, by improving placentation, with a beneficial effect particularly on the risks of early-onset compared with late-onset preeclampsia(6,10). The initiation of aspirin treatment is recommended, at the earliest, at 12 weeks of gestation in women with risk factors(6).
Preeclampsia was defined in accordance with the American College of Obstetricians and Gynecologists as systolic blood pressure (BP)≥140 mm Hg and/or diastolic BP≥90 mm Hg on at least two occasions measured 4 hours apart, developing from 20 weeks of gestation onward in previously normotensive women and proteinuria ≥300 mg in a 24-hour urine specimen. In the absence of proteinuria, it is considered the new onset of hypertension with new onset of any of the following: thrombocytopenia (platelet count <100×109/L), renal insufficiency (serum creatinine >1.1 mg/dL or doubling of the baseline creatinine in the absence of other renal disease), impaired liver function (elevated concentrations of liver transaminases to twice normal concentration), pulmonary edema and cerebral or visual symptoms(5). HELLP syndrome is considered the most severe variant of PE, characterized by more severe thrombocytopenia, more fulminant microangiopathic hemolytic anemia (MAHA) and more profoundly elevated liver function tests(11).
The diagnosis of severe PE/HELLP, along with their distinction from TTP and aHUS are critical because the only treatment is delivery, whereas pregnancy can continue in patients with TTP-aHUS(11,12).
Pregnancy-associated TMAs: thrombotic thrombocytopenic purpura – atypical hemolytic uremic syndrome (TTP-aHUS)
Thrombotic thrombocytopenic purpura is a rare (1 in 25,000 pregnancies) life-threatening hematologic disorder, in which microthrombi develop in small blood vessels due to the lack of ADAMTS13 enzyme activity, leading to the persistence of ultra-large multimers of von Willebrand factor (vWF), activating platelet receptors and, consequently, platelet aggregation(13). Rarely, congenital TTP (Upshaw-Schulman syndrome) arises from mutations in the ADAMTS13 gene(4). More frequently, an acquired form occurs due to autoantibody production that blocks enzyme activity(13). Approximately 10% of women with acquired, antibody-induced TTP (aTTP) and a quarter to half of those with congenital TTP (cTTP) present for the first time during pregnancy, often at the first pregnancy, or postpartum(11). This predisposition may reflect the physiological increase in vWF during pregnancy, which consumes ADAMTS13, and in patients with a genetic predisposition its activity can fall low enough for TMA to manifest(14). A severe deficiency (<5% of the activity in normal plasma) ± the presence of an inhibitor or IgG antibodies strongly supports the diagnosis for TTP. The diagnosis of congenital TTP is dependent on detecting ADAMTS13 activity <5%, in the absence of antibodies to ADAMTS13. The specificity of severe ADAMTS13 deficiency (<5%) in distinguishing acute TTP from HUS is 90%(15).
Fetal loss caused by widespread placental ischemia is frequent when TTP occurs in the first and second trimesters, but the incidence of healthy live births approaches 75% to 90% when TTP develops closer to term and when maternal treatment has been successful(11).
An atypical form of HUS is usually seen in association with pregnancy, with no evidence of infection (Shiga toxin-associated HUS)(16). Pregnancy-related atypical HUS is a very severe disease, linked to complement alternative pathway dysregulation, leading to complement-induced endothelial cell damage, with a poor prognosis for maternal kidney function if left without specific efficacious treatment. A study by Bruel et al. reported that in patients with aHUS during pregnancy and those with aHUS in the postpartum period shared the same severe renal outcome (risk of end-stage renal disease [ESRD] of 44-55%), in sharp contrast to the usual complete recovery of kidney function in patients with preeclampsia and HELLP syndrome(17). aHUS is rare and mainly develops in the postpartum period. As with TTP, there is an increased risk of fetal loss or intrauterine growth restriction in pregnant patients with aHUS and is a continued risk of relapse during subsequent pregnancies(18). Follow-up should include serial growth scans and determination of uterine artery flow(2).
Typically, the presentation in aHUS is represented by MAHA, thrombocytopenia, ADAMTS13 activity higher than 10% and serum creatinine above 2.2 mg/dL(11,18). The diagnosis of TMA requires evidence of a microangiopathic hemolytic anemia (hemoglobin level <10 g/dL, presence of schistocytes more than 1%, elevated LDH), undetectable serum haptoglobin, with thrombocytopenia, and the presence of TMA features in kidney (or another organ) biopsy(2). Thrombocytopenia during an acute episode in TTP is generally severe, with a median platelet count of 10-17×109/L at presentation. A higher platelet count (>30×109/L) is suggestive of an alternate TMA, but does not exclude TTP.
Gastrointestinal symptoms are common in TTP (35-40%). The nervous system is the most commonly affected visceral organ at presentation(19) which may be accompanied by renal insufficiency and fever(11). Acute renal failure requiring dialysis is present in 4% to 15% of patients. The absence of severe renal dysfunction helps to differentiate TTP from aHUS, in which oliguric or anuric renal failure is more common(19). As a result of renal impairment in TTP, urinalysis can show variable proteinuria and/or hematuria, and increased plasma urea and serum creatinine level below 2 mg/dL at presentation(18).
Laboratory testing in patients with TTP include: increased indirect bilirubin, a negative direct antiglobulin test, decreased RBC count, reticulocytosis, normal coagulation tests (prothrombin time, activated partial thromboplastin time, fibrinogen and D-dimers), which should be distinguished from similar disease processes such as immune thrombocytopenia (ITP) or disseminated intravascular coagulation (DIC)(20).
There is no test to rule in or out TTP with enough speed and accuracy to safely guide the initial therapy(21).
If acute TTP is suspected, plasma exchange (PEX) should be promptly initiated(12,21). The effectiveness of plasma therapy has been ascribed to the replacement of ADAMTS13 activity(12). Prophylactic plasma infusions in hereditary TTP result in an excellent fetal and maternal prognosis, by limiting placental micro-occlusion arterial thrombosis(2).
The complement inhibitor eculizumab has been shown to be effective in improving renal function in atypical HUS(21). Reports of the experience with eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria support its safety in this setting(16).
Discussion and conclusions
TMAs are medical emergencies requiring rapid diagnosis and appropriate treatment(20). The context (PE, HELLP, severe delivery hemorrhage) in which TMA occurs is of paramount importance(2). In the setting of obstetric complications, HELLP syndrome is the main differential diagnosis from acute fatty liver of pregnancy (AFLP), a rare life-threatening condition(13) (estimated to be 1 to 3 cases per 10,000 deliveries(22)), which typically occurs in the third trimester, but hypoglycemia and coagulopathy are key features of AFLP. The diagnosis can be confirmed with hepatic biopsy, demonstrating microvesicular steatosis(13). However, due to the acute presentation and coagulopathy, it is usually not possible to undertake liver biopsy, and the diagnosis is made by a combination of clinical and biochemical features(18). Obstetricians must clearly communicate to neonatologists the presence of maternal acute fatty liver of pregnancy to ensure that the newborn is appropriately screened and monitored for complications of hypoglycemia and metabolic derangements(22). Early diagnosis, prompted delivery and supportive care have resulted in improved maternal and neonatal morbidity and mortality(23).
Preeclampsia and HELLP must be distinguished from other TMA disorders that warrant non-delivery interventions. Unfortunately, delays in diagnosis and treatment may be life-threatening(4).
Complement has been involved in the etiology of TMA(24). Taken together, studies to date indicate complex interactions among complement dysregulation, pregnant state and pregnancy complications, including preeclampsia and HELLP syndrome. An intriguing question remains as to whether some forms of HELLP syndrome may be, in fact, cases of thrombotic microangiopathy due to complement dysregulation that can be treated with therapies other than induction of delivery(25).
Regarding late-onset congenital TTP (cTTP) presenting de novo in an obstetrical context, it usually occurs during the second half of pregnancy and early postpartum (mostly as a consequence of the progressive increase in von Willebrand factor multimers concentration throughout pregnancy), but rare cases may occur during the first trimester. In some rare cases of late-onset cTTP, the first pregnancy is not associated with a classical TTP but with a short-term outcome combining an early miscarriage and a transient thrombocytopenia. In these particular cases, the diagnosis of TTP is most often missed during the first pregnancy(26). Clinicians should be aware in cases of late onset congenital TTP that anemia may not be considered pathological and the thrombocytopenia may be at levels often seen in gestational or immune thrombocytopenia. The blood film confirms the presence of microangiopathy and evaluates platelet morphology and the accuracy of automated platelet counts(18). Pregnant patients who present with MAHA and thrombocytopenia should be screened for autoantibody, infections and HIV. TMA can also occur in response to drugs(20).
Even though pregnancy and postpartum have long been recognized as high-risk periods for different forms of TMA, pregnancy-associated TMA still raises challenging diagnostic and therapeutic issues and should be managed in a specialized center(2).
Conflict of interests: The authors declare no conflict of interests.