Thrombotic Thrombocytopenic Purpura in a Parturient Leading to Life-Threatening Thrombocytopenia and Neonatal Demise—A Case Report : Maternal-Fetal Medicine

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Case Report

Thrombotic Thrombocytopenic Purpura in a Parturient Leading to Life-Threatening Thrombocytopenia and Neonatal Demise—A Case Report

Berger, Amnon A.; Kowalczyk, John J.; Hess, Philip E.; Li, Yunping

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Maternal-Fetal Medicine ():10.1097/FM9.0000000000000177, December 8, 2022. | DOI: 10.1097/FM9.0000000000000177
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Abstract

Introduction

Thrombocytopenia is common in pregnancy and develops in up to 12% of pregnancies.1,2 Common causes of thrombocytopenia in pregnancy include gestational thrombocytopenia, preeclampsia with severe features (sPEC), and immune thrombocytopenia; however, these conditions rarely cause life-threatening thrombocytopenia.1

Thrombotic thrombocytopenia purpura (TTP) is a rare disease associated with severe thrombocytopenia and hemolytic anemia.2 Ischemic injury in the nervous system and major organs results from small clots that form in the smallest arteries. TTP is most often caused by a functional deficiency of ADAMTS13, a metalloprotease responsible for cleaving von Willebrand factor, and is diagnosed via a functional ADAMTS13 assay. However, these assays usually take days to result, and treatment should not be delayed until a final diagnosis is made. TTP can be hereditary or acquired; the latter is usually immune mediated and can be triggered or exacerbated by pregnancy.3 The congenital form of TTP is inherited in an autosomal recessive form, involves genetic mutations leading to dysfunctional enzymes, and can be treated by plasma infusion.4 The acquired form, however, is immune mediated and is caused by antibodies against ADAMTS13; the treatment involves immunosuppression with steroids and plasma exchange during the acute phase.1,4 Rituximab is increasingly used for curative or preemptive use.4

TTP is life threatening for both parturient and fetus, with frequent fetal loss in the first and second trimester caused by placental ischemia; live birth can be expected in 75% to 90% of cases when TTP is diagnosed close to term.1 The clinical overlap between TTP and sPEC in parturients with thrombocytopenia can complicate the differential diagnosis. Prompt diagnosis and treatment are keys to improve maternal and fetal outcomes.

Case presentation

A 31-year-old pregnant woman, gravida 3, para 1 at 26 week and 3 days of gestation, presented to an outside hospital with new onset of easy bruising and blurry vision. She had additional history of Factor V Leiden and deep vein thrombosis and was receiving prophylactic enoxaparin. She underwent obstetric ultrasound notable for severe fetal growth restriction (<1%). Her platelet count (PC) was found to be 19,000/μL, and she was transferred to our tertiary referral center.

Upon presentation, she was re-evaluated by the maternal fetal medicine specialists. The combination of thrombocytopenia and intrauterine growth restriction led to an initial diagnosis of sPEC and HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets). Two hours after her admission to our center, her PC further decreased to 14,000/μL and urgent cesarean delivery was recommended because of nonreassuring fetal heart rate. An obstetric anesthesia consult was requested, and upon evaluation, it was noted that she had only mild elevation of her blood pressure, the serum hepatic transaminases were normal, and haptoglobin level was undetectable, indicating hemolysis in a setting of thrombotic microangiopathy. She had also experienced mild acute kidney injury, with a peak serum creatinine level of 1.2 mg/dL from a baseline level of 0.8 mg/dL. A peripheral blood smear demonstrated schistocytes, further supporting the diagnosis of thrombotic microangiopathy. Even though preeclampsia is a common cause of thrombotic microangiopathy in pregnancy, lack of hepatic involvement suggested an alternative diagnosis. A presumptive diagnosis of TTP was made and hematology was consulted urgently. Continuous fetal monitoring was used from admission and continued throughout; it had showed category 3 tracing during the patient’s entire admission. Despite fetal distress, the likely poor fetal prognosis of an early second trimester pregnancy with TTP, and in accordance with maternal wishes, delivery was postponed until an urgent multidisciplinary meeting was held.

The multidisciplinary meeting resulted in a shared decision with the patient to defer cesarean delivery given increased maternal risks and likely poor fetal outcome regardless of delivery. While treatment for TTP was initiated, labor induction was begun in lieu of cesarean delivery for severe fetal distress. The patient was started on 1-mg/kg prednisone and total plasma exchange was initiated 12 hours after admission. This led to an immediate increase in PC. The diagnosis of TTP was later confirmed when undetectable ADAMTS13 levels resulted with positive anti-ADAMTS13 antibodies.

By the third hospital day, the patient’s PC recovered to greater than 150,000/μL. She had a successful vaginal delivery, with unfortunate neonatal death despite completion of betamethasone and neonatal resuscitation efforts. She was transitioned to rituximab for continued care and otherwise fared well and was discharged. She continued to receive care from hematology in the outpatient settings experiencing only ongoing blurry vision from a diagnosed retinal bleed in the setting of TTP.

The patient has given her consent to publish the clinical information in the journal.

Discussion

Thrombocytopenia complicates as many as 12% of pregnancies.2 Here, we present a rare case of TTP during pregnancy and life-threatening thrombocytopenia. The case highlights the importance of maintaining a broad differential diagnosis when identifying preeclampsia with severe features, as in this case, urgent cesarean delivery would not have provided a lifesaving treatment and may have led to major hemorrhage.

TTP is a rare, serious disease. The diagnostic symptoms include severe thrombocytopenia, abnormal destruction of red blood cells (hemolytic anemia), and disturbances in the nervous system. End-organ injury occurs as a result of microthrombosis that forms in the smallest arteries. Our patient demonstrated 3 of the following 5 classic symptoms of TTP: thrombocytopenia, microangiopathic hemolytic anemia, and renal involvement. She did not experience fever nor neurologic deficits. Her blurry vision was explained by retinal bleeding in the setting of severe thrombocytopenia and was, in hindsight, unlikely to be a neurologic symptom.

The diagnosis of TTP is challenging and is ultimately made with a functional ADAMTS13 assay. Antibody detection helps differentiating immune-mediated acquired TTP from the congenital form. However, in most cases, delaying treatment until a final diagnosis is made is unacceptable and poses a significant risk to the patient. Thus, a high level of suspicion must be maintained and the differential diagnosis considered in the context of each case.

The differential diagnosis of thrombocytopenia include ITP, gestational thrombocytopenia, sPEC, TTP/HUS (hemolytic-uremic syndrome), acute fatty liver of pregnancy (Table 1), and less common reasons. Our patient had a normal PC 2 months before admission that excludes ITP. In gestational thrombocytopenia, the PC is usually greater than 100,000 μL in an otherwise healthy pregnant woman. sPEC is also very common in pregnancy; in the United States, the incidence is estimated at 3.1% and is expected to continue to rise in coming years.5 Thrombotic microangiopathy is most commonly secondary to preeclampsia in pregnancy; however, the differential does include several other disease states.6

Table 1 - The differential diagnosis of thrombocytopenia in pregnancy*.
Clinical Features Gestational thrombocytopenia ITP TTP Preeclampsia HELLP AFLP aHUS
 Pathogenesis Unknown Autoimmune ADAMTS 13 deficiency Endothelial dysfunction, impaired placental angiogenesis Possibly a severe form of preeclampsia Mitochondrial dysfunction due to accumulation of long-chain fatty acids Complement-mediated thrombotic microangiopathy
 Clinical presentation Usually, healthy Usually, healthy Sick Varies Sick Sick Sick
 Incidence in thrombocytopenia 75% 1%–4% Rare 15%–22% <1% Rare Rare
 Hypertension −/+ ++/+++ ++ −/+ ++
 Proteinuria Hematuria +++ +++ +/− ++++
 Jaundice + ++
 Fever +/− −/+ +/−
 Hypoglycemia ++
 Neurologic symptoms ++ +/− +/− +/− −/+
 Impaired renal function + −/+ + ++ +++
 Hemolytic anemia ++ Schistocytes Less common + Less common +
 Platelet count (/μL) >100,000 Varies <20,000 Usually, >60,000 >20,000 >50,000 >20,000
 Elevated transaminases −/+ +/++ +++ ++++ −/+
 PT/PTT/INR NL NL NL/slightly − Usually, NL NL/slightly/− ­
 Fibrinogen NL NL NL NL NL/decrease
 Haptoglobin NL NL Markedly − NL/slightly/− NL/slightly/− NL
 ADAMTS13 activity NL NL + Markedly − NL NL NL
 Treatment modality No treatment needed IVIG, Early plasma exchange, Magnesium, Prompt delivery, Prompt delivery, Early plasma exchange,
Steroid, Steroid, Antihypertensive, Transfusion if indicated Supportive treatment, Hemodialysis,
Limit platelet transfusion Immunosuppression, Transfusion if indicated Transfusion if indicated Eculizumab Ravulizumab,
Platelet transfusion is contraindicated Transfusion if indicated
*This table presents the differential diagnosis of thrombocytopenia in pregnancy. It lists presenting symptoms, common manifestations, likely laboratory results, and hallmark treatment options for each condition.
AFLP: acute fatty liver of pregnancy; aHUS: atypical hemolytic uremic syndrome; HELLP: hemolytic anemia, elevated liver enzymes and low platelet; ITP: idiopathic thrombocytopenia; IVIG: intravenous immunoglobulins; NL: normal; PT/PTT/INR: prothrombin time/partial thromboplastin time/international normalized ratio; TTP: thrombotic thrombocytopenic purpura; −: Negative.

Differentiating between TTP and preeclampsia is supremely important (Table 1) because the treatment will be different. Our patient had only mildly elevated blood pressure, and normal liver transaminase serum levels, which made preeclampsia less likely.

The involvement of the obstetric anesthesiologists before proceeding to cesarean delivery ignited a multidisciplinary discussion, which led to further testing and reconsideration of a previous working diagnosis of preeclampsia. Prompt response, involvement of the hematology service, and initiation of therapy secured a favorable outcome to this parturient, albeit without changing the natural history for her fetus; however, cesarean delivery in the setting of a PC is 14,000/μL can be highly dangerous for the mother.

It is extremely important for the obstetric anesthesiologist to be involved in the holistic care of the parturient; they must be intimately familiar with the differential diagnosis and treatment. Signs of end-organ ischemia, extremely low PC, and rapid decline in PC must be recognized. There is significant overlap between TTP and preeclampsia; however, treatment modalities differ significantly (Table 1). In TTP, platelet transfusion is contraindicated, and immune modulation for acquired TTP, as well as plasma therapy, must be promptly initiated.

Importantly in our case, these hallmark signs were recognized early during evaluation by obstetric anesthesiologists and a multidisciplinary team was formed, including maternal fetal medicine, hematology, and intensive care unit. This further highlights the improved outcomes in tertiary centers with multidisciplinary care. Early intervention was likely lifesaving.

Funding

None.

Conflicts of Interest

None.

Editor Note

Yunping Li is an editorial board member of Maternal-Fetal Medicine. The article was subject to the journal’s standard procedures, with peer review handled independently of this editor and their research groups.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

References

1. Cines DB, Levine LD. Thrombocytopenia in pregnancy. Blood 2017;130(21):2271–2277. doi:10.1182/blood-2017-05-781971.
2. Bauer ME, Arendt K, Beilin Y, et al. The Society for Obstetric Anesthesia and Perinatology interdisciplinary consensus statement on neuraxial procedures in obstetric patients with thrombocytopenia. Anesth Analg 2021;132(6):1531–1544. doi:10.1213/ANE.0000000000005355.
3. Kremer Hovinga JA, Coppo P, Lämmle B, et al. Thrombotic thrombocytopenic purpura. Nat Rev Dis Primers 2017;3:17020. doi:10.1038/nrdp.2017.20.
4. Joly BS, Coppo P, Veyradier A. An update on pathogenesis and diagnosis of thrombotic thrombocytopenic purpura. Expert Rev Hematol 2019;12(6):383–395. doi:10.1080/17474086.2019.1611423.
5. Lisonkova S, Joseph KS. Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease. Am J Obstet Gynecol 2013;209(6):544.e1–544.e12. doi:10.1016/j.ajog.2013.08.019.
6. Gupta M, Feinberg BB, Burwick RM. Thrombotic microangiopathies of pregnancy: differential diagnosis. Pregnancy Hypertens 2018;12:29–34. doi:10.1016/j.preghy.2018.02.007.
Keywords:

Thrombocytopenia; Pregnancy; Plasma exchange; Preeclampsia; Fetal death; von Willebrand factor; Purpura, thrombocytopenic, idiopathic; HELLP syndrome

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