Hemophilia
Overview
Hemophilia (혈우병) is an X-linked recessive genetic disorder caused by a congenital shortage or deficiency of clotting factor proteins required for blood coagulation. It mainly manifests in males and is characterized by bleeding that does not stop after minor trauma or by spontaneous bleeding into joints and muscles. With appropriate prophylactic replacement therapy and recent advances in gene therapy, patients' quality of life and prognosis are greatly improving.
Main Content
Causes and Inheritance Pattern
The cause of hemophilia is a mutation in the gene for clotting factor VIII (FVIII) or factor IX (FIX). Both genes are located on the long arm of the X chromosome (Xq28, Xq27), so it is inherited in an X-linked recessive manner. Because males have only one X chromosome, a single mutated gene causes the disease, whereas females are mostly carriers. However, about 30% of patients arise from de novo mutations without family history. Female carriers can rarely show mild bleeding symptoms.
Types
- Hemophilia A: FVIII deficiency. It accounts for about 80–85% of all hemophilia and is the most common.
- Hemophilia B (Christmas disease): FIX deficiency. It accounts for about 15–20%.
- Hemophilia C: factor XI (FXI) deficiency. It has an autosomal inheritance pattern, unlike the others, and is often mild.
- Acquired hemophilia: a rare condition caused by autoantibodies inhibiting clotting factors; unlike congenital hemophilia, it is not inherited.
Severity is classified by plasma clotting factor activity. Less than 1% is severe, 1–5% is moderate, and 5–40% is mild.
Symptoms
The main symptom is a bleeding tendency. In infancy, bleeding at vaccination sites or into joints such as knees, ankles, and elbows (hemarthrosis) is common. Repeated joint bleeding destroys cartilage and synovium, causing hemophilic arthropathy and leading to chronic pain and joint deformity. Other manifestations include intramuscular bleeding, intracranial hemorrhage, hematuria, gum and nose bleeding, and delayed postoperative bleeding. In particular, intracranial hemorrhage and laryngeal and cervical bleeding are life-threatening emergencies, so clotting factor must be administered immediately.
Diagnosis
Diagnosis is made by combining family history, bleeding history, and blood coagulation test results. In hemophilia, activated partial thromboplastin time (aPTT) is prolonged, while prothrombin time (PT) remains normal. Measurement of clotting factor activity confirms the type and severity, and genetic testing identifies the exact mutation. In the neonatal period, early diagnosis is possible through umbilical cord blood testing or genetic testing; because hemophilia A and B have similar clinical features, factor activity testing is essential to distinguish them.
Treatment
The core treatment is replacement therapy that intravenously supplements the deficient clotting factor. There is 'on-demand' therapy, administered immediately when bleeding occurs, and 'prophylaxis,' administered regularly to prevent bleeding itself. In severe patients, prophylactic therapy is recommended as the standard to prevent joint damage.
Major therapeutic agents include plasma-derived and recombinant clotting factor products, and recently extended half-life products have come into wide use. In the 2020s, subcutaneously administered bispecific antibodies (such as emicizumab) emerged, greatly improving convenience of administration. Desmopressin (DDAVP) is used in mild hemophilia A to promote release of endogenous factor, and antifibrinolytic agents (tranexamic acid) are used adjunctively for mucosal bleeding.
The most serious treatment complication is the development of 'inhibitors.' The immune system recognizes the administered clotting factor as foreign and produces neutralizing antibodies; this occurs in about 25–30% of severe hemophilia A patients. In such cases, bypassing agents or immune tolerance induction (ITI) are needed.
Prevention and Management
Vigorous contact sports should be avoided, and safe exercises such as swimming and cycling are recommended. Regular dental and orthopedic care is necessary, and vaccinations should be given subcutaneously rather than intramuscularly. Education of patients and caregivers, self-infusion training for emergencies, genetic counseling, and psychosocial support are important. Bleeding diaries and national patient registries are used to optimize treatment and establish policy.
Recent Trends
Since 2022, gene therapy has been changing the treatment paradigm for hemophilia. The hemophilia B gene therapy Hemgenix (헴제닉스) received U.S. FDA approval in 2022, Roctavian (로크타비안) was approved for hemophilia A, and in 2024 Pfizer's Beqvez (베크베즈) received FDA approval. These therapies use AAV vectors to induce hepatocytes to produce clotting factor themselves, aiming to maintain factor levels for years with a single administration.
In 2024–2025, extended half-life products and subcutaneously administered bispecific antibodies (emicizumab, concizumab, etc.) became mainstream in prophylaxis. Next-generation gene therapy candidates that greatly reduce bleeding with once- or twice-yearly administration are competing, announcing phase 3 results. In Korea, discussions are underway on introducing gene therapy and expanding reimbursement, and long-term safety, cost-effectiveness, and management of liver toxicity have emerged as major issues. In addition, the World Health Organization (WHO) and the World Federation of Hemophilia (WFH) emphasize closing the treatment access gap in low-income countries as a key task.
Related Topics
- [[Hemophilia A]]
- [[von Willebrand disease]]
- [[Clotting factor]]
- [[Gene therapy]]
- [[X-linked recessive inheritance]]