What is the relationship between thrombotic thrombocytopenic purpura (TTP) and underlying conditions such as infections, pregnancy, certain medications, human immunodeficiency virus (HIV), systemic lupus erythematosus (SLE), and tumors?

Mechanisms of Secondary Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) is primarily caused by severe deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), which can be triggered by various underlying conditions including infections, pregnancy, certain medications, HIV, SLE, and tumors. 1

Pathophysiological Mechanisms

Infections

• Infections, particularly with cytomegalovirus, Helicobacter pylori, hepatitis C, HIV, and varicella zoster, can trigger secondary TTP through immune system activation 2
• Infectious agents may induce cross-reactive antibodies that target ADAMTS13, leading to its deficiency and subsequent microthrombi formation 1
• Infections can also cause endothelial damage, releasing unusually large von Willebrand factor (VWF) multimers that overwhelm available ADAMTS13 3

Pregnancy

• Pregnancy is a known trigger for TTP, likely due to the physiological decrease in ADAMTS13 activity during pregnancy combined with increased VWF levels 2
• Hormonal changes during pregnancy may affect immune regulation, potentially triggering autoantibody production against ADAMTS13 1
• Management of TTP during pregnancy requires special consideration, with recommended treatments being corticosteroids or IVIg 2

Medications

• Certain drugs can induce TTP through immune-mediated mechanisms or direct toxicity to endothelial cells 2
• Common culprit medications include quinine, ticlopidine, clopidogrel, chemotherapeutic agents, and immunosuppressants 2
• Some vaccines have been reported to trigger TTP, as seen in case reports of TTP following COVID-19 vaccination 4

HIV Infection

• HIV infection is strongly associated with secondary TTP, with a recommended approach of treating the underlying HIV infection first 2
• HIV may induce TTP through multiple mechanisms:
  • Direct viral damage to endothelial cells
  • Immune dysregulation leading to autoantibody formation
  • Opportunistic infections that trigger inflammatory responses 2
• Treatment of HIV-associated TTP should include antiviral therapy unless the patient has significant bleeding complications requiring immediate TTP-specific treatment 2

Systemic Lupus Erythematosus (SLE)

• SLE is a common autoimmune cause of secondary TTP 2
• The autoimmune dysregulation in SLE can lead to production of autoantibodies against ADAMTS13 2
• Patients with SLE may have concurrent antiphospholipid antibodies, which can complicate the clinical picture and management 2
• The presence of multiple autoantibodies in SLE patients may contribute to more severe ADAMTS13 deficiency 1

Tumors and Malignancies

• Lymphoproliferative disorders are listed as causes of secondary TTP 2
• Malignancies can trigger TTP through:
  • Tumor-induced immune dysregulation leading to autoantibody production
  • Direct bone marrow infiltration affecting platelet production
  • Paraneoplastic phenomena 5
• Bone marrow examination may be necessary to rule out underlying malignancies in patients presenting with TTP-like symptoms 2

Diagnostic Approach for Secondary TTP

• Evaluation of peripheral blood smear is crucial to identify schistocytes and rule out other causes of thrombocytopenia 2
• Testing for ADAMTS13 activity is essential, with levels below 10% being diagnostic for TTP 3
• Screening for underlying conditions should include:
  • HIV and hepatitis C testing in all adult patients 2
  • Helicobacter pylori testing in appropriate cases 2
  • Autoimmune markers including antinuclear antibodies 2
  • Evaluation for malignancies when clinically indicated 5

Treatment Considerations

• Primary treatment for acute TTP includes daily therapeutic plasma exchange to supply deficient ADAMTS13 1
• For secondary forms of TTP, treating the underlying condition is crucial:
  • Antiviral therapy for HIV-associated TTP 2
  • Eradication therapy for H. pylori-associated TTP 2
  • Discontinuation of offending medications 2
• Refractory cases may require more intensive therapy including:
  • Rituximab (anti-CD20 monoclonal antibody) 6
  • Twice-daily plasma exchange 6
  • Other immunosuppressive agents like cyclophosphamide, vincristine, or cyclosporine A 6

Clinical Pitfalls and Caveats

• TTP can be rapidly fatal if not promptly recognized and treated 3
• Secondary causes of TTP may be overlooked if focus is solely on treating the acute presentation 2
• Some patients may develop allergic reactions to plasma used in therapeutic plasma exchange, requiring alternative approaches 7
• Long-term follow-up is essential to monitor for relapses and development of other autoimmune conditions 1
• Distinguishing TTP from other thrombotic microangiopathies is crucial for appropriate management 3

Understanding the mechanisms by which these various conditions trigger TTP is essential for proper diagnosis, treatment, and prevention of recurrence in affected patients.