Thrombotic Thrombocytopenic Purpura

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.

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.

Type	Pathogenesis	Associated Factors
Acquired TTP	Autoantibody-mediated inhibition/clearance of ADAMTS13.	Female sex, African-American descent, autoimmune disease, pregnancy, infection, drugs (ticlopidine, clopidogrel).
Congenital TTP	Genetic 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.

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.

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.

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

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.

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

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

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.