CHRONIC HEMOLYSIS CAN HAVE SEVERE CONSEQUENCES · Debilitating fatigue Transfusions Thrombo-embolic...
Transcript of CHRONIC HEMOLYSIS CAN HAVE SEVERE CONSEQUENCES · Debilitating fatigue Transfusions Thrombo-embolic...
CHRONIC HEMOLYSIS CAN HAVE SEVERE CONSEQUENCES
Cold Agglutinin Disease is about more than avoiding the cold,
CAD is a rare type of autoimmune hemolytic anemia1
KNOW THE DISEASE AND RISKS Understand ingCAD.com
Debilitatingfatigue
TransfusionsThrombo-embolicevents
Severeanemia
Circulatorysymptoms
CAD=Cold Agglutinin Disease.
For patients, CAD is not just a benign condition
Patients are burdened by more than just anemia
CAD is a serious hemolytic disease with systemic acute and chronic repercussions2
In a retrospective review of a healthcare system database in patients with CAD (n=29):
Vulnerable to hemolytic
crisis
Afflicted with a lifelong
condition
Increased transfusion
burden
The disease course is unpredictable with events ranging in occurrence and severity1-3
experienced a hemolytic crisis72%
needed a transfusion65%
required emergency room visits*
53%
* Driven by severe anemia events in the 15 patients who were followed for 1 year.
100
90
80
70
60
50
40
30
20
10
00 5 10
Follow-up duration (years)
Su
rviv
al
pro
ba
bil
ity
(%
)
15
Number at risk
Matched cohortCAD cohort
720
72
580
50
480
41
352
31
275
21
208
17
157
14
113
9
79
5
44
2
31
1
28
1
25
1
10
1
10
1
0
0
Survival probability in patients with CAD from diagnosis at study entry
‡ Sponsored by Bioverativ Therapeutics Inc., an affiliate
of Sanofi.
DVT=deep vein thrombosis; LDH=lactate dehydrogenase;
MI=myocardial infarction; PE=pulmonary emobolism.
ONLY 61%of patients with
CAD were likely to be alive at
year 5 vs 82% of the matched cohort
COLD AGGLUTININ DISEASE CAN HAVE SEVERE CONSEQUENCES
Patients may face a significant thromboembolic threat3
In the first and only population-based study comparing patients with CAD (n=72) vs a general population cohort (n=720),‡ there was:
Increased mortality seen as early as year 1 after diagnosis4
• This study assessed mortality in CAD and measured survival using the Kaplan-Meier method
• Patients were identified in the Danish National Patient Registry, Civil Registration System, and National Health Service Prescription Database from 1999 to 2013
• Each patient was matched 1:10 based on age, sex, region, and adjusted based on Charlson Comorbidity Index score, including cancer and other conditions5
In the largest retrospective claims-database study of patients with CAD (n=814) vs a matched cohort without CAD (n=7960),* there was a:
55% increased risk of thromboembolic events
STROKE (P<0.0001)
PE (P<0.0001)
MI (P=0.002)
DVT (P=0.003)
Anemia is not the only predictor of risk—markers of hemolysis may
be signs of thromboembolic risk
• 90% of patients who experienced thromboembolic events had
evidence of active hemolysis† while only 23% had hemoglobin
of ≤8 g/dL
* Patients were matched 1:10 on sex, ethnicity, region, follow-up, age, and entry date.
†Elevated bilirubin and LDH.
Additional studies are needed to further understand the risks associated with CAD
Patients are at a significant increased risk for:
• 31% experienced a thromboembolic event vs 20% in the comparison cohort (P<0.0001)
On the surface of RBCs, bound cold agglutinins recruit
and activate C1
In patients with CAD, a clonal expansion of B cells produces IgM antibodies, also known as cold agglutinins, which bind to RBCs
Downstream of C1, activated C3 leads to extravascular hemolysis
Downstream of C1 and C3, activated C5 leads to intravascular hemolysis
Mechanism of CAD and the impact of the classical complement pathway6
ALTERNA
TIV
E
LECTIN
CLASSICAL
C3
C1
C5
RBC
IgM
Bcell
Extravascularhemolysis
Intravascularhemolysis
This C1-activated hemolysis leaves patients chronically compromised by an unstable hemolytic state
Activated C1 initiates the classical complement pathway triggering a cascade that results in both extravascular and intravascular hemolysis
IgM=immunoglobulin M; RBC=red blood cell.
The role of complement in Cold Agglutinin Disease
References: 1. Berentsen S, Beiske K, Tjønnfjord GE. Primary chronic cold agglutinin disease: an update on pathogenesis, clinical features and therapy. Hematology. 2007;12(5):361-370. 2. Mullins M, Jiang X, Bylsma LC, et al. Cold agglutinin disease burden: a longitudinal analysis of anemia, medications, transfusions, and health care utilization. Blood Adv. 2017;1(13):839-848. 3. Broome C, Cunningham JM, Mullins M, et al. Incidence of thromboembolic events is increased in a retrospective analysis of a large cold agglutinin disease (CAD) cohort. Poster presented at: American Society of Hematology 59th Annual Meeting and Exposition; December 9, 2017; Atlanta, GA. 4. Bylsma LC, Ording AG, Frøslev T, et al. Occurrence, survival, and thromboembolic risk in cold agglutinin disease: a population-based cohort analysis. Poster presented at: 23rd Congress of the European Hematology Association (EHA); June 14-17, 2018; Stockholm, Sweden. Poster PS1131. 5. Quan H, Li B, Couris CM, et al. Updating and validating the Charlson Comorbidity Index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011;173(6):676-682. 6. Berentsen S. Complement activation and inhibition in autoimmune hemolytic anemia: focus on cold agglutinin disease. Semin Hematol. 2018;55(3):141-149. 7. Berentsen S, Tjønnfjord GE. Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood Rev. 2012;26(3):107-115. 8. Aljubran SA, Lockey RF. Cold agglutinin disease workup. Medscape website. emedicine.medscape.com/article/135327-workup. Updated August 28, 2018. Accessed September 20, 2018. 9. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114-1121.
© 2019 Bioverativ Therapeutics Inc., an affiliate of Sanofi. All rights reserved. CAD-US-6038 v2 1/19
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Or visit CADunraveled.com
TWOmain criteria
must be met
Positive Coombs test results (direct antibody test)
Presence of an IgM autoantibody
1. 2.
Confirming a diagnosis of Cold Agglutinin DiseaseIf CAD is suspected, a blood sample must be kept at 37°C to 38°C from the time it is drawn until it is tested to avoid potential false-negatives. Refrigeration must be avoided.7,8
Currently, there are no FDA-approved treatments.2 Inhibiting chronic hemolysis is key to the potential treatment of CAD3
Sanofi Genzyme is committed to CAD researchIf you have any patients with CAD who are looking for educational resources, please give them the card attached or direct them to:
To diagnose CAD1,9
KNOW THE DISEASE AND RISKS UnderstandingCAD.com