hemophilia complications: inhibitor and transfusion...
TRANSCRIPT
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HEMOPHILIA COMPLICATIONS: INHIBITORAND TRANSFUSION TRANSMITTED INFECTION
Juspeni Kartika
Divisi Hematologi Onkologi Medik Ilmu Penyakit Dalam RSAM Bandar Lampung
2019
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DEFINISI
• Hemofilia A adalah kelainan koagulasi yang disebabkan
kegagalan produksi F VIII dan FIX yang ditandai dengan
perdarahan berulang ke dalam berbagai jaringan.
• Kelainan ini disebabkan mutasi gen defisiensi faktor
VIII, IX atau defek struktural menimbulkan gangguan
fungsi F VIII dan IX.
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EPIDEMIOLOGI • Hemofilia A ditemukan hampir di seluruh dunia.
• Prevalensi hemofilia 1: 5000-10.000 penduduk laki-lakiyang lahir hidup
• Insiden lebih tinggi penduduk Afrika, penduduk asliAmerika dan Asia.
• Hemofilia A kelainan yang diturunkan melaluikromosom X, secara X-linked recessive.
• Defek gen pada lengan panjang kromosom X pada bandq 2.8
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TERAPI PENGGANTI
• Prinsip penatalaksanaan mencegah &menatalaksana perdarahan akut, kerusakanotot, sendi, akibat lain dari perdarahan danpenataksanaan komplikasi terapi sepertipembentukan inhibitor dan infeksi.
• Terapi pengganti dapat diberikan kriopresipitatatau konsentrat F VIII berasal dari plasma ataukonsentrat F VIII rekombinan.
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Hemophilia and Its Treatment: Then and Now
• Replacement of the deficient factor is the mainstay oftreatment; it may be “on demand” when the factor isadministered during a bleeding episode, or“prophylactic” when infused as a regular regimen toprevent hemarthroses in severe deficiency.
Whole bloodFFP
Cryo-precipitate Plasma-derived factor concentrates
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Hemophilia and Its Complications
Musculosceletal Complications
Inhibitors• Inhibitors in hemophilia refer to IgG antibodies that neutralize clotting
factors
• The presence of a new inhibitor should be suspected in any patient who fails to respond clinically to clotting factors, particularly if he has been previously responsive
Transfusion-transmitted and other infection-related complications
• The emergence and transmission of HIV, HBV, and HCV through clotting factor products resulted in high mortality of people with hemophilia
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INHIBITOR FAKTOR VIII DAN IX
• Inhibitor adalah antibodi poliklonal Ig G denganafinitas tinggi terhadap F VIII dan IX yang mempunyaikemampuan secara fungsional menetralisir.
• Inhibitor terutama dari klas IgGl, lgG2,lgG4 danjarang IgG3.
• Penderita hemofilia A lebih sering membentukinhibitor dibandingkan hemofilia B.
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Insiden
• Inhibitor timbul 2O-40% pasien hemofilia A dan 1-6%pada penderita hemofilia B.
• Insiden lebih tinggi pada penduduk Afrika, asliAmerika dan Asia.
• Insiden inhibitor pada hemofilia berat 25-50%,sedangkan pada hemofilia ringan dan sedang 3-13%
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Faktor Yang Berhubungan Dengan Pembentukan
Inhibitor
Faktor pasian
• Faktor pasien termasuk tipe dan berat hemofilia,
ras, genotipe hemofilia" umur waktu pertama
mendapat terdapat pengganti F VIII.
Faktor Terapi
• Jenis produk F Vlll dan IX, Exposure day,
Intensitas terapi.
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FAKTOR RISIKO• Tipe mutasi
Predisposisi genetik berkembangnya inhibitor adalah adanyamutasi pada gen faktor VIII dan gen yang melibatkan responimun seperti lokus gen MHC kelas I dan II.
• Berat ringannya derajat hemofilia
• Riwayat keluargaRisiko membentuk inhibitor makin meningkat secarabermakna pada penderita hemofilia yang mempunyai riwayatkeluarga
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FAKTOR RISIKO• Ras
Bangsa Afrika, insiden penderita hemofilia beratmembentuk inhibitor, dua kali lebih tinggi daripadaKaukasian (51,9% dibandingkan 25,8%).
• Molekul Major Histocompability Complex (MHC)• Usia saat pertama kali diberikan replacement therapy• Jenis konsentrat Modifikasi dalam proses manufaktur
berpotensi memicu pembentukan inhibitor.• Intensitas dan cara pemberian replacement therapy
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TYPICAL PRESENTATION
• Silent and may not lead to a marked increase in the frequency or severity of bleeding
• Inhibitors may be identified when the response to infused factor is inadequate
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Inhibitor Screening For children, inhibitors should be screened once every five 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
Inhibitor measurement should also be done in all patients who have been intensively treated for more than five days, within four weeks of the last infusion
Inhibitors should also be assessed prior to surgery or if recovery assays are not as expected, and when clinical response to treatment of bleeding is sub-optimal in the post-operative period
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Diagnosis Inhibitor
• Inhibitor faktor VIII secara kuantitatif diperiksamenggunakan Bethesda Inhibitor Assay (BIA).
• Nijmegen modification assay.
• Titer ditunjukan dalam Bethesda unit (BU) dan 1 BUmenunjukkan jumlah inhibitor yang menginaktivasi50% FVIII yang bercampur dengan plasma pasien.
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• Titer Inhibitor digolongkan 3 katagori yaitu:
– Low titer inhibitor, low responder, bila titer inhibitor tidaklebih dari 5 BU setelah diberikan terapi pengganti.
– Low titer inhibitor, high responder, bila titer inhibitormeningkat lebih dari 5 BU setelah pemberian terapipengganti.
– High titer inhibitor, high responder, bila titer inhibitor lebihdari 5 BU dan kemudian meningkat setelah diberikan terapipengganti.
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Penatalaksanaan
• Bertujuan menghilangkan inhibitor, terdiri dari 2 komponen yaitu: • Penanganan perdarahan akut
– Penanganan perdarahan akut diberikan berdasarkan titerinhibitor
– High purity factor VIII concentrates, konsentrat porcine faktorVIII, prothrombin complex concentrates (PCCs) dan activatedprothrombin complex concentrates (aPCCs), recombinant humanfactor VIIa, terapi immune tolerance induction, terapi gen.
• Immune tolerance induction. – Immune tolerance induction dilakukan dengan cara penderita
diberikan faktor VIII dosis tinggi secara berulang.
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Inhibitor eradication
• Inhibitor eradication using immune tolerance induction (ITI) is appropriate for individuals with high titer inhibitors or high-responding individuals
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IMMUNE TOLERANCE INDUCTION• It involves the administration of repeated doses of
factor, typically without concurrentimmunosuppressive therapy, to tolerize the immunesystem to the factor and reduce antibody production.
• If initial ITI is unsuccessful immunosuppression
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TRANSFUSION
TRANSMITTED INFECTIONS
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Transfusion Transmitted Infections
One of the largest therapeutic problem during the continuous treatment of the patients are viral infections as Hepatitis B and C, and HIV, and the other infective diseases, which can be transmitted by the transfusion of blood
products.
Multitransfused hemophiliacs with antihemophilic products are endangered of acquiring viral hepatitis.
The cause of manifestation of these infections is on the fact that concentrating coagulation factors are prepared of plasma from thousand of blood donors that
didn’t undergo viral inactivation.
Although the majority of infected patients do not suffer acute symptoms and clear the infection spontaneously, the remaining portion become chronic carriers
of virus.
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Strategies to Reduce Risk of
Transfusion Transmitted Infections
Pathogen reduction methods
Bacterial detection methods
Removal of the initial whole blood collection (diversion)
Skin preparation
Quality control: processing, handling, and storage
Donor eligibility
• Screening for the
serological markers of
infections, and nucleic
acid testing (NAT) by
viral gene amplification
for direct and sensitive
detection of the known
infectious agents.
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Donor eligibility
• Subjects with recent dental treatments, minor surgery,or increased body temperature at presentation shouldbe excluded from donation to reduce asymptomaticdonor bacteremia
Quality control
• Continuous training and supervision of the responsiblepersonnel for donation and product processing, andconsistent storage temperatures (4°C for RBC and 22–24°Cfor PLT) need to be maintained.
Skin preparation
• Improved donor arm disinfection to reduce thenumbers of remaining bacteria on the phlebotomypuncture site.
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Removal of the initial whole blood collection:
• Removal of the first 30–40 ml of whole blood from the collection bag might reduce the contamination risk from skin bacteria.
Bacterial detection methods
• Automated bacterial culture method, direct bacterial staining, bacterial endotoxin and ribosomal assays, nucleic acids testing for bacterial DNA, and measures of O2 consumption or CO2 production
Pathogen reduction methods
• The goal of pathogen inactivation is to reducetransmissible pathogens (bacteria, viruses and protozoa)without compromising therapeutic efficacy of the bloodproduct or introducing secondary risks.
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TERIMA KASIH
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Hepatitis
• Hepatitis A- small risk of transmission– Vaccination recommended
• Hepatitis B - no transmissions since 1985– Vaccination recommended
• Hepatitis C - no transmissions since 1990– ~90% of patients receiving factor concentrates prior to 1985 are HCV antibody
positive
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Human Immunodeficiency Virus
• No transmissions of HIV through factor concentrates
since 1985 due to viral inactivation procedures
• HIV seropositive rate -
– 69.6% of patients with severe hemophilia A receiving
factor concentrates prior to 1985
– 48.6% of patients with severe hemophilia B receiving
factor concentrates prior to 1985
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