What is Congenital Hemophilia?
Congenital hemophilia is an inherited bleeding disorder characterized by an absent or reduced level of clotting factor VIII (8) or factor IX (9). In a person with normal amounts of clotting factors, when bleeding starts, all of the clotting factors work together to form a clot that stops the bleeding. People with hemophilia (PWH) are missing or have reduced amounts of one of these important clotting factors so bleeding continues until they receive treatment.
People with factor VIII deficiency (hemophilia A, or “classic hemophilia”) have abnormalities or changes in the gene for FVIII, called mutations. As a result, they have absent or low levels of factor VIII in the blood. Without enough factor VIII, the body cannot form a stable blood clot.
People with factor IX deficiency (hemophilia B, or “Christmas disease”) have abnormalities or changes in the gene for factor IX, called mutations. As a result, they have absent or low levels of factor IX in the blood. Without enough factor IX, the body cannot form a stable blood clot.
Secondary Hemostasis: Generating the stable fibrin clot
1. Upon vessel injury, tissue factor (TF) is exposed to circulating factor VII and activated factor VII (FVIIa) initiating coagulation by producing thrombin.
2. Initial thrombin activates platelets and factors V and VIII.
3. Activation of factor X by factors VIII and IX leads to generation of large amounts of thrombin.
4. The “thrombin burst” converts fibrinogen (factor I) to fibrin.
5. Activated factor XIII cross-links the fibrin mesh to stabilize the clot.
Classification of Hemophilia:
Hemophilia can be classified as mild, moderate or severe based upon the amount of clotting factor activity in the blood. Factor levels are expressed either as a percentage or sometimes as specific units of activity within an amount of blood. The reference value used to describe the average factor level in the general population is set to 100%, however, a factor level ranges between 50% and 100% in patients without a bleeding disorder.
This list below shows the three classes of severity based on the factor level:
- Mild Hemophilia: >5-<40% factor level
- Moderate Hemophilia: 1-5% factor level
- Severe Hemophilia: <1% factor level
History of Hemophilia
The earliest record of a bleeding disorder affecting young boys goes all the way back to the 2nd century AD. Back then, it was written in Jewish Rabbinical writings (the Talmud) that if a woman had 2 sons who died of bleeding during circumcision, she should not have further sons circumcised. Later, the Rabbi Maimonides added that this prohibition should hold even if the child were from a different father, showing that he realized that the bleeding disorder could have been passed on by the mother.
Then in 1803, a physician from Philadelphia wrote about “a hemorrhagic disposition existing in certain families” that was passed on in families (hereditary) that mostly affected males. Interestingly, it was not until 1828 that the word “hemophilia” first appeared in a description of a bleeding disorder at the University of Zurich.
In 1944, a doctor from Argentina described two patients with hemophilia and discovered that the blood from one could correct the clotting defect in the blood of the other. This led to the eventual understanding that hemophilia A and hemophilia B were two separate disorders.
Hemophilia has often been called the "Royal Disease." Queen Victoria of England (1837–1901) was a carrier of the disorder who passed the disorder on to several royal families by arranged marriages, including the Spanish, Prussian and Russian royal families. The Russian Tzar Nikolai’s focus on treatment for his affected son, Prince Alexei, was thought to be a factor in the fall of the Russian monarchy. Based upon recent genetic analysis of the Russian royal family, it was determined that the “royal disease” passed on by Queen Victoria was the less common hemophilia B.
What causes it?
Congenital hemophilia is an inherited disorder affecting approximately 20,000 people in the US with hemophilia according to the Centers for Disease Control and Prevention (CDC).
The incidence of hemophilia A is approximately 1 case per 5000 male individuals born. While the majority has a family history, about one third of affected individuals represent a spontaneous or new change to the factor VIII gene resulting in hemophilia.
The incidence of hemophilia B is approximately 1 case per 25,000 male individuals born. While most have a family history, about one in five affected individuals represent a spontaneous or new change to the factor IX gene resulting in hemophilia.
Humans have 22 pairs of chromosomes (autosomes) plus the sex chromosomes (X and Y). Men have X-Y chromosomes and women have X-X. Boys inherit the X from their mother and Y from their father. Girls inherit one X chromosome from each parent. Congenital hemophilia is a recessive disorder linked to the X-chromosome and therefore predominantly affects males if they receive the X from their mother that has an abnormality or mutation in the factor VIII or IX gene, which we’ll call an affected or abnormal chromosome.
As seen in the figures below, congenital hemophilia is generally inherited by affected sons through the mother as a carrier, who can pass on either her normal or abnormal X chromosome to her children.
Fathers with hemophilia only have the abnormal X chromosome that they pass on to all of their daughters who become carriers, and because all daughters are affected, they are often called “obligate” carriers. There are limited circumstances where a daughter can be born with hemophilia, either through having an affected father and carrier mother, or in cases of other genetic disorders where a female has only a single X chromosome (like in Turner’s syndrome).
Some women who are genetic carriers of hemophilia may have bleeding symptoms. Even with only one abnormal chromosome, women can have low levels of factor VIII or factor IX themselves due to partial inactivation of their “normal” functioning X chromosome, called lyonization. If their factor levels are below 40%, they meet the diagnostic criteria for having hemophilia. In addition, bleeding symptoms can occur with factor levels in the normal range, which can be referred to as a symptomatic carrier state.
Remember, 1/3 of cases of hemophilia A and 1/5 of cases of hemophilia B occur after spontaneous mutations or changes in the baby’s genes, where there is no family history and no genetic transmission from parents (the mother has normal X chromosomes and isn’t a carrier).
What are the symptoms?
Before you can treat a bleed, you must recognize that there might be a bleed by knowing the signs of bleeding. Bleeding can occur inside or outside the body. Bleeds inside the body can be harder to spot. Children may be too young to say how they feel. So knowing the unique signs or behaviors in children can help parents identify bleeds early.
There are many types of bleeds and they can happen anywhere in the body. Joint bleeds are the most common, accounting for 70-75% of all bleeds. Often there is no clear reason for the bleed. This is called a spontaneous bleed because there is no known trauma that caused the bleeding. More recently, in a study, it was concluded that often routine activities may result in bleeding without a specific trauma.
Joint bleeds happen when blood vessels in the tissue lining the joint (the synovium) are injured. The most common sites for joint bleeds are the knees, ankles, and elbows. Joint bleeds can also occur in any joint, including the shoulder and hip joints, hands and feet. Joint bleeds are the most common, accounting for 70-75% of all bleeds.
Repeated joint bleeds can lead to joint damage, called arthropathy or hemophilic arthropathy. A target joint refers to a joint that has frequent spontaneous bleeding, 3 or more times in a consecutive 6 month period.
During a joint bleed, the first sign may be a tingling or bubbling feeling. As the bleed progresses, there may also be limited motion, swelling, pain that worsens with time, or general unwillingness to move the joint. You may also eventually feel warmth on the skin over the joint or see swelling, but these are later signs. Swelling and warmth are late signs and this means the bleed has been going on for a while.
Muscle bleeds happen when blood vessels in a muscle are injured. Sometimes the cause of muscle bleeds is known, such as an injury. Spontaneous bleeds can also happen. The most common muscle bleeds occur in the calf, thigh, and upper arm. Yet bleeds in the psoas muscle (at the front of the hip) and the forearm muscles also occur. During a muscle bleed, the muscle swells and feels warm, stiff, and painful. Bruising may be seen if the bleed is the result of trauma near the skin. Bleeds in muscles can put pressure on nerves and blood vessels, which is called a compartment syndrome. This causes tingling and numbness and may cause permanent damage. A muscle spasm may occur when the muscle tightens up to protect itself, called Volkman’s sign. Development of a compartment syndrome represents a serious bleed and the hemophilia treatment center should be contacted immediately.
Bleeding in the head can be just under the skin or can be inside the skull in or around your brain. Bleeding in the head is usually, but not always caused by an injury. These bleeds can cause seizures and loss of consciousness and are a major cause of death in people with hemophilia. If you or your child suffers from a headache that does not get better for a long time or feel a lack of energy or feel very sleepy, it could point to a head bleed. Trouble walking in a straight line or difficulty walking at all, vision problems, bleeding from the ears or nose, vomiting, dizziness, or seizures are other symptoms that may occur. Bleeding in the head is serious and the hemophilia treatment center should be contacted immediately.
Spine bleeds can occur spontaneously or as a result of injury. Bleeds in the spine can put pressure on the spinal cord or the nerves going to your body. Your arms or legs may feel weak, or you may have pain or tingling. Trouble with urination or bowel movements can also be a sign of pressure on the spinal cord from a bleed. Bleeding in and around the spine and spinal cord is serious and the hemophilia treatment center should be contacted immediately.
Stomach and intestine (gastrointestinal [GI]) bleeds
Bleeds in the stomach or your intestine (GI) may occur for a variety of reasons. Sometimes they occur in conjunction with another medical problem, such as ulcers, or following a procedure like an endoscopic biopsy. Symptoms include vomiting blood or black, syrup-like material, or what is sometimes described as looking like coffee grounds. Also, red or black bowel movements resembling tar can occur. Bleeding in the stomach and intestines is serious and the hemophilia treatment center should be contacted immediately.
Serious or life-threatening bleeds
Any bleed with a major loss of blood is life threatening. Head trauma can be associated with scalp cuts and blood loss as well as bleeding in and around the brain. Throat bleeds can cause swelling that can make it hard to swallow or breathe. Bleeding in the throat can come from infection, injury, dental procedures, or elective surgery. Bleeds into the eyes, spine, and iliopsoas muscle can also be serious. Any bleed to the head, neck or throat, or abdomen has the potential to be life threatening and the hemophilia treatment center should be contacted immediately.
Taking into account normal growth and development helps us realize what types of bleeds we are more likely to see at different ages. Keep in mind that these are not the only patients in these age categories who bleed.
- Newborn: birth trauma, immunizations, circumcision, heel sticks
- Toddler: bruising, buttocks, scrotum, mouth bleeds, head trauma
- Preschool and School Age: joints and muscles, particularly ankles, knees, elbows
- Adolescents/Adults: joints and muscles, particularly ankles, knees, elbows. May also see more serious muscle bleeds e.g. iliopsoas
How is it diagnosed?
Because hemophilia is an inherited disorder, some families are aware of their family history. They may seek genetic counseling and testing prior to or during pregnancy. The diagnosis of hemophilia begins with a review of the family history, particularly on the maternal side.
In a patient with no family history of hemophilia (1/3 of hemophilia A, 1/5 of hemophilia B), diagnosis frequently occurs after common procedures in infancy and childhood, such as circumcision, heel sticks, immunizations, surgery (such as tonsillectomy or dental extractions, depending on the hemophilia severity) or injury.
The most important standardized tests of clotting are platelet count, prothrombin time (PT) and activated partial thromboplastin time (aPTT). These tests look at the number of platelets, the time it takes for the liquid portion (plasma) in your blood to clot, and reflect activities of the clotting factors.
Laboratory test results in newborns differ from adult results. Infants are born with low vitamin K levels and receive a dose of vitamin K shortly after birth. Vitamin K impacts the clotting test results and can complicate interpreting lab tests right after birth.
The platelet count and PT will be normal (for age), but the aPTT will be prolonged in hemophilia A and B. Specific factor VIII and IX assays are performed on plasma samples to measure the amount of factor VIII or IX in the patient to determine the level of deficiency and classify the hemophilia severity. The principal factor assays for factor VIII and IX are based upon the aPTT test.
Genetic testing plays a key role to identify the mutation in people with hemophilia A or B. Genetic testing is often done in conjunction with a genetic counsellor or with a specialist at the hemophilia treatment center.
Type of test and results in hemophilia
|Type of Test||Hemophilia A||Hemophilia B|
Prothrombin time (PT)
|Activated Partial Thromboplastin Time (aPTT)||Prolonged||Prolonged|
|Factor Level||Factor VIII < 40%||Factor IX < 40%|
|Genetic Testing||Factor VIII gene abnormality||Factor IX gene abnormality|
How is it treated?
A. History of Treatment
In the 1950s and early 1960s, hemophilia and other bleeding problems were still being treated with whole blood or fresh frozen plasma (FFP); treatment required significant volumes to get enough factor VIII or IX for serious bleeding. By the mid-1960s, the clotting factors were identified and named.
In a major breakthrough in 1965, Dr. Judith Graham Pool discovered that the precipitate left from thawing plasma was rich in factor VIII, which she termed cryoprecipitate. Blood banks were able to produce and store the component, ending the need for high-volume whole plasma transfusions for factor VIII patients. Factor IX deficient patients still had to rely on FFP.
By the 1970s, clotting factor concentrates made from plasma (blood) products containing factor VIII and IX became available, revolutionizing hemophilia care. They could be stored at home, making treatment easily accessible. Unfortunately, these concentrates were manufactured using human blood donations and had the risk of transmitting viruses.
Early focus on Hepatitis B and what was called non-A/non-B Hepatitis (now called hepatitis C). In the 1980s, it became clear that HIV/AIDS could be transmitted through the use of blood and blood products, including plasma derived clotting factors. People with severe hemophilia and their treatment team were forced to consider the risk of not treating bleeds against the risk of viral transmission from blood and factor products. Approximately half of the people with hemophilia in the United States taking treatment in the 1980’s would eventually become Hepatitis and/or HIV-infected. Thousands died, and others infected their partners/spouses, some of whom also succumbed to complications of HIV.
The safety and efficacy of clotting factor concentrates improved in the late 1980s and 1990s. Clotting factor products became safer as tighter blood donor screening methods were implemented and advanced methods of viral inactivation were utilized. In addition, synthetic (not derived from plasma) clotting factor products were manufactured using recombinant technologies where factor VIII and IX genes were used to produce factor proteins in cultured cells.
In 1992, the first recombinant factor VIII clotting factor product was approved by the Food and Drug Administration (FDA). In 1997, the first recombinant factor IX clotting factor product was granted FDA approval.
Current treatment with routine factor replacement in severe hemophilia reduces the frequency of bleeding and increases quality of life for those with hemophilia. Ongoing research is directed towards reducing the burden of treatment through modified factor products and alternative treatment options in the hopes of improving adherence and outcomes. In the future, gene therapy may provide an alternative to intravenous factor replacement therapy.
B. Treatment approaches
WFH Definitions of clotting factor replacement therapy
|Episodic (on-demand) treatment||Treatment given at the time of clinically evident bleeding|
|Primary prophylaxis||Regular continuous* treatment initiated in the absence of documented bone changes in the joints, determined by physical examination and/or imaging studies, and started before the second clinically evident large joint bleed and age 3 years|
|Secondary prophylaxis||Regular continuous* treatment started after 2 or more bleeds into large joints (ankles, knees, hips, elbows and shoulders) and before the onset of joint disease documented by physical examination and imaging studies|
|Tertiary prophylaxis||Regular continuous* treatment started after the onset of joint disease documented by physical examination and plain x-rays of the affected joints|
|Intermittent (periodic) prophylaxis||Treatment given to prevent bleeding for periods not exceeding 45 weeks in a year|
*Continuous prophylaxis is defined as the intent of treating for 52 weeks per year with patient adherence to administering a minimum prescribed number of infusions per week for at least 45 weeks a year.
Treatment of Bleeding Episodes
Each person with a bleeding disorder is unique; an individualized treatment approach or plan is important. Identifying and implementing therapies that stop bleeds quickly when they occur is very critical. The staff at the hemophilia treatment center can work with you to design a plan that meets your specific needs. Together, you will find the therapy that works best to treat bleeds.
The World Federation of Hemophilia (WFH) guidelines recommend immediate treatment once a bleed starts, ideally starting within 2 hours if possible. WFH also recommends additional support with rest, ice, compression and elevation (also known by the acronym R.I.C.E.). Early treatment of bleeds may limit the amount of blood in your joint or in other bleed locations. If you feel “bubbling or tingling”, this may be an early sign of bleeding and that is the time to treat. Don't wait for swelling or pain, which might signal that a lot of blood has already gotten into your joint.
Pain management is an important part of an overall treatment plan. Treatment of pain differs based on the source of the pain. Acute pain from a bleed would be treated differently than persistent (chronic) pain from arthritis caused from frequent bleeds into the same joint, also known as arthropathy or hemophilic arthropathy.
Pain medications (analgesics) are a common choice of treatment. It is important to know which pain medicines you can take and which you should avoid. You want to make sure nothing interferes with your clotting factor or bypassing agent working to stop bleeds as quickly as possible. Some pain medicines containing aspirin or the non-steroidal anti-inflammatory drugs (NSAIDS such as ibuprofen or naproxen) can affect your platelets or blood clotting. Avoid these medicines because they might make the bleed worse. You may not realize they are contained in over the counter medicines. Some spices and herbal remedies also impact blood clotting. Check with your doctor or nurse at the hemophilia treatment center to identify what pain medication you or child should use.
Prophylaxis is defined as the treatment by intravenous (IV) injection of clotting factor concentrates to prevent bleeding. In contrast, episodic or on-demand treatment uses factor concentrate to treat bleeding episodes when they happen.
WFH provides definitions of treatment regimens in their guidelines for hemophilia management as shown in the table above.
Studies have shown that primary and secondary prophylaxis with factor VIII can significantly reduce the frequency of bleeding episodes, improve orthopedic outcomes and provide quality-of-life benefits in people with hemophilia.
WFH recommends that prophylaxis should be the goal of all hemophilia care programs to reduce the frequency of bleeding episodes, preserve joint function and improve the quality of patients’ lives until a cure is available.
The National Hemophilia Foundation’s (NHF) Medical and Scientific Advisory Committee (NHF – MASAC) set forth recommendations for prophylaxis in MASAC#179 approved in December 2007.
In view of the demonstrated benefits of prophylaxis (regular administration of clotting factor to prevent bleeding) begun at a young age in persons with hemophilia A or B, MASAC recommends that prophylaxis be considered optimal therapy for individuals with severe hemophilia A or B (factor VIII or factor IX <1%). Prophylactic therapy should be instituted early (prior to the onset of frequent bleeding), with the aim of keeping the trough factor VIII or IX level above 1% between doses.
It is also recommended that individuals on prophylaxis have regular follow-up visits to evaluate joint status, to document any complications, and to record any bleeding episodes that occur during prophylaxis.
There are no clear cut guidelines as to when to stop prophylaxis. Joint bleeds with subsequent joint destruction are a lifelong problem for these individuals. Therefore, they may continue to benefit from prophylaxis throughout their life.
C. Joint Bleeds and Arthritis
Joint bleeding can lead to serious complications. Blood causes joint damage, first to the soft tissues (synovium) and then to the cartilage and bone. Not treating joint bleeds quickly may result in more blood in the joint. Ultimately, joint damage may progress to chronic pain, impact on joint motion, and impact on walking, usual activities, and self-care. Learning to listen to your body can help you identify joint bleeds more easily—making earlier treatment possible.
When a bleed in the joint happens, you may see the following signs and symptoms:
- Pain or aching in the joint (this usually gets worse the longer the bleed goes untreated)
- Tingling or bubbling feelings in the joint
- Not wanting to move the joint
- Unable to bend or straighten normally (decreased range of motion)
When these symptoms are present, it is time to start treatment. WFH recommends treatment within 2 hours of realizing that a bleed may have started.
After the bleeding has gone on for a while, the joint will swell, may feel numb and the skin around the joint may feel warm to the touch. These are late-symptoms. It is very important to treat joint bleeds early to avoid complications and not wait for the late symptoms before seeking treatment.
While you are recovering from a joint bleed, there are many do’s and don’ts to think about:
- Treat any joint bleeds as soon as possible with clotting factor, ideally within 2 hours and until the bleed resolves, and for the duration recommended by your HTC or hematologist
- Consider R.I.C.E. therapy: Rest, Ice, Compression, Elevation
- Resting a joint is very important. Allow an appropriate rest period before resuming activity to allow for bleed resolution (talk with your healthcare team for recommendations)
- Put a recovery and rehabilitation plan in place to get mobile following a joint bleed
- Incorporate a range of exercises into rehabilitation plans in consultation with your HTC healthcare team
- Ensure you use appropriate clotting factor during recovery
- Set functional goals that will restore the level of physical activity to what it was prior to the bleed
- Measure progress by keeping a journal
- Exercise a joint during an active bleed
- Return to a sport/activity following a bleed without discussing it with your hemophilia treatment center (HTC) or hematologist
- Forget to exercise other body parts as able while resting the joint that is healing
- Do high-impact sports or power lifting that may provoke a joint bleed
Your treatment center may have physical therapists on their team who conduct assessments during comprehensive care visits and perhaps following a bleed. They can help the treatment team design a tailored recovery and rehabilitation programs to get you or your child back to his or her usual pre-bleed joint function quickly. Initially, rehabilitation programs may involve soft-tissue mobilization (massage), hydrotherapy (water therapy), and/or at-home exercises. They also include review of daily tasks to look for potential causes for bleeds and how they can be avoided as you return to physical activity.
Ongoing monitoring of joint function helps determine the success of the exercise program. Key issues to evaluate are further bleeds, pain, swelling, range of movement, crepitus (sound of bones rubbing together), muscle strength, gait, and balance.
D. Other bleeds
Muscle bleeds are also characteristic of hemophilia. The large weight-bearing muscles are the most commonly affected, in particular the iliopsoas (next to the spine), calf, gluteal (buttock) and forearm muscles. Bleeding can occur for some time undetected before discomfort is noticed and as a result, patients can present with large, potentially debilitating bleeds. Compression of the nerves and blood vessels in a limb from muscle bleeding, called a compartment syndrome, represents a serious bleed and the hemophilia treatment center should be contacted immediately.
Bleeds in the head are a serious complication of hemophilia and are usually associated with trauma but can occur spontaneously. Intracranial bleeds are the number one bleeding-related cause of death in the person with hemophilia. All head injuries, however mild, need to be taken seriously, and the hemophilia treatment center should be contacted immediately.
Bleeding in the mouth from a laceration or bite (usually the tongue or cheek) is often persistent. Blood loss in a small child may be so great that blood transfusion is required. Bleeding under the tongue, behind the pharyngeal wall or in the neck is particularly dangerous because swelling in this area can close off the airway. These bleeds are a medical emergency and require prompt treatment. The hemophilia treatment center should be contacted immediately.
Peptic ulcer disease occurs about five times more frequently in the adult hemophilia A population compared with the general male population, and can be caused by the frequent ingestion of anti-inflammatory medication for pain relief of joint disease. Bleeding from ulcers can result in the symptoms described above, and the treatment center should be contacted immediately. Many medications, prescription and over the counter, can interfere with clotting. For that reason, it is not recommended that people with bleeding disorders take aspirin or aspirin containing products. They should also avoid non-steroidal anti-inflammatory medications (ibuprofen, naproxen).
Pseudotumors are collections of blood that are encapsulated like a cyst. They occur in soft tissues or bones following a prolonged bleeding episode. Most pseudotumors are not associated with pain unless there is rapid growth due to a bleed within the cyst or nerve compression from the cyst itself. As the volume of the tumor increases, it compresses and destroys the nearby muscle, nerve and/or bone. Pseudotumors can develop over a period of several years and usually develop in the lower half of the body, in the thigh, buttock or pelvis, but may occur anywhere. The only reliable treatment is surgical removal of the mass.
For people with bleeding disorders, surgery is certainly an issue that causes anxiety for the patient and family. Hemophilia treatment centers have developed expertise around administration of clotting factor replacement during surgery to allow for the simplest of biopsies or dental procedures to the most complicated of major surgeries. They will consult with the surgeon and anesthesiologist, as well as hospital pharmacists or blood banks to make sure that preparations are made in advance. You should discuss risks and benefits of any surgery in advance with your hematologist, the surgeon, and the anesthesiologists to make sure you are comfortable with the treatment plan.
If something happens in an emergency that requires surgery or if you are unconscious and unable to inform emergency staff, you should always have an emergency alert card and identification (e.g. medic alert bracelet) with you to alert the medical provider to contact your hematologist or hemophilia treatment center. It is important to know that EMT’s are not trained to look into wallets for medical information cards. When they do look there it is usually too late. Wearing a medic alert is the best way to alert anyone in the case of an emergency when the patient cannot speak for themselves.
Orthopedic Surgery in Hemophilia
For some people with congenital hemophilia, ongoing joint bleeding may result in joint damage, pain, or limitations in function that may ultimately require surgery to be considered. The choice to have an orthopedic procedure or orthopedic surgery should be made together with your hematologist, physical therapist, orthopedic surgeon, and your family—weighing what you may gain versus what you risk.
Elective orthopedic surgery is a serious consideration, especially for those with bleeding disorders. A few decades ago, orthopedic surgery was unthinkable in hemophilia. But with the advent of clotting factor, orthopedic surgery has been an option for patients since the late 1970s. Since the late 1980’s, the use of bypassing agents to prevent/control bleeding during surgery has made orthopedic and other surgery possible for patients with antibodies to factor VIII or IX (inhibitors, see below).
Preparing for surgery takes time and effort, but planning ahead is key to minimizing stress during your recovery. Prior to the procedure, your hematologist and surgeon will conduct a physical exam and order blood tests, further assessing your joint damage with physical exams, MRIs, or other x-rays. Months before surgery, your hemophilia treatment center (HTC) may recommend that you consider physical therapy to help improve your range of motion and strengthen your muscles. This may affect your ability to participate in post-operative rehabilitation.
If you are considering orthopedic procedure or orthopedic surgery, you need to get the facts about surgery to repair or replace damaged joints. The main potential benefits of orthopedic surgery in people with hemophilia include decreased pain, fewer bleeds, improved mobility (in certain instances), and improved quality of life.
Your treatment center will need to work with the surgeon and anesthesiologist to make sure that an adequate plan is in place to prevent/control bleeding during surgery and to address any unexpected bleeding before you go forward with any plan for surgery.
Joint Repair (Synovectomy): Synovectomy removes swollen tissue of the joint. It is performed once chronic inflammation of the joint lining (synovitis) has happened. Your treatment center might recommend that you undergo this procedure before permanent joint damage occurs. This may reduce the number of bleeds you have and help slow progression of joint disease. As in all cases of surgery, it is vital to prevent bleeding. During surgery and after surgery are critical times.
The least invasive type of synovectomy involves nothing more than an injection into the joint. During radiosynovectomy or chemical synovectomy, the doctor injects either a radioactive substance or a chemical that inhibits the synovium from overgrowing.
During radiosynovectomy or chemical synovectomy, a physician injects either a radioactive substances (called a radioisotope) or chemical into the affected joint. The radioisotope or chemical impacts the overgrowth of the synovial lining cells associated with synovitis. Both are associated with a decrease in bleeding in the particular joint for 6 or more months.
During arthroscopic synovectomy, part of the swollen synovial lining of the joint is removed. The surgeon uses an arthroscope connected to a camera to see directly inside the knee. Then, the surgeon inserts the surgical tool through another small incision in the skin to remove the swollen synovium. This procedure is done most often on knees, shoulders, and ankles. It is also done on hips and elbows. The procedure is performed in a hospital or surgery center and usually takes about 60 to 90 minutes.
Open synovectomy is performed by surgically opening the knee. The synovial membrane is then removed or burned off. More synovial tissue can be removed by undergoing this procedure. However, this procedure may require several days of hospitalization and more extensive treatment to prevent/control bleeding. Physical therapy and a rehabilitation program may also be recommended.
Your treatment center will need to work with the surgeon and anesthesiologist to make sure that an adequate plan is in place to prevent/control bleeding during surgery and to address any unexpected bleeding before you go forward with any plan for surgery.
Joint Replacement (Arthroplasty): During total joint replacement, or arthroplasty, the damaged bone and joint tissue are removed and replaced with metal, ceramic, and plastic parts. The artificial joint hardware the surgeon uses is called prosthesis. Knee and hip replacements have been performed successfully in adults with antibodies to factor (inhibitors, see below), although the long-term outcomes are less well understood.
Arthroplasty may result in decreased pain and bleeding. You may also have increased mobility and improved quality of life once the joint is fully healed. It is a big decision that is not without substantial risk and a prolonged recovery. The surgery requires admission to the hospital and is performed under general anesthesia. You must be committed to an intensive rehabilitation program after surgery and be very careful about preventing infection on an ongoing basis after the surgery.
Surgery can have benefits, but there are also potential risks. When surgeries fail, it is not always because of bleeding during surgery. Bleeds after surgery can occur into the new joint as the body is healing, and it’s the reason that treatment to prevent/control bleeding is continued often for weeks after an arthroplasty and while physical therapy is started. A serious bleed can delay your recovery time or even undermine the surgery you just had.
Infection may occur immediately after surgery or at any point for decades after surgery if any bacteria get in your bloodstream for any reason (e.g. poor dental hygiene, not using proper technique for infusions). Management of infections can include antibiotics, but may also include additional surgery to drain infections or remove or replace joint prosthesis (the hardware).
In addition to the potential complications of bleeding and infections, there is a small chance that blood clots form, even though you have a bleeding disorder. Blood clots or deep vein thrombosis (DVT, clots in the veins of the legs) are a risk in all people having total joint replacement, not just people with hemophilia. Data suggests the risk of DVT in people with hemophilia even with factor replacement is low compared to risk of bleeding and infection and low compared with people without hemophilia. Treatment to prevent/control bleeding will be given before, during, and after the procedure. Your hematologist will monitor you carefully for any sign of blood clots. They are a more significant issue if you stay in bed following surgery and do not get up and move around as directed.
- Knee - Elective total knee replacement surgery can relieve pain and help get your mobility back. It involves removing the damaged areas of the lower femur and upper tibia and replacing these areas with a metal and plastic prosthetic device. In this surgery, the damaged portions of the bone and cartilage are cut away. The end of the bone is reshaped so the replacement part can be attached.
- Hip - Elective total hip replacement surgery replaces damaged parts of the hip joint. Surgeons use metal and plastic "ball and socket" prosthetic parts. The femur is separated from the pelvic bone socket joint. The damaged ball is cut off the thigh bone. The damaged cartilage and bone are removed from the hip socket. A metal shell is pressed into the socket of the pelvic bone. The surgeon will hollow out the end of the thigh bone, and then the metal implant is placed into it. A metal ball is then attached to the implant.
- Shoulder - Elective shoulder surgery can help improve your range of motion and reduce pain in the joint. During shoulder surgery, damaged bone and cartilage are removed and replaced with a metal and plastic joint. The head of the upper arm bone is removed. The shoulder socket is smoothed and shaped. Then a plastic component is placed into the socket. The surgeon will then hollow out the upper arm bone. The metal stem of the prosthetic component is then placed into the bone. This acts like the upper arm bone's original head.
- Elbow - Everyday tasks like shaving and carrying groceries are often simpler and less painful after elbow surgery. Although elective elbow replacement has been done, it is not as common as knee or hip replacement. There are limits on how much a person can lift after elbow replacement. Other problems often arise after surgery. The elbow is a hinge joint consisting of 3 bones: the upper arm bone (humerus) and 2 forearm bones (radius and ulna). Elbow surgery may involve removing the damaged end of the radius—called radial head excision. Often, synovectomy will be done at the same time to remove damaged tissue. This procedure usually results in good pain relief and may improve forearm rotation. But the amount you can flex or extend your elbow will usually not change much.
Your treatment center will need to work with the surgeon and anesthesiologist to make sure that an adequate plan is in place to prevent/control bleeding during surgery and to address any unexpected bleeding before you go forward with any plan for surgery.
Joint Fusion (Arthrodesis): Ankle fusion (arthrodesis) is performed to improve the ability to walk or bear weight. Two bones are joined together or fused with screws, steel rods, or staples to relieve pain. The joint is no longer flexible (you can't move your foot up or down), so this is usually restricted to joints like the ankle.
Elbow surgery: The elbow is a hinge joint consisting of 3 bones: the upper arm bone (humerus) and 2 forearm bones (radius and ulna). Elbow surgery may involve removing the damaged end of the radius—called radial head excision. Often, synovectomy will be done at the same time to remove damaged tissue. Although elbow replacement has been done, it is not as common as knee or hip replacement. This procedure usually results in good pain relief and may improve forearm rotation. But the amount you can flex or extend your elbow will usually not change as much. There are limits on how much a person can lift after elbow surgery, so pain relief is a common reason for considering elbow procedures.
F. Viral/Infectious Transmission
In the 1960s scientists discovered that the plasma in whole blood was rich in factor proteins. This discovery made it possible to treat patients with hemophilia with the factor that they were missing for the first time. Manufacturers developed methods to pool donated plasma into factor concentrates. Unfortunately, the blood donor pool included people who were infected with viruses that were not necessarily known at the time, and for which testing was not immediately available for blood donor screening. These included hepatitis B, non-A non-B hepatitis (now hepatitis C) and HIV. The HIV virus that causes AIDS was identified in 1984 and screening of blood donors was initiated in 1985. Hepatitis C screening only became part of blood donation protocols in 1990. People with hemophilia who were treated with blood products prior to 1985 came in contact with the HIV. It is generally believed that about 90% of people with severe hemophilia treated prior to 1985 have contracted HIV. Other non-viral illnesses have also been seen, including the infectious agent called a prion that causes Creutzfeld Jacob Disease (CJD).
In order to prevent further exposure, methods were developed to inactivate these viruses in the donor blood supply. In addition, recombinant technology advanced the ability to make factor products with little or no human plasma. While recombinant products have increased the safety of these factor concentrates, virtually eliminating risk of transmission of viruses from human sources; some products still use human albumin as a stabilizer. There are still plasma derived clotting factors available today; these products undergo extensive testing and viral attenuation steps.
What is an inhibitor?
An inhibitor is an antibody that blocks the activity of factor VIII or IX. As a patient with hemophilia (PWH), your body does not normally have factor VIII or IX or has decreased amounts, so when you are a baby your body doesn’t learn to recognize those proteins as being part of your “self”. When your body comes in contact with replacement clotting factor, it might cause your body to mount an immune reaction thinking infused factor is a foreign invader. This exposure to factor that resulting in an antibody may be in early childhood if you have severe hemophilia, or may occur later in life during exposure for a trauma or surgery if you have mild hemophilia. Antibodies that are produced can either block factor activity or have no effect. If the antibody response results in blocking the activity of factor, then it’s called an inhibitor.
Inhibitor development may depend on many things. These include the type of hemophilia (A or B) and severity of your hemophilia (e.g., mild, moderate, severe), your family history, and race. Hemophilia with inhibitors is more common in people with hemophilia A (20%-30%) than hemophilia B (up to 6%). People with severe hemophilia are more likely to get inhibitors than those with mild hemophilia because their bodies make less factor VIII or IX and as such are more likely to see the replacement factor as foreign.
Having a family history of inhibitors could mean you are more likely to develop them because you may have inherited the same gene mutation. The factor that you infuse to prevent or treat bleeding may look different than your own factor, and for this reason people of African or Hispanic descent are also potentially at greater risk.
Your chances of getting an inhibitor also depends on the treatment you receive, and when you receive it. Your treatment center may want to check on your factor VIII or IX gene to see what type of gene abnormality you have. This blood test is called genotyping. Certain genotypes may have a higher risk for inhibitor development, and in general missing large parts of the gene (called deletions) is associated with higher risk than having just an one mistake in the amino acids building blocks that make up the factor protein (called missense). It may help find out if you have a higher risk so that your treatment center can then individualize your treatment.
Inhibitors do not exist at birth. They can only develop after the person with hemophilia has received replacement clotting factor. Most of the time, this happens within the first 50-75 infusions. Inhibitors may even appear after years of treatment, but this is rare. It also may occur in patients with mild or moderate hemophilia that receive factor VIII or IX for the first time. This occurs when they receive large amounts of factor for a surgery or a major bleeding episode or in adults who are getting factor for the first time in their lives.
What are the signs of inhibitors?
In order to identify an inhibitor, it's important to know if you're at risk and familiarize yourself with the common signs. If you are treating a bleed and notice:
- You are bleeding even though you are receiving factor regularly
- Treatment with factor for a bleed is not working
- You need higher doses of factor or more infusions
All of these may be signs of an inhibitor. You should contact your treatment center to schedule a blood test if you suspect you or your child may have an inhibitor.
If an inhibitor is suspected, your hematology treatment center will likely order a blood test called the Bethesda assay (sometimes called Nijmegan-modified Bethesda assay) or inhibitor assay, which is used to detect inhibitors and see how much they reduce factor VIII or IX activity. These are measured in "titers" or "Bethesda units (BUs)." High titer inhibitors (high BU) more significantly and quickly block the activity of administered factor from working in the bloodstream. The visual below shows how your titers affect how factor will work.
The effect of inhibitors on factor
If you have an inhibitor, you want your titers to be as low as possible. This indicates a lower level of inhibitory antibodies. When an inhibitor is <0.5 BU, it is said to be negative because the lowest amount the assay can test for is 0.5 BU.
As your titer rises, more and more factor will be needed to overcome the inhibitor to stop the bleed. Once your titer reaches 5 BUs, almost no factor escapes the inhibitor even if you took many times the normal dose. This means normal replacement factor will not work and bypassing agents are needed instead. Bypassing agents are hemostatic agents that help blood to clot by bypassing the steps where factor VIII or IX are required. Your physician or your child’s physician will work with you to monitor the inhibitor and prescribe an appropriate treatment plan.
What’s the impact on treatment?
Inhibitors are classified by titers, which impacts treatment recommendations.
- High titer inhibitor – Inhibitors of more than 5 BU are considered high titer. No amount of factor VIII or IX administered will make the blood clot. Bypassing agents are needed instead of factor VIII or IX.
- Low titer inhibitor – Inhibitors of less than 5 BU are considered low titer. In some cases, you could give more factor VIII or IX to overcome the inhibitor (e.g. give twice as much for a titer of 1 BU, four times as much for a titer of 2 BU, etc.). Sometimes, administering more factor can stimulate more antibodies to be produced, which is called an anamnestic response. Your center may test to see if your antibodies go up in response to factor to determine whether higher dose factor or bypassing agents would be the better option.
- High responder – If your antibodies go up over 5 in response to a test dose of factor, it’s called a high responding inhibitor. This means you probably need bypassing agents to control bleeding.
- Low responder – If your antibodies don’t really change in response to factor, you may be able to treat with higher doses of factor VIII or IX. Depending on the titer, bypassing agents might still be necessary, or the volume/dose of factor VIII or IX may increase to where it makes more sense to treat with bypassing agents.
Another consideration particularly for hemophilia B is that while inhibitors are much less likely to occur, those people that get them can develop some other complications. Anaphylaxis is a very severe allergic reaction that includes difficulty breathing, changes to your heart rate and could result in death. This can occur in up to 50% of persons with hemophilia B with inhibitors if they are administered any more factor IX. Because of the risks of anaphylaxis, most often the first few doses of factor IX or of a new factor IX product are administered in the treatment center where the treatment team can observe for side effects. Also, a kidney problem called nephrotic syndrome, can occur in patients with hemophilia B with inhibitors. You treatment team will monitor kidney function carefully.
Immune Tolerance Therapy (ITT) - For hemophilia A the goal is often to try to eliminate the inhibitor by tolerizing you to clotting factor again. This is done much the same way as somebody allergic to a cat is treated with regular allergy shots until they don’t react to cats, except in hemophilia the factor is given into the vein instead of as a shot). In hemophilia we call this Immune Tolerance Induction (ITI) or Immune Tolerance Therapy (ITT), where generally large amounts of factor VIII are administered daily or 3 times a week for a period of up to several years to try to tolerize the inhibitor so that routine prophylaxis with factor VIII can be reinstated.
While inhibitors are less common in hemophilia B, tolerization is more complicated due to the risks of anaphylaxis and nephrotic syndrome. ITI/ITT is therefore less commonly used in people with hemophilia B with inhibitors. There are much less data as well about the success rates of ITI in hemophilia B.
What’s the impact on joints?
Persons with inhibitors do not necessarily bleed more often, but they tend to have more difficult to control bleeds than those without inhibitors. As noted above, for people with severe hemophilia without inhibitors the recommended standard of care is routine factor replacement (prophylaxis). Depending on the person with hemophilia’s activity level and joints, prophylaxis with factor VIII or IX can significantly reduce or eliminate spontaneous bleeding. While bypassing agents have been more recently studied in prophylaxis, they are not as effective as factor in preventing bleeding. Therefore, on demand treatment of bleeding remains the treatment for the majority of people with inhibitors. Over time, people with inhibitors exhibit more joint bleeds than those without inhibitors, even if treated prophylactically, and are at greater risk for developing more changes in their joints over time. Studies like the European Study of Orthopedic Status (ESOS) have shown that people with inhibitors have greater arthritis and greater use of assistive devices as they age than similarly aged persons with hemophilia without inhibitors.
Tips for staying healthy
Health at every life stage
As you age, you'll start seeing more than just your hematologist. It's important to take care of other health issues. Health concerns facing men can include prostate issues, being overweight, diabetes, cancer, depression, and heart disease, among others. Many adults also need minor and major surgical procedures unrelated to hemophilia as they get older. Talk to your healthcare provider about any medical concerns. Your doctor will be able to refer you to an appropriate specialist, and coordinate any treatments needed during medical procedures or surgeries.
Exercise and nutrition
Exercise and nutrition are important topics for anyone looking to lead a healthy lifestyle. But when it comes to hemophilia, you should keep a healthy body weight. Healthy weight can mean less stress on joints, possibly a lower dose of clotting factor (dosage is based on weight), and potentially less cost to you and your insurance company. The physical therapist at your treatment center may recommend exercises during bleed recovery at an appropriate interval after the bleeding has stopped. This may help you to optimize your recovery following bleeding. You should talk to your treatment team about the timing and exercises that are right for you or your child.
Not all physical activity causes bleeds. Regular, low-risk activity under supervision of your treatment team can help strengthen your muscles and prevent bleeds and joint damage. Developing an exercise plan is a great way to preserve joint function. Here is why: exercise improves joint stability, strength, and range of motion.
In most cases, low-impact activities are encouraged. National Hemophilia Foundation (NHF) publishes a guide to “Playing it Safe” (see Document Downloads). Lower risk activities are less likely to cause bleeding. Here's a list of sports and activities you might want to talk to your HTC about:
- Stationary bike
- Table tennis
- Tai chi
Always follow your healthcare professional's advice about which activities to consider. When starting a new exercise regimen, always listen to your body. Some degree of discomfort may be expected, but if you experience a pain that is increasing, it's important to slow down or stop altogether.
Combine exercise and regular activity with a healthy diet and you can protect yourself or your child from joint disease, obesity, and diabetes. Overweight adults will be at increased risk of developing cardiovascular disease later in life, such as high blood pressure, heart attacks, and strokes. Speak with your healthcare profession and start small if you are not exercising at all, and slowly increase your activity. Any exercise at all is a benefit not only for your hemophilia but for your entire health and wellbeing.