Bernard-Soulier syndrome

1,618 views
1,455 views

Published on

Published in: Health & Medicine, Technology
0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
1,618
On SlideShare
0
From Embeds
0
Number of Embeds
7
Actions
Shares
0
Downloads
56
Comments
0
Likes
2
Embeds 0
No embeds

No notes for slide

Bernard-Soulier syndrome

  1. 1. TABLE OF CONTENTS:TABLE OF CONTENTS:..............................................................................................1BERNARD-SOULIER SYNDROME (BSS)................................................................2INTRODUCTION:.........................................................................................................2EPIDEMIOLOGY:.........................................................................................................2MAIN CHARACTERISTIC FEATURES:....................................................................3PATHOPHYSIOLOGY:.................................................................................................3MOLECULAR BASIS OF SYNDROME:....................................................................4CLINICAL PRESENTATION:......................................................................................6Diagnostic Approach for BSS........................................................................................7LABORATORY STUDIES............................................................................................8DIFFERENTIALS........................................................................................................11BSS should be differentiated from:..............................................................................11MANAGEMENT.........................................................................................................11PROBLEMS SPECIFIC TO WOMEN........................................................................13PROGNOSIS: .............................................................................................................14REFERENCES:............................................................................................................14 1
  2. 2. BERNARD-SOULIER SYNDROME (BSS)INTRODUCTION:BSS was initially explained in 1948. The initial discovery was made by 2 Frenchhematologists namely Jean Bernard and Jean-Pierre Soulier, and hence named thedisease accordingly1. It is a hereditary bleeding disorder. It is primarily differentiatedby means of thrombocytopenia and presence of large platelets. The initial discoverywas made in young boy, who presented with abnormal bleeding since birth and hisolder sister also had bleeding disorder, which led to her death. The test resultsestablished that there were abnormally large platelets present. These platelets werefound to be devoid of their normal function in primary platelet plug development andthus 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 2
  3. 3.  Age: bleeding in BSS may start during infancy and can continue with changeable severity throughout life time.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 reportedPATHOPHYSIOLOGY:The primary biochemical deficiency is the lack of or reduced expression ofglycoprotein 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 betweenvWF and platelet membrane, specially at position of vascular damage, resulting inimperfect platelet adhesion3.This is confirmed by the defective or absence of platelet aggregation, when exposedto ristocetin. Ristocetin is an antibiotic which normally causes platelets aggregation. 3
  4. 4. The final outcome is the absence of development of primary platelet plug, whichresult in greater bleeding tendency. The main cause of thrombocytopenia however isnot absolutely known, but it may be related to reduce platelet life period.MOLECULAR BASIS OF SYNDROME:The GPIb/ IX/ V complex presents the most important site mediating plateletinteraction 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 commonevolutionary derivation. A number of transcripts encode these 4 polypeptide chainsbut 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 ofBSS have been characterized up to date. This characterization is mainly on the basisof:  Functional  Immunological  Molecular levels.Mutations of GPIbα, GPIbβ and GPIX associated with Bernard-Soulier syndromeare mapped to the mature protein structure and indicates missense mutations or short 4
  5. 5. deletions, nonsense mutations leading to premature stop, or mutations causing a frameshift leading to stop. There are no reported mutations in GP V6, 17, 18The 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. 5
  6. 6. FIG1: GP I/IX/V complexFIG 2: Mutations of (A) GPIbα (B) GPIbβ and (C) GPIXCLINICAL PRESENTATION: 6
  7. 7.  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 Diagnostic Approach for BSS 7
  8. 8. LABORATORY STUDIESThe 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
  9. 9. 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 raisedPLATELET 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
  10. 10. 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
  11. 11. DIFFERENTIALSBSS should be differentiated from:  Glanzmann thrombasthenia:  May-Hegglin anomaly:  Von-Willebrand disease: MANAGEMENTManagement of BSS mainly consists of:  Preventive measures and local care  Specific treatmentPREVENTIVE MEASURES: 11
  12. 12.  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 importantSPECIFIC 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 o Tranexamic acid  These are also available as mouth wash for bleeding in mouth from 12
  13. 13. 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. PROBLEMS SPECIFIC TO WOMEN 13
  14. 14. MENORRHAGIA:Is the most important bleeding crisis for women following Puberty. Oralcontraceptives use can regulate menstural cycles thereby reducing heavy bleeding.Tranexamic acid (Cyklokapron® or Amicar®) is also indicated at same time. Theymainly act by down regulating destruction of clots that formed in the body. Bleedingis 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 bleedingduring pregnancy and bleeding at time of parturition.BSS expectant mother should be tracked in such treatment center having experiencein dealing such patients. They should also discuss the danger associated with epiduralin advance with the concerned physician.PROGNOSIS:The bleeding propensity is life-long in Bernard-Soulier syndrome (BSS) patients butthere may be reduction in bleeding tendency with age.REFERENCES: 14
  15. 15. 1. Bernard J. History of congenital thrombocytic hemorrhagic dystrophy. C R Acad Sci III. 1996 Aug;319(8):727-322. 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. 145–645. 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):4112–217. Ramasamy I. inherited bleeding disorders. Disorders of platelet adhesion and aggregation. Crit Rev Oncol Hematol. 2004; 49 (1) : 1-358. 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 15

×