aTTP/iTTP is a rare and life-threatening thrombotic microangiopathy, manifested by microvascular thrombi and consequent thrombocytopenia, hemolytic anemia, and organ ischemia.4-8
*aTTP is also known as iTTP. The terms can be used interchangeably.
- Acquired/Immune-mediated PTT
- The most common form of TTP; represents 95% of PTT cases
- Caused by autoantibody inhibition of ADAMTS13 activity
- Hereditary PTT (also known as congenital PTT, hereditary PTT, familial PTT or Upshaw-Schulman syndrome)
- rare form of TTP
- Caused by mutations in the ADAMTS13 gene
~95% of PTT cases are aTTP/iTTP8
The pathophysiology of aTTP/iTTP poses a triple threat; PEX and immunosuppressive therapy directly address only 2 of 3 aspects of the disease2,5,8,12-15
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Patient risk remains with aTTP/iTTP despite current PEX treatment and immunosuppressive therapy6
Mortality remains high
According to various studies, 8% to 20% of patients died despite PEX and immunosuppressive therapy.4-6,16†
†Literature review of studies with more than 100 patients with TTP.
Thromboembolic events caused by ischemia are common
Almost 35% of hospital deaths from TTP (613) were related to ischemia, including myocardial infarction and stroke, despite receiving PEX.6‡
‡Retrospective harm analysis of hospital admissions with TTP (N=8203).
Relapse threatens patients
Up to 50% of patients had ≥ 1 recurrence within 30 days of PEX discontinuation.4§
§Retrospective review of the French reference center for the registry of TMA (N=388).
Increased risk of stroke due to clinical remission‖
Stroke after PEX recovery occurred in 0% (0/22) of patients with moderately normal ADAMTS13 activity (>70%) and in 27.6% (8/29) of patients
Patients with ADAMTS13 activity ≤ 70% (PAG=0,007).17¶
¶Cohort study of 170 patients with aTTP/iTTP from 1995 to 2018.
ATP/iTTP harbors dangerous risksMORE INFORMATION ABOUT THE ATTP/ITTP DIFFERENTIATION
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‖Defined as a sustained clinical response without PEX and without anti-vWF therapy in the past 30 days or achieving ADAMTS13 remission (partial [between 20% and LLN] or complete [≥ LLN]), whichever occurs first.18
ADAMTS13 = a disintegrin and a metalloproteinase with a thrombospondin type 1 motif, member 13; aTTP = acquired thrombotic thrombocytopenic purpura; ISTH=International Society for Thrombosis and Haemostasis; iTTP = immune-mediated thrombotic thrombocytopenic purpura; LLN = lower limit of normality; MI = myocardial infarction; PEX=plasma exchange; TMA = thrombotic microangiopathy; TTP = thrombotic thrombocytopenic purpura; ULvWF = ultra-large von Willebrand factor; vWF=von Willebrand factor.
INFORMATION AND DISCLOSURES
IMPORTANT SAFETY INSTRUCTIONS
CABLIVI is contraindicated in patients with a previous severe hypersensitivity reaction to caplacizumab-yhdp or to any of the excipients. Hypersensitivity reactions included urticaria.
WARNINGS AND CAUTIONS:
- CABLIVI increases the risk of bleeding. In clinical trials, serious bleeding side effects such as epistaxis, bleeding gums, upper gastrointestinal bleeding, and metrorrhagia were reported in 1% of subjects each. Overall, bleeding events occurred in approximately 58% of CABLIVI-treated patients versus 43% of placebo-treated patients.
- Postmarketing cases of fatal and life-threatening bleeding have been reported in patients receiving CABLIVI.
- The risk of bleeding is increased in patients with underlying coagulopathies (eg, hemophilia, deficiency of other coagulation factors). It is also increased when CABLIVI is used concomitantly with drugs that affect hemostasis and coagulation.
- Avoid concomitant use of CABLIVI with antiplatelet or anticoagulant agents. If clinically significant bleeding occurs, discontinue use of CABLIVI. Von Willebrand factor concentrate can be administered to rapidly correct hemostasis. If CABLIVI restarts, monitor closely for signs of bleeding.
- Withhold CABLIVI for 7 days before scheduled surgery, dental treatment, or other invasive procedures. If emergency surgery is required, von Willebrand factor concentrate may be considered to correct hemostasis. Once the risk of surgical bleeding has been resolved and CABLIVI treatment is resumed, treatment should be closely monitored for signs of bleeding.
The most common adverse reactions (>15% of patients) were epistaxis (29%), headache (21%), and bleeding gums (16%).
SIMULTANEOUS ADMINISTRATION OF ANTICOAGULANTS OR ANTIPLACE:
Concomitant use of CABLIVI with anticoagulants or antiplatelet agents may increase the risk of bleeding. Avoid concomitant use if possible. Carefully assess and control bleeding with concomitant use.
There are no data from the use of CABLIVI in pregnant women reporting the drug-related risk of major birth defects and miscarriage.
- Fetal/Neonatal Side Effects:CABLIVI may increase the risk of bleeding in the fetus and newborn. Check newborns for bleeding.
- Maternal side effects:All patients receiving CABLIVI, including pregnant women, are at risk of bleeding. Pregnant women receiving CABLIVI should be carefully monitored for signs of excessive bleeding.
CABLIVI (caplacizumab-yhdp) is indicated for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP) in combination with plasma exchange and immunosuppressive therapy.
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Instructions for use
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References: 1.CABLIVI Prescribing Information: Genzyme Corporation.2.Scully M, Catalan SR, Peyvandi F and others; for HERCULES researchers. Treatment with caplacizumab in acquired thrombotic thrombocytopenic purpura.N incl. J Med.2019;380(4):335-346.3.Zheng XL, Vesely SK, Kataland SR, et al. ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura.J Thromb Haemost.2020;18(10):2486-2495. doi:10.1111/jth.15006.4.Grall, M., Azoulay, E., Galicier, L., et al. Thrombotic thrombocytopenic purpura misdiagnosed as autoimmune cytopenia: causes of misdiagnosis and implications for outcome. Experience of the French reference center for thrombotic microangiopathies.I'm J Hematol.2017;92(4):381-387.5.Scully M, Hunt BJ, Benjamin S, et al. Commissioned by the British Committee for Standards in Hematology. Guidelines for the diagnosis and treatment of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies.Br J Hematol.2012;158(3):323-335.6.Goel R, King KE, Takemoto CM, Ness PM, Tobian AAR. Stratified prognostic risk score predicting mortality in hospitalized patients with thrombotic thrombocytopenic purpura: national representative data from 2007 to 2012.Transfusion.2016;56(6):1451-1458.7.Peyvandi F, Scully M, Kremer Hovinga JA, et al. Caplacizumab reduces the incidence of serious thromboembolic events, exacerbations, and death in patients with acquired thrombotic thrombocytopenic purpura.J Thromb Haemost.2017;15(7):1448-1452.8.Joly BS, Coppo P, Veyradier A. Thrombotische trombozytopenische Purpura.sangre. 2017;129(21):2836-2846.9.Masias C, Wu H, McGokey M, Jay L, Cataland S, Yang S. No significant difference in outcome between first episodes and relapses in patients with thrombotic thrombotic thrombocytopenic purpura: The Ohio State University Registry experience.I'm J Hematol. 2018;93(3):E73-E75. doi:10.1002/ajh.25002.10Schieppati F, Russo L, Marchetti M, et al. Low ADAMTS-13 levels with high anti-ADAMTS-13 antibodies during remission of immune-mediated thrombotic thrombocytopenic purpura predict disease recurrence with high probability: a multi-institutional study.I'm J Hematol.2020;95(8):953-959. doi:10.1002/ajh.25845.11Knoebl P, Catalan S, Peyvandi F, et al. Efficacy and safety of open-label caplacizumab in patients with exacerbations of acquired thrombotic thrombocytopenic purpura in the HERCULES trial.J Thromb Haemost.2020;18(2):479-484. doi:10.1111/jth.14679.12Sayani FA, Abrams CS. How I treat refractory thrombotic thrombocytopenic purpura.Sangre.2017;130(14):1684. doi:10.1182/sangre-2017-08-803171.13Kremer Hovinga JA, Coppo P, Lämmle B, Moake JL, Miyata T, Vanhoorelbeke K. Purpura thrombocytopenia thrombotica.Nat Rev Dis-Primer.2017;3:17020. doi:10.1038/nrdp.2017.20.14Wood J-B. The TITAN study: evaluation of the efficacy and safety of an anti-von Willebrand factor nanobody in patients with acquired thrombotic thrombocytopenic purpura.Transfus ApherSci.2012;46(3):343-346.15.Azoulay E, Bauer PR, Mariotte E et al; Investigators nine-i. Expert statement on the management of patients with thrombotic thrombocytopenic purpura in the ICU.intensive medicine2019;45(11):1518-1539. doi:10.1007/s00134-019-05736-5.sixteen.Kremer Hovinga JA, Vesely SK, Terrell DR, Lammle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura.Sangre.2010;115(8):1500-1511. doi:10.1182/sangue-2009-09-243790.17H. Upreti, J. Kasmani, K. Dane et al. Reduced ADAMTS13 activity during TTP remission is associated with stroke in TTP survivors.Sangre.2019;134(13):1037-1045. doi:10.1182/sangre.2019001056.18Cuker A, Catalan SR, Coppo P, et al. Redefining outcomes in immuno-TTP: a consensus report from an international working group.Sangre.2021;137(14):1855-1861. doi:10.1182/sangre.2020009150.19Vincent JL, Castro P, Hunt BJ, et al. Thrombocytopenia in the ICU: disseminated intravascular coagulation and thrombotic microangiopathies: what ICU physicians need to know.intensive care.2018;22(1):158.20Chiasakul T, Cuker A. Clinical and laboratory diagnosis of TTP: an integrated approach.Hematology of the Soc Hematol Educ Program.2018;2018(1):530-538.21Canpolat N. Hemolytic uremic syndrome.Turkish Pediatrics Ars.2015;50(2):73-82.22Venugopal A. Disseminated intravascular coagulation.Indiano J Anaesth.2014;58(5):603-608.23H. Wada, T. Matsumoto, K. Suzuki et al. Differences and similarities between disseminated intravascular coagulation and thrombotic microangiopathy.Trombo J.2018;16:14.24Kataland SR, Wu HM. How I treat it: the clinical differentiation and initial management of adult patients with atypical hemolytic uremic syndrome.Sangre.2014;123(16):2478-2484.25Laurence J, Haller H, Mannucci PM, Nangaku M, Prague M, de Cordoba SR. Atypical uremic hemolytic syndrome (AHUa): essential aspects for a certain diagnosis.ClinAdv Haematol Oncol.2016;14 Attachment 11(11):2-15.26Supplement for: Scully M, Cataland SR, Peyvandi F, et al; for HERCULES researchers. Treatment with caplacizumab in acquired thrombotic thrombocytopenic purpura.N incl. J Med.2019;380(4):335-346. doi:10.1056/NEJMoa1806311.27Protocol for: Scully M, Catalan SR, Peyvandi F, et al; for HERCULES researchers. Treatment with caplacizumab in acquired thrombotic thrombocytopenic purpura.N incl. J Med.2019;380(4):335-346. doi:10.1056/NEJMoa1806311.28CABLIVI [instructions for use]. Cambridge, MA: Genzyme Corporation.29Zheng XL, Vesely SK, Kataland SR, et al. ISTH Guidelines for the Treatment of Thrombotic Thrombocytopenic Purpura.J Thromb Haemost. 2020;18(10):2496-2502. doi:10.1111/jth.1501030Centers for Medicare & Medicaid Services. ICD-10-CM/PCS MS-DRGv37 Definition Guide: MDC 8 Musculoskeletal and Connective Tissue Disorders.https://www.cms.gov/icd10m/version37-fullcode-cms/fullcode_cms/P0213.html. Updated September 12, 2019. Accessed January 9, 2023.31Centers for Medicare & Medicaid Services. 2023 CID-10-CM.https://www.cms.gov/files/zip/2023-code-tables-tabular-and-index.zip. Updated July 27, 2022. Accessed January 9, 2023.32.Centers for Medicare & Medicaid Services. 2023 CID-10 UNITS.https://www.cms.gov/files/zip/2023-icd-10-pcs-code-tables-and-index.zip. Accessed January 9, 2023.