What are the diagnostic criteria for thrombotic thrombocytopenic purpura (TTP)?

Diagnostic Criteria for Thrombotic Thrombocytopenic Purpura (TTP)

TTP is diagnosed by the combination of thrombocytopenia and microangiopathic hemolytic anemia (MAHA) with schistocytes on peripheral smear, plus severe ADAMTS13 deficiency (<10% activity), in the absence of another clear cause of thrombotic microangiopathy. 1, 2, 3

Essential Diagnostic Features

Core Laboratory Criteria

The two mandatory laboratory findings that must both be present are:

• Thrombocytopenia – platelet count typically <30,000/μL, though any degree of thrombocytopenia may occur 1, 2, 4
• Microangiopathic hemolytic anemia (MAHA) with all of the following 1, 2, 3:
  • Schistocytes (fragmented red blood cells) on peripheral blood smear 1, 2
  • Elevated lactate dehydrogenase (LDH) from red cell destruction 2, 3
  • Decreased hemoglobin (acute onset anemia) 1, 2
  • Decreased or undetectable haptoglobin 2, 3
  • Elevated indirect (unconjugated) bilirubin 5
  • Reticulocytosis as a compensatory response 5
  • Negative direct antiglobulin test (Coombs test) – this distinguishes TTP from autoimmune hemolytic anemia 5

Confirmatory Testing

• ADAMTS13 activity <10% is the pathophysiological hallmark and confirms TTP diagnosis when clinical features are consistent 2, 3, 6, 7
• Anti-ADAMTS13 autoantibodies distinguish acquired (immune-mediated) TTP from congenital TTP 3, 6, 4

Critical point: ADAMTS13 results often take several days, so treatment must be initiated based on clinical and routine laboratory findings before confirmation. 2, 3, 4

Additional Clinical Features (Not Required for Diagnosis)

The classic "pentad" of TTP includes thrombocytopenia, MAHA, neurological abnormalities, renal dysfunction, and fever, but only thrombocytopenia and MAHA are required for diagnosis—the other three features are present in a minority of cases. 1, 5

• Neurological symptoms – headache, confusion, altered mental status, seizures, focal deficits, or visual disturbances occur in many but not all patients 1, 5
• Renal dysfunction – elevated creatinine may be present but is typically less severe than in hemolytic uremic syndrome (HUS), where creatinine is often ≥1.5 mg/dL in adults 1, 5
• Fever – may occur but is not specific 1, 5

Mandatory Tests to Exclude Alternative Diagnoses

Rule Out Other Thrombotic Microangiopathies

• Normal coagulation studies (PT, aPTT, fibrinogen) – these must be normal or only mildly abnormal to exclude disseminated intravascular coagulation (DIC), which shows prolonged PT/aPTT, low fibrinogen, and markedly elevated D-dimer 5
• Hemolytic uremic syndrome (HUS) is distinguished by 1, 5:
  • More severe renal injury (creatinine ≥1.5 mg/dL in adults, ≥1.0 mg/dL in children <13 years) 1
  • History of acute or bloody diarrhea in the preceding 3 weeks 1
  • Less prominent neurological features 5
  • Normal or only mildly reduced ADAMTS13 activity (>10%) 3

Rule Out Other Causes of Thrombocytopenia with Hemolysis

• Drug-induced thrombocytopenia (heparin, quinidine, sulfonamides) does not cause microangiopathic hemolysis with schistocytes 5
• Malignant hypertension-associated thrombotic microangiopathy shows severe blood pressure elevation with advanced retinopathy and normal or only mildly reduced ADAMTS13 activity 5
• Immune thrombocytopenia (ITP) has isolated thrombocytopenia without hemolysis, no schistocytes, and normal ADAMTS13 activity 5

Diagnostic Algorithm

Step 1: Confirm Thrombocytopenia and MAHA

• Verify platelet count <100,000/μL (exclude pseudothrombocytopenia by reviewing peripheral smear) 8
• Confirm schistocytes on manual smear review by hematopathologist 8, 2
• Document hemolysis: elevated LDH, low/undetectable haptoglobin, elevated indirect bilirubin, reticulocytosis 2, 3
• Verify negative direct antiglobulin test 5

Step 2: Exclude DIC and Other Coagulopathies

• Obtain PT, aPTT, fibrinogen, D-dimer – these should be normal or near-normal in TTP 5
• If coagulation studies are markedly abnormal (prolonged PT/aPTT, low fibrinogen, very high D-dimer), DIC is more likely 5

Step 3: Assess for HUS Features

• Review history for bloody diarrhea in past 3 weeks 1
• Check creatinine – if ≥1.5 mg/dL (adults) or ≥1.0 mg/dL (children <13 years) with diarrheal prodrome, HUS is more likely 1
• Evaluate for proteinuria and hematuria 1

Step 4: Send ADAMTS13 Testing Immediately

• Measure ADAMTS13 activity before initiating plasma exchange if possible, but do not delay treatment 2, 3, 4
• Activity <10% confirms TTP; activity >10% suggests alternative thrombotic microangiopathy 2, 3, 6
• Send anti-ADAMTS13 antibody testing to distinguish acquired from congenital TTP 3, 6

Step 5: Initiate Empiric Treatment Without Waiting for ADAMTS13 Results

• If clinical suspicion is high (thrombocytopenia + MAHA with schistocytes + neurological symptoms), start plasma exchange immediately 2, 3, 4
• Add corticosteroids and consider rituximab 6, 4

Common Diagnostic Pitfalls

• Waiting for ADAMTS13 results before starting treatment – TTP has >90% mortality if untreated, so plasma exchange must begin immediately when clinical suspicion is high 2, 4
• Missing schistocytes on automated counts – manual peripheral smear review by a hematopathologist is mandatory 8, 2
• Confusing TTP with ITP – the presence of hemolysis with schistocytes immediately excludes isolated ITP 5
• Overlooking drug-induced or malignant hypertension-associated thrombotic microangiopathy – these do not cause schistocytes or have normal ADAMTS13 5
• Attributing neurological symptoms to other causes – any patient with thrombocytopenia, hemolysis, and neurological changes should be evaluated urgently for TTP 5

Mortality and Morbidity Considerations

Untreated TTP carries >90% mortality, but with prompt plasma exchange, survival exceeds 80-90%. 2, 4 The key to reducing mortality is immediate recognition and treatment initiation based on clinical and routine laboratory findings (thrombocytopenia + MAHA with schistocytes), without waiting for ADAMTS13 confirmation. 2, 3, 4 Delayed diagnosis or treatment significantly increases the risk of irreversible organ damage (stroke, myocardial infarction, renal failure) and death. 2, 4