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How to manage Inhibitor patients. Peyman Eshghi Prof. of Pediatric Hematology & Oncology Pediatric Congenital Hematologic Disorders Research Center, Mofid Children Hospital Shahid Beheshti University of Medical Sciences 28/3/1393.

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how to manage inhibitor patients

How to manage Inhibitor patients

Peyman Eshghi

Prof. of Pediatric Hematology & Oncology

Pediatric Congenital Hematologic Disorders Research Center,

Mofid Children Hospital

ShahidBeheshti University of Medical Sciences

28/3/1393

slide7

Anti-A2 antibodies reduce the catalytic activity of the factor X (FX) activating complex

  • Anti-A3 antibodies prevent factor IXa (FIXa) interaction with FVIIIa
  • The majority of anti-C2 antibodies prevent FVIII binding to phospholipids and to von Willebrand factor (vWF)
  • certain rare inhibitors to the C1 or C2 domains stabilize the binding of FVIII to vWF, thereby preventing FVIII binding to phospholipids
slide8
FVIII antibodies inhibit FVIII binding to VWF and to phospholipid

(Shimaet al, 1995)

VWF binds to the C2 domain of FVIII, which is one of the functional domains of FVIII

(Shimaet al.1995; Saenkoand Scandella1995)

slide10

DEFENITION: “Inhibitors” in hemophilia refer to IgGantibodies that neutralize clotting factors.

  • Cumulative incidence (i.e., lifetime risk) : in severe hemophilia A is in the range of 20–30% and approximately 5– 10% in moderate or mild disease AND affecting only 1 to 6 % in HB
  • AGE:
    • 3 years old in sever HA;
    • Adults-closer to 30 years of age- in mild and moderate HA and is often seen in conjunction with intensive FVIII exposure with surgery.
when to suppose
When to suppose
  • Severe hemophilia :
    • any patient who fails to respond clinically to clotting factors, particularly if he has been previously responsive
    • do not change the site, frequency, or severity of bleeding
  • Mild and moderate:
    • the inhibitor may neutralize endogenously synthesized FVIII, thereby effectively converting the patient’s phenotype to severe.
    • a greater predominance of mucocutaneous, urogenital, and gastrointestinal bleeding sites . Consequently, the risk of severe complications or even death from bleeding may be significant in these patients.
how confirmed
How confirmed
  • Confirmation of the presence of an inhibitor and quantification of the titer is performed in the laboratory, preferably using the Nijmegen-modified Bethesda assay
  • By definition, one Bethesda unit is the quantity of antibody which will inactivate 50% of normal FVIII activity in a mix of normal plasma and patient plasma (or dilutions thereof) after incubation at 37°C for 1–2 h
  • An inhibitor titer of 0.6 BU mL1 is to be taken as clinically significant
  • Very low titer inhibitors may not be detected by the Bethesda inhibitor assay, but by a poor recovery and/or shortened half-life (T-1/2) following clotting factor infusions.
when and how often to screen
When and how often to screen
  • For children : once every 5 exposure days until 20 exposure days, every 10 exposure days between 21 and 50 exposure days, and at least two times a year until 150 exposure days.
  • For adults with more than 150 exposure days : apart from a 6–12 monthly review,
  • any failure to respond to adequate factor concentrate replacement therapy in a previously responsive patient is an indication to assess for an inhibitor
  • In all patients who have been intensively treated for more than 5 days, within 4 weeks of the last infusion
  • Surgery:Priorto surgery or if recovery assays are not as expected, and when clinical response to treatment of bleeding is sub-optimal in the postoperative period
  • Patients switching to a new factor concentrate should be monitored for inhibitor development. (Level 2)
c lassification
Classification
  • low responding inhibitor is defined as an inhibitor level that is persistently <5 BU :
    • Some low titer inhibitors may be transient, disappearing within 6 months of initial documentation, despite recent antigenic challenge with factor concentrate
    • Some other low titer inhibitors may rise to High titer 3-5 days after exposure to factor concentrate (anamnestic response)
  • High responding inhibitor is defined by a level 5 BU mL
characteristics of inhibitor antibodies auto and allo abs
Characteristics of Inhibitor Antibodies(auto and allo Abs )
  • Antibodies to factor VIII are unlikely to fix complement or to precipitate.
  • neutralize FVIII coagulant activity in a time and temperature dependent manner: should be incubated in 37% for 1-2 Hr to detect(lupus anticoagulant typically prolongs the aPTT in a mixing study at time 0 to the same degree as after 1–2 h of incubation.)
  • The union of factor VIII with its inhibitor is not usually associated with allergic reactions.
slide17

When high titre FVIII inhibitors are present, activities of factors XII, XI and IX may be decreased; however, if the assays are repeated in increasing dilutions of patient plasma with physiological buffer, these clotting factor levels will increase into the normal range while the FVIII activity remains depressed

characteristics of inhibitor antibodies
Characteristics of Inhibitor Antibodies
  • Two patterns of reaction kinetics are seen:

-“Type 1” or “simple” kinetics ; completely neutralize factor VIII and are neutralized themselves in the reaction. They react with antigenic determinants near sites for procoagulant activity.

-“Type 2” or “complex” kinetics ; do not completely neutralize factor VIII [ after reaction,there is residual low levels of FVIII activity in their plasma ((usually 3–15% of normal) and retain some ability to neutralize additional factor VIII.] perhaps due to steric inhibition by VWF. These antibodies react with more distant sites.

-Gilles GG, Jacquemin MG, Saint Remy JMR. Factor VIII inhibitors. ThrombHaemost 1997; 78: 641-646.

-Gawryl MS, Hoyer LW. Inactivation of factor VIII coagulant activity by two different types of humanantibodies. Blood 1982’ 60:1103-1109.

unique aspects of inhibitors in hemophilia b
Unique aspects of inhibitors in Hemophilia B
  • Among persons with hemophilia B, inhibitorsaremuch less frequent, affecting only 1 to 6 %.
  • It mediates through IgG(mostly IgG4;a few IgG2&IgG1) ;sometimes IgE mediated (RAST+)
  • Up to 50% of hemophilia B patients with inhibitors may have severe allergic reactions, including anaphylaxis, to FIX administration. Such reactions can be the first symptom of inhibitor development.
slide21
Such reactions can occur with the first infusion of exogenous factor IX given after the inhibitor develops; that is, before the inhibitor has been diagnosed.
  • Treatment in a safe clinical setting is advised In first 10-15 ED , particularly those with a family history and/or with genetic defects predisposed to inhibitor development or if genetic defects is unknown
  • Factor IX inhibitor complexes can precipitate and eventually cause a nephrotic syndrome especially after ITI.
do not forget nice rice
DO NOT FORGET “NICE RICE”:
  • NO WEIGHT BEARING
  • IMMOBILIZATION
  • CONCENTERATE
  • EVALUATION
  • REST
  • ICE
  • COMMPRESION
  • ELEVATION
slide25

“Low-responder”

Inhiibitor<5 BU

“High-responder”

Human factor VIII is Enough to raise plasma Factor VIII level to 30% or more :

100 U/Kg bolus +

10U/Kg/hr continious infusion × 5 days

OR

50-100 U/Kg q8-12 hr × 5 days

Non – critical Hemorrhage

Critical Hemorrhage

Anti-human-

factor VIII

<5BU

Anti-human-

factor VIII

5 or more BU

Bypassing agent

)to avoid anamnesis)

Human factor VIII is Enough to raise plasma Factor VIII level to 30% or more :

100 U/Kg bolus +

10U/Kg/hr continious infusion ×5 days

OR

50-100 U/Kg q8-12 hr × 5 days

Bypassing agent

Carol K. Kasper.

T R E A T M E N T O F H E M O P H I L I A

SEPTEMBER 2004 • NO 34

fviii concentrates lt lr
FVIII concentrates :(LT-LR)
  • 25–40 IU/ kg/per BU. This will neutralize the inhibitor and then an extra dose must be added in order to achieve therapeutic plasmatic levels

S. HAYA et.al,Haemophilia(2007), 13 (Suppl. 5), 52–60

  • 20 IU/kg for each Bethesda Unit (BU) of inhibitor + an additional 40 IU/kg
  • double or triple the amount of FVIII that would have been considered adequate to achieve 30–50% incremental rise in FVIII activity in a non-inhibitor patient with haemophilia A
  • 200–300 IU/kg bolus followed by continuous infusion of FVIII at a rate of 4–14 IU/kg/h

subsequent dosing should be based on close laboratory monitoring with frequent APTT and FVIII:C measurements

bypassing therapies for patients with inhibitors
Bypassing therapies for patients with inhibitors
  • Factor eight inhibitor bypassing activity (FEIBA)
    • activated prothrombin complex concentrate (APCC) consisting of the vitamin K-dependent proteins: FII, FVII, FIX and FX in the native as well as in the activated forms
    • half-life of FEIBA is 4–7 h
    • complex formation of activated FX (FXa) and FII generating thrombin in the prothrombinase complex
  • Recombinant factor VIIa
    • enhances thrombin formation on the platelet surface by activating FX to Fxa
    • high concentrations of rFVIIa have the ability to activate FX independent of tissue factor (TF).
    • half-life of rFVIIa is between 2 and 3 h in adults and 1.5 h in children
slide28

Both FEIBA therapy and rFVIIa exhibited similar efficacy in the treatment of joint bleeding

• Both therapies exhibited similar pain reduction

• Statistical requirements for equivalence not met at all time points

• High incidence of product discordancy suggests variation among patients in

– Hemostatic efficacy

– Bleed resolution

– Pain reduction

• No reported study- or study-drug–related adverse events

• In the pain score, all statistics requirements for equivalence were met during all time points

Astermark et al. Blood. 2007;109(2):546-551. Donfield et al. Haemophilia. 2008;14(2):276-280.

defenite indications for rfviia in inhibitor patients
Defenite Indications for rFVIIa in inhibitor patients:
  • -In well known low titer but high responders (because of amnestic reactions)
  • - In patients who have been treated exclusively with recombinentproducts,and have never used pooled blood products
  • -Hemophilia B (and A)patients with allergic reactions to concentrated FIX ( and VIII)
slide31

COAGULATION ENZYMES

Thrombin

Factor VIIa

Factor IXa

Factor Xa

FEIBA Composition

ZYMOGENS

Prothrombin

Factor VII*

Factor IX

Factor X

1.4 +/- 1 U/U FEIBA

Low amounts

* Not mentioned in the SPC

slide32

II

Xa

IIa

Clot formation

Mode of Action of FEIBA

II

II

X

X

VIII / VWF

IIa

IIa

Xa

VIIa

VIIa

Xa

TF

Va

VIIIa

VII

TF-BearingCell

Platelet

TF

VIIa

VIIa

V

IX

Va

IX

IXa

IXa

X

X

VIIa

X

XIa

II

XI

IXa

VIIIa

Xa

ActivatedPlatelet

IX

Va

IX

IIa

VII

VII

Clot formation

slide33

FEIBA – Dosage Recommendation

unchanged since 1st licensure in 1979

Joint, muscle, soft tissue bleeds

50 to 100 U/kg*

at 6-12 h intervals

Max. 200 U/kg/d

Mucous membrane

hemorrhage

Other severe hemorrhage

Surgery

* For more details please consult your local approved prescribing information/SPC.

Acquired inhibitors

rfviia
rFVIIa
  • Novoseven-RT
    • 1mg
    • 2mg
    • 4mg
  • Aryoseven
    • 1.2mg
    • 2.4 mg
    • 4.8 mg
slide35

Tissue factor (TF)/FVIIa,

or TF/rFVIIa interaction,is necessary to initiatiatehaemostasis

At pharmacological concentrations rFVIIadirectly activates FX on the surface of locally activated platelets.

This activation will initiatethe ”thrombin burst”

independently of FVIII and FIX. This step is independent of TF.

rFVIIa Mode of Action

rFVIIa works locally at the site of vascular injury, where tissue factor (TF) is exposed and activated platelets are found1

The thrombin burst leads to the formation of a stable clot

rfviia spc
rFVIIaspc
  • Haemophilia A or B with inhibitors or acquired haemophilia.
    • For mild to moderate bleeding episodes (including ambulatory treatment):
    • 1-3 doses at 3 hour intervals (90g per kg b.w.) to achieve haemostasis, with additional dose to maintain haemostasis. Duration of ambulatory treatment should not exceed 24 hours.
    • For serious bleeding episodes, initial dose 90g per kg. b.w.; dose every two hours until clinical improvement. If continued therapy indicated, dosage interval can be increased successively.
  • Factor VII deficiency:
    • For bleeding episodes and for invasive procedures/surgery administer 15-30µg per kg b.w. every 4-6 hours until haemostasis achieved. Adapt dose and frequency to individual.
  • Glanzmann’sthrombasthenia:
    • For bleeding episodes and for invasive procedures/surgery administer 90µg (range 80-120µg) per kg b.w. every 2 hours (1.5-2.5 hours). At least three doses should be administered to secure effective haemostasis.
dosage recommendations for apcc in surgery
Dosage Recommendations for APCC in Surgery

Rodriguez-Merchan et al., Haemophilia 2010; 16 84–8.

dosage recommendations for rfviia in surgery
Dosage Recommendations for rFVIIa in Surgery

Rodriguez-Merchan et al., Haemophilia 2010; 16 84–8.

slide39

Monitoring:

    • TGA
    • TEG
    • Just clinical monitoring
  • Simultaneous use of pd-aPCC and rFVIIa is not recommended in EOS
  • Antifibrinolytics:
    • the first dose may be administered preoperatively
    • pd-aPCC package insert recommends that antifibrinolytics should not be used for at least 12 h after pd-aPCC doses
  • drains should be kept in place for at least 1 to 2 days following surgery and pd-aPCC (50 IU/kg) or rFVIIa 90 mic/kg should be administered before drain removal
  • Tapering: increasing the length of the dosing interval rather than decreasing the amount of the dose
  • VTE pharmacotherapy is not recommended for inhibitor patients
problem bleed definition
Problem Bleed: Definition

A bleeding episode that is unresponsive to initial therapy with a single inhibitor by-passing agent within a reasonable amount of time

  • Bleed resolution: The bleed must show improvement in
    • Pain
    • Objective measures (eg, range of motion, muscle size, hemoglobin, CT scan)
    • Surrogate end point (eg, neurological status)

Unresponsiveness

Worsening or lack of abatement of signs and symptoms

 Premature recurrence of a bleed due to suboptimal management

slide41

Increase dose and/or frequency

    • (above recommended dose if necessary)

Continue same treatment

Change product

Combined treatment with FEIBA and rFVIIa (sequentially or together)

Treatment options

slide42
ما چگونه شروع میکنیم؟
  • تعیین نوع دارو بر اساس: سابقه پاسخ قبلی , مناسب بودن یا نبودن رگ , درمان در منزل یا بیمارستان
  • دوزاژ:شدت خونریزی, سابقه پاسخ بیمار , مناسب بودن یا نبودن رگ و درمان در منزل یا بیمارستان ( در مورد دوز 270 میکرو گرم آریو سون ) , راند کردن با وزن
slide43
چگونه ادامه و یا تغییر می دهیم

تا 8 ساعت اول پاسخ را پایش میکنیم و تنها در صورت تشدید غیر قابل تحمل/حیاتی درمان را تغییر میدهیم : ابتدا افزایش دوزاژ یا دفعات و سپس تغییر دارو

پس از 8 ساعت در صورت تشدید نسبت به ساعات ایتدایی درمان را تغییر می دهیم: افزایش دوزاژ یا دفعات

پس از 24 ساعت در صورت عدم ادامه روند بهبود درمان را تغییر می دهیم : افزایش دوزاژ یا دفعات و سپس تغییر دارو

2 تا سه دوز 270 هر 2 تا 4 ساعت اگر سبب بهبود نسبی /کامل نشود دارو تغییر می یابد

بعد از سه دوز 8 ساعته با حداکثر سقف روزانه فایبا اگر سبب بهبود نسبی /کامل نشود دارو تغییر می یابد

sequential therapy a way to optimize treatment of resistant bleeds
Sequential Therapy A way to optimize treatment of resistant bleeds?
  • Rationale:
    • In at least 10-20% of bleeds don`t respond to monotherapy with rFVIIa or aPCC fail
    • Potential synergi between the two agents

Key et al Thromb Haemost 2002; 88:60-65

    • Addition of FII or FX to rFVIIa increases thrombin generation

Allen et al Br J Haematol 2006;134:314-319

  • Alternately antibody removal by plasmapheresis or combined sequential use of aPCC and rFVIIa mentioned in UKHCDO Guidelines 2008
slide46

Doses of APCC ranged from 35 to 80 U/kg/dose with a mean of 55 U/kg/dose.

Doses of rFVIIa ranged from 80 to 225 mcg/kg/dose, with a mean of 164 mcg/kg/dose.

modified algorithm for unresponsive bleed s teitel et al haemophilia 13 265 2007

Period 0

Initial bypassing agent

Continue

Decrease

Period 1

Increase dose and frequency

Continue

Decrease

Period 2

Switch products

Continue

Decrease

Period 3

Increase dose and frequency

Continue

Decrease

Period 4

Combination sequential therapy

Decrease

Continue

Modified Algorithm for unresponsive bleedsTeitel et al Haemophilia 13:265, 2007

8-12 hrs

(ICH 2-4 hrs)

12 hrs

(ICH 2-4 hrs)

24 hrs

(ICH 2-4 hrs)

24 hrs

(ICH 2-4 hrs)

24 hrs

(ICH 2-4 hrs)

Improved

Salvage therapy

Period 5

Worsened

allergic reactions to factor replacement products
Allergic reactions to factor replacementproducts
  • 1. To avoid the possibility of reaction, use the filter included in the factor package.
  • 2. Antihistamines such as Diphenhydramine (and on rare occasions, steroids) may be used to prevent or reduce symptoms.
  • 3. Sometimes, changing factor brand may reduce symptoms.
  • 4.rFVIIa in sever life threatening reactions in Hemophilia B cases .
protected forms of fviii and miscellaneous methods of therapy
‘Protected’ forms of FVIII and miscellaneous methods of therapy:
  • FVIII molecules complexed with factor IX and bound to platelet surfaces were inactivated by inhibitors at a much slower rate (T1/2: 13 min) compared to free FVIII (T1/2: one minute): PLATELET TRANSFUSION
  • concurrent administration of high-dose intravenous calcium infusion
  • Exchange plasmapheresis and extracorporeal adsorption:at a rate of 40 mL plasma/kg (3–4 L in adults) can reduce inhibitor levels by half
other treatment options
Other treatment options
  • Salvage therapy
    • Plasmapheresis/immunoabsorption
    • Platelets transfusion
    • High dose FVIII concentrate
    • Steroids
    • Rithuximab
    • Antifibrinolytics
prophylaxis in inhibitor patients definitions
Prophylaxis in Inhibitor Patients: Definitions

Primary (Early) prophylaxis* (long-term):

Starts during ITI or after ITI failure Aims: (1) to prevent target joint development (2) to avoid haemorrhages altogether

  • Secondary prophylaxis (intermittent or long-term)During ITI preventing breakthrough bleeds
  • Perisurgical coverage
  • Risk behavior, ICH risk, severe phenotype
  • Proregressive target joint
  • Aims: (1) to stop progression of joint disease (2) to prevent life threatening haemorrhages

Escuriola,-Ettingshausen personal communication Budapest symposium 2008

slide52

We recommend to do synoverthesis ASAP if Target Joint developed:it should not be postponed after secondary prophylaxis in Inhibitor cases

  • Intra-articular injections (e.g, steroids, hylan )may relieve persistent inflammation prior to a synovectomy
slide53

a prospective, randomized, crossover study on 34 patients

  • Dosage : 85 U/kg ± 15% TIW
  • Results:
    • 62% reduction in all bleeding episodes (P<0.001),
    • 61% reduction in hemarthroses (P<0.001),
    • 72%reduction in target-joint bleeding
slide55
CASE 1

HOW DO YOU MANAGE HIM IN YOUR CENTER?

INCREASE DOSE

INCREASE FREQUENCY

CHECK PTT AFTER INJECTION

CHECK INHIBITOR LEVEL

  • 13 Y HA ; NO hx of inhibitor
  • Comes to a primary care center
  • Acute knee bleeding
  • NO IMPROVEMENT TO 50 u/kg/ Q12 h FVIII AFTER 2 DAYS
slide56
CASE 2

What do you prescribe for his acute joint bleedings

FVIII 30 U/Kg

FVIII 100U/Kg

Bypassing agent

  • 5 Y HA
  • Routine screening for inhibitor shows 0.5 BU
slide57
Case 3

HOW DO YOU MANAGE HIM IN YOUR CENTER?

100U/kg bolus FVIII then 40-50 u/kg FVIII q8h +check aPTT q8h

rFVIIa 270 mic/kgQ2h +clinical F/U

FEIBA 100U/kg q8h + clinical F/U

  • 4y HA
  • 4 BU inhibitor
  • Historical peak titer=20 BU
  • Intracranail bleeding after car accident
slide58
Case 4

HOW DO YOU MANAGE HIM IN YOUR CENTER?

100U/kg bolus FVIII then 40-50 u/kg FVIII q8h + check PTT

rFVIIa 270 mic/kgQ2h

FEIBA 100U/kg q8h

  • 4y HA
  • 20 BU inhibitor
  • Intracranail bleeding after car accident
slide59
Case -5

How do you manage him?

FEIBA 50 U/Kg Q 12 Hr ; 1-2 Doses

rFVIIa 90 mic/Kg Q2-4 hr; 2-3 Doses

FVIII 100 U/Kg bolus;then 50 U/Kg Q8 hr ;for 1-2 day

  • 5 Y year severe HA boy
  • Weight=15Kg
  • Inh developed last year
  • Peak Inh titer= 4 BU
  • CC: pain or an unusual sensation in the R-elbow joint, palpable swelling and warmth of the skin over the joint.
  • no previous same Hx in that jointi n last Year
  • He started R.I.C.E immediately
slide60
Case -1,cotinue

How do you manage him?

Switch to another product

Higher Doses OR longer duration of the same product OR

The same treatment & check Inhibitor titer

  • He gets Complete pain relief within 8 hours and complete resolution of signs of bleeding after the initial injection
  • He returns after 72 hr with the same complaint
slide62
Case -5,cotinue

How do you manage him?

Higher Doses OR longer duration of FEIBA

rFVIIa 90 mic/Kg Q2-4 hr; 2-3 Doses

rFVIIa 270 mic/Kg Q2-4 hr; 2-3 Doses

Synoverthesis

  • He responded None or minimal improvement, and condition worsened, within approximately 8 h after the initial injection
  • We started FEIBA
  • Inh=15 BU
  • He has had the same problem monthly then after
  • He got Significant pain relief and/or improvement within approximately 8 hours after a single injection, but requiring more than one dose of replacement therapy within 72 hours for complete resolution
slide63
Case -5,cotinue

How long do you give him FEIBA after procedure?

48 hrs

4 days

4 days weekly till end of the procedures then prophylaxis

Prophylaxis (3 times /week) from the begining

  • After 2 months of prophylaxis with FEIBA , Chemical synoverthesis was done for him for about 3 weeks:
  • How long do you give him FEIBA after procedure?
slide64
Case -6

How do you manage him?

Continue Prophylaxis with adding steroid before injection

Continue prophylaxis with FEIBA

On demand Treatment with FEIBA

On demand Treatment with rFVIIa

Continue prophylaxis with rFVIIa

  • 3 Y year severe HB boy
  • Weight=15Kg
  • No Inh
  • On secondary prophylaxis with FIX
  • He had a severe respiratory distress once on the day of FXI injection
  • He improved by Steroids and bronchdilators
slide65
Case -7

How do you manage him?

Wait and watch at least till 6 hrs

Another dose of FEIBA

Switch to rFVIIa

Sequential combined BPA treatment

  • Case-1 has been referred with ICH after Head Trauma
  • We started FEIBA 100U/kg immediately
  • His condition worsened after 4 hrs both clinically and in CT
slide66
Case -7

What do you do for him

Plasmapheresis then High dose FVIII

check D-dimer and Platelet count and Fibrinogen

Adding tranexamic acid

Nothing to do without TEG or TGA

Adding Rithuximab and steroid

  • His condition worsened, despite of regimen 3 of sequential combined BPA therapy
  • You have to prepare him for neurosurgery
ad