What are the causes and treatments of chronic thrombocytopenia?

Causes and Treatment of Chronic Thrombocytopenia

Chronic thrombocytopenia is most commonly caused by immune-mediated mechanisms, with primary immune thrombocytopenia (ITP) being the most frequent diagnosis, but numerous other conditions including infections, medications, bone marrow disorders, and systemic diseases must be considered in the differential diagnosis. 1

Common Causes of Chronic Thrombocytopenia

Primary Causes:

• Immune Thrombocytopenia (ITP): A diagnosis of exclusion characterized by isolated thrombocytopenia without other abnormalities

Secondary Causes:

1. Infections:

   • HIV, HCV, and other viral infections 1
   • Bacterial infections (including sepsis)

2. Medication-induced thrombocytopenia:

   • Common culprits: 1, 2
     • Quinine/quinidine
     • Sulfonamides
     • NSAIDs
     • Anticonvulsants
     • Diuretics
     • Heparin (heparin-induced thrombocytopenia) 3

3. Autoimmune disorders:

   • Systemic lupus erythematosus (SLE) 1
   • Antiphospholipid syndrome 4
   • Other immunodeficiency disorders

4. Bone marrow disorders:

   • Myelodysplastic syndromes
   • Leukemias
   • Aplastic anemia
   • Fibrosis
   • Megaloblastic anemia 1

5. Liver disease:

   • Cirrhosis (including alcoholic liver disease) 1, 4
   • Portal hypertension with splenic sequestration

6. Other causes:

   • Malignancy (especially lymphoproliferative disorders) 1
   • Vitamin B12 or folate deficiency 5
   • Inherited thrombocytopenias (rare) 1
   • Immune checkpoint inhibitor therapy 1
   • Post-transfusion purpura 1

Diagnostic Approach

1. Confirm true thrombocytopenia:

   • Rule out pseudothrombocytopenia (EDTA-dependent platelet agglutination) by examining peripheral blood smear 1, 4
   • Collect blood in heparin or sodium citrate tube if suspected 4

2. Essential initial tests:

   • Complete blood count with differential
   • Peripheral blood smear examination 1, 5
   • Liver function tests 5
   • Testing for HIV and HCV 5
   • Antinuclear antibodies (ANA) and antiphospholipid antibodies 5
   • Pregnancy test in women of childbearing potential 5

3. Additional testing based on clinical suspicion:

   • Bone marrow examination (indicated in patients >60 years, those with systemic symptoms, or abnormal signs) 1, 5
   • B12 and folate levels 5
   • Iron studies 5

Treatment Approach

General Principles:

• Treatment should target the underlying cause when identified 5
• Platelet transfusions are recommended for active bleeding or platelet counts <10,000/μL 4
• Activity restrictions to avoid trauma are recommended for patients with platelet counts <50,000/μL 4

Treatment of Primary ITP:

1. First-line therapy:

   • Glucocorticoids 5
   • Intravenous immunoglobulin (IVIg) for acute management of severe thrombocytopenia 5

2. Second-line therapy:

   • Splenectomy for patients failing first-line therapy 1

3. Treatment for refractory ITP:

   • Thrombopoietin receptor agonists (TPO-RAs):
     • Eltrombopag: Starting dose 50 mg daily (25 mg for East Asian patients or those with hepatic impairment) 6
     • Romiplostim 1
   • Rituximab
   • Immunosuppressive agents (azathioprine, mycophenolate, cyclosporine)
   • Combination chemotherapy in severe cases 1
   • Hematopoietic stem cell transplantation in extremely refractory cases 1

Treatment of Secondary Thrombocytopenia:

• Drug-induced: Discontinue the offending medication 2
• Infection-related: Treat the underlying infection
• Heparin-induced thrombocytopenia: Discontinue heparin and use alternative anticoagulation (direct thrombin inhibitors or factor Xa inhibitors) 5
• Immune checkpoint inhibitor-related: Corticosteroids, IVIg, and possibly holding the checkpoint inhibitor 1

Monitoring and Prognosis

• Monitor platelet counts regularly; frequency depends on severity and treatment response
• Platelet count thresholds and associated risks: 5, 4

  • 50,000/μL: Generally asymptomatic

  • 20,000-50,000/μL: Risk of mild bleeding (petechiae, purpura, ecchymosis)
  • <10,000/μL: High risk of serious bleeding

Important Caveats

• Splenomegaly is uncommon in ITP (<3% of patients) and suggests an alternative diagnosis 1
• Patients with chronic refractory ITP may have significant quality of life impairments and increased mortality risk 1
• Platelet-associated IgG assays are not recommended for diagnosis of ITP 1
• Some patients with severe thrombocytopenia may prefer to accept lower platelet counts rather than undergo toxic treatments 1