Definition And Classification

  • Rare thrombotic microangiopathy (TMA).
  • Characterized by systemic microvascular thrombosis leading to end-organ ischemia.
  • Categorized into acquired (more common) and congenital forms.

Pathophysiology

  • Driven by deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats).
  • ADAMTS13 normally cleaves unusually large multimers of von Willebrand factor (vWF) into biologically less active forms.
  • Deficiency leads to accumulation of ultralarge vWF multimers.
  • Results in "spontaneous" platelet adhesion, aggregation, and extensive microvascular thrombosis.
TypePathogenesisAssociated Factors
Acquired TTPAutoantibody-mediated inhibition/clearance of ADAMTS13.Female sex, African-American descent, autoimmune disease, pregnancy, infection, drugs (ticlopidine, clopidogrel).
Congenital TTPGenetic mutation in ADAMTS13 gene (chromosome 9q34); inadequate enzyme production. Abnormal complement system implicated rarely.Also known as Upshaw-Shulman syndrome. Presents in infancy with jaundice/thrombocytopenia, or triggered later by pregnancy/infection.

Clinical Features

  • Classic pentad of findings (often presenting acutely):
    • Microangiopathic hemolytic anemia (MAHA).
    • Thrombocytopenia.
    • Neurologic symptoms: Subtle, shifting signs, changes in affect/orientation, aphasia, blindness, seizures.
    • Renal impairment: Progressive renal failure in 25% of chronic cases.
    • Fever.
  • Additional symptoms: Pallor, jaundice, malaise, nausea, vomiting, abdominal pain, chest pain.

Diagnostic Evaluation

Laboratory Findings

  • Hematology:
    • Thrombocytopenia (often severe, out of proportion to hemorrhage).
    • MAHA: Polychromasia, basophilic stippling, schistocytes, microspherocytes, helmet cells, burr cells, and nucleated red blood cells on peripheral smear.
    • Elevated reticulocyte count.
  • Hemolysis Markers:
    • Markedly elevated lactate dehydrogenase (LDH).
    • Reduced or absent haptoglobin.
    • Increased unconjugated bilirubin.
    • Hemoglobinuria and hemosiderinuria.
  • Immunology: Direct antiglobulin test (DAT/Coombs) negative.
  • Coagulation Profile: Usually nondiagnostic; occasionally concurrent disseminated intravascular coagulation (DIC) features (prolonged PT/PTT, elevated D-dimer, hypofibrinogenemia) observed.
  • Renal Function: Elevated blood urea nitrogen (BUN) and creatinine.

Confirmatory Testing

  • ADAMTS13 Assay: Severe deficiency (activity <10%) confirms diagnosis.
  • Autoantibodies: Presence of inhibitory anti-ADAMTS13 IgG autoantibodies confirms acquired TTP.

Clinical Scoring

  • PLASMIC Score: Utilized to identify patients with high likelihood of ADAMTS13 deficiency pending assay results.
  • Incorporates platelet count, hemolytic anemia, macrocytosis, coagulopathy, renal failure, and history of organ transplantation/malignancy.

Management And Treatment

  • Medical emergency; 80-90% mortality without timely intervention.
  • Diagnosis made clinically; treatment must initiate immediately without awaiting ADAMTS13 assay results.

Acquired Thrombotic Thrombocytopenic Purpura

Therapy ModalityDetails & Rationale
Plasma Exchange (Plasmapheresis)Mainstay of therapy. Removes anti-ADAMTS13 antibodies and replaces deficient enzyme via donor plasma. Achieves 50-80% remission rate.
CorticosteroidsAdministered in high doses alongside plasma exchange.
RituximabTargets B-cells producing ADAMTS13 autoantibodies. Given upfront or in refractory cases to reduce required plasmapheresis sessions and prevent relapse.
CaplacizumabAnti-vWF humanized monoclonal antibody. Blocks platelet interaction with ultralarge vWF multimers. Decreases time to platelet normalization.
Platelet TransfusionGenerally contraindicated. Potential to worsen consumptive coagulopathy and microvascular thrombosis. Reserved exclusively for life-threatening emergent bleeding.
Refractory/Relapsing DiseaseImmunosuppressives (cyclosporine, cyclophosphamide, vincristine, mycophenolate mofetil, azathioprine). Splenectomy considered for refractory cases.

Congenital Thrombotic Thrombocytopenic Purpura

  • Plasma Infusions: Mainstay of therapy. Replaces missing ADAMTS13 enzyme. Autoantibodies absent, obviating need for plasmapheresis.
  • Prophylaxis: Scheduled plasma infusions at 2-3 week intervals.
  • Novel Therapies: Recombinant ADAMTS13 concentrates (undergoing clinical trials). Plasma-derived Factor VIII concentrates containing ADAMTS13 offer alternative for patients with severe plasma reactions.