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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 Shahid Beheshti University of Medical Sciences 28/3/1393.

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How to manage Inhibitor patients

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  1. 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

  2. Especial issues on Inhibitor antibodies against coagulation factors

  3. 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

  4. 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)

  5. 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.

  6. 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.

  7. 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.

  8. 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)

  9. 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

  10. 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.

  11. 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

  12. 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.

  13. The differences in product associated inhibitors and the classic inhibitors.

  14. 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.

  15. 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.

  16. MANAGEMENT

  17. DO NOT FORGET “NICE RICE”: • NO WEIGHT BEARING • IMMOBILIZATION • CONCENTERATE • EVALUATION • REST • ICE • COMMPRESION • ELEVATION

  18. “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

  19. 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

  20. 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

  21. 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.

  22. 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)

  23. 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

  24. 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

  25. 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

  26. rFVIIa • Novoseven-RT • 1mg • 2mg • 4mg • Aryoseven • 1.2mg • 2.4 mg • 4.8 mg

  27. 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

  28. 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.

  29. Dosage Recommendations for APCC in Surgery Rodriguez-Merchan et al., Haemophilia 2010; 16 84–8.

  30. Dosage Recommendations for rFVIIa in Surgery Rodriguez-Merchan et al., Haemophilia 2010; 16 84–8.

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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

  37. Haemophila 2007;13:256-263

  38. 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.

  39. 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

  40. 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 .

  41. ‘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

  42. Other treatment options • Salvage therapy • Plasmapheresis/immunoabsorption • Platelets transfusion • High dose FVIII concentrate • Steroids • Rithuximab • Antifibrinolytics

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