What is Bernard-Soulier Syndrome?
Bernard-Soulier syndrome (BSS), sometimes referred to as Hemorrhagiparous Thrombolytic Dystrophy, is a very rare inherited disorder affecting the blood’s ability to clot. This condition is marked by abnormally large blood cells known as platelets, a low platelet count (thrombocytopenia), and an extended bleeding time. This syndrome was first noted in 1948, when a man who had experienced repeated bleeding episodes throughout his life was described by Jean-Bernard and Jean-Pierre Soulier. Tragically, at the age of 28, the man passed away from excessive bleeding in the brain after a bar brawl.
BSS is caused by a defect in the GPIb-IX-V complex, which is a crucial component on the surface of platelets that primarily attaches to a blood protein called von Willebrand factor (vWF). This complex has several other roles in promoting clotting and maintaining a balanced blood flow.
What Causes Bernard-Soulier Syndrome?
Bernard-Soulier Syndrome (BSS) is a condition that arises due to changes in specific genes responsible for encoding the GPIb-alpha (GPIBA), GPIB-beta (GPIBB), and GPIX (GP9) proteins. These proteins make up a critical component in the body known as the GPIb-IX-V complex. In a study involving 211 families with BSS, around 112 different genetic changes or “mutations” were detected. Many of these mutations occurred in people whose parents were closely related by blood, often leading to both parents passing on the same mutation.
Importantly, a fair number of these families included members who were “asymptomatic carriers”, meaning they had the genetic mutation but did not show symptoms of BSS. The inheritance of these mutations generally followed an “autosomal dominant” pattern. This means only one parent needs to pass on the mutation for their child to potentially develop BSS. The mutation known as the Bolzano mutation is a well-known example of this.
The mutations were primarily found in the GP1BA, GP1BB, or GP9 genes, comprising 28%, 28%, and 44% of cases respectively. These genetic changes can take various forms like alterations to a single gene letter (“missense”), deleting a portion of the gene (“deletion”), adding extra material to the gene (“insertion”), and others.
Most of these mutations are inherited in what is called an “autosomal recessive” pattern, meaning both parents need to pass on a mutation for their child to develop BSS. However, in rare cases, an “autosomal dominant” pattern of inheritance has been observed.
Patients with autosomal recessive inheritance, that is, with mutations in both copies of a gene, are classified as having biallelic BSS (bBSS). Those with a mutation in only one gene copy, or with autosomal dominant inheritance, are often referred to as monoallelic BSS (mBSS).
In bBSS, “loss-of-function” genetic variations, like deletions, insertions, and certain other mutations, in the GP1BA, GP1BB, or GP9 genes disrupt the formation of the GPIb/IX/V complex. This complex plays an essential role in blood clotting by serving as a receptor for von Willebrand factor and thrombin, two proteins crucial for this process. Various other mutations that lead to BSS have been found across the globe, including in China, Denmark, the Reunion (French) Isle, and the Czech Republic.
Risk Factors and Frequency for Bernard-Soulier Syndrome
This disease is thought to affect about 1 in 1 million people. However, the actual number might be greater, as the disease is often overlooked or misdiagnosed. The disease is inherited through genes that aren’t linked to gender, so it affects both males and females.
The disease often flies under the radar, so it usually isn’t spotted early in life. On average, patients are diagnosed when they’re 16 years old. Sometimes, patients are mistakenly diagnosed with a condition called idiopathic thrombocytopenic purpura (ITP), and some may even undergo an operation to remove the spleen. Because of this, it’s really important to understand the symptoms and causes of the disease so it can be correctly diagnosed.
Signs and Symptoms of Bernard-Soulier Syndrome
BSS, or Bernard-Soulier Syndrome, is a medical condition that involves bleeding. The symptoms often start at birth and continue throughout the individual’s life. They may include bleeding from various sites, nose bleeds, bleeding under the skin, bleeding following an injury or surgery, heavy menstrual bleeding in women, and more rarely, gastrointestinal bleeding and bloody urine. In certain instances, the only clinical signs may be unexplained bruising or purple patches on the skin. Although fatal bleeding is not common, it can occur in about 16% of cases.
Adults with BSS usually have the milder form, known as mBSS, and experience fewer bleeding episodes due to the preservation of platelet numbers. One noteworthy genetic variation linked to this condition is the ‘Ala156Val’ mutation, commonly referred to as the Bolzano mutation. Even though most patients with this mutation tend to have mild thrombocytopenia (low platelet count) and infrequent bleeding episodes, there have been reports of individuals with severe bleeding. Other genetic mutations have also been identified that cause only mild thrombocytopenia with infrequent bleeding episodes.
Assessing bleeding disorders like BSS often incorporates the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT). This tool has been tested and proven quite effective, with a positive predictive value of 90% and a negative predictive value of 100%. In the context of von Willebrand disease, another bleeding disorder, a BAT score greater than 6 indicates a 99% likelihood of an inherited platelet defect such as BSS. Additionally, other assessment tools, like the Molecular and Clinical Markers for the Diagnosis and Management (MCMDM) of type 1 von Willebrand’s disease (VWD) and the World Health Organization Bleeding Assessment Tool, have been developed and serve similar purposes.
Testing for Bernard-Soulier Syndrome
When a patient has a long history of bleeding that started in childhood, Bernard-Soulier Syndrome (BSS), a rare inherited bleeding disorder, could be a possible cause. Patients with BSS usually have a very low platelet count, which is between 20 to 100 billion/L; however, the count could go as low as 10 x 10^9/L.
Platelets are small, colorless cell fragments in our blood that form clumps and stop bleeding when needed. A hematology analyzer, a machine used in the examination of blood, can be used to measure the average volume of these platelets. If this measurement is more than 12.4 femtoliters (fl), a unit of volume used for cells and other small objects, the platelets are likely to be larger than usual.
Patients may go through a ‘bleeding time’ test, which measures the length of time for bleeding to stop. This duration is generally longer than usual in BSS patients. There is also a platelet function analyzer test where the ability of the platelets to clump together and form a clot is measured. In BSS patients, this process is often delayed.
A platelet aggregation test helps distinguish BSS from another similar disorder known as Von Willebrand Disease (VWD). It measures how well platelets clump together. In case of BSS, there is a reduced response to a substance called ristocetin, but generally normal response to other substances like ADP, collagen, and arachidonic acid.
Flow cytometry, a lab test that measures the physical characteristics of cells or particles, is a confirmatory test for BSS. It shows a noticeable reduction of certain types of proteins on the surface of the platelets, called CD42a (GPIX) and CD42b (GPIb-alpha). This test uses only a small amount of blood, making it suitable for newborns, infants, and young children.
Molecular genetics tests may also be done to identify genetic abnormalities.
A subtype of BSS that’s mainly found in Italy (due to a specific genetic mutation called the Bolzano mutation), and some other mutations, have normal amounts of a particular complex of proteins (GPIb-IX-V) on the surface of the platelets. However, these proteins are defective and hence, cannot bind to a protein called Von Willebrand factor, which under normal circumstances, helps platelets clump together and form a clot. Again, the platelet aggregation test becomes a useful tool for diagnosis in these cases.
Treatment Options for Bernard-Soulier Syndrome
If a person is diagnosed with BSS, a condition where the blood doesn’t clot as it normally should, it is extremely important that they understand the risks of bleeding. Carrying ‘alert cards’ or wearing ‘alert bracelets’ can help define their condition in case of an emergency. Registering with a center that can provide emergency treatment 24 hours a day can also be beneficial, especially if a bleeding episode occurs.
Those diagnosed with BSS also need to avoid certain activities and substances. They are usually advised against high-risk sports, particularly contact sports, to minimise the risk of injury and possible bleeding. Everyone involved –– patients, their families, and healthcare providers –– needs to be aware of what medications can increase these risks, such as antihistamines, anti-inflammatory drugs, and certain antibiotics. Some foods, drinks, and herbal treatments can also affect how well the blood clots so they need to be avoided.
One of the bigger challenges associated with BSS is that excessive bleeding can cause a deficiency in iron. Patients should be monitored for this and may need to take iron supplements. They should also be tested for specific genes (HLA-typing) to help match them to specific platelet transfusions, a treatment that involves replacing clotting cells in their blood, if needed.
When a BSS patient experiences a severe bleeding episode or is preparing for elective surgery, the first line of treatment is usually platelet transfusions. There are however, some risks that accompany each transfusion, such as the formation of unwanted antibodies and the very small risk of contracting an infection from the transfusion. The risk for infection is much higher if the platelets come from whole-blood rather than from a specific method called apheresis.
While it’s always best to use platelets that match a patient’s HLA type, this may not always be possible during emergencies. And, in cases where patients require frequent transfusions, they may develop an immune response against the transfused platelets, making future transfusions less effective. There’s a test for this, but it’s not perfect and can be both labor-intensive and costly.
Other medications, like Tranexamic acid, can be helpful in managing mucocutaneous bleeding and heavy menstrual periods along with local efforts like packing the nose or hormonal treatments. On the downside, these medications should be avoided in patients with lung bleeding or blood in their urine, as they may cause clots that could lead to lung or kidney problems.
Desmopressin, which is a medication that releases a specific blood clotting factor from the cells that line the blood vessels, has very limited utility for BSS patients due to the specific defects present in their blood cells. Nonetheless, it has been used in some cases, but care must be taken to avoid side effects like severe low sodium levels in the blood and seizures.
Some new strategies for managing BSS are not yet officially approved. For example, a medication called Eltrombopag has been used successfully to increase the count of blood cells that aid in clotting in patients diagnosed with certain inherited blood disorders, including BSS. Also, factor VII, a protein involved in blood clotting, has been used effectively in patients with another clotting disorder but is not yet approved for use in BSS patients. However, guidelines from the United Kingdom and the British Society of Haematology recommend its use for severe bleeding in BSS patients.
Additionally, certain stem cell transplants have have been performed in BSS patients. However, comprehensive data on this approach is limited, and it is usually reserved for patients with severe bleeding disorders who have developed many antibodies.
Managing BSS in pregnant patients requires particular care. Future parents should be counseled on the potential risks such as severe bleeding because of the condition. During pregnancy, the management of BSS requires the involvement of obstetrics and haematology experts. During labour, neuraxial anesthesia (epidural or spinal) is avoided due to the bleeding risks and certain medications can be used to control severe bleeding. Monitoring in the postpartom period is crucial, and newborns of mothers with BSS should be closely checked for any abnormality in their blood count.
What else can Bernard-Soulier Syndrome be?
When doctors try to diagnose BSS, a blood disorder, they start by thinking about a range of bleeding conditions, including deficiencies in clotting factors. They look at the patient’s symptoms and may focus on certain conditions based on these. For example, if a patient has bleeding from the skin and mucus membranes, has unusually large platelets, and a low platelet count, this suggests a disorder that affects platelets. Having large platelets or low platelet count is not a feature of hemophilia, a different blood disorder.
While doctors are making a diagnosis, immune thrombocytopenia (ITP) is frequently considered as it can appear quite similar to BSS. Here’s how they can be differentiated:
- ITP is typically not inherited, while BSS often is, particularly in areas where marriages between relatives are common.
- Patients with BSS usually don’t respond to the usual treatments for ITP like intravenous immunoglobulin and steroids.
Despite these differences, many patients are mistakenly diagnosed with ITP and might even receive unnecessary surgery before being correctly diagnosed with BSS.
Von Willebrand Disease (vWD) might also come up in a diagnosis because it shares a number of symptoms with BSS. Specific tests can differentiate BSS from vWD.
Some other inherited disorders that doctors might consider when diagnosing BSS are:
- May-Hegglin abnormality
- Myosin-Heavy chain 9 (MYH-9) disorders
- Grey Platelet syndrome, which lacks certain platelet granules
- Paris Trousseau Platelet disorder, associated with a specific chromosome abnormality
- DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly of the face, each associated with a specific chromosome deletion.
There is also a condition similar to BSS called Mediterranean macrothrombocytopenia, as well as extremely rare cases of an autoantibody to a specific platelet protein, confusingly referred to as Pseudo-BSS.
What to expect with Bernard-Soulier Syndrome
People with BSS, or Bernard-Soulier syndrome, can lead normal lives if they receive effective primary care and learn about how to avoid injuries. They also need to take certain precautions to stay safe. By practicing preventive care and planning carefully for any necessary surgeries, they can minimize the potential for bleeding episodes. It’s also important for these patients to always wear alert bracelets. These bracelets can inform emergency services about their condition in case of an accident.
Possible Complications When Diagnosed with Bernard-Soulier Syndrome
People with BSS often experience bleeding complications due to the condition’s nature. Other problems can include:
- The risk of transmitting infections from the blood, although this is small due to intensive screening of blood products. However, bacteria can still be transmitted due to the warmer storage conditions of platelets.
- Autoantibodies developing as a result of repeated blood transfusions. While immune system reactions can be avoided with HLA-matched products, this may not be an option in a hurry or emergency situations.
- Iron deficiency anemia, especially in women who have heavy menstrual bleeding. This can lead to constant tiredness and loss of work hours.
- Antibodies can be passed to the fetus during pregnancy, leading to potentially life-threatening neonatal thrombocytopenia.
Other illnesses can hide the presence of BSS and it may only be detected by chance or during a serious event. For instance, cases have been reported where a patient with multiple myeloma developed BSS, and another where a patient developed serious bleeding issues after thyroid surgery.
Patients with both BSS and coronary artery disease (CAD) especially need careful management. Before heart procedures, they should receive platelet transfusions to reduce their risk of bleeding. There is also an argument for reducing dual-antiplatelet therapy (DAPT) to single-antiplatelet therapy. Additional platelet transfusions, then drug-eluting stents should follow these coronary procedures. And lastly, after the procedure, DAPT is still supported.
Preventing Bernard-Soulier Syndrome
Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder that can often be mistaken for another condition known as ITP. As a result of this confusion, unnecessary medical actions might be done, for instance, removing the spleen. BSS usually shows up with symptoms like low blood platelet count and unusually large platelets.
BSS often gets confused with van Willebrand disease (vWD), especially type IIB vWD and platelet-type vWD, as they have similar symptoms. If there is little or no blood platelet clumping in response to a chemical called ristocetin, it’s a strong sign that the person might have BSS. A laboratory test known as flow cytometry generally confirms the diagnosis of BSS.
The best way to manage BSS is to take preventative measures to avoid bleeding problems. Those who have been diagnosed with the BSS and their families must be taught about how the disease works and the potential bleeding issues they may face. There are certain environmental and medicinal factors that can raise the risk of bleeding. These factors include participating in contact sports, accidental injuries, using a hard toothbrush, taking nonsteroidal anti-inflammatory drugs, and aspirin. It’s important to know about these risks and how to avoid them. The patients and their families also need to learn techniques to stop bleeding, like applying pressure for nosebleeds or gum bleeding.
Whenever a healthcare team is caring for someone with BSS, they must make plans to manage potential bleeding. Blood platelets that match the tissue type of the patient (HLA-matched platelets) must be ready for anyone needing planned surgeries. It’s also crucial that all these patients be able to access a hospital that can offer 24-hour emergency care in case of uncontrolled bleeding.