Introduction

Hemophilia A is a disorder characterized by a deficiency of the protein "clotting Factor VIII" in the bloodstream. This deficiency leads to prolonged bleeding following injuries such as tooth extractions, surgeries, and delayed or recurring bleeding during the wound-healing process. Hemophilia A is categorized into three main levels of severity: severe, moderate, and mild. The diagnosis, treatment, and frequency of bleeding episodes all vary based on the specific level of hemophilia a person possesses. This condition is inherited through a recessive X-linked mutation.

Hemophilia A is one of three distinct types of hemophilia, the others being Hemophilia B and Hemophilia C. These types are differentiated by their prevalence and the specific clotting factor that is deficient in each case. In the case of Hemophilia A, patients lack factor 8. Globally, approximately 18% of individuals are diagnosed with hemophilia, and within this percentage, Africa constitutes 3% of those diagnosed with the condition.

Punnett square of a woman is heterozygous for hemophilia with a normal man (Source)

Disease Information

The clinical symptoms of Hemophilia A are; Pain/Swelling in joints, unexplained nosebleeds that randomly occur, many large and deep bruises, unexplained excessive bleeding from cuts or injuries, or from surgery or dental work like tooth extractions, and blood in your urine or stool.

Normal Blood vessel tear versus Patient with Hemophilia which can cause excessive bleeding (Source)

Tests for diagnosing Hemophilia encompass various screening tests and clotting factor tests. Screening tests serve to determine whether blood clotting occurs normally. Examples of these tests include Complete Blood Count and Activated Partial Thromboplastin Time. On the other hand, clotting factor tests, also known as factor assays, ascertain the severity and specific type of hemophilia.

The treatment approach for individuals with Hemophilia A typically involves the replacement of the deficient blood clot factor, Factor VIII, with clotting factor concentrates administered intravenously. In addition to this, patients are prescribed episodic and prophylactic care to manage ongoing bleeding and prevent future bleeding episodes.

Regarding treatment options, two primary types of clotting factor concentrates are utilized: Plasma-Derived Factor Concentrates and Recombinant Factor Concentrates. Plasma-Derived Concentrates are derived from human plasma proteins, which are collected from multiple donors, tested for viruses, and processed into clotting factors. These factors are then freeze-dried and subjected to virus testing and inactivation protocols before use. In contrast, Recombinant Factor Concentrates are produced using DNA technology and do not contain human-derived concentrates. They are mainly employed for preventing and eradicating inactive bloodborne viruses.

However, it's important to note that some individuals treated with clotting factor concentrates may develop inhibitors, which are immune system responses that hinder the effectiveness of treatment, making the prevention of bleeding episodes more challenging.

Gene Information

The gene responsible for Hemophilia is F8, and it is situated on Xq28. The mutation occurs within the F8 gene, leading to insufficient production of Factor VIII. The Factor VIII protein is structured with six domains: A1, A2, B, A3, C1, and C2. This protein's configuration comprises a heavy chain consisting of A1-A2-B domains, and a light chain composed of A3-C1-C2 domains. Factor VIII is synthesized in sinusoidal endothelial cells and Kupffer cells located in the human liver. It exists in two isoforms: isoform a and isoform b. While isoform a circulates in the bloodstream and combines with the von Willebrand factor, isoform b plays a crucial role in clotting activity.

In investigations involving mRNA from Hemophilia A patients, researchers discovered a mutation within the F8 gene. This mutation results from an intrachromosomal inversion in intron 22, causing a repositioning of the gene segment and subsequent issues with pre-mRNA splicing. Consequently, this alteration leads to the production of a truncated protein.

Transcription, Translation and Secretion of F8 gene (Source)

Contemporary Research

Research into Hemophilia A has led to the exploration of gene therapy as a potential treatment avenue. One approach being investigated involves the bioengineering of mesenchymal stem cells to produce factor VIII, aiming to address the deficiency associated with Hemophilia.

While many innovative therapies focus on administering the deficient clotting factors through injections, alternative methods to manage bleeding are also being explored. These methodologies typically undergo clinical trials to assess their effectiveness before being submitted to the FDA for approval, a prerequisite for their prescription by healthcare professionals.

In June 2023, a significant development emerged as the Food and Drug Administration granted approval for Gene Therapy in severe Hemophilia A cases. Named Roctavian, this gene therapy entails a single-dose infusion utilizing a viral vector containing the gene responsible for clotting Factor VIII, the protein lacking in Hemophilia patients. Upon infusion, the gene is expressed in the liver, leading to increased Factor VIII levels in the blood and a reduced susceptibility to future bleeding incidents.

The process of gene therapy for Hemophilia using a virus (Source)

A study was undertaken to assess the safety and efficacy of the therapy in adults aged 18 to 70 with severe hemophilia A who had previously undergone Factor VIII replacement therapy. The study's importance was demonstrated through an analysis of 112 patients who received Roctavian three years prior and were followed up. The outcomes revealed a substantial reduction in the annualized bleeding rate, declining from 5.4 bleeds per year to 2.6 bleeds per year. Furthermore, patients were administered corticosteroids, an anti-inflammatory medication, to suppress the immune system's response, facilitating the efficient and safe functioning of the gene therapy.

Mechanism of Hemophilia A

This step-by-step model talks about how the factor concentrates act as a treatment.

Our Future View on Hemophilia A

• Margarita's Perspective : In my view, it's crucial for scientists to continue their dedicated efforts in exploring and researching various avenues with the goal of eventually finding a cure for hemophilia. Technologies such as Artificial Intelligence and Augmented Reality represent just a few of the tools that scientists and medical professionals can harness to develop effective treatments for this condition. Presently, I believe it's important to keep focusing on advancing Gene Therapy and Medicinal Drugs, aiming to prevent future bleeding episodes and potentially even achieve a complete cure for hemophilia.

• Beatrice's Perspective : At the moment, our utilization of technology and the wealth of new information available has allowed us to make significant strides in alleviating the challenges and symptoms associated with hemophilia. While treatments like gene therapy, clotting factor concentrates, and liver transplants have provided relief, our advanced technological capabilities can serve as a powerful asset in our pursuit of curing hemophilia. By further refining bioengineering and gene technology, we have the potential not only to conquer hemophilia but also to address a broader spectrum of genetic diseases.

Conclusion

In summary, Hemophilia A stands as a significant genetic disorder affecting millions across the globe. This condition arises when the absence of clotting factor VIII prevents blood from clotting properly. Manifestations of Hemophilia encompass excessive bleeding from minor injuries, joint pain, and other related symptoms. In the fight against this ailment, various treatment avenues and therapeutic approaches have been developed. Gene therapies involving the replacement of the missing clotting factor, as well as treatments like concentrates and single doses, have been employed. Our current era boasts an array of cutting-edge technologies, such as Artificial Intelligence and Augmented Reality. These advancements offer the promise of fostering continued progress in the realm of treatments, diagnostic tests, and clinical trials, with the ultimate aspiration of discovering a definitive cure for this unfortunate affliction.

Click to view enlarged poster.

    

Click to read full paper.

Impact Statement

Hello! My name is Bea Fernandez, and I am a student from the Philippines studying in Chinese International School. I have always enjoyed learning Biology and learning the wonders of life. I am grateful to have joined Elio Academy because it has further expanded my knowledge of the study of life. Together with my fellow schoolmate, Maita Cham, she and I wrote a report and poster on Hemophilia A. We wrote about how it is inherited, and the recently discovered and approved treatment for it. I have learned more about genetics and genomes during our lessons with Ms. Juhi. Our lesson in Cancer Biology piqued my interest as it is a disease that has been plaguing people for years. Although it was difficult to focus due to my time in the Philippines, I'm glad that Elio accommodates us by providing recorded videos, allowing me to review the lessons.

Impact Statement

Hi! My name is Margarita Cham. I am currently a junior at Chinese International School Manila. I've always been exposed to science; my family comprises primarily doctors, and it is my favorite subject at school. During my time at Elio, I got to expand my knowledge on Genetics and Cancer Biology, and through multiple sacrificed sleep schedules, I, along with my classmate Bea Fernandez was able to write a lengthy report and create a poster on Hemophilia A. I learned how to look for trustworthy sources, learn about proteins, genetics, cancer, and more in a microscopic level (which made it a thousand times more interesting), and gained various skills that I carry along with me as I enter the IB Diploma Program this school year. In the end, I am incredibly grateful to have spent this summer with Elio, as it unmistakably intensified my love for sciences, as well as served as a platform to meet friendly peers around the world with just a click of a button.

References

1. Commissioner, O. of the. (n.d.). FDA approves first gene therapy for adults with severe hemophilia a. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-adults-severe-hemophilia

2. Future therapies. National Hemophilia Foundation. (n.d.). https://www.hemophilia.org/bleeding-disorders-a-z/treatment/future-therapies

3. Mayo Foundation for Medical Education and Research. (2021, October 7). Hemophilia. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/hemophilia/symptoms-causes/syc-20373327

4. S;, K. B. F. (n.d.). Hemophilia A. National Center for Biotechnology Information. https://pubmed.ncbi.nlm.nih.gov/20301578/

5. Centers for Disease Control and Prevention. (2023, July 12). Diagnosis of hemophilia. Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/hemophilia/diagnosis.html.

6. El-Maarri O;Herbiniaux U;Graw J;Schröder J;Terzic A;Watzka M;Brackmann HH;Schramm W;Hanfland P;Schwaab R;Müller CR;Oldenburg J; (n.d.). Analysis of mrna in hemophilia a patients with undetectable mutations reveals normal splicing in the factor VIII gene. Journal of thrombosis and haemostasis : JTH. https://pubmed.ncbi.nlm.nih.gov/15670040/

7. Human Protein Atlas | F8 Protein. F8 protein expression summary - the human protein atlas. (n.d.). https://www.proteinatlas.org/ENSG00000185010-F8

8. Pezeshkpoor, B., Oldenburg, J., & Pavlova, A. (2022, December). Insights into the molecular genetic of hemophilia A and hemophilia b: The relevance of genetic testing in routine clinical practice. Hamostaseologie. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9779947/

9. Xia Z;Lin J;Lu L;Kim C;Yu P;Qi M; (n.d.). An intronic mutation C.6430-3C>G in the F8 gene causes splicing efficiency and premature termination in hemophilia a. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis. https://pubmed.ncbi.nlm.nih.gov/29652675/

10. Researching a treatment for hemophilia. Wake Forest University School of Medicine. (n.d.). https://school.wakehealth.edu/research/institutes-and-centers/wake-forest-institute-for-regenerative-medicine/research/cell-and-gene-therapy-research/researching-a-treatment-for-hemophilia

11. https://www.uniprot.org/

12. U.S. National Library of Medicine. (n.d.). F8 coagulation factor VIII [Homo Sapiens (human)] - gene - NCBI. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/gene/2157

13. Wikimedia Foundation. (2023, May 27). Factor VIII. Wikipedia. https://en.wikipedia.org/wiki/Factor_VIII.

Project done at Elio Academy of Biomedical Sciences

_By: Margarita Cham and Beatrice Fernandez_

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of Elio Academy.