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Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis

Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis
Authors:
Donald M Arnold, MD, MSc
Adam Cuker, MD, MS
Section Editor:
Mark Crowther, MD, MSc
Deputy Editor:
Jennifer S Tirnauer, MD
Literature review current through: Oct 2022. | This topic last updated: Aug 10, 2022.

INTRODUCTION — Immune thrombocytopenia (ITP, also called idiopathic thrombocytopenic purpura, immune thrombocytopenic purpura) is an acquired thrombocytopenia caused by autoantibodies against platelet antigens. It is one of the more common causes of thrombocytopenia in otherwise asymptomatic adults.

Major diagnostic concerns in an adult with suspected ITP are twofold:

Distinguishing ITP from other causes of thrombocytopenia, which often have a similar presentation but frequently require completely different management approaches

Determining whether the ITP is primary or secondary to an underlying condition that might also benefit from treatment

The lack of a sensitive or specific diagnostic test for ITP and the large number of other potential causes of thrombocytopenia, some of which may be overlooked (eg, drug-induced thrombocytopenia, hereditary thrombocytopenia), also contribute to the challenges in diagnosing ITP.

Here we discuss the clinical manifestations and diagnosis of primary ITP in adults, as well as the differential diagnosis of ITP and causes of secondary ITP due to other conditions.

Other issues are discussed in separate topic reviews:

Other causes of thrombocytopenia – Other common causes of thrombocytopenia include drug-induced thrombocytopenia, chronic liver disease or hypersplenism, and bone marrow suppression or transient drops in platelet count from an infection. Hereditary thrombocytopenias are less common but may be mistakenly diagnosed as ITP when first identified during adulthood. (See "Diagnostic approach to the adult with unexplained thrombocytopenia" and "Drug-induced immune thrombocytopenia".)

Pregnancy – ITP is often seen in otherwise healthy women, many of whom may have a platelet count first checked during pregnancy. However, pregnancy is also associated with other causes of thrombocytopenia including gestational thrombocytopenia (a physiologic condition) and pregnancy-associated microangiopathic syndromes. (See "Thrombocytopenia in pregnancy".)

Children – ITP in children, especially in children younger than age 10, is a clinically distinct condition from that in adults, with a higher likelihood of spontaneous remission, a lower incidence of underlying diseases and comorbidities, and often a lower risk of bleeding. During adolescence, ITP may be similar to typical childhood ITP or to ITP in adults. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis".)

Management – Treatment of ITP depends on the estimated risk of bleeding. (See "Immune thrombocytopenia (ITP) in children: Initial management" and "Immune thrombocytopenia (ITP) in children: Management of chronic disease" and "Initial treatment of immune thrombocytopenia (ITP) in adults" and "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults".)

TERMINOLOGY — We use the following terms herein; this terminology is consistent with a consensus statement from an international working group on ITP published in 2009 [1].

Additional terms characterizing bleeding severity and describing the response to ITP therapy are presented separately. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Definitions of bleeding severity'.)

Primary ITP – Primary ITP is acquired immune thrombocytopenia due to autoimmune mechanisms leading to platelet destruction and platelet underproduction that is not triggered by an apparent associated condition.

Secondary ITP – Secondary ITP is ITP associated with another condition such as those listed below (see 'Inciting events' below). By convention, the associated condition is noted in parentheses, as in "secondary ITP (lupus-associated)."

Drug-induced immune thrombocytopenia – Drug-induced immune thrombocytopenia (DITP) is thrombocytopenia due to drug-dependent platelet antibodies that cause platelet destruction. This syndrome should be distinguished from drug-induced bone marrow suppression, a non-immune phenomenon (table 1). (See "Drug-induced immune thrombocytopenia".)

The time elapsed since diagnosis determines whether ITP is referred to as newly diagnosed, persistent, or chronic.

Newly diagnosed – Up to three months since diagnosis

Persistent – Three to 12 months since diagnosis

Chronic – More than 12 months since diagnosis

Severe ITP – Severe ITP refers to ITP with bleeding symptoms sufficient to require treatment; this typically occurs when platelet counts are below 20,000/microL.

Other names for ITP – ITP has previously been called idiopathic thrombocytopenic purpura, immune thrombocytopenic purpura, or autoimmune thrombocytopenic purpura (AITP). These terms have been replaced by "immune thrombocytopenia" to reflect the known autoantibody mechanism and the absence of purpura in most patients.

PATHOGENESIS — The pathogenesis of ITP is incompletely understood. Reduced platelet lifespan due to clearance is the predominant cause of thrombocytopenia.

However, other mechanisms are likely important, including autoreactive cytotoxic T cells, as well as humoral and cellular autoimmunity directed at megakaryocytes, causing impaired platelet production.

The principal mechanism is thought to involve specific autoantibodies (typically, IgG), most often directed against platelet membrane glycoproteins such as GPIIb/IIIa [2-6]. Further discussion of autoantibody formation is provided separately. (See "Overview of autoimmunity".)

Inciting events — In some patients with ITP, there may appear to be inciting events. Genetic and acquired factors may contribute [7-9].

Secondary ITP – Causes of secondary ITP in adults include a number of chronic disorders and infectious diseases that are summarized in the table (table 2). Examples include:

Chronic lymphocytic leukemia (CLL)

Systemic lupus erythematosus (SLE)

Antiphospholipid syndrome (APS)

Common variable immune deficiency (CVID)

Autoimmune lymphoproliferative syndrome (ALPS)

Selective immunoglobulin (Ig) A deficiency

Measles, mumps, and rubella (MMR) vaccination

Helicobacter pylori infection

HIV infection

Hepatitis C virus (HCV) infection

Cytomegalovirus (CMV) infection

Varicella zoster virus (VZV) infection

Coronavirus disease (COVID-19) [10]

COVID-19 vaccines – Cases of ITP have been reported, including new-onset ITP and exacerbation of existing ITP, in individuals who have received a COVID-19 vaccine; however, there is no evidence to suggest that individuals who receive any of the COVID-19 vaccines have a higher rate of ITP than the background rate in the population. Details are discussed separately. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'COVID-19 vaccination'.)

In contrast, vaccine-induced immune thrombotic thrombocytopenia (VITT) is pathophysiologically and clinically more similar to autoimmune heparin-induced thrombocytopenia (HIT) than to ITP. (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

These inciting events can be categorized broadly into two main mechanisms: infections (typically viral) and systemic conditions that disrupt immune homeostasis (eg, autoimmune disease, lymphoid malignancy).

Infection – Some cases of ITP are associated with a preceding viral infection or, less commonly, bacterial infection. Antibodies against viral antigens may cross-react with normal platelet antigens (a form of molecular mimicry). Infection with HIV, hepatitis C virus (HCV), cytomegalovirus (CMV), and varicella-zoster virus (VZV) have been proposed to cause secondary ITP by this mechanism [11-14]. Bacterial products, such as lipopolysaccharide, may attach to platelet surfaces and can increase platelet phagocytosis [15]. Helicobacter pylori infection may contribute to the development of ITP in some cases by an unknown mechanism that might include molecular mimicry, immune alterations, and activities of bacterial products such as cytotoxin-associated gene A (CagA) [16].

Zika virus infection can cause secondary ITP. In a series of 37,878 individuals with Zika virus infection, 47 (0.1 percent) had thrombocytopenia without another cause, often severe [17]. Of the 12 who had platelet counts <50,000/microL, all had bleeding manifestations, most commonly petechiae and hematuria; there was one intracranial hemorrhage. Several of these individuals had an excellent platelet count response to ITP therapies (glucocorticoids alone, IVIG alone, or both in combination). (See "Zika virus infection: An overview".)

Immune alteration – Alterations in immune homeostasis might induce loss of peripheral tolerance and promote the development of self-reactive antibodies. This often occurs in the setting of other autoimmune conditions including the antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE), Evans syndrome, hematopoietic cell transplantation, chronic lymphocytic leukemia (CLL) and other low-grade lymphoproliferative disorders (especially those treated with purine analogs), common variable immunodeficiency, and the autoimmune lymphoproliferative syndrome [7,18,19].

Alternative immunologic mechanisms involving T cells have also been postulated to cause ITP, including T cell-mediated cytotoxicity and defects in the number and/or function of regulatory T cells (Tregs) [20-29]. The latter mechanism is supported by a study showing a reduced number and defective suppressive capacity of Tregs in patients with ITP versus controls and restored Treg numbers and regulatory function, especially in responders, following treatment with rituximab [27]. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Suppression'.)

In contrast to ITP associated with lymphoid malignancies such as CLL, reports of ITP in association with nonhematologic malignancies, especially breast cancer, are likely due to coincidence rather than a causal relationship [30-33].

Details of testing and the association with ITP are discussed separately. (See "Overview of the complications of chronic lymphocytic leukemia", section on 'Immune thrombocytopenia' and "Hematologic manifestations of systemic lupus erythematosus", section on 'Thrombocytopenia' and "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis" and "Extrahepatic manifestations of hepatitis C virus infection", section on 'Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia'.)

Antibody production — Antibody production in ITP appears to be driven by CD4-positive helper T cells reacting to platelet surface glycoproteins, possibly involving CD40:CD40L co-stimulation [34-36]. Splenic macrophages appear to be the major antigen-presenting cells [37].

Despite this likely mechanism, antiplatelet antibodies are not demonstrable in close to 50 percent of patients with ITP (ie, sensitivity of antiplatelet antibodies is low) [38]. Thus, we do not use assays for antiplatelet antibodies in ITP diagnosis or management [2,39-41]. (See 'Antiplatelet antibody testing' below.)

Platelet destruction — The primary site of platelet clearance for most patients is the spleen, which removes opsonized (antibody coated) cells including platelets. (See "Evaluation of splenomegaly and other splenic disorders in adults", section on 'Properties of the normal spleen'.)

The prominent role of splenic clearance explains the effectiveness of splenectomy in most patients. However, clearance may occur in other tissues as well, such as the liver, bone marrow, lymph nodes, and accessory splenic tissue. This helps explain why ITP can persist or recur post-splenectomy. (See "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults", section on 'Splenectomy'.)

EPIDEMIOLOGY — ITP is a common acquired bleeding disorder (figure 1). The reported incidence appeared to increase with the introduction of automated platelet counting in the 1970s; however, this was likely due to an increase in the incidental finding of thrombocytopenia rather than a true increase in the incidence of ITP [42,43].

A review of published reports determined an annual ITP incidence of approximately 1 to 6 per 100,000 adults in the era of routine complete blood counts; this estimate is based on three large retrospective studies from Europe and a study from Korea [42-46]. ITP is often a chronic disease in adults; thus, the prevalence significantly exceeds the incidence. In a review from the United States, prevalence was approximately 8 per 100,000 in children and 12 per 100,000 in adults [45].

Other studies have estimated that one-fifth to one-third of individuals with ITP will be asymptomatic at the time of diagnosis (ie, diagnosed because of an incidental finding of thrombocytopenia); thus, the incidence of symptomatic disease is likely to be much lower [47,48]. In a database review from the French National Health Insurance System that was limited to ITP cases requiring chronic therapy and/or hospitalization, the overall incidence was 2.9 per 100,000 person-years, with a peak in individuals >60 years, reaching 9 cases per 100,000 person-years in men >75 years of age [49].

Other studies have also documented the increasing incidence of ITP with increasing age [45,50]. Over time, there is a greater likelihood of having a lower platelet count; in a series of 269 individuals with ITP, 152 (57 percent) had a platelet count <20,000/microL at some point during their disease course [51].

ITP is generally thought to be a condition that affects young women. Some studies have corroborated a female predominance in younger adults, while others have not [42,45,48]. Most studies show a similar incidence in males and females over the age of 60 years.

CLINICAL MANIFESTATIONS — With wide availability of complete blood counts (CBCs), many patients with ITP are diagnosed as a result of chronic, asymptomatic thrombocytopenia. For patients with symptoms, these are primarily related to thrombocytopenia and bleeding, but patients can also experience fatigue and decreased quality of life. (See "Diagnostic approach to the adult with unexplained thrombocytopenia", section on 'When to worry about bleeding'.)

Bleeding — The incidence of bleeding in patients with ITP varies widely, mainly based upon the inception cohort from which the rate is calculated. The rate of bleeding in patients seen and followed in specialty clinics will be higher than that in a group of patients detected as a result of CBCs performed for other reasons and identified as having thrombocytopenia. Therefore, the rates of bleeding reported from expert clinics probably represent an overestimate of the actual bleeding risk in the general ITP population, while the bleeding risk determined from asymptomatic, screening detected individuals likely underestimates that of patients who are being evaluated because they have signs or symptoms of ITP.

Bleeding due to thrombocytopenia may ultimately occur in up to two-thirds of patients. When present, bleeding typically occurs in the skin or mucous membranes, a pattern sometimes referred to as "platelet-type" bleeding. Although the onset of symptoms may be abrupt, it is more often insidious.

Severity is variable, as discussed separately. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Definitions of bleeding severity'.)

Petechiae – Petechiae are flat, red, discrete lesions that do not blanch under pressure; these often occur in dependent areas of the body (lower legs in ambulatory patients; sacral area in recumbent patients) (picture 1 and picture 2). Petechiae must be distinguished from vasculitic purpura, as described below.

Purpura – Purpura refers to a lesion caused by coalescence of petechiae. Purpura on the skin is sometimes referred to as "dry purpura."

Hemorrhagic blisters in mucous membranes, such as the oral mucosa, are sometimes called "wet purpura"; this finding may be a predictor of more severe bleeding [52]. New development of wet purpura should prompt reappraisal of the platelet count and the need for ITP therapy.

Purpura due to thrombocytopenia is nonpalpable and often occurs in dependent areas of the body. In contrast, vasculitic purpura, which is due to capillary inflammation, is palpable and does not accumulate in dependent areas. Vasculitic purpura is often pruritic, whereas thrombocytopenic purpura is not. (See "Overview of and approach to the vasculitides in adults" and "Approach to the patient with retiform (angulated) purpura" and "Pigmented purpuric dermatoses (capillaritis)".)

Epistaxis – Minimal epistaxis, such as noted only with nose blowing, is common and may not be clinically important. Continuous epistaxis that requires intervention with nasal packing or cauterization may be predictive of greater risk for more serious bleeding.

Severe or critical hemorrhage – In contrast to minor bleeding such as petechiae and purpura, severe or critical bleeding is less common. This was illustrated in a systematic review of prospective clinical studies, which included 5336 adults with primary ITP [53]. The proportion of adults with bleeding was as follows:

ICH – 1.4 percent

Non-ICH severe bleeding – 9.6 percent

Reported rates of bleeding are variable, depending on the population, the definition of bleeding, and the methods of reporting. In a population-based study that included 3771 patients with ITP, the risk of severe gastrointestinal or central nervous system bleeding at disease onset was <1 percent [49]. In a prospective registry that included 269 patients with ITP, 152 (57 percent) had bleeding occurrences, most of which were localized to the skin or mouth [51]. These rates are likely higher than will be encountered in day-to-day clinical practice where many patients will be detected on routine CBCs, as opposed to studies in which patients were selected because they were identified as a result of signs or symptoms of thrombocytopenia.

Predictors of clinically important bleeding (which typically include severe and critical bleeding (see "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Definitions of bleeding severity')) in individual studies include the degree of thrombocytopenia (from <10,000 to <20,000, depending on the study), previous minor bleeding, use of nonsteroidal anti-inflammatory drugs (NSAIDs), female sex, and chronic ITP (diagnosis >12 months prior), although individual predictors are not consistent across all studies [53,54]. The frequency of bleeding may also increase with age and comorbidities. Major, spontaneous bleeding with a platelet count >20,000 is rare. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Prognosis'.)

Thrombocytopenia — ITP is defined by thrombocytopenia, and by consensus, the threshold for ITP is a platelet count <100,000/microL [1]. The severity of thrombocytopenia in patients with ITP is variable; the greatest concern for bleeding is with platelet counts <20,000/microL.

Large platelets are often noted on the peripheral blood smear. However, the absence of large platelets cannot be used to exclude the diagnosis of ITP. (See 'Laboratory testing' below.)

Importantly, however, ITP is not characterized by abnormal platelet morphology (eg, lack of granules, uniform populations of large or small platelets), or other abnormalities on the peripheral blood smear. If present, abnormal platelet morphology should prompt consideration of a hereditary platelet disorder. (See 'Laboratory testing' below.)

Correlation of bleeding and thrombocytopenia — Patients with more severe thrombocytopenia (eg, platelet count <20,000/microL) are more likely to have clinically important bleeding than those with higher counts. However, the correlation between platelet count and bleeding risk is weak, and few data describe the risk of clinically important bleeding at different levels of thrombocytopenia.

Furthermore, the incidence of bleeding in ITP cannot be inferred from rates of bleeding in other forms of thrombocytopenia associated with abnormal platelet function, because circulating platelets in patients with ITP are younger and may have greater hemostatic effectiveness [55]. As a result, bleeding manifestations in patients with ITP tend to be less severe at equivalent platelet counts than in patients with thrombocytopenia due to bone marrow suppression.

Because the risk of clinically important bleeding is low with platelet counts >20,000/microL, we generally do not use therapies to increase the platelet count in individuals with a stable platelet count >20,000/microL unless there are other comorbidities or medications that increase bleeding risk; this is consistent with a guideline from the American Society of Hematology (ASH) [56]. This slightly higher threshold allows a measure of safety and accommodates minor day-to-day fluctuations in platelet count, as discussed in detail separately. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Overview of decision-making'.)

Fatigue and quality of life — Fatigue is a common symptom among patients with ITP. It often correlates with thrombocytopenia but can occur even when the platelet count is only mildly reduced. Examples of studies that demonstrate this association include the following:

A 2021 study involving 1507 patients with ITP reported that fatigue was the most common, severe symptom associated with ITP at diagnosis, affecting over half of the individuals [57]. Fatigue often persisted and was the symptom that patients most wanted to have addressed.

A 2011 survey study of 585 members of the United Kingdom ITP support association and 68 individuals in the Oklahoma (United States) ITP registry documented that fatigue was common [58]. Significant fatigue (based on the fatigue impact scale [FIS]) was present in 39 and 22 percent of the United Kingdom and United States cohorts, respectively. Most of the patients believed that fatigue was worse when their platelet count was low (69 and 50 percent, respectively).

A 2008 study that surveyed health-related quality of life in 73 individuals with chronic ITP using the SF-36 questionnaire found that, compared with controls in the general United States population for whom SF-36 score results were available, the individuals with chronic ITP had lower scores across several domains including general health, vitality, social functioning mental health, and physical functioning [59]. Within the ITP group, scores were not dramatically different in those taking medications compared with those not taking medications. When compared with scores associated with other chronic conditions, individuals with ITP were most similar to those with diabetes mellitus; they were lower than individuals with hypertension and higher than people with congestive heart failure or people who were missing a limb.

The causes of fatigue in ITP are not well understood. Some experts have suggested that contributing factors may include associated conditions and comorbidities (eg, systemic lupus erythematosus [SLE], hypothyroidism), activity restrictions, adverse effects of medical therapies (eg, sleep disturbance from glucocorticoids), older age, higher stress level, autonomic dysfunction, and/or adverse effects caused by proinflammatory cytokines [58,60].

Thrombosis (rare) — Thrombocytopenia in people with ITP is not necessarily protective against thrombosis. Several studies have documented an increased risk of thrombosis in people with ITP compared with controls [61-64].

The pathogenesis of hypercoagulability in ITP is not well understood. It may relate to inflammation, antiphospholipid antibodies in some patients, or the effects of certain treatments such as splenectomy, glucocorticoids, and/or thrombopoietin receptor agonists (TPO-RAs).

No effects on WBCs and RBCs — Other cell lines (white blood cells [WBCs] or red blood cells [RBCs]) are characteristically normal in ITP (unless the ITP is secondary to a condition that affects these cell types). Coagulation parameters are also typically normal.

Abnormal findings in other cell lines in association with thrombocytopenia should prompt urgent evaluation for other conditions. As examples:

Immature white blood cells may suggest infection or leukemia

Schistocytes may suggest a microangiopathic process such as thrombotic thrombocytopenic purpura (TTP)

Prolonged clotting times may suggest liver disease or disseminated intravascular coagulation (DIC)

These and other potential alternative diagnoses are discussed in detail separately. (See "Diagnostic approach to the adult with unexplained thrombocytopenia".)

An exception to this rule is iron deficiency, which may occur in patients with ITP as a result of blood loss. Characteristic morphologic findings include hypochromic microcytic erythrocytes with poikilocytosis. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

DIAGNOSTIC EVALUATION — ITP is a diagnosis of exclusion that is made in patients with isolated thrombocytopenia (ie, without anemia or leukopenia). Thus, important components of the diagnostic evaluation include excluding other possible causes of thrombocytopenia and identifying conditions that may be responsible for secondary ITP.

Preliminary evaluation — The diagnosis of ITP requires that other potential causes of thrombocytopenia be excluded. Many potential causes will be apparent from the history, physical examination, and review of the complete blood count (CBC) (table 3). However, thrombocytopenia caused by a medication or ingested substance may require specific questioning (or detailed review of the hospital record) to identify the responsible agent.

Site of evaluation (inpatient versus outpatient) — For patients with presumed ITP who have severe bleeding, urgent hospitalization with early involvement of the consulting hematologist is appropriate to confirm the diagnosis, exclude other potential causes of bleeding, and assist with appropriate therapies. The 2019 American Society of Hematology Guidelines suggest for adults with newly diagnosed ITP and a platelet count <20,000/microL [56]. This subject is discussed in more detail separately. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'When to obtain hematology consultation'.)

Individuals with thrombocytopenia that is stable without bleeding may be managed as outpatients in many cases, as long as there is close hematologic monitoring and a plan for urgent management should bleeding arise. These individuals should receive education and expedited follow up with a hematologist.

Patients may require admission for other reasons, most frequently to facilitate investigations of the cause of the thrombocytopenia, to treat secondary causes, to address comorbidities with risk of bleeding, and if follow up cannot be assured. Patients with severe thrombocytopenia, those with wet purpura, or those with a history of bleeding may be hospitalized in the absence of bleeding as there is a perception they have a high risk of bleeding, and that such bleeding might be more easily treated in the hospital [56].

History — The history should elicit recent infections, medications (table 1), and underlying conditions such as rheumatologic disorders or liver disease, which may be associated with thrombocytopenia. It is especially important to ask about medications used only transiently; beverages, including tonic water (a source of quinine) (table 4); herbal remedies; and foods. If the patient is unable to provide this information, attempts should be made to query family members and/or the hospital record.

We also ask about bleeding symptoms, bruising, and petechiae. Additional details of the history related to other potential causes of thrombocytopenia (eg, family history of platelet disorders) are presented separately. (See "Diagnostic approach to the adult with unexplained thrombocytopenia", section on 'History'.)

Physical examination — The physical examination is focused on signs of bleeding, specifically on the skin and oral mucous membranes, which would suggest the need for more urgent evaluation and therapy; and the presence of lymphadenopathy or hepatosplenomegaly, which could suggest an underlying condition responsible for the thrombocytopenia.

Laboratory testing — Once other conditions associated with thrombocytopenia have been excluded, the minimum diagnostic investigations that should be done in patients suspected of having ITP are as follows, as stated in a number of guidelines [1,2,39,65,66]:

Peripheral blood smear – We review the peripheral blood smear (or request review by an experienced clinician or laboratory personnel) to confirm that thrombocytopenia is not artifactual due to platelet clumping (ie, pseudothrombocytopenia) and that there are no morphologic platelet abnormalities such as lack of platelet granules or uniformly large or small platelets, which could suggest a hereditary platelet disorder. While the presence of large platelets may be noted, there are no high-quality data to support the use of platelet size to confirm or exclude the diagnosis of ITP. (See "Diagnostic approach to the adult with unexplained thrombocytopenia", section on 'Peripheral blood smear' and "Automated hematology instrumentation", section on 'Platelet count and size'.)

HIV and HCV testing – We test all patients for HIV and hepatitis C virus (HCV) infection because thrombocytopenia is a common presenting finding for these conditions, and treatment of the underlying infection might improve the platelet count [65,66]. (See "Screening and diagnostic testing for HIV infection" and "Screening and diagnosis of chronic hepatitis C virus infection" and "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Evaluation for secondary ITP'.)

Recommendations from an expert panel include a broader scope of laboratory testing [65]; however, this approach requires additional validation. Additional investigations should be pursued if symptoms or signs suggestive of other conditions are present. (See 'Additional testing in selected patients' below.)

Additional testing in selected patients — The following testing may be reasonable for patients with suspected ITP, depending on the clinical setting:

Coagulation studies – Coagulation studies are not required in patients who have mild thrombocytopenia without clinically important bleeding. However, we perform a prothrombin time (PT) and activated partial thromboplastin time (aPTT) in individuals with moderate or severe thrombocytopenia, those with concerns about clinically important bleeding, and/or those who have planned invasive procedures. The purpose is to investigate and treat other potential causes of thrombocytopenia (eg, liver disease, disseminated intravascular coagulation [DIC]) and bleeding (eg, vitamin K deficiency). (See "Clinical use of coagulation tests" and "Approach to the adult with a suspected bleeding disorder".)

Helicobacter pylori testing – Testing for H. pylori is appropriate in patients with gastrointestinal symptoms suggestive of infection because of a reported association between ITP and H. pylori infection. Routine screening for H. pylori may be reasonable in asymptomatic individuals as well, especially those from countries where H. pylori infection is endemic (eg, Japan). H. pylori-induced ITP is expected to be rare in the United States and Canada. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'H. pylori testing'.)

Thyroid function testing – Thyroid function testing is appropriate in patients with symptoms of hypo- or hyperthyroidism because of rare reports of ITP associated with thyroid disorders. Patients who require surgery such as splenectomy to treat ITP (or an unrelated surgery) are often screened for occult hypo- or hyperthyroidism prior to the procedure due to the increased risk of perioperative complications [7,67,68].

Bone marrow examination – Bone marrow examination was previously considered a routine diagnostic test in patients with ITP who were >60 years of age to exclude the possibility of a myelodysplastic syndrome (MDS) [39,69,70]. However, this practice is no longer recommended, since long-term monitoring of older adults with ITP has not revealed an increased incidence of MDS [66,71,72]. In a blinded study of bone marrow biopsy specimens from individuals with ITP compared with nonthrombocytopenic controls, bone marrow examination was not helpful in distinguishing individuals with ITP from controls [72]. Typically, cellularity is normal, numbers of megakaryocytes are normal or increased, and erythropoiesis and myelopoiesis are normal. In some patients, a shift towards younger megakaryocytes with lesser degrees of nuclear polyploidy and less evidence of platelet production may be noted. (See "Megakaryocyte biology and the production of platelets", section on 'Immune thrombocytopenia (ITP)'.)

Bone marrow examination may be indicated for patients with other unexplained cytopenias (anemia, leukopenia), dysplasia on the peripheral blood smear, other unexpected hematologic findings, or other causes of thrombocytopenia, when suspected. (See "Bone marrow aspiration and biopsy: Indications and technique", section on 'Indications'.)

Patients whose platelet counts do not respond to ITP therapy may warrant a bone marrow examination to investigate for MDS or other platelet production abnormalities such as acquired amegakaryocytic thrombocytopenia.

Immunologic studies – Testing for antinuclear antibodies (ANAs) may not be necessary in patients without symptoms of rheumatologic conditions such as systemic lupus erythematosus (SLE). However, this testing may be appropriate in those with characteristic symptoms (eg, malar rash, constitutional symptoms, arthritis, myalgia) or other suggestive findings. Quantitative immunoglobulin levels may identify underlying common variable immune deficiency (CVID) or selective IgA deficiency, especially in younger patients. (See 'Inciting events' above and "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)

Vitamin B12 and folate levels – We do not routinely measure vitamin B12 and folate levels in otherwise asymptomatic patients. However, these vitamins are required for hematopoiesis, and their deficiency may present with mild thrombocytopenia. It is appropriate to measure levels in those with other findings attributable to these deficiencies (eg, neurologic or psychiatric changes, macrocytic anemia, hypersegmented neutrophils), dietary practices associated with decreased intake, or conditions that impair absorption such as gastric bypass procedures. (See "Late complications of bariatric surgical operations", section on 'Metabolic and nutritional derangements' and "Treatment of vitamin B12 and folate deficiencies".)

Other testing – Patients with a consistent history or physical findings suggestive of liver disease should be evaluated with liver function testing.

Patients who will receive rituximab should be tested for hepatitis B surface antigen (HBSAg) and hepatitis B core antibody (anti-HBc); this testing should be done prior to administration of intravenous immune globulin (IVIG) due to concerns that treatment with IVIG may cause false positive results from passively acquired anti-HBc antibodies. (See "Hepatitis B virus: Screening and diagnosis".)

Other testing may be indicated in patients with atypical clinical features. As an example, patients with bleeding out of proportion to the degree of thrombocytopenia may warrant evaluation for less common conditions such as type 2B von Willebrand disease (VWD), Bernard-Soulier syndrome, or other inherited or acquired platelet disorders [73]. Genetic testing may be indicated in suspected hereditary thrombocytopenia. Details of this testing are discussed separately. (See "Congenital and acquired disorders of platelet function".)

Antiplatelet antibody testing — Antiplatelet antibody testing has low sensitivity and does not correlate with clinical outcomes [2,38,73-80]. Thus, these tests are not recommended to aid in the routine diagnosis or management of ITP [69].

Diagnosis — ITP is a diagnosis of exclusion. It is defined as isolated thrombocytopenia (platelet count <100,000/microL) without anemia or leukopenia and without another apparent cause of thrombocytopenia [1,65,66,81].

We make a presumptive diagnosis of primary ITP when the history, physical examination, and laboratory testing (including review of the peripheral blood smear) do not reveal other potential etiologies for thrombocytopenia.

We make a presumptive diagnosis of secondary ITP in a patient with ITP and an underlying associated condition (table 2).

Importantly, a diagnosis of ITP does not imply that therapy is required, especially in a patient with mild thrombocytopenia and absence of clinical bleeding. Indications for ITP therapy are presented in detail separately. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Overview of decision-making'.)

Hematologist involvement — For individuals who are acutely ill or bleeding and require hospitalization, early involvement of the consulting hematologist is appropriate to confirm the diagnosis, exclude other potential causes of bleeding, and assist with appropriate therapies. (See 'Site of evaluation (inpatient versus outpatient)' above.)

Hematologist involvement is also appropriate, but less urgent, for patients with platelet counts persistently <100,000/microL, to establish a baseline for the platelet count, exclude alternative or secondary causes (by reviewing the blood smear and other clinical features), and plan a course of action should treatment be required in the future. For asymptomatic patients, platelet counts between 100,000 and 150,000/microL, hematologic consultation can be pursued but may not be required in all cases.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of ITP includes a variety of inherited and acquired conditions (table 3). Thrombocytopenic conditions that are frequently considered in the differential diagnosis include the following:

Drug-induced thrombocytopenia – Many drugs can cause thrombocytopenia (table 1).

Bone marrow suppression – Certain chemotherapy agents and medications used for other conditions (hydroxyurea for sickle cell disease) can cause predictable bone marrow suppression with pancytopenia. Other medications such as valproic acid and linezolid can cause isolated thrombocytopenia by impairing thrombopoiesis. (See "Megakaryocyte biology and the production of platelets".)

DITP – Drug-induced immune thrombocytopenia (DITP) is often clinically indistinguishable from ITP because patients are otherwise well except for thrombocytopenia and/or bleeding symptoms. Unlike ITP, DITP is induced and/or perpetuated by the presence of a drug or other ingested substance (eg, quinine, walnuts) and is expected to resolve upon drug discontinuation. Details of the evaluation of possible DITP are presented separately. Many drugs have been reported to be associated with the development of DITP, which may be due to the active ingredient, excipients or the dye used in the tablets. (See "Drug-induced immune thrombocytopenia".)

HIT – Heparin-induced thrombocytopenia (HIT) is a form of drug-induced thrombocytopenia associated with the potential for arterial and venous thrombosis, which can be potentially life-threatening. The characteristic temporal exposure to heparin, clinical findings, diagnosis, and management of HIT are discussed in detail separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Management of heparin-induced thrombocytopenia".)

DITMA – Certain medications (cancer therapies, immunosuppressive agents, antibiotics), drugs, and substances, including quinine and drugs of abuse, may cause thrombocytopenia as a component of a drug-induced thrombotic microangiopathy (DITMA). Unlike ITP, DITMA is associated with hemolytic anemia; sometimes DITMA is accompanied by signs or symptoms of systemic disease and/or organ involvement. (See "Drug-induced thrombotic microangiopathy (DITMA)".)

Infections – A variety of infections can cause thrombocytopenia by a variety of non-immune mechanisms including bone marrow suppression, hypersplenism, and platelet consumption. In addition, acute infections can cause an immune-mediated thrombocytopenia, in which case patients typically recall an acute symptomatic period with fever, rash, and/or constitutional symptoms. The thrombocytopenia associated with self-limited infections is typically transient. (See "Diagnostic approach to the adult with unexplained thrombocytopenia", section on 'Causes of thrombocytopenia'.)

Chronic infections with HIV or hepatitis C virus (HCV) often cause thrombocytopenia, in some cases as a form of secondary ITP and in other cases by non-immune mechanisms (eg, bone marrow suppression, hypersplenism). (See "Extrahepatic manifestations of hepatitis C virus infection", section on 'Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia'.)

Liver disease and hypersplenism – Liver disease and/or other causes of hypersplenism frequently cause mild thrombocytopenia by pooling of platelets in the spleen. Cirrhosis can also cause decreased levels of thrombopoietin, which contributes to thrombocytopenia. Unlike ITP, patients typically have elevations in transaminases and may have a palpable liver or spleen; however, hepatosplenomegaly may be difficult to appreciate in some patients. In severe cases of liver disease, patients may also have coagulation abnormalities, which are absent in ITP.

Microangiopathic processes – Microangiopathic processes include hereditary and acquired conditions associated with diffuse microvascular coagulation and/or thrombosis; these processes cause thrombocytopenia from platelet consumption in thrombi. Examples include thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and disseminated intravascular coagulation (DIC). Like ITP, these conditions cause thrombocytopenia and sometimes bleeding. Unlike ITP, TTP, HUS, and DIC are associated with microangiopathic hemolytic anemia (eg, schistocytes on the peripheral blood smear); DIC is also associated with coagulation abnormalities. Unlike individuals with ITP, who are otherwise well, patients with microangiopathic hemolytic anemia are often quite ill. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Diagnosis of immune TTP".)

Hereditary thrombocytopenia – A variety of hereditary thrombocytopenias have mild clinical phenotypes and only present during adulthood when there is a hemostatic challenge (eg, trauma, surgery) or a routine platelet count is measured. Like ITP, these disorders may be characterized by isolated thrombocytopenia with mild or no clinical bleeding. Unlike ITP, these conditions may have morphologic abnormalities of platelets on the peripheral blood smear. Examples include giant platelets (the size of red blood cells) in May-Hegglin anomaly or Bernard-Soulier syndrome, or an absence of platelet granules in gray platelet syndrome. Some individuals may also have other characteristic clinical features associated with inherited syndromes; these are discussed in detail separately. (See "Neonatal thrombocytopenia: Etiology", section on 'Genetic disorders' and "Congenital and acquired disorders of platelet function".)

Von Willebrand disease (VWD) is an inherited condition primarily due to mutations in the von Willebrand factor gene; the primary effect is impaired platelet adhesion to sites of injury and reduced factor VIII levels. However, patients with the type 2B subtype of VWD may also have mild thrombocytopenia. In patients with type 2B VWD, bleeding severity may be out of proportion to the platelet count, there may be a positive family history, and laboratory testing will reveal characteristic reduced ristocetin cofactor activity with a decrease in high molecular weight von Willebrand factor multimers. (See "Pathophysiology of von Willebrand disease".)

Myelodysplastic syndromes and other acquired bone marrow disorders – Myelodysplastic syndromes (MDS) are acquired bone marrow disorders associated with impaired hematopoiesis and a risk of progression to leukemia. Unlike ITP, these syndromes are typically progressive and often associated with other cytopenias (eg, anemia, leukopenia) as well as dysplastic cells and/or increased numbers of immature cells in the peripheral blood and bone marrow. Rarely, however, MDS may present with isolated thrombocytopenia; this finding is most often seen in those with an isolated deletion in the long arm of chromosome 20 (20q). (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)".)

Acquired pure megakaryocytic aplasia (amegakaryocytic thrombocytopenia) is a rare condition in which antibodies to the thrombopoietin receptor on megakaryocytes (platelet precursor cells in the bone marrow) cause very severe thrombocytopenia. Like ITP, amegakaryocytic thrombocytopenia is associated with isolated thrombocytopenia. (See "Hematologic manifestations of systemic lupus erythematosus", section on 'Thrombocytopenia'.)

A more comprehensive overview of our approach to determining the cause of thrombocytopenia in an adult is presented in detail separately. (See "Diagnostic approach to the adult with unexplained thrombocytopenia".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immune thrombocytopenia (ITP) and other platelet disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Immune thrombocytopenia (ITP) (The Basics)")

SUMMARY AND RECOMMENDATIONS

Pathogenesis – The pathogenesis of immune thrombocytopenia (ITP) is related to a combination of increased platelet destruction and impaired platelet production attributed to antiplatelet autoantibodies. (See 'Pathogenesis' above.)

Prevalence – ITP is a common acquired bleeding disorder (figure 1). ITP is often a chronic disease in adults; thus, the prevalence (approximately 12 per 100,000 adults) exceeds the incidence. (See 'Epidemiology' above.)

Clinical findings – The clinical manifestations of ITP are mostly related to bleeding; fatigue occurs in some patients. Bleeding may occur in up to two-thirds of patients; however, many are asymptomatic. Serious bleeding is seen most often in individuals with platelet counts <20,000/microL, but the overall correlation between bleeding and the platelet count is weak. (See 'Clinical manifestations' above.)

Evaluation – The diagnosis of ITP requires that other causes of thrombocytopenia be eliminated. Many potential causes are obvious from the history, physical examination, and review of the complete blood count (CBC) (table 3). However, thrombocytopenia caused by a medication, beverage, or food may require specific questioning (or review of the hospital record) to elicit the responsible agent (table 1 and table 4). For patients with presumed ITP who have severe bleeding, urgent hospitalization with early involvement of the consulting hematologist is appropriate; however, many cases of ITP can be safely diagnosed and managed without hospital admission. (See 'Preliminary evaluation' above.)

Post-diagnostic testing – Once other obvious conditions have been excluded, few remaining diagnostic studies are needed. We review the peripheral blood smear (or request review) and test all patients for HIV and hepatitis C virus (HCV) infection. (See 'Laboratory testing' above.)

Limited role of bone marrow and other tests – Additional laboratory testing reserved for selected patients may include coagulation studies, transaminase measurements, rheumatologic testing, and bone marrow examination. Bone marrow examination should be confined to patients with a suspected bone marrow disorder, rather than as a test for ITP. (See 'Additional testing in selected patients' above.)

Diagnosis – We make a presumptive diagnosis of primary ITP when the evaluation does not reveal other potential etiologies for thrombocytopenia. We make a presumptive diagnosis of secondary ITP in a patient with ITP and an underlying associated condition such as those listed in the table (table 2). (See 'Diagnosis' above.)

Differential – The differential diagnosis of ITP includes a variety of inherited and acquired conditions such as drug-induced thrombocytopenia, infections, liver disease and hypersplenism; microangiopathic processes; congenital thrombocytopenic conditions; and bone marrow disorders such as myelodysplastic syndromes (MDS). (See 'Differential diagnosis' above and "Diagnostic approach to the adult with unexplained thrombocytopenia".)

Other populations – ITP in children and during pregnancy is discussed separately. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis" and "Thrombocytopenia in pregnancy".)

Management – Management of ITP is discussed separately. (See "Initial treatment of immune thrombocytopenia (ITP) in adults" and "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults" and "Immune thrombocytopenia (ITP) in children: Initial management" and "Immune thrombocytopenia (ITP) in children: Management of chronic disease".)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges James N George, MD, and Lawrence LK Leung, MD, who contributed to many earlier versions of this topic review.

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