Thrombocytopenia attributable to pure aplasia or hypoplasia of megakaryocytes is rare.79 More common are instances in which amegakaryocytic thrombocytopenia anticipates the development of full-blown MDS or aplastic anemia and is associated with subtle abnormalities of other lineages, such as macrocytosis and dyserythropoiesis.80–84 Most commonly the disorder is caused by autoimmune suppression of megakaryocyte development, either idiopathic,85 associated with autoimmune disorders such as systemic lupus erythematosus (SLE)86 and eosinophilic fasciitis, or associated with infections such as hepatitis C.87 Antibodies against thrombopoietin (TPO)88 have been described to cause the disorder, as have antibodies against the TPO receptor.89 Patients may achieve durable remission with therapies designed to blunt the autoimmune response, such as cyclosporine or antithymocyte globulin (ATG).90
Table 117–3 summarizes the various types of ITP.
Table 117–3.Immune-Mediated Thrombocytopenia ||Download (.pdf) Table 117–3. Immune-Mediated Thrombocytopenia
Primary immune thrombocytopenia
Secondary immune thrombocytopenia
Antiphospholipid syndrome, systemic lupus erythematosus, and other connective tissue disorders
Infections: HIV, hepatitis C virus, hepatitis B virus, Helicobacter pylori, and others
Drugs and chemical substances
Malignancies including lymphoproliferative disorders
Common variable immune deficiency
Alloantibody-mediated thrombocytopenia/platelet destruction
Fetal/neonatal alloimmune thrombocytopenia
Platelet alloimmunization after platelet transfusions
PRIMARY IMMUNE THROMBOCYTOPENIA
ITP, formerly known as autoimmune thrombocytopenic purpura, is the most common cause of isolated thrombocytopenia in clinical practice. ITP is characterized by immune-mediated platelet destruction and impaired platelet production. ITP occurs in every age group. Childhood ITP typically is acute in onset, often developing after a viral infection or vaccination. Although thrombocytopenia may be severe, it usually resolves spontaneously, within a few weeks up to 6 months.91 In contrast to childhood ITP, adult ITP generally is a chronic disease of insidious onset and rarely resolves spontaneously.
“Purpura” was recognized by Hippocrates (c. 460 to c. 370 BC) and Galen (AD 129 to c. 200/c. 216) as a sign associated with fever. Chronic purpura was first described in details by Ibn-i Sina (Avicenna, c. 980 to c. 1037) in his famous book “The Canon of Medicine.” In 1705, Werlof suggested that purpura was related to infections and described it as “morbus maculosus haemorrhagicus.” Patients with purpura were diagnosed as having “Werlof disease” for centuries. After the discovery of platelets and their role in hemostasis, the relationship between purpura and low-platelet count was understood.92
In 1915, Erich Frank renamed this disorder as “essential thrombocytopenia,” and suggested that platelet production from megakaryocytes was impaired because of a toxic substance produced by the spleen.93 Kaznelson, inspired by Frank's theory, proposed splenectomy for a patient with chronic thrombocytopenic purpura. The treatment was successful, and splenectomy was first-line therapy for ITP until the introduction of glucocorticoids in 1950s.
In the first issue of the journal Blood (in 1946) Damashek and Miller reviewed the megakaryocyte count and marrow morphology of patients with “idiopathic thrombocytopenic purpura.”94 They showed that most ITP patients had an increased number of megakaryocytes, but very few of them were producing platelets, so “actual platelet-producing tissue” might be decreased.94
Although Marino first showed that antiplatelet antibodies might cause thrombocytopenia in animal studies in 1905, the Harrington-Hollingsworth experiment (1951) was an important milestone in the understanding of autoantibody-directed platelet destruction in the pathophysiology of ITP. In this pioneering work, normal volunteers (including Harrington himself, who received the highest dose) were infused with the plasma from patients with ITP, resulting in severe thrombocytopenia in the recipients, and they postulated that ITP could be caused by antiplatelet antibodies.95,96 Subsequently, Shulman and coworkers97 showed that the thrombocytopenic effect of ITP plasma was dose-dependent and associated with the globulin fraction. In the 1950s, glucocorticoids began to be used to treat ITP, and they became first-line therapy for adults. Shortly thereafter other immunosuppressive agents were introduced for the treatment of chronic ITP.92
In the early 1970s, two groups showed that platelets from chronic ITP patients had elevated levels of platelet-associated immunoglobulin G (PAIgG).98,99 In 1982, the first platelet target was identified: autoantibodies from patients with ITP failed to bind platelets deficient in the integrin αIIbβ3 complex (i.e., from patients with Glanzmann thrombasthenia).100 In the late 1980s, two specific assays for the target antigens were described: the immunobead assay101 and the monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay.102 These assays showed that the majority of antiplatelet antibodies in patients with ITP are directed against integrin αIIββ3(GPIIβ-IIIα)(approximately 80 percent), and the remainder are against the GPIb-IX-V complex and other platelet GPs such as GPIV and integrin α2β1 (GPIa-IIa).103,104 Some sera contain antibodies that recognize several antigens. Most antiplatelet autoantibodies are IgG; the remainder are IgM and IgA. Unfortunately, elevated levels of PAIgG later were found in patients with non-ITP. Therefore, PAIgG could not be used as a specific laboratory test for ITP in the same way that the direct antiglobulin test is used for the diagnosis of autoimmune hemolytic anemia.105,106 To date there is still no specific laboratory test for ITP, the diagnosis of ITP being based on exclusion of other causes.
Antibody-coated platelets bind tissue macrophages through Fcγ receptors, leading to their destruction primarily in the spleen and, to a lesser extent, in the liver and marrow.97,107,108 In 1981, Imbach reported successful treatment of pediatric ITP with intravenous immunoglobulin (IVIG) and suggested that the mechanism could involve blockade of macrophage Fc receptors. IVIG became first-line therapy in children, and now is also used in adults when a prompt increase is the platelet count is desired.109
Early studies of PAIgG reported that the antibodies in ITP were polyclonal.110 However, later studies showed that at least some ITP patients had clonal B-cell proliferation, as determined by DNA analysis for immunoglobulin heavy- and light-chain rearrangements and by flow cytometry of B cells from blood and spleen for surface Ig light chains.111,112 This led to the use in ITP of the chimeric anti-CD20 monoclonal antibody, rituximab, which was designed for the treatment of CD20-positive B-cell lymphomas. The rapid elimination of B cells with rituximab encouraged the use of this agent in the treatment of ITP.
Numerous abnormalities in cell-mediated immunity have been described in patients with ITP, including abnormalities in antigen-presenting cells, T lymphocytes, and cytokine release. Under normal conditions, antigen-presenting cells recognize and process foreign antigens and express the antigens on their surface in association with major histocompatibility complex (MHC) molecules. MHC–antigen complexes activate resting (naïve) CD4+ T cells to differentiate into a variety of phenotypes such as T-helper 1 (Th1) and T-helper 2 (Th2), Th17, and T-regulatory (Treg) cells. Th1 cells are involved in cell-mediated immunity and host defense against intracellular bacteria and protozoa. Th2 cells are involved in humoral immunity and host defense against extracellular parasites. Th17 cells are involved in host defense against extracellular bacteria and fungi. Treg cells (formerly known as suppressor T cells) play an important role in self-tolerance by inhibiting autoimmune responses. Abnormal T-cell responses drive the differentiation of autoreactive B-cell clones and autoantibody secretion. In patients with ITP, both Th1 and Th17 cells have been found to be upregulated, whereas the number and the suppressor functions of the Treg cells were found to be decreased.113–115 This imbalance is believed to induce an autoimmune responses against the platelets. It is unclear whether these abnormalities are causative or represent an epiphenomenon.114,115 In addition, CD8+ cytotoxic T cells might be involved in the pathogenesis of ITP through cell-mediated destruction of platelets and megakaryocytes and through suppression of megakaryocytes, impairing platelet production.115–117
Antiplatelet autoantibodies may also activate platelet destruction by activating complement through the classical complement pathway. Increased platelet-associated C3, C4, and C9 have been demonstrated on the platelets from patients with ITP.118,119 In vitro studies show that, in the presence of antiplatelet antibodies, C3 and C4 can bind platelets, increase the phagocytosis of the platelets by macrophages, and can cause their lysis by stimulating assembly of the membrane attack complex.120,121
Early studies demonstrated that platelet survival is shortened in ITP patients and returns to normal after splenectomy-induced remission.122 Platelet transfusion only transiently increases a patient's platelet count, and the transfused platelets also have a shortened survival, reflecting the fact that the major problem in ITP is platelet destruction. However, later studies showed that platelet life span was not short enough to account for the observed thrombocytopenia on the basis of destruction alone, again suggesting a concomitant defect in platelet production.123 Potential mechanisms for this observation were provided by later studies that autoantibodies against platelet surface GPs might interfere with the maturation of megakaryocytes, resulting in reduced platelet production, contributing to the severity of thrombocytopenia in some ITP patients.124 Antibodies that target the GPIb–IX–V complex may induce thrombocytopenia by decreasing platelet production, as GPIb autoantibodies inhibit megakaryopoiesis in vitro,124 and GPIb monoclonal antibodies inhibit proplatelet formation in vitro.125
In 1958, a hematopoietic growth factor regulating platelet production was proposed and named TPO by Kelemen.126 Although interleukin (IL)-3, IL-6, IL-11, granulocyte-macrophage colony-stimulating factor, and c-KIT ligand increase megakaryocyte or platelet counts in vivo and in vitro, animal studies of these factors proved that they are not the main regulator of megakaryopoiesis.127 In 1994, TPO was first characterized by five independent groups. TPO binds to its receptor MPL (formerly known as c-MPL), enhances megakaryocyte colony formation, and increases the size, number, and ploidy of megakaryocytes, and platelet production (Chap. 113).128–130 TPO is synthesized in greatest quantity in the liver but is found in other organs (kidney, muscle, and marrow stromal cells).128 TPO is also required to maintain the viability of hematopoietic stem cells.131 The regulation of TPO production is complex. Hepatic production of TPO is both constitutive (in the steady state) and inducible (by inflammation), and the concentration of TPO to which megakaryocytes are exposed is also determined by the platelet concentration. Platelets, bearing TPO receptors, remove the hormone from the circulation, at least partially accounting for the inverse relationship between TPO and platelet levels. TPO levels are markedly elevated in patients with thrombocytopenia associated with megakaryocytic hypoplasia, including disorders such as aplastic anemia or acute leukemia. In most reports, ITP patients have normal or slightly elevated TPO levels whether measured in plasma or serum, but the levels are always lower than the concentrations found in thrombocytopenias resulting from megakaryocytic hypoplasia.128–130,132,133 Initial studies with recombinant and pegylated TPO molecules showed successful responses in patients with thrombocytopenia, but development of autoantibodies against these molecules restricted their use in clinical settings. Based on the success of creating erythropoietin receptor agonist peptides, a number of screening efforts were undertaken to design small peptides or organic molecules that might bind to the TPO receptor and stimulate thrombopoiesis. One such molecule contains four copies of a 14-amino-acid peptide grafted onto an Ig Fc domain, forming a “peptibody” termed romiplostim. This agent, which binds to a region of the TPO receptor that overlaps that bound by authentic TPO, was shown to increase platelet counts in patients with ITP who had failed other modalities,134 and was approved by the FDA for this indication in 2008. Another small organic thrombopoietic molecule, eltrombopag, was developed almost simultaneously135 and approved in 2008 by FDA for the same indications.127 This agent activates TPO receptor signaling by binding to the transmembrane domain of the receptor, a site quite distinct from the binding site for TPO and romiplostim. Both TPO-receptor agonists are currently being evaluated for additional clinical indications in clinical trials.136
Some patients with ITP appear to display a genetic predisposition. ITP has been documented in monozygotic twins137 and shown to be highly prevalent in some families.138 In addition to contributing to the development of ITP, like in other autoimmune disorders heredity may also affect the response to ITP therapy. Human leukocyte antigen (HLA) class I and class II allele frequencies in patients with ITP have been studied by several investigators, with inconsistent results. Some investigators reported an increased frequency of HLA-Aw32, -DRw2, and -DRB1*0410.108,139–141 Investigation has focused on genetic differences associated with dysregulation of immune tolerance and humoral immunity, but results have been inconclusive. For example, genetic polymorphisms of cytotoxic T-lymphocyte antigen (CTLA)-4, tumor necrosis factor, and Fcγ receptors IIA and IIIA have been suggested to influence the development of ITP and the response to therapy,141–143 but as yet no strong association has been found.
Accumulating data indicate that the pathophysiology of ITP is more complex than previously thought, with ITP comprising a heterogenous group of disorders with different etiologies and responding to different treatment modalities. The identification of the different subsets of ITP patients will help to better define treatment options.
Definition and Classification
Although ITP has been recognized for centuries, there is as yet no consensus on either the definition or management of the disease. In 1996, the American Society of Hematology (ASH)144 published practice guidelines for the diagnosis and management of ITP. In 2003, the British Committee for Standards in Haematology published its own guidelines.145 In spite of these guidelines, the heterogeneity of the definitions and clinical criteria used in different studies has made it difficult to interpret the data regarding the incidence, pathogenesis, and treatment of ITP. In 2008, the International Working Group (IWG) proposed a standardization of terminology, definitions, and outcome criteria for ITP patients.146 In 2010, an international consensus report on the investigation and management of ITP was published.147 Shortly thereafter, in 2011, ASH updated its 1996 ITP guidelines.148
The IWG definition proposed use of the term “immune thrombocytopenia” instead of “idiopathic thrombocytopenic purpura” as the basis for the ITP acronym, because the immune nature of ITP is clear but most ITP patients do not have purpura. A platelet count of 100 × 109/L was proposed as the threshold level to entertain the diagnosis of ITP, because a sustained lower platelet count (100 to 150 × 109/L) can be seen in otherwise healthy individuals,11,12 and long-term observation of these indicate that 88 percent reach normal platelet counts or remain stable.13 ITP is classified based on the absence or presence of other diseases as “primary” or ‘“secondary.” “Primary ITP”’ denotes the absence of any other identified pathology. All other autoimmune thrombocytopenias are classified as “secondary ITP” (see Table 117–3), and the associated primary disorder is indicated in parenthesis, for example “secondary ITP (SLE-associated)” or “secondary ITP (drug-induced).” Heparin-induced thrombocytopenia (HIT) or alloimmune thrombocytopenias are not classified as ITP, and maintain their standard classifications.146
The IWG described three phases of ITP: (1) newly diagnosed ITP (within 3 months of diagnosis); (2) persistent ITP (patients who do not achieve a stable remission between 3 and 12 months after diagnosis); and (3) chronic ITP (continuing for more than 12 months). ITP was formerly classified as mild, moderate, and severe depending on the platelet counts. However, the degree of thrombocytopenia does not always correlate with bleeding. The IWG proposed that the term “severe ITP” only be used for patients with clinically significant bleeding requiring additional therapy regardless of platelet count.146
One of the major problems with comparing ITP studies had been the definition of response to therapy. The IWG proposed the following terms and criteria for response to ITP treatment: “complete response, CR” (platelet count exceeding 100 × 109/L and no bleeding symptoms), “response, R” (platelet count higher than 30 × 109/L or at least a twofold increase from the baseline count and no bleeding symptoms), “no response, NR” (platelet count below 30 × 109/L or less than a twofold increase from the baseline count, or presence of bleeding symptoms). “Duration of response” is measured from the time between first measured CR or R to relapse. “Corticosteroid dependence” is defined as the need for ongoing or repeated glucocorticoid use for at least 2 months to maintain CR or R. Patients who relapsed after splenectomy (failure to maintain CR or R) and required therapy are classified as “refractory ITP.” “On-demand therapy” is a term used for therapies employed to temporarily increase the platelet count in special situations such as trauma or surgery. “Adjunctive therapies” are treatments that are not designed to increase platelet counts, but that may decrease bleeding symptoms by other means, for example, treatment with oral contraceptives or antifibrinolytic drugs.146
ITP is relatively common, but demographic studies have yielded a wide range of incidence rates largely because of differences in the age and gender distribution of the populations studied and differences in cutoff platelet counts used to define the disease. ITP can affect males and females of any age. In one detailed study, the reported incidence of ITP was 3.9 per 100,000 per year. Although the overall incidence was higher in women than in men, a male predominance was seen in patients younger than 18 years of age and older than 65 years of age.149
ITP is of acute onset in children, often developing after vaccination or after a viral illness, and resolves spontaneously in 90 percent of cases. In adults, however, ITP usually is a chronic disease. Table 117–4 highlights the differences in ITP in children and adults. Approximately 25 percent of adult ITP patients are diagnosed incidentally on routine complete blood counts. Symptoms and signs of ITP depend not only on the platelet count, but also on the nature of coexisting conditions that can increase the tendency to bleed, such as uremia, trauma, and ingestion of drugs that affect platelet function (Table 117–5). Approximately one-third of patients have platelet counts greater than 30 × 109/L at diagnosis and no significant bleeding.150 Common bleeding signs include purpura (ecchymoses and petechiae), epistaxis, menorrhagia, and gingival bleeding. Hematuria, hemoptysis, and gastrointestinal bleeding are less common. Intracerebral hemorrhage is rare and generally occurs in patients with platelet counts less than 10 × 109/L and usually is associated with trauma or vascular lesions. The incidence of life-threatening complications is highest in patients older than age 60 years.150–154 The majority of ITP patients have a good prognosis, the mortality rate being only slightly higher than that of the general population. However, ITP patients who present with severe thrombocytopenia (<30 × 109/L) and do not respond to any therapy within 2 years, have a fourfold increased risk of death compared to the general population.155
Table 117–4.Clinical Features of Idiopathic Thrombocytopenic Purpura in Children and Adults ||Download (.pdf) Table 117–4. Clinical Features of Idiopathic Thrombocytopenic Purpura in Children and Adults
| ||Children ||Adults |
|Occurrence || || |
|Peak age (years) ||2–4 ||15–40 |
|Sex (Female-to-Male) ||Equal ||1.2–1.7 |
|Presentation || || |
|Onset ||Acute (most with symptoms lasting <1 week) ||Insidious (most with symptoms lasting >2 months) |
|Symptoms ||Purpura (<10% with severe bleeding) ||Purpura (typically bleeding not severe) |
|Platelet count ||Most cases <20,000/μL ||Most cases <20,000/μL |
|Course || || |
|Spontaneous remission ||83% ||2% |
|Chronic disease ||24% ||43% |
|Response to splenectomy ||71% ||66% |
|Eventual complete recovery ||89% ||64% |
|Morbidity and mortality || || |
|Cerebral hemorrhage ||<1% ||3% |
|Hemorrhagic death ||<1% ||4% |
|Mortality of chronic refractory disease ||2% ||5% |
Table 117–5.Situations That Increase the Bleeding Risk in Immune Thrombocytopenia Patients ||Download (.pdf) Table 117–5. Situations That Increase the Bleeding Risk in Immune Thrombocytopenia Patients
|Drugs: Anticoagulants, antiplatelet drugs, nonsteroidal antiinflammatory drugs, chemotherapy |
|Gastrointestinal pathologies that may cause bleeding (e.g., active peptic ulcer, inflammatory bowel disease) |
|Miscellaneous disorders that disturb hemostasis (e.g., congenital bleeding disorders, hepatic cirrhosis, uremia) |
|Older age (>60 years) |
|Nutritional factors such as herbal teas, kinin, and tonic water |
|Previous history of bleeding |
|Sport and occupational activities that increase bleeding risk |
|Trauma, surgery, and childbirth |
|Uncontrolled hypertension |
The purpuric lesions seen in ITP are not palpable, do not blanch with pressure, and often develop on distal regions of the extremities and on skin areas exposed to pressure (e.g., around tight belts and stockings and at tourniquet sites). Hemorrhagic bullae, which may develop in the buccal mucosa, generally reflect acute, severe thrombocytopenia. Bleeding after surgery, trauma, or tooth extraction is common.
Besides the physical findings associated with platelet-type bleeding, the history and physical examination are usually unremarkable, except for the possibility of similar symptoms in other family members. Family history is especially important to discriminate familial thrombocytopenic syndromes from ITP. The spleen usually is not enlarged but may be palpable in some patients, a finding considered to occur with the same incidence as in normal adults.156 Constitutional symptoms, such as fever, significant weight loss, marked splenomegaly, hepatomegaly, and lymphadenopathy provide evidence that the thrombocytopenia has another cause. The presence of skeletal, cardiac, renal abnormalities, hearing loss, albinism. or immune deficiencies in patients with thrombocytopenia should trigger suspicion of IPDs.
Fatigue is one of the common, but often neglected, complaints of patients with primary ITP. In a survey including UK and U.S. ITP cohorts, the prevalence of fatigue was found to be significantly higher in adult primary ITP patients (39 percent and 22 percent for the UK and U.S. cohorts, respectively) compared with healthy controls.157 Fatigue has also been described in 20 percent of pediatric patients with ITP; fatigue resolved with the elevation of platelet counts.158 Although glucocorticoids and immunosuppressive agents may induce fatigue, fatigue can occur in untreated ITP patients. The mechanism of fatigue in patients with ITP is unknown.
Patients with ITP are at slightly increased risk of venous and arterial thrombosis.159 A recent retrospective study evaluating 986 patients with ITP showed the cumulative incidences of venous and arterial thrombosis to be 1.4 percent and 3.2 percent, respectively. This study found that increased thrombotic risk was associated with splenectomy, older age (>60 years), with the presence of more than two thrombotic risk factors at the time of diagnosis, and with glucocorticoid therapy.160
In ITP patients the blood film usually demonstrates isolated thrombocytopenia without erythrocyte or leukocyte abnormalities. Platelet anisocytosis is a common finding. Mean platelet volume and platelet distribution width are increased. Platelets may be abnormally large or abnormally small. The former reflect accelerated platelet production,161 and the latter represent platelet fragments associated with platelet destruction.162 The observation of giant platelets should trigger consideration of IPDs, which often are misdiagnosed as ITP.163 The bleeding time correlates inversely with platelet count if the count is less than 50 × 109/L, but may be normal in patients with mild or moderate thrombocytopenia,164 making it an unreliable test for use in such patients. The ultrastructure of ITP platelets viewed by electron microscopy is similar to that of normal platelets.165
Hemoglobin concentration and hematocrit are generally normal in patients with ITP. Anemia that is not easily explained (e.g., resulting from iron deficiency in bleeding patients or associated with thalassemia minor in endemic areas) must be investigated further. Autoimmune hemolytic anemia with a positive direct antiglobulin (Coombs) test and reticulocytosis may accompany ITP; this association is termed Evans syndrome.166 Neither erythrocyte poikilocytosis nor schistocytes should be present. Total leukocyte counts and differential are generally normal. Although atypical lymphocytes and eosinophilia may occur in children with ITP, leukocytosis and leukopenia with immature cells are not consistent with the diagnosis.
Marrow examination, which is not always required to make a diagnosis of ITP in adults, generally reveals a normal or increased number of megakaryocytes of normal morphology, although a decreased number of megakaryocytes does not rule out ITP. Erythropoiesis and myelopoiesis are normal. The international consensus report states that a marrow examination should usually be reserved for patients older than age 60 years, for those with systemic symptoms or other signs, and for those for whom splenectomy is contemplated. Biopsy for morphologic examination should be carried out, along with aspirate for flow cytometric and cytogenetic analysis.147 The ASH 2011 guidelines, however, conclude that a marrow examination is unnecessary when the presentation is typical, even if the patients are older or being considered for splenectomy.148
In ITP patients, initial workup should be targeted to exclude secondary causes of thrombocytopenia (see Table 117–3). Testing for viral etiology (hepatitis C virus [HCV], HIV, and in endemic areas hepatitis B virus [HBV]) and Helicobacter pylori is also recommended.147,148 Quantitative immunoglobulin assessment should be considered for pediatric cases to rule out common variable immunodeficiency (CVID).147 Mild thrombocytopenia has been reported in patients with hypo- or hyperthyroidism, which returns to normal after appropriate therapy. Thyroid-stimulating hormone (TSH) and antithyroid antibodies may help to evaluate thyroid status in those patients.147 Other tests to consider include blood group analysis and a pregnancy test for female patients of childbearing age, antiphospholipid antibodies, antinuclear antibody (ANA), viral polymerase chain reaction (PCR) for parvovirus, and cytomegalovirus (CMV). The results of these tests can change the treatment strategy.147 On the other hand, the ASH 2011 guidelines do not recommend routine testing for antiphospholipid antibodies and ANAs in the initial workup of ITP,148 unless signs or symptoms of an autoimmune disorder are present in the patient. Other tests, such as TPO levels, reticulated platelets, PAIgG, platelet survival studies, bleeding time, and serum complement levels are not recommended for the diagnosis and management of ITP patients in either of these guidelines.147,148
What little is known of the natural course of moderate or severe ITP derives from before the glucocorticoid era, and suggests that left untreated, ITP in adults typically is a chronic disease, in contrast to ITP in children. In adults, the rate of spontaneous remission is reported as 9 percent,167 and can occur even after 3 years in patients who present with severe thrombocytopenia.168 Although ITP is a benign disease, side effects of the therapies can cause serious morbidity and even mortality. Treatment for patients with ITP should be based on bleeding signs and symptoms and on the presence of factors that increase the bleeding risk (see Table 117–5). Possible side effects of the drugs and other treatments used in ITP should always be considered.
Observation Because a significant portion of ITP patients are diagnosed incidentally in routine evaluation, signs and symptoms of bleeding are important in determining whether any treatment is required. The primary therapeutic goal is not simply to increase the platelet count, but to reach a safe platelet count where the risk of bleeding is minimal. Patients with no bleeding and consistent platelet counts in excess of 30 × 109/L do not require treatment and can be observed periodically. These patients are at low risk for clinically important bleeding. Simple observation is not recommended for patients with platelet counts lower than 10 × 109/L, in those with platelet counts between 10 and 30 × 109/L and significant mucosal bleeding, or in those with risk factors for bleeding (see Table 117–5).169 The presence of extensive purpura or hemorrhagic bullae in mucosal tissues (wet purpura) should be regarded as a harbinger of life-threatening bleeding and treated as such. Because ITP patients often have large platelets that may not be recognized by automated cell counters, a blood film should be evaluated before starting therapy in ITP patients with very-low platelet counts who are not bleeding. Identification of secondary ITP cases is very important, and management of these patients should include treatment of the underlying pathology, if possible.
Emergency Treatment of Acute Bleeding Resulting from Severe Thrombocytopenia Bleeding symptoms generally are not severe in adult patients with ITP, even with very-low platelet counts. However, life-threatening bleeding can occur, especially after trauma. Emergency treatment should be instituted in patients with intracranial or gastrointestinal bleeding, massive hematuria or internal hematoma, or those in need of emergency surgical intervention or about to go into labor. Patients who experience significant bleeding should be hospitalized and monitored closely. Recommended treatment includes IVIG and parenteral glucocorticoids in combination. IVIG is given as 1 g/kg per day for 2 days, and high-dose parenteral glucocorticoid therapy includes high-dose prednisone or methylprednisolone (1 g/day for 1 to 3 days). In most patients, IVIG increases the platelet count within 2 to 3 days.147,148 Although platelet transfusions may not increase the platelet counts because the transfused platelets are destroyed rapidly, they nevertheless may contribute to the formation of platelet plugs at sites of bleeding and improve hemostasis. Platelet transfusion following IVIG infusion may increase the platelet count because IVIG may improve platelet survival.147,148,170 Aminocaproic acid, which inhibits fibrinolysis, can be used to reduce bleeding170 and is safe except in the presence of hematuria, in which case it can cause thrombi of the glomeruli, renal pelves, and ureters. This agent does not affect platelet count or function. Aminocaproic acid is usually administered intravenously (initial dose 0.1 g/kg over 30 minutes, then given either by continuous infusion at 0.5 to 1.0 g/h or as an equivalent intermittent dose every 2 to 4 hours). Aminocaproic acid also can be administered orally in a similar dose in emergency situations because it is absorbed very rapidly from the gastrointestinal tract.147,148 Vincristine can be used in combination with glucocorticoids and IVIG in older patients.108 Other hemostatic therapies, such as recombinant factor VIIa and fibrinogen infusions, have been reported to be effective in some ITP patients with life-threatening bleeding, but the risk-to-benefit ratio needs to be evaluated in controlled studies.171,172 Emergency splenectomy has been reported to be successful in refractory ITP with bleeding, but reports of its use in this situation are rare.173 Because of this, this therapy should only be considered in the most dire circumstances. Although there are some case reports describing successful results with plasmapheresis, this treatment is not recommended in current ITP guidelines.147,148
Glucocorticoid Therapy Glucocorticoids are accepted as the standard therapy for initial treatment in adult patients with ITP.147,148 Glucocorticoids increase the platelet count in several ways, including by inhibiting phagocytosis of antibody-coated platelets by macrophages, decreasing autoantibody production, and improving marrow platelet production.174,175 These agents also appear to reduce capillary leakage, thereby decreasing blood loss.176 The major drawback of glucocorticoid therapy is that often the adverse effects of the treatment are worse than the disease itself. Important side effects, which can be severe, include facial swelling (chipmunk or moon facies), weight gain, folliculitis, hyperglycemia, hypertension, cataracts, osteoporosis, aseptic bone necrosis, opportunistic infections, and behavioral disturbances.177,178
Still under investigation is which glucocorticoid and dosing regimen is best for raising the platelet count. Prednisolone, dexamethasone and methylprednisolone are all used. Generally, oral prednisone 1 to 2 mg/kg per day (or methylprednisolone at equivalent doses) is preferred as first-line therapy.147,148 Patients usually respond to prednisone therapy within 3 weeks. In approximately two-thirds of patients, platelet counts increase to greater than 50 × 109/L within 1 week, but decrease again when the prednisone dose is decreased.152,177 Although no consensus exists regarding the duration of initial therapy, treatment should continue until platelet counts reach a safe range. In patients who respond, the recommendation is to continue glucocorticoid therapy 1 mg/kg per day for a total of 3 weeks before initiating a slow tapering of doses.148 Sustained remission rates with glucocorticoid therapy are variable, reported rates ranging from 5 to 50 percent.108,155,177 If the patient does not respond to 3 weeks of prednisone therapy, other therapeutic options should be considered.
In addition to the standard 1 to 2 mg/kg per day dose of prednisone, lower179,180 and higher doses181–184 of prednisone, dexamethasone, and methylprednisolone have been investigated, with good results. The major aim of the high-dose glucocorticoid regimes is to reduce duration of therapy, and therefore reduce the side effects of the glucocorticoids. Studies with dexamethasone 40 mg/day for 4 consecutive days for one course, or with the same dose for four courses given every 2 weeks have been reported to produce responses in 50 percent and 89.2 percent of newly diagnosed ITP patients, respectively.185,186 High-dose methylprednisolone therapy has also been shown to be effective, with an 80 percent response rate.187 Despite the favorable results of these studies, high-dose glucocorticoid regimens as first-line therapy still have not been validated with randomized controlled trials. ASH 2011 guidelines recommend longer courses of standard doses of glucocorticoids (prednisone 1 to 2 mg/kg per day) as a first-line treatment of ITP.148
Splenectomy Splenectomy was demonstrated to be an effective treatment for patients with ITP a century ago188 and after the glucocorticoid era, it has been used for decades as a standard second-line therapy. The spleen is the major site both for synthesis of antiplatelet antibodies and for destruction of antibody-coated platelets. Splenectomy will decrease antibody production and platelet destruction, and will be effective in patients in whom antibody-mediated platelet destruction rather than platelet production is the major cause of thrombocytopenia. Although splenectomy has been reported to be less preferred in recent ITP cohorts because of the emergence of new therapies such as TPO receptor agonists and rituximab,189 splenectomy still produces the highest cure rates for ITP patients compared to all other therapies. Approximately 85 percent of patients with persistent or chronic ITP respond well to splenectomy, and 60 to 66 percent of the patients remain in remission after 5 years.189–191 These high cure rates makes splenectomy an important therapeutic option in the treatment of chronic ITP. The duration of the disease prior to splenectomy does not affect the outcome of the procedure, as it can be effective even years after ITP is diagnosed.192,193 Splenectomy can be performed during pregnancy (preferably during the second trimester), and does not affect the response rates to other treatments except anti-D therapy in chronic ITP patients. Also, the cost of splenectomy is lower than that of newer treatments such as rituximab and TPO-receptor agonists.191
On the other hand, splenectomy is an invasive procedure, causes the permanent loss of an organ, and increases the risk of serious bacterial infection, bleeding and thrombosis. Because ITP can remit spontaneously, splenectomy should be postponed at least 6 to 12 months after diagnosis if possible.147,148 Splenectomy is not recommended in patients with CVID, with chronic infections such as chronic hepatitis and HIV, or with known thrombophilia.
No validated clinical or laboratory tests exist that can predict whether splenectomy will be effective in elevating platelet counts in ITP patients. Although it has been suggested that ITP patients with predominant splenic sequestration (as determined by radioisotope techniques) have better response rates than patients with predominantly nonsplenic sequestration, these data have not been validated in other studies189 and the required radioisotope techniques are not widely available.
Over the past decade minimally invasive laparoscopic splenectomy has gained preference over open splenectomy. Modern laparoscopic approaches reduce mortality rates (<1 percent), even in patients with severe thrombocytopenia.194 The mortality rate increases in older patients, in patients with severe thrombocytopenia, and in the presence of coexisting illnesses.177,195 Postsplenectomy sepsis is a major cause of morbidity and mortality in ITP. Extended steroid or other immunosuppressive therapy preceding splenectomy may increase the risk of perioperative infection. To minimize the risk of sepsis, patients should be immunized at least 2 weeks before splenectomy with polyvalent pneumococcal vaccine, Haemophilus influenzae type B vaccine, and quadrivalent meningococcal polysaccharide vaccine.196 Interestingly, newer studies of ITP patients undergoing splenectomy show enteric organisms to be responsible for most of the cases of postsplenectomy sepsis, probably because of the widespread vaccination of ITP patients.191 Splenectomized patients should be informed to be alert for the symptoms and signs of infection and be prepared for an emergency situation. Any fever should be carefully evaluated, and the patient treated with broad-spectrum antibiotics.
Splenectomy also increases the risk of thrombosis in ITP patients. In a large cohort of 9976 ITP patients, in whom 1762 underwent splenectomy; the cumulative incidences of abdominal venous thromboembolism and deep vein thrombosis/pulmonary embolism were increased in splenectomized patients compared to nonsplenectomized patients (1.6 percent vs. 1 percent for abdominal venous thrombosis, 4.3 percent vs. 1.7 percent for deep vein thrombosis–pulmonary embolism, respectively).197 Several mechanisms may contribute to this enhanced risk for thrombosis, including postsplenectomy thrombocytosis and a failure to clear platelets, other cells and microparticles that express the procoagulant lipid phosphatidylserine. Perioperative measures such as antiembolic stockings and anticoagulant prophylaxis should be considered in those cases.
Both the time required to reach a normal platelet count and the magnitude of platelet recovery are accepted as useful predictors of the long-term efficacy of splenectomy. In most cases, platelet counts recover within 10 days. Patients who attain a normal platelet count within 3 days of splenectomy generally have a good long-term response.198 In patients refractory to splenectomy, the presence of accessory splenic tissue should be suspected, particularly if the blood film shows no evidence of splenectomy (i.e., pitting and Howell-Jolly bodies are absent in the erythrocytes; Chap. 55). Such patients should be screened with sensitive radionuclide or magnetic resonance scans to identify residual or accessory splenic tissue.
Intravenous Immunoglobulin IVIG was first shown to be effective in childhood ITP in 1981,109 then later in adult patients.199 IVIG rapidly increases the platelet count in more than 75 percent of patients with chronic ITP and normalizes the platelet count in approximately 50 percent of the patients.177,178 The effect of IVIG is similar whether or not the patient has undergone splenectomy and is transient, generally lasting only 3 to 4 weeks. Postulated mechanisms for the action of IVIG include blockade of macrophage Fc receptors, which slows clearance of antibody-coated platelets, antiidiotype neutralization of antiplatelet autoantibodies, cytokine modulation, immunomodulation (increased suppressor T-cell function and decreased autoantibody production), complement neutralization, and dendritic cell priming.178,200,201 The recommended total dose of IVIG is 2 g/kg administered either as 0.4g/kg per day on 5 consecutive days or as 1 g/kg per day on 2 consecutive days. If the need to increase the platelet count is urgent, the preferred dosing is 1 g/kg per day for 2 days combined with glucocorticoids.148 For maintenance therapy, 0.5 to 1.0 g/kg as a single dose may be used, administered every 3 to 4 weeks, or as needed. Although the annual total world consumption of IVIG exceeds 100 tons, the cost of IVIG is still high, and this also limits the use of IVIG in adults.202 Adverse effects of IVIG therapy include headache, backache, nausea, fever, aseptic meningitis, alloimmune hemolysis, hepatitis, renal failure, pulmonary insufficiency, and thrombosis. Anaphylactic reactions may occur in patients with congenital IgA deficiency.177 The patient may become refractory to the effect with repeated infusions of IVIG.203 IVIG is used as a first-line therapy in childhood ITP, because the thrombocytopenia is usually transient. In adult ITP, however, IVIG is usually reserved for patients with life-threatening bleeding, when a prompt increase in platelet count is needed,147,148 or as first-line therapy when glucocorticoids are contraindicated.148
Anti-(Rh)D Anti-(Rh)D is a polyclonal γ-globulin containing high titers of antibodies against the Rho(D) antigen of erythrocytes. It is administered intravenously for treatment of ITP. Anti-(Rh)D binds Rh-positive erythrocytes and leads to their destruction in the spleen. Because splenic Fc receptors are blocked, more antibody-coated platelets survive in the circulation.204,205 Anti-(Rh)D also can also modulate Fcγ receptor expression and regulate the production of various cytokines, including IL-6, IL-10, and tumor necrosis factor-α.206 A positive direct antiglobulin test, a decrease in serum haptoglobin levels, and mild and transient hemolysis occur in all Rh-positive patients after anti-(Rh)D infusion, generally without requiring a blood transfusion.205 The rate of serious hemolytic reactions has been estimated as one in 1115 patients; any reaction occurs within 4 hours of administration in almost all cases.207 Anti-(Rh)D therapy is not effective in patients who have undergone splenectomy or in Rh-negative patients, and is not recommended in patients with a positive direct antiglobulin test.148
It is recommended that anti-(Rh)D be given as a single dose of 50 to 100 mcg/kg by intravenous infusion over 3 to 5 minutes.204,208,209 Adverse effects of anti-(Rh)D therapy resemble those observed with both γ-globulin infusion and autoimmune hemolytic anemia; symptoms include headache, asthenia, chills, fever, abdominal pain, diarrhea, vomiting, dizziness, and myalgia. Patients can experience immediate anaphylactic reactions and both type I (IgE-mediated) and type III (immune complex–mediated) hypersensitivity reactions.204,205,208,210,211 Although anti-(Rh)D reportedly increases platelet counts within 1 week in more than 70 percent of patients who are Rh-positive and have their spleen,212 and may obviate the need for splenectomy,211 a randomized, controlled trial comparing anti-(Rh)D with conventional therapy showed no differences in the rates of spontaneous remission or the need for splenectomy.209 Anti-(Rh)D is listed in current ASH ITP guidelines as a first-line agent when glucocorticoids are contraindicated.148 Anti-(Rh)D is currently not available in Europe.
Rituximab B lymphocytes play many roles in the pathophysiology of ITP, including producing antibodies, presenting antigens, and regulating the functions of T cells and dendritic cells. B cells are targeted therapeutically with rituximab, a chimeric monoclonal antibody against CD20, which binds B cells and causes Fc-mediated lysis, thereby depleting these cells from blood, lymph nodes, and marrow. Rituximab rapidly depletes B cells in patients with autoimmune diseases, with the effect usually lasting 6 to 12 months.114,213–217
The optimal dosing regimen and duration of therapy have not been determined for patients with ITP. Usual rituximab doses are in the range of 100 to 375 mg/m2. Most studies have used weekly infusion for 4 consecutive weeks at, the dose used to treat B-cell lymphoma (375 mg/m2). Studies with low-dose rituximab (100 mg weekly for 4 weeks) showed similar activity to the standard dose.218 Published studies with rituximab, however, have generally not been controlled and are extremely heterogeneous in terms of rituximab dosing and response criteria. Approximately 40 to 60 percent of the ITP patients demonstrate a response to rituximab at 1 year, and 20 to 25 percent of those have a long-term response (at 5 years).215,219 Splenectomy does not affect response rates to rituximab therapy.135,216 In ITP patients who have relapsed more than 1 year after rituximab therapy, retreatment with the drug will induce similar responses in 75 percent of patients who responded initially.220 In spite of the apparent benefit of rituximab, its use is still considered “off-label” for ITP.
Different patterns of response have been reported in ITP patients treated with rituximab. Although the majority of patients responded within 4 to 6 weeks (early responders), response was delayed for several months in some patients (late responders). In ITP patients who responded to rituximab, the increase in platelet count was associated with reduction in the quantity of platelet-associated autoantibodies. Rituximab also indirectly affects T cells, as depletion of autoreactive B cells prevents T-cell activation. Interestingly, despite the depletion of peripheral B cells, platelet-associated autoantibodies were still found in the plasma of ITP patients who do not respond to rituximab.221 A study analyzing the spleens of ITP patients who did not respond to rituximab therapy demonstrated the presence in the spleen of long-lived plasma cells that produced antiplatelet antibodies for as long as 6 months after rituximab therapy ended. However, this class of cells was not found in the spleens of patients who had not received rituximab. The authors of this study suggested that depletion of peripheral B cells by rituximab promotes the differentiation of long-lived plasma cells in the spleen of ITP patients, which might be responsible for the persistence of antiplatelet antibodies.222
In a meta-analysis of 306 ITP patients treated with rituximab, adverse reactions were reported as mild-to-moderate in 66 patients (21.6 percent) and life-threatening in 10 patients (3.7 percent); nine patients (2.9 percent) died.215 Although some of these deaths were attributed to ITP-related complications and not to rituximab itself, this mortality rate is higher than expected. Infusion-related reactions in rituximab therapy can be severe, and rarely fatal. Premedication with methylprednisolone is recommend to avoid these reactions.219 The risk of infection can increase as a result of depletion of B cells, decreased antibody production, and, rarely, neutropenia.219 Treatment can also reactivate latent viruses, especially hepatitis B. Alteration of T- and B-cell populations, and decreased antibody titers against HBV may stimulate HBV replication, and rarely cause fatal fulminant hepatitis. All patients should be screened for HBV before rituximab therapy.223 Although preventive lamivudine or entecavir can be used in HBV-positive ITP patients, it is instead recommended that alternative therapies be used.219 Other viral reactivation syndromes are less common; progressive multifocal leukoencephalopathy (caused by reactivation of polyomavirus JC) is extremely rare.
Thrombopoietin Receptor Agonists The observation that platelet production in patients with ITP is impaired, the massive megakaryopoiesis seen in the marrow of mice and humans treated with recombinant TPO (far greater than seen in patients with ITP), and the unexpectedly normal or only modestly elevated TPO levels in patients with ITP suggested the potential benefit of megakaryocyte-stimulation therapy in patients with refractory ITP. Early use of an altered form of a recombinant TPO molecule to stimulate platelet production in normal platelet donors was halted because of its stimulation of autoantibodies that cleared endogenous TPO. Because of this untoward effect, the use of recombinant TPO was abandoned, and a search for molecules that might bind to and stimulate the TPO receptor ensued. Since then, the TPO receptor agonists romiplostim and eltrombopag have been clinically shown to stimulate platelet production.224,225
Romiplostim This drug is a peptibody that carries four copies of a 14-amino-acid TPO-receptor–binding peptide fused to an immunoglobulin scaffold, and binds to the TPO-binding site of the TPO receptor with high affinity. The TPO receptor agonist induces megakaryocyte proliferation and differentiation by activating Janus-type tyrosine kinase (JAK)–signal transducer and activator of transcription (STAT) and mitogen-activated protein (MAP) kinase pathways.224 The insertion of dimeric peptide into the IgG1 heavy chain increases the half-life of the molecule.225 Romiplostim has no homology with endogenous TPO, thus the risk of the development of antibodies against TPO is very low. Romiplostim and TPO may also increase platelet responses to agonists. Weekly subcutaneous injection of romiplostim at doses of 1 to 3 mcg/kg produced a dose-dependent increase in the platelet count, starting from day 5, with peak platelet levels reached by days 12 to 15, and platelet counts returning to baseline by day 28.131,135,224 Therapy for ITP is usually initiated at a dose of 1 mcg/kg per week, and the dose is then increased by 1 mcg/kg to a maximum of 10 mcg/kg until the patient reaches target platelet counts (>50 × 109/L). Higher starting doses up to the maximum dose can be used in emergency situations. If the platelet count does not increase to safe levels after 4 weeks of romiplostim treatment at the maximum dose, the drug should be discontinued. Because platelet responses are highly variable, patients should be evaluated periodically, and the dose adjusted based on the platelet counts. Although discontinuation of romiplostim is recommended when the platelet count exceeds 400 × 109/L, it should be kept in mind that platelet counts can drop to extremely low levels. Close monitoring of the platelet counts is therefore crucial. Romiplostim can be used in patients with hepatic or renal insufficiency, but is not recommended in pregnant patients because it can cross the placenta. Two parallel placebo-controlled trials examined response rates to romiplostim in both splenectomized and nonsplenectomized patients treated for 24 weeks.134 Durable platelet responses and overall platelet responses were achieved by 38 percent and 79 percent of splenectomized patients, and by 61 percent and 88 percent of nonsplenectomized patients who were given the drug. A newer study evaluating long-term (up to 5 years) results of romiplostim therapy showed that a platelet count of greater than 50 × 109/L was achieved at least once by 95 percent of treated ITP patients.226 Recent evaluation of large databases of patients who were administered Romiplostim has revealed a reasonable number in whom discontinuation of the drug was not met with relapse of thrombocytopenia, or at least not severe thrombocytopenia.227
Eltrombopag This agent is a small (442 Da) nonpeptide molecule that binds to the transmembrane domain of the TPO receptor and triggers megakaryocyte growth and differentiation, increasing platelet production. Eltrombopag has some distinctive features compared to recombinant human thrombopoietin (rhTPO) and romiplostim: Eltrombopag does not compete with TPO binding, and while it induces the phosphorylation of STAT proteins, it does not affect the AKT pathway.228 Eltrombopag has no effect on platelet activation in response to agonists.225 In healthy volunteers, daily doses given for 10 days elevated platelet counts beginning at 8 days and peaking at 16 days. Eltrombopag is used orally at daily doses of 25 to 75 mg, and should be given 2 hours before or after meals because food can affect its absorption. Ethnic differences in eltrombopag pharmacokinetics have been described. Lower initial doses and slower titration is preferred in East Asian patients.229 Divalent cations such as calcium interfere with absorption of the drug, so it should not be taken with dairy products or antacids. Eltrombopag can also interfere with the uptake and metabolism of statins, increasing their plasma concentrations. Eltrombopag is metabolized in the liver, and causes liver function abnormalities in approximately 13 percent of patients administered the drug. Reduced initial doses are recommended in patients with liver disease.225 Eltrombopag increases platelet counts (50 × 109/L) in 80 percent of splenectomized and 88 percent of nonsplenectomized chronic ITP patients.230 A newer study evaluated repeated short-term doses of eltrombopag (50 mg daily for up to 6 weeks followed by up to 4 weeks off therapy over three cycles) and suggested that eltrombopag can be used as on-demand therapy and repeated courses would be effective and safe.231
Newer Thrombopoietin Receptor Agonists Other congeners are currently being evaluated. An oral, nonpeptide TPO-receptor agonist, avatrombopag, binds to the transmembrane domain of TPO receptor, and increases platelet counts. Lack of significant food interaction is an important feature of this new drug.136 Its use is pending FDA approval.
Common side effects of TPO receptor agonists include mild headache, arthralgia, nasopharyngitis, fatigue, diarrhea, and nausea. These side effects are generally mild and usually of insufficient severity to cause the discontinuation of the drugs. Abnormalities of liver function tests (elevated alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin levels) occur in approximately 2 percent of ITP patients receiving eltrombopag therapy but not with romiplostim.225 Autoantibodies against romiplostim may develop but rarely have neutralizing activity.
TPO-receptor agonists can induce extreme thrombocytosis, sometimes exceeding 1000 × 109/L. Careful dose titration is very important, because cessation of the TPO-receptor agonists cause rebound thrombocytopenia in approximately 10 percent of ITP patients.225 Rates of thromboembolic events were reported as 6.5 percent and 4 percent with extended romiplostim and eltrombopag treatment, respectively.225,231 The authors of these studies concluded that thromboembolic events are not associated with the dose of TPO receptor agonists or platelet counts, and at least one acquired and inherited thrombotic risk factor was present in most of the patients who experienced thrombosis while they were taking TPO-receptor agonists.226,231 Nevertheless, the frequency of thrombosis in these studies was slightly higher than observed in other ITP studies.160 Secondary myelofibrosis (increased marrow reticulin) is sometimes associated with therapy with TPO receptor agonists, and is usually reversible. Concerns have also been expressed that these drugs might accelerate the progression of hematologic and solid malignancies. Under normal circumstances, expression of the TPO receptor (mpl) is highly restricted to hematological tissues including marrow, spleen, placenta, brain and fetal liver cells. TPO receptor expression has been demonstrated on the leukemic cells of patients with acute myelogenous leukemia (AML) and MDS, but not in lymphoid malignancies, myeloproliferative neoplasms, or other nonhematologic malignancies.232 Although romiplostim therapy was discontinued in a study of its use in patients with low-/intermediate-risk MDS and thrombocytopenia because of increased blast and AML rates (interim hazard ratio: 2.51), long-term analysis of the study showed similar survival and AML rates in the romiplostim and control groups.233 The question of whether use of TPO-receptor agonists increases the risk of leukemia warrants further study.
Azathioprine This purine analogue is converted to 6-mercaptopurine following gastrointestinal absorption and works by suppressing the immune response. At least 4 months of azathioprine therapy at doses ranging from 50 to 250 mg/day are necessary to evaluate therapeutic efficacy. One study reported that azathioprine produced a sustained normalization of the platelet counts in up to 45 percent of patients with refractory ITP.234 Azathioprine can be used in pregnancy if necessary (see “Thrombocytopenia During Pregnancy” below). As with other immunosuppressive drugs, major adverse effects are marrow suppression and possible increased risk of secondary malignancy.177,235
Cyclophosphamide This alkylating drug can be used orally (50 to 200 mg/day) or parenterally (1.0 to 1.5 g/m2 IV every 4 weeks) in patients with refractory ITP.236,237 It increases platelet counts in 60 to 80 percent of patients with ITP, and 20 to 40 percent of those patients will remain in remission for 2 to 3 years177 after receiving 2 to 3 months of therapy. Its beneficial action is linked to its immunosuppression. The major complications of cyclophosphamide therapy are marrow suppression, hemorrhagic cystitis, infertility, alopecia, and secondary malignancy.
Cyclosporine Cyclosporine is an immunosuppressive drug inhibiting T-cell function, and is primarily used to prevent rejection in patients with organ transplantation. Although cyclosporine may induce a durable remission in patients with ITP when used at relatively low doses (2.5 to 3.0 mg/kg/day),238 experience with cyclosporine in ITP patients is usually based on small case series. Cyclosporine has several side effects, some potentially serious, including fever, increased risk of opportunistic infections, gingival hyperplasia, diarrhea, peptic ulcer, pancreatitis, renal dysfunction, elevated liver enzymes, hypertension, peripheral neuropathy, convulsions, hirsutism, and increased risk of secondary malignancy.
Danazol This synthetic androgen, with reduced virilizing effects compared to other androgens, has been used to treat patients with refractory ITP. Given at doses of 400 to 800 mg/day for at least 6 months, reported response rates range from 10 to 80 percent.177,235 Danazol is postulated to decrease Fc receptor numbers on phagocytic cells by antagonizing the effects of estrogens.153 Danazol should not be given to pregnant women or patients with liver disease. Common side effects of danazol therapy are weight gain, fluid retention, seborrhea, hirsutism, secondary amenorrhea, vocal changes, acne, hepatic toxicity, headache, lethargy, cholesterol spectrum abnormalities (i.e., reduced high-density lipoprotein [HDL] cholesterol) and myalgia. Because liver dysfunction is common with these doses of danazol therapy, liver function should be evaluated monthly.153,177,235
Dapsone Dapsone possesses antibacterial and antiinflammatory effects; it is primarily used for leprosy, malaria, and some types of dermatitis. When used at a dose of 75 to 100 mg/day, dapsone may increase platelet counts in patients with persistent, refractory, or chronic ITP.147,239,240 The median time to response is long, up to 2 months. Partial and CR rates are approximately 50 percent and 20 percent, respectively, but platelet counts return to baseline levels after discontinuation of the therapy.239,240 The mechanism of dapsone action in ITP is not known. The most important side effects are nausea, headache, skin rashes, hepatitis, cholestasis, dose-dependent hemolysis, and methemoglobinemia. Dapsone should not be given to patients with glucose-6-phosphate dehydrogenase deficiency.
Vinca Alkaloids Both vincristine and vinblastine transiently increase the platelet count in approximately 70 percent of ITP patients within 5 to 21 days, but produce sustained remissions in only 10 percent of treated patients.108,153,177,235 The recommended dose of vincristine is 1 to 2 mg and of vinblastine is 0.1 mg/kg (maximum: 10 mg), both given by bolus injection at 1-week intervals for a minimum of three courses. It has been proposed that vinca alkaloids bind to platelet microtubules and thereby are transported to the spleen, where they subsequently inhibit the phagocytic functions of splenic macrophages. They may also stimulate megakaryopoiesis. Peripheral neuropathy, neutropenia, jaw pain, alopecia, and constipation are complications of treatment with vinca alkaloids.235,241–243
Other Therapies ITP patients with H. pylori infection should receive eradication therapy.148 Many other therapies, including interferon-α,244 immunoadsorption with staphylococcal protein A,245 ascorbic acid,246 colchicine,247 and plasmapheresis,248 have been studied for refractory ITP cases, but none has been clearly demonstrated to be effective.
Accessory Therapies Adjunctive therapies include agents designed to reduce bleeding without necessarily affecting the platelet count. Aminocaproic acid or tranexamic acid, both of which inhibit fibrinolysis, can be used for excessive mucosal bleeding. Local bleeding can be controlled by compression and use of gelatin sponges, fibrin sealants, or antifibrinolytic-embedded gauze. Avoiding the use of antiplatelet drugs, contact sports, and activities that increase bleeding risk, and educating patients about maintaining dental hygiene are very important. Menorrhagia is a common problem in patients with chronic ITP; gynecologic evaluation of uterine problems is crucial. Oral contraceptives and hormonal intrauterine devices together with antifibrinolytic drugs may help to reduce excessive menstrual bleeding in these patients.
SECONDARY IMMUNE THROMBOCYTOPENIA
Secondary ITP is defined as immune-mediated platelet destruction in the presence of other conditions, including infections, lymphoproliferative disorders, solid tumors, SLE, or the antiphospholipid syndrome (APS) (Fig. 117-4).249 ITP can sometimes be the presenting sign of the illness, or may develop during the course of the disease or with certain therapies. Thrombocytopenia in a patient with chronic disease may develop for other reasons, and the diagnosis of immune-mediated platelet destruction may require more detailed tests. Generally, thrombocytopenia is not severe in patients with secondary ITP, but bleeding risk may be enhanced at a particular platelet count because of the underlying disorder. The treatment strategy should be tailored to the individual patient.
Estimated fraction of the various forms of secondary ITP based on clinical experience of the authors. The incidence of Helicobacter pylori (HP) ranges from approximately 1 percent in the United States to 60 percent in Italy and Japan. The incidence of the HIV and hepatitis C virus approximates 20 percent in some populations. Miscellaneous causes of immune thrombocytopenia, for example, posttransfusion purpura, myelodysplasia, drugs that lead to the production of autoantibodies, and other conditions, are not discussed further in this chapter. Post marrow or solid-organ transplantation autoimmune lymphoproliferative syndrome (ALPS) occurred in approximately 1 percent of the authors’ patients. In the absence of a systematic analysis of the incidence of secondary ITP, the data shown represent the authors’ assessment based on our experience and the findings reported in the literature. APS, antiphospholipid syndrome; CLL, chronic lymphocytic leukemia, CVID, common variable immune deficiency; SLE, systemic lupus erythematosus. (Reproduced with permission from Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: Pathogenic and clinical diversity. Blood 113(26):6511–6521, 2009.)
IMMUNE THROMBOCYTOPENIA IN PATIENTS WITH ANTIPHOSPHOLIPID SYNDROME, SYSTEMIC LUPUS ERYTHEMATOSUS AND OTHER CONNECTIVE TISSUE DISORDERS
Thrombocytopenia in the Antiphospholipid Syndrome
APS is characterized by recurrent arterial and/or venous thrombosis and well-defined morbidity during pregnancy in the presence of antiphospholipid antibodies (APLAs) (Chap. 132).250 APS may affect any organ in the body, including the heart, brain, kidney, skin, lung, and placenta. This syndrome predominantly affects females (female-to-male ratio 5:1), especially during the childbearing years.251 APLAs (lupus anticoagulant; anticardiolipin antibodies; anti–β2-GPI antibodies) represent a heterogeneous family of antibodies that react with anionic phospholipids and phospholipid–protein complexes. Despite overwhelming evidence that APLAs are associated with thrombosis, the mechanisms remain uncertain. Many have been proposed, including endothelial cell damage and apoptosis, inhibition of prostacyclin release from endothelial cells, inhibition of the protein C–protein S anticoagulant system, induction of tissue factor, activation of platelets and the complement system, interference with antithrombin, impairment of fibrinolytic activity, and inhibition of annexin V binding to membrane phospholipids, eliminating the antithrombotic effect of annexin V.252–255 APS is considered one of the most common causes of acquired thrombophilia.256,257
Thrombocytopenia is reported in approximately 20 to 40 percent of patients with APS, usually is mild (70 to 120 × 109/L), and does not require clinical intervention. Severe thrombocytopenia (platelet counts <50 × 109/L) occurs in 5 to 10 percent of patients.258–260 Although thrombocytopenia was a clinical criterion used to define the syndrome in the initial classification of APS,261 it was not included in the most recently proposed classification.262 Because ITP patients who present with APLAs are at increased risk for thrombosis,263 measurement of APLA, especially lupus anticoagulant, in patients diagnosed with ITP may identify a subgroup at high risk for developing APS. The pathogenesis of thrombocytopenia in APS is not clear. Potential mechanisms explaining thrombocytopenia in APS patients include APLA-related direct platelet destruction, immune platelet destruction by antibodies against platelet GPs, complement-mediated platelet destruction, and platelet aggregation and consumption. Evidence indicates APLAs bind platelet membranes and cause platelet destruction, but the link is not definitive. Some investigators suggest that antibodies against platelet GPs, rather than APLAs, are responsible for thrombocytopenia in patients with APS. Antibodies against the integrin αIIββ3 or GPIb–IX–V complexes are found in approximately 40 percent of thrombocytopenic patients with APS.264 Such antibodies do not cross-react with antibodies against phospholipids or β2-GPI.265 Immunosuppressive treatment in these patients increases the platelet count and reduces the titers of anti-GP antibodies but not the titers of APLAs.266 These data suggest that thrombocytopenia is a secondary immune phenomenon that develops concomitantly with APS. Against this conclusion, platelet antigens in thrombocytopenic patients with APS were found to be different from those in ITP and the antibodies to display virtually no reactivity with membrane GPs.267 CD40 ligand on platelets is another possible antibody target. Anti-CD40 ligand antibodies have been found in patients with APS (13 percent) and ITP (12 percent), but not in healthy controls; and it was suggested that these antibodies cause thrombocytopenia.268 Platelet activation, aggregation, and consumption (APS-associated thrombotic microangiopathy) may also contribute to thrombocytopenia.260 Another issue of clinical importance in evaluating thrombocytopenia associated with APS is the risk for future development of thrombosis. In one study in which APS patients were divided into three groups according to platelet counts as normal, moderately thrombocytopenic (50 to 100 × 109/L), or severely thrombocytopenic (<50 × 109/L), the rates of future thrombosis were 40 percent, 32 percent, and 9 percent, respectively.269 These data show that moderate thrombocytopenia does not prevent thrombosis in patients with APS. Antithrombotic prophylaxis should be considered in these patients whenever it is possible.258,269
Although thrombocytopenia is a common finding in patients with APS, bleeding complications are rare, even with severe thrombocytopenia. Bleeding in an APS patient with moderate thrombocytopenia should trigger evaluation for the presence of antiprothrombin antibodies270 and other disorders that may affect hemostasis, such as DIC, liver insufficiency, and uremia. Severe thrombocytopenia may require therapy, with treatment strategies similar to those used for patients with ITP. Glucocorticoids are effective in only 15 percent of patients.258 IVIG and immunosuppressive drugs such as azathioprine and cyclophosphamide can be used in patients with severe bleeding and “catastrophic” APS. In general, splenectomy should be postponed as long as possible, and is only preferred in patients with severe bleeding. Splenectomy may produce sustained remission in approximately two-thirds of patients as in patients with primary ITP.167,271,272 Because of their increased risk of thrombosis, patients should be prophylactically anticoagulated in the immediate postoperative period. Rituximab has been used to treat refractory thrombocytopenia in patients with APS, with a wide range of results.273–275 Although there is no consensus on dosing and schedule with rituximab therapy, it is generally administered as in patients with ITP (see ITP therapy in “Therapy and Course” above). TPO receptor agonists may increase thrombosis risk in patients with APS and SLE and these diagnoses in a patient with ITP were accepted as exclusion criteria in some randomized controlled studies of TPO-receptor agonists.136 Two case reports described acute renal failure (one was a result of thrombotic microangiopathy) after use of eltrombopag.276,277
Thrombocytopenia in Patients with Systemic Lupus Erythematosus and Other Connective Tissue Disorders
SLE is a complex autoimmune disease that primarily afflicts women of childbearing age. The autoimmune attack in SLE is not organ specific; it may affect any tissue in the body. The diagnostic criteria for SLE are based on a classification system proposed by the American College of Rheumatology.278,279 The presence of hematologic findings (leukopenia, thrombocytopenia, or hemolytic anemia) is one of the criteria in the diagnosis and classification of SLE. Thrombocytopenia is common in patients with SLE, occurring in 20 to 40 percent of patients, and may be a presenting symptom.280 Immunologic destruction of platelets is also seen in several other autoimmune conditions, including polyarteritis nodosa, rheumatoid arthritis, mixed connective tissue disease, and Sjögren syndrome, albeit at much lower rates than in SLE.
The causes of thrombocytopenia in SLE are many and include platelet destruction (ITP, DIC, thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic syndrome [HUS], sepsis, drugs), ineffective hematopoiesis (megaloblastic anemia), abnormal platelet pooling (hypersplenism), marrow hypoplasia (from drugs and infections), and dilutional thrombocytopenia related to therapy. Severe thrombocytopenia is relatively rare, occurring in 5 percent of patients.280 Although clinically significant bleeding is uncommon even in patients with severe thrombocytopenia, fatal gastrointestinal, cerebral, and pulmonary bleeding have been reported. Among the many potential contributors to thrombocytopenia in SLE patients, platelet destruction by autoantibodies is the major mechanism. Antiplatelet antibodies are present in up to 60 percent of SLE patients.281,282 The presence of antiplatelet antibodies is correlated with low platelet counts and increased disease severity.282 Besides the antiplatelet antibodies, APLAs (see “Thrombocytopenia in the Antiphospholipid Syndrome” above) and circulating immune complexes that bind platelets may nonspecifically accelerate platelet destruction.283 Specific antiplatelet antibodies, especially those against integrin, have an important role in the pathogenesis of thrombocytopenia in SLE patients.281,282,284 In general, marrow megakaryocytes are normal or increased, and platelet production is not affected in SLE patients with thrombocytopenia. However, decreased numbers of megakaryocytes and even amegakaryocytic thrombocytopenia have been reported.86,285 High levels of TPO in the plasma, and both anti-TPO and anti-TPO receptor antibodies have been reported in SLE patients,286,287 the latter associated with a decrease in marrow megakaryocytes and thrombocytopenia.287 Thrombocytopenia in SLE is associated with serious organ pathology, leading to neuropsychiatric disease,288 renal disease,289,290 and APS,291 and is an independent indicator of poor prognosis.290,292,293 A study of selected SLE families in which at least one affected member was thrombocytopenic reported genetic linkage to loci at chromosomes 11p13 and 1q22–23.294 A severe lupus phenotype was much more common in patients with thrombocytopenia and their affected family members than in patients from families with no thrombocytopenic patients. Therefore, thrombocytopenia in a family member may herald severe lupus in familial SLE.
There are no well-established treatment strategies for severe thrombocytopenia in patients with SLE. Because SLE ranges in severity from milder forms with easily controlled symptoms and signs to severe forms that can be fatal, the treatment of severe thrombocytopenia should be tailored to the individual patient. Patients with severe thrombocytopenia are generally treated with glucocorticoids as first-line therapy, but sustained remission is infrequent. Because most patients with severe thrombocytopenia also have nephritis and neurologic symptoms, they receive immunosuppressive therapy either alone or combination with glucocorticoids.295–298 IVIG is reserved for use in patients with severe bleeding.299,300 It is well-known that B lymphocytes play an important role in the pathogenesis of SLE. Although lymphopenia is common in patients with active SLE, autoantibody-producing B cells have been shown to be expanded, and B cells were found to be more sensitive to inflammatory cytokines.301 B-cell targeted therapy—rituximab—is effective in the treatment of refractory SLE patients, especially those with nephritis and severe thrombocytopenia.301 A retrospective study evaluating the long-term effects of rituximab therapy in 65 patients with refractory ITP associated with SLE and mixed connective tissue disease reported an overall response rate of 80 percent.302 Although case series indicate that splenectomy yields sustained remission in 61 percent of SLE patients with severe thrombocytopenia296 and is relatively safe in terms of perioperative complications,303 splenectomy may increase the risk of thrombotic complications in SLE patients,304 and may also increase the risk of infection if the patients require further immunosuppressive therapy.
THROMBOCYTOPENIA IN INFECTIOUS DISEASES
The first recorded observation of purpura was made in patients with fever, and purpura was accepted as a sign of severe infections for centuries. Thrombocytopenia can be seen in patients with viral, bacterial, fungal and parasitic infections. Infection can decrease platelet levels in several ways: by decreasing production in the marrow, by increased immune destruction, or by inducing microangiopathy as seen in patients with infection induced DIC or HUS. In addition, drugs used for the treatment of an infection can contribute to thrombocytopenia (see “Drug-Induced Thrombocytopenia” below).
Viral infections are an important cause of secondary ITP. ITP can be seen after a viral infection, especially in children, and usually resolves within 2 to 8 weeks. In patients with viral infections such as rubella, mumps, and infectious mononucleosis, thrombocytopenia can be present with other clinical signs and symptoms. Adult patients with isolated thrombocytopenia with no obvious causes should be screened for HIV, HCV and, in endemic areas, for HBV. Because other clinical symptoms and signs associated with infection with these viruses may not be present initially, and it may not be possible to distinguish these cases from primary ITP.
HIV is a leading cause of isolated thrombocytopenia in Western countries. Thrombocytopenia associated with HIV infection has numerous causes, many of which can be present simultaneously. These include accelerated platelet destruction primarily related to immune complexes, decreased platelet production, especially in advanced disease, splenic sequestration, and, rarely, platelet consumption associated with TTP. Medications, concurrent infections such as hepatitis C, and hematologic malignancies may contribute to the development of thrombocytopenia (Chap. 83).305–308
HCV is another important cause of thrombocytopenia in adults. It is a hepatotrophic RNA virus of the Flaviviridae family. HCV infection is chronic in approximately 85 percent of the infected individuals and progresses to cirrhosis in 20 percent of these individuals. The World Health Organization (WHO) estimates that approximately 3 percent of the world's population is infected with HCV, the prevalence ranging from 0.5 to 2 percent in Western countries to 20 percent in some underdeveloped countries.309 HCV causes thrombocytopenia through different mechanisms, including hypersplenism, decreased TPO level associated with liver insufficiency, the effect of drugs (pegylated interferon [IFN] and ribavirin), and immune-mediated platelet destruction.310 Immune dysregulation in HCV is associated with several autoimmune disorders, including arthritis, Sjögren syndrome, cryoglobulinemia, and immune cytopenias.311 As a potential mechanism of immune destruction, one study demonstrated binding of both free and IgG-complexed HCV to platelets.312 In secondary ITP associated with HCV infection, antiviral therapy with pegylated IFN and ribavirin will decrease viral load and may also treat thrombocytopenia. However, platelet counts can be unaffected or even decrease after these therapies. Severe thrombocytopenia interferes with optimal HCV treatment, and may increase bleeding risk. In this situation, the ASH 2011 guideline recommends IVIG as a first-line therapy, because glucocorticoids may increase viral load.148 Glucocorticoids and splenectomy both appear to be effective treatments for thrombocytopenia, but their use should be balanced against other considerations after discussion with a hepatologist. TPO receptor agonists may increase the risk of abdominal thrombosis in HCV patients with liver cirrhosis.313
The potential role of H. pylori in the pathogenesis of chronic ITP is controversial. Japanese and Italian studies showed that eradication of H. pylori with antibiotics resulted in marked platelet count increases in patients with ITP. However, this success was not reproduced in American and other European studies.314 It appears that response rates are higher in countries where H. pylori infection is endemic. ITP patients treated for H. pylori had higher platelet counts than untreated ITP patients, even if the therapy was unsuccessful in eradicating the infection.315 It has therefore been speculated that the antibiotic therapy, rather than eradication of H. pylori, may be the factor improving platelet counts. However, meta-analysis found that H. pylori eradication therapy was much more likely to increase platelet counts in patients with H. pylori infection than in uninfected patients,316 strengthening the case for a causal relationship between infection and thrombocytopenia. On the other hand, eradication was shown to be less effective in patients with severe thrombocytopenia.310 The recent ASH ITP guideline suggests that ITP patients be screened for H. pylori and for eradication therapy to be used if testing is positive.148