What is thrombotic thrombocytopenic purpura (TTP)?

What is Thrombotic Thrombocytopenic Purpura (TTP)?

Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy caused by severe deficiency of the ADAMTS13 enzyme (activity <10%), resulting in microangiopathic hemolytic anemia and severe thrombocytopenia due to disseminated platelet-rich microthrombi in small vessels—a condition with >90% mortality if untreated but 80–90% survival with prompt plasma exchange. 1, 2, 3

Pathophysiology

• ADAMTS13 deficiency is the defining pathophysiologic mechanism: this metalloprotease normally cleaves ultra-large von Willebrand factor (VWF) multimers into smaller forms; when ADAMTS13 activity falls below 10%, uncleaved VWF multimers remain in circulation and spontaneously bind platelets under high shear stress, forming microthrombi throughout arterioles and capillaries. 1, 3, 4

• Two forms exist based on etiology:

  • Acquired (immune-mediated) TTP accounts for the majority of adult cases and results from autoantibodies against ADAMTS13. 1, 3, 5
  • Congenital (hereditary) TTP arises from biallelic mutations in the ADAMTS13 gene and typically presents in childhood or during pregnancy. 3, 5

• The microthrombi cause mechanical shearing of red blood cells as they pass through occluded vessels, producing the characteristic schistocytes and hemolytic anemia. 2, 3

Clinical Presentation

• Only two features are mandatory for diagnosis: thrombocytopenia (typically <30 × 10⁹/L) and microangiopathic hemolytic anemia with schistocytes on peripheral smear. 1

• The classic "pentad" (thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, renal dysfunction, fever) is NOT required—most patients present with only 2–3 features, and waiting for all five delays life-saving treatment. 1, 6

• Neurologic manifestations are the most distinctive clinical feature and include headache, confusion, seizures, focal deficits, visual disturbances, or altered mental status; these result from microvascular ischemia in the central nervous system. 1, 3, 5

• Renal dysfunction in TTP is typically mild (creatinine often <1.5 mg/dL in adults), distinguishing it from hemolytic-uremic syndrome (HUS), which presents with severe renal failure and usually follows bloody diarrhea. 1

• Fever may occur but is nonspecific. 1

Laboratory Diagnosis

Essential Diagnostic Findings

• Thrombocytopenia: platelet count is usually <30 × 10⁹/L, though any degree of thrombocytopenia can occur. 1

• Microangiopathic hemolytic anemia (MAHA) must be present and includes:

  • Schistocytes (fragmented red cells) on peripheral blood smear—the single most important finding that distinguishes TTP from isolated immune thrombocytopenia (ITP). 1, 3
  • Elevated lactate dehydrogenase (LDH) from red cell destruction. 1, 6
  • Decreased or undetectable haptoglobin. 1
  • Elevated indirect (unconjugated) bilirubin. 1
  • Reticulocytosis as a compensatory response to hemolysis. 1
  • Negative direct antiglobulin test (Coombs test)—this excludes autoimmune hemolytic anemia. 1

Confirmatory Testing

• ADAMTS13 activity <10% confirms TTP when clinical features are compatible; this test should be ordered immediately but treatment must not be delayed while awaiting results. 1, 2, 3

• Anti-ADAMTS13 autoantibodies identify acquired (immune-mediated) TTP and distinguish it from congenital TTP. 1, 3, 5

Exclusion of Mimics

• Normal coagulation studies (PT, aPTT, fibrinogen) are critical to exclude disseminated intravascular coagulation (DIC), which shows prolonged PT/aPTT, low fibrinogen, and markedly elevated D-dimer. 1

• Creatinine <1.5 mg/dL (adults) or <1.0 mg/dL (children <13 years) helps distinguish TTP from HUS, which presents with severe renal failure. 1

• Absence of severe hypertension with retinal changes excludes malignant hypertension-associated thrombotic microangiopathy, in which ADAMTS13 activity remains >10%. 1

• Presence of schistocytes and hemolysis immediately excludes drug-induced thrombocytopenia and isolated ITP, neither of which cause microangiopathic hemolytic anemia. 1

Diagnostic Algorithm

1. Confirm thrombocytopenia and MAHA: platelet count <100 × 10⁹/L, manual peripheral smear showing schistocytes, hemolysis labs (elevated LDH, low haptoglobin, elevated indirect bilirubin, reticulocytosis), and negative Coombs test. 1

2. Exclude DIC immediately: obtain PT, aPTT, fibrinogen, D-dimer—results should be normal or only mildly abnormal in TTP. 1

3. Assess for HUS features: inquire about recent diarrheal illness, measure creatinine, evaluate urine for protein/hematuria. 1

4. Order ADAMTS13 activity and inhibitor testing immediately—but do not delay plasma exchange while awaiting results if clinical suspicion is high. 1, 2, 3

5. Initiate empiric therapy when thrombocytopenia + MAHA with schistocytes ± neurologic signs are present: start daily plasma exchange, add corticosteroids, and consider rituximab. 1, 3, 5

Treatment

• Daily therapeutic plasma exchange (TPE) is the cornerstone of treatment and must be initiated immediately when TTP is suspected; TPE supplies functional ADAMTS13 and removes autoantibodies. 1, 3, 5, 6

• Corticosteroids are added to suppress autoantibody production in acquired TTP. 3, 5

• Rituximab (anti-CD20 monoclonal antibody) is frequently added to front-line therapy to target B cells producing ADAMTS13 autoantibodies. 3, 5

• Caplacizumab (anti-VWF antibody fragment) inhibits the interaction between VWF multimers and platelets; when available, it is added to front-line therapy and has shown beneficial effects without immunosuppressive side effects. 2, 5

• TPE is generally continued until platelet count exceeds 150 × 10³/µL and LDH normalizes for 2–3 consecutive days. 6

• Refractory or relapsed cases may require twice-daily plasma exchange, cyclophosphamide, vincristine, cyclosporine A, bortezomib, N-acetylcysteine, or salvage splenectomy. 3, 5

Critical Mortality and Morbidity Considerations

• Untreated TTP carries >90% mortality; prompt plasma exchange raises survival to 80–90% or higher. 1, 3

• Immediate recognition based on routine labs (thrombocytopenia + MAHA with schistocytes) is critical—waiting for ADAMTS13 results markedly increases risk of irreversible organ injury and death. 1, 2

• Neurologic sequelae are common in survivors, including cognitive impairment and stroke; long-term follow-up is essential to monitor for relapse and manage chronic complications. 3, 5, 4

• Relapse occurs in approximately 30–50% of patients with acquired TTP, necessitating lifelong monitoring of platelet counts and clinical symptoms. 3, 5

Common Diagnostic Pitfalls

• Delaying treatment while awaiting ADAMTS13 results is the most lethal error—empiric plasma exchange must begin immediately when clinical features suggest TTP. 1, 2, 3

• Mistaking TTP for ITP because both present with thrombocytopenia; the presence of hemolysis with schistocytes immediately excludes isolated ITP and mandates consideration of thrombotic microangiopathy. 1

• Overlooking neurologic symptoms or attributing them to other causes delays diagnosis; any patient with thrombocytopenia, hemolysis, and neurologic changes should be evaluated urgently for TTP. 1

• Failing to recognize that TTP paradoxically increases thrombotic risk rather than bleeding risk, unlike other causes of thrombocytopenia. 7