Bernard-Soulier syndrome

TABLE OF CONTENTS:

INTRODUCTION:........................................................................................................2

EPIDEMIOLOGY:.........................................................................................................2

MAIN CHARACTERISTIC FEATURES:....................................................................2

PATHOPHYSIOLOGY:.................................................................................................3

MOLECULAR BASIS OF SYNDROME:....................................................................2

CLINICAL PRESENTATION:......................................................................................2

LABORATORY STUDIES............................................................................................8

DIFFERENTIALS........................................................................................................11

MANAGEMENT.........................................................................................................11

PROBLEMS SPECIFIC TO WOMEN........................................................................14

PROGNOSIS:..............................................................................................................14

REFERENCES:............................................................................................................15

1

BERNARD-SOULIER SYNDROME (BSS)

INTRODUCTION:

BSS was initially explained in 1948. The initial discovery was made by 2 French

hematologists namely Jean Bernard and Jean-Pierre Soulier, and hence named the

disease accordingly1. It is a hereditary bleeding disorder. It is primarily differentiated

by means of thrombocytopenia and presence of large platelets. The initial discovery

was made in young boy, who presented with abnormal bleeding since birth and his

older sister also had bleeding disorder, which led to her death. The test results

established that there were abnormally large platelets present. These platelets were

found to be devoid of their normal function in primary platelet plug development and

thus led to prolong bleeding.

EPIDEMIOLOGY:

Frequency: it is rare disorder with expected occurrence rate of

<1/million population.

Race: common in white people and Japanese population.

Morbidity/Mortality: severity is variable ranging from mild to severe

in case of surgery and sever injury.

Sex: male female ration is same

Age: bleeding in BSS may start during infancy and can continue with

changeable severity throughout life time.

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MAIN CHARACTERISTIC FEATURES:

The major characteristic properties of BSS are summarized as:

Autosomal recessive disorder2

Heterozygote generally donot show bleeding problems

Unusually large platelets (therefore it is also called as giant platelet disorder)2

Mild / Moderate thrombocytopenia

BM megakaryocytes show normal numbers

Prolonged skin bleeding time2

Inconsistent bleeding time with respect to thrombocytopenia2

Parental history for comparable bleeding is inconclusive

Consanguinity is frequently reported

PATHOPHYSIOLOGY:

The primary biochemical deficiency is the lack of or reduced expression of

glycoprotein Ib/IX/V complex, which is mainly present on platelet surface.

Glycoprotein Ib/IX/V complex is main receptor for binding to von Willebrand factor

(vWF), and the consequence of reduced expression is incomplete binding between

vWF and platelet membrane, specially at position of vascular damage, resulting in

imperfect platelet adhesion3.

This is confirmed by the defective or absence of platelet aggregation, when exposed

to ristocetin. Ristocetin is an antibiotic which normally causes platelets aggregation.

The final outcome is the absence of development of primary platelet plug, which

result in greater bleeding tendency. The main cause of thrombocytopenia however is

not absolutely known, but it may be related to reduce platelet life period.

3

MOLECULAR BASIS OF SYNDROME:

The GPIb/ IX/ V complex presents the most important site mediating platelet

interaction with VWF.

This complex is composed of 4 proteins:

Disulphide-linked chains of GP Ib

α - chain (135 kDa)

β – chain (25 kDa)

Non-covalently connected subunits

GPIX (22 kDa)

GPV (82 kDa)

They all contribute to same functional and structural properties signifying a common

evolutionary derivation. A number of transcripts encode these 4 polypeptide chains

but with exception of GPIb β. These genes show uninterrupted (intron - depleted)

open reading frames.

All 4 genes which encode this complex are cloned. A total of 17 different types of

BSS have been characterized up to date. This characterization is mainly on the basis

of:

Functional

Immunological

Molecular levels.

Mutations of GPIbα, GPIbβ and GPIX associated with Bernard-Soulier syndrome

are mapped to the mature protein structure and indicates missense mutations or short

deletions, nonsense mutations leading to premature stop, or mutations causing a frame

shift leading to stop. There are no reported mutations in GP V6, 17, 18

4

The different mutations are divided into 2 major groups:

First type of mutations : these are mainly located in LRR i-e Leucine

rich repeats. These mutations mainly lead to the conformational

modifications of molecules. In minority of cases, there is increased

proteases sensitivity and decrease in the receptors adhesive function.

Also these receptors are expressed at reduced levels than normal on

platelet surface membrane. Mutations affecting LRR region of GPIba,

results in variable production of the remaining chains ranging from

normal to very small amounts. While mutations affecting the LRR

region of GPIX, results in diminished production of other chains,

which suggests that GPIX has a main role in receptor complex

stability.

Second type of mutations: these result in the production of truncated

molecule which is lacking transmembrane domain, also in some cases

lacking its expression on the platelet surface as well. The additional

chains whereas are produced in residual amounts.

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FIG1: GP I/IX/V complex

FIG 2: Mutations of (A) GPIbα (B) GPIbβ and (C) GPIX

6

CLINICAL PRESENTATION:

BSS symptoms show variable presentation between different individuals.

Signs and symptoms of disorder are frequently first observed during

childhood.

Usually common presentation of BSS is:

Cutaneous hemorrhages

o Purpura

o Bruises

Epistaxis (which may sometimes be difficult to control)

Gingival bleeding

Heavy menstural bleeding (menorrhagia)

Bleeding after parturition

Haemarthrosis

Abnormal bleeding after

o surgery

o circumcision

o dental work

Rarely blood vomitus

Presence of blood in stool (gut bleeding)

BSS poses more problem in women as compared to men and this is

mainly due to

o Menstruation and

o Child birth

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Diagnostic Approach for BSS

LABORATORY STUDIES

The different laboratory tests for diagnosis of BSS include:

COMPLETE BLOOD COUNT (CBC):

Thrombocytopenia

Mild or moderate

Ranges from 20x109/L – near normal

Giant platelets in peripheral smear observed

80% usually larger than 2.5 µm

8 µm diameter cells also observed

8

FIG 3: Peripheral smear of patient with BSS.

BT / PFA-100 CLOSURE TIME:

Each has restricted sensitivity (~40%) still in indicative patients

Neither therefore are superior screening tests to detect functional platelet

function

BT is prolonged

PFA-100 closure time is raised

PLATELET AGGREGATION STUDIES: 7

Ristocetin induced aggregation of platelets is absent

Aggregation response is normal with additional agonists like epinephrine,

arachidonic acid, ADP and collagen.

9

FLOW CYTOMETRY:

By this technique protein expression is measured on the cell surface with the

help of monoclonal antibodies.

IN BSS

Reduced GPIb/IX/V expression

Cell surface marker is CD42b

In qualitative CD42b defect, flow cytometry is normal

10

DIFFERENTIALS

BSS should be differentiated from:

Glanzmann thrombasthenia:

May-Hegglin anomaly:

Von-Willebrand disease:

MANAGEMENT

Management of BSS mainly consists of:

Preventive measures and local care

Specific treatment

11

PREVENTIVE MEASURES:

Avoidance of anti-platelet drugs

Aspirin

NSAID’s

Dental hygiene

Mensturational bleeding hormonal control

Contraceptives

Treatment plan before surgery

Patient education

Avoid trauma

For epistaxis

Nasal packing

Gingival bleeding

Gel foam is applied soaked in tropical thrombin

Moderate / severe cases

Activity restriction is important

SPECIFIC TREATMENT CHOICES:

ANTI-FIBRINOLYTIC AGENTS:

These are mainly useful in management of menorrhagia

Also used for mild bleeding problems like bleeding from mucous

membranes for example epistaxis.

Common drugs include

o Epsilon amino caproic acid (EACA. Amicar®) is used

12

o Tranexamic acid

These are also available as mouth wash for bleeding in mouth from

o Tonsillectomy sites

o After dental extract

DESMOPRESSIN ACETATE (DDAVP) 8

It cut down the bleeding duration but in some of the patients not all

with BSS

It is helpful for small bleeding episodes

Exact mechanism is not clear

it may due to increased VWF binding with residual GP1b especially

in patients exclusive of absolute deficiency

PLATELET TRANSFUSIONS:

Should be conserved for

o surgery

o Life threatening bleeding

o Failure to other agents

Patient may produce antibodies against GP Ib/IX/V. As this complex is

present on donor platelets but not in patient’s platelets.

Recombinant activated Factor VII (rFVIIa): 9

It is used in BSS patients but with limited experience.

Precise mechanism is unknown, but increased thrombin synthesis and

fibrin deposition is observed at vascular injury site.

13

PROBLEMS SPECIFIC TO WOMEN

MENORRHAGIA:

Is the most important bleeding crisis for women following Puberty. Oral

contraceptives use can regulate menstural cycles thereby reducing heavy bleeding.

Tranexamic acid (Cyklokapron® or Amicar®) is also indicated at same time. They

mainly act by down regulating destruction of clots that formed in the body. Bleeding

is usually severe at first menstruation cycle.

PREGNANCY AND CHILD BIRTH BLEEDING:

BSS is very rare that is why there is not much documentation available about bleeding

during pregnancy and bleeding at time of parturition.

BSS expectant mother should be tracked in such treatment center having experience

in dealing such patients. They should also discuss the danger associated with epidural

in advance with the concerned physician.

PROGNOSIS:

The bleeding propensity is life-long in Bernard-Soulier syndrome (BSS) patients but

there may be reduction in bleeding tendency with age.

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REFERENCES:

1. Bernard J. History of congenital thrombocytic hemorrhagic dystrophy. C R

Acad Sci III. 1996 Aug;319(8):727-32

2. López JA, Andrews RK, Afshar-Kharghan V, Berndt MC. Bernard-Soulier

syndrome. Blood 1998 Jun 15; 91(12):4397-418.

3. Simon D, Kunicki T, Nugent D. Platelet function defects. Haemophilia. 2008

Nov; 14(6):1240-9.

4. Andrews R, Berndt M, Lopez J. The glycoprotein Ib-IX-V complex. In:

Michelson AD, editor. Platelets.2nd edition. San Diego, CA: Academic Press;

2006. pp. 145–64

5. Lanza F. Bernard-Soulier syndrome (hemorrhagiparous thrombocytic

dystrophy) Orphanet J Rare Dis. 2006; 1:46.

6. Kahn ML, Diacovo TG, Bainton DF, Lanza F, Trejo J, Coughlin SR.

Glycoprotein V-deficient platelets have undiminished thrombin responsiveness

and do not exhibit a Bernard-Soulier phenotype. Blood. 1999;94(12):4112–21

7. Ramasamy I. inherited bleeding disorders. Disorders of platelet adhesion and

aggregation. Crit Rev Oncol Hematol. 2004; 49 (1) : 1-35

8. Franchini M. The use of desmopressin as a hemostatic agent. Am J Hematol,

2007 Aug; 82(8): 731-5.

9. Peters M, Heijboer H. treatment of a patient with Bernard Soulier syndrome

and recurrent nosebleeds with recombinant Factor VIIa. Thrombosis and

Hemostasis 1998; 352

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