Asymptomatic Joint Bleeding and Joint Health in Hemophilia: A Review of Variables, Methods, and Biomarkers

Figures & data

Table 1 Systematic Literature Review Inclusion and Exclusion Criteria

Inclusion Criteria	Exclusion Criteria
Original article Congenital hemophilia Included quantifiable information on joint health  MRI scoring  HEAD US scoring  Gilbert  Pettersson  ROM  HJHS/HJHS 2.1  Arthropathy diagnosis code  Orthopedic score (WFH)  Petrini score	Review article or case study Duplicate results Not in English Included joint interventions – such as physiotherapy, surgery or radiosynovitis Non-relevant disease model Absence of hemophilia patients

Abbreviations: HEAD US, Hemophilia Early Arthropathy Detection with Ultrasound; HJHS, Hemophilia Joint Health Score; MRI, magnetic resonance imaging; ROM, range of motion; WFH, World Federation of Hemophilia.

Figure 1 PRISMA systematic literature review flow chart.

Table 2 Gene Mutations and Genotypes Associated with Joint Health in Patients with Hemophilia

Gene/Genotype	Mutation Type	Joint Health
Inflammatory and immune genes
NOD2	Nonsynonymous	Increased risk of ROM abnormalities^Citation24
TLR10	Missense	Increased risk of ROM abnormalities^Citation24
HLA B27		Greater risk of developing chronic synovitis^Citation27,Citation28
MTHFR 677TT		Higher number of affected joints^Citation30
MTHFR 1298AC		Higher degree of effusion^Citation30
TNFα‐308GA		Increased number of subchondral cysts^Citation30
Genes encoding coagulation factors
FVIII	Missense, nonsense, frameshift, intron 22 inversion	No association with HJHS or Gilbert score^Citation25
	Inversion, deletion, insertion, nonsense	Increased risk for a severe phenotype (>10 Pettersson score)^Citation26
FIX	Inversion, deletion, insertion, nonsense	Increased risk for a severe phenotype (>10 Pettersson score)^Citation26
Gene encoding homeostatic iron regulator protein
HFE	C282Y, H63D	Increased number of hemarthrosis per year and number of affected joints^Citation29

Abbreviations: HJHS, Hemophilia Joint Health Score; ROM, range of motion.

Table 3 Properties of Magnetic Resonance Imaging (MRI) and Ultrasound

Properties	MRI	Ultrasound
Physiology and anatomy
Detection of hemosiderin deposition	✓	✘
Detection of synovial inflammation	✓	✓
Detection of synovial hypertrophy and hyperplasia	✓	✓
Detection of soft tissue changes	✓	✓
Detection of osteochondral changes	✓	✓
Detection of joint effusions/hemarthrosis	✓	✓
Detection of cartilage and bone surface abnormalities	✓	✓
Detection of osteopenia	✓	✓
Methodology
Visualization of internal joint structure and soft tissue types	✓	✘
Detection of different signal intensities	✓	✘
High spatial resolution	✓	✘
Not operator-dependent	✓	✘
Possible to scan multiple joints at once	✘	✓
Patient perspective
No need for sedation in children	✘	✓
Fast	✘	✓
Health care systems
Economical	✘	✓
Routine use	✘	✓
Readily available	✘	✓

Abbreviation: MRI, magnetic resonance imaging.

Table 4 Potential Biomarkers of Bone Health

Biomarkers	Decreased Levels in Patients with Hemophilia vs Healthy Controls	Increased Levels in Patients with Hemophilia vs Healthy Controls	Significant Correlation with Joint Scores
Inflammation	CRPM^Citation81	hsCRP^Citation81 TNF-α^Citation84	TNF-α^Citation84
Cartilage destruction	ADAMTS5^Citation81	C2M^Citation81 CTX-II^Citation81 COMP^Citation81	CTX-II^Citation81,Citation82 C1,2C^Citation82 CS-846^Citation82 COMP^Citation82
Bone turnover	PINP^Citation81 sRANKL^Citation83 OPG^Citation83	CTX-I^Citation81 Sclerostin^Citation52	sRANKL^Citation83 OPG^Citation83 Sclerostin^Citation52
Vascularization and angiogenesis		Microvascular density^Citation88 VEGF expression^Citation87,Citation88 VEGFA^Citation87 SDF-1α^Citation87 MMP-9^Citation87 HIF-1α^Citation87 VEGFR1/CD11b^Citation87 CD34/VEGFR1^Citation87 VEGF/CD68^Citation87 VEGFR2/AC133^Citation87
Others	VitaminD^Citation90^–^Citation92		Iron accumulation in cartilage^Citation86 VitaminD^Citation90^–^Citation92

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