Joshi A*, Gupta AS**.
(* Senior Resident ** Professor. Department of Obstetrics and Gynecology, Seth G S Medical College and K E M Hospital, Mumbai, India.)
Essential thrombocythemia (also known as essential thrombocytosis) is a rare blood disorder characterized by excessive production of platelets by megakaryocytes of the bone marrow. Management of pregnancy in such patients is a challenge and needs a multidisciplinary team approach with a hematologist. Here we present a case of a patient incidentally diagnosed of this condition in her second pregnancy.
Essential thrombocythemia is a form of chronic myeloproliferative disorder. The annual incidence of cases reported worldwide varies between 0.59 to 2.53 per 1,00,000 individuals. It is predominantly a disorder of the older age with a median occurrence around 65-70 years. However, with the advent of automated platelet counting the disease has been diagnosed in asymptomatic middle age group patients with a preponderance noted in the female population.
A 25 year old, G2P1L1 with previous lower segment cesarean section, a known case of essential thrombocytosis registered for antenatal care in our hospital at 20 weeks of gestation. She had registered previously at 3 months of gestation in a private hospital. On routine investigations, her platelet count was found to be elevated (11 lac/cubic mm) while hemoglobin and white blood cell count was normal. She had no complaints and there was no significant medical illness in the past. She was referred for a hematology opinion. She visited a private hematology consultant who advised iron studies, vitamin B12 levels, LDH, ANA, hemoglobin electrophoresis, erythropoietin levels and genetic studies (JAK2, CALR and MPL mutations). On evaluation, her ANA levels were found to be weakly positive, rest all tests were normal and the gene mutations were all negative. She was started prophylactically on 75 mg aspirin daily.
She then registered at our institute and had regular follow up visits with our institutional hematologist. On reviewing her reports, a provisional diagnosis of essential thrombocytosis was made. She was advised to undergo a bone marrow aspiration to confirm the diagnosis and the plan was to start on low molecular weight heparin and interferon if the result came positive. Bone marrow aspiration biopsy revealed a normocellular bone marrow with increase in erythroid as well as megakaryocytic series. Final impression was essential thrombocythemia. She was started on injection LMWH 0.4 ml subcutaneous once a day, interferon alpha 3 million units twice a week subcutaneous to be continued throughout pregnancy. Aspirin was to be continued throughout pregnancy and routine follow up with monthly complete hemogram reports was advised. Her hemogram reports showed a gradual decline in the platelet count on treatment from 11 lacs/cc to 8 lacs/cc, 6 lacs/cc and finally 4 lacs/cc in labor. She had regular antenatal follow up. On routine blood investigations she was diagnosed to be hypothyroid and treatment was started for the same. Rest all investigations were normal. Her antenatal course was uneventful.
She had a previous LSCS done 3 years back in view of failure of induction. In this pregnancy she was willing for a vaginal birth after cesarean section. Hence, the plan of action for her was to await for spontaneous onset of labor till term. Injection LMWH was to be stopped 12 hours prior to delivery and it was to be restarted 12 hours after delivery.
She came in labor at 40 weeks. On examination her general condition was fair, she was afebrile, had a pulse rate of 88 beats/ min, and blood pressure was 110/70 mm of Hg. Cardiovascular and respiratory system examination was within normal limit. On per abdomen examination uterus was full term, Vertex in left occipito anterior position was 3/5th palpable, fetal heart rate was 144 bpm and uterine activity was 1/10/10-15. On per vaginal examination os was 2.5 cm dilated, 40% effaced, station -1, membranes present and show was present. Her night dose of LMWH was omitted. She progressed spontaneously and had an uneventful vaginal delivery. She delivered a male child of 2.56 kg. Her postnatal course was uneventful. LMWH was restarted 24 hours post-delivery. A hematology review was taken postpartum and she was advised to continue LMWH for 6 weeks postpartum and to continue aspirin and interferon treatment lifelong.
Essential thrombocythemia is a rare variety of myeloproliferative blood disorder. The diagnosis is confirmed when other secondary causes of thrombocythemia are excluded. The modified criteria by British Committee for Standards of Hematology suggest the presence of the following criteria:
A sustained platelet count ≥ 450,000/ microliter.
Presence of acquired pathogenic mutations (like JAK2, MPL)
No other myeloid malignancies (like polycythemia vera, primary myeloproliferative fibrosis)
No reactive cause for thrombocytosis with normal iron stores.
Bone marrow aspirate biopsy showing increased megakaryocyte numbers associated with predominant large megakaryocytes with hyper-lobulated nuclei and abundant cytoplasm.
The presence of 1+2 or 1+3,4,5 is required to diagnose the patient as a case of essential thrombocytosis. The association of this condition with pregnancy poses an increased risk of thrombosis and hemorrhage.
The clinical presentation of the patient may vary from vague common symptoms to serious potentially life-threatening manifestations. Generalized headaches, paresthesia, fatigue, easy bruising and bleeding tendencies are some of the common symptoms. However, some patients may have major thrombotic events in the form of stroke, transient ischemic attacks, infarction and pulmonary embolism or major hemorrhagic complications in terms of severe bleeding episodes.
Abruptio placenta, intrauterine fetal death and preterm labor are the commonest complications encountered with this condition. These are predominately seen in the later half of pregnancy. Thromboembolic complications were more common than hemorrhagic complications. Also, fetal complications were encountered more frequently than maternal complications. These include pregnancy loss (abortion, stillbirth) and intrauterine growth restriction. First trimester pregnancy loss was noted to be more common. The live birth rate noted by Brière et al was merely 50-57%. The increased platelet count can cause micro-infarctions in the placental bed and lead to activation of platelet function which is largely responsible for the adverse fetal effects. Hemorrhagic manifestations are few and occur primarily due to proteolytic reduction of the von Willebrand Factor (vWF) multimers which results in a state of acquired von Willebrand disorder leading to bleeding tendencies. The vWF is a protein required for platelet adhesion and effective coagulation. Hemorrhage occurs rarely and especially in patients with very high platelet count, hence the need for cytoreduction. 
Most of the patients are incidentally diagnosed on a routine laboratory investigation. This can be attributed to the indolent course of the disease. Investigations mainly deal with ruling out conditions that can lead to secondary thrombocytosis, these include chronic inflammatory conditions, infections, iron deficiency anemia, protracted bone marrow disorders and malignancy. An evaluation of genetic mutations especially JAK2, CALR and MPL is also done. The presence of a genetic mutation is seen in almost 60% of the cases, JAK-2 being the commonest one forming almost 50% of those cases. Studies have shown a better pregnancy outcome for patients with CALR mutations as compared to JAK2 mutations. Being a somatic mutation, newborns are generally not tested for this gene. However, for patients with a positive family history of hereditary thrombocytosis, a genetic mutation testing maybe carried out for the offspring.
The main goal of treatment is to avoid thrombotic or hemorrhagic complications. Hence, the aim of the therapy is cytoreduction. Interferon alpha is an antiproliferative agent which inhibits the progenitor cells of megakaroytes in the bone marrow, thereby decreasing the platelet count in the peripheral blood. Multiple studies have demonstrated that the drug is effective in as many as 90% of the patients. Although interferon alpha is FDA category C drug, it is the cytoreductive agent of choice since other drugs like hydroxyurea are teratogenic. Its pegylated formulation is an emerging choice due to its longer half-life. However, owing to the limited data on safety profile of the pegylated formulation, it is not yet preferred in pregnancy.
The increased thrombotic tendency in these patients leads to repeated placental infarcts and chorionic villi fibrosis thereby increasing the tendency for abortions. Here the role of acetylsalicyclic acid (ASA) and low molecular weight heparin (LMWH) is of utmost importance. Low dose ASA acts by selectively decreasing the thromboxane A2 levels which in turn decreases the rate of placental infarcts, leading to a positive pregnancy outcome. A study by Grieshammer et al showed a live birth rate of almost 68% in patients treated with ASA proving the beneficial role of this drug.
The routine use of LMWH in all cases is controversial since the average risk of venous thromboembolism (VTE) in antenatal period is only 1-3%. However, for patients with a past history of VTE or DVT, antenatal prophylaxis with heparin is a must. In other cases, LMWH can act as a prophylactic measure to counteract the enhanced coagulation status of pregnancy. There have been no randomized controlled trials by far to determine the adjunct role of LMWH in these patients. These lack of controlled studies makes it difficult to define a standard form of therapy.
Patients of essential thrombocythemia with pregnancy need multi modal management. Strict vigilance of clinical and laboratory parameters throughout pregnancy is vital. Improved diagnostic methods and discovery of newer medications has led to better pregnancy outcomes over the past decade.
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Joshi A, Gupta AS. Pregnancy Complicated By Essential Thrombocythemia: Risks And Challenges. JPGO 2018. Volume 5 No.10. Available from: http://www.jpgo.org/2018/10/pregnancy-complicated-by-essential.html