Thrombotic thrombocytopenic purpura (TTP), also known as Moschcowitz disease, is a rare, life-threatening form of thrombotic microangiopathy (TMA). The condition is characterized by widespread formation of microscopic blood clots in small vessels throughout the body, leading to profound peripheral thrombocytopenia and microangiopathic hemolytic anemia (MAHA). TTP encompasses two major subtypes: congenital TTP (cTTP), arising from inherited genetic defects, and acquired TTP (aTTP), which has an immune-mediated mechanism. Both forms carry significant risk of serious organ damage.

The clinical presentation of TTP involves thrombocytopenia, which may manifest as petechiae, purpura, or abnormal bleeding. Microangiopathic hemolytic anemia produces fatigue, pallor, and jaundice due to red blood cell destruction. Neurological manifestations—including confusion, headache, stroke, and seizures—reflect microvascular involvement in the central nervous system. Renal impairment, fever, and abdominal pain are also documented features. Organ failure of variable severity may occur, reflecting the distribution and extent of microvascular thrombosis across multiple systems.

TTP is fundamentally linked to severe deficiency or dysfunction of ADAMTS13, a metalloprotease enzyme responsible for cleaving ultra-large von Willebrand factor (VWF) multimers. In congenital TTP, pathogenic variants in the ADAMTS13 gene—including single nucleotide variants and deletions—cause inherited enzyme deficiency. Six pathogenic variants have been catalogued in ClinVar. In acquired TTP, autoantibodies directed against ADAMTS13 inhibit its activity, classifying it as an immune-mediated disorder. Uncleaved ultra-large VWF multimers accumulate, promoting widespread platelet aggregation and microvascular thrombosis.

Diagnosis of TTP involves laboratory evaluation demonstrating thrombocytopenia, schistocytes on peripheral blood smear, elevated lactate dehydrogenase, and reduced haptoglobin consistent with hemolysis. ADAMTS13 activity testing is central to confirming TTP and distinguishing it from other thrombotic microangiopathies; activity levels below 10% are characteristic. Detection of anti-ADAMTS13 inhibitory antibodies supports the diagnosis of immune-mediated TTP. Congenital TTP is confirmed through genetic testing identifying pathogenic ADAMTS13 variants. TTP carries ORPHA reference Orphanet:54057.

Two FDA-approved therapies are available for TTP. Caplacizumab (CABLIVI), approved February 2019, is an anti-von Willebrand factor nanobody with active orphan drug designation. ADZYNMA (recombinant ADAMTS13-krhn), approved November 2023, is a recombinant enzyme replacement specifically applicable to congenital TTP. Additional agents under orphan drug designation include anfibatide and defibrotide. Plasma exchange has historically been a documented therapeutic approach for acquired TTP in published literature. Immunosuppressive strategies targeting autoantibody production are also described in the medical literature for immune-mediated disease.

TTP is an aggressive condition historically associated with high mortality when untreated. With contemporary therapeutic approaches, survival rates have improved substantially, though the disease remains potentially fatal during acute episodes. Survivors of acquired TTP carry risk of disease relapse, and ongoing ADAMTS13 deficiency may contribute to recurrent thrombotic events. Neurological sequelae and cardiovascular complications have been documented in long-term follow-up studies. Congenital TTP follows a chronic, relapsing course requiring ongoing management. Individual outcomes vary considerably based on disease subtype, severity, and timing of intervention.

Nineteen active or recently active clinical trials are registered for TTP on ClinicalTrials.gov. Studies include a Phase 2 pilot of efgartigimod for immune-mediated TTP (NCT06831058), investigations of daratumumab in iTTP (NCT07513948), and long-term follow-up studies of recombinant ADAMTS13 (ADZYNMA) in congenital TTP (NCT07353099, NCT07429942). Research is also examining microvascular damage in TTP (NCT07615244) and immunological mechanisms (NCT06945861). A retrospective analysis of caplacizumab efficacy in aTTP is ongoing at the University of Cologne (NCT04985318). Multiple orphan drug programs targeting VWF and ADAMTS13 pathways are in various stages of development.