Immune-mediated thrombotic thrombocytopenic purpura (ORPHA:93585)
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.
Epidemiology
The annual incidence of TTP is estimated at 0.25 to 1/250, 000. Immune-mediated TTP is much more common than congenital TTP, accounting for over 95% of all TTP cases, and has a 3:1 female-to-male ratio.
Clinical description
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. Immune-mediated TTP is usually idiopathic but rarely may occur in association with a connective tissue disease (mostly systemic lupus erythematosus and Sjögren's syndrome), infections (typically HIV infection), or after ticlopidine intake. Patients with a history of immune-mediated TTP are at risk of a relapse during pregnancy.
Etiology
The majority of cases of immune-mediated TTP are associated with the presence of autoantibodies directed against the von Willebrand factor-cleaving protease, ADAMTS13, resulting in a severe (< 10% of normal activity) ADAMTS13 deficiency. A trigger, including physical stress (surgery), infections, drug intake or a pregnancy, may precipitate the disease.
Diagnostic methods
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.
Differential diagnosis
The main differential diagnoses are congenital TTP and atypical hemolytic uremic syndrome as well as antiphospholipid syndrome, Evans syndrome, disseminated intravascular coagulation, cobalamin deficiency and, in pregnant patients, HELLP syndrome.
Management and treatment
The treatment of immune-mediated TTP is based on a triplet regimen of therapeutic plasma exchange (TPE; with 1.5 x plasma volume exchange), immunosuppression with corticosteroids and B-cell depletion (rituximab), and caplacizumab, an inhibitor of vWF-platelet interaction. This treatment 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. Thromboprophylaxis may be introduced when platelet count is above 50,000/mm3. Whilst exacerbations and refractory disease are rare with the triplet regimen, this can be managed with a more intensive treatment including twice-daily TPE. For patients in clinical remission but with a persistently undetectable ADAMTS13 activity, preemptive administrations of rituximab prevents relapse.
Prognosis
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 10-15%. With the recent addition of caplacizumab, mortality may further decrease to < 10%. 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 relapse. Patients may also develop additional autoimmune diseases.

                            Last update: 
                            November 2020


                            - Expert reviewer(s): 
                            Pr Paul COPPO