Haemophilia: When the Blood Refuses to Stop
The term “Haemophilia” originates from the Ancient Greek words “Haima (meaning blood) & “Philia” (meaning love / affection for – Love for blood / affinity for blood. In 1829, the term ‘haemorrhaphilia’ was coined by Friedrich Hoph for tendency to prolonged bleeding.
Haemophilia is an inherited (meaning it is passed down through families via genes) bleeding disorder characterized by a deficiency or dysfunction of specific blood-clotting proteins (clotting factors), primarily factor VIII (Haemophilia A/HA) or factor IX (Haemophilia B/HB), leading to prolonged & excessive bleeding, either spontaneously or secondary to trauma or after surgery. The core issue in Haemophilia is a lack of or a malfunctioning of specific proteins called clotting factors, which are essential for the blood to clot properly.
Bleeding episodes usually occur in muscles and joints (causing disabilities), serious bleeding episodes (deep internal bleeding) involving deep muscles (Compartment Syndrome), joints & GIT. Life threatening bleeding episodes like intracranial hemorrhage (bleeding in the brain) a leading cause of death, retropharyngeal bleeding (bleeding in the throat can obstruct the airways; iliopsoas muscle bleeding (Haematoma) can lead to hypovolemic shock and haemorrhage.
World Haemophilia Day: Is observed every year on April 17th. This year’s theme (WFH) is “Access for All: Women and Girls bleed too” – a significant step in addressing the often-overlooked needs of Women and Girls with bleeding disorders (WGBDs). Despite advancements in Haemophilia treatment and care WGBDs continue to face challenges in diagnosis, treatment and overall quality of life.
Types of Haemophilia : (a) Haemophilia A (Factor VIII/F8 deficiency) – most common type (1 in 5000 male live births). X Linked. (b) Haemophilia B (Factor IX/F9 deficiency) also known as Christmas disease – is named after 5 years old Canadian boy Stephen Christmas, the first person diagnosed with the condition in 1952. Prevalence 1 in 25000 to 30000 male births. (c) Haemophilia C (Factor XI/ F11 deficiency) is rare (1 in 1 million people), however significantly higher in Askenazi Jews. Autosomal Recessive. (d) Acquired Haemophilia : is a rare autoimmune bleeding disorder due to development of autoantibodies (inhibitors) most commonly against coagulation factor VIII (F8). In about 50% of cases an underlying condition, such as autoimmune disorder or cancer, can be identified.
X-Linked Recessive Inheritance: because the genes are on the X chromosome in Haemophilia A and B, males (XY) who have only one X chromosome are affected while females (XX) who have two X chromosomes are usually the carriers. Mutation in the F8 or F9 genes can lead to a wide range of clinical presentation, from mild to severe, depending on the specific mutations & the level of clotting factors activity.
Age at Diagnosis : is 36 months with mild Haemophilia (Factor level 6% to 40%), some cases may not be apparent until adulthood ; 8 months for moderate Haemophilia (factor level 1% to 5% ; 1 month for those with severe Haemophilia (factor level < 1%). Some studies show a median age at diagnosis of around 5 to 8 months in severe cases. Normal Clotting Factor Levels : Factor VIII & IX: 50% to 150% ; Factor 11:70-120% ; Factor V, Factor VII & Factor X : 70-150% .
Burden of Haemophilia in India : according to the Haemophilia and health collective of north (HHCN) which is a national level organisation, India has the second largest population of Haemophilia cases in the world, with an estimated 1,36,000 cases affected by Haemophilia A (18 April 2024). However, only around 21,000 are registered at present. Nearly 80% Haemophilia cases are undiagnosed in India as several hospitals and medical institutions lack screening capabilities for blood clotting, affecting the diagnosis of new cases. In Jammu & Kashmir (UT) the No. of Patients of Haemophilia A, B & other coagulation bleeding disorders that are registered in GMC/ SMGS hospital, Jammu and GMC Srinagar are 176 & 440 respectively. India is the first country to classify Haemophilia patients as disabled under the rights of persons with disability act in 2016.
Treatment Options Available: (1) Factor replacement therapy – involves replacing the missing clotting factor (Plasma derived / recombinant, SHL/ EHL factor VIII for Haemophilia A and factor IX for Haemophilia B through infusions (injections into a vein). (2) Prophylactic care: regular infusions of factors especially with severe Haemophilia. (3) Episodic care – infusions of factors during episodes of bleeding. (4) By passing agents when inhibitors develop: Novoseven (recombinant) & APCC (Plasma derived) (5) Non-Factor products in Haemophilia A (Emicizumab). (6) Haemostatic rebalancing agents for Haemophilia A & B. (7) Physiotherapy along with factor replacement.
Era of Gene Therapy : Haemophilia is entering an era of gene therapy, offering the potential for long term, potentially curative treatment by introducing a functional gene into liver cells, enabling the body to produce its own clotting factors, reducing the need for frequent factor replacement injections. It is a promising new treatment option that involves providing patients with a healthy copy of the defective gene
How it Works : A genetically modified adeno-associated virus (AAV ; single stranded DNA virus) vector is used to deliver the functional gene to the liver. The AAV vector is engineered to deliver either the FVIII or FIX gene. The liver cells then produce the missing clotting factor, which is secreted into the bloodstream, preventing or reducing bleeding episodes.
Benefits of Gene Therapy (a) reduced treatment burden: Gene therapy can significantly reduce the need for regular factor replacement injections, improving quality of life. (b) Potential for a cure: By correcting the underlying genetic defect, gene therapy offers the potential for a long-term, potentially curative treatment. (c) Improved bleeding control: By increasing endogenous clotting factor levels, gene therapy can help prevent or reduce bleeding episodes.
Current Status : gene therapy for Haemophilia B in adults has been approved for use in USA, Germany, Italy & across the NHS in England by relevant regulatory authorities. HEMGENIX is an FDA-approved gene therapy for the treatment of adults with Haemophilia B. ROCTAVIAN (Valoctocogene roxaparvovec)- is an FDA approved gene therapy for treatments of adults with severe Haemophilia A specifically those without pre-existing antibodies to AAV5 vector as detected by an FDA approved test. Liver toxicity and immunogenicity are key concerns, requiring careful monitoring and management.
Current Status of Gene Therapy in India: India has made a significant breakthrough in treating severe Haemophilia A with a first-in-human gene therapy trial at Christian Medical College (CMC), Vellore, resulting in zero bleeding episodes in five patients over an extended period. This trial, using a lentiviral vector, offers a promising, potentially durable, and cost-effective alternative to current treatments.
The Breakthrough : Indian scientists, supported by the Department of Biotechnology, have successfully developed and tested a lentiviral vector-based gene therapy for severe Haemophilia A. The Department of biotechnology is under the union ministry of science and technology which is under Hon’ble Minister of State in PMO office Dr. Jitendra Singh Rana who is an eminent physician(Prof. of Medicine), diabetologist and an author. He is constantly monitoring the developments of gene therapy clinical trials in India
The Trial : A first-in-human clinical trial conducted by Centre for Stem Cell Research (CSCR) at CMC, Vellore, under Dr. Alok Srivastav, involving five patients, showed a zero bleeding rate over an extended period, with the production of Factor VIII for a prolonged time demonstrating the potential of this gene therapy to eliminate the need for frequent factor VIII replacement therapy in Haemophilia A patients. The centre is now planning to conduct further clinical trials to assess long-term efficacy and the safety of this gene therapy. The lentiviral (RNA virus) vector used in the trial is considered safer and potentially suitable for children, offering new possibilities for gene therapy in resource-constrained settings. Cost-Effectiveness: local manufacturing of the vector could significantly reduce costs and make the treatment more accessible. Currently the traditional treatment cost in India vary widely, ranging from approximately INR 1,95,000.00 to INR 5,52,500 per year depending on severity of the condition and specific treatment regimen. A 2024 study estimated the 10 year per patient cost for severe Haemophilia A to be around Rs. 2.54 crore. High cost of gene therapy remains a barrier to access for many. In USA the cost of gene therapy for Haemophilia B is Rs. 28.52 crore (USD 3.5 mn) & for Haemophilia A Rs. 25.12 crore (USD 2.9 mn per treatment).The cost of gene therapy for Haemophilia in India is estimated to be around Rs. 2.54 crore per patient over a ten-year period. The cost is expected to come down by the time it is approved for use in India.
Future Direction in gene therapy for Hemophilia : The focus is on enhancing efficacy, durability, and safety, including exploring novel vectors, optimising gene delivery and addressing immune responses with the ultimate goal of achieving a functional cure through one time treatment. Other advances in Haemophilia include gene editing therapy / Technology (CRISPR-Cas9) & Cell therapy.
Dr. Kuldeep Kr Koul is a President HHCN & Former Prof. & Head PG Dept. of Pathology, GMC Jammu
