When should Thrombotic Thrombocytopenic Purpura (TTP) be suspected in patients with reduced ADAMTS13 (A Disintegrin and Metalloprotease with a Thrombospondin type 1 motif, member 13) activity?

When to Suspect Reduced ADAMTS13 Activity and TTP

TTP should be suspected in patients presenting with thrombotic microangiopathy (TMA) who have ADAMTS13 activity <10%, especially when accompanied by microangiopathic hemolytic anemia, thrombocytopenia, and organ dysfunction.

Clinical Presentation Suggesting TTP

• TTP is characterized by the classic pentad of thrombocytopenia, microangiopathic hemolytic anemia, fever, renal dysfunction, and neurological symptoms, though not all features may be present 1
• Suspect TTP in patients with unexplained thrombocytopenia and evidence of hemolysis (elevated LDH, reduced haptoglobin, indirect hyperbilirubinemia) 2
• Neurological manifestations (which occur in 10-20% of cases) may include neurological symptoms, motor symptoms, generalized weakness, vision changes, seizures, and encephalopathy 2

Laboratory Findings Suggestive of TTP

• Severe drop in platelets with concurrent hemolytic anemia occurring precipitously 2
• Presence of schistocytes >1% on peripheral blood smear, though absence of schistocytes does not exclude early TMA 2
• Evidence of non-immune hemolytic anemia (negative direct Coombs test) 2
• Elevated LDH, reduced haptoglobin, and elevated indirect bilirubin 2
• Renal involvement (hematuria, proteinuria, elevated creatinine) 2

ADAMTS13 Testing and Interpretation

• ADAMTS13 activity <10% is diagnostic of TTP 2
• Testing for ADAMTS13 activity and anti-ADAMTS13 antibodies should be performed urgently when TMA is suspected 2
• Even after 1-3 sessions of plasma exchange therapy, ADAMTS13 testing still maintains diagnostic value with sensitivities of 89%, 83%, and 78% respectively 3
• Presence of anti-ADAMTS13 antibodies suggests immune-mediated TTP, while their absence with low ADAMTS13 activity may indicate congenital TTP 2

Risk Stratification Tools

• The PLASMIC score can help risk-stratify patients with suspected TTP while awaiting ADAMTS13 results 2
• PLASMIC score components include: Platelet count, combined hemoLysis variable, absence of Active cancer, absence of Stem-cell or solid-organ transplant, MCV, INR, and Creatinine 2
• Intermediate to high PLASMIC score (>5 points) suggests high likelihood of TTP and should prompt immediate treatment in adults 2

Special Populations

• In patients with systemic lupus erythematosus (SLE), TTP should be considered when TMA is present 2
• In children, TTP is less common, and plasma exchange has been associated with considerable morbidity, so it may be reasonable to defer plasma exchange for 24-48 hours until ADAMTS13 results confirm the diagnosis 2
• In patients on immune checkpoint inhibitors who develop TMA, urgent ADAMTS13 testing is recommended to distinguish TTP from other causes 2

Clinical Implications of Reduced ADAMTS13

• Untreated TTP has a high mortality rate, making rapid diagnosis crucial 1
• Patients with severe ADAMTS13 deficiency (<10%) but no detectable inhibitor typically respond well to plasma exchange with rising ADAMTS13 levels 4
• Patients with high-titer inhibitors (>5 units/mL) may not show improvement in ADAMTS13 activity despite plasma exchange and have higher rates of recurrence and mortality 4
• Recovery of ADAMTS13 activity to >10% within 7 days of starting plasma exchange is associated with better clinical outcomes 3

Pitfalls and Caveats

• Platelet transfusions should be avoided in suspected TTP as they may worsen microvascular thrombosis, especially when diagnosis is delayed 5
• Rapid turnaround time for ADAMTS13 testing is critical - implementation of rapid assays has been associated with reduced unnecessary plasma exchange and improved outcomes 6, 5
• Waiting for ADAMTS13 results should not delay initiation of plasma exchange in adults with high clinical suspicion of TTP 2
• In patients with TMA but normal ADAMTS13 activity (>10%), other causes such as complement-mediated TMA, antiphospholipid syndrome, or drug-induced TMA should be considered 2