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  • Writer's pictureThe Rare360 Editorial Team

Understanding Hemophilia: Symptoms, Diagnosis, and Treatment Options

Updated: Jan 16

A person injeccting syringe to collect blood sample

Basis of Hemophilia: Genetic Origins and Blood Clotting Factors

Hemophilia is a rare inherited bleeding disorder in which the blood does not clot properly due to insufficient blood-clotting proteins known as clotting factors. Blood contains many proteins called clotting factors that can help to stop bleeding. People with hemophilia have low levels of either factor VIII (8), IX (9) or factor XI (11). The severity of hemophilia in a person is determined by the specific clotting factor's level in their bloodstream. As the level of the factor decreases, the risk of bleeding incidents rises, potentially leading to serious health complications.


If you have hemophilia, you might experience spontaneous bleeding or prolonged bleeding after an injury or surgery, as compared to individuals with normal blood clotting. Minor cuts generally do not pose a significant issue. The major concern revolves around internal bleeding within the body, especially in sensitive areas like the knees, ankles, and elbows. Such internal bleeding can cause damage to organs and tissues and even pose life-threatening risks.


The root cause of all hemophilia types lies in genetic mutations that influence the development of clotting factors. These specific genes responsible for clotting factor regulation are located on the X chromosome. Consequently, hemophilia is classified as an X-linked recessive disease, increasing the likelihood of its occurrence in males.


Key Statistics and Advancements in Hemophilia

According to a recent study on hemophilia occurrence in the United States, as published on the CDC website, the following key statistics shed light on the prevalence of hemophilia:

  • The current number of males with hemophilia living in the United States is estimated to be between 30,000 and 33,000.

  • The estimated prevalence of hemophilia in the United States is 12 cases per 100,000 U.S. males for hemophilia A and 3.7 cases per 100,000 U.S. males for hemophilia B.

  • The estimated incidence of hemophilia among U.S. births is 1 birth per 5,617 male births for hemophilia A and 1 birth per 19,283 male births for hemophilia B.

  • Among all males with hemophilia, just over 4 in 10 have the severe form of the disorder.


Advancements in hemophilia treatment, particularly clotting factor infusions, have significantly improved life expectancy. Proper treatment has brought life expectancies of people with hemophilia close to those of the general population. Individuals with non-severe hemophilia have a roughly 19% higher all-cause death rate compared to those without hemophilia. With consistent treatment, individuals with hemophilia are closing the life expectancy gap, with a difference of only about 10 years compared to individuals without hemophilia.


Exploring the Types of Hemophilia

Hemophilia manifests in several types, with the most prevalent being Hemophilia A and Hemophilia B. There are also rare forms such as Hemophilia C and Acquired Hemophilia. These different types are classified based on the levels of clotting factors in the blood, resulting in the following categories:

  • Mild: Approximately 25% of cases fall under the mild category, where individuals have factor levels in the range of 6–30%.

  • Moderate: Around 15% of cases are classified as moderate, characterized by factor levels between 1–5%.

  • Severe: The majority, approximately 60% of cases, are severe, with individuals having factor levels of less than 1%.


Let’s understand the different types of hemophilia:

  • Hemophilia A: Also known as “classic hemophilia,” it is caused by the deficiency of clotting factor VIII, a protein critical to healthy clotting. The condition results from an inherited mutation of the F8 gene, located on the X chromosome. the mutation in the F8 gene leads to reduced production of clotting factor VIII, resulting in bleeding episodes, particularly in muscles and joints. Hemophilia A can range from mild to severe, depending on the extent of factor VIII deficiency.

  • Hemophilia B: Hemophilia B, sometimes referred to as Christmas disease in honor of Stephen Christmas, who was the subject of the first medical report on the condition in 1952, is characterized by a deficiency in clotting factor IX (FIX). It is an inherited form of hemophilia caused by an F9 gene mutation on the X chromosome. Hemophilia B can cause bleeding in muscles and joints, similar to Hemophilia A, but it is four times less common than hemophilia A.

  • Hemophilia C: This is a mild form of the disease which is caused by a deficiency of factor XI. It is also known as Rosenthal syndrome or factor XI deficiency. Factor XI plays a vital role in initiating a critical chain of events by aiding in the formation of thrombin, a protein that converts fibrinogen into fibrin. Fibrin, in turn, binds platelets together to form blood clots. Unlike Hemophilia A and B, the mutation responsible for Hemophilia C is located on a different chromosome and is not sex-linked and affects both males and females equally.

  • Acquired Hemophilia: This is a rare but potentially serious bleeding disorder that occurs when the body’s immune system starts attacking one of its own clotting factors (usually factor VIII) for no apparent reason. This can lead to severe and sometimes life-threatening bleeding complications. Acquired hemophilia may be associated with various factors, including pregnancy, autoimmune conditions like lupus, cancer, multiple sclerosis, and interactions with certain medications.

Recognizing Signs Across Age Groups

Hemophilia manifests in various ways, with the primary symptom being abnormal or excessive bleeding and bruising. The severity of these symptoms is often determined by the type and degree of hemophilia:

  • Prominent Bruises: Individuals with hemophilia may develop significant bruises, even from minor incidents, as a result of bleeding beneath the skin's surface.

  • Prolonged Bleeding: Hemophilia can lead to extended bleeding following surgeries, dental work, or minor cuts, surpassing the typical bleeding duration.

  • Spontaneous Bleeding: In severe cases, spontaneous bleeding episodes can occur without any apparent cause, such as unexpected nosebleeds.


The intensity of bleeding and bruising typically corresponds to the severity of hemophilia:

  • Severe Hemophilia: Those with severe hemophilia often experience spontaneous or unexplained bleeding.

  • Moderate Hemophilia: Individuals with moderate hemophilia may encounter prolonged bleeding following serious injuries.

  • Mild Hemophilia: Mild cases might result in unusual bleeding, primarily after significant surgical procedures or injuries.


Other Symptoms

  • Internal bleeding can trigger joint pain, most commonly affecting the ankles, knees, hips, and shoulders. These joints may become swollen, feel warm to the touch, or cause discomfort.

  • Although rare, severe cases of hemophilia can lead to life-threatening brain bleeds. Symptoms may include persistent headaches, double vision, or excessive drowsiness, necessitating immediate medical attention.


Hemophilia Symptoms in Infants and Children

Diagnosing hemophilia in babies and young children can be distinct, with unique signs to watch for:

  • Excessive Bleeding: Male infants may exhibit excessive bleeding after circumcision, providing an early indicator of hemophilia.

  • Swelling and Head Lumps: After minor head injuries, babies and toddlers might develop noticeable lumps on their heads, resembling goose eggs.

  • Irritability and Reluctance to Move: Internal bleeding in muscles or joints can lead to irritability, reluctance to crawl or walk, and visible signs of bruising and swelling in infants and toddlers.

  • Hematomas: Hematomas, characterized by masses of congealed blood under the skin, may develop in babies and toddlers, especially following injections.

  • These symptoms serve as crucial markers for the identification of hemophilia in infants and children, facilitating early intervention and appropriate management.


Navigating the Diagnostic Journey for Hemophilia

When it comes to diagnosing hemophilia, several crucial steps are involved to ensure a comprehensive understanding of the condition:

  • Family History Assessment: The diagnostic process often commences with a thorough evaluation of the patient's family history. This step aims to identify any instances of bleeding disorders within the family. Discussion might encompass instances of bleeding following surgery or injury and any unexplained deaths among brothers, sisters, or other male relatives, like, grandfathers, maternal uncles, or cousins. This helps healthcare professionals determine if hemophilia may be a contributing factor.

  • Observation of Symptoms: In cases where hemophilia is not diagnosed during the newborn period, families may begin noticing unusual bruising when the child reaches the standing or crawling stage. Individuals with severe hemophilia often experience significant bleeding issues early in life, often leading to diagnosis within the first year. On the other hand, those with milder forms of hemophilia may not receive a diagnosis until later in life.

  • Clotting Factor Tests: Clotting factor tests, also referred to as factor assays, measure the activity of clotting factor proteins present in the blood. Since different forms of hemophilia arise from insufficiencies in specific clotting factors, these tests serve as the primary means to definitively diagnose the exact type of hemophilia. The results from clotting factor tests are typically expressed as a percentage of normal activity. In theory, an individual without hemophilia would exhibit approximately 100% normal clotting factor activity. However, it's important to note that clotting factor activity can naturally vary from person to person, and activity levels ranging between 50% and 150% are generally considered to be within the normal range. Hemophilia is typically diagnosed when clotting factor activity falls below 40% of the normal range.

  • Screening Tests: Screening tests offer a general assessment of overall blood health and clotting function. While they are not intended for the definitive diagnosis of hemophilia, they can be valuable in confirming the presence of a blood clotting disorder and ruling out non-hemophilia-related conditions that can lead to similar clotting issues.

Screening Test

Purpose of test

Complete Blood Count (CBC)

To measures the size and number of oxygen-carrying red blood cells in the bloodstream. A CBC also assesses the amount of hemoglobin, the number of infection-fighting white blood cells and platelets, which are cell fragments that play a key role in blood clotting.

Activated Partial Thromboplastin Time (APTT)

To assess how well certain clotting proteins — specifically FVIII, FIX, FXI, and FXII — are working by measuring how long it takes for a clot to form in a blood sample.

Prothrombin Time Test (PTT)

​To measure the activity of several clotting proteins, specifically FI, FII, FV, FVII, and FX.

Fibrinogen test

To measure the amount of fibrinogen in the blood and/or how well this protein is helping to form clots.


It’s important to note that these tests must be ordered by a healthcare provider based on your symptoms and medical history.


Hemophilia Treatment Approaches: A Comprehensive Overview

The treatment options for hemophilia aim to prevent and manage bleeding episodes. These options may include:

  • Replacement Therapy This is the main treatment for severe hemophilia, which involves replacing the missing clotting factor through a vein. This therapy can be given to treat a bleeding episode in progress or on a regular schedule to help prevent bleeding episodes.

    • Factor Replacement: The primary treatment for hemophilia involves infusing the missing or deficient clotting factor. Hemophilia A is treated with factor VIII replacement, while hemophilia B is treated with factor IX replacement.

    • Prophylactic Treatment: Some individuals receive regular, scheduled infusions of clotting factor concentrates to prevent bleeding episodes.

  • On-Demand Treatment: Infusions of clotting factor concentrates are administered when bleeding occurs. This approach is often used for mild cases or when prophylactic treatment is not feasible.

  • Bypassing Agents: For individuals with inhibitors (antibodies) against clotting factors, bypassing agents like activated prothrombin complex concentrate (aPCC) or recombinant factor VIIa can help promote clot formation.

  • Nonfactor Replacement Therapies: A new class of therapeutic agents that act by enhancing coagulation (emicizumab) and inhibiting anticoagulant pathways (fitusiran and concizumab) have been established, and clinical trials using these nonfactor products are ongoing.

  • Gene Therapy: Experimental gene therapy is being explored as a potential long-term treatment to address the genetic cause of hemophilia by introducing functional clotting factor genes. After 3 decades of clinical trials, repeated proof-of-concept success has now been demonstrated in hemophilia A and B gene therapy. Current clinical hemophilia gene therapy efforts are largely focused on the use of systemically administered recombinant adeno-associated viral (rAAV) vectors for F8 or F9 gene addition.

    • HEMGENIX is an FDA-approved gene therapy for the treatment of adults with hemophilia B (congenital Factor IX deficiency).

    • ROCTAVIAN is an FDA-approved gene therapy for the treatment of adults with severe hemophilia A (congenital factor VIII deficiency).

  • Desmopressin (DDAVP): This medication is used for some individuals with mild hemophilia A to stimulate the release of stored factor VIII.

  • Physical Therapy: Physical therapy can help manage joint pain and improve joint function, which is crucial in preventing joint damage from recurrent bleeding.

  • Pain Management: Pain relief medications may be prescribed to manage discomfort associated with bleeding and joint pain.

  • Surgical Interventions: In some cases, surgical procedures may be required to address complications from joint damage or internal bleeding.

  • Complications Management: Comprehensive care may involve managing complications related to hemophilia, such as infections resulting from treatment, hepatitis, or HIV.

  • Emotional and Psychological Support: Hemophilia can have a significant impact on a person's emotional well-being. Counseling and support groups can help individuals and their families cope with the challenges of living with a chronic condition.

  • Lifestyle and Home Remedies: Regular exercise such as swimming, bicycle riding and walking can build muscles while protecting joints. Avoiding certain pain medications that can make bleeding worse such as aspirin and ibuprofen (Advil, Motrin IB, others) is also recommended.


Treatment plans are individualized based on the type and severity of hemophilia, the presence of inhibitors, and the patient's overall health. Regular follow-up with a healthcare team, including hematologists and specialized hemophilia treatment centers, is essential to ensure appropriate and effective care.


Conclusion

In conclusion, understanding hemophilia is vital for both patients and their caregivers. Hemophilia is a rare inherited bleeding disorder characterized by insufficient blood-clotting proteins, known as clotting factors. These factors are essential for the formation of blood clots, and their deficiency can lead to prolonged bleeding, even from minor injuries. Hemophilia comes in various types, with Hemophilia A and Hemophilia B being the most common, while Hemophilia C and Acquired Hemophilia are rarer forms. The severity of hemophilia depends on the levels of specific clotting factors in the blood, ranging from mild to severe.


The prevalence of hemophilia varies, with an estimated 30,000 to 33,000 affected males in the United States. Advances in treatment, primarily through clotting factor infusions, have significantly improved life expectancy for individuals with hemophilia, bringing it close to that of the general population. Treatment options include replacement therapy, on-demand treatment, bypassing agents, gene therapy, and nonfactor replacement therapies.


Understanding the diagnostic journey is also crucial, as early diagnosis and intervention are essential for effectively managing hemophilia. The diagnostic process involves assessing family history, observing symptoms, and conducting clotting factor and screening tests. Early identification can lead to more effective management and improved quality of life.



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