Bernard-Soulier Syndrome (BSS)

Bernard-Soulier syndrome (BSS) is a rare autosomal-recessive inherited mucocutaneous bleeding disorder of blood clotting (coagulation) characterized by unusually large platelets, and unusually giant low platelet count (thrombocytopenia), and prolonged bleeding time (difficulty in clotting) bleed excessively and incur spontaneous ecchymoses. BSS involves a defect of the GPIb-IX-V complex, an essential platelet receptor complex that principally binds with the von Willebrand factor (vWF). Affected individuals tend to bleed excessively and bruise easily. Most cases of Bernard-Soulier syndrome are inherited in an autosomal recessive genetic pattern.

Symptoms

The symptoms of Bernard-Soulier syndrome, which are typically apparent at birth and continue throughout life, may include the tendency to bleed excessively from cuts and other injuries, nosebleeds (epistaxis), and/or an unusually heavy menstrual flow in women. Some babies and children with BSS have no symptoms and the disorder does not present until adult life. People with this disease also bruise easily and the bruises tend to linger. Bleeding from very small blood vessels under the skin (subcutaneous) may cause small or widespread areas of small red or purple-colored spots (purpura or petechiae). Spontaneous bruising, gum bleeding, epistaxis, and heavy menstrual bleeding are common presentations

Bernard–Soulier syndrome often presents as a bleeding disorder with symptoms of:^[rx]

Perioperative (and postoperative) bleeding
Bleeding gums
Bruising
Epistaxis (nosebleeds)
Abnormal bleeding (from small injuries)
Unusual menstrual periods

Causes

BSS is a genetic disorder that affects the ability of the platelets in the circulating blood to bind with a damaged blood vessel and hence clot blood. These platelets are missing an essential protein called the glycoprotein Ib-IX-V complex (GPIb). The Gp1b complex is composed of 4 protein subunits that bind closely together (GP1b-alpha, GP1b-beta, GP9, and GP5). BSS is caused by mutations in one of the Gp1b complex genes- so far mutations have been found in BP1b-alpha, Gp1b-beta, and GP9 but no mutations have been found in GP5. Normally the GP1b complex sticks out of the platelet’s surface and binds with another protein found in the circulating blood called von Willebrand factor. If one of these proteins is missing or abnormal, they cannot bind correctly to begin the clotting process and excessive bleeding results.

Bernard-Soulier syndrome is usually inherited in an autosomal recessive genetic pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier of the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

BSS is the result of genetic mutations encoding for GPIb-alpha (GPIBA), GPIB-beta (GPIBB), and GPIX (GP9), which are 3 of the four subunits that make the GPIb-IX-V complex.[rx] Nearly 112 mutations were identified in a study of nearly 211 families with BSS. The mutations were mainly identified in the GP1BA (28%), GP1BB (28%), or GP9 (44%) genes.[rx] These mutations are heterogeneous and could be nonsense, missense, frameshift, deletion, or insertion.[rx][rx] The majority of these mutations are inherited in an autosomal recessive pattern; however, rare cases of autosomal dominant inheritance have been reported.[rx] Patients with mutations in both alleles (autosomal recessive inheritance) are referred to as having biallelic BSS (BSS), and those with a mutation in only a single allele (autosomal dominant inheritance) are often referred to as monoallelic BSS (BSS).[rx]

Related Disorders

Symptoms of the following disorders can be similar to those of Bernard-Soulier syndrome. Comparisons may be useful for a differential diagnosis:

May-Hegglin anomaly is a rare inherited disorder of blood platelets and certain white blood cells characterized by abnormally large platelets. Some people with this disorder have symptoms from birth while others are without symptoms for life. Symptoms may include nosebleeds, purple-colored spots on the skin (purpura), excessive bleeding from the mouth during dental work, and/or headaches. Some people with the May-Hegglin anomaly may experience muscular weakness on one side of the body because of abnormal bleeding inside the brain (intracranial hemorrhage). (For more information on this disorder, choose “May Hegglin” as your search term in the Rare Disease Database.) May Hegglin does not usually cause bleeding in newborn babies, unlike BSS.

Hemophilia is a rare inherited blood clotting (coagulation) disorder caused by inactive or deficient blood proteins (usually factor VIII). Factor VIII is one of several proteins that facilitate blood clotting. Hemophilia is found in males almost exclusively and can be classified as mild, moderate, or severe depending upon the percentage of clotting factors present in a person’s blood. The most serious symptom of hemophilia is uncontrolled internal bleeding that may begin spontaneously without any apparent cause. Internal bleeding may cause permanent damage to the joints and muscles. People with hemophilia bleed for a longer period than people who have the normal percentage of active clotting factors in their blood. Bruises and trauma can trigger episodes of serious internal bleeding in males with this disorder. (For more information on this disorder, choose “Hemophilia” as your search term in the Rare Disease Database.)

Thrombasthenia of Glanzmann and Naegeli is a rare inherited blood clotting (coagulation) disorder characterized by impaired function of the specialized red blood cells (platelets) that are essential for proper blood clotting. Symptoms may include abnormal bleeding, and/or hemorrhage, easy bruising, bleeding from the gums, nosebleeds (epistaxis), and/or large red or purple-colored spots on the skin (purpura). The symptoms of Thrombasthenia of Glanzmann and Naegeli are not progressive and may improve with age. (For more information on this disorder, choose “Thrombasthenia” as your search term in the Rare Disease Database.)

Von Willebrand disease is a rare inherited blood clotting (coagulation) disorder that varies widely in its effects. Most people have relatively mild diseases and are not diagnosed until they are adults. A small number start to have problems during infancy or early childhood, such as prolonged bleeding and an abnormally slow blood clotting time. Symptoms may include bleeding from the gastrointestinal tract, nosebleeds, bleeding from the gums, and/or easy bruising. People with this disorder may also bleed easily after an injury, childbirth, and/or surgery. These symptoms occur because of a deficiency of factor VIII and the von Willebrand factor. (For more information on this disorder, choose “von Willebrand” as your search term in the Rare Disease Database.)

Storage pool disease (SPD) is a rare inherited disorder of blood platelets characterized by clotting dysfunction due to the platelets’ inability to store certain clotting factors. Symptoms occur mostly in women and may include mild bleeding, nosebleeds, and/or slightly heavier than normal menstrual periods. People with Storage pool disease may also have abnormally low levels of blood platelets (thrombocytopenia).

Platelet disorders are also associated with congenital conditions such as Wiskott-Aldrich syndrome, Down syndrome, and thrombocytopenia with absent radius syndrome. For more information on these disorders choose “Wiskott- Aldrich,” “Down Syndrome,” and “Thrombocytopenia with Absent Radius,” as your search terms in the Rare Disease Database.)

Diagnosis

The diagnosis of Bernard-Soulier syndrome is made by a combination of blood testing to reveal whether platelets are at abnormally low levels (thrombocytopenia), microscopic examination to determine the presence of abnormally large platelets and irregularly shaped platelets, and a test called ‘flow cytometry, which can measure the level of expression of the missing protein ion the outside of platelets affected by Bernard-Soulier syndrome. In recent years, most families are offered molecular genetic testing to identify which gene carries the mutations.

BSS diagnosis is confirmed by Flow cytometric analysis of platelets showing defective binding with CD42a (GPIX), CD42b (GP Ibα), CD42c (GP Ibβ), and CD42d (GPV) antibodies. The defective fragments of GP Ib-IX-V complex after separating with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) may be identified by immunoblotting

History and Physical

The typical presentation of Bernard-Soulier syndrome starts at birth and continues throughout life. It is characterized by bleeding from different sites, epistaxis, cutaneous bleeding, hemorrhage post-trauma, e.g., brain hemorrhage after head trauma, prolonged bleeding after dental procedures, and heavy menstrual bleeding in females.[rx][rx] More rarely reported symptoms are gastrointestinal bleeding and hematuria. Clinical features could be limited to unexplained purpura or bruising only. On the other hand, bleeding could be fatal in about 16% of reported cases.[rx][rx] Spontaneous intracranial hemorrhages or intraarticular hemorrhages are not common. Fatalities from BSS are very rare.[rx]

Complete blood count (CBC) was performed on EDTA blood through Sysmex Kx 2100 automated analyzer Peripheral smear for each sample was also examined. Bleeding time was done by Ivy’s method and the established reference range was 2-9 minutes. Patients with suggestive history and screening tests were evaluated by Platelet Aggregometry. Blood was drawn from a forearm venipuncture with minimal venous occlusion for the platelet aggregation test. The blood samples were processed within two hours of collection.

The citrated blood was centrifuged at 1000-1200 rpm for 7-8 minutes to obtain platelet-rich plasma and collected in a separate tube. The remaining sample was centrifuged at 3500 rpm to obtain platelet-poor plasma (PPP). The platelet count of PRP was adjusted between 200-400 x 10⁹/L. PRP was allowed to stand at room temperature for 30 minutes.

Platelet aggregation was performed by turbidometric technique on Chronolog aggregometer by adding 10 µm/ml Adenosine diphosphate (ADP) and 1.25 mg/ml Ristocetin and collagen 2 μg/ml, Epinephrine 10 µm/ml in 250µL PRP in separate cuvettes. Platelet aggregation was recorded as the percentage change in light transmission after three minutes (maximal platelet aggregation percentage). Samples from normal patients were treated similarly to prepare PRP and PPP and ran simultaneously to serve as controls. The percentage of aggregation was compared with controls and the normal reference ranges provided by the company.

The patients with BSS who present in adulthood are usually those with BSS. Such patients have less bleeding episodes due to preserved platelet numbers.[rx][rx] A significant monoallelic mutation is the ‘Ala156Val’ mutation in the GPIB-alpha, called the Bolzano mutation.[rx][rx] Although most patients will only have mild thrombocytopenia, and infrequent bleeding episodes, a few patients have been described where the bleeding was very severe.[rx] Similarly, other mutations have also been described where only mild thrombocytopenia was noted with mild bleeding episodes.[rx]

The International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) is a useful assessment tool for assessing bleeding disorders. Its utility was tested in a small study, including patients with known inherited platelet disorders. The study demonstrated a specificity of 100%, a positive predictive value of 90%, and a negative predictive value of 100% with the use of this assessment tool.[rx] Similarly, other bleeding assessment tools like Molecular and Clinical Markers for the Diagnosis and Management of type 1-VWD and World Health Organization Bleeding Assessment Tool are also present for similar purposes. An electronic version of MCMDM-type-1 vWD was developed in 2010.[rx]

BSS should be considered in the differential diagnosis of any patient who presents with a prolonged bleeding history, especially if the bleeding history started from early childhood.

Most patients with BSS have a platelet count between 20 to 100 billion/L. However, a count as low as 10 x 10^9/L has been reported.[rx] The peripheral smear would usually present with thrombocytopenia and large platelets. The bleeding time is significantly prolonged.[rx] The platelet function analyzer (PFA-100) closure time is prolonged, usually in the adenosine-diphosphate (ADP) and epinephrine cartridges.[rx]

The platelet aggregation studies (also called light transmission aggregometry) demonstrate a reduced response to ristocetin that is not corrected by the addition of normal plasma. This feature helps to distinguish BSS from von Willebrand disease (VWD). The responses to ADP, collagen and arachidonic acid are normal. However, in a few patients, platelet aggregation in response to thrombin is reduced.[rx]

Flow cytometry of platelet glycoprotein is a confirmatory test. It demonstrates marked reduction of CD42a (GPIX) and CD42b (GPIb-alpha). Since flow cytometry requires only small volumes of blood, this is an appropriate test for neonates, infants, and young children.[rx] Molecular genetics can identify genetic abnormalities and identify affected family members as well.

In patients with mBSS, specifically, in those with Bolzano mutation or other similar mutations, the GPIb-IX-V complex is present in normal numbers, albeit is defective and cannot bind to VWF. In such patients, the near absent ristocetin-induced platelet aggregation serves as a good diagnostic tool.[rx] It is crucial to maintain a high index of suspicion in such patients and pursue molecular testing.[rx]

Treatment

Platelet transfusion is used to treat Bernard-Soulier syndrome when surgery is necessary or when there is a risk of life-threatening hemorrhage. Some patients with Bernard-Soulier syndrome become resistant (refractory) to platelet transfusions because they develop antibodies against the GPIb protein- to reduce this risk it is now recommended that specially selected platelet transfusions (from HLA-matched single donors) should be used. Where HLA-matched platelets are not available, leucocyte-depleted platelets can be used (these are platelet transfusions from which contaminating white blood cells-leucocytes- have been removed). People with this disorder should not take aspirin or other related drugs because these medications affect the blood’s ability to clot (platelet aggregation). It is suggested that acetaminophen, which is present in medications such as Tylenol, is used for the relief of mild pain. Antifibrinolytic agents (drugs which delay the breakdown of blood clots) are often useful to help reduce bleeding after a minor surgery (eg dental surgery) or for prolonged nosebleeds. The most commonly used antifibrinolytic drug is tranexamic acid (also known as epsilon aminocaproic acid).

Preventive Care

Patients diagnosed with BSS should be educated extensively about the risks of bleeding. They should carry ‘alert cards’ or wear ‘alert bracelets’ clearly identifying the diagnosis of BSS. They should be registered with a center that can provide emergent treatment 24 hours a day should they present with a bleeding episode. The patients should also be educated on maintaining dental hygiene, avoiding high-risk sports (especially contact sports), and applying pressure for epistaxis.[rx]
Patients, their family members, and their providers should be advised extensively on which medications can increase the risk of bleeding (anti-histamines, non-steroidal anti-inflammatory drugs, and certain antibiotics). Similarly, foods, beverages, and herbal medicines that can affect the platelet function or number must be avoided.
All patients with BSS, especially women, can suffer from iron deficiency due to excessive bleeding and should be monitored closely for the same and supplemented with iron if needed.[rx]
HLA-typing should be done for each patient at the time of diagnosis. All attempts should be made to procure HLA-matched platelets before transfusion.

Treatment Directed Towards Bleeding Episodes

Platelet transfusions – These are the first line of treatment in patients with BSS, who present with acute hemorrhage or are preparing for elective surgery. However, with each transfusion comes the risk of alloantibody formation and a minuscule risk of transmission of pathogens.
- Transmission of bacteria – As platelets are stored at a higher temperature (20 to 24 degrees Celcius), there is always a risk of bacterial growth and transmission. The risk is much higher with whole-blood-derived platelets compared to apheresis-derived platelets.[rx]
- Alloimmunization – HLA-matched platelets are ideal for transfusion; however, they may not be available in emergent conditions.[rx]
- Antibodies against glycoproteins – Although this is a more common phenomenon in patients with Glanzman thrombocytopenia (GT); patients with BSS can also develop antibodies against glycoproteins that they lack.[rx]
Antifibrinolytic therapy – Tranexamic acid has been used successfully in the management of mucocutaneous bleeding, and menorrhagia, in conjunction with local efforts like nasal packing, compression sponges, hormonal treatment, etc. However, the use of antifibrinolytics should be avoided in patients with pulmonary hemorrhage or those with active hematuria due to the risk of formation of intraluminal clots leading to respiratory failure and renal failure, respectively.
Desmopressin (DDAVP) – Releases vWF from the platelets. Due to a defective GPIB-IX-V complex, the utility of DDAVP in the management of BSS is severely limited. Only anecdotal reports suggest the use of DDAVP.[rx] However, clinicians must be aware of the potential adverse effect of severe hyponatremia and seizures associated with repeated DDAVP use.[rx]

Potentially beneficial strategies not approved for patients with BSS:

In a small phase II clinical trial, the thrombopoietin receptor agonist, Eltrombopag, was successfully used in increasing the platelet count in patients diagnosed with inherited thrombocytopenias. One of the five patients had monoallelic BSS. Eltrombopag is not approved for treating thrombocytopenia secondary to BSS.[rx]
Recombinant factor VII (rfVII) has been approved for use in patients with Glanzmann’s thrombasthenia (GT), but not in patients with BSS. There are reports of successful use of rfVII in patients with BSS. The United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) 2006 guidelines and the British Society of Haematology (BSH) platelet transfusion guidelines both recommend the use of recombinant factor VII (rfVII) in patients with GT or BSS in the event of severe bleeding.[rx][rx]
Allogeneic stem cell transplant has been used in patients with BSS. However, there is scarce data.[rx][rx] This is usually reserved for patients with too many antibodies and with a severe bleeding disorder.

Pregnancy in patients with BSS requires special consideration.[rx]

Counseling prospective parents: Identify potential risk factors (consanguineous marriage, parents are carriers, etc.) for the fetus to develop BSS. In women with BSS, the potential risk of hemorrhage should be discussed. Neonates will not develop homozygous BSS unless both parents are carriers.
Antenatal: Manage specialized units in consultation with high-risk obstetrics and hematology. The mother should be checked for HLA type, and anti-platelet antibodies, and assessed for the risk of developing neonatal alloimmune thrombocytopenia (FNAIT).
Labour: Neuraxial anesthesia is contraindicated as hemostasis cannot be guaranteed. The use of uterotonics is encouraged in the second stage of labor. HLA-matched platelets and tranexamic acid should be used if needed. The rfVII can be used in severe bleeding.
Post-partum: All patients must be monitored for eight weeks, at least for bleeding symptoms.
Neonates: The risk of FNAIT is high, especially in mothers diagnosed with BSS requiring multiple platelet transfusions throughout their lives. Such patients have anti-GPI antibodies that can cross the placenta and affect the normal platelets of the neonate. Monitor the blood count of neonates very closely.
Genetic counseling is recommended for people with Bernard-Soulier syndrome and their families. Another treatment is symptomatic and supportive.