The long-term use of TPO-RA has allowed specialists to report long-lasting responses. This finding, together with the good safety profile associated with these drugs
[8][9], has prompted their continuous use. Another argument to support this measure is the drop in platelet counts to pre-treatment values as early as 2 weeks after treatment suspension, which has been occasionally described
[10]. Nevertheless, cases of long-term remission after treatment withdrawal (so-called sustained remission off-treatment (SROT)) have also been reported
[11][12][13][14], which may be due to immunomodulatory actions performed by this therapeutic group
[12]. This last observation encouraged some practitioners to reduce progressively the TPO-RA dose, and finally to suspend treatment, provided that a drop in the platelet count was not detected. This procedure not only saves costs but also reduces the risk of TPO-RA-associated adverse events
[11]. Normally, candidates for achieving SROT after progressive dose reduction followed by suspension are those who present with stable platelet counts (50–100 × 10
9/L) during a 4–6-month period on TPO-RA treatment, regardless of disease stage
[11][12][14]. Patients must be properly informed about this therapeutic option for them to decide after balancing risks and benefits.
3. Primary ITP in Selected Patient Populations
3.1. Pediatric Patients
Primary ITP is usually self-limiting in children. The highest incidence is reported in 2–8 y.o. patients and a history of a triggering infectious episode is not an infrequent occurrence. The trend to spontaneous remission is observed even after 2 years of evolution. The diagnostic approach is similar to that in adults. Although most pediatric patients with newly diagnosed primary ITP do not present with relevant bleeding symptoms and do not require treatment, it is mandatory that parents and children be aware of the risks associated with a severe or potentially fatal hemorrhage.
Hospitalization is recommended for pediatric patients with active hemorrhage, bleeding risk factors or platelet counts ≤ 20 × 10
9/L. In order to make therapeutic decisions, platelet counts should not be the only factor taken into account. Other variables such as mucocutaneous symptoms, the type of active hemorrhage and bleeding risk factors such as other hemostatic disorders and anticoagulant or antiplatelet drugs, should also be considered on a case-by-case basis. The aim of the treatment should focus on the control of clinically relevant hemorrhages rather than the platelet count recovery. First-line treatments are either corticosteroids, such as prednisone (oral) or methylprednisolone (i.v.), or high-dose IVIg. In the event of no response to the first chosen agent, the alternative one can be tried
[15][16]. TPO-RA can be used as a second-line option
[17][18]. Failure of the first and second treatment lines should prompt not only bone marrow examination but also the consideration of other drugs such as mycophenolate mofetil or rituximab, even though the experience with these agents is limited in children. Splenectomy may be an option in scenarios of life-threatening hemorrhage. Finally, dapsone has been shown to be effective and safe in pediatric ITP patients refractory to steroids and may be another third-line option
[19].
3.2. Elderly Patients
The incidence of primary ITP goes up to 9 per 100,000 individuals per year in >75 y.o. patients
[1]. Nevertheless, the fact that some comorbidities causing thrombocytopenia can lead to an inaccurate diagnosis due to “ITP imitation” must be kept in mind. Furthermore, the incidence of these entities, such as megaloblastic anemias, myelodysplastic syndromes (MDS) or acute leukemias, increases with age. For this reason, differential diagnosis is particularly important. When reasonable doubts arise, bone marrow analysis, including cytogenetic and flow cytometry approaches, is recommended.
Elderly primary ITP patients are at higher risk of bleeding, thromboembolism and infection, and they frequently require antiplatelet and anticoagulant therapies. Platelet counts are the main determinants of bleeding risk and should be maintained at values >30 × 10
9/L in >75 y.o. patients, as well as in those >60 years with concomitant bleeding risk factors
[20][21]. TPO-RAs, IVIg and vinca alkaloids can be considered when a rapid platelet count increase is required
[20].
The therapeutic attitude with elderly ITP patients with no active bleeding consists of the use of corticosteroids for first-line treatment, still at lower doses (prednisone at 0.5 mg/kg/day) and for shorter periods than those used with younger patients
[1][20]. IVIg are indicated in the event of severe thrombocytopenia only (<10 × 10
9/L) or with high bleeding risk
[21]. According to the patient’s comorbidities, dexamethasone at standard doses may be an option. The choice of the second-line treatment should be made on an individual basis, and the patient should participate actively
[1]. The good safety/efficacy profile of TPO-RAs in elderly patients makes them the main second-line therapeutic option
[1][22]. Furthermore, their sustained response rates seem to be comparable to those observed with TPO-RAs in other adult populations
[14][23][24]. Nevertheless, it must be remarked that the risk of thromboembolism associated with these drugs is higher in the elderly since the concomitant presence of several other thromboembolic risk factors is not uncommon
[25]. An alternative option for patients at high thromboembolic risk can be fostamatinib
[26][27]. Rituximab may also be considered, although long-term remissions are scarce, and more associated toxicities have been reported
[1][21]. Finally, immunosuppressants or immunomodulators such as mycophenolate mofetil, cyclosporine, azathioprine, danazol or dapsone may be a valid option for those elderly patients presenting with moderate symptoms since the safety/efficacy profile of these agents is well-known. Nevertheless, many of these drugs require several months to achieve the intended effect
[1][20]. Splenectomy is not recommended in the elderly, except in isolated cases of multirefractory patients, because the procedure is less effective and triggers more bleeding and infectious complications than in other populations.
3.3. Pregnant Patients
When primary ITP is suspected in a pregnant woman, other pregnancy-related causes of thrombocytopenia should be ruled out. In fact, although thrombocytopenia is the second most frequently occurring hematologic disorder in pregnancy, around 80% of cases are of gestational origin. The hallmark of these is a progressive decrease in platelet counts, starting in the mid-second trimester and persisting in the third
[28]. The procedure to diagnose primary ITP in pregnancy requires assessment of blood pressure, urine proteins, hemostatic status and antiphospholipid and antinuclear antibodies (ANAs)
[29].
Severe complications are not frequently found in pregnant women with primary ITP, and neonatal incidence of thrombocytopenia or bleeding events is low. Particularly risky scenarios would be those of patients unable to maintain stable platelet counts > 30 × 10
9/L with standard treatments, or patients with a history of previous pregnancies with severe neonatal thrombocytopenia. Recommended platelet counts to undergo vaginal delivery are >50 × 10
9/L. This value goes up to >70 × 10
9/L in the event that cesarean delivery is required or epidural anesthesia is going to be used. The choice of type of labor will be made according to obstetric criteria only
[30].
Pregnant women with platelets > 30 × 10
9/L do not systematically require treatment. With lower values, the first-line options are glucocorticoids and IVIg. Starting with prednisone is recommended. This should be used at doses of 10–20 mg/day since these are the lowest ones enough to achieve platelet counts in the range of 20–30 × 10
9/L. Dexamethasone should not be used because it may induce adverse events for the fetus, such as oligohydramnios. IVIg has to be administered only in the event of side effects associated with steroids, severe hemorrhage or requirement for particularly rapid platelet count recovery, especially when delivery is close in time
[31]. The usefulness of TPO-RAs as a second-line option has not been established yet, since enough clinical evidence is lacking (only isolated cases and one case series have been reported
[32][33]). The data sheets for these drugs do not include this indication. The use of TPO-RAs during pregnancy should be considered only if the potential benefit to the mother justifies the potential risk to the fetus
[32]. Furthermore, any decision concerning this medication should be made in accordance with the patient’s wishes, once she has been properly informed. If TPO-RAs are finally chosen, it is advisable to avoid them in the first trimester. Rituximab does not seem to be teratogenic. However, it has been associated with prolonged B-cell lymphocytopenia and the requirement to delay vaccination in neonates exposed in utero. For this reason, this agent should not be used within at least 6 months of planned conception
[34]. Fostamatinib has been associated with fetal mortality in animal models
[35].
Azathioprine and cyclosporin could be used without teratogenic risk. Nevertheless, the high rate of preterm birth and intrauterine growth retardation, which is associated with these medications, whose cause is not well-known, has to be kept in mind. Finally, data regarding the safety/efficacy of splenectomy in pregnant patients are limited. If the procedure is finally chosen, it should be performed during the second trimester, keeping in mind that an associated risk of neonatal thrombocytopenia exists
[1].
After labor, platelet counts must be assessed in the neonate. If these are <100 × 10
9/L, they should be monitored daily. With values < 50 × 10
9/L, cranial ultrasound should be performed, and if hemorrhage was detected, IVIg and steroids, preferably prednisone, should be administered at minimal doses and for a short period of time, pursuing a platelet count target of >100 × 10
9/L. There is little evidence about the use of platelet transfusion in this situation, but it could be useful in cases with no clinical improvement. The dose and frequency of transfusion should be adjusted according to platelet count and clinical evolution. In those neonates presenting with other bleeding locations or platelet counts < 30 × 10
9/L, one unique dose of IVIg is recommended in order to achieve rapid response. Finally, those neonates with thrombocytopenia lasting beyond 3 weeks from birth should quit breastfeeding
[1].