Patients diagnosed with MPN in their youth pose particular management problems over and above those faced by older patients. These include the potential for enhanced risk of long-term treatment toxicity, as well as management of fertility and pregnancy, including consideration of potential heritability of the disease. An inherited tendency to develop MPN was previously assumed to be uncommon. However, during the 1990s, studies of large kindreds with an apparent predisposition to an MPN phenotype (i.e., thrombocytosis) allowed the identification of mutations in 5′ untranslated [10] region of the thrombopoietin (TPO) gene and in cMpl, the cognate receptor for TPO [11]. Interest in a potential genetic predisposition to MPN was rekindled following the discovery of the JAK2V617F mutation in 2005, as previously described. However, this mutation has not been reported in constitutional DNA, and families have been reported in which members affected with MPN are discordant for the JAK2V617F mutation. In addition, epidemiological studies indicate that inherited factors may predispose to the development of many MPNs. The largest study assessed the risk of MPN in 24,577 first-degree relatives of 11,039 MPN patients in Sweden. The results suggest that these relatives have a significantly increased risk of developing an MPN. For example, a first-degree relative of a subject with PV has a relative risk (RR) of 5.7 (95 % confidence interval 3.5–9.1); for ET, the RR is 7.4 (3.7–14.8). For all of these cases, there was no evidence of anticipation of the age at presentation [12]. In Spring 2009, three papers appeared in the same edition of the journal Nature Genetics describing a common haplotype (single-nucleotide polymorphism) designated 46/1 conferring susceptibility to JAK2V617F-positive MPNs [13–15]. The exact mechanism of this predisposition remains uncertain, but one hypothesis suggests the “fertile ground” idea, that is, that the presence of 46/1 increases the probability of the V617F mutation occurring downstream. Despite this evidence of genetic susceptibility, routine testing of the offspring of MPN patients would not at present be recommended.

Patients with MPN are generally treated according to an assessment of their risk of thrombotic or hemorrhagic potential (Fig. 18.2). Agents such as low-dose aspirin (LDA), hydroxycarbamide, anagrelide, or interferon alpha are used to reduce the risk of thrombotic events; patients with PV may require venesection and aspirin, either alone or in addition to the cytoreductive agents listed. LDA and low molecular weight heparin (LMWH) are variably used in pregnancy, which is clearly a time of transient increased thrombotic risk. However, of the cytoreductive agents, only interferon alpha would generally be recommended for the management of high-risk patients in pregnancy. Hydroxycarbamide and anagrelide both have potential to harm the fetus [16] and should ideally be stopped prior to conception (see below); for male patients wishing to father a child, both anagrelide and interferon are appropriate, but hydroxycarbamide should be stopped for 3 months prior to trying to conceive and substituted with another agent where appropriate. There is increasing interest in the utility of a pegylated interferon as a better-tolerated agent with the potential to induce complete remission at a clinical and molecular level in a cohort of patients [17]. However, the safety of this agent in pregnancy has yet to be established. JAK2 inhibitors are currently the subject of clinical trials, largely in patients with PMF, and are not yet licensed or considered standard of care. Only a very small proportion of patients with MPN will undergo bone marrow transplantation when the severity of their disease merits this high-risk approach; the management of fertility and pregnancy in this cohort of patients is beyond the scope of this text.

The development of long-term complications of ET and PV, such as transformation to acute leukemia and the more aggressive disorder myelofibrosis, appears to be dependent upon time. These complications are an inherent tendency of these conditions, possibly related to genetic instability that has been described in association with the JAK2V617F mutation. Leukemic transformation may also be related to the use of drugs such as alkylating agents. However, current therapeutic options are not thought to significantly increase the risk of leukemic transformation although there is ongoing debate with regard to the leukemogenic potential of hydroxycarbamide [9]. Whether treatment strategies can influence the risk of myelofibrotic transformation is currently the subject of debate. Pregnancy does not affect the risk of either leukemic or myelofibrotic transformation.

ET is the commonest MPN in women of child-bearing age, and a significant number of pregnancies have been described in the literature, but these data do not enable confident management guidelines to be drawn up. A number of factors have variably been used to identify high-risk pregnancies in patients with MPN, and these are shown in Table 18.2. Analysis of pregnancy outcomes in women with ET suggests that the presence of JAK2V617F may increase the risk of pregnancy loss [18]. However, the strength of this association is not sufficient to recommend adjusting management strategy on this basis. It should be noted that thrombophilia screening, unless in specific situations (e.g., a strong personal or family history of thrombotic events), does not contribute to risk assessment for pregnancy in MPNs. The current literature for pregnancy outcome in MPN is relatively sparse, and it is important to recognize that it is likely to be subject to reporting bias; the details are summarized as follows: