Abstract
Thrombotic thrombocytopenic purpura (TTP) is a serious but rare cause of thrombocytopenia in pregnancy which poses a significant morbidity and mortality burden to the maternofetal dyad. Diagnosing TTP in pregnancy is challenging due to its non-specific clinical presentation, and the potential for similar or concomitant presentation with other thrombotic microangiopathies. We present an atypical case of TTP diagnosed in an asymptomatic 28-year-old female, at 35 weeks’ gestation. TTP must be considered a differential for thrombocytopenia, especially in the context of autoimmune disease and even in the absence of typical signs or symptoms. Increasingly available diagnostic tools may help redefine our understanding of TTP presentations in pregnancy.
Introduction
Isolated thrombocytopenia in pregnancy can be both physiological and pathological, posing a difficult clinical conundrum. Physiologically, platelets can decrease up to 20% by time of delivery, with almost 10% of women having levels below 150 × 109/L. 1 Platelets less than 100 × 109/L occur in fewer than 1% of uncomplicated pregnancies and are therefore rarely attributed to gestational thrombocytopenia. 1 A wide differential diagnosis for pathological aetiologies of thrombocytopenia should be considered, as demonstrated in Figure 1.
Differential diagnosis of thrombocytopenia in pregnancy.
The diagnosis of thrombotic microangiopathies (TMA) in pregnancy is challenging given the overlap of clinical features and potential for concomitant presentations. 2 Thrombotic thrombocytopenic purpura (TTP) in particular, presents a diagnostic dilemma given the low incidence and risk of delayed diagnosis. Pregnancy is a recognised risk for TTP, albeit rare occurring in less than 0.0005% of pregnancies.3,4 It increases the risk of preeclampsia, preterm birth, fetal growth restriction and fetal death. 5 Historically, TTP was associated with the clinical pentad of microangiopathic haemolytic anaemia, thrombocytopenia, renal dysfunction, neurologic abnormalities and fever.
We present a case of TTP with isolated thrombocytopenia in the third trimester of pregnancy without neurologic manifestations and a review of pregnancy-specific diagnostic and management updates.
Case report
A 28-year-old female in her third pregnancy was found to have acute thrombocytopenia (platelets 23 × 109/L) and normocytic anaemia (Hb 89 g/L) on routine bloods at 34 weeks’ gestation. This was in the context of quiescent systemic lupus erythematosus (SLE), managed with prednisolone, hydroxychloroquine and azathioprine, with 6-methylmercaptopurine levels within normal limits. The pregnancy was complicated by a small for gestational age fetus, with estimated fetal weight on the 7th percentile at 31 weeks. The woman had a background of preeclampsia with haemolysis, elevated liver enzymes and low platelet (HELLP) syndrome in her first pregnancy, with delivery necessitated via caesarean section at 32 weeks’ gestation.
The woman was afebrile, normotensive, euvolemic, and neurologically intact. There was no right upper quadrant tenderness, splenomegaly nor evidence of active synovitis, petechiae, bruising or malar rash.
Secondary investigations revealed normal hepatorenal function (creatinine 0.57 mg/dL; RR 0.4–0.8 mg/dL) but elevated lactate dehydrogenase (357 U/L; RR: 120–250 U/L) and mild red cell fragmentation. Soluble fms-like tyrosine kinase-1/placental growth factor ratio was normal, lupus anticoagulant and antiphospholipid antibodies were negative. ADAMTS13 activity was reduced (3 U/dL; RR 60–130 U/dL) and a low titre of ADAMTS13 inhibitor was detected (0.7BU; RR <0.4BU). Acquired TTP was diagnosed, and prednisolone was up-titrated without effect. Daily plasma exchange via a Permacath was commenced. Following eight plasma exchanges, platelets peaked at 140 × 109/L but subsequently fell to 103 × 109/L despite ongoing treatment.
At 36 weeks labour was induced with a balloon catheter and artificial rupture of membranes. A healthy 2082 g female was born with Apgar score of 9 at 1 and 5 min. Postpartum the woman received cycles of weekly intravenous rituximab at a dose of 375 mg/m2. Prior to discharge, the infant required a 30-day special care nursery admission for prematurity, transient tachypnoea, and hypoglycaemia.
Discussion
Diagnosis
Differentiating TMA in pregnancy is challenging given overlapping clinical features. Pathologies such as TTP or complement-mediated TMA (cTMA) often present with more severe thrombocytopenia.3,6 Unlike pre-eclampsia or HELLP, they can occur at gestations less than 20 weeks and do not recover with delivery.3,6,7 While cTMA is typically associated with renal impairment, TTP classically presents with neurological and haematological manifestations.6,7
Our case deviated from this, presenting without neurological symptoms. The Australian TTP registry reports the pentad in only 7% of patients, with neurological manifestations in 71% of cases, although this may not be equally reflected in the pregnant population. 8 A cross-sectional analysis identifying 42 cases of TTP in pregnancy, noted neurologic symptoms in only 57% of patients. 4 Similarly, a review of 166 women with pregnancy-associated TTP reported highly variable symptomology and disease expression. 9
It has been hypothesised that pre-existing immunosuppression with corticosteroids in SLE patients could modulate the classically rapid development of TTP features such as neurological phenomena. 10 This suggests, TTP may present atypically in pregnancy and should be considered a differential, especially in the context of pre-existing autoimmune disease. SLE can also flare in pregnancy, with manifestations of TMA. 11 There are reports of up to a 2.2% incidence of TTP among SLE patients, with up to a 46% mortality rate in this population. 12
A high index of suspicion and low threshold for diagnostic tests, such as ADAMTS13 activity assay, is crucial to confirm TTP. 2 Physiologically, pregnancy induces an increasingly hypercoagulable state with a propensity for ADAMTS13 deficiency and VWF factor excess in later gestations.7,13 It is not uncommon for ADAMTS13 activity levels to reach 25 to 30 U/dL in healthy pregnancies. 13 However, activity less than 10 U/dL is highly suggestive of TTP. 3 Given both congenital and acquired TTP can present for the first time in pregnancy, further testing for autoantibodies can differentiate these aetiologies and guide management strategy.
Where ADAMTS13 assays are not rapidly available, modern clinical prediction tools, including PLASMIC or French TMA scores, may assist with determining pre-test probability, as demonstrated in Figure 2.6,14,15 However, these have not been validated in pregnant populations.
Management
The cornerstone of management is initiating plasma exchange, which provides a source of functional ADAMTS13 in congenital cases and further removes antibodies in acquired TTP. 16 It is associated with 90% response and survival rates. 16 Acquired TTP may also require adjuvant immunosuppressive therapy. Mainstay treatments include corticosteroids and anti-CD20 therapy, such as rituximab.7,13,16
In non-pregnant populations, rituximab has proven efficacious and lowered relapse rates, with a response rate of 80% in refractory cases. 17 However, platelet normalisation may take up to 35 days and although under-researched in pregnancy, rituximab has been shown to cross the placenta, warranting close monitoring of immune effects in exposed neonates.17,18 While no clear teratogenic pattern has emerged, limited cohort size and lack of long-term data prompts caution in its use. 18 In severe cases, benefits likely outweigh risks, although it was not administered antenatally in this case given the time until effect.
Delivery will not treat TTP, but may facilitate use of immunosuppressive therapy, when maternal or fetal compromise is evident. Depending on gestation, urgent delivery may be considered in undifferentiated TMA, to treat obstetric aetiologies (pre-eclampsia, HELLP) and hasten remission of other TMA (TTP, cTMA).3,7,13 While caesarean delivery is more common in this population, if remission is achieved with ADAMTS13 activity greater than 25 U/dL, vaginal delivery could be considered. 13 Available studies suggest aiming for platelets above 70 × 109/L, prior to caesarean section or neuraxial analgesia. 19
Relapse in subsequent pregnancy occurs in approximately 50% of acquired TTP survivors.7,9 Pregnancy may also trigger relapse in women with TTP history outside of pregnancy.7,13 While it predominantly occurs in the third trimester or postpartum period, there remains a need for obstetric awareness, preconception counselling and multidisciplinary follow-up.3,7,13
Conclusion
Differentiating TMA in pregnancy is essential to initiate appropriate management. Identifying TTP is complicated by infrequency and variability of presentation in pregnancy. Clinicians should maintain high indices of suspicion, especially in asymptomatic women with pre-existing autoimmune disease.
Footnotes
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical approval
This manuscript was exempt as determined by the affiliated institutions.
Informed consent
Written informed consent was obtained from the woman for her anonymized information to be published in this article.
Guarantor
JES acts as a guarantor of this manuscript.
Contributorship
The manuscript's conception was by JES, LC and AMC. BN wrote the initial draft of the manuscript. JES, AMC, LC, NW, HS and LM were involved in revisions of the manuscript.
