Centre National de Référence sur les Microangiopathies Thrombotiques
Avancer dans la recherche pour mieux comprendre et traiter les microangiopathies thrombotiques
Pathologies
PTTi – Immune Thrombotic Thrombocytopenic Purpura
Immune thrombotic thrombocytopenic purpura (ITTP) is a major form of thrombotic microangiopathy (TMA), linked to a severe acquired deficiency in ADAMTS13 (<10%). This deficiency is most often secondary to the presence of inhibitory autoantibodies directed against the ADAMTS13 enzyme.
ADAMTS13 is a plasma metalloproteinase essential for the cleavage of ultra-large multimers of von Willebrand factor (VWF). Under normal conditions, this cleavage limits platelet adhesion and aggregation in the microcirculation. In severe deficiency, the accumulation of ultra-large VWF multimers leads to spontaneous platelet activation, resulting in the diffuse formation of microthrombi.
This microthrombosis obstructs the microcirculation and induces tissue ischemia responsible for the clinical manifestations of the disease.
Support
PTTi constitutes an absolute medical emergency. Management relies on a combined strategy aimed at restoring ADAMTS13 activity, eliminating autoantibodies, and inhibiting microthrombi formation.
1. Plasma exchange
Daily plasma exchange is the first-line treatment. It allows:
• The elimination of circulating autoantibodies,
• The contribution of functional ADAMTS13,
• The progressive restoration of microvascular hemostasis.
They should be continued until stable normalization of platelets and biological improvement (LDH, reticulocytes).
2. Associated treatments
Systemic corticosteroid therapy
Corticosteroid therapy is systematically administered. Its immunomodulatory effect helps reduce the production of autoantibodies. Data from the literature report a clinical response in approximately 50–60% of cases, depending on the study. It is used at high doses in the acute phase, with gradual tapering.
Rituximab
Rituximab is an anti-CD20 monoclonal antibody targeting B lymphocytes involved in the production of anti-ADAMTS13 autoantibodies.
Its early introduction, from the acute phase in association with plasma exchange and corticosteroid therapy, is now recommended in moderate to severe forms.
Its therapeutic objectives are:
• Durable suppression of self-reactive B clones,
• Restoration of ADAMTS13 activity,
• Significant reduction in the risk of relapse.
Studies show a rapid improvement in biological parameters and a sustained reduction in recurrences.
Caplacizumab
Caplacizumab is a humanized nanobody directed against the A1 domain of von Willebrand factor.
It inhibits the vWF–platelet interaction, thus blocking the formation of microthrombi independently of immunological status.
Its main effects are:
• Rapid normalization of platelet count,
• Reduced risk of organ damage in the acute phase,
• Reduction in mortality and early morbidity.
It is currently integrated into first-line strategies in combination with plasma exchange, corticosteroid therapy, and rituximab.
Clinical presentation
The clinical picture combines mechanical hemolytic anemia (schistocytes, negative Coombs test), peripheral thrombocytopenia, and signs of organ failure. Neurological manifestations are frequent and sometimes fluctuating (confusion, headache, focal neurological deficit, seizures). Subclinical cardiac involvement is common and associated with an increased risk of mortality. Renal insufficiency may be present but is generally less severe than in HUS.
Diagnosis
The diagnosis is based on the demonstration of a collapsed ADAMTS13 activity (<10%) associated with the presence of anti-ADAMTS13 autoantibodies. Biological investigation should in no case delay treatment, which must be initiated urgently upon clinical suspicion.