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TABLE OF CONTENTS

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TABLE OF CONTENTS:..............................................................................................1 BERNARD-SOULIER SYNDROME (BSS)................................................................2 INTRODUCTION:.........................................................................................................2 EPIDEMIOLOGY:.........................................................................................................2 MAIN CHARACTERISTIC FEATURES:....................................................................3 PATHOPHYSIOLOGY:.................................................................................................3 MOLECULAR BASIS OF SYNDROME:....................................................................4 CLINICAL PRESENTATION:......................................................................................6 Diagnostic Approach for BSS........................................................................................8 LABORATORY STUDIES............................................................................................8 DIFFERENTIALS........................................................................................................11 BSS should be differentiated from:..............................................................................11 MANAGEMENT.........................................................................................................11 PROBLEMS SPECIFIC TO WOMEN........................................................................14 PROGNOSIS: .............................................................................................................14 REFERENCES:............................................................................................................15

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 Race: common in white people and Japanese population. and hence named the disease accordingly1.BERNARD-SOULIER SYNDROME (BSS) INTRODUCTION: BSS was initially explained in 1948.  Morbidity/Mortality: severity is variable ranging from mild to severe in case of surgery and sever injury. It is primarily differentiated by means of thrombocytopenia and presence of large platelets. 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. The initial discovery was made by 2 French hematologists namely Jean Bernard and Jean-Pierre Soulier.  Sex: male female ration is same 2 . These platelets were found to be devoid of their normal function in primary platelet plug development and thus led to prolong bleeding. The initial discovery was made in young boy. It is a hereditary bleeding disorder. EPIDEMIOLOGY:  Frequency: it is rare disorder with expected occurrence rate of <1/million population.

This is confirmed by the defective or absence of platelet aggregation. Ristocetin is an antibiotic which normally causes platelets aggregation. and the consequence of reduced expression is incomplete binding between vWF and platelet membrane. resulting in imperfect platelet adhesion3. which is mainly present on platelet surface. 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. Glycoprotein Ib/IX/V complex is main receptor for binding to von Willebrand factor (vWF). Age: bleeding in BSS may start during infancy and can continue with changeable severity throughout life time. 3 . when exposed to ristocetin. specially at position of vascular damage.

These genes show uninterrupted (intron . The main cause of thrombocytopenia however is not absolutely known. A number of transcripts encode these 4 polypeptide chains but with exception of GPIb β.The final outcome is the absence of development of primary platelet plug. This complex is composed of 4 proteins:  Disulphide-linked chains of GP Ib   α . A total of 17 different types of BSS have been characterized up to date. which result in greater bleeding tendency. MOLECULAR BASIS OF SYNDROME: The GPIb/ IX/ V complex presents the most important site mediating platelet interaction with VWF. All 4 genes which encode this complex are cloned. 4 . but it may be related to reduce platelet life period. This characterization is mainly on the basis of:    Functional Immunological Molecular levels.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.depleted) open reading frames.

also in some cases lacking its expression on the platelet surface as well. results in variable production of the remaining chains ranging from normal to very small amounts. In minority of cases. results in diminished production of other chains. GPIbβ and GPIX associated with Bernard-Soulier syndrome are mapped to the mature protein structure and indicates missense mutations or short deletions.  Second type of mutations: these result in the production of truncated molecule which is lacking transmembrane domain. Mutations affecting LRR region of GPIba. or mutations causing a frame shift leading to stop. nonsense mutations leading to premature stop. there is increased proteases sensitivity and decrease in the receptors adhesive function. 5 . 17. There are no reported mutations in GP V6. which suggests that GPIX has a main role in receptor complex stability. 18 The different mutations are divided into 2 major groups:  First type of mutations: these are mainly located in LRR i-e Leucine rich repeats. The additional chains whereas are produced in residual amounts. Also these receptors are expressed at reduced levels than normal on platelet surface membrane. These mutations mainly lead to the conformational modifications of molecules. While mutations affecting the LRR region of GPIX.Mutations of GPIbα.

FIG1: GP I/IX/V complex FIG 2: Mutations of (A) GPIbα (B) GPIbβ and (C) GPIX CLINICAL PRESENTATION: 6 .

 Usually common presentation of BSS is:  Cutaneous hemorrhages o o       Purpura Bruises Epistaxis (which may sometimes be difficult to control) Gingival bleeding Heavy menstural bleeding (menorrhagia) Bleeding after parturition Haemarthrosis Abnormal bleeding after o o o surgery circumcision 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 7 . BSS symptoms show variable presentation between different individuals.  Signs and symptoms of disorder are frequently first observed during childhood.

5 µm 8 µm diameter cells also observed 8 .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.

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. 9 . ADP and collagen. arachidonic acid.

 IN BSS    Reduced GPIb/IX/V expression Cell surface marker is CD42b In qualitative CD42b defect. flow cytometry is normal 10 .FLOW CYTOMETRY:  By this technique protein expression is measured on the cell surface with the help of monoclonal antibodies.

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 12 .

Amicar®) is used 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.  Recombinant activated Factor VII (rFVIIa):9  It is used in BSS patients but with limited experience.o Epsilon amino caproic acid (EACA. As this complex is present on donor platelets but not in patient’s platelets. 13 .

Bleeding is usually severe at first menstruation cycle. Precise mechanism is unknown. 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. 14 . PROBLEMS SPECIFIC TO WOMEN MENORRHAGIA: Is the most important bleeding crisis for women following Puberty. BSS expectant mother should be tracked in such treatment center having experience in dealing such patients. but increased thrombin synthesis and fibrin deposition is observed at vascular injury site. They mainly act by down regulating destruction of clots that formed in the body. 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. Oral contraceptives use can regulate menstural cycles thereby reducing heavy bleeding. Tranexamic acid (Cyklokapron® or Amicar®) is also indicated at same time.

2nd edition. 49 (1) : 1-35 8. Coughlin SR. editor. Trejo J.94(12):4112–21 7. 1999. History of congenital thrombocytic hemorrhagic dystrophy. Disorders of platelet adhesion and aggregation. 145–64 5. Simon D. Blood 1998 Jun 15. inherited bleeding disorders. The use of desmopressin as a hemostatic agent. Blood. 14(6):1240-9. Nugent D. Bernard-Soulier syndrome (hemorrhagiparous thrombocytic dystrophy) Orphanet J Rare Dis. Bernard J. Kunicki T. López JA. Berndt MC. Kahn ML. Afshar-Kharghan V. Lanza F. Andrews R. The glycoprotein Ib-IX-V complex. Andrews RK. 352 15 . 2006. 2006. Ramasamy I. In: Michelson AD. Glycoprotein V-deficient platelets have undiminished thrombin responsiveness and do not exhibit a Bernard-Soulier phenotype. CA: Academic Press. Berndt M.319(8):727-32 2. 9. C R Acad Sci III. 4. Peters M. Haemophilia. Heijboer H. 2007 Aug. Thrombosis and Hemostasis 1998. San Diego. 82(8): 731-5. 1996 Aug. Platelets. treatment of a patient with Bernard Soulier syndrome and recurrent nosebleeds with recombinant Factor VIIa. 91(12):4397-418. Bernard-Soulier syndrome. Lopez J. Platelet function defects. 1:46. Bainton DF. Lanza F. pp. 2004. 2008 Nov. Diacovo TG. 6. Crit Rev Oncol Hematol. Franchini M. 3.REFERENCES: 1. Am J Hematol.