Epidemiology

Immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia. The estimated incidence is 100 cases per 1,000,000 patients, and half of the cases are seen in children. In children, the gender distribution is equal, whereas in adults, women are three times more likely to be affected than are men.¹ ITP is defined as chronic if it lasts for longer than 6 months. Eighty percent of children with ITP have the acute form, whereas 80% of adults with ITP develop the chronic illness.²

Pathophysiology

Thrombocytopenia in ITP is primarily the result of accelerated platelet destruction. Autoantibodies bind to platelet antigens and thus lead to accelerated clearance by macrophages found primarily in the spleen and the liver. This increased clearance is magnified by decreased production caused by intramedullary destruction of platelets and megakaryocyte inhibition.³ Thrombocytopenia, in turn, leads to bleeding through loss of the integrity of the vascular wall and deficits in thrombus formation.

Presenting Signs and Symptoms

ITP is classically described as occurring after a prodromal infection. This presentation accounts for 60% of cases in patients 1 to 10 years of age. Outside this age range, thrombocytopenia occurs without any preceding symptoms and is often found incidentally.

Patient’s symptoms of bleeding depend on the severity of the thrombocytopenia. Patients with platelet counts higher than 50,000/mm³ are asymptomatic. Patients with platelet counts lower than 50,000/mm³ may report easy bruising with minor trauma, whereas patients with platelet counts between 10,000 and 30,000/mm³ can have spontaneous petechiae and bruising. Patients with platelet counts lower than 10,000/mm³ are at risk for internal bleeding, including intracranial hemorrhage (ICH).⁴

ICH is the major cause of mortality in patients with ITP.¹ The mortality rate of patients with ITP and ICH is greater than 50%.⁵ Atraumatic ICH secondary to ITP is rare, estimated to occur in 0.1% to 1% of patients with ITP. In one report of patients with ICH, 70% had platelet counts lower than 10,000/mm³.⁵ Despite the rarity of this complication, patients with ITP and any cranial or neurologic complaint should be evaluated for ICH.

Differential Diagnosis and Medical Decision Making

Primary and secondary forms of immune-mediated destruction of platelets are recognized. ITP generally refers solely to the primary form of this disease. The secondary form is associated with rheumatic disease, connective tissue disorders, malignant disease, drug exposure, immune deficiencies, and infections, including human immunodeficiency virus infection and hepatitis C. Because no specific diagnostic criteria exist for ITP, it is a diagnosis of exclusion.

The importance of pursuing alternative diagnoses is highlighted by the associated morbidity and mortality of the other diagnoses. The patient’s history can point toward an alternate cause of the thrombocytopenia. Constitutional symptoms such as fever or weight loss suggest malignant disease or infection. Recent initiation of medications such as heparin, clopidogrel, or vancomycin may indicate drug-induced thrombocytopenia.

In ITP the remainder of the laboratory evaluation should be within normal limits. Thrombocytopenia with other abnormalities suggests alternative diagnoses. For example, thrombocytopenia with anemia is found in patients with thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS). Thrombocytopenia and additional cytopenias are found in leukemia and myelodysplastic disorders. Thrombocytopenia and coagulation abnormalities are found in disseminated intravascular coagulation (DIC).

the peripheral blood smear should be examined. The smear can differentiate true thrombocytopenia from spurious causes of thrombocytopenia such as platelet clumping, platelet satellitism, and abnormally large platelets. Furthermore, the peripheral blood smear can identify manifestations of the primary cause of thrombocytopenia, such as schistocytes in TTP-HUS, evidence of parasitic infections, or findings suggestive of leukemia.

In the patient with suspected ITP, the physician must identify the degree of any bleeding complications. A careful skin examination can quantify the degree of petechiae or bruising. Rectal examination can identify gastrointestinal bleeding. Additionally, any intracranial symptoms, especially in the context of trauma, should be evaluated by computed tomography for possible ICH.

Patients with a history of ITP often have relapses. Most adults with ITP have one or more relapses, commonly during a steroid taper. Relapses are also seen in patients treated with intravenous immune globulin (IVIG) after steroids have failed. Patients with an ITP relapse are treated in the same manner as patients with an initial presentation of ITP. Patients with ITP relapse should also have a nonemergency surgical consultation for possible splenectomy.

Treatment

ITP is treated by immunomodulation. The first-line treatment is with parenteral steroids. Most patients presenting with ITP are well and do not need treatment in the ED and can be managed with an early referral to a hematologist. Treatment should be started in patients who are ill, have bleeding complications, need emergency surgery, or have severe thrombocytopenia.

Initiation of treatment should be coordinated with a hematologist, for several reasons. Early leukemia can manifest with isolated thrombocytopenia, especially in pediatric patients. Leukemia should also be considered in adults who have prominent and persistent constitutional symptoms. In a patient who is presenting with leukemia, empiric steroids can lead to alteration of the bone marrow aspirate that causes difficulty and delay in diagnosis.

Steroids are usually started at a dose 1 to 1.5 mg/kg of prednisone per day. IVIG (usual dose of 1 g/kg) is reserved for infants and patients with severe disease or internal bleeding. Anti-D immune globulin is used as an adjunct in Rh-positive patients (usual dose of 75 mcg/kg). Patients with a recurrence of ITP are treated in the same manner as patients with an initial presentation of ITP and should be considered for escalation of therapy. Patients who have chronic or refractory ITP should be considered for splenectomy. The rate of remission of ITP after splenectomy in children is 70% to 80%. The remission rate in adults is unpredictable, ranging from 60% to 70%.¹ Platelet transfusion leads to a rapid but transient increase in platelet count and is therefore indicated only in certain settings, such as in patients with bleeding complications, patients undergoing emergency surgery, and those with severe thrombocytopenia.

Follow-Up, Next Steps of Care, and Patient Education

Most patients with suspected ITP are treated and managed as outpatients. however, patients with severe thrombocytopenia—defined as a platelet count lower than 10,000/mm³, patients with head trauma, and those with bleeding complications—should be admitted. Patients should be considered for admission if their platelet count is lower than 30,000/mm³, if they work in a profession (e.g., construction) in which trauma is inevitable, or if the diagnosis is in question. Ultimately, disposition should be based on the patient’s appearance, the severity of thrombocytopenia, concomitant use of antiplatelet agents, and the patient’s access to expeditious follow-up.

Patients who are managed as outpatients should be advised to avoid any antiplatelet agents. Patients, especially children, should limit their activities in situations associated with possible trauma (e.g., construction work, contact sports, gym class). Discharge instructions should instruct patients to return if they have any signs of bleeding, abdominal pain, trauma, or neurologic symptoms.

Perspective

The thrombotic microangiopathies are a group of disorders characterized by intravascular aggregation of platelets that leads to organ ischemia. These disorders include TTP and HUS. Although the two diseases have different names, they share a common mechanism, as well as overlapping clinical features. TTP and HUS are generally believed to lie on a spectrum of disease, as opposed to being distinct clinical entities. Therefore, they are discussed together.

Epidemiology

TTP and HUS are rare diseases. TTP has an estimated prevalence of 4 to 11 cases per million people,⁶ and HUS has an incidence of 1 to 10 cases per 100,000.⁷ TTP is associated with black race, female sex, and obesity.⁸ Pregnant and peripartum patients account for 12% to 25% of patients with TTP.⁹

Despite the rarity, TTP and HUS are associated with significant morbidity and mortality. Untreated TTP has a mortality rate of 90%,¹⁰ and adults with typical HUS have a 45% mortality rate.¹¹ Children less than 10 years of age have a 15% chance of developing HUS in the setting of diagnosed Escherichia coli O157:H7 infection.¹² Although 90% of children with typical Shiga toxin–associated HUS recover with supportive care,^13,