Disertasi

Hemophilia Genotype Initiative Study in Indonesia (HeGiSi): Kajian Hubungan Genotipe dengan Fenotipe, Inhibitor FVIII, Hemophilia Joint Health Score, serta Kualitas Hidup Pasien Hemofilia A di RSCM = Hemophilia Genotype Initiative Study in Indonesia (HeGiSi): Analysis Association of Genotype and Phenotype, FVIII Inhibitor FVIII, Hemophilia Joint Health Score, and Quality of Life of Hemophilia A Patients in Cipto Mangunkusumo Hospital.

Hemofilia A merupakan gangguan pembekuan darah yang disebabkan kekurangan faktor VIII (FVIII) akibat mutasi gen FVIII. Mutasi tersebut dikategorikan menjadi null atau non-null mutation dan menyebabkan gangguan produksi FVIII atau terbentuknya FVIII non-fungsional. Diagnosis hemofilia ditegakkan berdasarkan pemeriksaan kadar FVIII, tanpa melihat data molekular genetik setiap individu hemofilia. Penelitian sebelumnya menyatakan hubungan antara mutasi genetik (genotipe) dengan fenotipe hemofilia. Namun, saat ini belum ada data mengenai mutasi genetik yang terjadi pada pasien hemofilia di Indonesia. Penelitian ini bertujuan untuk mengembangkan database genetik pasien hemofilia A di RSCM, identifikasi profil genotipe, dan menganalisis hubungan genotipe dengan fenotipe hemofilia meliputi derajat keparahan, awitan diagnosis, perdarahan sendi, dan nonsendi, annual bleeding rate (ABR), annual joint bleeding rate (AJBR), inhibitor FVIII, dan life threatening bleeding (LTB), hemophilia joint health score (HJHS), serta kualitas hidup. Penelitian observasional analitik dengan desain potong lintang dilakukan di RSCM periode Mei 2024 hingga Maret 2025 terhadap 96 unrelated subjek hemofilia A. Prevalensi null dan non null mutation sebesar 84,4% dan 15,6% dalam penelitian ini. Null mutation lebih banyak ditemukan pada hemofilia A berat. Spektrum mutasi genetik yang terdeteksi adalah intron 22 inversion (57,3%), nonsense (13,5%), missense (12,5%), intron 1 inversion (9,4%), large deletion (4,2%) dan non-conserved splice site (3,1%). Penelitian ini menemukan tiga novel varian yang belum pernah dilaporkan sebelumnya. Pasien dengan null mutation berisiko lebih tinggi untuk mengalami hemofilia berat (OR 9,63, p < 0,005), median AJBR lebih tinggi (2 (0–6); p 0,006), dan risiko LTB lebih besar (OR 4,13; p 0,025) dibandingkan pasien dengan non-null mutation. Terdapat hubungan antara genotipe FVIII dengan inhibitor FVIII, namun hubungan tersebut tidak bermakna. Tidak ada hubungan bermakna antara genotipe FVIII dengan awitan diagnosis, perdarahan sendi, dan non-sendi, ABR, HJHS, maupun kualitas hidup.
Kata kunci : fenotipe, genotipe, hemofilia A, mutasi gen FVIII; null mutation; non-null mutation


Hemophilia A is blood coagulation disorder caused by deficiency of factor VIII (FVIII) due to FVIII genetic mutation. The genetic mutation is categorized into null or non-null mutation and causes FVIII production disruption or formation of nonfunctional FVIII. Diagnosis of hemophilia is confirmed through FVIII level without identifying the underlying genetic molecular of each patient. Several studies have reported association between genotype and clinical phenotype of hemophilia patient. However, there is no available data on genetic mutation of hemophilia patients in Indonesia. This study aims to develop a genetic database, identify genotype profile, and the association between genotype and phenotypes including severity, onset of diagnosis, joint and non-joint bleeding, annual bleeding rate (ABR), annual joint bleeding rate (AJBR), inhibitor FVIII, life threatening bleeding (LTB), hemophilia joint health score (HJHS), and quality of life for hemophilia A patients in RSCM. An observational analytic study with cross-sectional design was carried out in RSCM from May 2024 until March 2025 in 96 hemophilia patients without family history of hemophilia. Prevalence of null and non-null mutation were 84.8% and 15.6% respectively. Null mutation was found more often in severe hemophilia A patients. Detected genetic mutation spectrum included intron 22 inversion (57.3%), nonsense (13.5%), missense (12.5%), intron 1 inversion (9.4%), large deletion (4.2%) and non-conserved splice site (3.1%). This study discovered three novel variants that had not been previously reported. Patients with nullmutation had a higher risk for severe hemophilia (OR 9.63, p < 0,005), higher median AJBR (2 (0–6); p 0.006), and higher risk for LTB (OR 4.13; p 0.025) in comparison to patients with non-null mutation. There was an association between FVIII genetic mutation with inhibitor FVIII although not significant. There was no significant association between FVIII genetic mutation with onset of diagnosis nor joint or non-joint bleeding, ABR, HJHS, and quality of life.
Keyword : FVIII genetic mutation, genotype, hemophilia A, non-null mutation, null mutation; phenotype.