Nous tractaments de la púrpura trombocitopènica trombòtica ... · thrombotic thrombocytopenic...
Transcript of Nous tractaments de la púrpura trombocitopènica trombòtica ... · thrombotic thrombocytopenic...
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Nous tractaments de la púrpura trombocitopènica trombòtica adquirida
Dr. Miquel Lozano MoleroCap de Secció de Hemoteràpia. Professor Associat Mèdic
Servei d’Hemoteràpia i HemostàsiaHospital Clínic de Barcelona. Universitat de Barcelona
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aTTP
HL , Female, 23 years-old
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Thrombotic Microangiopathies
• Disorders defined by the presence of a microangiopathic hemolytic anemia (with the characteristic hallmark of schistocytes in the peripheral blood smear), thrombocytopenia and organ malfunction of variable intensity
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Hereditary or Acquired TTP
Drug-mediated (toxic dose-related)
Hereditary or Acquired complement mediated
Coagulation mediated (DGKE,
PLG, THBD)
Drug-mediated (immune)
Shiga toxin-mediated
Metabolims-mediated (cobalamindeficiency)
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TMA: etiology
• Primary:– Thrombotic thrombocytopenic purpura (TTP):
• Acquired:• Congenital:
– Atypical hemolytic uremic syndrome (aHUS):• Secondary:
– Connective tissue diseases and their allied diseases:– Malignancies:– Hematopoietic stem cell transplantation:– Drugs:– E Coli O157:H7 infection:– Pregnancy:– Other:
Fujimura Y, et al. Intern Med 2010; 49:7-15
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TMA: etiology and frequencies (Japanese registry)
• Primary: 49.5%– Thrombotic thrombocytopenic purpura (TTP):
• Acquired: 30.9%• Congenital: 4.5%
– Atypical hemolytic uremic syndrome (aHUS): 11.5%• Secondary: 50.5%
– Connective tissue diseases and their allied diseases: 24.0%– Malignancies: 6.6 %– Hematopoietic stem cell transplantation: 5.9%– Drugs: 3.8%– E Coli O157:H7 infection: 3.4%– Pregnancy: 1.6%– Other: 5.0%
Fujimura Y, et al. Intern Med 2010; 49:7-15
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Crawley JTB, et al. Blood 2011; 118: 3212-3221
ADAMTS13 (a disintegrin-like and metalloproteasewith thrombospondin repeats”
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Crawley JTB, et al. Blood 2011; 118: 3212-3221
ADAMTS13 (a disintegrin-like and metalloproteasewith thrombospondin repeats”
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TTP: Pathogenesis
http://what-when-how.com/acp-medicine/platelet-and-vascular-disorders-part-2/Kremer Hovinga JA, et al. Nat Rev Dis Primers. 2017:17020. doi: 10.1038/nrdp
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TMA Diagnosis
Plasma exchange using FFP as a replacement solution
Scully M, et al. Br J Haemat 2014; 64: 759-766
If ADAMTS 13 < 5-10% with inhibitor
Add- Corticosteroids
- Rituximab*
*patients with neurologic or cardiac involvement
ADAMTS 13 < 5-10%
Hereditary TTPPlasma infusion
ADAMTS 13 > 5-10% without inhibitor
Kidney injury
aHUS+
eculizumab
Rule out secondary causes
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Mainstay for the treatment of aTTP
Immunosupression(corticosteroids
and/or rituximab)
• Suppress autoantibody production
Daily PEX until confirmed platelet
normalization
• Remove anti-ADAMTS13 autoantibodies and ULvWF.
• Replace functional ADAMTS13
Standard of care based on two pillars
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Treatment Outcome
Kremer Hovinga JA, et al. Nat Rev Dis Primers. 2017:17020. doi: 10.1038/nrdp
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Current and Emerging Therapeutic Approaches for aTTP
Veyradier A. N Engl J Med 2016;59-766
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Nanobodies
www.ablinx.com
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Nanobody Development
www.ablinx.com
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Anti-VWF Nanobody
www.ablinx.com
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Anti-VWF Nanobody = Caplacizumab
• Caplacizumab: (Cablivi®, Sanofi) has been approved for the treatment of acquired thrombotic thrombocytopenic purpura in the EU (August 2018) and USA (February 2019)
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TITAN Study
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Normalization of platelet count
Peyvandi F, et al. N Engl J Med 2016;374:511-22
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Peyvandi F, et al. N Engl J Med 2016;374:511-22
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Thromboembolic events and mortality
Peyvandi F, et al. J Thromb Haemost 2017; 15: 1448–52
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Adverse Events and Serious Adverse Events
Peyvandi F, et al. J Thromb Haemost 2017; 15: 1448–52
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HERCULES Trial
Scully M, et al. N Eng J Med 2019;380:335-46
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HERCULES Trial
Scully M, et al. N Eng J Med 2019;380:335-46
Composite outcome:- TTP-related death - Recurrence of TTP- Thromboembolic event- Refractory TTP- Normalization of organ-damage markers
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HERCULES Trial
Scully M, et al. N Eng J Med 2019;380:335-46
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HERCULES Trial
Scully M, et al. N Eng J Med 2019;380:335-46
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HERCULES Trial
Scully M, et al. N Eng J Med 2019;380:335-46
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HERCULES Trial
Scully M, et al. N Engl J Med 2019;380:335-46
120 patients, at the end of caplacizumab/placebo administration:-29 (24%) ADAMTS13 activity < 10%
- 20 (69%) no relapses- 9 (31%) relapsed
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Caplacizumab
• Does not remove the antibody blocking ADAMTS-13 activity• Prevents platelets being consumed in microthrombi with ULvWF multimers:
– faster normalization of platelets– reduction of tissue damage
• Platelet count or organ damage markers not anymore markers of disease activity• We will have to find new ways of monitoring• New paradigm in the treatment of acquired TTP
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Mainstay for the treatment of aTTP
Immunosupression(Corticosteroids AND
rituximab)
• Suppress autoantibody production
Daily PEX until confirmed platelet
normalization
• Remove anti-ADAMTS13 autoantibodies and ULvWF.
• Replace functional ADAMTS13
Caplacizumab
• Immediate blocking of binding of vWF to platelets
• Protection against microvascular thrombosis and organ damage
• Reduction in exacerbations
• Reduction in days and complications of PEX
Future standard of care based on three pillars?
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Current and Emerging Therapeutic Approaches for aTTP
Veyradier A. N Engl J Med 2016;59-766
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https://clinicaltrials.gov/ct2/show/NCT03922308
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Conclusions
• In the last 20 years huge advances in the knowledge of the pathophysiology of acquired TTP have occured
• Accordingly the therapeutic approach have changed significantly• New drugs will change the way how we manage patients with the condition reducing
even further the morbidity and mortality of the disease
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