Hemophilia

What is Hemophilia?

Hemophilia is a common inherited bleeding disorder, often leading to severe bleeding. It gets its name from the Greek words for ‘love of blood’. Hemophilia A and B are both caused by a lack or improper function of clotting factors VIII and IX, respectively. These cause longer-than-normal and excessive bleeding following minor injuries or sometimes even for no apparent reason. Hemophilia C, triggered by a deficiency in clotting factor XI, is less common. There is also a condition known as acquired hemophilia, which can occur due to aging or after childbirth, but this usually improves with appropriate treatment.

Hemophilia is often referred to as ‘the disease of the kings’ because it has been seen in the lineage of Queen Victoria of England. The disorder was first mentioned in the Babylonian Talmud in the second century AD, where it was noted a woman lost her first two sons to bleeding following circumcision.

The earliest modern mention of hemophilia was by American doctor, Dr. John Conrad Otto. He identified the disease as inheritable in families and found it only affected males born to unaffected mothers. He dubbed these males ‘the bleeders’. The term ‘hemophilia’ was first penned by Johann Lukas Schönlein in his University of Zurich dissertation.

Dr. Nasse was the first to provide a genetic description of hemophilia, introducing Nasse’s Law. This law specifies that hemophilia is passed down exclusively from unaffected mothers to their sons.

What Causes Hemophilia?

Hemophilia is usually a condition you are born with and it’s caused by a lack of clotting factors in the blood, which are proteins that help stop bleeding. Most of the time, it’s because there’s something wrong or changed in the gene responsible for these clotting factors.

Researchers have found over a thousand changes in the genes responsible for clotting factors VIII and IX. About 30% of these genetic changes happen on their own and not through inheritance. The genes for these clotting factors are located on the X chromosome.

Hemophilia A and B are inherited through a pattern linked to the X chromosome. This means that all the daughters of men who have hemophilia will carry the disease, but their sons won’t be affected. On the other hand, women who carry the disease have a 50% chance of having sons with hemophilia and a 50% chance of having daughters who carry the disease.

Girls can also get hemophilia if there’s a total inactivation of the X chromosome, if they are missing all or part of the X chromosome, like in Turner Syndrome, or if both parents carry the changed gene.

Risk Factors and Frequency for Hemophilia

Hemophilia is a condition that affects people of all ethnicities equally across the globe. It’s estimated that approximately 1 in 10,000 babies born will have hemophilia, with about 400,000 people currently living with the condition worldwide. Two types of hemophilia exist: A and B. Hemophilia A is more common, affecting about 80-85% of the global hemophilia population. It occurs in 1 out of every 5,000 male babies born. Hemophilia B is less common and occurs in 1 out of every 30,000 male babies born. Hemophilia is linked to the X chromosome, meaning areas with high rates of marriages between relatives, like Egypt, may have higher incidences of the disease. Hemophilia C is rarer, affecting 1 in 100,000 people. However, Ashkenazi Jews are more prone to a deficiency in Factor XI, a vital clotting factor, with a prevalence rate of about 8%. Despite these facts, advances in early diagnosis and treatment now allow those affected by hemophilia to expect a normal lifespan.

• Hemophilia affects people of all ethnicities equally.
• Hemophilia affects roughly 1 in 10,000 babies at birth globally.
• Currently, there are approximately 400,000 people worldwide living with hemophilia.
• Hemophilia A is the most widespread, affecting 80-85% of those with hemophilia. It occurs in 1 out of every 5,000 male babies born.
• Hemophilia B is less common and occurs in 1 out of 30,000 male babies born.
• Relative marriages, as commonly found in Egypt, can increase the prevalence of hemophilia due to its X-linked inheritance pattern.
• Hemophilia C, although less common, occurs in 1 out of 100,000 people. This is more prevalent among the Ashkenazi Jews, with a rate of about 8% due to a deficiency in clotting Factor XI.
• Thanks to medical advances, those with hemophilia can now expect to live a normal lifespan with early diagnosis and proper treatment.

Signs and Symptoms of Hemophilia

Hemophilia is a condition that leads to excessive bleeding after minor injuries, or may even cause unexplained bleeding. It is generally assessed based on how much clotting factor, necessary for blood clot formation, is present in the blood. The severity of the condition often corresponds with the frequency and intensity of bleeding.

• Hemophilia with 5-40% normal clotting factor activity (mild): Unusual bleeding may occur after significant accidents or surgery, but spontaneous bleeding is rare. It is often diagnosed unintentionally or through pre-surgical labs.
• Hemophilia with 1-5% normal clotting factor activity (moderate): Bleeding is usually triggered by trauma, injury, dental procedures, or surgeries, with a possibility of recurring joint bleeding in up to 25% cases. Diagnosis typically gets delayed.
• Hemophilia with less than 1% normal clotting factor activity (severe): Spontaneous bleeding can happen quite often. Symptoms often emerge in the first few months of life.

People with severe hemophilia can experience internal bleeding affecting various body organs. The common areas affected by bleeding include the knees, elbows, ankles, shoulders, wrists, and hips. This may lead to symptoms such as pain, swelling, warmth, and limited motion in the affected joints. Repeated episodes of bleeding into the joints can result in long-term joint damage.

Other possible complications include brain bleeds which can manifest with symptoms such as falls, confusion, fatigue, and in serious cases, coma. Spontaneous or trauma-induced bleeding in the abdominal area may cause symptoms like abdominal pain, distension, bloody stools or vomit, and tenderness in the area over the kidneys or bladder. Similar types of bleeding can occur in the chest or spine, causing symptoms like chest pain, breathlessness, back pain, numbness, or weakness. Bleeding in the eyes could lead to visual changes. Increase in heart rate, breathing rate, or a drop in blood pressure signal more serious bleeds.

Bleeding in the brain, belly, chest, and throat can be quite dangerous. Abnormal bruising or bleeding after vaccination are also common. Sometimes, excessive bleeding or bruising can be mistaken for child abuse. Joint and muscle bleeding is a common symptom in severe cases. Intracranial bleeding remains the leading cause of death among patients with Hemophilia.

Testing for Hemophilia

Hemophilia is typically diagnosed based on family history, signs of abnormal bleeding, and lab testing. Certain blood tests are necessary for families who are known carriers of hemophilia or have a history of excessive bleeding. Genetic tests during pregnancy, such as chorionic villous sampling or amniocentesis, are often reserved for families with a history of hemophilia. It’s important to clue in on issues such as prolonged bleeding after events like circumcision or blood draw as these may be indicators of hemophilia.

Right after birth, the baby’s blood can be tested for clotting factors to check for hemophilia, especially if there’s a strong family history. It’s important to remember that the clotting factor IX levels can be naturally low at birth and doesn’t necessarily point towards hemophilia.

As the child grows up, blood tests like complete blood count, prothrombin time, partial thromboplastin time, and bleeding time are still essential. People with hemophilia will show prolonged partial thromboplastin time as the clotting process gets disrupted. This prolonged time is confirmed using a mixing study, and if confirmed, it should be followed by a factor VIII and IX assay.

One important aspect of dealing with hemophilia is checking for factor VIII inhibitors. Some patients with hemophilia develop antibodies against factor VIII, which makes factor VIII infusions ineffective. These inhibitors are measured using quantitative inhibitor assays.

Another factor to consider is Von Willebrand disease which is also a bleeding disorder, but unlike hemophilia, it arises due to a deficiency in Von Willebrand factor, and it primarily causes bleeding from the skin and mucous membranes. Moreover, its symptoms are more common in both males and females.

Healthcare providers must be vigilant in spotting signs of internal bleeding in patients with hemophilia. Quick test ordering is necessary to rule out life-threatening situations, such as brain or abdominal bleeding. Brain bleeds can be especially tricky in babies and young children who cannot explain their symptoms. Similarly, adults with hemophilia might face cognitive issues due to ongoing, silent brain microbleeds, and detecting these requires brain imaging. Joint, abdominal or chest bleeds can also be assessed using ultrasound, CT scan or MRI.

Treatment Options for Hemophilia

Treatment options for hemophilia are primarily divided into two categories: managing sudden episodes of bleeding and prevention.

The key to managing a sudden, acute bleeding episode in someone with hemophilia is to stop the bleeding as quickly as possible, preferably within two hours of the symptoms starting. Treatments should not be delayed, even if the results from diagnostic tests are not ready or if there are no physical symptoms. Hemophilia patients who experience severe bleeding episodes usually need hospitalization and should be treated following the World Federation of Hemophilia’s guidelines. The treatment involves promptly replacing the missing clotting factor with a high dose of clotting factor concentrate. In severe cases, clotting factor concentrate needs to be given first or simultaneously with any planned surgery.

Aside from treating acute bleedings, another element of treatment in hemophilia is prevention, known as prophylaxis. The benefits of prophylaxis include reducing the frequency and severity of bleeding episodes, lowering the need for hospitalizations, and improving the patients’ quality of life. The World Federation of Hemophilia offers detailed guidelines for prophylaxis, categorizing it as primary, secondary, continuous, or intermittent.

Most hemophilia treatments are based on replacing the missing clotting factor called factor VIII or IX. These factors are infused into the patient’s bloodstream. The frequency and schedule of factor infusions can vary, and are tailored to each patient’s individual needs.

In addition to the traditional clotting factors derived from plasma, recombinant factor VIII is also available. First introduced in the 1990s, recombinant factor VIII, produced using gene cloning techniques, has provided a safer and more effective treatment option for hemophilia.

Other options for hemophilia treatment include desmopressin and antifibrinolytic medications like tranexamic acid and epsilon aminocaproic acid. Desmopressin is a synthetic medication that can increase clotting factor levels, while antifibrinolytic medications promote the stability of clots.

Gene therapy and monoclonal antibodies, such as emicizumab and concizumab, represent recent advancements in hemophilia treatment.

Joint bleeding is a common complication of hemophilia. Management of joint bleeds involves a comprehensive strategy that includes prevention, on-demand factor infusion, pain management, and sometimes surgery. Apart from treatment, another important aspect of managing hemophilia is physical activity. Regular physical activity helps in overall fitness and helps prevent joint and muscle bleeds.

Despite better life expectancy and improved treatment options, the costs related to hemophilia treatment are significant. In the US, the average annual treatment cost is about $150,000 to $300,000, while in Europe, it ranges from 77,000 euros to 112,000 euros. Hemophilia can significantly impact patients and their caregivers’ quality of life, so it’s crucial to educate patients about their condition and treatment compliance.

What else can Hemophilia be?

When a person experiences bleeding after a minor injury or unexplained bouts of bleeding, it could be a sign of hemophilia. However, it’s important to point out that many other conditions can cause similar symptoms. These may include von Willebrand disease, scurvy (a vitamin C deficiency), diseases that affect blood platelet function, an absence or shortage of certain blood clotting factors, Ehlers-Danlos syndrome, Fabry disease, or a critical condition known as disseminated intravascular coagulation. Even instances of child abuse could be mistakenly identified as hemophilia.

It’s important to run the necessary tests to rule out these other conditions before confirming a diagnosis of hemophilia. In von Willebrand disease, patients typically bleed more from mucous membranes, which line the inside of the body’s passageways, compared to the musculoskeletal bleeding (from the muscles or bones) seen in hemophilia. Scurvy, Ehlers-Danlos syndrome, and Fabry disease also mainly result in bleeding from mucous membranes.

A diagnosis of Ehlers-Danlos syndrome, a condition that causes overly flexible joints and stretchy skin, is generally made through examining the patient’s symptoms, genetic testing, and tissue biopsy. In Fabry disease, patients may have problems with their kidneys and heart, as well as skin lesions and pain in their extremities. This condition is also usually diagnosed through observing clinical symptoms and genetic testing.

In conditions where platelets, blood cells essential for clotting, do not function properly, the bleeding is typically from mucous membranes rather than from muscles or bones. Diagnosis of such platelet dysfunction disorders is often done by studying how platelets group together or through electron microscopic examination of platelets.

Sometimes, people with certain clotting factor deficiencies may also suffer from thrombosis, the formation of harmful blood clots, especially in patients deficient in factor VII or fibrinogen, or those with combined factor V and VIII deficiency. A diagnosis of such clotting factor deficiencies is usually confirmed with specific tests that measure the levels of various clotting factors.

In cases of disseminated intravascular coagulation (DIC), a condition that mimics hemophilia, the diagnosis can sometimes prove difficult. However, DIC usually accompanies another medical condition such as leukemia. In suspected cases of child abuse, any discrepancies in the history of injuries should be sought out. Other signs like malnutrition or fractures of various ages showing on X-rays may also indicate child abuse.

What to expect with Hemophilia

In the 1950s and 60s, those with severe hemophilia had a life expectancy of just 11 years. This was mainly because of serious internal bleeding, often inside the skull or crucial organs, which would often lead to death in childhood or adolescence.

In 1964, Judith Pool made a major breakthrough in treating hemophilia. She discovered cryoprecipitate in plasma, which contains large amounts of factor VIII concentrate – an essential component for blood clotting. This discovery greatly improved hemophilia treatment because, before this, patients could only be treated with whole blood or fresh plasma, which did not contain enough factor VIII or IX proteins. These proteins are needed to help blood clot and prevent major bleeding.

In the 1970s, another significant improvement was made with the introduction of powdered blood clotting factors. Additionally, a new treatment was introduced in Sweden which helped prevent major bleeding episodes and complications of joint diseases. This method of protecting against these severe outcomes was also adopted by other nations.

In 1977, researchers unveiled desmopressin. This was a safer, cheaper, and better treatment option. Importantly, it minimized the risk of bloodborne infections, a risk which was present with the repeated use of plasma-derived products.

However, in the 1980s, patients with severe hemophilia were infected with HIV and hepatitis C from contaminated blood clotting factors. This drove the development of methods for screening and removing viruses from blood, significantly improving the safety of plasma-derived products. Also, with advances in DNA technology, it became possible to industrially produce recombinant factor VIII and IX.

Thanks to these various innovations, hemophilia patients today have much better prospects. They have access to a variety of treatments for both preventing and treating active bleeding, as well as improved management of blood-borne infections. With new treatments for HIV and hepatitis C also now available, people with hemophilia can now live life more normally. In fact, in developed countries, provided they respond well to the treatment and do not have other health conditions, hemophiliacs can expect to live almost as long as people without the condition.

Unfortunately, this isn’t yet the case in developing countries. There, where access to healthcare and resources for treatment are limited, the mortality rate is still almost twice that of the general population.

Possible Complications When Diagnosed with Hemophilia

People with hemophilia, a blood disorder, often face complicated side effects from their treatment. The main one is the development of inhibitors. These are antibodies that work against factor VIII and IX, essential elements that help blood clotting. This issue makes the treatment for hemophilia less effective. If there’s repeated bleeding despite the infusions of clotting factors, it could be a sign of these inhibitors. They’re more common in people with severe hemophilia A, but can arise in any type.

It’s crucial for both children and adults with hemophilia to have regular checks for these inhibitors. For children, this involves testing at various intervals around their treatment exposures until they reach 150 total exposures, as well as before surgery or switching treatment. If the bleeding doesn’t stop after surgery, they might have these inhibitors.

There are two types of inhibitors: high responding and low responding. High responding inhibitors tend to persist and can make clotting factor infusions ineffective if the inhibitors are not treated for a long time. Low responding inhibitors are temporary and usually disappear within six months.

Immediate consultation with a healthcare provider is needed to manage bleeding in patients with inhibitors. Various treatment options include higher doses of clotting factors, other forms of factor VIII, recombinant factor VII activated, and prothrombin complex concentrates. Immune tolerance induction is also used to eradicate inhibitors. This involves daily doses of factor concentrates that could go on for years in some cases, combined with suppressive medications if needed.

Additionally, monoclonal antibodies show promise in treating patients with inhibitors. These antibodies mimic the function of activated factor VIII molecule, and are not impaired by these inhibitors.

Patients with a severe form of hemophilia often experience musculoskeletal complications because of repeated bleeding in their muscles. Up to 90% of these patients end up having chronic degenerative changes in their major joints, including ankles, knees, and elbows. There’s also a serious risk of developing pseudotumors due to under-treated bleeding, typically in muscles adjacent to bones. If not treated timely, these conditions can result in neurovascular compromise and possibly need for amputations. Treatment generally calls for long term infusion of clotting factors and careful monitoring.

Moreover, fractures can happen in patients with the degenerative changes in their joints. These are treated by elevating the clotting factor levels and managing the fracture depending on its severity and location.

Another significant challenge for people with hemophilia is the potential transmission of blood-borne infections. In the past, samples of clotting factors were contaminated with HIV and Hepatitis C, leading to increased mortality rates among these patients. However, nowadays, the risk of infection has been significantly reduced due to diligent donor selection, improved screening methods, and advanced manufacturing procedures.

While great strides have been made in hemophilia treatments, additional challenges such as non-lipid enveloped viruses and prion diseases continue to emerge. Though, the current anti-HIV medications are safe to use for patients with no contraindications. For those with Hepatitis C and hemophilia, pegylated interferon and ribavirin are the go-to treatments.