Diseases of Platelet Number: Immune Thrombocytopenia, Neonatal Alloimmune Thrombocytopenia, and Posttransfusion Purpura

Epidemiology

The natural history of ITP differs in children and adults. In most children, ITP presents acutely and resolves within several weeks, often not requiring any intervention. Seasonal variability suggests that viral infections may trigger the disease in many children. Conversely, ITP in adults tends to be insidious in onset and is more often characterized by a chronic or remitting and relapsing course.

Pathophysiology

ITP is caused by increased platelet destruction and impaired platelet production, and the principal mechanism is thought to be due to autoantibodies. The antibody hypothesis began with the observation that blood from patients with ITP was able to cause a reduction in the platelet count in healthy volunteers. In one of the first experiments, William Harrington infused blood from ITP patients into normal volunteers and observed a decrease in the platelet counts in most recipients. The circulating factor responsible for this effect was first identified as platelet-associated immunoglobulin G (PAIgG). With the development of more specific assays, it was determined that the antibodies were directed against platelet GPs, specifically GPIIbIIIa and GPIbIX. GP-specific assays for the detection of autoantibodies exhibited improved specificity but had low sensitivity (50% to 66%), meaning that many ITP patients had a negative test and only ITP patients had a positive test. Anti-GP autoantibodies target platelets for destruction in the RES by binding to the Fc-receptor on phagocytic cells, particularly the spleen. Peptides from phagocytosed platelets may be processed and presented to specific T cells, which in turn stimulate B cells to produce additional platelet autoantibodies. This process, known as epitope spreading, may explain why patients have circulating autoantibodies targeting a variety of platelet antigens. Antibody-induced platelet destruction in ITP can also be caused by complement activation and platelet apoptosis.

The low sensitivity of platelet antibody testing (anti-GPIIbIIIa or anti-GPIbIX) may be explained by the presence of autoantibodies against other target proteins (e.g., anti-GPV, which was found in 64.7% of patient samples in one cohort study ), low-avidity platelet antibodies, or the sequestration of autoantibodies in other body compartments. In a study of 18 patients with ITP, 10 (56%) had antiplatelet antibodies detectable in BM aspirate fluid, including 5 patient who did not have detectable circulating antibodies. Similarly, a study of spleen tissue from patients with ITP identified antibody-secreting cells as the major splenic B-cell population in patients who were refractory to rituximab.

In addition to accelerated platelet destruction, platelet production also may be impaired in ITP. Evidence supporting reduced platelet production derives from radiolabeled autologous platelet studies demonstrating normal or reduced platelet turnover and from clinical studies that have consistently demonstrated the capacity of TPO-RAs to increase platelet counts in patients with severe thrombocytopenia. Megakaryocytes also express GP receptors, which render them targets of ITP autoantibodies. Indeed, in vitro studies demonstrated suppression of megakaryocyte growth and maturation when the cells were incubated with IgG from ITP patients.

In addition to the effect of autoantibodies, cytotoxic T cells from ITP patients may have direct cytolytic effects on platelets. Some patients with active ITP but without detectable platelet autoantibodies had CD8 ⁺ T cells that induced platelet lysis in vitro. In contrast, CD8 ⁺ T cells from patients in remission did not show significant platelet reactivity. In another study, despite demonstrating the increased cytotoxic potential of CD8 ⁺ T cells in a sample of patients with ITP, no correlation was found between this cytotoxic potential and the presence or absence of platelet antibodies. Furthermore, compared with cells from controls, CD3 ⁺ cells from ITP patients exhibited increased expression of genes involved in cell-mediated cytotoxicity, including tumor necrosis factor-α (TNF-α), perforin, and granzyme A and B, and CD8 ⁺ T cells exhibited increased expression of FasL (Fas–Fas ligand) and TNF-α.

Another mechanism of thrombocytopenia in ITP is non–FcR-mediated platelet destruction. Platelet autoantibodies have been shown to cause desialylation of platelet GPs, leading to recognition and clearance of platelets in the liver by the Ashwell-Morell receptors. Antibody-mediated desialylation may also impair platelet production.

In the broadest sense, autoimmunity develops because of a breakdown in regulatory checkpoints that occurs during development or maturation of the immune system. Although the precise events that trigger the loss of self-tolerance to platelet GPs are largely unknown, patients with ITP have been shown to exhibit several immune alterations to platelet antigens including dysfunctional cellular immunity because of T helper (Th)0/Th1 polarization, decreased regulatory T-cell function, and autoreactive platelet-specific cytotoxic T cells. In addition, ITP patients may have increased circulating levels of cytokines and soluble factors that promote the survival of self-reactive T and B cells, including B-cell activating factor, a proliferation-inducing ligand, and B-cell lymphoma-2–interacting mediator of cell death. Reduced levels of proapoptotic cytokines that regulate self-reactive T cells, including Fas, interferon-γ, interleukin-2 receptor β (IL2RB), Bax, and caspases 8 and A20, have also been demonstrated.

Primary and Secondary Immune Thrombocytopenia

Primary ITP, previously called idiopathic thrombocytopenic purpura, occurs in the absence of an identifiable cause. Secondary ITP occurs because of an underlying cause such as infection, pregnancy, drugs, or lymphoproliferative disease (see box on Causes of Secondary ITP ).

Infection may stimulate the formation of platelet-reactive autoantibodies. Cross-reactive antibodies (molecular mimicry) have been identified in Helicobacter pylori , human immunodeficiency virus (HIV), and hepatitis C virus (HCV) infections. Regarding H. pylori , a meta-analysis that included 788 patients showed that H. pylori eradication resulted in higher platelet counts in ITP patients compared with untreated or noneradicated controls. Another systematic review evaluating 696 patients reported that 43% of treated patients achieved platelet counts greater than 100 × 10 ⁹ /L; however, the effect was highly dependent on geographic location, with the beneficial effect mainly observed in patients from Japan. There is no clear guidance on when to screen for H. pylori . Guidelines from the American Society for Hematology suggest that screening be considered for patients with ITP for whom eradication therapy would be used. The most recent ITP consensus report recommends testing for H. pylori in adults with typical ITP, in those with digestive symptoms, and those from areas of high prevalence.

ITP also may present in the setting of pregnancy. Mild ITP may be difficult to differentiate from incidental thrombocytopenia of pregnancy, and pregnancy-related vascular disorders, such as preeclampsia, microangiopathy caused by HELLP syndrome (characterized by hemolysis, elevated liver enzymes, and a low platelet count), and acute fatty liver must be excluded. In these pregnancy-related disorders, platelet counts tend to be mildly reduced and hypertension is common. Incidental thrombocytopenia of pregnancy (also called gestational thrombocytopenia ) represents a physiologic change in platelet count that occurs late in pregnancy and is associated with a mild reduction in platelet count, which does not respond to immune-modulating therapy. In contrast, pregnancy-associated ITP may present at any time during pregnancy, and the thrombocytopenia can range from mild to severe. Typically, platelet counts increase with ITP-specific therapies such as IVIg or corticosteroids. Platelet count thresholds for instituting treatment are the same as those for women with ITP who are not pregnant (e.g., platelet count less than 20 × 10 ⁹ /L). Vaginal deliveries are thought to be safe for mothers with ITP, even if the platelet count is very low, and most clinicians try to maintain the count greater than 20 to 30 × 10 ⁹ /L. A higher platelet count is generally recommended for caesarean section delivery (50 × 10 ⁹ /L) and epidural anesthesia (70 to 80 × 10 ⁹ /L). Although evidence is lacking, IVIg and corticosteroids are generally safe in pregnancy, but corticosteroids can be associated with hypertension, gestational diabetes, intrauterine growth restriction, and other pregnancy-associated morbidities. Splenectomy is rarely performed during pregnancy because most women can successfully be managed with less-aggressive treatments. Immunosuppressant medications, such as azathioprine, have been used in pregnancy but should be reserved for refractory pregnancy-associated ITP with bleeding. Rituximab is not recommended during pregnancy, although it is likely to be safe. Rituximab may interfere with fetal and neonatal B-cell development, which may lead to increased susceptibility to infections. TPO-RAs may be considered in exceptional circumstances during pregnancy if other treatments have failed and the risk of severe bleeding is high. For mothers with active ITP or even with ITP that is in remission, there is a 10% risk of thrombocytopenia in the newborn because of passive transfer of maternal antiplatelet autoantibodies.

Clinical and Laboratory Features of Immune Thrombocytopenia

Investigations of Patients With Suspected Immune Thrombocytopenia

Patients presenting with newly identified thrombocytopenia require a careful history and physical examination to uncover the underlying cause of the thrombocytopenia and to assess the risk of bleeding. If splenomegaly is present on physical examination, the thrombocytopenia may be caused by hypersplenism, and imaging is warranted. A panel of laboratory tests are needed to identify possible causes of the thrombocytopenia (see box on Laboratory Basic Evaluation for Patients With Suspected ITP ). A complete blood count and review of the blood film are required to exclude other hematologic conditions, such as hereditary forms of thrombocytopenia (e.g., May-Hegglin) or pseudothrombocytopenia ( Fig. 129.1 ). HIV and HCV testing should be performed in patients with suspected ITP, and H. pylori testing should be considered in patients from certain countries (e.g., Japan). Hepatitis B testing at baseline is reasonable if immunosuppressive treatments such as rituximab are being considered and to exclude the possibility of false-positive anti–hepatitis B core antibody testing after IVIg. There are insufficient data to support routine screening for antinuclear antibodies or antiphospholipid antibodies unless other signs and symptoms of systemic lupus erythematosus or antiphospholipid syndrome are present. BM aspiration and biopsy should be done for patients with abnormalities in other cell lines such as anemia, leukopenia, or macrocytosis; however, most patients with typical ITP do not require BM examination. Quantitative Ig levels may be useful in children to exclude common variable immune deficiency. Thyroid testing can uncover subclinical hypothyroidism or hyperthyroidism that can lead to mild thrombocytopenia. Coagulation tests such as D-dimer, partial thromboplastin time (PTT), and fibrinogen may be helpful in excluding chronic disseminated intravascular coagulation in patients with malignancy (see Chapter 126 ). Antiplatelet antibody tests are rarely used in routine clinical practice.

Prognosis

Treatment

Most patients with platelet counts greater than 30 × 10 ⁹ /L and without bleeding can be managed safely with observation alone. This is especially true for children with ITP who are at low risk of serious bleeding. Furthermore, in up to 80% of cases, childhood ITP resolves within 6 months with no treatment. If patients present with bleeding, such as epistaxis or mucosal hemorrhage, treatment is required. For adults, a period of observation is reasonable if there is no evidence of bleeding and the platelet count is stable and greater than 30 × 10 ⁹ /L, because some patients will have spontaneous remission. The American Society of Hematology (ASH) 2019 guidelines recommend treatment for newly diagnosed ITP patients who are asymptomatic or have minor mucocutaneous bleeding with a platelet count less than 30 × 10 ⁹ /L.

Treatment Options

Corticosteroids with or without IVIg are first-line treatments for patients with newly diagnosed ITP. Treatment options for second-line therapies include rituximab, splenectomy, TPO-RAs, fostamatinib, and immune suppressant medications. We recommend an approach that uses the least toxic treatments with the aim of resolving bleeding or preventing severe bleeding and that aligns with patient preferences to optimize health-related quality of life ( Fig. 129.2 , and see Box on Treatment Options for ITP and box on First-Line Therapy ).