Primary immune thrombocytopenia (ITP), previously known as idiopathic thrombocytopenic purpura, is an autoimmune disorder characterized by excessive platelet destruction and impaired platelet production. It is the most common hemorrhagic disorder encountered in clinical practice. The annual incidence is approximately 5–10 per 100,000 people. The incidence is similar in males and females, although women of childbearing age have a higher incidence compared to men. In individuals over 60 years old, the incidence is double that of those under 60, and the risk of bleeding increases with age. This section primarily discusses adult ITP.
Etiology and Pathogenesis
The underlying cause of ITP remains unclear. The mechanisms of pathogenesis are as follows:
Increased Platelet Destruction
In approximately 50%–70% of ITP patients, one or more autoantibodies against platelet glycoproteins can be detected in plasma or on the platelet surface. Platelets sensitized by autoantibodies are phagocytized and destroyed by the mononuclear phagocyte system. In addition, cytotoxic T lymphocytes (CTLs) in ITP patients can directly destroy platelets.
Reduced Platelet Production
Autoantibodies can damage megakaryocytes or inhibit the release of platelets from megakaryocytes, leading to insufficient platelet production in ITP patients. Active CTLs can also impair platelet production by inhibiting the apoptosis of megakaryocytes. Furthermore, relatively insufficient plasma thrombopoietin (TPO) levels in ITP patients represent another important mechanism contributing to decreased platelet production.
Clinical Manifestations
Recurrent Mucocutaneous Bleeding
This is characterized by petechiae and ecchymoses on mucocutaneous surfaces, epistaxis, gingival bleeding, menorrhagia, and prolonged bleeding after trauma. Severe cases may lead to internal organ bleeding or intracranial hemorrhage. Some patients may present with isolated thrombocytopenia without bleeding symptoms.
Fatigue
Some individuals experience significant fatigue.
Other Symptoms
Excessive bleeding or chronic menorrhagia may lead to anemia due to blood loss.
Laboratory Tests
Complete Blood Count Test
Platelet count is reduced with a relatively enlarged mean platelet volume. Some patients may exhibit normocytic or microcytic hypochromic anemia. No abnormalities are observed in blood cell morphology.
Coagulation and Platelet Function Tests
Coagulation function is normal, with prolonged bleeding time and a positive tourniquet test. Platelet function is generally normal.
Bone Marrow Examination
The number of megakaryocytes in the bone marrow is normal or increased. Abnormalities include impaired megakaryocyte maturation, an increased proportion of immature megakaryocytes, and significantly reduced platelet-producing megakaryocytes.
Serological Tests
Plasma TPO levels are normal or slightly elevated. Approximately 70% of patients test positive for autoantibodies against platelet glycoproteins. Patients with concurrent autoimmune hemolytic anemia (Evans syndrome) may have a positive Coombs test and elevated serum bilirubin levels.
Diagnosis and Differential Diagnosis
Key Points for Diagnosis
ITP remains primarily a clinical diagnosis of exclusion. The diagnostic criteria are as follows:
- At least two assessments showing decreased platelet count, with no abnormalities in blood cell morphology.
- The spleen is generally non-enlarged on physical examination.
- Bone marrow examination reveals a normal or increased number of megakaryocytes, with evidence of maturation impairment.
- Secondary causes of thrombocytopenia are ruled out.
The severity of bleeding is graded using a bleeding scoring system, which quantifies bleeding severity in ITP patients and provides risk assessment. The system consists of two components: age and bleeding symptoms. The bleeding score for ITP patients is calculated as the sum of the age score and the highest score among bleeding symptoms.
Differential Diagnosis
It is necessary to exclude the following:
- Pseudothrombocytopenia.
- Hereditary or congenital thrombocytopenia syndromes.
- Secondary thrombocytopenias, such as aplastic anemia, hypersplenism, myelodysplastic syndromes, leukemia, systemic lupus erythematosus, and drug-induced immune thrombocytopenia.
Classification and Staging
Classification and staging:
- Newly Diagnosed ITP: Refers to ITP diagnosed within 3 months.
- Persistent ITP: Refers to persistent thrombocytopenia between 3 and 12 months after diagnosis.
- Chronic ITP: Refers to thrombocytopenia persisting for more than 12 months.
- Severe ITP: Defined as platelet count <10×10⁹/L, accompanied by active bleeding or a bleeding score ≥5.
- Refractory ITP: Refers to patients unresponsive to first-line therapies, thrombopoietin receptor agonists, and rituximab, or those who fail splenectomy or experience relapse after the procedure, with ITP confirmed upon reevaluation.
Treatment
There is currently no curative treatment for ITP. Treatment aims to minimize toxicity, maintain platelets at a safe level, reduce and prevent bleeding complications, and improve the quality of life. Individualized treatment is essential, taking patient preferences and specific circumstances into account.
For patients without significant bleeding tendency, with a platelet count above 30×109/L, and without plans for surgery, trauma, or activities with a high risk of bleeding, the risk of bleeding is relatively low and observation with follow-up is sufficient. Patients with active bleeding (bleeding score ≥2), regardless of the degree of thrombocytopenia, should receive treatment.
General Management
Patients with significant bleeding tendencies should remain on strict bed rest, avoid medications that may induce or exacerbate bleeding, and refrain from using antiplatelet drugs. Steps are taken to control hypertension effectively and prevent trauma.
Emergency Management
Emergency management is indicated for patients with platelet counts below 10×10⁹/L and extensive or severe bleeding; those with suspected or confirmed intracranial hemorrhage; or for individuals undergoing imminent surgery or delivery.
- Intravenous Immunoglobulin (IVIG): Administered as 400 mg/(kg·day) for 5 days or 1.0 g/(kg·day) for 2 days.
- High-dose Methylprednisolone: Administered at 1 g/day via intravenous infusion for 3 days, followed by gradual tapering.
- Thrombopoietin Receptor Agonists (TPO-RAs): Recombinant human thrombopoietin (rhTPO), eltrombopag, avatrombopag, or romiplostim.
- Platelet Transfusion.
- Other Measures: Such as vinca alkaloids or emergency splenectomy.
In critical conditions, a combination of these treatments may be employed.
First-Line Treatment for Newly Diagnosed Patients
Glucocorticoids are typically the first-line treatment:
- High-dose Dexamethasone (HD-DXM): 40 mg/day for 4 days. A repeat course may be given after 10 days in non-responders. Usage is cautious in elderly patients and those with diabetes, hypertension, or glaucoma.
- Prednisone: 1 mg/(kg·day), with a maximum dose of 80 mg/day. Once effective, tapering should begin promptly, aiming for discontinuation within 6–8 weeks. For maintenance therapy, the dose should not exceed 5 mg/day. If no response is observed within 2 weeks, prednisone should be ceased as soon as possible.
IVIG is administered as per emergency protocols, typically for the following scenarios:
- Emergency management of ITP.
- Patients intolerant to glucocorticoids or as preoperative preparation for splenectomy.
- Pregnancy-associated ITP or before delivery. Caution is exercised in patients with IgA deficiency or renal insufficiency.
Second-Line Treatment for ITP
Second-line treatment is indicated for patients who fail initial glucocorticoid therapy, experience relapse within six months, or have contraindications to glucocorticoids.
Pharmacological Therapy
Treatment options include:
- Thrombopoietin Receptor Agonists (TPO-RAs): Agents such as rhTPO, eltrombopag, avatrombopag, hetrombopag, and romiplostim are included. These medications typically take effect within 1–2 weeks. However, efficacy is generally not sustained after discontinuation, necessitating individualized maintenance therapy. Monitoring for the risk of thrombosis is important during treatment.
- Anti-CD20 Monoclonal Antibody: Administered as 375 mg/m2 or 100 mg per infusion intravenously, once weekly for four doses, or as a single 375 mg/m2 dose. Efficacy is typically achieved within 4–8 weeks after the first dose. Use is contraindicated in patients with active hepatitis B infection.
Splenectomy
Splenectomy is considered for patients who fail standardized glucocorticoid therapy, cannot maintain efficacy on a safe dose of prednisone (5 mg/day), have contraindications to glucocorticoids, and whose ITP diagnosis has been established for more than 12–24 months.
Preoperative diagnostic reevaluation for ITP is required. Vaccination against pneumococcal bacteria, Neisseria meningitidis, and Haemophilus influenzae is recommended approximately two weeks prior to surgery. Patients’ risks for thrombosis and infection should be carefully monitored.
Third-Line Treatment for ITP
Treatment options include:
- Decitabine: Administered at 3.5 mg/(m2·day) for three days, with subsequent doses given every three weeks for a total of 3–6 cycles. Treatment should be discontinued if there is no response after three cycles.
- All-Trans Retinoic Acid (ATRA): Administered orally at 20 mg/day in two divided doses, in combination with danazol (400 mg/day in two divided doses) for 16 weeks.
- Other Immunosuppressive Agents: Agents such as vincristine, cyclosporine, azathioprine, and mycophenolate mofetil may be used. Due to a lack of sufficient evidence from clinical trials, these treatments require individualized selection based on specific patient circumstances.