What are the clinical essentials of managing Thrombotic Thrombocytopenic Purpura (TTP)?

Clinical Essentials of Thrombotic Thrombocytopenic Purpura (TTP)

Immediate Recognition and Treatment Initiation

Start therapeutic plasma exchange (TPE), corticosteroids, and rituximab immediately when TTP is suspected—do not wait for ADAMTS13 results, as treatment delays directly increase mortality. 1, 2

Critical Diagnostic Features to Recognize

• Thrombocytopenia with microangiopathic hemolytic anemia (elevated LDH, reduced haptoglobin, indirect hyperbilirubinemia) occurring precipitously suggests TTP 2
• Schistocytes >1% on peripheral blood smear confirm microangiopathic hemolysis, though their absence does not exclude early disease 2
• Negative direct Coombs test distinguishes this from immune-mediated hemolysis 2
• Neurological manifestations occur in 10-20% and include altered mental status, seizures, focal deficits, vision changes, or encephalopathy 2
• Renal involvement manifests as hematuria, proteinuria, or elevated creatinine 2

Risk Stratification While Awaiting ADAMTS13

• Use the PLASMIC score (Platelet count, hemoLysis, Absence of cancer, Absence of transplant, MCV, INR, Creatinine) to risk-stratify patients 3, 2
• PLASMIC score ≥5 points indicates intermediate-to-high risk and warrants immediate treatment in adults 3, 2
• In children, defer TPE for 24-48 hours until ADAMTS13 results confirm diagnosis, as TPE carries considerable morbidity in pediatric patients 3, 2

Diagnostic Workup (Perform Simultaneously with Treatment)

Essential Laboratory Tests

• ADAMTS13 activity <10% is diagnostic of TTP, but treatment must not be delayed awaiting results 1, 2
• Anti-ADAMTS13 antibody testing distinguishes acquired (immune) from congenital TTP 2, 4
• Complete blood count to document thrombocytopenia and anemia 1
• Peripheral blood smear to confirm schistocytes 1
• LDH, haptoglobin, reticulocyte count, indirect bilirubin to assess hemolysis 1, 2
• Coagulation studies (PT, aPTT, fibrinogen) to exclude DIC 1
• Blood type and antibody screen, direct antiglobulin test 1
• Urinalysis and creatinine to assess renal involvement 1, 2

First-Line Treatment Protocol

Corticosteroids

• Methylprednisolone 1 g IV daily for 3 days, with the first dose given immediately after the first TPE session 1
• Transition to prednisone 1-2 mg/kg/day following initial high-dose therapy 1

Therapeutic Plasma Exchange

• Daily TPE is the cornerstone of treatment, supplying deficient ADAMTS13 and removing autoantibodies 1, 4, 5
• Continue TPE daily until platelet count >150,000/µL and LDH normalizes for 2-3 consecutive days 6
• TPE should be initiated within hours of suspected diagnosis in adults 1, 2

Rituximab

• Rituximab should be offered as part of initial therapy for acquired TTP 1
• Complete the full course of rituximab (375 mg/m² weekly for 4 weeks) if initiated 1
• Rituximab targets the autoimmune mechanism and reduces relapse rates 4, 5

Caplacizumab

• Caplacizumab should be considered for patients with severe ADAMTS13 deficiency, particularly with elevated inhibitor or anti-ADAMTS13 IgG 1
• Dosing: 11 mg IV bolus at least 15 minutes before first TPE, then 11 mg subcutaneous daily after each TPE session 7
• Continue for 30 days after last TPE, with possible extension up to 28 additional days if ADAMTS13 activity remains suppressed 7
• Discontinue caplacizumab if no exacerbation occurs within 3-5 days after stopping TPE 1
• Caplacizumab reduces time to platelet recovery and decreases TTP-related death and recurrence (12.7% vs 49.3% composite endpoint) 7

Critical Management Pitfalls to Avoid

Transfusion Management

• Avoid platelet transfusions unless life-threatening hemorrhage occurs, as they may worsen thrombosis 1
• Transfuse RBCs only to minimum necessary to relieve symptoms or achieve hemoglobin 7-8 g/dL in stable patients 1
• Coordinate with blood bank before any transfusions 1

Anticoagulation and Antiplatelet Agents

• Avoid concomitant antiplatelet agents or anticoagulants during caplacizumab treatment due to increased bleeding risk 7
• Withhold caplacizumab 7 days prior to elective surgery or invasive procedures 7

Monitoring During Active Treatment

• Daily assessment of platelet count, hemoglobin, LDH, and clinical status during active TPE 1
• Weekly hemoglobin monitoring until steroid taper is complete 1
• Serial ADAMTS13 activity levels guide treatment duration and identify persistent disease 1, 6

Refractory or Severe TTP

• For patients not responding to standard therapy, consider additional immunosuppression: cyclosporine, cyclophosphamide, vincristine, mycophenolate mofetil, or anti-thymocyte globulin 1
• Twice-daily TPE may be considered in refractory cases 5
• Salvage splenectomy remains an option for truly refractory disease 5

Special Populations

Lupus-Associated TTP

• In patients with systemic lupus erythematosus presenting with TMA, TTP should be considered and ADAMTS13 testing performed 3, 2
• Comanagement with experienced hematologist is preferable when expertise is available 3
• Distinguish from antiphospholipid syndrome-related TMA and complement-mediated TMA 3

Emerging TPE-Free Approach

• Recent evidence suggests caplacizumab plus immunosuppression without TPE may rapidly control thrombotic microangiopathy in experienced centers 8
• Four patients in one cohort failed to respond to caplacizumab alone and required TPE initiation, highlighting that this approach requires careful patient selection and monitoring 8
• This approach should only be considered in experienced centers with immediate TPE availability if needed 8

Long-Term Considerations

• TTP has a relapsing tendency, requiring long-term follow-up 5
• Monitor for other autoimmune diseases during follow-up 5
• Assess for psychophysical sequelae that may persist after acute episode 5