eMedicine Specialties > Pediatrics: General Medicine > Hematology

Bernard-Soulier Syndrome

John D Geil, MD, Associate Professor of Pediatrics, Division of Hematology/Oncology, University of Kentucky College of Medicine; Consulting Staff, Department of Pediatric Hematology/Oncology, University of Kentucky Children's Hospital

Updated: Jun 30, 2009

Introduction

Background

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. Bernard-Soulier syndrome is one of a group of hereditary platelet disorders characterized by thrombocytopenia, giant platelets, and a tendency toward bleeding. Other disorders in this category are the May-Hegglin anomaly and gray platelet syndrome.

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

Pathophysiology

The underlying biochemical defect is the absence or decreased expression of the glycoprotein Ib/IX/V complex on the surface of the platelets.¹ 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. This is demonstrated by the lack of aggregation of platelets 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 and increased bleeding tendency. The cause of the thrombocytopenia is not definitely known, but it is probably related to a decreased platelet life span.

Frequency

United States

This syndrome is rare, with an estimated occurrence of less than 1 case per million population.

Mortality/Morbidity

The severity of bleeding tendency varies. Bleeding can be severe with injury or surgery.

Race

Bernard-Soulier syndrome is a rare disorder described primarily in whites of European ancestry, as well as in the Japanese population. However, prevalence in other ethnic groups is unknown.

Sex

Males and females are affected with equal frequency.

Age

Bleeding due to Bernard-Soulier syndrome may begin in infancy and may continue with varying severity throughout life.

Clinical

History

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

Physical

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

Causes

Bernard-Soulier syndrome is inherited in an autosomal recessive fashion; thus, males and females are affected with equal frequency. Heterozygotes usually have no bleeding manifestations.

Differential Diagnoses

Glanzmann Thrombasthenia
May-Hegglin Anomaly
Von Willebrand Disease

Other Problems to Be Considered

Idiopathic (autoimmune) thrombocytopenic purpura (ITP)
Other inherited giant platelet disorders, such as gray platelet syndrome
Medication effect

Workup

Laboratory Studies

• CBC count: Thrombocytopenia is a frequent finding in patients with Bernard-Soulier syndrome (BSS) but does vary. Giant platelets are seen on the peripheral smear, possibly exceeding the size of a RBC.
• Bleeding time: Bleeding time is usually prolonged. The template bleeding time has largely been replaced by automatic platelet function analyzers (PFA), such as the PFA-100.
• Platelet aggregation studies: 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: Flow cytometry can demonstrate abnormalities of platelet membrane glycoprotein.

Treatment

Medical Care

• Care of Bernard-Soulier syndrome (BSS) is generally supportive.
• Avoid antiplatelet medication, such as aspirin.
• Specific treatment of bleeding episodes includes the following:
  • Antifibrinolytic agents, such as epsilon aminocaproic acid (Amicar) or tranexamic acid (Cyklokapron), may be useful for mucosal bleeding.
  • For surgery or life-threatening hemorrhage, platelet transfusion is the only available therapy. Platelet transfusions should be reserved for surgery or potentially life-threatening bleeding. 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.
  • Desmopressin acetate (DDAVP) has been shown to shorten the bleeding time in some, but not all, patients with Bernard-Soulier syndrome. DDAVP may be useful for minor bleeding episodes. The exact mechanism for this is unknown, but it may relate 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 in patients with congenital platelet disorders, including Bernard-Soulier syndrome.² Once again, the exact mechanism of action is unknown, but it may work by increasing thrombin generation and the deposition of fibrin at the site of vascular injury.

Consultations

• Consult a pediatric hematologist.

Activity

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

Medication

In general, no medications are needed in Bernard-Soulier syndrome (BSS). Antifibrinolytic agents (eg, aminocaproic acid, 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 Bernard-Soulier syndrome. Recently, recombinant activated factor VII has been used to treat congenital platelet disorders.

Antifibrinolytics

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

Aminocaproic acid (Amicar)

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

Dosing

Adult

30 g/d PO/IV in divided doses q3-6h; not to exceed 30 g/d

Pediatric

Loading dose: 100-200 mg/kg PO/IV
Maintenance dose: 100 mg/kg/dose q4-6h; not to exceed 30 g/d

Interactions

Coadministration with estrogens may cause increase in clotting factors, leading to a hypercoagulable state

Contraindications

Documented hypersensitivity; evidence of active intravascular clotting process; disseminated intravascular coagulopathy (differentiate between disseminated intravascular coagulopathy and hyperfibrinolysis because aminocaproic acid can be fatal in patients with disseminated intravascular coagulation)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus

Precautions

Do not administer unless a definite diagnosis of hyperfibrinolysis has been made; caution with cardiac, hepatic, or renal disease; avoid rapid IV administration because this may induce hypotension, bradycardia, and/or arrhythmia

Tranexamic acid (Cyklokapron)

Alternative to aminocaproic acid. Inhibits fibrinolysis by inhibiting plasminogen activators.

Dosing

Adult

25 mg/kg/dose PO tid/qid for 2-8 d

Pediatric

Administer as in adults

Interactions

Thrombolytics antagonize effect; anti-inhibitor coagulant complex or factor IX complex may increase thrombosis risk

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal dysfunction or upper urinary tract bleeding and history of thromboembolic disease or DIC

Vasopressin analogs

Desmopressin stimulates factor VIII, prostaglandins, and plasminogen release, but the mechanism of action is not clear and may not be common to all 3 substances. These agents possess 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)

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

Dosing

Adult

IV (DDAVP): 0.3 mcg/kg IV
Intranasal (Stimate 1.5 mg/mL; 150 mcg/spray):
<50 kg: 150 mcg (1 spray in one nostril) intranasally
>50 kg: 300 mcg (1 spray in each nostril) intranasally

Pediatric

Administer as in adults

Interactions

Coadministration with demeclocycline and lithium decrease effects; fludrocortisone and chlorpropamide increase effects of desmopressin

Contraindications

Documented hypersensitivity; platelet-type von Willebrand disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Avoid overhydration in patients using desmopressin to benefit from its hemostatic effects; restrict free water intake to avoid hyponatremia; mild facial flushing and headache are possible

Clotting factors

Hemostasis is the physiological 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 IX) function as cofactors in the blood coagulation cascade.

Factor VIIa, Recombinant (NovoSeven)

Vitamin K-dependent glycoprotein indicated for the treatment of bleeding episodes in patients with hemophilia A or B and inhibitors. 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, FIX to factor IXa, and factor II to factor IIa.
Experience with the use of recombinant activated factor VII is limited in patients with congenital platelet disorders. Safety and efficacy are still are being evaluated.

Dosing

Adult

15-30 mcg/kg IV bolus q4-6h until hemostasis is achieved

Pediatric

Not established, limited data exist; administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor for signs or symptoms of activation of the coagulation system or thrombosis; because of limited experience, use caution with prolonged dosing; risk of thrombotic adverse events after treatment is unknown

Follow-up

Prognosis

• The tendency to bleed is lifelong in patients with Bernard-Soulier syndrome (BSS) but may somewhat diminish with age.

Patient Education

• Educate patients about the disease and the need to avoid trauma.
• Emphasize good dental hygiene.
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize bleeding tendency prior to elective surgery
• Failure to inform the patient and family of activity restrictions

Multimedia

Media file 1: Peripheral smear of a patient with Bernard-Soulier syndrome (BSS) showing giant platelets. These platelets are not counted as platelets in most particle counters.

References

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2. Pham A, Wang J. Bernard-Soulier syndrome: an inherited platelet disorder. Arch Pathol Lab Med. Dec 2007;131(12):1834-6. [Medline].

3. Cohn RJ, Sherman GG, Glencross DK. Flow cytometric analysis of platelet surface glycoproteins in the diagnosis of Bernard-Soulier syndrome. Pediatr Hematol Oncol. Jan-Feb 1997;14(1):43-50. [Medline].

4. Enomoto TM, Thorborg P. Emerging off-label uses for recombinant activated factor VII: grading the evidence. Crit Care Clin. Jul 2005;21(3):611-32. [Medline].

5. Franchini M, Zaffanello M, Veneri D. Recombinant factor VIIa. An update on its clinical use. Thromb Haemost. Jun 2005;93(6):1027-35. [Medline].

6. Hacihanefioglu A, Tarkun P, Gonullu E. Use of recombinant factor VIIa in the management and prophylaxis of bleeding episodes in two patients with Bernard-Soulier syndrome. Thromb Res. 2007;120(3):455-7. [Medline].

7. Jantunen E. Inherited giant platelet disorders. Eur J Haematol. Oct 1994;53(4):191-6. [Medline].

8. Kunishima S, Kamiya T, Saito H. Genetic abnormalities of Bernard-Soulier syndrome. Int J Hematol. Nov 2002;76(4):319-27. [Medline].

9. Lopez JA, Andrews RK, Afshar-Kharghan V, Berndt MC. Bernard-Soulier syndrome. Blood. Jun 15 1998;91(12):4397-418. [Medline]. [Full Text].

10. Mhawech P, Saleem A. Inherited giant platelet disorders. Classification and literature review. Am J Clin Pathol. Feb 2000;113(2):176-90. [Medline].

11. Nurden AT. Inherited abnormalities of platelets. Thromb Haemost. Aug 1999;82(2):468-80. [Medline].

12. Nurden AT. Qualitative disorders of platelets and megakaryocytes. J Thromb Haemost. Aug 2005;3(8):1773-82. [Medline].

13. Poon MC, d'Oiron R. Recombinant activated factor VII (NovoSeven) treatment of platelet-related bleeding disorders. International Registry on Recombinant Factor VIIa and Congenital Platelet Disorders Group. Blood Coagul Fibrinolysis. Apr 2000;11 Suppl 1:S55-68. [Medline].

14. Tefre KL, Ingerslev J, Sorensen B. Clinical benefit of recombinant factor VIIa in management of bleeds and surgery in two brothers suffering from the Bernard-Soulier syndrome. Haemophilia. Jan 2009;15(1):281-4. [Medline].

15. Watanabe R, Ishibashi T, Saitoh Y, et al. Bernard-soulier syndrome with a homozygous 13 base pair deletion in the signal peptide-coding region of the platelet glycoprotein Ib(beta) gene. Blood Coagul Fibrinolysis. Jun 2003;14(4):387-94. [Medline].

16. Zieger B, Jenny A, Tsakiris DA, et al. A large Swiss family with Bernard-Soulier syndrome - Correlation phenotype and genotype. Hamostaseologie. May 2009;29(2):161-7. [Medline].

Keywords

Bernard-Soulier syndrome, BSS, hereditary platelet disorder, bleeding disorder, coagulation disorder, giant platelets, thrombocytopenia, bleeding tendency, May-Hegglin anomaly, gray platelet syndrome, von Willebrand factor, vWF, treatment, diagnosis

Contributor Information and Disclosures

Author

John D Geil, MD, Associate Professor of Pediatrics, Division of Hematology/Oncology, University of Kentucky College of Medicine; Consulting Staff, Department of Pediatric Hematology/Oncology, University of Kentucky Children's Hospital
John D Geil, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, and Society for Neuro-Oncology
Disclosure: Nothing to disclose.

Medical Editor

Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories
Gary R Jones, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Gary D Crouch, MD, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Associate Professor, Uniformed Services University of the Health Sciences
Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology
Disclosure: Nothing to disclose.

CME Editor

David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville
David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology
Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

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