What is the diagnostic workup and treatment approach for a patient suspected of having Thrombotic Thrombocytopenic Purpura (TTP)?

TTP Diagnostic Workup

When TTP is suspected, immediately order ADAMTS13 activity and inhibitor testing, perform a peripheral blood smear to confirm schistocytes, and initiate therapeutic plasma exchange (TPE) without waiting for ADAMTS13 results, as delays beyond 24 hours significantly increase mortality risk. 1, 2

Immediate Clinical Assessment

Risk Stratification

• Apply the PLASMIC score to identify intermediate-to-high risk patients (score ≥5) requiring immediate treatment, which includes: platelet count <30,000/µL, hemolysis variables present, no active cancer, no transplant history, MCV <90 fL, INR <1.5, and creatinine <2.0 mg/dL 1
• The PLASMIC score serves as a rapid bedside tool to estimate pretest probability of severe ADAMTS13 deficiency while awaiting confirmatory testing 3

Essential Laboratory Testing

• Order ADAMTS13 activity and inhibitor levels immediately but do not delay treatment while awaiting results - turnaround time is typically several days at reference laboratories 1, 3
• Confirm thrombocytopenia (typically platelet count <30,000/µL) and microangiopathic hemolytic anemia (MAHA) through: 1
  • Peripheral blood smear showing schistocytes (fragmented red blood cells)
  • Elevated serum lactate dehydrogenase (LDH)
  • Decreased hemoglobin and haptoglobin
  • Elevated indirect bilirubin
• Obtain coagulation studies (PT, aPTT, fibrinogen) which should be normal or only mildly abnormal - this distinguishes TTP from disseminated intravascular coagulation (DIC) 1

Diagnostic Confirmation

ADAMTS13 Testing

• TTP diagnosis is confirmed by ADAMTS13 activity <10% with or without detectable inhibitory autoantibodies in patients with severe thrombocytopenia and MAHA 1, 4
• ADAMTS13 activity >10% in a similar clinical context supports alternative diagnoses such as atypical hemolytic uremic syndrome (aHUS) or other thrombotic microangiopathies 1, 4
• Inhibitor testing helps distinguish immune-mediated (acquired) TTP from congenital TTP 3, 4

Differential Diagnosis Exclusions

• Rule out complement-mediated thrombotic microangiopathy and antiphospholipid syndrome, particularly in patients with systemic lupus erythematosus 1
• Exclude sepsis, E. coli O157 infection, atypical hemolytic uremic syndrome, and disseminated intravascular coagulation through clinical history and coagulation studies 5, 4

Immediate Treatment Initiation

Plasma Exchange Protocol

• Initiate therapeutic plasma exchange immediately when TTP is suspected - median time from suspected diagnosis to first plasma exchange should be <10.7 hours, with delays >24 hours associated with markedly increased mortality (aHR 1.40) and major thrombotic events (aHR 2.9) 1, 2
• Perform daily TPE using fresh frozen plasma until platelet count normalizes (≥150,000/µL) 1
• If plasma exchange is delayed 8-24 hours, administer plasma infusion as a temporizing measure, though this occurred in only 45% of cases in real-world practice 2

Adjunctive Immunosuppression

• Administer high-dose corticosteroids, such as methylprednisolone 1 gram IV daily for 3 days, with the first dose given after the first TPE session 1
• Offer rituximab as part of initial therapy for acquired TTP to eliminate autoantibodies and reduce relapse risk 1, 6

Caplacizumab Therapy

• Consider caplacizumab for patients with severe ADAMTS13 deficiency, particularly with elevated inhibitor levels 1, 5
• Caplacizumab is FDA-approved for treatment of adult patients with acquired TTP in combination with plasma exchange and immunosuppressive therapy 5
• Administer a single 11 mg bolus IV injection prior to first plasma exchange, followed by daily 11 mg subcutaneous injections after completion of plasma exchange for the duration of daily plasma exchange period and for 30 days thereafter 5
• Caplacizumab results in quicker platelet count normalization, prevention of exacerbations, reduced plasma exchange requirements, and shorter hospital stays 6

Critical Management Pitfalls

Transfusion Precautions

• Avoid platelet transfusions unless life-threatening hemorrhage occurs, as they may worsen thrombosis 1
• Minimize RBC transfusion, targeting hemoglobin 7-8 g/dL in stable patients 1

Bleeding Risk with Caplacizumab

• Patients receiving caplacizumab have increased bleeding risk - advise patients that bruising and bleeding may occur more easily, with prolonged bleeding from cuts and increased risk of nosebleeds and gum bleeding 5
• Monitor for signs of excessive bleeding including red or dark brown urine, red or tar black stools, headache, dizziness, or weakness 5

Treatment Delays

• Inappropriate Emergency Department triage occurs in 59% of suspected TTP cases, contributing to treatment delays 2
• 59% of patients experience delayed plasma exchange >8 hours from suspected diagnosis, with only 45% receiving interim plasma infusion 2