Bernard-Soulier syndrome

Bernard-Soulier syndrome
Bernard-Soulier syndrome. (Image courtesy of Melih Aktan M.D.)
ICD-10	D69.1
ICD-9	287.1
OMIM	231200
DiseasesDB	1356
eMedicine	ped/230
MeSH	D001606

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [3]

Synonyms and keywords:BSS, giant platelet syndrome; hemorrhagic parous thrombocytic dystrophy; macrothrombocytopenia, familial Bernard-Soulier type; platelet glycoprotein Ib deficiency; Von Willebrand factor receptor deficiency.

Overview

Bernard-Soulier syndrome (BSS) belongs to one the rare hereditary platelet disorders. Bernard-Soulier syndrome characteristically is defined by the presence of giant platelets and thrombocytopenia. Bernard-Soulier syndrome (BSS) was first discovered in 1948. Bernard-Soulier syndrome may be classified into 4 subtypes. Bernard-Soulier syndrome is the result of the absence or decreased expression of the GPIb/IX/V complex on the surface of the platelets. Bernard-Soulier syndrome may be caused by abnormality in the genes for glycoprotein Ib/IX/V. The prevalence of Bernard-Soulier syndrome is approximately 1 per 100,000 individuals worldwide. The initial laboratory test to be done is blood cell counts and blood smears. There are no established risk factors for Bernard-Soulier syndrome. There is sufficient evidence to recommend routine screening for Bernard-Soulier syndrome with newer technologies in current clinical practice. If left untreated, patients with Bernard-Soulier syndrome may progress to develop bleeding manifestations like mucocutaneous bleeding, which can be prolonged and severe. Patients with Bernard-Soulier syndrome usually remarkable for dysfunctional platelets. There is no specific treatment for Bernard-Soulier syndrome, the mainstay of therapy is supportive care.

Historical Perspective

• Bernard-Soulier syndrome (BSS)/ Hemorrhage parous thrombocytic dystrophy/ Congenital hemorrhagic parous thrombocytic dystrophy is very rare disease and it occurs less than 1 case per million population. It as few as only ~100 cases have been reported in the literature.

• Bernard-Soulier syndrome (BSS) was first discovered in 1948 by Jean Bernard and Jean-Pierre Soulier who were French hematologists.
• Bernard-Soulier syndrome (BSS) is an autosomal recessive disease and is often associated with consanguinity.
• Nurden and Caen reported in 1975 that platelets in patients with BSS had absence of major surface membrane glycoprotein complex.

Classification

Bernard Soulier syndrome is classified into 4 subtypes:

Phenotype	Genomic Location	Inheritance	Gene	Locus MIM number
Bernard-Soulier syndrome, type A1	17p13.2	Autosomal Recessive	GP1BA	606672
Bernard-Soulier syndrome, type B	22q11.21	Autosomal Recessive	GP1BB	138720
Bernard-Soulier syndrome, type C	3q21.3	Autosomal Recessive	GP9	173515
Giant platelet disorder, isolated	22q11.21	Autosomal Recessive	GP1BB	138720

Pathophysiology

• It is thought that Bernard-Soulier syndrome is the result of the absence or decreased expression of the GPIb/IX/V complex on the surface of the platelets.
• The GPIb/IX/V complex is the receptor for von Willebrand factor (vWF).
• The GPIb/IX/V complex plays a very important role in hemostasis and thrombosis.
• The GPIb/IX/V complex and von Willebrand factor (vWF) ensure normal primary hemostasis by initiating platelet adhesion at sites of vascular injury.
• The GPIb/IX/V complex binds to von Willebrand factor (vWF). This makes the initial contact, or adhesion, of platelets to exposed vascular endothelium.
• The GPIb/IX/V complex along with von Willebrand factor (vWF) also attach to ruptured plaques in damaged blood vessels.
• This attachment to ruptured plaque in damaged blood vessels is particularly seen at high shear flow rates (>800s-1).
• In the formation of deep venous thrombosis GPIb/IX/V complex along with von Willebrand factor (vWF) plays a very critical role.
• GPIb-IX-V complex is multisubunit in nature consists of 4 subunits.
• Each of the 4 multisubunit is a member of the leucine-rich motif, which contains ~24 amino acid and are involved in such processes such as cell signaling, cell adhesion, and development.
• In addition to its important role in binding to von Willebrand factor (vWF), this N-terminal domain of GPIbα is a pivotal binding site for multiple ligands mediating platelet interactions with matrix which are involved in thrombosis and inflammation.
• On activated platelets and endothelial cells other adhesive ligand include P-selectin, αMβ2 /CD11b/CD18.
• The GPIb-IX-V complex plays very crucial role in coagulation especially in intrinsic pathway which has tendency to bind the receptors for thrombin, Factors XI and XII (having the shortest half life of all clotting factors), kininogen and at last to high molecular weight (HMW).
• With the help of actin filaments, Phe568 and Trp570, GPIb-IX-V plays a crucial role in maintaining the platelets shape.
• GPIb-IX-V/VWF adhesion was enhanced by NADPH (Nicotinamide adenine dinucleotide phosphate) oxidase, (p47 subunit), PI 3-kinase, Hic-5, TRAF4 (TNF receptor-associated factor 4) Lyn, and Syk (spleen tyrosine kinase) proteins.

Causes

• Bernard-Soulier syndrome may be caused by abnormalities in the genes for glycoprotein Ib/IX/V.
• The genes for glycoprotein Ib/IX/V encode for proteins that are usually found on the surface of platelets, the glycoprotein Ib/IX/V receptor.
• Platelets do not adhere to damaged endothelium due to lack of receptors.
• Mutations are found in BP1b-alpha (MW 135 kDa), Gp1b-beta (MW 26 kDa) and GP9 (MW 20 kDa) but not on GP5 (MW 82 kDa).

Differentiating Bernard-Soulier syndrome from Other Disease

• Bernard-Soulier syndrome must be differentiated from
  • Wiskott-Aldrich syndrome (small platelets)
  • X-linked thrombocytopenia (small platelets)
  • May-Hegglin syndrome (giant platelets)
  • Sebastian syndrome (giant platelets)
  • Fechtner syndrome (giant platelets)
  • Epstein syndrome (giant platelets)
  • Idiopathic thrombocytopenic purpura (ITP)- most commonly misdiagnosed BSS as ITP

Epidemiology and Demographics

• The prevalence of Bernard-Soulier syndrome is approximately 1 per 100,000 individuals worldwide.
• Bernard-Soulier syndrome is very rare; until now only ~100 cases have been reported.
• The severity of Bernard-Soulier syndrome increases with age.
• Bernard-Soulier syndrome more commonly affects infants than children and older people.
• Bernard-Soulier syndrome usually affects individuals from Japan, Europe and North America.
• Males and females are affected with equal frequency.
• The majority of Bernard-Soulier syndrome cases are reported in whites of European ancestry.

Risk Factors

• There are no established risk factors for Bernard-Soulier syndrome.
• Autosomal recessive genetic pattern is characteristic of Bernard-Soulier syndrome.
• Bernard-Soulier syndrome patients can be carriers when they receive one normal gene and one abnormal gene.
• Risk of Bernard-Soulier syndrome in a child is 25% to 50% with each pregnancy when two carrier parents both pass the abnormal gene.

Screening

• There is sufficient evidence to recommend routine screening for Bernard-Soulier syndrome with newer technologies in current clinical practice like the following.

PFA-100(Platelet Function Analyzer)

• The most common screening test used for screening the patients with BSS
• PFA-100 helps in differentiate between
  • Aspirin-induced defect and
  • Severe platelet dysfunction
• In other bleeding disorders like storage pool disorders PFA-100 is less sensitive.

Ultegra

• Ultegra an automated whole blood assay.
• Ultegra is very easy to use and can be done at the bedside.
• Ultegra helps in measuring platelet aggregation based on how strong activated platelets binding to fibrinogen.

Natural History, Complications, and Prognosis

• If left untreated, patients with Bernard-Soulier syndrome may progress to develop bleeding manifestations like mucocutaneous bleeding, which can be prolonged and severe.
• Common complications of Bernard-Soulier syndrome include ante, intra, or postpartum hemorrhage in pregnant patients.
• Prognosis is generally good in patients with Bernard-Soulier syndrome is but it is largely based on the severity of the condition.

Diagnosis

Diagnostic Study of Choice

• The diagnostic study of choice for Bernard-Soulier syndrome is ristocetin-induced agglutination.
• Ristocetin is a drug that increases adherence between VWF and GP1b, and this aggregation is not seen in Bernard-Soulier syndrome.

History and Symptoms

The majority of patients with Bernard-Soulier syndrome show the following symptoms: Common symptoms of Bernard-Soulier syndrome patients include:

• Nosebleeds (Epistaxis)
• Prolonged bleeding time (in some cases it is more than 20 minutes)
• Easy bruising
• Severe Menorrhagia in females
• Heavy bleeding following minor injury
• Prolonged bleeding after surgery
• Gingival bleeding
• Cutaneous bleeding
• Petechiae

Less common symptoms of Bernard-Soulier syndrome include:

• Occasionally patients present with:
  • Bastrointestinal bleeding
  • Bleeding after childbirth
  • Blood in stool
  • Blood in vomiting
  • Bleeding without trauma

Physical Examination

Patients with Bernard-Soulier syndrome usually have:

• Mucosal bleeding
• Bruising

Laboratory Findings

• The initial laboratory test to be done is blood cell counts and blood smears.
• The diagnosis of Bernard-Soulier syndrome is based on the presence of a large platelets (diameter 4–10 μ m) with a rounded shape.
• One of the diagnostic criteria of Bernard-Soulier syndrome is prolonged bleeding time.
  • Moderately prolonged bleeding time: 5–10 min
  • Severely prolonged bleeding time: >20 min
• On blood smear manual counting is necessary as the large platelets are often mistaken as lymphocytes.
• FVIII-von Willebrand factor levels are measured.
• Aggregation responses to thrombin is decreased.
• In Bernard-Soulier syndrome patients we can observe the defect in prothrombin consumption.
• Defect in prothrombin consumption is due to effective binding of FXI due to a lack of GPIb and decrease in GPIb-fibrin-dependent thrombin.
• CD42 a-d a monoclonal antibody detected in flow cytometry also helps in the diagnosis and confirmation of the diagnosis in the patients with Bernard-Soulier syndrome.
• Genetic testing also aids in diagnosing patients with Bernard-Soulier syndrome.
• Immunoblotting also helps in diagnosing patients with Bernard-Soulier syndrome.
• Other new tests like platelet glycoprotein analysis by SDS-polyacrylamide gel separation are still being studied.

Electrocardiogram

• There are no ECG findings associated with Bernard-Soulier syndrome.

X-ray

• There are no x-ray findings associated with Bernard-Soulier syndrome.

Echocardiography or Ultrasound

• There are no ultrasound findings associated with the Bernard-Soulier syndrome.

CT scan

• There are no CT scan findings associated with Bernard-Soulier syndrome.

MRI

• There are no MRI findings associated with the Bernard-Soulier syndrome.

Treatment

Medical Therapy

• There is no specific treatment for Bernard-Soulier syndrome; the mainstay of therapy is supportive care.
• Pharmacologic medical therapy is recommended among patients with bleeding episodes:

Antifibrinolytic agents

• ε-aminocaproic acid
• Tranexamic acid
• Both are very effective in controlling the mucosal bleeding

Platelet transfusion

• Platelet transfusion is the alternative when the patient is undergoing any surgical procedure.

Desmopressin acetate (DDAVP)

• Desmopressin helps in shorten the bleeding time by increasing the release of vWF from endothelium.
• Desmopressin also helps in minor bleeding episodes.
• In patients who are suffering with congenital platelet disorders recombinant activated factor VII have been shown useful.

Surgery

• Surgical intervention is not recommended for the management of Bernard-Soulier syndrome.

Primary Prevention

• There are no established measures for the primary prevention of the Bernard-Soulier syndrome.

Secondary Prevention

• There are no established measures for the secondary prevention of Bernard-Soulier syndrome.