Immune Thrombocytopenia - Clinical Tree

Immune thrombocytopenia (ITP), formerly called idiopathic thrombocytopenic purpura, is a common acquired bleeding disordered characterized by isolated thrombocytopenia in the absence of a clinically apparent cause. Currently there is no diagnostic test for ITP; thus establishing the diagnosis can be difficult and requires a thorough search for underlying conditions. Primary ITP (which is often simply designated “ITP”) is clinically indistinguishable from secondary ITP that occurs in the setting of certain drugs, autoimmune disorders such as systemic lupus erythematosus (SLE), lymphoproliferative disorders and infections such as human immunodeficiency virus (HIV), hepatitis C, and Helicobacter pylori .

This chapter will focus on the diagnostic challenges and management algorithms for ITP in adults. An overview of ITP in children is presented in Box 8.1 . Patients may be identified as having ITP based on a routine blood count without any symptoms or may present acutely with the abrupt onset of bleeding. Most adults with new-onset ITP typically have a relapsing and remitting course, whereas in children the condition often resolves spontaneously or with minimal treatment.

Box 8.1

Overview of Primary Immune Thrombocytopenia in Children

Incidence, Clinical Manifestations, and Natural History

1.
Incidence of ITP in children is approximately 2–5 per 100,000 with a peak between age 2 and 5 years; diagnosis is frequently preceded by infection.
2.
Severe bleeding occurs in 3% of children at the time of diagnosis.
3.
Incidence of intracranial hemorrhage is 0.4%.
4.
Complete remission occurs in 75% of children (platelet count >150 × 10 ⁹ /L) within 6 months, with or without pharmacologic therapy.

Initial Management Options

1.
Watchful waiting is appropriate for most children with no bleeding or minimal bleeding, irrespective of platelet count.
2.
First-line pharmacologic interventions :
- a.
  IVIG : Given as a single dose of 0.8–1 g/kg. Side effects include headache and nausea and vomiting.
- b.
  Corticosteroids : A variety of corticosteroid regimens are used (e.g., prednisone 1–2 mg/kg per day for several weeks with taper; or methylprednisolone 30 mg/kg per day for 3–4 days with no taper). Side effects include behavioral changes, weight gain, hypertension, and gastritis.

Management Options for Chronic Immune Thrombocytopenia

1.
Periodic re-treatment with first-line therapies (IVIG, corticosteroids). Prolonged courses of corticosteroids should be avoided.
2.
Rituximab : A series of 49 patients reported a 69% overall response rate. No severe or delayed toxicities attributable to rituximab were reported.
3.
TPO receptor agonists: In a multicenter placebo-controlled randomized trial, 25/63 (40%) of children with chronic ITP who received eltrombopag achieved a platelet count response (platelet count >50 × 10 ⁹ /L) compared with 1/29 (3%) of children who received placebo. Two children in the eltrombopag group discontinued treatment due to elevated liver aminotransferases. Comparable response rates have been observed in randomized trials of romiplostim in children.
4.
Splenectomy: Causes a sustained remission in 70%–80% of children but carries a high risk of overwhelming infection.

ITP , Immune thrombocytopenia; IVIG , intravenous immunoglobulin; TPO , thrombopoietin.

Epidemiology

The incidence of ITP in adults is approximately 3 to 6 per 10,000 adults per year. Multiple studies of the epidemiology of ITP in adults have documented consistent observations: (1) The incidence has increased during the past several decades, principally because of increased detection of asymptomatic patients with mild thrombocytopenia. Currently, as many as one-third of ITP patients may be discovered unexpectedly. (2) The incidence increases with age. (3) The female predominance characteristically present in previous case series is not evident in patients older than 60 years. Among older patients with ITP, men appear to predominate. The predominance of young women with ITP is similar to other autoimmune disorders, such as SLE and thrombotic thrombocytopenic purpura. The predominance of men among older patients with ITP is similar to the increased incidence of lymphoproliferative disorders, which can be associated with ITP. Because ITP in adults is typically a persistent disorder and because the mortality is low, the prevalence of ITP exceeds the incidence. Recent studies have estimated the 1-year period prevalence of ITP to be 7.1 to 9.5 per 10 ⁵ adults.

Pathogenesis

ITP was initially considered to be caused by increased platelet destruction. This concept was supported by dramatic in vivo studies in human volunteers demonstrating the presence of antiplatelet antibodies in the plasma of patients with ITP. The initial report of Harrington, Hollingsworth, and others described how the authors infused themselves and their colleagues with plasma from patients with acute, severe ITP and subsequently developed prompt, profound thrombocytopenia. Shulman and others extended these studies with quantitative assessment of infusions of ITP plasma into asplenic individuals. Increasing volumes of plasma from an ITP patient transfused into a normal subject caused increasingly severe thrombocytopenia; however, larger volumes of ITP plasma were required to cause the same degree of thrombocytopenia in an asplenic subject. This observation identified the principal role of the spleen in removing antibody-sensitized platelets. Subsequent studies have documented the presence of platelet-specific autoantibodies directed against platelet glycoproteins (GPs), specifically anti-GPIIbIIIa and anti-GPIbIX in patients with ITP. In prospective studies the prevalence of these antibodies was 40% to 60%.

Besides increased platelet production, decreased platelet production is also an important mechanism of the thrombocytopenia in ITP. Platelet survival studies using autologous radiolabeled platelets in patients with ITP have shown that the rate of platelet production does not compensate adequately for the degree of platelet production. Anti-GP antibodies have also been shown to impair growth and survival of bone marrow megakaryocytes in some patients with ITP. The clinical importance of decreased platelet production in the pathogenesis of ITP is emphasized by the effectiveness of treatment with thrombopoietin (TPO) receptor agonists, which increase megakaryocyte numbers in the bone marrow and ultimately lead to increased platelet production.

Clinical Presentation

Thrombocytopenia

Very few platelets are required to provide adequate hemostasis. Clinical studies in other disorders, such as aplastic anemia and thrombocytopenia following chemotherapy for acute leukemia, suggest that spontaneous, clinically important bleeding occurs only with platelet counts below 5 to 10 × 10 ⁹ /L. Because patients with ITP have a relative increase in younger, hemostatically intact platelets, these patients may have an even lower risk for bleeding at comparable platelet counts. Although there is no absolute platelet count threshold below which bleeding is inevitable, treatment is generally recommended for a platelet count below 20 × 10 ⁹ /L to avoid bleeding complications. This threshold may be lower in patients with chronic ITP who have not experienced bleeding complications even at low platelet count levels, or higher in patients who have additional bleeding risks including anticoagulant or antiplatelet medications or in the context of invasive procedures or surgery. Based on little evidence, minimum platelet count levels of 50 × 10 ⁹ /L are often stated for minor procedures; and 80 to 100 × 10 ⁹ /L for surgery at critical sites, such as neurosurgery or epidural anesthesia. Evidence-based platelet count thresholds for patients treated with anticoagulant or antiplatelet medications are lacking; empirically, a minimal threshold of 30 to 50 × 10 ⁹ /L is often used.

Bleeding

Mucocutaneous bleeding is the principal symptom of patients with ITP, manifested by spontaneous skin bruises and petechiae and oral mucous membrane purpura. Menorrhagia is also common. Gastrointestinal bleeding is uncommon but can be severe. Intracranial bleeding, the most critical complication of ITP, has been reported to occur in 1.0% of children and 1.4% of adults. A consistent clinical observation is that most patients with ITP never have clinically important bleeding, even when their platelet counts are very low. Cutaneous bleeding symptoms are often referred to as “dry purpura,” to distinguish them from overt mucous membrane bleeding, such as oral purpura, epistaxis, or gingival bleeding, referred to as “wet purpura.” Wet purpura may be associated with greater risk for major bleeding.

Fatigue

Evaluation of patients with ITP by standardized questionnaires to assess health-related quality of life have documented that symptoms in addition to bleeding are important. Fatigue is frequently described as a major problem. Patients often relate fatigue to the severity of their thrombocytopenia and treatment to increase platelet counts has been shown to improve health-related quality of life. A survey of patients with ITP using a validated symptom assessment scale documented significant symptoms of fatigue in 22% to 39% of patients with ITP. Fatigue was significantly associated with lower platelet counts, bleeding symptoms, and treatment with corticosteroids. Fatigue was not associated with age, gender, or duration of ITP. The biologic basis of fatigue in ITP is not known but is likely linked through inflammatory processes.

Long-Term Outcomes

Death rarely occurs, and when it occurs it may be more commonly related to complications of treatment than to bleeding. Two large cohort studies of 115 and 191 patients who presented with platelet counts less than 30 × 10 ⁹ /L have reported that only 4% and 17% of patients continued to have bleeding symptoms requiring treatment at the end of the observation time (median follow-up times, 5 and 11 years). In the combined experience of these two cohort studies, 7 (2.3%) patients died, 4 (1.3%) from infections related to immunosuppressive treatment or splenectomy and 3 (1.0%) from bleeding. Other studies have reported that patients with ITP have increased risk for infection and all-cause mortality compared with the general population. An increase in the rate of venous thrombosis has been documented in some reports.

Evaluation of a Patient With Suspected Immune Thrombocytopenia

In many patients, the history, physical examination, and examination of the peripheral blood smear are sufficient to exclude other possible etiologies of thrombocytopenia. A platelet count response to immune-modulating treatment with corticosteroids or intravenous immunoglobulin (IVIG) and the severity of the thrombocytopenia provide additional diagnostic confirmation of the diagnosis of ITP.

Spleen size is normal in patients with ITP. One large study reported palpable spleens in 7 of 271 (2.6%) patients, a frequency similar to the 2.9% incidence of palpable spleens in healthy college students. Enlargement of the spleen may indicate a nonimmune cause of the thrombocytopenia, such as liver disease or hypersplenism; or secondary ITP in the setting of a lymphoproliferative disorder, common variable immune deficiency or Coombs-positive hemolytic anemia (Evan syndrome).

Several features of peripheral blood morphology are important for the investigation of patients with suspected ITP ( Table 8.1 ). First, actual thrombocytopenia, rather than in vitro platelet clumping (pseudothrombocytopenia), should be confirmed. Second, platelet morphology should be normal, although some reports describe larger platelets in ITP, postulated to represent younger reticulated platelets produced in response to the accelerated peripheral platelet destruction. Giant platelets, approaching or exceeding the size of red blood cells, may indicate an inherited thrombocytopenic disorder rather than ITP. Third, there should be no abnormalities of red cell or white cell number or morphology, other than expected associated conditions such as iron deficiency from chronic blood loss or incidental conditions such as thalassemia minor.

TABLE 8.1

The Peripheral Blood Smear in Immune Thrombocytopenia

Features Consistent With the Diagnosis of Immune Thrombocytopenia

1.
Thrombocytopenia, with normal platelet size and morphology, or slightly larger than normal platelets.
2.
Normal red cell number and morphology. Exceptions may be abnormalities from expected associated conditions, such iron deficiency from chronic bleeding, or incidental conditions, such as thalassemia minor.
3.
Normal white cell number and morphology.

Features Not Consistent With the Diagnosis of Immune Thrombocytopenia

1.
Predominance of giant platelets, similar to the diameter of red cells.
2.
Red cell abnormalities such as schistocytes, oval macrocytes, teardrop cells, and nucleated red cells.
3.
Leukocytosis or leucopenia with immature or abnormal cells.

Guidelines published by the American Society of Hematology recommend that all patients with suspected ITP should be tested for HIV and hepatitis C because these infections may not be clinically apparent and can cause secondary ITP, which responds to treatment of the underlying cause. Testing for hepatitis B infection is also reasonable, anticipating that many patients will require immunosuppressant medications such as rituximab, which can cause hepatitis B reactivation. Other screening tests could include thyroid-stimulating hormone levels, because autoimmune thyroid disease is a common association, and H. pylori testing in geographic regions where colonization is endemic and has been linked to the development of ITP (e.g., Japan and Italy). Testing for antiplatelet antibodies is not a necessary part of routine investigations of patients with suspected ITP, mostly because the sensitivity of this test is low ; however, some studies have shown that the presence of a platelet GP-specific antibody directly on the platelet surface is specific for the diagnosis of ITP.

Bone marrow aspirate and biopsy examinations are not required to rule in the diagnosis of ITP but should be used to rule out other causes of the thrombocytopenia when atypical features are present (abnormalities in other cell lines, or lack of response to IVIG or corticosteroids). In a blind study of biopsy specimens, assessors were unable to distinguish ITP bone marrows from normal bone marrows based on morphologic examination.

Differential Diagnosis of Immune Thrombocytopenia

Establishing the correct diagnosis of thrombocytopenia remains one of the most important challenges in the management of patients with ITP. The clinical and laboratory features are nonspecific (e.g., isolated thrombocytopenia), and there currently is no diagnostic test. Thus investigations should focus on excluding other causes of nonimmune and secondary immune causes of the thrombocytopenia ( Table 8.2 ).

TABLE 8.2

Differential Diagnosis of Immune Thrombocytopenia

Disorders	Clinical Features
Pseudothrombocytopenia
EDTA-dependent clumping	Actual platelet count normal but falsely low on laboratory report because platelets are clumped in vitro and on blood smear
Platelet satellitism	Actual platelet count normal; in vitro platelets adhere to granulocytes or monocytes
Common Causes of Thrombocytopenia
Drug-induced thrombocytopenia	Initially indistinguishable from ITP. Diagnosis established by prompt recovery upon withdrawal of the drug and, in some circumstances, rechallenge. May also be caused by nutrition products, herbal remedies, foods, and quinine-containing beverages.
Pregnancy	Asymptomatic, mild thrombocytopenia is common near term. This most often represents incidental thrombocytopenia of pregnancy (gestational thrombocytopenia) but may be an exacerbation of ITP. More severe thrombocytopenia may accompany pregnancy-related hypertensive disorders including preeclampsia and HELLP syndrome.
Hypersplenism	Asymptomatic, mild thrombocytopenia may be the initial clue to occult liver disease
Infection	Asymptomatic mild thrombocytopenia may occur with HIV infection, HCV infection, viral immunizations, EBV infection. More severe thrombocytopenia may be prominent with rickettsial infections, Ehrlichia , leptospirosis.
Less Common Causes of Thrombocytopenia
Congenital thrombocytopenias	Often mistaken for ITP and inappropriately treated
Bernard-Soulier syndrome	Giant platelets. Autosomal recessive, therefore consanguinity common. Bleeding symptoms greater than expected because of GPIbIX abnormality and defective vWF binding.
MYH9 -related thrombocytopenia	Giant platelets, granulocyte inclusions. Autosomal dominant. Typically mild bleeding symptoms. May also have sensorineural deafness and nephritis
Fanconi syndrome	Autosomal recessive, short stature. May present in adults with isolated thrombocytopenia but typically progresses to aplasia or myelodysplasia.
Wiskott-Aldrich syndrome	X-linked. Small platelets. Typically associated with eczema and immunodeficiency but may present as isolated thrombocytopenia.
Thrombocytopenia with absent radius	Autosomal recessive, associated with multiple skeletal anomalies. Typically presents as severe thrombocytopenia in infancy but may cause mild thrombocytopenia in adults.
Other uncharacterized congenital thrombocytopenias	May be autosomal dominant, recessive, or X-linked. A family history is the key to diagnosis.
Von Willebrand disease, type 2B	Autosomal dominant thrombocytopenia due to in vivo platelet clumping and clearance caused by abnormal vWF. Bleeding symptoms greater than expected because of associated vWF deficiency.
Myelodysplasia	May present as isolated thrombocytopenia in older patients.
Chronic disseminated intravascular coagulation	May initially be detected because of thrombocytopenia
Thrombotic thrombocytopenic purpura	Typically acute onset with multiple organ dysfunction but may present with only thrombocytopenia and anemia
Acquired pure megakaryocytic aplasia	Indistinguishable from ITP until a marrow aspirate is done because of poor response to treatment.

EBV , Epstein-Barr virus; HCV , hepatitis C virus; HELLP, hemolysis, elevated liver enzymes, and low platelet count; HIV, human immunodeficiency virus; ITP , immune thrombocytopenia; vWF , von Willebrand factor.

Nonimmune Thrombocytopenia

Pseudothrombocytopenia

Pseudothrombocytopenia is a phenomenon of platelet clumping due to naturally occurring autoantibody against an epitope on GPIIbIIIa that is exposed by the EDTA anticoagulant used for routine blood sample collections. The platelet count level is falsely low because the platelet clumps are not counted by the blood analyzer. Platelet counts in citrate-anticoagulated blood are usually, but not always, normal because calcium chelation by citrate prevents the alteration of the GPIIbIIIa molecule. Pseudothrombocytopenia may also result from in vitro platelet adherence (“satellitism”) to leukocytes. These phenomena are identified by examination of the peripheral blood film ( Fig. 8.1 ). Pseudothrombocytopenia occurs in approximately 1 in 1000 people and is not clinically significant.

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