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Acquired thrombotic thrombocytopenic purpura
A rare, non-hereditary thrombotic thrombocytopenic purpura (TTP), characterized by profound peripheral thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and single or multiple organ failure of variable severity.
ORPHA:93585Classification level: Subtype of disorder
- Acquired TTP
- Autoimmune thrombotic thrombocytopenic purpura
- Thrombotic thrombocytopenic purpura due to anti-ADAMTS-13 antibodies
- Prevalence: Unknown
- Inheritance: Multigenic/multifactorial
- Age of onset: All ages
- ICD-10: M31.1
- OMIM: -
- UMLS: C2584778
- MeSH: C536901
- GARD: -
- MedDRA: -
The annual incidence of TTP is estimated at up to 1/250, 000. Acquired TTP is much more common than congenital TTP (see this term), accounting for over 95% of all TTP cases, and has a 3:1 female-to-male ratio.
Disease onset is typically sudden and occurs in adulthood (median age: 40 years). Prodromic manifestations including fatigue, arthralgias, myalgias and abdominal and/or lumbar pain are frequently observed around the time of diagnosis. Thrombotic microangiopathy is associated with MAHA, consumptive peripheral thrombocytopenia and variable organ injury due to disseminated microvascular thrombosis. Manifestations due to cerebral (headache, confusion, seizure, focal deficiency, altered mental state and coma; 50-80% of cases), cardiac (infarction, congestive heart failure, arrhythmias, cardiogenic shock, and sudden cardiac arrest), and gastrointestinal (abdominal pain, nausea, vomiting, and diarrhea) involvement are observed. Renal involvement is usually mild. The disease course is variable. Patients may suffer from only one acute TTP episode; however, relapses have been reported in 30-40% of patients. Acquired TTP is usually idiopathic but rarely may occur in association with a connective tissue disease (mostly systemic lupus erythematosus and Sjögren's syndrome) (see these terms), infections (typically HIV infection), or after ticlopidine intake. Patients with a history of acquired TTP are at risk of a relapse during pregnancy.
The majority of cases of acquired TTP are associated with the presence of autoantibodies directed against the von Willebrand factor-cleaving protease ADAMTS13, usually resulting in a severe (< 10% normal activity) ADAMTS13 deficiency. A trigger, including physical stress (surgery), infections, drug intake or a pregnancy may precipitate the disease.
Biological features are consistent with hemolysis (high reticulocyte count, indirect bilirubin and LDH levels and a low haptoglobin level). The direct antiglobulin test is negative whereas peripheral blood smear reveals schistocytes. A very low platelet count (≤ 30 000/mm3) and mild renal involvement (serum creatinine ≤ 200 µmol/L) can predict a severe acquired ADAMTS13 deficiency. A severe decrease in ADAMTS13 activity (< 10% normal levels) in the presence of anti-ADAMTS13 autoantibodies confirms diagnosis.
The main differential diagnoses are congenital TTP and atypical hemolytic uremic syndrome as well as antiphospholipid syndrome, Evans syndrome (see these terms), disseminated intravascular coagulation, cobalamin deficiency and, in pregnant patients, HELLP syndrome (see this term).
Management and treatment
Therapeutic plasma exchange (TPE; with 1.5 x plasma volume exchange) is the mainstay of treatment. TPE should be initiated as soon as the clinical diagnosis of TTP is made or suspected and should be continued daily until remission. Steroids, in the absence of uncontrolled infection, are often used as adjuvant first line therapies. Antiplatelet agents may be introduced when platelet count is above 50.000/mm3. Patients with refractory disease or those who experience exacerbations after standard TPE require treatment intensification with rituximab. In more severe cases, a salvage therapy combining twice-daily TPE, cyclophosphamide, splenectomy or vincristine may be proposed.
In the absence of treatment, TTP is a rapidly fatal disease (mortality rate > 90%), however, the introduction of TPE has led to a decrease in the rate of mortality to around 15%. Even with optimal management, neurological (attention deficit, memory loss) and physical (fatigue) sequelae may persist. A systematic long term follow-up is required for all patients, due to the risk of developing other autoimmune diseases.