A Postpartum Rebound of Platelet Count in Patient with Type 2 Calreticulin -Mutant Essential Thrombocythemia: A Case Report

Essential thrombocythemia (ET) is an uncommon myeloproliferative neoplasm (MPN). It is more commonly encountered in females; around 20% of them are below 40 years old. The optimal management of ET during pregnancy and after delivery is still not well established. Here, we report a case of a young lady with ET who developed a marked rebound in her platelet count two weeks after delivery. She was on Pegylated Interferon (PEG-IFN) alfa 2-a during pregnancy, but she had stopped it on her own one month before delivery. We resumed her therapy, and subsequently, her platelet count reduced dramatically within four weeks to the acceptable range. This case emphasizes the importance of platelet count follow-up after delivery and outlines the management approach in such cases.


Introduction
Myeloproliferative neoplasms(MPNs), formerly named myeloproliferative disorders, are a group of diseases characterized by the excessive clonal production of red blood cells, platelets, or white blood cells, mainly in the bone marrow and occasionally in the liver and generally classi ed as Philadelphia positive MPNs which is represented by chronic myeloid leukemia (CML) [1]; and Philadelphia negative MPNs mainly ET, polycythemia vera(PV), and idiopathic myelo brosis [2]. Essential thrombocythemia (ET) is an uncommon myeloproliferative neoplasm (MPN) characterized by the overproduction of platelets by bone marrow megakaryocytes [3]. Eventually, it may progress to myelo brosis or acute myeloid leukemia [4].ET is usually sporadic and rarely can be familial [5]. Based on the latest world health organization (WHO) criteria for MPNs, ET is considered as a diagnosis of exclusion ( Table 1 ) ET is more prevalent in females, and approximately 80% of them are above 40 years old. Nonetheless, ET still occurs in women within the reproductive age [7].ET increases the risk of thrombotic and bleeding events[8]. As we know, pregnancy is one of the hypercoagulable states [9]. Accordingly, pregnant women with ET are at high risk for thrombosis and its complications on the mother and fetus [10]. Thus, several guidelines and experts recommend ET management with interferon (IFN) therapy during pregnancy, especially in patients with a high risk for pregnancy termination [11].
Interestingly, many patients with ET may develop a rebound in platelet count during the postpartum course, which increases the risk of thrombosis during this prothrombotic period [11,12]. Herein, we present a case of type 2 CALR -mutant Essential Thrombocythemia, who stopped her regular Pegulated Interferon Alfa-2a dose during pregnancy on her own and developed a marked rebound in her platelet counts during the postpartum period.

Case Presentation
A 30-year-old female was referred to us due to the persistent elevation in her platelet counts. The patient also reported fatiguability and generalized body pain for several weeks. Her past medical and family history was unremarkable. Complete blood count (CBC) revealed a platelet count of 2,030 × 103/μL.
Other relevant laboratory results on presentation are shown below in Table 2. Physical examination was normal with no organomegaly or lymphadenopathy. MPNs, speci cally ET, was suspected, and the workup was initiated to con rm that. The bone marrow biopsy result was consistent with ET. The tests for driver gene mutations were requested, and the patient was positive for a type 2, 5bp insertion mutation within exon 9 of the calreticulin( CALR ) gene. Janus kinase 2 (JAK2V617F) and BCR-ABL1 gene fusion mutations were negative.
The ET diagnosis was con rmed, and the patient started on Pegylated Interferon Alfa-2a at a dose of 135 micrograms weekly. Her platelet counts were controlled for several months after the initiation of therapy.
However, during her second child's pregnancy, the patient stopped taking her weekly dose of Peginterferon Alfa-2a since the 20 th week of gestation without seeking medical advice. After that, she was delivered her child prematurely at the 24 th week of gestation through vaginal delivery. Her baby was intubated and admitted to the neonatal intensive care unit (NICU). Two weeks after delivery, during postnatal follow, the patient was found to have a platelet count exceeded 1.5 million. However, the period after delivery was uneventful.

Discussion
ET remains the most encountered MPN in young women within the reproductive age [13]. As mentioned in the introduction, ET patients who get pregnant are at higher risk for thrombotic complications. It was found that the rate of rst-trimester spontaneous abortions and premature deliveries in ET patients were higher than that in healthy individuals [11]. Additionally, pregnancy complications, like intrauterine growth restriction and placental abruption, are common in pregnant ladies with ET [14]. Treatment of ET during pregnancy has shown a considerable improvement in maternal and fetal outcomes [15]. Interferon-alpha therapy is considered the safest drug of choice for ET treatment during pregnancy [15]. Our patient had stopped her Peginterferon alfa by the end of the rst half of pregnancy. Unfortunately, her platelet counts were increased, and she delivered her baby prematurely at the 24th week of gestation, which may support the relation between ET treatment and pregnancy outcomes.
Janus kinase 2 (JAK2V617F), Myeloproliferative leukemia (MPL), and calreticulin( CALR ) gene mutations have been detected in the vast majority of patients with ET [16]. JAK2(V617F)mutation and MPL gene mutation have been reported in up to 60% and 5% of ET cases, respectively [16].Most of the ET cases which were negative for JAK2 and MPL genetic mutation found to be positive for CALR mutation [16]. However, approximately 10-15% of cases are negative for all three mutated genes "triple-negative" [17]. Calreticulin (CALR) is a calcium-binding protein located abundantly in the endoplasmic reticulum and involved in variable biological functions [18]. CALR regulates the folding process of newly synthesized glycoprotein and contributes to calcium hemostasis [18]. It was recently found that CALR mutation independently activates the thrombopoietin receptor, promoting megakaryocyte proliferation and subsequently the development of ET [19]. There are two main types of CALR gene mutation, A 52-bp deletion (type 1 mutation) and a 5-bp insertion (type 2 mutation) [19]. In ET, type 1 mutation is related to a higher risk of transformation to myelo brosis. Whereas, type 2 variant, which was detected in our patient, is strongly linked to ET with a more indolent disease course, higher platelet counts, and lower risk of thrombosis [19].
Typically, platelet counts decline during pregnancy and eventually return to pre-gestational level within the rst 4-6 weeks after delivery [9]. The mechanism for this phenomenon is not clearly explained [9].
Nonetheless, this decline in platelet counts may play a protective role against thrombosis during pregnancy [9]. As has been mentioned above, many patients with ET develop a rebound in platelet count after delivery. Experts suggest that platelet count should be repeated after six weeks of delivery [15]. Of note, the platelet count's rebound may occur as early as two weeks postpartum, like in our patient and other reported cases [20]. There is still no enough data regarding the rebound management in platelet count during the postpartum period. The cytoreductive medication was initiated in some cases soon after delivery, whereas others were managed conservatively with a spontaneous decline of platelet count [20]. The management should be individualized according to the disease-related factors and risk of thrombosis [20]. We managed our patient by resuming her usual dose of Peginterferon Alfa-2a, resulting in a dramatic response with more than 50% reduction in her platelet count within a short period.

Conclusion
Our patient developed a signi cant rebound in her platelet count during the early postpartum period. She did not develop any thrombotic or bleeding complications during that time. Evidence for management of platelet rebound after delivery is still scarce. We treated our patient successfully with IFN therapy. Accordingly, we highly suggest this therapy, considering its safety pro le and e cacy to lower platelet count, to prevent thrombosis during this prothrombotic period.