Details of Disease

General Information of Disease (ID: DIS1S8P6)

• Disease Name: Hemophilia
• Synonyms: hemophilia
• Disease Class: 3B10: Coagulation defect
• Definition: Hemophilia is a genetic disorder characterized by spontaneous hemorrhage or prolonged bleeding due to factor VIII or IX deficiency.
• Disease Hierarchy:
  DISEXNCF: Coagulation protein disease
  DIS1S8P6: Hemophilia
• ICD Code:
  ICD-11: ICD-11: 3B10.0
  ICD-10: ICD-10: D66-D68
  ICD-9: ICD-9: 286
  Expand ICD-9: 286
• Disease Identifiers:
  MONDO ID: MONDO_0018660
  UMLS CUI: C0684275
  MedGen ID: 146334
  Orphanet ID: 448
  SNOMED CT ID: 90935002

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 9 Approved Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Factor 8	DMAB6PM	Approved	NA	[1]
Factor ix human	DMOWD3Z	Approved	NA	[1]
Factor viia	DMZUW6P	Approved	NA	[1]
Factor viii	DMPMP8S	Approved	NA	[1]
Human factor viii	DMX4GVY	Approved	NA	[1]
Moroctocog alfa	DMP7Y3H	Approved	NA	[1]
Rec-antihemophilic factor	DMRQGJI	Approved	NA	[1]
Recombinant factor viii	DM82C1H	Approved	NA	[1]
Von willebrand factor	DMGB7RV	Approved	NA	[2]

This Disease is Treated as An Indication in 11 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
SK-NBP601	DMUY09W	Preregistration	NA	[3]
BAX-817	DMB147A	Phase 3	NA	[4]
BAY 94-9027	DM09M3H	Phase 3	NA	[5]
Fitusiran	DMMQ7BY	Phase 3	Small interfering RNA	[6]
NN1841	DMDGK83	Phase 3	NA	[7]
PF-06741086	DMW63TQ	Phase 3	Antibody	[8]
Activated recombinant FVII-albumin fusion protein	DMKY9GI	Phase 2/3	NA	[9]
CB-813	DMXQGKL	Phase 1	Small molecular drug	[10]
Eptacog alfa	DMAQYRL	Phase 1	NA	[11]
F-7TG	DML4JXZ	Phase 1	NA	[12]
Factor VIII gene therapy	DM9RN83	Phase 1	NA	[13]

This Disease is Treated as An Indication in 2 Discontinued Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
BAY 86-6150	DM6R3WC	Discontinued in Phase 2/3	NA	[14]
Coagulin-B	DM3MDLV	Discontinued in Phase 1/2	NA	[15]

This Disease is Treated as An Indication in 9 Investigative Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Factor IX-XTEN	DMSQ3I9	Investigative	NA	[16]
Factor VIII-XTEN	DM1AYVU	Investigative	NA	[17]
Factor-VIIa-XTEN	DMDWSH1	Investigative	NA	[18]
Full-length Factor VIII molecule	DM4M91Z	Investigative	NA	[17]
HL-2353	DMGROH0	Investigative	NA	[19]
MOD-5023	DMKWBNA	Investigative	NA	[18]
Recombinant coagulation factors	DMFAST4	Investigative	NA	[20]
Recombinant Factor X	DMX6LV3	Investigative	NA	[20]
SMaRT FVIII	DMGJTL3	Investigative	NA	[17]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 13 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
F10	TTCIHJA	Limited	Biomarker	[21]
ADAMTS5	TTXSU2Y	Strong	Biomarker	[22]
BPI	TTXCSDR	Strong	Biomarker	[23]
CPB2	TTP18AY	Strong	Biomarker	[24]
F2	TT6L509	Strong	Biomarker	[25]
F3	TT38MDJ	Strong	Biomarker	[26]
F7	TTF0EGX	Strong	Altered Expression	[27]
F8	TT1290U	Strong	Biomarker	[28]
HAL	TTXQOZW	Strong	Biomarker	[29]
IFNL3	TTRF4Q2	Strong	Genetic Variation	[30]
VIPR1	TTCL30I	Strong	Biomarker	[31]
VWF	TT3SZBT	Strong	Genetic Variation	[32]
CCR5	TTJIH8Q	Definitive	Genetic Variation	[33]

This Disease Is Related to 11 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
ABR	OTZQK8JF	Strong	Biomarker	[34]
AMBP	OTLU8GU8	Strong	Biomarker	[35]
C4orf3	OT6TFN1O	Strong	Biomarker	[36]
CARD14	OTADQHOV	Strong	Biomarker	[37]
CCL3L1	OTQXCYB1	Strong	Biomarker	[38]
CLTC	OTBFASMA	Strong	Biomarker	[39]
HAP1	OT6SG0JQ	Strong	Genetic Variation	[40]
HPSE2	OTGEPP8V	Strong	Genetic Variation	[41]
NFYA	OTWFFOVH	Strong	Genetic Variation	[40]
PROCR	OTRHED17	Strong	Altered Expression	[42]
SERPINA10	OTZ8OZ67	Strong	Biomarker	[43]

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6755).
• [3] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800035403)
• [4] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800032604)
• [5] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021112)
• [6] ClinicalTrials.gov (NCT03549871) A Study of Fitusiran in Severe Hemophilia A and B Patients Previously Receiving Factor or Bypassing Agent Prophylaxis (ATLAS-PPX). U.S. National Institutes of Health.
• [7] ClinicalTrials.gov (NCT01253811) Safety and Efficacy of Monthly Replacement Therapy With Recombinant Factor XIII (rFXIII) in Paediatric Subjects With Congenital Factor XIII A-subunit Deficiency. U.S.National Institutes of Health.
• [8] ClinicalTrials.gov (NCT03938792) Study of the Efficacy and Safety PF-06741086 in Adult and Teenage Patients With Severe Hemophilia A or B. U.S. National Institutes of Health.
• [9] ClinicalTrials.gov (NCT02484638) Study of Recombinant Factor VIIa Fusion Protein (rVIIa-FP, CSL689) for On-demand Treatment of Bleeding Episodes in Patients With Hemophilia A or B With Inhibitors.
• [10] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027663)
• [11] ClinicalTrials.gov (NCT02084810) Investigating the Bioequivalence of Eptacog Alfa A 6 mg and NovoSeven in Healthy Male Subjects. U.S. National Institutes of Health.
• [12] GTC BIOTHERAPEUTICS REPORTS THIRD QUARTER 2010 FINANCIAL RESULTS. U.S. Securities and Exchange Commission. October 27, 2010.
• [13] Clinical pipeline report, company report or official report of BioMarin.
• [14] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021847)
• [15] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009990)
• [16] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2364).
• [17] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2607).
• [18] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2363).
• [19] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [20] Semuloparin for the prevention of venous thromboembolic events in cancer patients. Drugs Today (Barc). 2012 Jul;48(7):451-7.
• [21] Prohemostatic Activity of Factor X in Combination With Activated Factor VII in Dilutional Coagulopathy.Anesth Analg. 2019 Aug;129(2):339-345. doi: 10.1213/ANE.0000000000003858.
• [22] Serological biomarkers in hemophilic arthropathy: Can they be used to monitor bleeding and ongoing progression of blood-induced joint disease in patients with hemophilia?.Blood Rev. 2020 May;41:100642. doi: 10.1016/j.blre.2019.100642. Epub 2019 Nov 20.
• [23] Construct validity of patient-reported outcome instruments in US adults with hemophilia: results from the Pain, Functional Impairment, and Quality of life (P-FiQ) study.Patient Prefer Adherence. 2017 Aug 9;11:1369-1380. doi: 10.2147/PPA.S141390. eCollection 2017.
• [24] Thrombin activatable fibrinolysis inhibitor pathway alterations correlate with bleeding phenotype in patients with severe hemophilia A.J Thromb Haemost. 2020 Feb;18(2):381-389. doi: 10.1111/jth.14656. Epub 2019 Oct 15.
• [25] Timely and large dose of clotting factor IX provides better joint wound healing after hemarthrosis in hemophilia B mice.Int J Hematol. 2019 Jul;110(1):59-68. doi: 10.1007/s12185-019-02639-5. Epub 2019 Apr 20.
• [26] Targeting protease nexin-1, a natural anticoagulant serpin, to control bleeding and improve hemostasis in hemophilia.Blood. 2019 Nov 7;134(19):1632-1644. doi: 10.1182/blood.2019000281.
• [27] Safety and efficacy of recombinant activated coagulation factor VII in congenital hemophilia with inhibitors in the home treatment setting: A review of clinical studies and registries.Am J Hematol. 2017 Sep;92(9):940-945. doi: 10.1002/ajh.24811. Epub 2017 Jul 19.
• [28] Paradigm shift for the treatment of hereditary haemophilia: Towards precision medicine.Blood Rev. 2020 Jan;39:100618. doi: 10.1016/j.blre.2019.100618. Epub 2019 Oct 15.
• [29] Common themes and challenges in hemophilia care: a multinational perspective.Hematology. 2019 Dec;24(1):39-48. doi: 10.1080/10245332.2018.1505225. Epub 2018 Aug 3.
• [30] Interferon lambda 3 rs12979860 polymorphism in patients with haemophilia and HCV infection: a predictor of spontaneous viral clearance and sustained virological response.Thromb Haemost. 2014 Jun;111(6):1067-76. doi: 10.1160/TH13-11-897. Epub 2014 Feb 13.
• [31] Hepatitis C virus quasispecies in the natural course of HCV-related disease in patients with haemophilia.Haemophilia. 2004 Jan;10(1):81-6. doi: 10.1046/j.1365-2516.2003.00846.x.
• [32] Targeted re-sequencing of F8, F9 and VWF: Characterization of Ion Torrent data and clinical implications for mutation screening.PLoS One. 2019 Apr 26;14(4):e0216179. doi: 10.1371/journal.pone.0216179. eCollection 2019.
• [33] Effects of the CCR5-Delta32 mutation on hepatitis C virus-specific immune responses in patients with haemophilia.Immunol Invest. 2009;38(1):1-13. doi: 10.1080/08820130802307294.
• [34] Development of Haemophilia Treatment in the Eastern Part of Germany over the Last Decade in the Kompetenznetz Hmorrhagische Diathese Ost (KHDO).Hamostaseologie. 2020 Feb;40(1):119-127. doi: 10.1055/s-0039-3399493. Epub 2019 Nov 11.
• [35] The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab.Haemophilia. 2019 Jul;25(4):676-684. doi: 10.1111/hae.13762. Epub 2019 Apr 29.
• [36] An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia.Nat Med. 2015 May;21(5):492-7. doi: 10.1038/nm.3847. Epub 2015 Apr 13.
• [37] Haemophilic arthropathy: A narrative review on the use of intra-articular drugs for arthritis.Haemophilia. 2019 Nov;25(6):919-927. doi: 10.1111/hae.13857. Epub 2019 Oct 22.
• [38] Copy number variations of CCL3L1 and long-term prognosis of HIV-1 infection in asymptomatic HIV-infected Japanese with hemophilia.Immunogenetics. 2007 Oct;59(10):793-8. doi: 10.1007/s00251-007-0252-4. Epub 2007 Sep 14.
• [39] Molecular diagnosis of haemophilia A at Centro Hospitalar de Coimbra in Portugal: study of 103 families--15 new mutations.Haemophilia. 2012 Jan;18(1):129-38. doi: 10.1111/j.1365-2516.2011.02570.x. Epub 2011 Jun 6.
• [40] Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A.Blood. 2006 Dec 1;108(12):3739-45. doi: 10.1182/blood-2006-05-024711. Epub 2006 Aug 22.
• [41] Hemophilia B in a female carrier due to skewed inactivation of the normal X-chromosome.Am J Hematol. 1998 May;58(1):72-6. doi: 10.1002/(sici)1096-8652(199805)58:1<72::aid-ajh13>3.0.co;2-7.
• [42] Factor VIIa interaction with EPCR modulates the hemostatic effect of rFVIIa in hemophilia therapy: Mode of its action.Blood Adv. 2017 Jun 27;1(15):1206-1214. doi: 10.1182/bloodadvances.2016004143.
• [43] Suppressing protein Z-dependent inhibition of factor Xa improves coagulation in hemophilia A.J Thromb Haemost. 2019 Jan;17(1):149-156. doi: 10.1111/jth.14337. Epub 2018 Dec 16.