Haemophilia A: A Review of Clinical Manifestations, Treatment, Mutations, and the Development of Inhibitors
Abstract
:1. Methods
2. Physiology of the Blood Coagulation System
2.1. Haemostasis
2.1.1. Classical Theory
2.1.2. The Cellular Model of Thrombin Formation
- Initiation: Haemostasis is initiated by vascular rupture, giving rise to the exposure of the tissue factor (TF), which is not usually in contact with blood. When this union with FVIIa occurs, a tenase complex is formed that activates FX by joining FV, forming a new complex, enzyme prothrombinase, which generates thrombin. In addition to activating FV, it is also activated by FXI, which results in FXa and thrombin, but in minimal amounts, since it is inhibited by the thrombin-inhibiting factor [5]. The extrinsic pathway is now the initiating physiological pathway that produces small amounts of thrombin and activates platelets, as mentioned above [2].
- Amplification: This stage occurs through positive feedback on the intrinsic and common pathways, generating large amounts of thrombin. It is known as amplification [2], as described below. The reduced amounts of thrombin (FIIa) formed in the initiation phase activate the FV cofactors, FXI, FXIII, and platelets, through protease-activated receptors; FVIII is separated from VWF by thrombin and the other factors are activated for the next phase [6,7].
- Spread: At this stage, the phase of fibrinogenesis and platelet aggregation begins [2]. It occurs on the surfaces of previously activated platelets, leaving receptors exposed for the binding of activated coagulation factors. It binds FXI, activating more FIX molecules by binding to its cofactor FVIII and forming a more potent defence complex, forming more FXa. FXA binds the FV cofactor again, which leads to the generation of more thrombin, but it is no longer inhibited [6,7].
3. Haemophilia A
3.1. History
3.2. Genetic Etiology
3.3. Epidemiology
3.4. Clinical Features
- ▪
- Mild deficiency (5–40% FVIII activity): It usually only presents with bleeding after surgical procedures.
- ▪
- Moderate deficiency (1 to 5% FVIII activity).
- ▪
Bleeding in FVIII Deficiency
- Hemarthroses (70–80% incidence): the most common events occur in the knee, ankle, and elbow joints, and less frequently in the shoulders, wrists, and hips.
- Muscles: there is an incidence of 70–80%.
- Other important haemorrhages occur with an incidence of 5–10%.
- Central nervous system: there is an incidence of <5%. It is the main cause of mortality in severe haemophilia patients, but, fortunately, its incidence has been declining with the widespread introduction of prophylaxis. All head injuries that are accompanied by headache, drowsiness, or vomiting should be considered as possible intracranial bleeding and treated immediately. If the severe pain is at the level of the back, it may be a symptom of bleeding at the level of the spinal cord.
3.5. Description of Factor VIII
3.6. Inhibitors in Haemophilia
3.7. Pathophysiology of the Inmune Response to FVIII
3.8. Development of Inhibitors in Haemophilia A
- ▪
- Negative inhibitor titre: The titre is below the limit of detection of inhibitors in the local laboratory. If the reference value of the local laboratory is not available, any titre <0.6 Bethesda unit (BU) will be considered negative [27].
- ▪
- A low titre of inhibitor: Any titre that is between the limit of detection of inhibitors of the local laboratory and ≤5 BU will be considered a low-titre inhibitor. If the local laboratory reference value is not available, any titre ≥0.6 BU will be considered a low-titre inhibitor [27].
- ▪
- A high titre of inhibitor: Any titre ≥5 BU at any time after diagnosis will be considered a high-titre inhibitor [27].
3.8.1. Incidence of Inhibitors in a Previously Treated Patient (PTP) in Haemophilia
3.8.2. Incidence of Inhibitors in Treatment-Naive Patients (PUP)
3.9. Risk Factors Associated with the Development of Inhibitors
3.9.1. Immune Response in Haemophilia
3.9.2. Major Histocompatibility Complex in Haemophilia
3.9.3. TNF-α
3.9.4. Race and Ethnicity
3.10. Mutation Responsible for Haemophilia A
- Large deletions or insertions: These are those in which more than 50 bp [52] is added or lost, which alters the reading frame.
- Small deletions or insertions: These are defined by the loss of less than 50 base pairs (bp), generating changes in the reading (frameshift) and generating a premature stop codon [52]. This class of mutations is caused by polymerase slippage during the DNA replication phase [30]. Most patients with severe haemophilia A have large deletions and insertions [30].
- Mutations of amino acid change or missense:
- This produces a stop codon, where a termination codon is produced (TAA, TAG, TGA). It is responsible for a severe phenotype [22].
3.10.1. Background in the Literature on the Relationship between FVIII Mutations and Inhibitor Development
3.10.2. History of Variants or Mutations in Colombia
3.11. Laboratory Diagnostic Test
3.11.1. Methods That Measure the Functional Activity of FVIII
3.11.2. Chromogenic Method (Ccro) of FVIII
3.11.3. Coagulometric or One-Stage Assay
3.11.4. Quantitative Measurement of Factor VIII Inhibitors
3.12. Treatment
- ▪
- Primary: This begins before the second joint bleed, without the presence of joint damage, and prophylaxis treatment started before the age of three.
- ▪
- Secondary: This begins after two or more joint bleeds, but before joint damage is established.
- ▪
- Tertiary: This begins after joint damage has been confirmed by diagnostic means.
3.12.1. Pharmacokinetics (PK)
3.12.2. Population Pharmacokinetics
3.12.3. Types of FVIII Products Used in Haemophilia A
Plasma-Derived Factor
Recombinant Factor VIII Concentrates
3.12.4. Emicizumab
3.12.5. Treatment of Patients with Inhibitors
Immune Tolerance Regimens
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
Initials | Definition |
aa | Amino acid |
ADN | Deoxyribonucleic acid |
ARN | Ribonucleic acid |
EDTA | Ethylenediaminetetraacetic acid |
FVIII | Factor VIII |
FIX | Factor IX |
FvW | Von Willebrand factor |
HAMSTeRS | The Haemophilia A Mutation, Structure, Test and Resource Site |
INV1 | Intron-1 inversion |
INV22 | Intron-22 inversion |
ITI | Immunetolerance |
Kb | Kilobase |
Pb | Base pair |
PCR | Polymerase chain reaction |
BU | Bethesda units |
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Risk Factors | Summary | Support Level | ||
---|---|---|---|---|
Non-Modifiable Genetic Risk Factors | ||||
Type of FVIII mutation (null vs. non-null) and the position of the mutation | Type of mutation | Risk of inhibitor formation | Well established | |
Null | Multidomain deletions | 75% | ||
Light-chain missense mutations | 30–40% | |||
Intron-22 inversion | 20–25% | |||
Domain deletions unique | 15–25% | |||
Small insertions/deletions in non-A zone | 15–20% | |||
Heavy-chain missense mutations | 10–20% | |||
Not null | FVIII missense mutations | <10% | ||
Small insertions/deletions in zone A | <5% | |||
Mutations at the splice site | <5% | |||
Family history | Risk 3.2 times higher (95% CI 2.1–4.9) if there was a family member with inhibitors | Well established | ||
Ethnicity | 1.9- to 4.7-fold increased risk in non-Caucasians (Black African > Latin American > Caucasian ancestry) | Established, but not well understood | ||
TNF-α IL-10 CTLA-4 polymorphisms | TNF-α −308 A/A increases risk IL-10: allele 134 increases the risk CTLA-4: T-allele decreases risk | Some evidence, but not well understood | ||
FVIII haplotypes | Haplotypes H3 or H4 have a higher risk of inhibitors since current FVIII products consist mainly of haplotypes H1 and H2 | Reports discordant | ||
Class I/II MHC genes or HLA polymorphisms | 2-fold increased risk for HLADR15 and HLA-DQ6 and inhibitor formation | Reports discordant | ||
Potentially Modifiable Environmental Risk Factors | ||||
Trauma/surgeries | Major surgeries and trauma leading to treatment spikes increase the risk of inhibitor development | Established, but not well understood | ||
Inflammation/infection | Could increase the formation of inhibitors | Established, but not well understood | ||
Intense exposure, particularly at a young age | Increased risk of inhibitor formation | Established, but not well understood | ||
Type of factor concentrate | Some studies suggest that conventional recombinant factor carries a higher risk of inhibitor formation than plasma-derived factor | Reports discordant | ||
Early initiation of prophylaxis | Could confer true protection | No concrete evidence |
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Sarmiento Doncel, S.; Díaz Mosquera, G.A.; Cortes, J.M.; Agudelo Rico, C.; Meza Cadavid, F.J.; Peláez, R.G. Haemophilia A: A Review of Clinical Manifestations, Treatment, Mutations, and the Development of Inhibitors. Hematol. Rep. 2023, 15, 130-150. https://doi.org/10.3390/hematolrep15010014
Sarmiento Doncel S, Díaz Mosquera GA, Cortes JM, Agudelo Rico C, Meza Cadavid FJ, Peláez RG. Haemophilia A: A Review of Clinical Manifestations, Treatment, Mutations, and the Development of Inhibitors. Hematology Reports. 2023; 15(1):130-150. https://doi.org/10.3390/hematolrep15010014
Chicago/Turabian StyleSarmiento Doncel, Samuel, Gina Alejandra Díaz Mosquera, Javier Mauricio Cortes, Carol Agudelo Rico, Francisco Javier Meza Cadavid, and Ronald Guillermo Peláez. 2023. "Haemophilia A: A Review of Clinical Manifestations, Treatment, Mutations, and the Development of Inhibitors" Hematology Reports 15, no. 1: 130-150. https://doi.org/10.3390/hematolrep15010014