Continuing Education Activity

Bernard-Soulier syndrome is a rare inherited blood clotting disorder that is characterized by unusually giant platelet cells, thrombocytopenia, and prolonged bleeding time. Affected individuals tend to bleed excessively and incur spontaneous ecchymoses. This activity reviews the evaluation and treatment of Bernard-Soulier syndrome and highlights the role of the healthcare team in evaluating and managing patients with this condition.

Objectives:

• Review the history and physical presentation of Bernard-Soulier syndrome.
• Explain the pathophysiology behind Bernard-Soulier syndrome.
• Outline the treatment and management options available for Bernard-Soulier syndrome.
• Describe interprofessional team strategies for improving care coordination and communication to advance Bernard-Soulier syndrome treatment and improve outcomes.

Introduction

Bernard-Soulier syndrome (BSS) is an extremely rare inherited blood clotting disorder that is characterized by giant platelet cells, thrombocytopenia, and prolonged bleeding time. In 1948, Jean-Bernard and Jean-Pierre Soulier described the first male patient who presented with repeated episodes of bleeding throughout his life and eventually died at the age of 28 years from an intracranial hemorrhage sustained after a bar fight.[1][2] BSS involves a defect of the GPIb-IX-V complex, an essential platelet receptor complex that principally binds with the von Willebrand factor (vWF). However, it has multiple other functions in inducing thrombosis and hemostasis.[3]

Etiology

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.[4] 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.[4] These mutations are heterogeneous and could be nonsense, missense, frameshift, deletion, or insertion.[5][4] The majority of these mutations inherited in an autosomal recessive pattern; however, rare cases of autosomal dominant inheritance have been reported.[4] Patients with mutations in both alleles (autosomal recessive inheritance) are referred to as having biallelic BSS (bBSS), and those with a mutation in only a single allele (autosomal dominant inheritance) are often referred to as monoallelic BSS (mBSS).[2]

Epidemiology

The prevalence of the disease is estimated to be 1 per million. However, due to under-recognition and misdiagnosis, the prevalence may be much higher than the estimated value.[4][6] BSS is inherited via autosomal genes, hence it is prevalent in both male and female patients.[2][7] 

As the disease is widely underrecognized, it is not often diagnosed in the early stages of life, and the average age of diagnosis is 16 years. Many patients are diagnosed with idiopathic thrombocytopenic purpura (ITP) and even go on to receive a splenectomy. Hence, it is imperative to understand the presenting features and pathophysiology of BSS to correctly diagnose the disease.[4] 

Pathophysiology

The GPIb-IX-V complex is expressed on the platelet surface. By facilitating platelet adhesion to the subendothelium, the GPIb-IX-V complex leads to clot formation whenever the vascular subendothelium is exposed or a plaque ruptures, hence the activity of GPIb-IX-V complex is also critical in deep venous thrombosis (DVT).[3] 

The most important function of the GPIb-IX-V complex is to bind with VWF and initiate a signaling cascade that would activate the platelet integrin GPIIb-IIIa leading to platelet aggregation. Although VWF is also a weak agonist, a full activation signal is required via the thromboxane A2 and ADP dependent signaling pathway to activate the platelets.[3][8]

The N-Terminal of GPIb-Alpha plays a critical role in platelet mediated coagulation by providing binding sites to high molecular weight (HMW) kininogen, Factors XI, and XII and alpha-thrombin. The same N-terminal of GPIb-alpha is a primary binding site for multiple ligands. It serves as a pivotal point for the cross-talk between platelets and leukocytes in thrombosis and inflammatory response.[3][8]

The GPIb-IX-V also plays a role in maintaining platelet shape by linking the platelet surface to a sub-membranous network of actin filaments, the platelet membrane skeleton. This involves the central portion of the cytoplasmic tail of GPIb-alpha, particularly Phe568 and Trp570, which provides a binding site for the actin-associated protein, filamin A.[3]

Considering all the functions of the GPIb-IX-V complex, one can understand that a mutation in the encoding genes could lead to reduced activation of the platelets, defective adhesion, and subsequently inadequate clot-forming capability. In addition to this, the defects in the complex can also explain the giant platelets in patients with BSS.

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.[8][7] 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.[2][1] Spontaneous intracranial hemorrhage or intraarticular hemorrhages are not common. Fatalities from BSS are very rare.[2]

The patients with BSS who present in adulthood are usually those with mBSS. Such patients have less number of bleeding episodes due to preserved platelet numbers.[2][9] A significant monoallelic mutation is the 'Ala156Val' mutation in the GPIB-alpha, called the Bolzano mutation.[9][9] Although most patients will only have mild thrombocytopenia, and infrequent bleeding episodes, a few patients have been described where the bleeding was very severe.[9] Similarly, other mutations have also been described where only mild thrombocytopenia was noted with mild bleeding episodes.[2]

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.[10] 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.[10] 

Evaluation

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 platelet count between 20 to 100 billion/L. However, a count as low as 10 x 10^9/L has been reported.[8] The peripheral smear would usually present with thrombocytopenia and large platelets. The bleeding time is significantly prolonged.[11] The platelet function analyzer (PFA-100) closure time is prolonged, usually in the adenosine-diphosphate (ADP) and epinephrine cartridges.[11]  

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.[7] 

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.[12] 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.[3] It is crucial to maintain a high index of suspicion in such patients and pursue molecular testing.[9]

Treatment / Management

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.[2]
• Patients, their family members, and their providers should be advised extensively over 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.[2] 
• 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.[13]
  • Alloimmunization - HLA-matched platelets are ideal for transfusion; however, they may not be available in emergent conditions.[2] 
  • 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.[7]
• Antifibrinolytic therapy - Tranexamic acid has been used successfully in the management of mucocutaneous bleeding, 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.[14] However, clinicians must be aware of the potential adverse effect of severe hyponatremia and seizures associated with repeated DDAVP use.[14]

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.[15]
• 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.[11][16]
• Allogeneic stem cell transplant has been used in patients with BSS. However, there is scarce data.[17][18] This is usually reserved for patients with too many antibodies and with a severe bleeding disorder.

Pregnancy in patients with BSS requires special consideration.[2]

1. 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.
2. Antenatal: Manage specialized units in consultation with high-risk obstetrics and hematology. The mother should be checked for HLA type, anti-platelet antibodies, and assessed for the risk of developing neonatal alloimmune thrombocytopenia (FNAIT).
3. 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. 
4. Post-partum: All patients must be monitored for eight weeks, at least for bleeding symptoms. 
5. 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 neonate very closely. 

Differential Diagnosis

The differential diagnosis for BSS starts with considering a wide variety of bleeding disorders, including factor deficiencies. Mucocutaneous bleeding, coupled with large platelets and thrombocytopenia, points towards a platelet disorder. The presence of large platelets or thrombocytopenia on peripheral smear review is NOT a feature of hemophilia. 

Immune Thrombocytopenia

Many patients with BSS are diagnosed with immune thrombocytopenia due to similar presentations. Features which may help in differentiating BSS from ITP are:

• Presence of family history of ITP
• Failure to respond to first-line treatment like intravenous immunoglobulin and steroids
• Typical findings for BSS on light aggregation studies and flow cytometry

Despite this, many patients mistakenly diagnosed with ITP end up receiving splenectomy before being diagnosed with BSS.[2] 

Von-Willebrand Disease (vWD)

The patients with type IIB vWD has the closest clinical phenotype with BSS. Due to the increased affinity of large multimers with platelets, the platelets are cleared rapidly, leading to thrombocytopenia. The platelets are also large in type IIB vWD. However, the platelets express an increased aggregation in response to ristocetin. In comparison, patients with BSS always have low to absent aggregation of platelets in response to ristocetin.[19] Also, patients with platelet type vWD carry a mutation in the GP1b-alpha. However, this mutation increases the affinity of platelets to vWF.[20]

Other Inherited Disorders in the Differential Diagnosis of BSS

1. May-Hegglin abnormality
2. Myosin-Heavy chain 9 (MYH-9) disorders
3. Grey Platelet syndrome-lack of intra-platelet granules and confirmed by electron microscopy.[21]
4. Paris Trousseau Platelet disorder (PTPD) - deletion of the terminal end of the long arm of chromosome 11 that includes band 11q24.1, 11q terminal deletion disorder.[22]
5. DiGeorge syndrome (DGS); velocardiofacial syndrome (VCFS, or Shprintzen syndrome);[23] conotruncal anomaly face - all syndromes share the microdeletion of chromosome 22q11.2 - Patients usually are heterozygotes for BSS.[24]
6. Mediterranean macrothrombocytopenia[25]

Rare cases of autoantibody to GPIb complex have been described, which are called Pseudo-BSS.[26][27]

Prognosis

If BSS patients received good primary care and education about avoiding trauma, and follow precautions, they can live their lives quite normally. Preventive care and meticulous planning for elective surgeries is needed to minimize bleeding events. Alert bracelets must be worn by patients at all times to alert emergency services in case of trauma.[1]

Complications

The patients with BSS frequently suffer from bleeding complications due to the nature of the disease. Other complications include:

1. Transmission of bloodborne pathogens - although the risk is minimal due to extensive screening of blood products. Still, bacterial transmission can occur due to platelets being stored at a higher temperature. 
2. Development of autoantibodies due to repeated blood transfusions.
3. Iron deficiency anemia, especially in women who suffer from menorrhagia- results in constant fatigue and loss of work hours. 
4. Transmission of antibodies across the placenta may lead to fetal/neonatal alloimmune thrombocytopenia.

Consultations

All health-care providers caring for patients diagnosed with BSS must emphasize on preventive care to patients and families. In addition to these, the following consultants must be involved.

• A hematologist (pediatric or adult) must be involved in case the patient requires emergency or elective surgery.
• In the event of planning for pregnancy, high-risk obstetrics and gynecology teams must be involved.
• Transfusion medicine must be consulted whenever blood products are required to meticulously screen for antibodies and provide for HLA-matched platelets. 

Deterrence and Patient Education

Bernard-Soulier syndrome is a rare inherited bleeding disorder. It is most commonly misdiagnosed as immune thrombocytopenia, which leads to unnecessary interventions like splenectomy. The most common presentation is that of bleeding child, presenting with thrombocytopenia and giant platelets. The most common differential diagnosis is vWD, especially type IIB vWD and platelet-type vWD, that have a similar presentation. Low to complete absence of platelet aggregation in response to ristocetin, strongly points towards a diagnosis of BSS. Flow cytometry usually clinches the diagnosis of BSS. 

Preventative measures are the best for preventing bleeding complications from BSS. Patients diagnosed with BSS and their families must be educated about the nature of the disease and the potential bleeding complications. They must be taught about the environmental (contact sports, trauma, using a soft toothbrush, etc.) and medicinal (non-steroidal anti-inflammatory drugs, aspirin, etc.) factors that can increase the risk of bleeding, and how to avoid them. The patients and the families should be educated on techniques to stop bleeding (pressure application for epistaxis, gum bleeding, etc.).

Healthcare teams involved in the management of patients diagnosed with BSS must plan ahead of time to mitigate bleeding. HLA-matched platelets must be made available for patients requiring elective surgeries. All patients must be registered in a hospital that can provide 24-hour emergency care in the advent of uncontrolled bleeding. 

Pearls and Other Issues

1. Maintain a high index of suspicion for BSS in a bleeding patient with large platelets and thrombocytopenia, especially if they do not respond to the first-line treatment for ITP. 
2. Low to absent response to ristocetin is a reliable indicator for the diagnosis of BSS (rules out vWD). Flow cytometry is used to confirm the diagnosis. 
3. Platelet transfusion is the first line of treatment for a bleeding patient. Antifibrinolytic can be used to control mucocutaneous bleeding. 
4. Desmopressin has no role in the treatment of BSS.
5. Activated rfVII is not approved for BSS, but has been used in anecdotal cases with success.
6. HLA-matched platelets must be used in all planned surgeries. 
7. Prevention of bleeding is the best approach in patients diagnosed with BSS. Extensive education programs must be conducted for patients and families with BSS.

Enhancing Healthcare Team Outcomes

The diagnosis of BSS requires a high index of suspicion. A diagnosis of BSS must be considered in any bleeding patient with thrombocytopenia and large platelets, especially if they present in childhood. All patients with BSS must be registered in centers that can provide 24-hour, tertiary level care in the event of bleeding. All healthcare providers involved in the management of patients with BSS must be in close communication with each other when managing them for elective or emergent procedures. 

Due to the rarity of the condition, there is only level 3 evidence at best to support this information.