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Mingot-Castellano, M.E.; Canaro Hirnyk, M.; Sánchez-González, B.; Álvarez-Román, M.T.; Bárez-García, A.; Bernardo-Gutiérrez, �.; Bernat-Pablo, S.; Bolaños-Calderón, E.; Butta-Coll, N.; Caballero-Navarro, G.; et al. Clinical Approach to Immune Thrombocytopenia. Encyclopedia. Available online: https://encyclopedia.pub/entry/50914 (accessed on 01 August 2024).
Mingot-Castellano ME, Canaro Hirnyk M, Sánchez-González B, Álvarez-Román MT, Bárez-García A, Bernardo-Gutiérrez �, et al. Clinical Approach to Immune Thrombocytopenia. Encyclopedia. Available at: https://encyclopedia.pub/entry/50914. Accessed August 01, 2024.
Mingot-Castellano, María Eva, Mariana Canaro Hirnyk, Blanca Sánchez-González, María Teresa Álvarez-Román, Abelardo Bárez-García, Ángel Bernardo-Gutiérrez, Silvia Bernat-Pablo, Estefanía Bolaños-Calderón, Nora Butta-Coll, Gonzalo Caballero-Navarro, et al. "Clinical Approach to Immune Thrombocytopenia" Encyclopedia, https://encyclopedia.pub/entry/50914 (accessed August 01, 2024).
Mingot-Castellano, M.E., Canaro Hirnyk, M., Sánchez-González, B., Álvarez-Román, M.T., Bárez-García, A., Bernardo-Gutiérrez, �., Bernat-Pablo, S., Bolaños-Calderón, E., Butta-Coll, N., Caballero-Navarro, G., Caparrós-Miranda, I.S., Entrena-Ureña, L., Fernández-Fuertes, L.F., García-Frade, L.J., Gómez Del Castillo, M.D.C., González-López, T.J., Grande-García, C., Guinea De Castro, J.M., Jarque-Ramos, I., ...Pascual-Izquierdo, C. (2023, October 30). Clinical Approach to Immune Thrombocytopenia. In Encyclopedia. https://encyclopedia.pub/entry/50914
Mingot-Castellano, María Eva, et al. "Clinical Approach to Immune Thrombocytopenia." Encyclopedia. Web. 30 October, 2023.
Clinical Approach to Immune Thrombocytopenia
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This entry is adapted from the peer-reviewed paper 10.3390/jcm12206422

Primary immune thrombocytopenia (ITP) is a complex autoimmune disease whose hallmark is a deregulation of cellular and humoral immunity leading to increased destruction and reduced production of platelets. The heterogeneity of presentation and clinical course hampers personalized approaches for diagnosis and management.

primary immune thrombocytopenia glucocorticoids intravenous immunoglobulins

1. Introduction

1.1. Definition and Epidemiology

Primary ITP is defined as a platelet count < 100 × 109/L whose cause has not been identified. The concept of “secondary ITP” arises from scenarios where low platelet counts are subsequent to diagnosed diseases known to cause immune destruction of platelets. The incidence of primary ITP is two to four cases per 100,000 individuals per year, in both adults and children. The prevalence is higher in adults (10 per 100,000 vs. 5 per 100,000 individuals in children) because the rate of chronicity is greater in this population [1].

1.2. Diagnosis

Despite the important advances achieved in the therapeutic field in the last decade, there has been little progress in the diagnosis of the disease, and reliable markers or confirmatory tests are lacking. Diagnosis continues to be essentially clinical and based on excluding other causes of thrombocytopenia. When a patient is suspected of primary ITP, once the clinical history, physical examination, peripheral blood smear, immunoglobulin level and viral serology have allowed us to rule out other processes, the general rule consists of limiting tests to a minimum, since most of them will not be very informative. The paradigmatic laboratory finding is isolated thrombocytopenia, and careful examination of the peripheral blood smear is mandatory. In primary ITP patients, platelets are usually large and granular, with elevated mean platelet volumes and immature fractions. The systematic analysis of bone marrow is not recommended, except in the event that treatment response is inadequate, or when other abnormalities in the peripheral blood smear or the clinical presentation lead us to suspect other disorders. These limitations may result in an incorrect diagnosis in one out of seven patients identified as having primary ITP [2]. Further measures to overcome this challenge are required.

1.3. Etiology

There are many pathophysiological mechanisms that play a causal role in primary ITP, which explains the heterogeneity of the disease. Nevertheless, the consequences are basically of two types. On the one hand, there is an increase in platelet destruction, which is mainly, but not solely, caused by the onset of autoantibodies able to opsonize the cell surface for the subsequent complement- or phagocyte-mediated cell killing. The increased rate of platelet desialylation, which accelerates liver clearance, and a greater apoptosis rate also contribute to the low counts. On the other hand, platelet turnover decreases because of a lower rate of cell production. This is owing to autoantibodies targeting the thrombopoietin (TPO) receptor and preventing TPO from stimulating the proliferation and differentiation of megakaryocytes, as well as an apoptotic imbalance concerning these cells [3].
The autoantibodies identified in patients with primary ITP can bind a large variety of targets that are frequently located at the platelet surface, for instance, glycoproteins (GP) GPIIb/IIIa or GPIb/IX. Bleeding manifestations are not the only symptoms of primary ITP. Fatigue is also frequently found, and some patients are predisposed to experience thromboembolic events, infection or other autoimmune diseases. Primary ITP shows a self-limiting course in the majority of children and in one-third of adults. According to the standardized terminology [4], the disease can be defined according to the time elapsed since diagnosis: (i) “newly diagnosed primary ITP” encompasses all cases at diagnosis; (ii) “persistent primary ITP” refers to the period lasting between 3 and 12 months from diagnosis and (iii) “chronic primary ITP” is the term reserved for patients with primary ITP lasting for more than 12 months.

2. Follow-Up of Patients with Primary ITP—Scenarios and Recommendations

The fact that the diagnosis of primary ITP is performed by exclusion may lead to situations where the definitive diagnosis has not been made before the initiation of treatment. Patients should be closely followed up by experienced practitioners, with the aim to rule out other diseases responsible for the symptoms attributed to primary ITP, and to control the subsequent onset of other disorders, especially when patients have persistent or chronic primary ITP, or are elderly. Furthermore, follow-up is required for the early identification of thrombocytopenia-derived complications and side effects of treatments.

2.1. Hospitalization

The hospital admittance criteria for primary ITP patients are as follows [1]:
  • Grade 2 hemorrhage according to the World Health Organization (WHO), and platelets < 30 × 109/L.
  • Grade ≥3 hemorrhage (requires red blood cell transfusion), regardless of platelet counts.
  • Adults who are newly diagnosed with primary ITP and present with platelet counts < 20 × 109/L, even if they are asymptomatic or present with minor mucocutaneous hemorrhage. This decision is supported by the following arguments: possible uncertainty regarding diagnosis; the requirement to monitor platelet count evolution; possible bleeding complications; and the need to guarantee that treatment is administered correctly.
  • The following patient profiles could also benefit from hospitalization:
    ○
    Those refractory to treatment.
    ○
    Those whose diagnosis is not reliable enough.
    ○
    Those presenting with relevant comorbidities.
    ○
    Those using concomitant medication are associated with high hemorrhagic risk.
    ○
    Those presenting with significant mucosal bleeding.
    ○
    Those either with low social support, living far away from the hospital or whose follow-up cannot be guaranteed.
Those adult patients with newly diagnosed primary ITP with platelet counts > 20 × 109/L who either are asymptomatic or present with minor mucocutaneous bleeding are recommended to receive ambulatory treatment instead of hospitalization.

2.2. Follow-Up of Diseases Frequently Associated with Primary ITP

During follow-up, close monitoring for early detection of diseases classically overrepresented in primary ITP patients is advisable. The prevalence of diabetes, renal failure, hypertension, vascular disease and thyroid disease is 2–2.5-fold higher than that of the normal population, the prevalence of other autoimmune diseases is 5-fold higher and that of hematological malignancies is up to 6–20-fold higher.

2.3. Surgery

The optimal platelet count target to avoid surgery-associated risk is still controversial. As a general rule, it is accepted that presurgical treatment is required when platelet counts are <50 × 109/L, while it would not be needed with counts > 100 × 109/L [5]. Nevertheless, these values not only are merely indicative, but they are not directly applicable to primary ITP either, since bleeding manifestations are less frequent in patients with this condition than in patients with other thrombocytopenias [6]. For minor procedures with a standard bleeding risk, platelet counts > 50 × 109/L are recommended, which should increase to >70–100 × 109/L to undergo major surgery or procedures on the central nervous system.
In emergency situations, the approach must be the same as that followed in the scenario of severe bleeding, i.e., one or more of these actions should be taken: administration of IVIg; administration of corticosteroids, preferably dexamethasone to take advantage of its rapid-acting profile; and platelet transfusion, ideally after the aforementioned measures have been applied. TPO-RAs are not the best option when surgery is to be performed shortly since they induce platelet generation in the long term. However, their use could be considered to maintain suitable platelet counts after surgery, especially after complex procedures.
Finally, when surgery is going to be planned, the time spent for an agent to achieve a sufficient platelet count increase must be considered when setting the date of the procedure. There is currently no agent that should definitely be chosen ahead of others for presurgical preparation. The same therapies that are suitable for first- and second-line treatment can be used for presurgical preparation with the same hierarchy [7].

2.4. Suspension of Treatment with TPO-RA

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 × 109/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 × 109/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 × 109/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 × 109/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 × 109/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 × 109/L. This value goes up to >70 × 109/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 × 109/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 × 109/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 × 109/L, they should be monitored daily. With values < 50 × 109/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 × 109/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 × 109/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].

References

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Subjects: Hematology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
María Eva Mingot-Castellano
,
Mariana Canaro Hirnyk
,
Blanca Sánchez-González
,
María Teresa Álvarez-Román
,
Abelardo Bárez-García
,
Ángel Bernardo-Gutiérrez
,
Silvia Bernat-Pablo
,
Estefanía Bolaños-Calderón
,
Nora Butta-Coll
,
Gonzalo Caballero-Navarro
,
Isabel Socorro Caparrós-Miranda
,
Laura Entrena-Ureña
,
Luis Fernando Fernández-Fuertes
,
Luis Javier García-Frade
,
María del Carmen Gómez del Castillo
,
Tomás José González-López
,
Carlos Grande-García
,
José María Guinea de Castro
,
Isidro Jarque-Ramos
,
Reyes Jiménez-Bárcenas
,
Elsa López-Ansoar
,
Daniel Martínez-Carballeira
,
Violeta Martínez-Robles
,
Emilio Monteagudo-Montesinos
,
José Antonio Páramo-Fernández
,
María del Mar Perera-Álvarez
,
Inmaculada Soto-Ortega
,
David Valcárcel-Ferreiras
,
Cristina Pascual-Izquierdo
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Revisions: 2 times (View History)
Update Date: 30 Oct 2023
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