Bernard-Soulier Syndrome

Bernard-Soulier syndrome (BSS) was first described in 1948 as a congenital bleeding disorder characterized by thrombocytopenia and large platelets. The disorder was recognized to be familial and inherited in an autosomal recessive manner. In the 1970s, the molecular defect was shown to involve the absence of a platelet membrane glycoprotein (GPIb/IX/V) complex which is the receptor for von Willebrand factor (vWF).

BSS is one of a group of hereditary platelet disorders characterized by macrothrombocytopenia and a tendency toward bleeding. It is the second most common inherited platelet defect. Other disorders in the category of macrothrombocytopenia are the May-Hegglin anomaly and gray platelet syndrome.

Treatment is generally supportive. Patients should be educated about the disease and the need to avoid trauma and nonsteroidal anti-inflammatory drugs (NSAIDS). Emphasis should be placed on good dental hygiene.

The underlying biochemical defect in BSS is the absence or decreased expression of the GPIb/IX/V complex on the surface of the platelets.[4, 5, 6, 7] This complex is the receptor for von Willebrand factor (vWF), and the result of decreased expression is deficient binding of vWF to the platelet membrane at sites of vascular injury, resulting in defective platelet adhesion. GPIb/IX/V complex is located in the platelet cytoskeleton and hence is also essential to the production of platelets from the megakaryocytes in the bone marrow (which explains the large size and decreased numbers of platelets in this syndrome).

Defective platelet adhesion is demonstrated by the lack of platelet aggregation in response to ristocetin, an antibiotic that normally causes platelets to aggregate. The end result is the lack of formation of the primary platelet plug, together with an increased bleeding tendency. The cause of the thrombocytopenia is not definitely known but is thought probably to be related to the absence of the GPIb/IX/V complex and its role in the production and shedding of platelets from the marrow megakaryocytes.[8]

BSS is inherited in an autosomal recessive fashion; thus, males and females are affected with equal frequency. (A rare variant with autosomal dominant inheritance has been described.) Heterozygotes have been thought to usually have no bleeding manifestations. However, a study by Bragadottir et al indicated that individuals who are heterozygous for BSS mutations have lower platelet counts, more mucocutaneous bleeding, and higher vWF levels than do controls without these mutations, although bleeding is much milder than in persons who are homozygous for BSS.[9]

BSS is rare, with an estimated occurrence of less than 1 case per million population. Bleeding due to BSS may begin in infancy and may continue with varying severity throughout life, although it may somewhat diminish with age. Males and females are affected with equal frequency. To date, BSS has been described primarily in whites of European ancestry, as well as in the Japanese population; its prevalence in other ethnic groups is unknown.

Symptoms of Bernard-Soulier syndrome (BSS) are consistent with low or dysfunctional platelets and include easy bruising, nosebleeds, mucosal bleeding, menorrhagia, and, occasionally, gastrointestinal bleeding. The severity of symptoms may vary considerably.

The physical examination findings are consistent with low or dysfunctional platelets and may include increased bruising and mucosal bleeding.

A retrospective study from Pakistan, by Farhan et al, found that among 49 patients with BSS, epistaxis was one of the most common presenting symptoms, occurring in 73.4% of subjects. Complete blood counts (CBCs) revealed platelet reductions in 85.7% of patients, with the platelet counts ranging from 20 x 109/L to 130 x 109/L. Anemia and prolonged bleeding time occurred in 67.3% and 93.8% of patients, respectively, while mild bleeding episodes were experienced by 65.3% of patients. As evidenced by peripheral blood smears, all patients were found to have giant platelets. The investigators also found a family history of consanguinity in 81% of subjects.[10]

A complete blood count (CBC) is indicated and usually shows lower platelets counts with elevated mean platelet volume. Thrombocytopenia is a frequent, but not invariable, finding in patients with Bernard-Soulier syndrome (BSS). Giant platelets are seen on the peripheral smear (see the image below), possibly exceeding the size of a red blood cell.

Peripheral smear of patient with Bernard-Soulier syndrome (BSS) showing giant platelets. These platelets are not counted as platelets in most particle counters.

Bleeding time is usually prolonged. The template bleeding time has largely been replaced by automatic platelet function analyzers (PFAs), such as the PFA-100.

Platelets do not aggregate in response to ristocetin. This is not corrected by the addition of normal plasma, as seen in von Willebrand disease. Platelets have normal aggregation in response to adenosine diphosphate (ADP), epinephrine, and collagen.

Flow cytometry can demonstrate abnormalities of platelet membrane glycoprotein.

A study by Bonnard et al indicated that assessment of both the immature platelet count and P-selectin expression could aid in distinguishing immune thrombocytopenia from inherited thrombocytopenia. A significantly lower immature platelet fraction was found in study patients with immune thrombocytopenia than in those with the inherited condition. On the other hand, there was significantly higher platelet activation in patients with immune thrombocytopenia, indicating greater P-selectin expression.[11]

Care of Bernard-Soulier syndrome (BSS) is generally supportive. In most cases, no medications are needed. In all cases, antiplatelet medications (eg, aspirin) should be avoided. Bleeding episodes may require specific treatment, as follows.

Antifibrinolytic agents, such as ε-aminocaproic acid or tranexamic acid, may be useful for mucosal bleeding.

An international, retrospective study by Orsini et al examining the risk of surgery-associated bleeding complications in patients with inherited platelet disorders found the incidence of surgical bleeding to be greatest in cases of biallelic BSS (44.4%).[12] For surgery or potentially life-threatening hemorrhage, platelet transfusion is the only available therapy; it should be reserved for these settings.

The patient may develop antiplatelet antibodies because of glycoproteins Ib/IX/V, which are present on the transfused platelets but absent from the patient’s own platelets. Pregnant women with BSS are at risk for postpartum hemorrhage.[13] The neonate born of a mother with BSS has a risk of significant bleeding due to neonatal alloimmune thrombocytopenia.[14]

Desmopressin acetate (DDAVP) has been shown to shorten the bleeding time in some, but not all, patients with BSS. DDAVP may be useful for minor bleeding episodes. The exact mechanism by which it acts is unknown but may be related to increased levels of von Willebrand factor (vWF) binding to some residual glycoprotein Ib in patients without an absolute deficiency.

Recombinant activated factor VII has been used to treat patients with congenital platelet disorders, including BSS, when other treatments have failed.[15] Once again, the exact mechanism of action is unknown, but this agent may work by increasing the generation of thrombin and the deposition of fibrin at the site of vascular injury.

 For patients with moderate to severe symptoms, some restriction of activity may be necessary.

Consultation with a pediatric hematologist is appropriate.

In general, no medications are needed in Bernard-Soulier syndrome (BSS). Antifibrinolytic agents (eg, ε-aminocaproic acid and tranexamic acid) may be useful for mucosal bleeding. For surgery or life-threatening hemorrhage, platelet transfusion is the only available therapy.

Desmopressin acetate (DDAVP) has been shown to shorten the bleeding time in some, but not all, patients with BSS. Recombinant activated factor VII has also been used to treat congenital platelet disorders with severe bleeds.

Class Summary

Fibrinolytic agents are used to enhance hemostasis when fibrinolysis contributes to bleeding.

Tranexamic acid (Cyklokapron)

Tranexamic acid is an alternative to aminocaproic acid. It inhibits fibrinolysis via inhibition of plasminogen activators.

Aminocaproic acid (Amicar)

Aminocaproic acid inhibits fibrinolysis via inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. The main problems are that the thrombi forming during treatment are not lysed and that effectiveness is uncertain.

Class Summary

Desmopressin acetate (DDAVP) stimulates factor VIII, prostaglandins, and plasminogen release, but the mechanism of action is not clear and may not be common to all 3 substances. This agent exerts an effect on vessel walls that produces an increase in platelet adhesion. This local hemostatic action may account for its hemostatic properties.

Desmopressin acetate (DDAVP, Stimate)

DDAVP is used to decrease bleeding time in some, but not all, patients with BSS. It may be useful for minor bleeding episodes. The exact mechanism is unknown but may involve increased levels of vWF binding to some residual glycoprotein Ib in patients without an absolute deficiency.

Class Summary

Hemostasis is the physiologic response to bleeding. Injury and factors released by platelets initiates the coagulation cascade, which is mediated by blood clotting factors. This results in formation of an insoluble fibrin clot, thus reinforcing the initial platelet plug. Clotting factors (ie, antihemophilic factor [factor VIII], factor VII, or factor IX) function as cofactors in the blood coagulation cascade.

Factor VIIa, Recombinant (NovoSeven)

Recombinant factor VIIa is a vitamin K-dependent glycoprotein indicated for the treatment of bleeding episodes in patients with hemophilia A or B and inhibitors. It promotes hemostasis by activating the extrinsic pathway of the coagulation cascade, forming complexes with tissue factor, and promoting activation of factor X to factor Xa, factor IX to factor IXa, and factor II to factor IIa.

Experience with the use of recombinant factor VIIa is limited in patients with congenital platelet disorders. Safety and efficacy are still being evaluated.