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. 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.
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. 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. These mutations are heterogeneous and could be nonsense, missense, frameshift, deletion, or insertion. The majority of these mutations inherited in an autosomal recessive pattern; however, rare cases of autosomal dominant inheritance have been reported. 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).
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. BSS is inherited via autosomal genes, hence it is prevalent in both male and female patients.
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.
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).
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.
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.
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.
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.
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. 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. Spontaneous intracranial hemorrhage or intraarticular hemorrhages are not common. Fatalities from BSS are very rare.
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. A significant monoallelic mutation is the 'Ala156Val' mutation in the GPIB-alpha, called the Bolzano mutation. Although most patients will only have mild thrombocytopenia, and infrequent bleeding episodes, a few patients have been described where the bleeding was very severe. Similarly, other mutations have also been described where only mild thrombocytopenia was noted with mild bleeding episodes.
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. 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.
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. The peripheral smear would usually present with thrombocytopenia and large platelets. The bleeding time is significantly prolonged. The platelet function analyzer (PFA-100) closure time is prolonged, usually in the adenosine-diphosphate (ADP) and epinephrine cartridges.
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.
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. 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. It is crucial to maintain a high index of suspicion in such patients and pursue molecular testing.
Treatment Directed Towards Bleeding Episodes
Potentially beneficial strategies not approved for patients with BSS:
Pregnancy in patients with BSS requires special consideration.
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.
Many patients with BSS are diagnosed with immune thrombocytopenia due to similar presentations. Features which may help in differentiating BSS from ITP are:
Despite this, many patients mistakenly diagnosed with ITP end up receiving splenectomy before being diagnosed with BSS.
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. Also, patients with platelet type vWD carry a mutation in the GP1b-alpha. However, this mutation increases the affinity of platelets to vWF.
Other Inherited Disorders in the Differential Diagnosis of BSS
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.
The patients with BSS frequently suffer from bleeding complications due to the nature of the disease. Other complications include:
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.
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.
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.
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