Zheng XL, Vesely SK, Cataland SR, et al. ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020 Jul 17. doi: 10.1111/jth.15006. Epub ahead of print. PMID: 32914582.
Zheng XL, Vesely SK, Cataland SR, et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020 Jul 15. doi: 10.1111/jth.15010. Epub ahead of print. PMID: 32914526.
Joly BS, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura. Blood. 2017 May 25;129(21):2836-2846. doi: 10.1182/blood-2016-10-709857. Epub 2017 Apr 17. Review. PubMed PMID: 28416507.
Definition, Etiology, PathogenesisTop
Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy characterized by thrombocytopenia, anemia with schistocytes, neurologic impairment, renal impairment, and fever. Not all 5 signs need to be present; the presence of thrombocytopenia and hemolytic anemia with schistocytes only is sufficient for the diagnosis. Thrombocytopenia is caused by the formation of intravascular platelet aggregates, which develop due to endothelial injury and the presence of ultra large von Willebrand factor (vWF) molecules in plasma (in healthy persons vWF is degraded by the plasma metalloproteinase ADAMTS-13 [vWF-cleaving protease]). Hemolytic anemia and the presence of schistocytes (fragments of erythrocytes) result from red blood cell damage related to platelet aggregates in the microcirculation.
Immune TTP is caused by autoantibodies to ADAMTS-13 and ADAMTS-13 deficiency. Acquired TTP may also develop in patients with bacterial infections; HIV infection; in the course of treatment with various drugs, including calcineurin inhibitors, quinine, interferon alpha, ticlopidine, clopidogrel, simvastatin, trimethoprim, gemcitabine, and bleomycin; in pregnancy; or in patients with cancer or after organ transplant. Platelet aggregates present in microcirculation cause hemolytic anemia with schistocytes in peripheral blood films and features of ischemia of various organs and systems, most frequently the central nervous system. Thrombi form in capillaries and arterioles in all organs, with particularly extensive involvement of the vessels of the brain, heart, kidneys, pancreas, and adrenal glands.
Chronic or familial TTP is associated with an inherited ADAMTS-13 deficiency.
Clinical Features and Natural HistoryTop
TTP is more prevalent in women, usually between the ages of 30 to 40 years. The onset is acute and may be preceded by a mild upper respiratory tract infection. Manifestations include signs and symptoms of thrombocytopenia, hemolysis (anemia and jaundice), neurologic symptoms (these may include behavioral abnormalities, headache, visual disturbances, paresthesias, aphasia, coma), fever, abdominal pain, myalgia (frequent), and enlargement of the liver and spleen. Familial TTP may present for the first time during pregnancy.
1. Complete blood count (CBC): Normocytic anemia, erythroblasts and schistocytes present in peripheral blood smears, thrombocytopenia, increased reticulocyte counts.
2. Blood biochemical tests: Elevated serum unconjugated bilirubin and lactate dehydrogenase (LDH) levels. Features of impaired renal function in some patients.
3. Other studies: Markedly decreased concentrations and decreased activity of ADAMTS-13 (<10%) as well as positive antibodies to ADAMTS-13 in immune TTP. Direct antiglobulin test results are negative.
Diagnosis is usually based on clinical features. Confirmation of microangiopathic hemolytic anemia and thrombocytopenia without an identifiable cause is sufficient for establishing the diagnosis. Documenting reduced ADAMTS-13 levels and positive antibodies to ADAMTS-13 may be performed if available. If TTP is highly suspected, do not wait until ADAMTS-13 testing results are available; initiate treatment as soon as possible.
Disseminated intravascular coagulation, Evans syndrome, catastrophic antiphospholipid syndrome, bacterial sepsis, hemolytic-uremic syndrome, and other microangiopathies.
1. Therapeutic plasma exchange (TPE, or plasmapheresis) of 1 to 1.5 total plasma volume per day using donor plasma as the replacement fluid (the most effective treatment). Continue plasmapheresis until the resolution of neurologic symptoms and normalization of platelet counts and LDH levels. If plasma exchange is not immediately available, a plasma infusion (25-30 mL/kg of frozen plasma per day) can be used as a temporizing measure.
2. Glucocorticoids: Recent guidelines from the International Society on Thrombosis and Haemostasis (ISTH) recommend adding glucocorticoids to TPE over TPE alone. No dose or schedule is recommended, but a typical course might be prednisone 1 mg/kg for the first 5 to 7 days followed by a rapid taper.
3. Rituximab 375 mg/m2 once weekly for 4 to 8 weeks, particularly in patients not responding to plasmapheresis or glucocorticoids, or with relapse. Rituximab should be considered in newly presenting patients, as it may facilitate recovery and reduce the risk of relapse.
4. Caplacizumab is a single-domain antibody that targets the A1 domain of vWF and blocks vWF binding to glycoprotein Ib on platelets, thereby preventing the formation of microvascular thrombosis. The ISTH guideline panel suggests using caplacizumab over not using caplacizumab for patients with acute TTP because it has been associated with a reduction in the number of TTP exacerbations during or within 30 days of stopping TPE.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Scully M, Cataland SR, Peyvandi F, et al; HERCULES Investigators. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2019 Jan 24;380(4):335-346. doi: 10.1056/NEJMoa1806311. Epub 2019 Jan 9. PMID: 30625070. Zheng XL, Vesely SK, Cataland SR, et al. Good practice statements (GPS) for the clinical care of patients with thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020 Aug 4. doi: 10.1111/jth.15009. Epub ahead of print. PMID: 32914535. This drug may be associated with bleeding adverse effects, and it may not be available in many centers (the listed cost in some jurisdictions is >200,000 Canadian dollars for a course of treatment).
5. Immunosuppressive drugs: These treatments can be used for patients who deteriorate despite other treatments (eg, vincristine, cyclophosphamide, azathioprine, bortezomib, or others).
6. Splenectomy may lead to improvement in some patients. Optimally it should be performed in remission after the first relapse.
7. Packed red blood cell transfusions are used to control anemia.
8. Platelet concentrates should be reserved only for patients with life-threatening hemorrhages.
9. Chronic TTP: Administer frozen plasma 20 mL/kg every 3 to 4 weeks.
Mortality rates are 90% in untreated patients and 10% to 20% in patients treated with plasma exchange. TTP relapses in 30% of patients, and in half of these cases relapse occurs within 2 months of the first episode. Rituximab therapy may reduce the rate of relapse.