Published online Sep 05, 2023.
https://doi.org/10.3346/jkms.2023.38.e318
Case 14: A 37-Year-Old Pregnant Woman With Thrombocytopenia
PRESENTATION OF CASE 14
Dr. Tong Yoon Kim: A 37-year-old woman was admitted to this hospital due to thrombocytopenia.
She was 14 weeks pregnant and had a history of thrombocytopenia in her twenties. She had been diagnosed with hypothyroidism and was on oral levothyroxine medication. She had no known autoimmune diseases or history of ingesting herbal medicines.
On examination, her temperature was 36.5°C, heart rate 83 beats per minute, blood pressure 120/64 mmHg, respiratory rate 18 breaths per minute, and room air-oxygen saturation 100%. She had no other symptoms.
The complete blood count showed thrombocytopenia with a count of 88 × 109/L. Combined anemia with a hemoglobin level of 11.0 g/dL was also noted. Her mean corpuscular volume was 97.2, and there had been an increase in lactate dehydrogenase (LDH, 1,738 U/L). The total bilirubin was 1.05 mg/dL, while serum iron level was 120 mcg/dL. Her total iron binding capacity was 388 mcg/dL, transferrin 333 mg/dL and ferritin level was 15.5 ng/mL. Folate and vitamin B12 levels were within the normal range. The Coombs test was negative for both direct and indirect tests. We evaluated for autoimmune conditions such as antinuclear antibodies; anti-DNA lupus anticoagulant Ab showed negative, and complement C3 and C4 were within normal ranges. Detailed laboratory findings are described in Table 1.
Table 1
Laboratory data of the patients
CLINICAL IMPRESSION
Dr. Youngwoo Jeon: Gestational thrombocytopenia.
ADDITIONAL LABORATORY FINDINGS
Dr. Youngwoo Jeon: Given the absence of other symptoms and the patient’s pregnant state, we did not perform additional computed tomography. We carried out further laboratory investigations to determine the underlying condition. Shall we review these laboratory studies?
Dr. Tong Yoon Kim: In the LDH isoenzyme, the ratio of LDH-1 and LDH-2 was greater than one, suggesting hemolytic anemia. Bone marrow biopsy revealed erythroid hyperplasia without evidence of dysplasia cells. We performed a flow cytometric analysis (FACS) of peripheral blood on red cells and granulocytes. FACS of red cells showed that the population of partially deficient cells (type II) was 65.74% (Fig. 1A). FACSs of granulocytes in paroxysmal nocturnal hemoglobinuria (PNH) using a combination of CD15 and CD24 were the population of complete deficiency cells (type III) were 88.46% (Fig. 1B).
Fig. 1
FACS in PNH cells. FACS of red cells in CD55 and CD59 population of complete deficiency cells (type III) were 7.65%, and the population of partially deficient cells (type II) was 65.74% (A). FACSs of granulocytes in paroxysmal nocturnal hemoglobinuria using a combination of CD15 and CD24 were type III and type II, 88.46% and 3.04%, respectively (B).
FACS = flow cytometric analysis, PE-A = phycoerythrin area, FITC-A = fluorescein isothiocyanate area, SSC-A = side scatter area, UL = upper left, LR = lower right.
DIFFERENTIAL DIAGNOSIS
Dr. Youngwoo Jeon: This 37-year-old woman presented with a history of thrombocytopenia. When hospitalized, she was 14 weeks pregnant with no other symptoms and was admitted for further evaluation. Although mild thrombocytopenia is frequent in pregnant women,1 most of gestational thrombocytopenia are benign conditions. However, critical differential diagnosis exists, and these can be made upon detailed history taking and appropriate additional blood tests such as the FACS for PNH.
Chronic thrombocytopenia
In the differential diagnosis of chronic thrombocytopenia, distinguishing between the severity and other symptoms is key. Clinicians generally focus on the degree of thrombocytopenia, as idiopathic thrombocytopenic purpura is the most common form. However, it’s necessary to identify the etiology and other potential causes of thrombocytopenia. In this case, features of hemolytic anemia such as an elevated LDH level were observed.
We evaluated the Coombs test for autoimmune hemolytic anemia (AIHA) and examined red blood cell morphology to differentiate microangiopathic hemolytic anemia (e.g., thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, and hemolytic uremic syndrome). Further, tests for autoimmune diseases such as systemic lupus erythematosus and anti-phospholipid diseases showed no evidence. In the case of a negative Coombs test, AIHA was ruled out, and we proceeded with a PNH test. We evaluated this through flow cytometry analysis of the glycosylphosphatidylinositol (GPI) anchor protein. Abnormal clones of PNH cells were observed, confirming PNH.
PNH in pregnancy
Dr. Tong Yoon Kim: PNH is a rare disease entity causing thrombocytopenia. Without symptoms such as thrombotic events or hemoglobinuria, PNH is not often considered. However, recognizing PNH is essential due to the availability of prophylactic eculizumab during pregnancy. Without eculizumab, there is an increased risk of fetal or maternal death due to thrombotic events linked to PNH.2 Female patients are typically diagnosed with PNH during pregnancy because of the elevated activity of the complement pathway during this period. In this patient, eculizumab was administered as a weekly intravenous infusion at a dose of 600 mg for 4 weeks, followed by 900 mg every 14 days. No thrombotic events were observed during pregnancy or the postpartum period. No other complications during the delivery occurred and there was no evidence of neonatal complications.
FINAL DIAGNOSIS
Dr. Youngwoo Jeon: PNH.
GENERAL INTRODUCTION OF THE DISEASE MANAGEMENT
Dr. Youngwoo Jeon: PNH is a form of hemolytic anemia resulting from clonal expansion, rendering cells fragile to complement reaction. These abnormal cells originate from a somatic phosphatidylinositol glycan anchor biosynthesis class A (PIGA) mutation. The product of the PIGA gene is responsible for synthesizing GPI anchors, and deficient GPI-anchored proteins cause PNH blood cells to lyse and exacerbate the risk for venous and arterial thrombosis.3
Prior to the introduction of complement inhibitors for PNH, the median survival for patients with PNH was 15 to 20 years, with thrombosis as the leading cause of mortality. With the advent of eculizumab, a monoclonal antibody that blocks terminal complement at C5, the survival rate of patients with PNH now aligns with that of age-matched controls.4 When therapy needs to be initiated, it is recommended to vaccinate the patient against Neisseria due to the vulnerability to infectious diseases associated with complement deficiencies.
In the case of an acute thrombotic event, anticoagulation with heparin or low-molecular-weight heparin is necessary; direct oral anticoagulants should be used with caution as they have not been extensively studied in PNH. Eculizumab or ravulizumab were recommended to be started as soon as possible to prevent further thrombosis.5
Pain without thrombosis may occur due to the abnormal relaxation of smooth muscle for free hemoglobin scavenges nitric oxide. These symptoms can include abdominal or back pain, esophageal spasms, difficulty swallowing food and liquids, and even central nervous symptoms mimicking transient ischemic attack symptoms due to vasoconstriction of vessels. These vascular symptoms often resolve within hours after administration of eculizumab or ravulizumab.
PNH clones often coexist with acquired aplastic anemia (AA).6 For patients who are candidates for allogeneic hematopoietic stem cell transplantation, this procedure has the potential to eradicate both the AA and the PNH clone. Eculizumab is beneficial before the transplant to prevent further pain and thrombosis.7
DISCUSSION
Dr. Youngwoo Jeon: Given the rarity of PNH, it's challenging to routinely test for PNH in all pregnant patients. Under what circumstances should we consider testing for PNH?
Dr. Tong Yoon Kim: Thrombocytopenia, defined as a platelet count < 150 × 109/L, has a prevalence of about 6.6% at the end of pregnancy.1 When thrombocytopenia is associated with anemia, it’s essential to consider the cause of the anemia. A differential diagnosis is required, especially if there are indications of hemolysis. Any Coombs-negative hemolytic anemia or unexplained hemoglobinuria needs to be tested for PNH. Also, PNH is closely related to bone marrow dysfunction, including AA and myelodysplastic syndrome. Cytopenia accompanied by thrombosis, refractory iron deficiency, or cytopenia showing no responsiveness to therapy necessitates PNH testing.
Dr. Youngwoo Jeon: Are there any risks associated with using eculizumab during pregnancy or breastfeeding?
Dr. Tong Yoon Kim: Previously, pregnancy was discouraged for patients with PNH due to risks of maternal and fetal mortality. However, with the prophylactic use of eculizumab, survival outcomes have improved. After 20 weeks of pregnancy, complement activation increases and breakthrough hemolysis is common. More than 50% of patients required increased dosing of eculizumab. It has been reported that eculizumab does not cross the placenta at effective doses and is not excreted in breast milk. For this reason, the prophylactic use of eculizumab until three months post-partum in pregnant women with PNH is recommended. Thus, the benefits outweigh any potential risk of eculizumab in pregnant patients with PNH.
Related questions
Available at https://doi.org/10.3346/jkms.2023.38.e312
Disclosure:The authors have no potential conflicts of interest to disclose.
Author Contributions:
Conceptualization: Kim TY.
Data curation: Kim TY.
Supervision: Jeon Y.
Writing - original draft: Kim TY, Jeon Y.
Writing - review & editing: Lee J.
ACKNOWLEDGMENTS
The Case Conference section is prepared from monthly case conference of Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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