Bernard-Soulier Disease (BSS)

At a Glance

Bernard Soulier Syndrome (BSS) is a rare inherited bleeding disorder, rarely acquired with myelodysplasia/acute myelogenous leukemia (AML), with an estimated prevalence of 1 in 1 million births. BSS is an autosomal recessive disorder, rarely autosomal dominant, with asymptomatic heterozygous carriers.

BSS is characterized by moderate to severe mucocutaneous bleeding and surgical bleeding, large granular platelets, variable thrombocytopenia (range 15,000-200,000), and abnormal platelet aggregation in the presence of ristocetin, a peptide antibiotic. It is seen with increased frequency in consanguineous marriages and typically presents in early childhood, often in infancy.

Common bleeding symptoms reported include menorrhagia, ecchymosis without trauma, gastrointestinal hemorrhage, dental bleeding, epistaxis, and petechiae.

Mutations in genes responsible for GP-1bα, GP-1bβ, or GP-IX can lead to a defective or improperly assembled GP-1b/IX/V complex. This complex is the principal receptor for von Willebrand factor (VWF) and is crucial to proper platelet adhesion to an injured subendothelium under shear stress.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

If there is clinical suspicion for BSS, it is reasonable to begin the evaluation with a complete blood count (CBC), manual peripheral blood smear review and a platelet function analyzer (PFA-100). There will be variable thrombocytopenia with large platelets seen on a smear. In nearly all cases of BSS, the closure time with a PFA-100 is prolonged.

To verify the diagnosis, light transmission platelet aggregometry should be done to demonstrate the significantly reduced or isolated absent platelet aggregation in the presence of ristocetin and low dose thrombin. Verification of the molecular defect and definitive confirmation of this diagnosis requires flow cytometry demonstrating absent or severe expression reduction of GP-1bα, GP-1bβ, or GP-IX.(Table 1)

Table 1.

Test Results Indicative of the Disorder
PFA-100 Platelet aggregometry Flow cytometry
prolonged collagen/epinephrine and collagen/ADP closure times absent or reduced with ristocetin and thrombin absent or reduced GP-1bα or β or GP-IX expression

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

There are a few challenges in making the diagnosis of BSS. It is likely that prevalence is much higher than reported because of misdiagnosis. Because of variable thrombocytopenia, BSS is commonly confused with chronic ITP and only after failed first line treatments for ITP is a diagnosis of BSS entertained.

Because of the large platelet size, the macrothrombocytopenia syndromes may be considered prior to a diagnosis of BSS. MHY9 syndromes are associated with sensorineural hearing loss, cataracts, and nephritis, as well as inclusion bodies in the white blood cells.

Type 2B von Willebrand disease (VWD) is a subtype of VWD due to a gain of function mutation that leads to an increased affinity of the mutant VWF for blood platelets. Patients with type 2B VWD present with variable thrombocytopenia and excessive bleeding symptoms. Contrary to BSS, in type 2B VWD, there is brisk platelet aggregation to very low doses of ristocetin.

A thorough drug history is recommended prior to performing a PFA-100 or other platelet studies, since recent NSAID or Aspirin use (within the previous 8 days) can lead to false positive results. In addition, there are herbal medications and foods (garlic and fatty foods) that can prolong the closure time in the collagen/epinephrine cartridge. Abstaining from these foods/herbals prior to testing is recommended.

What Lab Results Are Absolutely Confirmatory?

Demonstration of severe reduction or absence of either GP-1bα/β or GP-IX by flow cytometry confirms the diagnosis. Molecular verification of the known genetic mutations via PCR-direct DNA sequencing is available commercially.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Failure to make a timely diagnosis of BSS can lead to excessive bleeding and fatal bleeding, especially following surgical procedures. It is crucial that type 2B VWD, MYH9 macrothrombocytopenia syndromes and chronic idiopathic thrombocytopenic pupura (ITP) are considered, as they all require vastly different medical management strategies.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Rarely, in screening for BSS, the PFA-100 can be normal if there is a subvariant mutation involved. However, classically, there is significant prolongation of the closure time with PFA-100.

The PFA-100 performance is affected by the hematocrit, VWF and platelet count. If the platelet count is low (<100,000), the hematocrit is low (<28%), or the VWF antigen is low (as seen in VWD), prolongation of the closure time can occur, leading to an incorrect diagnosis.

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