The Patient

A 22-year-old woman is referred for persistent elevated platelet count. She is well and her past history is negative. Physical examination is notable for splenomegaly (palpable 2 cm below the costal arch). Current CBC shows platelet count of 900,000/μl with normal hematocrit and WBC count. The diagnostic workup, including bone marrow histology, was consistent with JAK2V617F mutated essential thrombocythemia (ET). Counseling for pregnancy planning is also requested.

Risk Stratification

Age (patients older than 60) and a history of previous thrombotic event(s) are the most important predictors of thrombosis in patients with ET, whereas a clear association between platelet count and thrombotic events has never been demonstrated. Paradoxically, a very high platelet count (>1500 x 109/L) is a risk factor for bleeding rather than thrombosis, probably due to the impairment of von Willebrand factor multimerization found both in patients with ET and in those with reactive thrombocytosis. Recently, leukocytosis and the presence of the V617F JAK2 mutation have been recognized as risk factors for thrombosis. Remarkably, JAK2 mutation is associated with increased leukocyte and platelet activation, platelet-leukocyte interactions, and expression of tissue factor and fibrinogen on leukocyte surfaces. These alterations might play a role in the pathogenesis of thrombosis in ET, but further studies are required to ascertain whether such findings should modify the risk classification of patients. To date, a young, asymptomatic woman should be considered “low-risk,” irrespective of her platelet and leukocyte count or JAK2 mutational status.

Management of “Low-Risk” Patients

Avoiding cytoreduction is generally recommended for low-risk ET patients. The natural history of these patients left untreated was prospectively evaluated in a controlled study that compared 65 patients fulfilling the criteria for low risk for thrombosis and 65 age- and sex-matched normal controls. After a median follow-up of 4.1 years, the incidence of thrombosis was similar in both groups (1.91 percent vs 1.5 percent per patient-year) and no major bleeding was observed. Thrombotic deaths are rare in low-risk ET patients, and there are no data indicating that fatalities can be prevented by starting cytoreductive drugs early. Therefore, withholding chemotherapy is justifiable in young, asymptomatic individuals with a platelet count below 1500 x 109. If cardiovascular risk factors together with ET are identified (e.g., smoking, obesity, hypertension, hyperlipidemia, diabetes, and other thrombophilic factors), specific management of such situations is recommended. Aspirin at doses ranging from 30 to 500 mg/day has been found to control microvascular symptoms, such as erythromelalgia and transient neurological and ocular disturbances including dysarthria, scintillating scotoma, amaurosis fugax, migraine, and seizure. However, the benefit of low-dose aspirin (100 mg daily) as primary prophylaxis of vascular events in asymptomatic individuals has not been demonstrated by appropriate clinical trials.

Pregnancy in ET

Pregnancy is a challenging event in young women with ET. No controlled studies addressing the management of pregnancy in ET have been published, and current recommendations are based on pooled data from small cohort studies and clinical expertise. In the literature, about 400 pregnancies in about 200 women are reported. First-trimester abortion is the most frequent complication, occurring in about one-third of pregnancies. Interestingly, the incidence of maternal complications is relatively low: 3 percent for major thromboembolic and 2 percent for major bleeding events. The presence of the JAK2V617F mutation seems to be an independent predictor of pregnancy complications. Pregnancies in ET should be stratified according to underlying risk factors in low-, high-, and highest-risk pregnancies. Risk factors include: previous major thrombotic or bleeding complications, previous severe pregnancy complications (>3 first-trimester or >1 second- or third-trimester losses, birth weight <5th percentile of gestation, preeclampsia, intrauterine death, or stillbirth), and platelet count >1500 x 109/L. Women with low-risk pregnancies are treated with low-dose aspirin, whereas women with high- and higher-risk pregnancies may benefit from low-dose aspirin plus interferon alpha ± low-molecular-weight heparin throughout pregnancy and for at least six weeks post-partum. Although interferon alpha does not appear to cross the placenta, it is probably excreted in breast milk and thus breast-feeding is contraindicated. Anagrelide and hydroxyurea should be avoided in pregnancy due to the risk of teratogenic effects, though successful pregnancy outcomes have been reported.

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