2. Diagnosis and Management of Inhibitors in Hemophilia
Glenn Pierce MD PhD
WFH Board of Directors
La Jolla, California USA
World Federation of Hemophilia (WFH)
Indonesian Hemophilia Society (IHS)
Symposium on Hemophilia Care
Sanur, Bali, Indonesia
22 April 2017
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3. Topics to Cover
What are inhibitors (neutralizing antibodies)? Assays for inhibitors Genetic and Environmental risk factors How are inhibitors managed? Immune Tolerance Regimens
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4. Detection and Cause of Inhibitors (Neutralizing Antibodies)

5. Hemophilia and Inhibitors
Inhibitor development is the most severe complication of therapy
Development of alloantibodies to replacement therapy
Neutralize replacement factor and in moderate/mild hemophilia neutralizes residual factor VIII activity
NO EFFECT
Epidemiology: Incidence of development of inhibitor
Hemophilia A: 25–30% severe;
Hemophilia B: 3–5%
White GC et al. Thromb Haemost 2001; 85: 560.
Hay CR et al. Thromb Haemost 1998; 79:
Kessler CM. Blood (Am Soc Hematology Educational Program) 2005:
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6. How Is a Factor VIII Inhibitor Identified?
Clinical:
Bleeding unresponsive to FVIII
Patients’ bleeding episodes less well controlled
Biochemical:
Prolonged aPTT and aPTT mix
Anti-Factor VIII detection by Bethesda assay
Verbruggen B. The factor VIII inhibitor assays can be standardized: results of a workshop. J Thromb Haemost. 2011; 9:
Favaloro EJ, Verbruggen B, Miller CH. Laboratory testing for factor inhibitors. Haemophilia. 2014;20 Suppl 4:94-8.
Barrowcliffe TW, Hubbard AR, Kitchen S. Standards and monitoring treatment. Haemophilia. 2012; 18 Suppl 4:61-5.
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7. Diagnostic Laboratory Tools
Reduced recovery (recovery <60% suggests inhibitor)
Increased clearance (no measurable factor one hour after infusion)
Persistently prolonged aPTT following replacement therapy
aPTT mixing studies (50% patient plasma % normal plasma) fails to normalize aPTT
FVIII: Inhibitor titer >0.6 BU/mL (Bethesda, Nijmegen modification)
Lupus anticoagulant test negative (no effect of added phospholipid)
Modified assay: Plasma heated to 56°C for 30 min to destroy replacement FVIII
Miller CH. Validation of Nijmegen-Bethesda assay modifications to allow inhibitor measurement during replacement therapy and facilitate inhibitor surveillance. J Thromb Haemost. 2012; 10:
Verbruggen B. Diagnosis and quantification of factor VIII inhibitors. Haemophilia. 2010; 16:20-4.
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8. aPTT Mix Test aPTT pt plasma + Ca + Tissue TP = Clot
aPTT MIX 1:1 Normal + pt plasma + Ca + Tissue TP = Clot
Condition aPTT 1:1 Mix Comments
Normal 35 sec. 35 sec. No effect
Factor Def 60 sec. 35 sec. By providing 50% factor activity, will correct aPTT
Inhibitor 60 sec. 59 sec. Cannot dilute effect of inhibitor
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9. Nijmegen Bethesda Assay
Each Bethesda unit of inhibitor consumes a 50% level
Modified assay: Plasma heated to 56°C for 30 min to destroy replacement FVIII
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10. Classification of Inhibitors
Clinically relevant inhibitor development
≥ 2 positive titers + decreased FVIII recovery
High-titer inhibitor
Inhibitor titer ≥5 BU/mL. Usually strong anamnestic response to re-exposure
Low-titer inhibitor
Inhibitor titer <5 BU/mL. Usually weak anamnestic response to re-exposure
May treat with FVIII at higher doses
High Titer (>5 BU BU BU 10
Time
100
Low Titer (<5 BU) 10
Time
100 BU BU 10
Time
100
Transient 10
Time
100
= infusion
White GC 2nd et al. Thromb Haemost (2001); 85: 560
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11. Inhibitor Development
Most inhibitors develop within first 50 exposure days
Median age 1.7 – 3.3 years in EU/NA1
Of the ~30% who develop FVIII inhibitors2,3
High titer: ~10-15% (>5 BU)
Low titer: ~10% (<5 BU)
Transient: ~5% (<5 BU)
Bray GL et al. Blood 1994; 83: White GC et al. Thromb Haemost 2001; 85: 560. Astermark J. et al. Haemophilia 2006; 12:
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12. FIX Inhibitors
Associated with anaphylactoid reactions to factor IX1 Reactions may occur prior to identification of inhibitor May preclude treatment with FIX or PCC/APCC May require desensitization ITI may be associated with nephrosis at 6-9 months2
FIX Inhibitors
In approximately 3-5% of persons with hemophilia B, inhibitors to FIX develop. Treatment is complicated in these patients by the fact that some experience severe allergic or anaphylactic reactions to FIX infusions simultaneously with the appearance of or before the development of the inhibitor. In addition, the anaphylactoid reactions may preclude treatment with FIX or PCC/aPCC. Use of any FIX-containing product in these patients requires desensitization. Immune tolerance programs have been used in these patients; however, immune tolerance has been associated with nephrotic syndrome that usually occurs 6-9 months into the immune tolerance induction (ITI) regimen.
1Warrier I et al. J Pediatr Hematol Oncol. 1997;19(1):23-27.
2Ewenstein BM et al. Blood. 1997;89:1115,1116.
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13. Three Components to Inhibitor Risk
Immune
response
genes
FVIII-gene
mutation
Environmental
Factors
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14. Inhibitor Risk Factors
INHIBITORS
Environmental Factors
Nonpatient-related
Genetic Factors
Patient-related
F8 dependent
Race Ethnicity
Family history
Immune Response Genes
Severity
F8-Gene Mutations
MHC
IL-10
TNF
CTLA4
Treatment regimen
Type of Concentrate
Danger Signals
Age of 1st treatment early vs late
Prophyl. vs on demand
Intensity of treatment
Recombinant vs PD
vWF vs non vWF
Vaccination
Inflammation
Severe bleed
Tissue damage
Oldenburg; Gouw, van den Berg, Oldenburg, et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood : ; doi: /blood
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15. Mutation Type and Inhibitor Prevalence
100 75 50 25
Single
Domain
25%
Multi
88%
Light chain
40%
Heavy chain
17%
Non A-Run
21%
A-Run 3%
C1-C2
10%
Non C1-C2
Large
Deletions
41%
Nonsense
31%
Small Deletions
16%
Intron 22/1
Inversions
21%/17%
Missense 5%
Splice site 3%
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Schwaab R. et al. Thromb Haemost (1995);74: , Oldenburg et al. Haematologica (2000);85:7-13

16. Immune Response Genes and Inhibitor Development
Schematic model of anti-FVIII inhibitor formation. The causative FVIII mutation and HLA class II will be the main contributors to the risk of development of antibodies; from very low risk (green) unlikely to experience any antibodies with commercially available FVIII concentrates to very high risk (red). The final immune response and outcome will then be fine-tuned by T-regulatory cells and a variety of immune regulatory molecules, the activity of which will be defined genetically by therapy-related factors and immune system challenges.
Astermark J. FVIII inhibitors: pathogenesis and avoidance.
Blood. 2015; 125:
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17. Prophylaxis vs on-demand treatment During first 50 days of exposure
Environmental Risk Factors for High-Titer Inhibitors in PUPs: CANAL Study
First FVIII exposure
Duration of treatment (>5 days) RR=4.1
Surgical procedures RR=3.2
Prophylaxis vs on-demand treatment
60% lower risk with prophylaxis RR=0.4
During first 50 days of exposure
Treatment intensity (>50 IU/kg) RR=3.0
Positive family history, high risk FVIII gene mutations, and intensive treatment at initial bleed result in 57% inhibitor development
Gouw SC, van der Bom JG, van den Berg MH, Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood 2007; 109: ; ter Avest. Risk stratification for inhibitor development at first treatment for severe hemophilia A: a tool for clinical practice. J Thromb Haemost 2008; 6:
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18. Summary of Inhibitor Studies with pd-FVIII and rFVIII
Iorio A, Halimeh S, Holzhauer S, et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010;8:
Incidence rate and 95% confidence interval of all inhibitors in PUPs with HA. Study author and year of publication are indicated on the y-axis and the incidence rate (0–50%) on the x-axis. Studies ordered by pdFVIII and rFVIII usage and by year of publication. The pooled estimate is based on random effects, and shown for subgroups and for the whole population. (R) or (PD) are indicated in brackets when only data of the relevant subgroup of patients are considered
Confounders: Study period, frequency of inhibitor testing, and median follow up accounted for most variability
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19. Plasma-derived FVIII versus recombinant FVIII
No Increased Risk of Inhibitors for pdFVIII vs rFVIII in previously transfused Patients Who Switch Product
Plasma-derived FVIII versus recombinant FVIII
Risk of inhibitor RR=0.8
Risk of high titer inhibitor RR=0.9
PD FVIII/VWF versus recombinant FVIII
Risk of inhibitor RR=1.0
Risk of high titer inhibitor RR=1.1
Switch between FVIII products
Risk of inhibitor RR=1.1
Gouw SC et al. Blood (2007); 109(6): ; Xi M, Makris M, Marcucci M, Santagostino E, Mannucci PM, Iorio A, J Thromb Haemost Sep;11(9):
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20. How Are Inhibitor Patients Tolerized?

21. History of Immune Tolerance Induction: First Observation
1974: Young boy with FVIII deficiency and high titer inhibitor with life-threatening bleed
Treatment
Standard therapy: Prothrombin complex concentrate
Added high dose FVIII
Outcome
Child recovered
Inhibitor titer after 3 weeks of therapy 256  38 BU1
Treatment discontinuation: inhibitor rebounded
Reinstituted daily high dose FVIII/PCC  disappearance of inhibitor2,3
Brackmann HH, Gormsen J. Lancet 1977; 2: 933
Brackmann HH et al. Vox Sang 1996; 70 (Suppl 1): 30-5
Brackmann HH et al. Prog Clin Biol Res 1984; 150:
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22. Treatment Plan for New Inhibitor Patients
1. Eradicate inhibitor
Immune Tolerance: FVIII U/kg/d or qod
2. Stop bleeding
If >5 BU: FEIBA* U/kg q 8-12h (< 200 U/kg/day)
FVIIa 90 mcg/kg q 2-3h)
If <5 BU: FVIII to achieve > 0.50 IU/ml (50%)
*Factor VIIII Inhibitor Bypass Activity
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23. Immune Tolerance – Clinical Results
Prior immune tolerance therapy options
Bonn protocol (high dose FVIII + activated PCC) (FVIII 200 IU/kg/day)
Van Creveld (Dutch) protocol (low dose FVIII 50 IU/kg/day or qweekly)
Malmö protocol (immunoadsorption +/- high-dose FVIII IVIG + immunosuppression (cyclophosphamide)
*One Turkish study used 25 IU/kg tiweek, 4/7 tolerized over 1-4 months
Randomized controlled trial, International-ITI study, evaluated
Daily FVIII 200 IU/kg vs FVIII 50 IU/kg x 3 weekly
No difference in inhibitor clearance, but less bleeding and shorter time to inhibitor disappearance in high dose cohort
DiMichele DM, Br J Haematol. 2012;159:123-34; Hay CR1, DiMichele DM, Blood. 2012;119: ; Athale AH, Marcucci M, Iorio A, Cochrane Database Syst Rev Apr 24;4
Oldenburg J et al. Vox Sang 1999; 77 (Suppl 1): 49-54; Mauser-Bunschoten EP et al. Vox Sang 1996; 70 (Suppl 1): 66-7; Freiburghaus C et al. Haemophilia 1999; 5: 32-9; *Kavakli K et al, Haemophilia 1998;4:104-8
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24. International ITI Study: No difference between treatment arms
Success: 66 of 115 patients reached endpoint
46 (69.7%) complete success
3 (4.5%) partial success
17 (25.8%) failure
24 of 58 Low Dose (50 IU/kg tiweekly)
vs.
22 of 57 High Dose (200 IU/kg/day)
(P = 0.909)
Low Dose subjects bled more often (odds ratio, 2.2; P = .0019)
No bleeding in 8 of 58 Low Dose subjects vs 21 of 57 High Dose subjects
Hay & DiMichele, Blood, 2012; 119:
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25. Differences Between Hemophilia A and B
Factor VIII inhibitors
Inhibitors develop in ~ 30% severe patients
50% high titer
Infusion reactions uncommon
Success rate with immune tolerance ~75%
Immune tolerance not complicated by nephrosis
Factor IX inhibitors
Inhibitors develop in <5% of severe patients
80% high titer
Infusion reactions common
Anaphylaxis, angioedema
May require desensitization, steroids, diphenhydramine
Success rate with immune tolerance ~25%
Immune tolerance may be complicated by nephrosis
membranous glomerulonephritis
edema, decreased albumin, months
Reactions may preclude use of any product containing factor IX
APCC, pdFIX, rFIX
Ewenstein BM, et al. Blood 89:1115-6,1997; Dioun AF et al. J Allergy Clin Immunol 192:113-7, 1998
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26. How Are Inhibitor Patients Treated?

27. Treatment Options for Inhibitors
Factor VIII & Inhibitors
High dose factor VIII
Bypassing products
NovoSeven
FEIBA
Factor IX & Inhibitors
High dose factor IX
Bypassing products
NovoSeven
FEIBA in some circumstances
Hedner, U. Recombinant activated factor VII: 30 years of research and innovation. Blood Reviews 2015;29:S4 - S8. Santagostino, E et al. Recombinant activated factor VII in the treatment of bleeds and for the prevention of surgery-related bleeding in congenital haemophilia with inhibitors. Blood Reviews 2015; 29:S9 - S18.
Kempton, Meeks. Toward optimal therapy for inhibitors in hemophilia. Blood :
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28. FEIBA mechanism of action
FEIBA contains Factors II, VII, IX, X and variable amounts of their activated forms; small amounts of FVIII too
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29. Rfactor viia mechanism of action
rFVIIa activates FIXa to activate FX to Fxa to produce thrombin
This thrombin burst is less than the thrombin burst triggered by the intrinsic pathway via Tenase (FIXaFVIIIaFXa)
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30. Treatment Options/Regimens and Safety
NovoSeven®
- Single dose 270 µg/kg
90 µg/kg at 2-3 hour interval until hemostasis is achieved
Works via activation of FX to FXa= thrombin burst
FEIBA® (aPCC)
U/ kg recommended at hour intervals
200 U/kg/day should not be exceeded
Produces anamnestic response in up to 31% of hemophilia patients
Contains “mainly non-activated” FII, FIX, FX, FVIIa. Activates FXa
Both drugs: good safety profile in inhibitor patients except thrombosis risk
rFVIIa / 105 infusions
pd-aPCC / 105 infusions
van Veen JJ. Major surgery in severe haemophilia A with inhibitors using a recombinant factor VIIa and activated prothrombin complex concentrate hybrid regimen. Haemophilia Jul;20(4):
Antunes SV Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia 2014;20(1):65-72.
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31. Treatment with rFVIIa and FEIBA (aPCC)
Black Box warnings:
Serious arterial and venous thrombotic events following administration of NovoSeven® RT have been reported.
Monitor patients for signs or symptoms of activation of the coagulation system and for thrombosis
Risk of thrombotic and thromboembolic events following infusion of FEIBA VH or FEIBA NF, particularly following the administration of high doses and/or in patients with thrombotic risk factors.
Recombinant factor VIIa (rFVIIa; NovoSeven®) is approved for the treatment of bleeding episodes in patients with haemophilia A or B and inhibitors.1
Until recently, the only recommended dose was 90 µg/kg bodyweight, repeated at 2–3-hour intervals to obtain haemostasis.
With this regimen, an average of 2.2 injections are required to achieve haemostasis.2
NovoSeven® prescribing information, 2007
Key et al. Thromb Haemost 1998; 80:912―918
Kempton, Meeks. Toward optimal therapy for inhibitors in hemophilia. Blood :
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32. Thank You

33. Inhibitor Risk Relative to F8 Genotype
5883 patients
with severe hemophilia A
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Gouw SC, van den Berg HM, Oldenburg J et al. Blood 2012
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34. Immune Response Genes Immune response gene Odds ratio 95% CI P value
MHC class-II
DRB11501
1.91
0.8–4.11 —
DQB10602
2.72
ns2
IL-10
1.23
1.01–1.53
0.043
Allele 134 positive
5.44
2.1–13.74
<0.0014
A>G -1082
1.64
TNF-
Genotype A2
4.85
1.0–22.55
Homozygous
196
CTLA-4
SNPS -318
0.37
0.1–0.87
0.0127
CT60
Hay et al. Thromb Haemost 1997;77:234–7; Oldenburg et al. Thromb Haemost 1997;77:238–42; Lozier et al. Haemophilia 2011;17:641–9; Astermark et al. Blood 2006;107:3167–72; Pavlova et al. J Thromb Haemost 2009;7:2006–15; Astermark Blood 2006;108:3739–45; Astermark et al. J Thromb Haemost 2007;5:263–5; Astermark et al, Blood. 2013;121(8):
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35. SIPPET Study Results Survey of Inhibitors in Plasma-Products Exposed Toddlers
In PUPs, does recombinant FVIII result in more inhibitor formation than plasma-derived FVIIII?
251 patients analyzed from 42 sites, 14 countries
Randomized, prospective trial
4 rFVIII vs 4 plasma-derived FVIII containing VWF utilized
Variety of regimens: on demand, different prophylaxis schedules
Cumulative incidence 26.8% (CI ) and 44.5% (CI ), respectively
rFVIII was associated with an 87% higher incidence of inhibitor development than pdFVIII (HR 1.87, CI )
Multiple methodologic differences from previous studies
Conflicting results, however this is the only prospective, randomized study
Bethesda positive >0.4 BU; study terminated prematurely due to 50% usage of Gen 2 FVIII; 1-50 EDs analyzed; ~75% of subjects from India, Egypt, Iran
Peyvandi, Mannucci et al, N Engl J Med 2016;374:
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36. The relative risk for regular prophylaxis was 1
The relative risk for regular prophylaxis was 1.0 in the period from 1 to 10 exposure days, 0.95 from 11 to 20 exposure days, 0.22 from 21 to 30 exposure days, 0.27 from 31 to 40 exposure days, and 0.32 from 41 to 75 exposure days
50 ED
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37. Mild/Moderate- Less at 50ED but continued increase
Cumulative Inhibitor Incidence in 1112 Non- severe Hemophilia A Patients vs. Cumulative Exposure Days to Factor VIII Concentrates
50 ED
Mild/Moderate- Less at 50ED but continued increase
Cumulative inhibitor incidence in 1112 nonsevere hemophiliaA patients, according to cumulative exposure days to factor VIII concentrates.
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Eckhardt CL et al. Blood 2013;122:1954–1962 96
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38. ITI – Success or Failure Defined
When to stop
Time to ITI success is variable: 3 months - 2+ years
Criteria for successful ITI
Undetectable inhibitor level (<0.6 or 1.0 BU/mL)
FVIII plasma recovery >66%
FVIII T1/2 >6h after 72 h washout
Absence of anamnesis upon further FVIII exposure
Criteria for failure of ITI
Failure to achieve full or partial success within 33 months
Less than a 20% reduction in the inhibitor titer for any 6-month period during ITI after the first 3 months of treatment
Astermark J et al. Haemophilia 2006; 12: ; DiMichele DM et al. Haemophilia 2007; 13 (Suppl 1): 1-22.
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39. Why Does ITI Work? Hypothetical Mechanisms
Generation of peripheral tolerance
Burn out FVIII-specific B-cell clones
Add immunoregulatory molecules to high dose FVIII (eg, rituximab)
Rituximab some evidence of efficacy in ~40-50% of refractory inhibitor patients
Ongoing prevention research:
Oral tolerance with rFVIII made in plants
IgG induces T-reg mediated tolerance through amino acid sequences in Fc- role of this mechanism in Fc fusions rFVIII and rFIX?
Transplacental transfer of rFVIIIFc in nonclinical studies to induce tolerance in offspring
Gupta N, Sci Transl Med Feb 18;7(275):275ra21. doi: /scitranslmed.aaa1957; Scott DW, Haemophilia 2014 May;20 Suppl 4:80-6;Wang X...Herzog R, Blood 2015 Apr 9;125:
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40. Santagostino Study: Main Efficacy Results
25%
50%
64%
31%
53%
66% 10 20 30 40 50 60 70
9 hours
24 hours
48 hours
% episodes controlled successfully
VAS
270 μg/kg single dose
3  90 μg/kg multiple dose
Santagostino conducted a randomised clinical trial in patients with haemophilia A and inhibitors to assess the efficacy and safety of two different regimens of rFVIIa in the treatment of haemarthroses:
90 μg/kg repeated as necessary every 3 ± 1 hours
single dose of 270 μg/kg.
Treatment response was assessed by patients and caregivers. Improvement in signs and symptoms (swelling, pain and functional limitation) from baseline was recorded on a visual analogue scale (VAS) at 1, 3, 6, 9, 12, 24 and 48 hours after the onset of treatment. A score of 0 meant “no improvement versus baseline” while a score of 100 meant “complete relief”.
Additionally, patients and caregivers rated the efficacy of treatment at 9, 24 and 48 hours as “effective” (definite relief of signs and symptoms), “partially effective” (modest improvement) or “ineffective” (no improvement).
Successful therapy was defined as a rating of “effective” plus a VAS score of at least 70. Failure was defined as a rating of “ineffective” and a VAS score of 30 or less. Combinations not meeting these criteria were considered partial responses.
As shown here, rates of treatment success were similar for standard and high dose therapy at 9, 24 and 48 hours. However, the median number of injections needed was significantly greater for standard dose therapy (3) than for high dose therapy (1; P=0.0001).
The total amount of rFVIIa required was the same for both dosage regimens (270 μg/kg).
Santagostino et al. J Thromb Haemost 2006; 4:367–371
Santagostino et al. J Thromb Haemost 2006; 4:367–371.
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41. Treatment of Bleeds High titer inhibitors (>5 BU/mL)
Bypassing agents
Recombinant factor VIIa (NovoSeven®)
Plasma derived activated prothrombin complex concentrate (aPCC, FEIBA™)
Recombinant Porcine factor VIII
Concomitant medication
Tranexamic acid (25 mg/kg po q6h) as adjunctive therapy together with rFVIIa
Tranexamic acid use not documented together with FEIBA
Leissinger C, Thromb Haemost. 2014;112:445-58; Kempton CL, Haemophilia. 2012; 18: ; Leissinger CA, Konkle BA, Antunes SV, Expert Rev Hematol. 2015; 8:375-82
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42. Efficacy – plasma derived aPCC /PCC
DiMichele D and Négrier C. Haemophilia. 2006;12(4): Négrier C et al. Thromb Haemost (1997); 77: Hilgartner MW et al. Transfusion (1990); 30: Hilgartner MW et al. Blood (1983); 61(1): Sjamsoedin LJM et al. NEJM (1981); 305:
Astermark J et al. Blood (2007) 109:
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43. Efficacy – rFVIIa
Key NS et al. Thromb Haemost (1998);80: Santagostino E et al. J. Thromb Haemost (2006);4:
Kavakli IH et al. Thromb Haemost (2006); 95: Ingerslev J et al. Blood Coag Fibrin (1998); 9(S1): S107-S110
Parameswaran MA et al. Haemophilia (2005); 11: Astermark J et al. Blood (2007) 109:
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